Abstract Book - PDF - San Antonio Breast Cancer Symposium
Abstract Book - PDF - San Antonio Breast Cancer Symposium
Abstract Book - PDF - San Antonio Breast Cancer Symposium
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<strong>Cancer</strong><br />
Research<br />
December 15, 2012 • Volume 72 • Number 24 • Supplement to <strong>Cancer</strong> Research • Pages 1s–608s<br />
Driving Innovation to<br />
Prevent and Cure <strong>Cancer</strong><br />
www.aacrjournals.org
Publishing<br />
Information<br />
<strong>Cancer</strong><br />
Research<br />
Print ISSN: 0008-5472 • Online ISSN: 1538-7445<br />
AACR Officers<br />
Frank McCormick, President<br />
Charles L. Sawyers, President-Elect<br />
Judy E. Garber, Past President<br />
William H. Hait, Treasurer<br />
Margaret Foti, Chief Executive Officer<br />
Publications Committee<br />
Michael E. Berens<br />
Gideon M. Bollag<br />
Michael A. Caligiuri, Chairperson<br />
Richard M. Caprioli<br />
Arul M. Chinnaiyan<br />
Joseph F. Costello<br />
Chi Van Dang<br />
Jessica Clague DeHart<br />
Lisa Diller<br />
Levi A. Garraway<br />
John D. Groopman<br />
Ernest T. Hawk<br />
<strong>San</strong>dra J. Horning<br />
Nancy E. Hynes<br />
Pasi A. Jänne<br />
Emma M. Lees<br />
Guillermina Lozano<br />
Richard M. Marais<br />
William G. Nelson<br />
David R. Parkinson<br />
David Piwnica-Worms<br />
Robert H. Vonderheide<br />
Publishing Staff<br />
Publisher<br />
Diane Scott-Lichter<br />
Director, Editorial<br />
Helen Barsky Atkins<br />
Asst. Director, Editorial Systems<br />
& Managing Editor<br />
Kelly A. Hadsell<br />
Senior Associate Editor<br />
Arthur M. Buchberg<br />
Editorial Staff<br />
Crystal Cheepudom<br />
Amir Kalili<br />
Naima D. Stone<br />
Timothy Rinehart<br />
Patricia Russo<br />
Associate Director, Production<br />
Charlene Squibb<br />
Production Staff<br />
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Associate Director,<br />
Sales and Marketing<br />
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Circulation and Fulfillment<br />
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Marketing and<br />
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Paul Driscoll<br />
Design Staff<br />
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Publishing Information: <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Co-Directors<br />
Carlos L. Arteaga<br />
C. Kent Osborne<br />
Peter M. Ravdin<br />
Executive Committee<br />
Carlos L. Arteaga<br />
Gary C. Chamness<br />
Margaret Foti<br />
Susan G. Hilsenbeck<br />
Ismail Jatoi<br />
C. Kent Osborne<br />
Peter M. Ravdin<br />
Andrea Richardson<br />
Ian M. Thompson, Jr.<br />
Symposia Director<br />
Rich Markow<br />
Meeting Profile<br />
For 35 years, the mission of the <strong>San</strong><br />
<strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong> has<br />
been to provide state-of-the-art information<br />
on breast cancer research. The<br />
symposium aims to achieve a balance<br />
of clinical, translational, and basic<br />
research, providing a forum for interaction,<br />
communication, and education<br />
<strong>Cancer</strong> Research [ISSN 0008-5472;<br />
CNREA8] is published twice a month,<br />
one volume per year, by the American<br />
Association for <strong>Cancer</strong> Research, Inc.<br />
Postage paid at Philadelphia, PA, and<br />
additional mailing offices. POSTMAS-<br />
TER: Send address changes to Member<br />
Services, AACR, 615 Chestnut Street,<br />
17th Floor, Philadelphia, PA 19106-<br />
4404 or E-mail: membership@aacr.<br />
org. Copyright 2012 by the American<br />
Association for <strong>Cancer</strong> Research,<br />
Inc. Printed on acid free paper in the<br />
United States of America.<br />
Subscription Information<br />
AACR Members. Subscription options<br />
are print with online access or see<br />
http://www.aacr.org and go to the membership<br />
page for further information.<br />
Institutions and Nonmembers.<br />
E-mail contacts listed below are for<br />
single-site online access only (limited<br />
to library) and optional print subscriptions.<br />
USA, Canada, and Mexico:<br />
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Site Licenses. Send site license (online<br />
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for a broad spectrum of researchers,<br />
health professionals, and those with a<br />
special interest in breast cancer.<br />
In 2007, the <strong>Cancer</strong> Therapy & Research<br />
Center (CTRC) at UT Health<br />
Science Center <strong>San</strong> <strong>Antonio</strong> and the<br />
American Association for <strong>Cancer</strong><br />
Research (AACR) announced a collaboration<br />
for the future of the <strong>San</strong><br />
<strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong>.<br />
The symposium has been renamed<br />
the CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong><br />
<strong>Cancer</strong> <strong>Symposium</strong>. Complementing<br />
the clinical strengths of the highly<br />
regarded annual <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong><br />
<strong>Cancer</strong> <strong>Symposium</strong>, the AACR’s scientific<br />
prestige in basic, translational,<br />
and clinical cancer research will<br />
create a unique and comprehensive<br />
scientific meeting that will advance<br />
breast cancer research for the benefit<br />
of patients.<br />
In 2005, Baylor College of Medicine became<br />
a joint sponsor of the symposium<br />
and will remain a part the CTRC-AACR<br />
collaboration.<br />
Publishing Information: <strong>Cancer</strong> Research<br />
Change of Address. Send change<br />
of address notifications 60 days in<br />
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made within 90 days of the issue’s<br />
publication date will be honored while<br />
supplies last. Member subscribers<br />
should contact membership@aacr.org,<br />
phone 215-440-9300, fax 215-440-9412.<br />
Institutions and nonmember subscribers<br />
should direct claims to Turpin<br />
Distribution at the appropriate address<br />
above or by e-mail turpinna@turpindistribution.com.<br />
Single Issue Sales. Single issues<br />
and back stock of the journal may be<br />
ordered from the AACR main office<br />
by calling 866-423-3965 (toll-free) or<br />
215-440-9300. Prices are available upon<br />
request.<br />
Copyright and Permissions<br />
As a not-for-profit organization<br />
incorporated in the United States,<br />
AACR adheres to U.S. copyright law<br />
(PL 94-553), which became effective<br />
Future Meeting Dates<br />
December 10–14, 2013<br />
December 9–13, 2014<br />
December 8–12, 2015<br />
Copyright and Permissions<br />
As a collaborating partner, the AACR<br />
is publishing the abstracts of the<br />
<strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
in this Supplement to <strong>Cancer</strong> Research<br />
on behalf of the <strong>Symposium</strong> organizers.<br />
Permission to reprint or re-use any<br />
abstract in this Supplement must be<br />
obtained from the copyright holder.<br />
For more information, contact the<br />
Symposia Director (below).<br />
<strong>Symposium</strong> Contact<br />
Mr. Rich Markow, Symposia Director<br />
<strong>Cancer</strong> Therapy & Research Center<br />
UTHSCSA<br />
7979 Wurzbach Road, MC 8224<br />
<strong>San</strong> <strong>Antonio</strong>, TX 78229<br />
Phone: 210-450-1550<br />
Fax: 210-450-1560<br />
E-mail: sabcs@uthscsa.edu<br />
Website Address: www.sabcs.org<br />
January 1, 1978. The law stipulates<br />
that copyright for works is vested<br />
in the author from the moment of<br />
creation and remains the property of<br />
the author until legally transferred.<br />
Authors who wish to publish articles<br />
and other material in AACR journals<br />
must formally transfer copyright to<br />
AACR. The copyright transfer form<br />
must be signed by all authors before<br />
AACR can proceed with publication.<br />
Appropriate forms for transfer of<br />
copyright will be requested from all<br />
authors after a manuscript has been<br />
deemed potentially acceptable.<br />
To read the complete version of<br />
AACR’s Copyright and Permissions<br />
Policy, please visit http://www.aacr.<br />
org/home/scientists/publications-ofthe-aacr/copyright-and-permissionspolicy.aspx.<br />
This policy includes further<br />
information on authors’ rights of<br />
usage, permission requests from third<br />
parties, free access to AACR journals,<br />
funding agency requirements, and the<br />
National Institutes of Health Public<br />
Access Policy.<br />
<strong>Cancer</strong> Research is abstracted or indexed<br />
in Biological <strong>Abstract</strong>s, Biochemistry<br />
& Biophysics Citation Index, Basic<br />
BIOSIS, BIOSIS Previews (R) Database,<br />
Chemical <strong>Abstract</strong>s, Index Medicus,<br />
MEDLINE, Current Contents/Clinical<br />
Medicine, Reference Update, and Science<br />
Citation Index (expanded).<br />
No responsibility is accepted by the<br />
Editors or by AACR, Inc. for the opinions<br />
expressed by contributors or for<br />
the content of the advertisements.<br />
<strong>Cancer</strong> Research Supplement
Editor-in-Chief<br />
George C. Prendergast<br />
<strong>Cancer</strong><br />
Research<br />
Special Advisors to the<br />
Editor-in-Chief<br />
Olivera J. Finn<br />
Giorgio Trinchieri<br />
Deputy Editor for Meeting<br />
Reports<br />
Mariano Barbacid<br />
Deputy Editor for<br />
Breaking Advances<br />
William A. Weiss<br />
Breaking Advances Editors<br />
Kenneth D. Aldape<br />
Frances Balkwill<br />
Paul B. Fisher<br />
Davide Ruggero<br />
Deputy Editor for Reviews<br />
Danny R. Welch<br />
Reviews Editors<br />
Suzanne A. Eccles<br />
Jeremy R. Graff<br />
Martine F. Roussel<br />
Senior Editors<br />
Clinical Studies<br />
Theodore S. Lawrence<br />
Integrated Systems & Technologies<br />
Martin W. Brechbiel<br />
Arul M. Chinnaiyan<br />
Trachette L. Jackson<br />
Sofia D. Merajver<br />
David W. Speicher<br />
Microenvironment & Immunology<br />
Hellmut G. Augustin<br />
Mario P. Colombo<br />
Yves A. DeClerck<br />
Suzanne Ostrand-Rosenberg<br />
Kornelia Polyak<br />
Mark J. Smyth<br />
Laurence Zitvogel<br />
Molecular & Cellular Pathobiology<br />
John D. Carpten<br />
Junjie Chen<br />
Kathleen R. Cho<br />
Mark W. Dewhirst<br />
Karen E. Knudsen<br />
Hiroyuki Mano<br />
Jeffrey E. Settleman<br />
Prevention & Epidemiology<br />
Saraswati Sukumar<br />
Stephen M. Schwartz<br />
Tumor & Stem Cell Biology<br />
Laura E. Benjamin<br />
Maria A. Blasco<br />
Myles A. Brown<br />
Lewis Chodosh<br />
Philip W. Hinds<br />
Nancy E. Hynes<br />
Rakesh Kumar<br />
Toshikazu Ushijima<br />
Jane E. Visvader<br />
Max Wicha<br />
Therapeutics, Targets & Chemical<br />
Biology<br />
Robert Clarke<br />
<strong>Antonio</strong> T. Fojo<br />
Janet A. Houghton<br />
William G. Nelson<br />
Patrick M. O’Connor<br />
Yves Pommier<br />
David B. Solit<br />
Kenneth D. Tew<br />
Editorial Board<br />
Cory A. Abate-Shen<br />
James L. Abbruzzese<br />
Gregory P. Adams<br />
Natalie G. Ahn<br />
Arthur S. Alberts<br />
Adriana Albini<br />
Alexander R.A. Anderson<br />
Andrew E. Aplin<br />
Leonard H. Augenlicht<br />
Albert S. Baldwin<br />
Glen N. Barber<br />
Menashe Bar-Eli<br />
Per H. Basse<br />
Paula J. Bates<br />
Stephen B. Baylin<br />
David G. Beer<br />
Doris M. Benbrook<br />
Gabriele Bergers<br />
Jay A. Berzofsky<br />
Darell D. Bigner<br />
Diane F. Birt<br />
Mikhail V. Blagosklonny<br />
Carl P. Blobel<br />
Melissa Bondy<br />
Rolf A. Brekken<br />
Angela M. H. Brodie<br />
Lisa H. Butterfield<br />
Bruno Calabretta<br />
Anthony J. Capobianco<br />
Giuseppe Carruba<br />
Graham Casey<br />
Esteban Celis<br />
James R. Cerhan<br />
Timothy C. Chambers<br />
Jia Chen<br />
Cheng-Yang Chou<br />
David C. Christiani<br />
Robert J. Coffey<br />
Michael Cole<br />
David R. Corey<br />
Vittorio Cristini<br />
Tom Curran<br />
Rajvir Dahiya<br />
William S. Dalton<br />
Mary B. Daly<br />
Chi Van Dang<br />
Ramana V. Davuluri<br />
Michael J. Detmar<br />
Ivan Dikic<br />
Julie Y. Djeu<br />
Ethan Dmitrovsky<br />
Zigang Dong<br />
Martin Eilers<br />
Wafik S. El-Deiry<br />
Lee M. Ellis<br />
Manel Esteller<br />
Stephen P. Ethier<br />
Jia Fan<br />
Eric R. Fearon<br />
Dean W. Felsher<br />
Napoleone Ferrara<br />
Soldano Ferrone<br />
Susan M. Fischer<br />
Richard Fishel<br />
James M. Ford<br />
Albert J. Fornace<br />
Steven M. Frisch<br />
Simone Fulda<br />
Amy M. Fulton<br />
Dmitry I. Gabrilovich<br />
Thomas F. Gajewski<br />
Joel R. Garbow<br />
Robert A. Gatenby<br />
Richard B. Gaynor<br />
Adi F. Gazdar<br />
Edward P. Gelmann<br />
Amato J. Giaccia<br />
Susan K. Gilmour<br />
David Gius<br />
Candece L. Gladson<br />
Andrew K. Godwin<br />
Marc T. Goodman<br />
Steven Grant<br />
Mark Greene<br />
Andrei V. Gudkov<br />
David H. Gutmann<br />
William C. Hahn<br />
Susan E. Hankinson<br />
Stephen S. Hecht<br />
Kristian Helin<br />
Mary J.C. Hendrix<br />
Roy S. Herbst<br />
Peter J. Houghton<br />
Suyun Huang<br />
Tim H-M Huang<br />
Mien-Chie Hung<br />
Kent W. Hunter<br />
John T. Isaacs<br />
William B. Isaacs<br />
Jean-Pierre Issa<br />
Kuan-Teh Jeang<br />
Daniel E. Johnson<br />
Randall S. Johnson<br />
Peter A. Jones<br />
Carl H. June<br />
Scott E. Kern<br />
Khandan Keyomarsi<br />
Roya Khosravi-Far<br />
Timothy J. Kinsella<br />
Erik Knudsen<br />
H. Phillip Koeffler<br />
Guido Kroemer<br />
Jonathan M. Kurie<br />
Natasha Kyprianou<br />
Lucia R. Languino<br />
Edmund C. Lattime<br />
Gustavo W. Leone<br />
Jason S. Lewis<br />
Linheng Li<br />
Michael P. Lisanti<br />
A. Thomas Look<br />
Philip Maini<br />
Linda H. Malkas<br />
Sridhar Mani<br />
James A. McCubrey<br />
Rene H. Medema<br />
Giovanni Melillo<br />
Andrew Mellor<br />
Stephen J. Meltzer<br />
Alea A. Mills<br />
Debabrata Mukhopadhyay<br />
Hasan Mukhtar<br />
Alexander Muller<br />
David H. Munn<br />
Maureen E. Murphy<br />
Akira Nakagawara<br />
Keiichi Nakayama<br />
Steven Narod<br />
Peter S. Nelson<br />
Tetsuo Noda<br />
Jeffrey A. Norton<br />
Giuseppina Nucifora<br />
Olufunmilayo Olopade<br />
Andrew F. Olshan<br />
Torben F. Orntoft<br />
Donald M. O’Rourke<br />
Alan B. Packard<br />
Renata Pasqualini<br />
Linda Z. Penn<br />
Russell O. Pieper<br />
Christoph Plass<br />
Elizabeth A. Platz<br />
Eckhard R. Podack<br />
Vito Quaranta<br />
Andrew A. Quong<br />
Nancy Raab-Traub<br />
Ayyappan Rajasekaran<br />
Ratna Ray<br />
Melvin Reichman<br />
Tannishtha Reya<br />
Ulrich Rodeck<br />
Eric K. Rowinsky<br />
Anil K. Rustgi<br />
Marianne D. Sadar<br />
Edward A. Sausville<br />
Janet A. Sawicki<br />
Jeffrey Schlom<br />
Hans-Joachim Schmoll<br />
Michael J. Seckl<br />
Gregg L. Semenza<br />
Charles L. Sentman<br />
Julian M. Simon<br />
Frank J. Slack<br />
Michael B. Sporn<br />
M. Sharon Stack<br />
Patricia S. Steeg<br />
Joann B. Sweasy<br />
Bin T. Teh<br />
Rajeshwar R. Tekmal<br />
Joseph R. Testa<br />
Andrew M. Thorburn<br />
Donald J. Tindall<br />
Nicholas Tonks<br />
David A. Tuveson<br />
Cornelia M. Ulrich<br />
Alejandra C. Ventura<br />
Paula M. Vertino<br />
Robert H. Vonderheide<br />
Kristiina Vuori<br />
Cheryl L. Walker<br />
Jean Y.J. Wang<br />
Liwei Wang<br />
Jeffrey S. Weber<br />
Robert J. Wechsler-Reya<br />
Louis M. Weiner<br />
Cynthia Wetmore<br />
T.C. Wu<br />
Xifeng Wu<br />
Keping Xie<br />
Ningzhi Xu<br />
Xiang-Xi Xu<br />
Minoru Yoshida<br />
Ming You<br />
Dihua Yu<br />
Ming-Ming Zhou<br />
Mary M. Zutter<br />
<strong>Cancer</strong> Research Supplement
<strong>Cancer</strong> Research<br />
A Journal of the American Association for <strong>Cancer</strong> Research<br />
Volume 72 • Number 24 • Supplement 3<br />
December 15, 2012 • Pages 1s–608s<br />
2012 <strong>Abstract</strong>s<br />
35th Annual <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
December 4–8, 2012<br />
<strong>San</strong> <strong>Antonio</strong>, Texas, USA<br />
www.sabcs.org<br />
Program Schedule<br />
Invited <strong>Abstract</strong>s<br />
1s<br />
78s<br />
<strong>Abstract</strong>s<br />
General Sessions [S1-1 – S6-7]<br />
Poster Discussion Sessions [PD01-01 – PD10-09]<br />
Poster Session 1 [P1-01-01– P1-15-12]<br />
Poster Session 2 [P2-01-01– P2-16-04]<br />
Poster Session 3 [P3-01-01– P3-14-06]<br />
Poster Session 4 [P4-01-01– P4-17-09]<br />
Poster Session 5 [P5-01-01– P5-21-04]<br />
Poster Session 6 [P6-01-01– P6-14-05]<br />
Poster Session Ongoing Trial 1 [OT1-1-01– OT1-4-06]<br />
Poster Session Ongoing Trial 2 [OT2-1-01– OT2-3-11]<br />
Poster Session Ongoing Trial 3 [OT3-1-01– OT3-4-06]<br />
89s<br />
110s<br />
147s<br />
214s<br />
285s<br />
351s<br />
420s<br />
486s<br />
556s<br />
566s<br />
576s<br />
Author Index for <strong>Abstract</strong>s<br />
587s<br />
Note Regarding the Citation of <strong>Abstract</strong>s<br />
<strong>Abstract</strong>s published in this Supplement can be cited as shown in the following example:<br />
Impact of breast cancer CME: Physician practice pattern, knowledge, and competence assessments. Haas M, Heintz A, Stacy T.<br />
<strong>Cancer</strong> Res 2012;72(24 Suppl.):<strong>Abstract</strong> nr P6-14-05.
December 4–8, 2012<br />
Program Schedule<br />
DECEMBER 4–8, 2012<br />
35TH ANNUAL<br />
SAN ANTONIO BREAST CANCER SYMPOSIUM<br />
SAN ANTONIO, TEXAS, USA<br />
WWW.SABCS.ORG<br />
www.aacrjournals.org 1s <strong>Cancer</strong> Res; 72(24Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
We are proud to acknowledge the following for their contributions to<br />
and generous support of our program (at press time).<br />
Premier<br />
Genentech, A Member of the Roche Group<br />
Angel<br />
Amgen<br />
Celgene Corporation<br />
Eisai, Inc.<br />
Genomic Health, Inc.<br />
Novartis Oncology<br />
Patron<br />
AlphaMed Press/The Oncologist<br />
Eli Lilly and Company<br />
Major Supporter<br />
AstraZeneca<br />
Celltrion Healthcare Co., Ltd.<br />
GE Healthcare<br />
Nektar Therapeutics<br />
Contributor<br />
Agendia, Inc.<br />
Bristol-Myers Squibb<br />
Fresenius Kabi Deutschland GMBH<br />
Merck<br />
Myriad Genetic Laboratories, Inc.<br />
NanoString Technologies, Inc.<br />
Pfizer<br />
DONOR<br />
Almac<br />
Ambry Genetics<br />
BioMed Central<br />
Boehringer Ingelheim Pharmaceuticals, Inc.<br />
Caris Life Sciences<br />
Carl Zeiss Meditec, Inc.<br />
DARA Biosciences<br />
Dilon Diagnostics<br />
Dune Medical Devices<br />
Elekta, Inc.<br />
Endomagnetics Ltd.<br />
Faxitron Bioptics<br />
Genoptix, Inc.<br />
GlaxoSmithKline (Commercial)<br />
GlaxoSmithKline (R&D)<br />
HistoRx, Inc.<br />
Inspire<br />
Leica Microsystems<br />
Mammotome<br />
ProStrakan<br />
Scion Medical Technologies<br />
Varian Medical Systems<br />
Veridex, LLC<br />
Xentech<br />
CONFERENCE GRANT<br />
American <strong>Cancer</strong> Society, Texas Division<br />
National <strong>Cancer</strong> Institute<br />
SABCS gratefully acknowledges<br />
Susan G. Komen for the Cure® for generous support of<br />
AACR Outstanding Investigator Award<br />
for <strong>Breast</strong> <strong>Cancer</strong> Research,<br />
CTCR-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Educational Sessions,<br />
AACR Scholar-in-Training Awards<br />
SABCS wishes to thank Avon Foundation for support of the<br />
Avon Foundation-AACR International<br />
Scholar-In-Training Grants<br />
Future <strong>Symposium</strong> Meeting Dates<br />
36th Annual SABCS December 10–14, 2013<br />
37th Annual SABCS December 9–13, 2014<br />
38th Annual SABCS December 8–12, 2015<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 2s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
2012 CTRC-AACR<br />
<strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong><br />
<strong>Symposium</strong><br />
Program Schedule<br />
(AT PRESS TIME)<br />
Refer to www.sabcs.org for the most current information.<br />
Room Locations<br />
Exhibit Halls A, B, C & D: Street Level<br />
Ballrooms A & B: Street Level<br />
Bridge Hall: Street Level<br />
Room 206 A-B: Concourse Level<br />
Tuesday, December 4, 2012<br />
8:00 am–7:30 pm<br />
REGISTRATION<br />
Bridge Hall<br />
Pre-registered attendees can obtain materials. Those who<br />
have not yet registered may do so.<br />
12:30 pm–2:00 pm<br />
Career Development Forum: A Networking Session for<br />
Young Investigators<br />
Room 206 A–B<br />
Networking and career development opportunities for early career<br />
scientists. The session is open to early-career scientists, defined as<br />
graduate students, postdoctoral or clinical fellows, or medical students<br />
and residents, who are registered attendees of the SABCS.<br />
Space in the workshop is limited to 200 participants; registrations will be<br />
accepted on a first-come, first-served basis and is free of charge.<br />
Discussion topics & mentors*<br />
Balancing Research and Clinical Practice I<br />
Judy E. Garber, Dana-Farber <strong>Cancer</strong> Institute<br />
Ann H. Partridge, Dana-Farber <strong>Cancer</strong> Institute<br />
Balancing Research and Clinical Practice II<br />
Clifford A. Hudis, Memorial Sloan-Kettering <strong>Cancer</strong> Center<br />
Eric P. Winer, Dana-Farber <strong>Cancer</strong> Institute<br />
Careers in Industry<br />
Steven Shak, Genomic Health, Inc.<br />
Careers in Industry<br />
Mika Derynck, Genentech, Inc.<br />
Careers in Translational Research<br />
Carlos L. Arteaga, Vanderbilt-Ingram <strong>Cancer</strong> Center<br />
Grant Writing - Basic/Translational<br />
Yi Li, Baylor College of Medicine <strong>Cancer</strong> Center<br />
Grant Writing - Clinical/Translational<br />
Virginia F. Borges, University of Colorado Denver<br />
Matthew J. Ellis, Washington University Siteman <strong>Cancer</strong> Center<br />
How to Become a Clinical Trialist<br />
John R. Yarnold, The Royal Marsden Hospital<br />
Nancy U. Lin, Dana-Farber <strong>Cancer</strong> Institute<br />
How to Get the Most Out of Your Fellowship Years<br />
Ian Elliott Krop, Dana-Farber <strong>Cancer</strong> Institute<br />
How to Get the Most Out of Your Fellowship Years<br />
Rachel Schiff, Baylor College of Medicine<br />
How to Get the Most Out of Your Predoctoral Experience<br />
Rong Li, UT Health Science Center at <strong>San</strong> <strong>Antonio</strong><br />
How to Make the Most Out of Being A Cooperative Group Member<br />
Kathy D. Miller, Indiana University School of Medicine<br />
Hope S. Rugo, UCSF Helen Diller Family Comprehensive <strong>Cancer</strong> Center<br />
Making the Transition From Fellowship to Faculty<br />
Pepper Jo Schedin, University of Colorado Anschutz Medical Campus<br />
Bryan P. Schneider, Indiana University Melvin and Bren Simon <strong>Cancer</strong><br />
Center<br />
Mentoring and Supervising<br />
Cathrin Brisken, Ecole Polytechnique Fédérale de Lausanne<br />
Jason S. Carroll, <strong>Cancer</strong> Research UK Cambridge Research Institute<br />
Negotiating a Job Offer or Promotion<br />
Melissa L. Bondy, Baylor College of Medicine <strong>Cancer</strong> Center<br />
Oral Presentation Skills<br />
Laura J. van ‘t Veer, UCSF Helen Diller Family Comprehensive<br />
<strong>Cancer</strong> Center<br />
Douglas Yee, Masonic <strong>Cancer</strong> Center, University of Minnesota<br />
Publication Strategies<br />
Harold J. Burstein, Dana-Farber <strong>Cancer</strong> Institute<br />
Searching for a Job and Interviewing<br />
Michael T. Lewis, Baylor College of Medicine <strong>Cancer</strong> Center<br />
Setting Up and Managing a Laboratory<br />
Jeffrey M. Rosen, Baylor College of Medicine<br />
Tenure and Promotion<br />
Suzanne A.W. Fuqua, Baylor College of Medicine <strong>Cancer</strong> Center<br />
Sharon H. Giordano, The University of Texas MD Anderson<br />
<strong>Cancer</strong> Center<br />
The Path Leading to Clinical Trials<br />
Massimo Cristofanilli, Fox Chase <strong>Cancer</strong> Center<br />
* Topics and mentors are subject to change<br />
2:00 pm–7:30 pm<br />
Educational Sessions<br />
Ballrooms A & B and Exhibit Hall D<br />
Supported by an educational grant from<br />
Susan G. Komen for the Cure®<br />
An update on advances in the technologies available for translational<br />
research. Sessions are to provide people with a better understanding<br />
of the topics of special current interest they hear using the techniques<br />
described. These presentations also provide researchers with a guide to<br />
the techniques they should be considering for their studies.<br />
2:00 pm–3:30 pm<br />
The Practical Use of Molecular Profiling<br />
Ballroom A<br />
Moderator: Peter M. Ravdin, MD, PhD<br />
UT Health Science Center <strong>San</strong> <strong>Antonio</strong><br />
<strong>San</strong> <strong>Antonio</strong>, TX<br />
Molecular profiling for in situ carcinoma of the breast<br />
Lawrence J. Solin, MD, FACR, FASTRO<br />
Albert Einstein Medical Center<br />
Philadelphia, PA<br />
The practical use of molecular profiling: The view of a<br />
medical oncologist<br />
<strong>Antonio</strong> C. Wolff, MD<br />
Johns Hopkins Kimmel <strong>Cancer</strong> Center<br />
Baltimore, MD<br />
Use of genomic tests in routine practice and clinical<br />
research in metastatic breast cancer<br />
Lajos Pusztai, MD, DPhil<br />
Yale <strong>Cancer</strong> Center<br />
New Haven, CT<br />
www.aacrjournals.org<br />
3s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Biology of Triple-Negative <strong>Breast</strong> <strong>Cancer</strong><br />
Ballroom B<br />
Moderator: Nicholas Turner, MD<br />
Royal Marsden Hospital<br />
London, UNITED KINGDOM<br />
New vulnerabilities for TNBC – from genetics to<br />
therapeutics<br />
Thomas Westbrook, PhD<br />
Baylor College of Medicine<br />
Houston, TX<br />
Triple negative breast cancer: Subtypes, molecular targets,<br />
and therapeutic approaches<br />
Jennifer A. Pietenpol, PhD<br />
Vanderbilt University School of Medicine<br />
Nashville, TN<br />
The clonal and mutational evolution of primary triple<br />
negative breast cancers<br />
Samuel Aparicio, PhD<br />
University of British Columbia<br />
Vancouver, CANADA<br />
Clinical Trial Designs for New Therapies<br />
Exhibit Hall D<br />
Moderator: Susan G. Hilsenbeck, PhD<br />
Baylor College of Medicine<br />
Houston, TX<br />
Early phase trials - What are they for?<br />
Susan G. Hilsenbeck, PhD<br />
Baylor College of Medicine<br />
Houston, TX<br />
What agents should go into trials?<br />
Angela DeMichele, MD, MSCE<br />
University of Pennsylvania Perelman School of Medicine<br />
Philadelphia, PA<br />
What endpoints should we use?<br />
Clifford A. Hudis, MD<br />
Memorial Sloan-Kettering <strong>Cancer</strong> Center<br />
New York, NY<br />
Randomized clinical trial designs: Still important<br />
Sally Hunsberger, PhD<br />
National <strong>Cancer</strong> Institute<br />
Rockville, MD<br />
What have we learned?<br />
Susan G. Hilsenbeck, PhD<br />
Baylor College of Medicine<br />
Houston, TX<br />
4:00 pm–5:30 pm<br />
Navigating the Obstacles and Risks of Survivorship<br />
Ballroom A<br />
Moderator: Susan W. Rafte<br />
Pink Ribbons Project<br />
Houston, TX<br />
Emerging sexual pharmacology for the breast cancer<br />
survivor<br />
Michael Krychman, MD<br />
The Southern California Center for Sexual Health and Survivorship<br />
Newport Beach, CA<br />
Cognitive changes and breast cancer treatments<br />
Patricia A. Ganz, MD<br />
University of California, Los Angeles<br />
Los Angeles, CA<br />
Risk of second primary breast cancer and other serious late<br />
complications issues among survivors of breast cancer<br />
Jonine L. Bernstein, PhD<br />
Memorial Sloan-Kettering <strong>Cancer</strong> Center<br />
New York, NY<br />
Mammary Cell Lineages and <strong>Breast</strong> <strong>Cancer</strong> Subtypes<br />
Ballroom B<br />
Moderator: Michael T. Lewis, PhD<br />
Baylor College of Medicine<br />
Houston, TX<br />
Primitive normal human mammary cells – the forerunners<br />
of malignant populations<br />
Connie Eaves, PhD<br />
University of British Columbia<br />
Vancouver, CANADA<br />
Deciphering the cellular hierarchy of the mammary gland<br />
and its implication for breast cancer<br />
Marielle Ousset, PhD<br />
Université Libre de Bruxelles<br />
Bruxelles, BELGIUM<br />
Understanding human cancer with single cell genetics<br />
Nicholas E. Navin, PhD<br />
UT MD Anderson <strong>Cancer</strong> Center<br />
Houston, TX<br />
Controversies in the Surgical Management of <strong>Breast</strong> <strong>Cancer</strong><br />
Exhibit Hall D<br />
Moderator: Ismail Jatoi, MD, PhD, FACS<br />
UT Health Science Center <strong>San</strong> <strong>Antonio</strong><br />
<strong>San</strong> <strong>Antonio</strong>, TX<br />
Sentinel node biopsy in breast cancer: Before or after<br />
neoadjuvant chemotherapy<br />
Eleftherios Mamounas, MD<br />
Aultman Hospital<br />
Canton, OH<br />
Evolving trends in implant breast reconstruction<br />
Andrea L. Pusic, MD, MHS, FRCSC<br />
Memorial Sloan-Kettering <strong>Cancer</strong> Center<br />
New York, NY<br />
The role of MRI in management of primary breast cancer<br />
Ismail Jatoi, MD, PhD, FACS<br />
UT Health Science Center <strong>San</strong> <strong>Antonio</strong><br />
<strong>San</strong> <strong>Antonio</strong>, TX<br />
6:00 pm–7:30 pm<br />
Tumor Dormancy and Late Recurrences<br />
Ballroom A<br />
Moderator: George W. Sledge, Jr, MD<br />
Indiana University Simon <strong>Cancer</strong> Center<br />
Indianapolis, IN<br />
Mechanisms of breast cancer dormancy and recurrence<br />
Lewis A. Chodosh, MD, PhD<br />
Perelman School of Medicine<br />
University of Pennsylvania<br />
Philadelphia, PA<br />
Tumor dormancy from an experimental biologist’s<br />
perspective<br />
Ann F. Chambers, PhD<br />
London Regional <strong>Cancer</strong> Program<br />
London, CANADA<br />
Attacking tumor dormancy in the clinic: How do we design<br />
the trials?<br />
George W. Sledge, Jr, MD<br />
Indiana University Simon <strong>Cancer</strong> Center<br />
Indianapolis, IN<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 4s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
Inflammation and <strong>Breast</strong> <strong>Cancer</strong><br />
Ballroom B<br />
Moderator: Charlotte Kuperwasser, PhD<br />
Tufts University School of Medicine<br />
Boston, MA<br />
Mechanism-based insights into prognosis and treatment<br />
of breast cancer derived from high resolution multiphoton<br />
imaging<br />
John Condeelis, PhD<br />
Albert Einstein College of Medicine<br />
Bronx, NY<br />
<strong>Breast</strong> cancer stroma: a predictor of clinical outcome and<br />
tumour heterogeneity<br />
Morag Park, PhD<br />
McGill University<br />
Montreal, CANADA<br />
Links between inflammation, breast cancer and obesity<br />
Charlotte Kuperwasser, PhD<br />
Tufts University School of Medicine<br />
Boston, MA<br />
Her2-Positive <strong>Breast</strong> <strong>Cancer</strong><br />
Exhibit Hall D<br />
Moderator: Eric P. Winer, MD<br />
Dana-Farber <strong>Cancer</strong> Institute<br />
Boston, MA<br />
Adjuvant therapy of HER2 positive breast cancer – the next<br />
installment<br />
Karen Gelmon, MD<br />
BC <strong>Cancer</strong> Agency<br />
Vancouver, CANADA<br />
Advances in HER2+ breast cancer<br />
Nancy U. Lin, MD<br />
Dana-Farber <strong>Cancer</strong> Institute<br />
Boston, MA<br />
Neoadjuvant approach in HER2 over-expressing breast<br />
cancer: Therapeutic implications and biomarker discovery<br />
Mothaffar Rimawi, MD<br />
Baylor College of Medicine<br />
Houston, TX<br />
Wednesday, December 5, 2012<br />
7:00 am–5:15 pm<br />
Registration<br />
Bridge Hall<br />
7:00 am–8:30 am<br />
Continental Breakfast<br />
Exhibit Hall C<br />
7:45 am–8:00 am<br />
WELCOME AND Opening Remarks<br />
Exhibit Hall D<br />
8:00 am–8:30 am<br />
PLENARY LECTURE 1<br />
Exhibit Hall D<br />
Hormones and the <strong>Breast</strong>: Local and Environmental Interactions<br />
Cathrin Brisken, MD, PhD<br />
Ecole Polytechnique Fédérale de Lausanne<br />
Lausanne, SWITZERLAND<br />
8:30 am–11:15 am<br />
GENERAL SESSION 1<br />
Exhibit Hall D<br />
Moderator: Kathy S. Albain, MD, FACP<br />
Loyola University Chicago Stritch School of Medicine<br />
Maywood, IL<br />
8:30 S1-1. Relative effectiveness of letrozole compared with tamoxifen<br />
for patients with lobular carcinoma in the BIG 1-98 trial<br />
Metzger O, Giobbie-Hurder A, Mallon E, Viale G, Winer E, Thürlimann B,<br />
Gelber RD, Colleoni M, Ejlertsen B, Bonnefoi H, Coates AS, Goldhirsch A,<br />
Gusterson B. BIG 1-98 Collaborative Group, International <strong>Breast</strong> <strong>Cancer</strong><br />
Study Group.<br />
8:45 S1-2. ATLAS – 10 v 5 years of adjuvant tamoxifen (TAM) in ER+<br />
disease: Effects on outcome in the first and in the second decade<br />
after diagnosis<br />
Davies C, Pan H, Godwin J, Gray R, Peto R, on Behalf of ATLAS<br />
Collaborators Worldwide. University of Oxford, Oxford, United Kingdom;<br />
Glasgow Caledonian University, Glasgow, United Kingdom.<br />
9:00 S1-3. Discussion<br />
William E. Barlow, PhD, Fred Hutchinson <strong>Cancer</strong> Research Center,<br />
Seattle, WA<br />
9:15 S1-4. Final analysis of overall survival for the Phase III CONFIRM<br />
trial: fulvestrant 500 mg versus 250 mg<br />
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov<br />
R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K,<br />
Garnett S, Rukazenkov Y, Martin M. Hospital of Prato, Prato, Italy; Centre<br />
Hospitalier Universitaire Sart Tilman, Liège, Belgium; First Faculty of<br />
Medicine of Charles University, Prague, Czech Republic; Instituto Nacional<br />
del Cáncer, <strong>San</strong>tiago, Chile; Dnipropetrovsk Municipal Clinical Hospital,<br />
Dnipropetrovsk, Ukraine; Republican Clinical Oncological Center, Kazan,<br />
Russian Federation; AZ Klina, Brasschaat, Belgium; Hospital Nossa<br />
Senhora da Conceição, Porto Alegre, Brazil; Medical Radiological Science<br />
Center, Obninsk, Russian Federation; Russian <strong>Cancer</strong> Research Centre,<br />
Moscow, Russian Federation; Kansas City <strong>Cancer</strong> Center, Kansas City;<br />
AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom; Hospital<br />
Universitario Gregorio Maranon, Madrid, Spain.<br />
9:30 S1-5. PIK3CA mutations are linked to PgR expression: A Tamoxifen<br />
Exemestane Adjuvant Multinational (TEAM) pathology study<br />
Sabine VS, Crozier C, Drake C, Piper T, van de Velde CJH, Hasenburg A,<br />
Kieback DG, Markopoulos C, Dirix L, Seynaeve C, Rea D, Bartlett JMS.<br />
Ontario Institute for <strong>Cancer</strong> Research, Toronto, ON, Canada; University<br />
of Edinburgh <strong>Cancer</strong> Research Centre, Institute of Genetics & Molecular<br />
Medicine, Edinburgh, Scotland, United Kingdom; Leiden University<br />
Medical Center, Leiden, Netherlands; University Hospital, Freiburg,<br />
Germany; Elblandklinikum, Riesa, Germany; Athens University Medical<br />
School, Athens, Greece; St. Augustinus Hospital, Antwerp, Belgium;<br />
Erasmus Medical Center-Daniel den Hoed, Rotterdam, United Kingdom;<br />
University of Birmingham, Birmingham, United Kingdom.<br />
9:45 S1-6. Results of a randomized phase 2 study of PD 0332991, a<br />
cyclin-dependent kinase (cdk) 4/6 inhibitor, in combination with<br />
letrozole vs letrozole alone for first-line treatment of ER+/HER2-<br />
advanced breast cancer (BC)<br />
Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel<br />
R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Breazna A,<br />
Kim ST, Randolph S, Slamon DJ. University of California, Los Angeles, CA;<br />
Irish Cooperative Oncology Research Group, Dublin, Ireland; Orszagos<br />
Onkologiai Intezet, Budapest, Hungary; Szent Margit Korhaz, Budapest,<br />
Hungary; Dnipropetrovsk City Multiple-Discipline Clinical Hospital,<br />
Ukraine; Municipal Treatment-and-Prophylactic Institution “Donetsk<br />
City Oncological Dispensary”, Ukraine; Technical University of Munich,<br />
Germany; Comprehensive Blood and <strong>Cancer</strong> Center, Bakersfield, CA; Petz<br />
Aladar Megyei Oktato Korhaz, Gyor, Hungary; University Hospital Mainz,<br />
Germany; Lviv State Oncologic Regional Treatment and Diagnostic<br />
Center, Ukraine; Comprehensive <strong>Cancer</strong> Centers of Nevada, Henderson,<br />
NV; Kyiv City Clinical Oncology Center, Ukraine; Pfizer Oncology, New<br />
York, NY; Pfizer Oncology, <strong>San</strong> Diego, CA.<br />
www.aacrjournals.org<br />
5s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
10:00 S1-7. Phase III trial evaluating the addition of bevacizumab to<br />
endocrine therapy as first-line treatment for advanced breast<br />
cancer - First efficacy results from the LEA study<br />
Martin M, Loibl S, von Minckwitz G, Morales S, Crespo C, Anton A,<br />
Guerrero A, Aktas B, Schoenegg W, Muñoz M, Garcia-Saenz JA, Gil M,<br />
Ramos M, Carrasco E, Liedtke C, Wachsmann G, Mehta K, De la Haba<br />
JR, On behalf of GEICAM (Spanish <strong>Breast</strong> <strong>Cancer</strong> Research Group), GBG<br />
(German <strong>Breast</strong> Group). Instituto de Investigacion <strong>San</strong>itaria Gregorio<br />
Marañon, Madrid, Spain; GBG (German <strong>Breast</strong> Group), Neu-Isenburg,<br />
Germany; University Women´s Hospital Essen, Germany; Medical<br />
Practice Berlin, Germany; University Women´s Hospital Muenster,<br />
Germany; Klinikum Boeblingen, Germany; H. Arnau Vilanova de Lerida,<br />
Spain; Hospital U. Ramon y Cajal, Spain; Hospital Universitario Miguel<br />
Servet, Spain; Instituto Valenciano de Oncologia, Spain; Hospital Clinic i<br />
Provincial, Spain; Hospital Clinico U. <strong>San</strong> Carlos, Spain; Instituto Catala d’<br />
Oncologia Hospitalet, Spain; GEICAM (Spanish <strong>Breast</strong> <strong>Cancer</strong> Research<br />
Group), Spain; Hospital U. Reina Sofia, Spain; Centro Oncologico de<br />
Galicia, Spain.<br />
10:15 S1-8. Prolactin-humanized mice: an improved animal recipient<br />
for therapy response-testing of patient-derived breast cancer<br />
xenotransplants<br />
Rui H, Utama FE, Yanac AF, Xia G, Peck AR, Liu C, Rosenberg AL, Wagner<br />
K-U, Yang N. Thomas Jefferson University, Philadelphia, PA; Eppley<br />
Institute for Research in <strong>Cancer</strong> and Allied Diseases, Omaha, NE.<br />
10:30 S1-9. Comparative performance of breast cancer Index (BCI) vs.<br />
Oncotype Dx and IHC4 in the prediction of late recurrence in<br />
hormonal receptor-positive lymph node-negative breast cancer<br />
patients: A TransATAC Study<br />
Sgroi DC, Sestak I, Cuzick J, Zhang Y, Schnabel CA, Erlander MG, Goss PE,<br />
Dowsett M. Massachusetts General Hospital, Harvard Medical School,<br />
Boston, MA; Centre for <strong>Cancer</strong> Prevention, Queen Mary University,<br />
London, United Kingdom; bioTheranostics Inc., <strong>San</strong> Diego, CA;<br />
Breakthrough <strong>Breast</strong> <strong>Cancer</strong> Centre, Royal Marsden Hospital, London,<br />
United Kingdom.<br />
10:45 S1-10. Association between the 21-gene recurrence score (RS)<br />
and benefit from adjuvant paclitaxel (Pac) in node-positive (N+),<br />
ER-positive breast cancer patients (pts): Results from NSABP B-28<br />
Mamounas EP, Tang G, Paik S, Baehner FL, Liu Q, Jeong J-H, Kim S-R,<br />
Butler SM, Jamshidian F, Cherbavaz DB, Sing AP, Shak S, Julian TB,<br />
Lembersky BC, Wickerham DL, Costantino JP, Wolmark N. National<br />
Surgical Adjuvant <strong>Breast</strong> and Bowel Project Operations and Biostatistical<br />
Centers; Aultman Hospital; Graduate School of Public Health, University<br />
of Pittsburgh; Genomic Health, Inc.; Allegheny <strong>Cancer</strong> Center at<br />
Allegheny General Hospital; University of Pittsburgh <strong>Cancer</strong> Institute.<br />
11:00 S1-11. Meta-analysis Results from the Collaborative Trials in<br />
Neoadjuvant <strong>Breast</strong> <strong>Cancer</strong> (CTNeoBC)<br />
Cortazar P, Zhang L, Untch M, Mehta K, Costantino J, Wolmark N,<br />
Bonnefoi H, Cameron D, Gianni L, Valagussa P, Zujewski JA, Justice R,<br />
Loibl S, Wickerham L, Bogaerts J, Baselga J, Perou C, Blumenthal G,<br />
Blohmer J, Mamounas E, Bergh J, Semiglazov V, Prowell T, Eidtmann<br />
H, Paik S, Piccart M, Sridhara R, Fasching P, Swain SM, Slaets L, Tang<br />
S, Gerber B, Geyer C, Pazdur R, Ditsch N, Rastogi P, Eiermann W,<br />
vonMincwitz G. FDA; HELIOS Klinikum Berlin-Buch, Berlin, Germany;<br />
NSABP, Pittsburgh, PA; University of Pittsburgh; Institut Bergonié , INSERM<br />
U916, and Université Bordeaux Segalen, Bordeaux, France; University of<br />
Edinburgh, Edinburgh, Scotland, United Kingdom; <strong>San</strong> Raffaele Scientific<br />
Insitute, Milan, Italy; Fondazione Michelangelo, Milan, Italy; NCI, Bethesda,<br />
MD; Lineberger Comprehensive <strong>Cancer</strong> Center, Chapel Hill, NC; GBG<br />
Forschungs GmbH, Germany; Medstar Washington Hospital Center,<br />
Washington, DC; St. Gertrauden Hospital, Berlin, Germany; University<br />
Women’s Hospital, Kiel, Germany; University Womens Hospital, Erlangen,<br />
Germany; University Women’s Hospital, Rostock, Germany; University<br />
Women’s Hospital, Munich, Germany; Private Practice, Munich, Germany;<br />
Karolinska Institutet and University Hospital, Stockholm, Sweden; EORTC<br />
Headquarters, Brussels, Belgium; Memorial Sloan Kettering <strong>Cancer</strong><br />
Center, NY; NN Petrov Res. Inst. Of Oncology, St.-Petersburg, Russian<br />
Federation; Jules Bordet Institute, Brussels, Belgium.<br />
11:15 am–12:00 pm<br />
William L. McGuire Memorial Lecture<br />
Exhibit Hall D<br />
Neoadjuvant Systemic Therapy: Promising Experimental Model, or<br />
Improved Standard of Care?<br />
Gabriel N. Hortobagyi, MD<br />
UT MD Anderson <strong>Cancer</strong> Center<br />
Houston, TX<br />
12:00 pm–1:35 pm<br />
Lunch<br />
12:30 pm–1:35 pm<br />
Clinical Science Forum<br />
Treatment on the Edges: Discordance Between Stage and Biology<br />
Ballroom A<br />
Moderator: Kathy S. Albain, MD, FACP<br />
Loyola University Chicago Stritch School of Medicine<br />
Maywood, IL<br />
Bad stage, but good biology<br />
Kathy S. Albain, MD, FACP<br />
Loyola University Chicago Stritch School of Medicine<br />
Maywood, IL<br />
Low stage…but adverse biology<br />
Martine J. Piccart, MD, PhD<br />
Jules Bordet Institute<br />
Brussels, BELGIUM<br />
12:30 pm–1:35 pm<br />
Basic Science Forum<br />
Metastasis – Niches<br />
Ballroom B<br />
Moderator: Yibin Kang, PhD<br />
Princeton University<br />
Princeton, NJ<br />
<strong>Cancer</strong> stem cells interactions with their niche determine<br />
formation of breast cancer metastasis<br />
Joerg Huelsken, PhD<br />
Federal Technical University Lausanne<br />
Lausanne, SWITZERLAND<br />
Tumor-stromal interactions in bone metastasis<br />
Yibin Kang, PhD<br />
Princeton University<br />
Princeton, NJ<br />
1:45 pm–3:15 pm<br />
Mini-<strong>Symposium</strong> 1<br />
The mTOR Pathway: Role in Metabolism and as a<br />
Therapeutic Target<br />
Exhibit Hall D<br />
Moderator: Carlos L. Arteaga, MD<br />
Vanderbilt-Ingram <strong>Cancer</strong> Center<br />
Vanderbilt University<br />
Nashville, TN<br />
Targeting PI3K<br />
Lewis Cantley, PhD<br />
Beth Israel Deaconess Medical Center<br />
Boston, MA<br />
Translating regulation of mTOR and protein synthesis to the<br />
clinic for advanced breast cancer<br />
Robert Schneider, PhD<br />
NYU School of Medicine<br />
New York, NY<br />
Clinical development of mTOR inhibitors<br />
Fabrice André, MD, PhD<br />
Gustave Roussy Institute<br />
Villejuif, FRANCE<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 6s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
3:15 pm–4:00 pm<br />
GENERAL SESSION 2<br />
Exhibit Hall D<br />
Moderator: Anthony Lucci, Jr., MD, FACS<br />
UT MD Anderson <strong>Cancer</strong> Center<br />
Houston, TX<br />
3:15 S2-1. The role of sentinel lymph node surgery in patients<br />
presenting with node positive breast cancer (T0-T4, N1-2) who<br />
receive neoadjuvant chemotherapy - results from the ACOSOG<br />
Z1071 trial<br />
Boughey JC, Suman VJ, Mittendorf EA, Ahrendt GM, Wilke LG, Taback B,<br />
Leitch AM, Flippo-Morton TS, Byrd DR, Ollila DW, Julian TB, McLaughlin<br />
SA, McCall L, Symmans WF, Le-Petross HT, Haffty BG, Buchholz TA, Hunt<br />
KK. Mayo Clinic, Rochester, MN; MD Anderson <strong>Cancer</strong> Center, Houston,<br />
TX; Magee-Womens Surgical Associates, Pittsburgh, PA; University<br />
of Wisconsin-Madison, WI; Columbia University Medical Center, New<br />
York, NY; University of Texas Southwestern Medical Center, Dallas,<br />
TX; Carolinas Medical Center, Charlotte, NC; University of Washington<br />
Medical Center, Seattle, WA; University of North Carolina - Chapel Hill,<br />
NC; Allegheny General Hospital, Pittsburgh, PA; Mayo Clinic, Jacksonville,<br />
FL; Duke University Medical Center, Durham, NC; The <strong>Cancer</strong> Institute of<br />
New Jersey, New Brunswick, NJ.<br />
3:30 S2-2. Sentinel lymph node biopsy before or after neoadjuvant<br />
chemotherapy - final results from the prospective German,<br />
multiinstitutional SENTINA-trial<br />
Kuehn T, Bauerfeind IGP, Fehm T, Fleige B, Helms G, Lebeau A, Liedtke C,<br />
von Minckwitz G, Nekljudova V, Schrenk P, Staebler A, Untch M. Klinikum<br />
Esslingen, Esslingen, Baden Wuerttemberg, Germany; Klinikum Landshut,<br />
Landshut, Bayern, Germany; Universitaetsfrauenklinik Tuebingen, Baden<br />
Wuerttemberg, Germany; Helios Klinikum Berlin-Buch, Berlin, Germany;<br />
University Medical Center Hamburg-Eppendorf, Hamburg, Germany;<br />
University Medical Center, Muenster, Nordrhein-Westfalen, Germany;<br />
German <strong>Breast</strong> Group, Neu- Isenburg, Hessen, Germany; AKH-LFKK, Linz,<br />
Austria; University Medical Center, Tuebingen, Baden-Wuerttemberg,<br />
Germany.<br />
3:45 S2-3. Disparities in the utilization of axillary sentinel lymph node<br />
biopsy among black and white patients with node-negative breast<br />
cancer from 2002-2007<br />
Black DM, Jiang J, Kuerer HM, Buchholz TA, Smith BD. MD Anderson<br />
<strong>Cancer</strong> Center, Houston, TX.<br />
4:00 pm–5:00 pm<br />
SUSAN G. KOMEN FOR THE CURE® BRINKER AWARDS FOR<br />
SCIENTIFIC DISTINCTION LECTURES<br />
Exhibit Hall D<br />
The Basic Science Award is presented to a researcher whose scientific<br />
discoveries or novel technologies have added substantively to our<br />
understanding of the basic biology of breast cancer and the intrinsic<br />
molecular processes that drive the disease, and/or whose work has<br />
bridged the gap between basic research and patient care. This year the<br />
award is being presented to:<br />
Yosef Yarden, PhD<br />
Department of Biological Regulation<br />
Weizmann Institute of Science<br />
Rehovot, ISRAEL<br />
How Does HER2 Contribute to <strong>Breast</strong> <strong>Cancer</strong> Progression?<br />
The Clinical Research Award is presented to a clinical or translational<br />
researcher who has advanced the identification of new prevention,<br />
detection or treatment approaches for breast cancer and promoted their<br />
incorporation into clinical care. This year the award is being presented to:<br />
Hyman B. Muss, MD<br />
Lineberger Comprehensive <strong>Cancer</strong> Center<br />
The University of North Carolina, Chapel Hill<br />
Chapel Hill, NC<br />
Older Women and <strong>Breast</strong> <strong>Cancer</strong>: Challenges and Opportunities<br />
5:00 pm–7:00 pm<br />
Poster Discussion 1: Endocrine Resistance<br />
Ballroom A<br />
Viewing 5:00 pm<br />
Discussion 5:15 pm<br />
Rachel Schiff, PhD, Chair<br />
Baylor College of Medicine<br />
Houston, TX<br />
Steffi Oesterreich, PhD, Discussant<br />
University of Pittsburgh <strong>Cancer</strong> Institute<br />
Pittsburgh, PA<br />
and<br />
Suleiman Massarweh, MD, Discussant<br />
University of Kentucky and Markey <strong>Cancer</strong> Center<br />
Lexington, KY<br />
PD01-01 Overcoming endocrine therapy resistance related to PTEN loss<br />
by strategic combinations with mTOR, AKT, or MEK inhibitors<br />
Fu X, Kumar V, Shea M, Biswal NC, Nanda S, Chayanam S, Mitchell<br />
T, Hergenroeder G, Meerbrey KL, Joshi A, Westbrook TF, Mills GB,<br />
Creighton CJ, Hilsenbeck SG, Osborne CK, Schiff R. Lester & Sue<br />
Smith <strong>Breast</strong> Center, Baylor College of Medicine, Houston, TX; Dan<br />
L Duncan <strong>Cancer</strong> Center, Baylor College of Medicine, Houston, TX;<br />
Baylor College of Medicine, Houston, TX; M.D. Anderson <strong>Cancer</strong><br />
Center, Houston, TX.<br />
PD01-02 Increased expression of phosphorylated mTOR in metastatic<br />
breast tumors compared to primary tumors in patients who<br />
received adjuvant endocrine therapy<br />
Hoefnagel LDC, Beelen KJ, Opdam M, Vincent A, Linn SC, vanDiest<br />
PJ. University Medical Center, Utrecht, Netherlands; The Netherlands<br />
<strong>Cancer</strong> Institute, Amsterdam, Netherlands.<br />
PD01-03 Phosphorylated p-70S6K predicts tamoxifen resistance in<br />
postmenopausal breast cancer patients randomized between<br />
adjuvant tamoxifen versus no systemic treatment<br />
Beelen KJ, Opdam M, Severson TM, Koornstra RHT, Vincent A,<br />
Wesseling J, Muris JJ, Berns EMJJ, Vermorken JB, vanDiest PJ, Linn<br />
SC. The Netherlands <strong>Cancer</strong> Institute, Amsterdam, Netherlands;<br />
Erasmus University Medical Center-Daniel den Hoed <strong>Cancer</strong> Center,<br />
Rotterdam, Netherlands; Antwerp University Hospital, Edegem,<br />
Belgium; University Medical Center, Utrecht, Netherlands.<br />
PD01-04 Deep kinome sequencing identifies a novel D189Y mutation<br />
in the Src family kinase LYN as a possible mediator of<br />
antiestrogen resistance in ER+ breast cancer<br />
Fox EM, Balko JM, Arteaga CL. Vanderbilt-Ingram <strong>Cancer</strong> Center,<br />
Vanderbilt University, Nashville, TN.<br />
PD01-05 Analysis of patients with ER-positive breast tumors treated<br />
with neoadjuvant aromatase inhibition identifies chemokine<br />
receptors as potential modulators of endocrine resistance<br />
Ribas R, Ghazoui Z, Dowsett M, Martin L-A. The Institute of <strong>Cancer</strong><br />
Research, London, United Kingdom; Royal Marsden Hospital,<br />
London, United Kingdom.<br />
PD01-06 Inhibition of the Ret receptor tyrosine kinase in combination<br />
with endocrine therapy impacts on migration and metastatic<br />
potential of estrogen receptor positive breast cancer models<br />
Hynes NE, Gattelli A, Nalvarte I, Roloff T. Friedrich Miescher Institute<br />
for Biomedical Research, Basel, Switzerland.<br />
PD01-07<br />
High throughput sequencing following cross-linked immuneprecipitation<br />
(HITS-CLIP) of Argonaute protein reveals novel<br />
miRNA regulatory pathways of estrogen receptor in breast<br />
cancer<br />
Kabos P, Kline E, Brown J, Flory K, Sartorius C, Hesselberth J, Pillai<br />
MM. University of Colorado Denver, Aurora, CO.<br />
www.aacrjournals.org<br />
7s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
PD01-08 Differences in estrogen receptor signaling in non-malignant<br />
primary ER-positive breast epithelial cells and breast cancer<br />
Lim E, He HH, Chi D, Yeung TY, Schnitt S, Liu SX, Garber J, Richardson<br />
A, Brown M. Dana-Farber <strong>Cancer</strong> Institute, Boston, MA; Harvard<br />
School of Public Health, Boston, MA; Harvard Medical School, Boston,<br />
MA; Beth Israel Deaconess Medical Center, Boston, MA; Brigham and<br />
Women’s Hospital, Boston, MA.<br />
5:00 pm–7:00 pm<br />
Poster Discussion 2: HER2<br />
Ballroom B<br />
Viewing 5:00 pm<br />
Discussion 5:15 pm<br />
Andrea Richardson, MD, PhD, Chair<br />
Dana-Farber <strong>Cancer</strong> Institute<br />
Boston, MA<br />
Marc Van de Vijver, MD, PhD, Discussant<br />
Academic Medical Center<br />
Amsterdam, NETHERLANDS<br />
and<br />
<strong>Antonio</strong> C. Wolff, MD, Discussant<br />
The Sidney Kimmel Comprehensive <strong>Cancer</strong> Center at<br />
Johns Hopkins<br />
Baltimore, MD<br />
PD02-01 Her2 expression measured by AQUA analysis on BCIRG-005<br />
and BCIRG-006 predicts the benefit of Herceptin therapy<br />
Christiansen J, Barakat N, Murphy D, Rimm DL, Dabbas B, Nerenberg<br />
M, Beruti S, Quinaux E, Hall J, Press M, Slamon D. Genoptix Medical<br />
Laboratory; Yale University; IDDI; University of Southern California;<br />
University of California, Los Angeles.<br />
PD02-02 The effect of HER2 expression on luminal A breast tumors<br />
Ellsworth RE, Valente AL, Shriver CD. Henry M. Jackson Foundation,<br />
Windber, PA; Windber Research Institute, Windber, PA; Walter Reed<br />
National Military Medical Center, Bethesda, MD.<br />
PD02-03 Added value of HER-2 amplification testing by multiplex<br />
ligation-dependent probe amplification (MLPA)<br />
van Slooten H-J, Kuijpers CC, Moelans CB, Horstman A, Al-Janabi<br />
S, Hinrichs JW, van Diest PJ, Jiwa M. Symbiant Pathology Expert<br />
Centre, Alkmaar, Netherlands; University Medical Centre Utrecht,<br />
Netherlands.<br />
PD02-04 Automated quantitative RNA in situ hybridization for<br />
resolution of equivocal and heterogeneous ERBB2 (HER2)<br />
status in invasive breast carcinoma<br />
Wang Z, Portier BP, Gruver AM, Bui S, Wang H, Su N, Vo H-T, Ma X-J,<br />
Luo Y, Budd GT, Tubbs RR. Cleveland Clinic, Cleveland, OH; Advanced<br />
Cell Diagnostics, Hayward, CA.<br />
PD02-05 Comparison of fluorescence in situ hybridization (FISH) and<br />
dual-ISH (D-ISH) in the determination of HER2 status<br />
Mansfield AS, Sakai Y, Walsh FJ, Wiktor AE, Sukov WR, Dogan A,<br />
Jenkins RB. Mayo Clinic, Rochester, MN.<br />
PD02-06 Concordance between immunohistochemistry and FISH<br />
(fluorescence in situ hybridization) & SISH(silver in situ<br />
hybridization) for assessment of the HER2<br />
Lee M-R, Cho S-H, Kim D-C, Lee K-C, Lee J-H, Kwon H-C, Lee H-W,<br />
Lee S-e. Dong-A University Medical Center, Busan, Korea.<br />
PD02-07 Next-generation sequencing of FFPE breast cancers<br />
demonstrates high concordance with FISH in calling<br />
HER2 amplifications and commonly detects other clinically<br />
relevant genomic alterations<br />
Lipson D, He J, Yelensky R, Miller V, Sheehan C, Brennan K, Jarosz M,<br />
Stephens P, Cronin M, Ross J. Foundation Medicine, Inc, Cambridge,<br />
MA; Albany Medical College, Albany, NY.<br />
5:00 pm–7:00 pm<br />
POSTER SESSION 1 & RECEPTION<br />
Exhibit Halls A-B<br />
Detection/Diagnosis: Axillary Staging and Sentinel Nodes<br />
P1-01-01 Fluorescence mapping with indocyanine green for sentinel<br />
lymph node detection in early breast cancer – results of the<br />
ICG-10 study<br />
Benson JR, Loh S-W, Jones LA, Wishart GC. Addenbrooke’s Hospital,<br />
Cambridge, Cambridgeshire, United Kingdom.<br />
P1-01-02 Withdrawn<br />
P1-01-03 Comparison of sentinel lymph node biopsy guided by the<br />
multi-modal method of indocyanine green fluorescence,<br />
radioisotope and blue dye versus the radioisotope in breast<br />
cancer; A randomized phase II trial<br />
Jung S-Y, Kim S-K, Kim SW, Lee S, Lee J, Shin I-s, Kwon Y, Lee E.<br />
National <strong>Cancer</strong> Center, Goyang, Korea.<br />
P1-01-04 Tc 99m Tilmanocept and Sulfur Colloid Injection: A<br />
comparison of preoperative imaging and intraoperative<br />
lymphatic mapping of breast cancer patients – Localization<br />
rate and degree of localization<br />
Cope FO, Metz WL, Hartman RD, Joy MT, Potter BM, Abbruzzese<br />
BC, Shuping JL, Blue MS, Christman LA, King DW. Navidea<br />
Biopharmaceuticals, Dublin, OH; STATKING Consulting, Inc.,<br />
Fairfield, OH.<br />
P1-01-05 The Efficacy of Arm Node Preserving Surgery Using Axillary<br />
Reverse Mapping for Preventing Lymphedema in Patients<br />
with <strong>Breast</strong> <strong>Cancer</strong>: The results from a 2-year follow-up<br />
Lee J-H, Son G-T, Choi J-E, Kang S-H, Lee S-J, Bae Y-K. Yeungnam<br />
University college of medicine, Daegu, Republic of Korea.<br />
P1-01-06 Evaluation of the stage IB designation of the 7th edition of the<br />
AJCC staging system: Biologic factors are more important<br />
Mittendorf EA, Ballman KV, McCall LM, Hansen N, Lucci A, Gabram<br />
S, Urist M, Crow J, Hurd T, Hunt KK, Giuliano AE. The University of<br />
Texas MD Anderson <strong>Cancer</strong> Center; Mayo Clinic; American College<br />
of Surgeons Oncology Group; Northwestern University; Emory<br />
University; University of Alabama Birmingham; University of Texas<br />
Health Science Center <strong>San</strong> <strong>Antonio</strong>; Cedars-Sinai Medical Center.<br />
P1-01-07 The Institut Curie Nomogram including HER2 status predicts<br />
additional axillary metastasis in breast cancer patients with a<br />
positive sentinel node biopsy: a multicentric validation<br />
Ngo C, De Rycke Y, Belichard C, Guilhen N, Doridot V, Rouzier R,<br />
Coutant C, Hudry D, Fritel X, Fourchotte V, Feron J-G, Pierga J-Y,<br />
Salomon A, Alran S. Institut Curie, Paris, France; Poitiers University<br />
Hospital, Poitiers, France; Centre de <strong>San</strong>té République, Clermont-<br />
Ferrand, France; Hopital Tenon, Paris, France; Centre Georges<br />
François Leclerc, Dijon, France.<br />
P1-01-08 A Nomogram for predicting two or less axillary lymph node<br />
involvement for breast cancer<br />
Ahn SK, Kim JS, Kim Mk, Lee JW, Kim T, Kim JY, Moon HG, Han W,<br />
Noh D-Y. Seoul National University College of Medicine, Seoul, Korea.<br />
P1-01-09 Which nomograms may be the best for predicting<br />
nonsentinel lymph node metastasis in breast cancer patients:<br />
a meta-analysis<br />
Chen K, Jin L, Zhu L, Shan Q, Su F. Sun Yat-sen Memorial Hopsital,<br />
Guangzhou, Guangdong, China.<br />
P1-01-10 Comparison of sentinel lymph node positivity rates pre and<br />
post introduction of OSNA molecular analysis<br />
Rusby J, Agabiti E, Waheed S, Barry P, Roche N, Allum W, Gui G,<br />
MacNeill F, Christaki G, Osin P, Nerurkar A. Royal Marsden NHS<br />
Foundation Trust, London, United Kingdom.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 8s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P1-01-11<br />
P1-01-12<br />
P1-01-13<br />
P1-01-14<br />
P1-01-15<br />
P1-01-16<br />
P1-01-17<br />
P1-01-18<br />
P1-01-19<br />
P1-01-20<br />
Is OSNA mRNA copy number in sentinel lymph node biopsy<br />
predictive of further disease in the axilla?<br />
Rusby JE, Agabiti E, Waheed S, Barry P, Roche N, Allum W, Gui G,<br />
MacNeill F, Christaki G, Osin P, Nerurkar A. Royal Marsden NHS<br />
Foundation Trust, London, United Kingdom.<br />
The Performance of the One Step Nucleic Acid Amplification<br />
(OSNA) Assay in <strong>Breast</strong> <strong>Cancer</strong> Patients with Receiving<br />
Preoperative Systemic Therapy<br />
Yagata H, Yamauchi H, Horii R, Osako T, Iwase T, Akiyama F, Kinoshita<br />
T, Tsuda H, Tsugawa K, Nakamura S. St. Luke’s International Hospital,<br />
Tokyo, Japan; <strong>Cancer</strong> Institute Hospital of the Japanese Foundation<br />
for <strong>Cancer</strong> Research, Tokyo, Japan; National <strong>Cancer</strong> Center Hospital,<br />
Tokyo, Japan; St. Marianna University School of Medicine, Kanagawa,<br />
Japan; Showa University School of Medicine, Tokyo, Japan.<br />
Patterns of definitive axillary management in the era prior to<br />
reporting ACOSOG Z0011: comparison between NCCN Centers<br />
and hospitals in Michigan<br />
Breslin T, Hwang S, Mamet R, Hughes M, Otteson R, Edge S, Moy B,<br />
Rugo H, Wong Y-N, Wilson J, Laronga C, Weeks J, Silver S, Marcom<br />
P. University of Michigan, Ann Arbor, MI; Duke University; City of<br />
Hope; Dana-Farber/Brigham and Women’s <strong>Cancer</strong> Center; Roswell<br />
Park <strong>Cancer</strong> Institute; University of California <strong>San</strong> Fransisco; Fox<br />
Chase <strong>Cancer</strong> Center; Ohio State University; Moffitt <strong>Cancer</strong> Center;<br />
Massachusetts General Hospital <strong>Cancer</strong> Center.<br />
Effects of axillary lymph node dissection on survival of<br />
patients with sentinel lymph node metastasis of breast cancer<br />
in the Surveillance, Epidemiology and End Results (SEER)<br />
database using a propensity score matching analysis<br />
Bendifallah S, Chereau E, Bezu C, Coutant C, Rouzier R. Tenon, Paris,<br />
France; Centre Leclerc, Dijon, France.<br />
Accuracy of sentinel lymph node in determining the<br />
requirement for second axillary surgeries in early breast<br />
cancer with retrospective application of the Z0011 criteria<br />
Waters PS, Fennessy PJ, Alazawi D, Sweeney KJ, Kerin MJ. National<br />
University of Ireland, Galway, Ireland.<br />
Intraoperatively-palpable “non-sentinel” nodes: should they<br />
be removed?<br />
Crivello ML, Ruth K, Sigurdson ER, Egleston BL, Boraas M, Bleicher RJ.<br />
Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA.<br />
The impact of triple negativity on lymph node positivity in<br />
breast cancer<br />
Weber JJ, Bellin LS, Milbourn DE, Wong J. East Carolina University,<br />
Brody School of Medicine, Greenville, NC; University of North<br />
Carolina, Lineberger Comprehensive <strong>Cancer</strong> Center, Chapel Hill, NC.<br />
The results of 55 consecutive cases of intra-operative sentinel<br />
node analysis using real time polymerase chain reaction<br />
detection of cytokeratin 19 and mammoglobin expression<br />
(Metasin) to direct immediate axillary clearance<br />
Nadi K, Sharaiha Y, Sai-Girdhar P, Huws A, Khawaja S, Holt S. Prince<br />
Philip Hospital, Llanelli, United Kingdom.<br />
Prediction of axillary lymph node status in male breast<br />
carcinoma<br />
Vaysse C, Sroussi J, Mallon P, Feron J-G, Rivain A-L, Ngo C, Belichard<br />
C, Lasry S, Pierga J-Y, Couturaud B, Fitoussi A, Laki F, Fourchotte V,<br />
Alran S, Kirova YM, Vincent-Salomon A, Sastre-Garau X, Sigal-Zafrani<br />
B, Rouzier R, Reyal F. Institut Curie, Paris, France.<br />
Clinicopathlogic Analysis of Invasive <strong>Breast</strong> Carcinoma with<br />
Micropapillary Component<br />
Yamanaka T, Suganuma N, Yamanaka A, Kojima I, Nishiyama<br />
S, Mukaibashi T, Nakayama H, Matsuura H, Matsuzu K, Chiba A,<br />
Inaba M, Rino Y, Yoshida A, Shimizu S, Masuda M. Yokohama City<br />
University, Yokohama-City, Kanagawa, Japan; Kanagawa <strong>Cancer</strong><br />
Center, Yokohama-City, Kanagawa, Japan; Ito Hospital, Tokyo, Japan.<br />
P1-01-21<br />
P1-01-22<br />
P1-01-23<br />
P1-01-24<br />
P1-01-25<br />
P1-01-26<br />
P1-01-27<br />
P1-01-28<br />
Sentinel Lymph Node detection after previous breast tumour<br />
surgical resection: identification rate and false negative rate<br />
through a prospective multi institutional study<br />
Classe J-M, Andrieux N, Tunon de Lara C, Charitansky H, Lecuru F,<br />
Houpeau J-L, Faure C, De Blaye P, Houvenaeghel G, Kere D, Marchal<br />
F, Raro P, Lefebvre C, Dupré P-F, Rodier J-F. Institut de <strong>Cancer</strong>ologie<br />
de l’Ouest, Nantes Saint Herblain, France; Institut Bergonié, Bordeaux,<br />
France; Institut Claudius Regaud, Toulouse, France; Centre Hospitalier<br />
Georges Pompidou, Paris, France; Centre Oscar Lambret, Lille, France;<br />
Centre léon Bérard, Lyon, France; Centre Hospitalier Les Oudairies,<br />
La Roche sur Yon, France; Institut Paoli Calmettes, Marseille, France;<br />
Institut Jean Godinot, Reims, France; Centre Alexis Vautrin, Nancy,<br />
France; Centre Hospitalier Universitaire, Angers, France; Centre<br />
Hospitalier Morvan, Brest, France; Centre Paul Strauss, Strasbourg,<br />
France.<br />
The utility of axillary ultrasound and sentinel lymph node<br />
biopsy in the management of metaplastic breast carcinoma<br />
Hieken TJ, Fazzio RT, Reynolds C, Jones KN, Ghosh K, Glazebrook KN.<br />
Mayo Clinic, Rochester, MN.<br />
Increased Diagnostic Performance of Sentinel Lymph Node<br />
Biopsy Combined with Radiologic-pathologic Factors After<br />
Neoadjuvant Chemotherapy in <strong>Breast</strong> <strong>Cancer</strong> Patients with<br />
Cytologically Proven Node Metastasis at Diagnosis<br />
Park S, Koo JS, Kim MJ, Park JM, Cho JH, Hwang H, Park HS, Kim E-K,<br />
Kim SI, Park B-W. Yonsei University College of Medicine, Seoul, Korea.<br />
Which combinations are helpful to predict axillary<br />
lymph node metastasis in T1 breast cancer with<br />
ultrasonography and contrast-enhanced MRI and contrastenhanced<br />
18 F-FDG PET-CT?<br />
Hwang SO, Park HY, Jung JH, Kim WW, Lee YH, Lee JJ, Choi HH,<br />
Hwangbo SM. Kyungpook National University School of Medicine,<br />
Daegu, Korea; Hyosung Hospital, Daegu, Korea.<br />
Sentinel lymph node biopsy in breast cancer: The approach<br />
in day surgery under local anaesthesia for quality-of-life and<br />
significant cost reduction<br />
Ricci F, Capuano LG, Saralli E, Di Legge P, Violante A, Polistena A,<br />
Scala T, Pacchiarotti A, Cannas P, Cianni R, Fanelli G, Bellardini P, De<br />
Masi C. S.M. Goretti Hospital, Latina, Italy; LILT, Latina, Italy.<br />
Procoagulant biomarkers may direct axillary nodal surgery<br />
Shaker H, Bundred NJ, Glassey E, Kirwan CC. University Hospital<br />
of South Manchester, Manchester, United Kingdom; University of<br />
Manchester, United Kingdom.<br />
Novel diagnostic procedure of metastasis to the sentinel<br />
lymph node of breast cancer using a semi-dry dot-blot<br />
method<br />
Otsubo R, Oikawa M, Shibata K, Hirakawa H, Yano H, Matsumoto<br />
M, Hatachi T, Nakao K, Hayashi T, Abe K, Kinoshita N, Nakashima M,<br />
Taniguchi H, Omagari T, Itoyanagi N, Nagayasu T. Nagasaki University<br />
Hospital, Nagasaki, Japan; The Japanese Red Cross Nagasaki Genbaku<br />
Hospital, Nagasaki, Japan; Aiyuukai Memorial Hospital, Chiba, Japan;<br />
Nagasaki University Atomic Bomb Disease Institute, Nagasaki, Japan;<br />
St. Francis Hospital, Nagasaki, Japan.<br />
What is the actual impact of micrometastases in sentinel<br />
lymph nodes in regards to global survival and disease free<br />
survival<br />
Barbosa EM, Araujo Neto JT, Filho EC, Infante KP, Felzener MM,<br />
Matielle CR, Modesto MG, Basso R, Goes JCS. Instituto Brasileiro de<br />
Controle do <strong>Cancer</strong> - IBCC, Sao Paulo, Brazil.<br />
www.aacrjournals.org<br />
9s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P1-01-29 Intraoperative molecular analysis of sentinel lymph node as a<br />
new predictor of axillary status in early breast cancer patients<br />
Peg V, Espinosa-Bravo M, Vieites B, Vilardell F, Antúnez JR, <strong>San</strong>cho<br />
de Salas M, <strong>San</strong>sano I, Delgado Sánchez JJ, Pinto W, Gozalbo F,<br />
Petit A, Rubio I. Hospital Universitario Vall d’Hebron, Barcelona,<br />
Spain; Hospital Universitario Virgen del Rocío, Sevilla, Spain; Hospital<br />
Universitari Arnau de Vilanova de Lleida, Lleida, Spain; Complejo<br />
hospitalario Universitario <strong>San</strong>tiago de Compostela, <strong>San</strong>tiago de<br />
Compostela, Spain; Hospital Universitario de Salamanca, Salamanca,<br />
Spain; Hospital Universitario 12 de Octubre, Madrid, Spain; Hospital<br />
Universitario e Gran Canaria Doctor Negrín, Las Palmas de Gran<br />
Canaria, Spain; Instituto Valenciano de Oncología (IVO), Valencia,<br />
Spain; Hospital Universitari de Bellvitge, Hospitalet de Llobregat,<br />
Spain.<br />
Detection/Diagnosis: Biopsy Techniques<br />
P1-02-01 Flat epithelial atypia diagnosed on breast core biopsy:<br />
what next?<br />
Plichta JK, Lapetino S, Rumas N, Rajan P, Godellas C, Perez C. Loyola<br />
University Medical Center, Maywood, IL.<br />
P1-02-02 Receptor discordance in breast cancer recurrence: Is re-biopsy<br />
a necessity?<br />
Fujita T, Sawaki M, Hattori M, Kondo N, Horio A, Ushio A, Gondo N,<br />
Hiroji I. Aichi <strong>Cancer</strong> Center Hospital, Nagoya, Japan.<br />
Tumor Cell and Molecular Biology: Etiology/Carcinogenesis<br />
P1-03-01 Evidence for the Warburg effect in mammary atypia from<br />
high-risk African American women<br />
Seewaldt V, Hoffman A, Ibarra-Drendall C. Duke University,<br />
Durham, NC.<br />
P1-03-02 ‘Normal’ tissue adjacent to breast cancer is not normal<br />
Clare SE, Pardo I, Mathieson T, Lillemoe HA, Blosser RJ, Choi M,<br />
Sauder CAM, Doxey DK, Badve S, Storniolo AMV, Atale R, Radovich<br />
M. Indiana University School of Medicine, Indianapolis, IN; Susan<br />
G. Komen for the Cure Tissue Bank at the IU Simon <strong>Cancer</strong> Center,<br />
Indiana University School of Medicine, Indianapolis, IN.<br />
P1-03-03 Milk deposition in women’s mammary duct has been a<br />
potential risk factor of breast tumor<br />
Xu Z, Gu Y, Gong G, Zhang Y. <strong>Breast</strong> Disease Institution of Jilin<br />
Province, Changchun, Jilin, China; Spinal Disease Institution of Jilin<br />
Province, Changchun, Jilin, China.<br />
Tumor Cell and Molecular Biology: Oncogenes/Tumor Suppressor Genes<br />
P1-04-01 Loss of Notch4 reduces mammary tumorigenesis by MYC and<br />
activated KRAS<br />
Rodriguez EM, Bishop JM. G. W. Hooper Research Foundation,<br />
University of California, <strong>San</strong> Francisco, CA.<br />
P1-04-02 The role of the mTORC1/S6K1 signaling pathway in ER-positive<br />
breast cancer<br />
Holz MK, Unger HA, Sedletcaia A. Stern College for Women of<br />
Yeshiva University; Albert Einstein College of Medicine.<br />
P1-04-03 Knocking down Suppressor of Cytokine Signaling 7 in<br />
breast cancer: The role in Insulin-like Growth Factor - I /<br />
Phospholipase Cγ-1 signaling<br />
Sasi W, Ye L, Jiang WG, Mokbel K, Sharma A. St George’s Hospital<br />
Medical School, University of London, United Kingdom; Cardiff<br />
University School of Medicine, Cardiff, Wales, United Kingdom; The<br />
London <strong>Breast</strong> Institute, The Princess Grace Hospital, London, United<br />
Kingdom.<br />
P1-04-04 KSR1 is involved in functional interaction between p53 and<br />
BRCA1 and is an independent predictor of overall survival in<br />
breast cancer<br />
Zhang H, Lombardo Y, Filipovic A, Periyasamy M, Coombes RC,<br />
Stebbing J, Giamas G. Imperial College London, United Kingdom.<br />
P1-04-05 Role of the Rb and p53 Tumor Suppressor Pathways in<br />
Mammary Tumorigenesis<br />
Jones RA, Liu JC, Zhe J, Schimmer AA, Eldad Z. University Health<br />
Network, Toronto, ON, Canada.<br />
P1-04-06 Insertional mutagenesis identifies HACE1 as a HER2/Neu<br />
Cooperating <strong>Breast</strong> <strong>Cancer</strong> Tumor Suppressor Gene<br />
Goka E, Miller P, Baker K, Stark G, Lippman ME. University of Miami<br />
Miller School of Medicine, Miami, FL; Cleveland Clinic, Cleveland, OH;<br />
University of Miami, FL.<br />
P1-04-07 The mRNA Expression of DAP1 in Human <strong>Breast</strong> <strong>Cancer</strong>:<br />
Correlation with Clinicopathological Parameters<br />
Wazir U, Jiang WG, Sharma AK, Mokbel K. St Georges’ Healthcare<br />
NHS Trust, London, United Kingdom; Cardiff University-Peking<br />
University Oncology Joint Institute, Cardiff, United Kingdom; The<br />
London <strong>Breast</strong> Institute, The Princess Grace Hospital, London, United<br />
Kingdom.<br />
P1-04-08 Evidence for anti-apoptosis function of GNB1 in human<br />
breast cancer<br />
Wazir U, Kasem A, Sharma AK, Jiang W, Mokbel K. The London <strong>Breast</strong><br />
Institute, The Princess Grace Hospital, London, United Kingdom;<br />
Cardiff University-Peking University Oncology Joint Institute, Cardiff,<br />
United Kingdom; St Georges’ Healthcare NHS Trust, London, United<br />
Kingdom.<br />
P1-04-09 mTORC1 and Rictor expression in human breast cancer:<br />
correlations with clinicopathological parameters and disease<br />
outcome<br />
Wazir U, Kasem A, Sharma AK, Jiang WG, Mokbel K. The London<br />
<strong>Breast</strong> Institute, The Princess Grace Hospital, London, United<br />
Kingdom; Cardiff University-Peking University Oncology Joint<br />
Institute, Cardiff, United Kingdom; St Georges’ Healthcare NHS Trust,<br />
London, United Kingdom.<br />
P1-04-10 PDGFRA signaling in Inflammatory breast cancer<br />
Joglekar M, van Golen K. University of Delaware, Newark, DE.<br />
P1-04-11 EZH2 Expands <strong>Breast</strong> Stem Cells via NOTCH Signaling, Acting<br />
to Accelerate <strong>Breast</strong> <strong>Cancer</strong> Initiation<br />
Kleer CG, Li X, Moore HM, Toy KA, Gonzalez ME. University of<br />
Michigan, Ann Arbor, MI.<br />
Tumor Cell and Molecular Biology: Tumor Progression, Invasion, and<br />
Metastasis<br />
P1-05-01 Chemokine-mediated nuclear translocation and novel nuclear<br />
role for LIM and SH3 Protein-1(LASP-1) in breast cancer<br />
Raman D, Duvall-Noelle NL, Richmond A. Vanderbilt University<br />
Medical Center, Nashville, TN.<br />
P1-05-02 Epithelial-to-epithelial transition precedes collective breast<br />
cancer invasion<br />
Cheung KJ, Ewald AJ. Johns Hopkins School of Medicine,<br />
Baltimore, MD.<br />
P1-05-03 A requirement for neural precursor cell-expressed<br />
developmentally downregulated gene 9 during the initiation<br />
of mammary tumorigenesis in MMTV-neu mice<br />
Serzhanova VA, Little JL, Izumchenko E, Seo S, Kurokawa M,<br />
Egleston B, Klein-Szanto AA, Golemis EA. Fox Chase <strong>Cancer</strong> Center,<br />
Philadelphia, PA; Ben Gurion University of the Negev, Beer Sheva,<br />
Israel; University of Tokyo, Japan.<br />
P1-05-04 Expression of Quiescin Sulfhydryl Oxidase 1 is associated<br />
with a highly invasive phenotype and correlates with a poor<br />
prognosis in Luminal B breast cancer<br />
Katchman BA, Ocal T, Hostetter G, Cunliffe HE, Wantanabe A, Lake<br />
DF. Arizona State University, Tempe, AZ; Mayo Clinic Arizona,<br />
Scottsdale, AZ; Translational Genomic Research Institute,<br />
Phoenix, AZ.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 10s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P1-05-05<br />
Podocalyxin is a key regulator of breast cancer progression<br />
and metastasis<br />
Snyder KA, Hughes MR, Graves M, Roskelly C, McNagny KM.<br />
University of British Columbia, Vancouver, BC, Canada.<br />
A novel mutation in the tyrosine kinase domain of ErbB2:<br />
molecular and proteomic investigation of its role in breast<br />
cancer invasion<br />
O’Hara J, Kast J. University of British Columbia, Vancouver, BC,<br />
Canada.<br />
Prognostic relevance of Claudin-2 expression in metastatic<br />
breast cancer<br />
Hedenfalk I, Kimbung S, Kovacs A, Skoog L, Einbeigi Z, Walz T,<br />
Malmberg M, Loman N, Fernö M, Hatschek T, TEX Study Group.<br />
Lund University, Lund, Sweden; CREATE Health Strategic Center<br />
for Translational <strong>Cancer</strong> Research, Lund University, Lund, Sweden;<br />
Sahlgrenska University Hospital, Gothenburg, Sweden; Karolinska<br />
University Hospital, Solna, Sweden; Linköping University Hospital,<br />
Linköping, Sweden; Helsingborg General Hospital, Helsingborg,<br />
Sweden.<br />
Targeting integrin signaling suppresses invasive recurrence<br />
in a three-dimensional model of radiation treated ductal<br />
carcinoma in situ<br />
Nam J-M, Ahmed KM, Costes S, Zhang H, Sabe H, Shirato H, Park<br />
CC. Hokkaido University Graduate School of Medicine, Sapporo,<br />
Hokkaido, Japan; Ernest Orlando Lawrence Berkeley National<br />
Laboratory, Berkeley, CA; UCSF, <strong>San</strong> Francisco, CA.<br />
FH535 inhibited migration and growth of breast cancer cells<br />
Dorchak JA, Iida J, Clancy R, Luo C, Chen Y, Hu H, Mural RJ, Shriver CD.<br />
Windber Research Institute, Windber, PA; Walter Reed National Military<br />
Medical Center, Bethesda, MD.<br />
Targeting breast cancer metastasis through disruption of<br />
novel PELP1-G9a complex<br />
Mann M, Chakravarty D, Kim CA, Vadlamudi RK. University of Texas<br />
Health Science Center at <strong>San</strong> <strong>Antonio</strong>, TX; Weill Cornell Medical<br />
College, New York, NY.<br />
Biological characterization of tumor-associated leukocytes in<br />
positive and negative lymph node breast cancer patients<br />
ElGhonaimy EA, El-Shinawi M, Abd-El-Tawab R, El Mamlouk T, Sloane<br />
BF, Mohamed MM. Faculty of Science, Cairo University, Giza, Cairo,<br />
Egypt; Faculty of Medicine, Ain Shams University, Cairo, Egypt;<br />
Wayne State University, Detroit, MI.<br />
Metastatic xenograft models of human estrogen receptor<br />
negative breast cancer primary cultures are driven by the<br />
recruitment of myeloid-derived suppressor cells<br />
Drews-Elger K, Iorns E, Brinkman JA, Berry DL, Lippman ME, El-Ashry<br />
D. Sylvester Comprehensive <strong>Cancer</strong> Center, Braman Family <strong>Breast</strong><br />
<strong>Cancer</strong> Institute, University of Miami, FL; Science Exchange, Palo Alto,<br />
CA; Georgetown University Medical Center, Washington, DC.<br />
CLIC3 is associated with invasive behaviour and poorer<br />
prognosis in estrogen receptor-negative breast cancer<br />
Macpherson IR, Dozynkiewicz M, Kalna G, Speirs C, Chaudhary S,<br />
Edwards J, Timpson P, Norman J. University of Glasgow, United<br />
Kingdom; Beatson Institute for <strong>Cancer</strong> Research, Glasgow, United<br />
Kingdom.<br />
Multiscale computational modeling of breast cancer invasion:<br />
Towards a predictive patient-based tool<br />
Trucu D, Thompson A, Chaplain MAJ. University of Dundee, United<br />
Kingdom; Ninewells Hospital, University of Dundee, United Kingdom.<br />
P1-05-15<br />
Identification of a novel Hypoxia Inducible Factor-1 regulated<br />
gene involved in breast cancer growth and metastasis<br />
Peacock DL, Schwab LP, Seagroves TN. University of Tennessee<br />
Health Science Center, Memphis, TN.<br />
Sushi Domain Containing 2 (SUSD2): a plasma membrane<br />
protein that increases immune evasion in breast<br />
tumorigenesis<br />
Watson AP, Davis EM, Egland KA. <strong>San</strong>ford Research/USD,<br />
Sioux Falls, SD.<br />
S100A7/RAGE axis enhances breast cancer growth by<br />
activating Stat3 signaling<br />
Nasser MW, Wani NA, Qamri Z, Ahirwar D, Powell CA, Ganju RK. The<br />
Ohio State University, Columbus, OH.<br />
Determining the molecular mechanism of the breast cancerinduced<br />
brain metastasis and a role of a novel pan-TGF-β<br />
inhibitor as a potential therapy for brain metastasis in a<br />
mouse xenograft model<br />
De Mukhopadhyay K, Elkahloun AG, Hinck AP, Yoon K, Cornell JE,<br />
Shu L, Yang J, Sun L. University of Texas Health Science Center,<br />
<strong>San</strong> <strong>Antonio</strong>, TX; National Human Genome Research Institute-NIH,<br />
Bethesda, MD.<br />
Modeling <strong>Cancer</strong> Recurrence and the Therapeutic Effect of<br />
Adjuvant Systemic Therapy<br />
Ganesan S, Bhanot G, Boemo M, Lee JH. <strong>Cancer</strong> Institute of New<br />
Jersey- UMDNJ, New Brunswick, NJ; Rutgers University,<br />
VPiscataway, NJ.<br />
Fluorescent Hyaluronan Probes Distinguish Heterogeneous<br />
<strong>Breast</strong> <strong>Cancer</strong> Cell Subsets and Predict their Invasive Behavior<br />
Veiseh M, Kwon DH, Borowsky AD, Toelg C, Leong H, Lewis J, Turley<br />
EA, Bissell MJ. Lawrence Berkeley National Laboratories, Berkeley,<br />
CA; University of California Davis, Davis, CA; London Health Sciences<br />
Centre-London Regional <strong>Cancer</strong> Program; University of Western<br />
Ontario, London, ON, Canada.<br />
The role of epsin in promoting Epithelial-Mesenchymal<br />
Transition and metastasis by activating NF-kB signaling in<br />
breast cancer<br />
Cai X, Brophy ML, Hahn S, McManus J, Chang B, Pasula S, Chen<br />
H. Oklahoma Medical Research Foundation, Oklahoma City, OK;<br />
University of Oklahoma Health Science Center, Oklahoma City, OK.<br />
<strong>Breast</strong> cancer cells that undergo an Epithelial-to-Mesenchymal<br />
transition co-opt LPP, a regulator of mesenchymal cell<br />
migration and invasion<br />
Ngan E, Northey JJ, Ursini-Siegel J, Siegel PM. McGill University,<br />
Montreal, QC, Canada; Lady Davis Institute for Medical Research,<br />
Montreal, QC, Canada.<br />
Blockade of mTORC1 decreases CXCR4-mediated migration<br />
and metastasis<br />
Dillenburg Pilla P, Patel V, Dorsam RT, Masedunskas A,<br />
Amornphimoltham P, Weigert R, Molinolo AA, Gutkind JS. NIH,<br />
Bethesda, MD.<br />
Pharmacologic reversion of epigenetic silencing of the PRKD1<br />
promoter blocks breast tumor cell invasion and metastasis<br />
Borges S, Doppler H, Andorfer CA, Perez EA, Sun Z, Anastasiadis PZ,<br />
Thompson AE, Geiger XJ, Storz P. Mayo Clinic, Jacksonville, FL; Mayo<br />
Clinic, Rochester, MN.<br />
P1-05-06<br />
P1-05-16<br />
P1-05-07<br />
P1-05-08<br />
P1-05-09<br />
P1-05-10<br />
P1-05-11<br />
P1-05-12<br />
P1-05-13<br />
P1-05-14<br />
P1-05-17<br />
P1-05-18<br />
P1-05-19<br />
P1-05-20<br />
P1-05-21<br />
P1-05-22<br />
P1-05-23<br />
P1-05-24<br />
www.aacrjournals.org<br />
11s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Tumor Cell and Molecular Biology: Angiogenesis<br />
P1-06-01 Upregulation of metabolism as a potential resistance<br />
mechanism to bevacizumab in primary breast cancer<br />
Mehta S, Hughes NP, Adams RF, Li SP, Han C, Kaur K, Taylor NJ,<br />
Padhani AR, Makris A, Buffa FM, Harris AL. Weatherall Institute of<br />
Molecular Medicine, Oxford, United Kingdom; Stanford University,<br />
Stanford, CA; Oxford University Hospitals NHS Trust, Oxford, United<br />
Kingdom; Mount Vernon <strong>Cancer</strong> Centre, Northwood, Middlesex,<br />
United Kingdom; <strong>Cancer</strong> and Haematology Centre, Churchill<br />
Hospital, Oxford, United Kingdom; Paul Strickland Scanner Centre,<br />
Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.<br />
P1-06-02 A newly angiogenic biomarker Vasohibin-1 expression in<br />
ductal carcinoma in situ of the breast<br />
Tamaki K, Tamaki N, Kamada Y, Uehara K, Miyashita M, Ishida T,<br />
Ohuchi N, Sasano H. Nahanishi Clinic Okinawa, Naha, Okinawa,<br />
Japan; Tohoku University Graduate School of Medicine, Sendai,<br />
Miyagi, Japan; Tohoku University Hospital, Sendai, Miyagi, Japan.<br />
P1-06-03 Microvessel density as determined by computerized image<br />
analysis of CD34 and CD105 expression correlates with poor<br />
outcome in triple-negative breast cancer<br />
De Brot M, Rocha RM, Soares FA, Gobbi H. Universidade Federal de<br />
Minas Gerais, Belo Horizonte, MG, Brazil; Hospital A.C. Camargo, Sao<br />
Paulo, SP, Brazil.<br />
Prognostic and Predictive Factors: Biomarkers - Methods<br />
P1-07-01 Attainment of extremely high concordance rates between<br />
fluorescence in situ hybridization and immunohistochemistry<br />
in testing for human epidermal growth factor receptor 2<br />
(HER2) in breast cancer using a normalized scoring system for<br />
immunohistochemistry: A four year experience with over<br />
9000 cases<br />
Gown AM, Goldstein LC, Tse CH, Hwang HC, Kandalaft PL. PhenoPath<br />
Laboratories, Seattle, WA.<br />
P1-07-02 Withdrawn<br />
P1-07-03 Quantification of HER2 expression at the single cell level<br />
and HER2 intratumoral heterogeneity of breast cancer tissue<br />
samples using automated image analysis<br />
Geretti E, Paragas V, Onsum M, Kudla A, Moulis S, Luus L, Wickham T,<br />
McDonagh C, MacBeath G, Hendriks B. Merrimack Pharmaceuticals,<br />
Cambridge, MA.<br />
P1-07-04 Comparison of HER2 expression by immunohistochemistry<br />
(IHC) using automated imaging system and fluorescence in<br />
situ hybridization (FISH). A retrospective analysis of<br />
2853 cases<br />
Collins R, Xiang D, Christie A, Leitch M, Euhus D, Rao R, Haley B,<br />
Sarode V. University of Texas Southwestern Medical Center,<br />
Dallas, TX.<br />
P1-07-05 Evaluation of tissue processing factors affecting HER2 IHC<br />
staining intensity in breast cancer cell lines<br />
Jensen K, Erickson J, Webster S, Pedersen HC. Dako Denmark,<br />
Glostrup, Denmark; Dako North America, Carpinteria, CA.<br />
P1-07-06 Effect of biospecimen variables on proteomic biomarker<br />
assessment in breast cancer<br />
Meric-Bernstam F, Akcakanat A, Chen H, Sahin A, Tarco E, Carkaci<br />
S, Adrada B, Singh G, Anh-Do K, Garces Z, Mittendorf EA, Babiera G,<br />
Wagner J, Bedrosian I, Krishnamurthy S, Symmans WF, Gonzalez-<br />
Angulo AM, Mills G. UT MD Anderson <strong>Cancer</strong> Center, Houston, TX;<br />
Ohio State University, Columbus, OH.<br />
P1-07-07 Inflammatory gene expression variations in the interval<br />
between core needle biopsy and excisional biopsy in early<br />
breast cancer<br />
Jeselsohn RM, Regan MM, Werner L, Fatima A, He HH, Brown M,<br />
Iglehart JD, Richardson AL, Come S. Beth Israel Deaconess Medical<br />
Center, Boston, MA; Dana Farber <strong>Cancer</strong> Institute, Boston, MA;<br />
Brigham and Women’s Hospital, Boston, MA.<br />
P1-07-08 Effect of sample preservation method and transportation<br />
duration on tumor gene expression profiling in breast cancer<br />
Fumagalli D, Jose V, Salgado R, Majjaj S, Singhal S, Vincent D,<br />
Maetens M, Larsimont D, Symmans F, Dinh P, Piccart M, Michiels<br />
S, Sotiriou C, Loi S. Institut Jules Bordet, Brussels, Belgium; <strong>Breast</strong><br />
International Group (BIG), Brussels, Belgium; The University of Texas<br />
MD Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
P1-07-09 Estrogen receptor positivity: 10% or 1%?<br />
Yi M, Huo L, Koenig KB, Mittendorf EA, Meric-Bernstam F, Kuerer HM,<br />
Bedrosian I, Symmans WF, Hortobagyi GN, Crow JR, Shah RR, Hunt<br />
KK. University of Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
P1-07-10 Comparison of three commercial ER/PR assays on a single<br />
clinical outcome series<br />
Kornaga EN, Klimowicz AC, Konno M, Guggisberg N, Ogilvie T,<br />
Cartun RW, Morris DG, Webster MA, Magliocco AM. Alberta Health<br />
Services, Calgary, AB, Canada; Calgary Laboratory Services, Calgary,<br />
AB, Canada; Hartford Hospital, Hartford, CT; University of Calgary, AB,<br />
Canada; H. Lee Moffitt <strong>Cancer</strong> Center & Research Institute, Tampa, FL.<br />
P1-07-11 Characterization of progesterone receptor biomarker for<br />
predicting antiprogestin activity in human cancers<br />
Bonneterre J, Bosq J, Lange C, Gilles E. Centre Oscar Lambret, France;<br />
Institut Gustave Roussy, France; University of Minnesota; Invivis<br />
Pharmaceuticals.<br />
P1-07-12 Using Natural Language Processing to Identify and Extract<br />
HER2 Value from a large EMR system<br />
Zheng C, Avila C, Haque R. Kaiser Permanente Southern California,<br />
Pasadena, CA.<br />
P1-07-13 Prognostic relevance of statistically standardized estrogen<br />
receptor (ER), progesterone receptor (PR), and human<br />
epidermal growth factor receptor 2 (HER2) in tamoxifen(TAM)-<br />
treated NCIC CTG MA.14 patients<br />
Chapman J-AW, Sgroi D, Goss PE, Richardson E, Binns SN, Zhang Y,<br />
Schnabel CA, Erlander MG, Pritchard KI, Han L, Shepherd LE, Pollak<br />
MN. NCIC Clinical Trials Group, Queen’s University, Kingston, ON,<br />
Canada; Harvard University, Boston, MA; bioTheranostics, Inc., <strong>San</strong><br />
Diego, CA; Sunnybrook Odette <strong>Cancer</strong> Centre, University of Toronto,<br />
ON, Canada; Jewish General Hospital, McGill University, Montreal,<br />
QC, Canada.<br />
P1-07-14 Enabling biomarker validation in breast cancer molecular<br />
subtypes: sensitivity and specificity of array-based subtype<br />
classification in 983 patients<br />
Györffy B, Lanczky A. Semmelweis University.<br />
P1-07-15 Revisiting chromosome 17q copy number aberrations in early<br />
high-risk breast cancer<br />
Kotoula V, Bobos M, Eleftheraki AG, Timotheadou E, Razis E, Goussia<br />
A, Levva S, Kalogeras KT, Pectasides D, Fountzilas G. Hellenic<br />
Cooperative Oncology Group (HeCOG), Athens, Greece.<br />
P1-07-16 Liver derived epithelial cells as source of false positive<br />
circulating tumor cells in early breast cancer<br />
Habets L, Körber W, Frenken B, Danaei M, Kusche M, Peisker U, Kroll<br />
T, Pachmann K. Metares.e.V, Aachen, NRW, Germany; Brustzentrum<br />
Aachen Kreis Heinsberg, Aachen, NRW, Germany; Medizinische<br />
Universitätsklinik Jena, Thueringen, Germany.<br />
P1-07-17 V Array: A novel tool for constructing virtual tissue<br />
microarrays (TMAs), an evaluation of its use in optimizing TMA<br />
construction for Ductal Carcinoma in Situ (DCIS)<br />
Quintayo MA, Starczynski J, Yan FJ, Bartlett JMS, Benko L, Hanna W,<br />
Nofech-Mozes S, Rakovitch E. Ontario Institute of <strong>Cancer</strong> Research,<br />
Toronto, ON, Canada; Sunnybrook Health Sciences Centre, Toronto,<br />
ON, Canada; Leica Microsystems, Buffallo Grove, IL.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 12s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P1-07-18 Association between Bone Turnover Markers in patients<br />
with breast cancer and bone metastases on treatment with<br />
bisphosphonates (ZOMAR study)<br />
Tusquets I, De la Piedra C, Manso L, Crespo C, Gómez P, Calvo L,<br />
Ruiz M, Martínez P, Perelló A, Antón A, Codes M, Margelí M, Murias<br />
A, Salvador J, Seguí MA, De Juán A, Gavilá J, Luque M, Pérez D,<br />
Zamora P, Arizcum A, Chacón JI, Heras L, Barnadas A. Hospital<br />
del Mar, Barcelona, Spain; Instituto de Investigación <strong>San</strong>itaria<br />
Fundación Jiménez Díaz, Madrid, Spain; Hospital 12 de Octubre,<br />
Madrid, Spain; Hospital Universitario Ramón y Cajal, Madrid, Spain;<br />
Hospital Universitario Vall d’Hebrón, Barcelona, Spain; Hospital<br />
Universitario A Coruña Juan Canalejo, A Coruña, Spain; Hospital<br />
Universitario Virgen del Rocío, Sevilla, Spain; Hospital de Basurto,<br />
Vizcaya, Spain; Hospital Son Dureta, Palma de Mallorca, Spain;<br />
Hospital Miguel Servet, Zaragoza, Spain; Hospital Virgen Macarena,<br />
Sevilla, Spain; H. Universitario Trias y Pujol, Barcelona, Spain;<br />
Hospital Universitario Insular de Gran Canaria, Gran Canaria, Spain;<br />
Hospital Nuestra Señora de Valme, Sevilla, Spain; Hospital Parc Taulí<br />
Sabadell, Barcelona, Spain; Hospital Marqués Valdecilla, <strong>San</strong>tander,<br />
Spain; Instituto Valenciano de Oncología, Valencia, Spain; Hospital<br />
General de Asturias, Oviedo, Spain; Hospital Costa del Sol, Málaga,<br />
Spain; Hospital La Paz, Madrid, Spain; Hospital Palencia Río Carrión,<br />
Palencia, Spain; Hospital Virgen de la Salud, Toledo, Spain; Hospital<br />
Cruz Roja Hospitalet del Llobregat, Barcelona, Spain; Hospital <strong>San</strong>ta<br />
Creu i <strong>San</strong>t Pau, Barcelona, Spain.<br />
P1-07-19 Mass Spectrometry Based Quantitative Analysis of the HER<br />
Family receptors in FFPE <strong>Breast</strong> <strong>Cancer</strong> Tissue<br />
Hembrough TA, Scaltriti M, Serra V, Jimenez J, Perez J, Liao W-L,<br />
Thyparambil S, Cortes J, Baselga J, Burrows J. OncoPlex Diagnostics,<br />
Inc., Rockville, MD; Vall d’Hebron Istitute of Oncology, Barcelona,<br />
Spain; Massachusetts General Hospital, Boston, MA.<br />
Epidemiology, Risk, and Prevention: Prevention - Preclinical Studies and<br />
Model Systems<br />
P1-08-01 Effects Of An Allosteric AKT Inhibitor (MK2206)<br />
Administered With Or Without The Aromatase Inhibitor<br />
Vorozole In An ER + Rat Mammary <strong>Cancer</strong> Model: Preventive<br />
And Therapeutic Effects<br />
Lubet RA, Ellis MJ, Grubbs CJ. National <strong>Cancer</strong> Institutes, Bethesda,<br />
MD; University of Washington at Saint Louis, MO; University of<br />
Alabama at Birmingham, AL.<br />
P1-08-02 Gene expression changes in methylnitrosourea (MNU)-induced<br />
ER + mammary cancers following short-term treatment of rats<br />
with SERMs (Tamoxifen and Arzoxifene)<br />
Lubet R, Vedell P, Grubbs C, Bernard P, You M. National <strong>Cancer</strong><br />
Institute, Bethesda, MD; Medical School of Wisconsin, Milwaukee, WI;<br />
Hunstman <strong>Cancer</strong> Center, Salt Lake City, UT; University of Alabama at<br />
Birmingham, AL.<br />
Epidemiology, Risk, and Prevention: Prevention - Clinical Trials<br />
P1-09-01 Long-term effect of tamoxifen use on the risk of contralateral<br />
breast cancer<br />
Mellemkjær L, Steding-Jessen M, Frederiksen K, Andersson M, Olsen<br />
JH. Danish <strong>Cancer</strong> Society Research Center, Copenhagen, Denmark;<br />
Copenhagen University Hospital, Rigshospitalet, Copenhagen,<br />
Denmark.<br />
P1-09-02 Pilot study of a 1-year intervention of high-dose vitamin D in<br />
women at high risk for breast cancer<br />
Sivasubramanian PS, Hershman DL, Maurer M, Kalinsky K, Feldman<br />
S, Brafman L, Refice S, Kranwinkle G, Crew KD. Columbia University,<br />
New York, NY.<br />
P1-09-03 Chemoprevention in patients with newly diagnosed<br />
breast cancers<br />
Refinetti AP, Chun J, Schnabel F, Guth A, Axelrod D. NYU Langone<br />
Medical Center, New York, NY.<br />
P1-09-04 Down-regulation of trefoil protein 1(TFF1) in normal breast<br />
tissue of postmenopausal women at increased risk for breast<br />
cancer on exemestane<br />
Gatti-Mays M, Kallakury BVS, Makariou E, Venzon D, Permaul<br />
E, Isaacs C, Cohen P, Warren R, Gallagher A, Eng-Wong J.<br />
Georgetown University Hospital, Washington, DC; National <strong>Cancer</strong><br />
Institute, National Institutes of Health, Bethesda, MD; Lombardi<br />
Comprehensive <strong>Cancer</strong> Center, Georgetown University Medical<br />
Center, Washington, DC.<br />
P1-09-05 The RAZOR trial: a phase II prevention trial of screening<br />
plus goserilin and raloxifene versus screening alone in premenopausal<br />
women at increased risk of breast cancer<br />
Motion J, Ashcroft L, Dowsett M, Cuzick J, Hickman J, Evans G,<br />
Eccles D, Eeles R, Greenhalgh R, Affen J, Bundred S, Boggis C,<br />
Sergeant J, Fallowfield L, Adams J, Howell A. University Hospital<br />
South Manchester, Manchester, United Kingdom; The Christie NHS<br />
Foundation Trust, Manchester, United Kingdom; Royal Marsden<br />
Hospital, London, United Kingdom; Queen Mary, University of<br />
London, United Kingdom; Princess Anne Hospital, Southampton,<br />
United Kingdom; The Institute of <strong>Cancer</strong> Research, Royal Marsden<br />
Hospital, London, United Kingdom; University of Sussex - (SHORE-C),<br />
Brighton, United Kingdom; University of Manchester, United<br />
Kingdom; Manchester Royal Infirmary, Manchester, United Kingdom.<br />
P1-09-06 Biological Effects of Green Tea Capsule Supplementation in<br />
Pre-surgery <strong>Breast</strong> <strong>Cancer</strong> Patients<br />
Yu S, Spicer D, Hawes D, Wu A. University of Southern California, Los<br />
Angeles, CA.<br />
P1-09-07 Topical 4-OHT trial in women with DCIS of the breast: Vreport<br />
of plasma and breast tissue concentration of tamoxifen<br />
metabolites<br />
Lee O, Chatterton RT, Muzzio M, Page K, Jovanovic B, Helenowski I,<br />
Dunn B, Heckman-Stoddard B, Foster K, Shklovskaya J, Skripkauskas<br />
S, Bergan R, Khan SA. Northwestern University, Chicago, IL; IIT<br />
Research Institute, Chicago, IL; National <strong>Cancer</strong> Institute,<br />
Bethesda, MD.<br />
Epidemiology, Risk, and Prevention: Prevention - Nutritional Studies<br />
P1-10-01 Curcumin suppresses MMP-9 expression via inhibition of<br />
PKCα/MAPKs and NF-κB/AP-1 activation in MCF-7 cells<br />
Kim SK, Kim YW, Youn HJ, Jung SH. Chonbuk National University<br />
Medical School, Jeonju, Jeollabukdo, Republic of Korea.<br />
P1-10-02 Comparative Preventive Efficacy of Select Chinese Herbs in<br />
<strong>Breast</strong> Carcinoma Derived Isogenic Cells with Modulated<br />
Estrogen Receptor Functions<br />
Telang NT, Li G, Katdare M, Sepkovic DW, Bradlow HL, Wong GYC.<br />
Palindrome Liaisons, Montvale, NJ; American Foundation for Chinese<br />
Medicine, New York, NY; Skin of Color Research Institute, Leroy T.<br />
Canoles Jr. <strong>Cancer</strong> Research Center, Hampton University, Eastern<br />
Virginia Medical School, Hampton, VA; David & Alice Jurist Institute<br />
for Research, Hackensack University Medical Center, Hackensack, NJ;<br />
David & Alice Jurist Institute for Research, Hackensack, NJ; American<br />
Foundation for Chinese Medicine, Beth Israel Medical Center,<br />
New York, NY.<br />
Epidemiology, Risk, and Prevention: Prevention - Behavioral Interventions<br />
P1-11-01 Physical Activity Reduces the Risk of <strong>Breast</strong> <strong>Cancer</strong><br />
Hardefeldt PJ, Edirimanne S, Eslick GD. University of Sydney, NSW,<br />
Australia; Nepean Hospital, University of Sydney, Penrith, NSW,<br />
Australia.<br />
www.aacrjournals.org<br />
13s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Treatment: Chemotherapy - Advanced Disease<br />
P1-12-01 Evaluation on efficacy and safety of capecitabine plus<br />
docetaxel versus docetaxel monotherapy in metastatic breast<br />
cancer patients pretreated with anthracycline: Results from a<br />
randomized phase III study (JO21095)<br />
Sato N, Yamamoto D, Rai Y, Iwase H, Saito M, Iwata H, Masuda N,<br />
Oura S, Watanabe J, Kuroi K. Niigata <strong>Cancer</strong> Center Hospital, Niigata,<br />
Japan; Kansai Medical University Hirakata Hospital, Hirakata, Osaka,<br />
Japan; Sagara Hospital, Kagoshima, Japan; Kumamoto University<br />
Hospital, Kumamoto, Japan; Juntendo University Hospital, Bunkyo,<br />
Tokyo, Japan; Aichi <strong>Cancer</strong> Center Hospital, Nagoya, Aichi, Japan;<br />
National Hospital Organization Osaka National Hospital, Osaka,<br />
Japan; Wakayama Medical University, Wakayama, Wakayama, Japan;<br />
Shizuoka <strong>Cancer</strong> Center, Nagaizumi-cho, Suntou-gun, Shizuoka,<br />
Japan; Tokyo Metropolitan <strong>Cancer</strong> and Infectious Diseases Center<br />
Komagome Hospital, Bunkyo, Tokyo, Japan.<br />
P1-12-02 Results of a phase 2, multicenter, single-arm study of<br />
eribulin mesylate as first-line therapy for locally recurrent or<br />
metastatic HER2-negative breast cancer<br />
Vahdat L, Schwartzberg L, Glück S, Rege J, Liao J, Cox D,<br />
O’Shaughnessy J. Weill Cornell Medical College, New York, NY; The<br />
West Clinic, Memphis, TN; Sylvester Comprehensive <strong>Cancer</strong> Center,<br />
Miami, FL; Eisai Inc, Woodcliff Lake, NJ; Texas Oncology-Baylor<br />
Charles A. Sammons <strong>Cancer</strong> Center, Dallas, TX.<br />
P1-12-03 Low-dose capecitabine monotherapy in HER-2 negative<br />
metastatic breast cancer: a retrospective study<br />
Ambros T, Zeichner SB, Zaravinos J, Montero AJ, Ahn E, Mani A,<br />
Kronish L, Mahtani RL, Vogel CL. University of Miami, FL; Mount Sinai<br />
Medical Center, Miami Beach, FL; Memorial Hospital West, Pembroke<br />
Pines, FL; SUNY Downstate, Brooklyn, NY.<br />
P1-12-04 Carboplatin, nab-paclitaxel and bevacizumab as first-line<br />
treatment for metastatic breast cancer<br />
Lo SS, Guo R, Czaplicki KL, Robinson PA, Gaynor E, Barhamand FB,<br />
Schulz WC, Kash JJ, Horvath LE, Bayer RA, Petrowsky C, De la Torre<br />
R, Park JH, Albain KS. Loyola University Medical Center, Maywood,<br />
IL; Hematology Oncology Consultants Ltd., Naperville, IL; Swedish<br />
Americal Regional <strong>Cancer</strong> Center, Rockford, IL; Edward <strong>Cancer</strong><br />
Center, Naperville, IL; Central Dupage <strong>Cancer</strong> Center, Winfield, IL;<br />
CDPG Oncology at Delnor, Delnor, IL.<br />
P1-12-05 First-line chemotherapy with pegylated liposomal doxorubicin<br />
versus capecitabine in elderly patients with metastatic breast<br />
cancer: results of the phase III OMEGA study of the Dutch<br />
<strong>Breast</strong> <strong>Cancer</strong> Trialists’ Group (BOOG)<br />
Smorenburg CH, Seynaeve C, Wymenga MANM, Maartense E,<br />
de Graaf H, de Jongh FE, Braun HJ, Los M, Schrama JG, Portielje<br />
JEA, Hamaker M, van Tinteren H, de Groot SM, van Leeuwen-Stok<br />
EAE, Nortier HWR. Medical Center Alkmaar, Alkmaar, Netherlands;<br />
Erasmus Medical Center-Daniel den Hoed <strong>Cancer</strong> Center,<br />
Rotterdam, Netherlands; Medisch Spectrum Twente, Enschede,<br />
Netherlands; Reinier de Graaf Hospital, Delft, Netherlands; Medical<br />
Center Leeuwarden, Leeuwarden, Netherlands; Ikazia Hospital,<br />
Rotterdam, Netherlands; Vlietland Hospital, Schiedam, Netherlands;<br />
St. Antonius Hospital, Nieuwegein, Netherlands; Spaarne Hospital,<br />
Hoofddorp, Netherlands; Haga Hospital, The Hague, Netherlands;<br />
Diaconessehuis, Utrecht, Netherlands; Antoni van Leeuwenhoek<br />
Hospital/Netherlands <strong>Cancer</strong> Institute, Amsterdam, Netherlands;<br />
Comprehensive <strong>Cancer</strong> Centre the Netherlands, Amsterdam,<br />
Netherlands; Dutch <strong>Breast</strong> <strong>Cancer</strong> Trialists’ Group BOOG, Amsterdam,<br />
Netherlands; Leiden University Medical Center, Leiden, Netherlands.<br />
P1-12-06 N0937 (Alliance): Preliminary results of a phase II clinical trial<br />
of cisplatin and the novel agent brostallicin in patients with<br />
metastatic triple negative breast cancer (mTNBC)<br />
Moreno-Aspitia A, Rowland, Jr. KM, Allred JB, Liu H, Stella PJ, Gross<br />
HM, Soori GS, Karlin NJ, Perez EA. Mayo Clinic, Jacksonville, FL; Carle<br />
Foundation - Carle <strong>Cancer</strong> Center, Urbana, IL; Mayo Clinic, Rochester,<br />
MN; St. Joseph Mercy Health System, Ann Arbor, MI; Hematology<br />
& Oncology of Dayton, Inc., Dayton, OH; Missouri Valley <strong>Cancer</strong><br />
Consortium CCOP, Omaha, NE; Mayo Clinic, Scottsdale, AZ.<br />
P1-12-07 A Retrospective Analysis of nab-Paclitaxel as First-Line<br />
Therapy for Metastatic <strong>Breast</strong> <strong>Cancer</strong> Patients with Poor<br />
Prognostic Factors<br />
O’Shaughnessy J, Gradishar W, Bhar P, Iglesias J. Baylor Sammons<br />
<strong>Cancer</strong> Center, Texas Oncology and US Oncology, Dallas, TX;<br />
Maggie Daley Center for Women’s <strong>Cancer</strong> Care, Robert H. Lurie<br />
Comprehensive <strong>Cancer</strong> Center, Northwestern University Feinberg<br />
School of Medicine, Northwestern Memorial Hospital, Chicago,<br />
IL; Celgene Corporation, Durham, NC; Celgene Corporation,<br />
Mississauga, ON, Canada.<br />
P1-12-08 Withdrawn<br />
Treatment: Chemotherapy - Adjuvant<br />
P1-13-01 A randomized trial of CEF versus dose dense EC followed by<br />
paclitaxel versus AC followed by paclitaxel in women with<br />
node positive or high risk node negative breast cancer, NCIC<br />
CTG MA.21: Results of the final relapse free survival analysis<br />
Burnell MJ, Shepherd L, Gelmon K, Bramwell V, Walley B, Vandenberg<br />
E, Chalchal H, Pritchard K, Whelan T, Albain K, Perez E, Rugo H,<br />
O’Brien P, Chapman J, Levine M. NCIC Clinical Trials Group, Queen’s<br />
University, Kingston, ON, Canada; British Columbia <strong>Cancer</strong> Agency<br />
(BCCA), Vancouver, BC, Canada; University of Calgary, AB, Canada;<br />
Saint John Regional Hospital, Saint John, NB, Canada; London<br />
Regional <strong>Cancer</strong> Centre, London, ON, Canada; Sunnybrook <strong>Cancer</strong><br />
Centre, Toronto, ON, Canada; Juravinski <strong>Cancer</strong> Centre, Hamilton<br />
Health Sciences Centre, Hamilton, ON, Canada; Loyola University<br />
Medical Center, Maywood, IL; Mayo Clinic Jacksonville, FL; University<br />
of California, <strong>San</strong> Francisco, CA; McMaster University, Hamilton, ON,<br />
Canada; Allan Blair <strong>Cancer</strong> Centre, Regina, SK, Canada.<br />
P1-13-02 Withdrawn<br />
P1-13-03 Mature analysis of UK Taxotere as Adjuvant Chemotherapy<br />
(TACT) trial (CRUK 01/001); effects of treatment and<br />
characterisation of patterns of breast cancer relapse<br />
Bliss JM, Ellis P, Kilburn L, Bartlett J, Bloomfield D, Cameron D, Canney<br />
P, Coleman RE, Dowsett M, Earl H, Verril M, Wardley A, Yarnold J,<br />
Ahern R, Atkins N, Fletcher M, McLinden M, Barrett-Lee P. Institute<br />
of <strong>Cancer</strong> Research, Sutton, Surrey, United Kingdom; Guy’s Hospital,<br />
Kings Health Partners AHSC, London, United Kingdom; Velindre NHS<br />
Trust <strong>Cancer</strong> Centre, Cardiff, United Kingdom; Edinburgh <strong>Cancer</strong><br />
Research Centre, University of Edinburgh, United Kingdom; The<br />
Christie Hospital, Manchester, United Kingdom; Northern Centre<br />
for <strong>Cancer</strong> Care, Newcastle upon Tyne, United Kingdom; Brighton<br />
& Sussex University Hospitals, Brighton, United Kingdom; Ontario<br />
Institute for <strong>Cancer</strong> Research, Toronto, Canada; Beatson West of<br />
Scotland <strong>Cancer</strong> Centre, Glasgow, United Kingdom; Leeds Institute of<br />
Molecular Medicine, University of Leeds, Leeds, United Kingdom; ICR<br />
and Royal Marsden NHS Trust, London, United Kingdom; University<br />
of Cambridge, University of Cambridge and NIHR Cambridge<br />
Biomedical Research Centre, Cambridge, United Kingdom; Weston<br />
Park Hospital, Sheffield, United Kingdom; NHS National Services<br />
Scotland, Edinburgh, United Kingdom.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 14s <strong>Cancer</strong> Research
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P1-13-04<br />
P1-13-05<br />
P1-13-06<br />
P1-13-07<br />
P1-13-08<br />
P1-13-09<br />
P1-13-10<br />
Optimal duration of adjuvant chemotherapy for high risk<br />
node negative breast cancer patients: 6-year results of the<br />
prospective randomized phase III trial PACS 05<br />
Kerbrat P, Coudert B, Asselain B, Levy C, Lortholary A, Marre A, Delva<br />
R, Rios M, Viens P, Brain E, Serin D, Edel M, Mauriac L, Campone<br />
M, Mouret-Reynier M-A, Bachelot T, Foucher-Goudier M-J, Roca L,<br />
Martin A-L, Roche H. Centre Eugene Marquis, Rennes, France; Centre<br />
Georges François Leclerc, Dijon, France; Institut Curie, Paris, France;<br />
Centre Francois Baclesse, Caen, France; Centre Catherine de Sienne,<br />
Nantes, France; Centre Hospitalier, Rodez, France; ICO Centre Paul<br />
Papin, Angers, France; Centre Alexis Vautrin, Vandoeuvre-les-Nancy,<br />
France; Institut Paoli Calmettes, Marseille, France; Institut Curie,<br />
Saint Cloud, France; Institut Sainte-Catherine, Avignon, France;<br />
Centre Hospitalier Emile Muller, Mulhouse, France; Institut Bergonié,<br />
Bordeaux, France; ICO Centre René Gauducheau, Saint Herblain,<br />
France; Centre Jean Perrin, Clermont-Ferrand, France; Centre Léon<br />
Berard, Lyon, France; Centre Hospitalier Bretagne-Sud, Lorient,<br />
France; Centre Val d’Aurelle, Montpellier, France; R&D Unicancer,<br />
Paris, France; Institut Claudius Regaud, Toulouse, France.<br />
The association between timing in adjuvant chemotherapy<br />
administration and overall survival for women with breast<br />
cancer within the National Comprehensive <strong>Cancer</strong> Network<br />
(NCCN)<br />
Vandergrift JL, Breslin TM, Niland JC, Edge SB, Wolff AC, Marcom<br />
PK, Rugo HS, Moy B, Wilson JL, Ottesen RA, Weeks JC, Wong Y-N.<br />
National Comprehensive <strong>Cancer</strong> Network, Fort Washington, PA;<br />
University of Michigan Comprehensive <strong>Cancer</strong> Center, Ann Arbor,<br />
MI; City of Hope Comprehensive <strong>Cancer</strong> Center, Duarte, CA; Dana-<br />
Farber/Brigham Women’s <strong>Cancer</strong> Center, Boston, MA; Roswell Park<br />
<strong>Cancer</strong> Institute, Buffalo, NY; The Sidney Kimmel Comprehensive<br />
<strong>Cancer</strong> Center at Johns Hopkins, Baltimore, MD; Duke <strong>Cancer</strong><br />
Institute, Durham, NC; UCSF Helen Diller Family Comprehensive<br />
<strong>Cancer</strong> Center, <strong>San</strong> Francisco, CA; The Ohio State University<br />
Comprehensive <strong>Cancer</strong> Center and James <strong>Cancer</strong> Hospital and<br />
Solove Research Institute, Columbus, OH; Massachusetts General<br />
Hospital <strong>Cancer</strong> Center, Boston, MA; Fox Chase <strong>Cancer</strong> Center,<br />
Philadelphia, PA.<br />
Withdrawn<br />
Association between Delayed Initiation of Adjuvant<br />
Chemotherapy and Survival in <strong>Breast</strong> <strong>Cancer</strong>: A Single-<br />
Institution Study and a Systematic Review and Meta-analysis<br />
Yu K-D, Fan L, Yang C, Shao Z-M. <strong>Cancer</strong> Center and <strong>Cancer</strong> Institute,<br />
Shanghai Medical College, Fudan University, Shanghai, China.<br />
Chemotherapy for <strong>Breast</strong> <strong>Cancer</strong> Causes Sustained Alteration<br />
in Number and Type of B Lymphocytes<br />
Verma R, Smalle N, McCurtin RE, Horgan K, Carter CRD, Hughes TA.<br />
Leeds General Infirmary, Leeds, West Yorkshire, United Kingdom; St<br />
James’s University Hospital, Leeds, West Yorkshire, United Kingdom;<br />
University of Leeds, West Yorkshire, United Kingdom.<br />
A multicenter randomized study comparing the dose dense<br />
G-CSF-supported sequential administration of FEC followed<br />
by docetaxel versus paclitaxel as adjuvant chemotherapy in<br />
women with axillary lymph node positive breast cancer<br />
Mavroudis D, Malamos N, Boukovinas I, Kakolyris S, Kourousis C,<br />
Athanasiadis A, Ziras N, Makrantonakis P, Polyzos A, Christophylakis<br />
C, Georgoulias V. Hellenic Oncology Research Group (HORG),<br />
Athens, Greece.<br />
Efficacy, toxicity and quality of life in older patients with earlystage<br />
breast cancer treated with oral Tegafur-uracil or classical<br />
CMF (cyclophosphamide, methotrexate, and fluorouracil): an<br />
exploratory analysis of National Surgical Adjuvant Study for<br />
<strong>Breast</strong> <strong>Cancer</strong> (N-SAS BC) 01 Trial<br />
Hara F, Watanabe T, Shimozuma K, Ohashi Y. NHO Shikoku <strong>Cancer</strong><br />
Center, Matsuyama, Ehime, Japan; Hamamatsu Oncology Center,<br />
Hamamatsu, Shizuoka, Japan; College of Life Sciences, Ritsumeikan<br />
University, Kusatsu, Shiga, Japan; School of Public Health, University<br />
of Tokyo, Bunkyo-ku, Tokyo, Japan.<br />
P1-13-11 Adjuvant treatment of early-stage breast cancer with<br />
eribulin mesylate following dose-dense doxorubicin and<br />
cyclophosphamide: preliminary results from a phase 2,<br />
single-arm feasibility study<br />
Traina TA, Hudis C, Fornier M, Lake D, Lehman R, Berkowitz AP,<br />
Rege J, Liao J, Cox D, Seidman AD. Memorial Sloan-Kettering <strong>Cancer</strong><br />
Center, New York, NY; Eisai Inc, Woodcliff Lake, NJ.<br />
P1-13-12 Withdrawn<br />
P1-13-13 First planned efficacy analysis of the NNBC 3-Europe trial:<br />
Addition of docetaxel to anthracycline containing adjuvant<br />
chemotherapy in high risk node-negative breast cancer<br />
patients<br />
Thomssen C, Kantelhardt EJ, Meisner C, Vetter M, Schmidt M, Martin<br />
P-M, Veyret C, Augustin D, Hanf V, Paepke D, Meinerz W, Hoffmann<br />
G, Wiest W, Sweep FCGJ, Schmitt M, Jaenicke F, von Minckwitz G,<br />
Harbeck N, On Behalf of the NNBC 3-Europe Study Group. Martin-<br />
Luther University Halle-Wittenberg, Halle an der Saale, Germany;<br />
Eberhard-Karls-University Tuebingen, Tuebingen, Germany;<br />
Johannes Gutenberg-Universität Mainz, Mainz, Germany; Medical<br />
Faculty Marseille, Marseille, France; Henri Becquerel Center, Rouen,<br />
France; Klinikum Deggendorf, Deggendorf, Germany; Klinikum Fürth,<br />
Fürth, Germany; Technical University Munich, München, Germany;<br />
St. Vincenz-Hospital, Paderborn, Germany; St. Josefs-Hospital,<br />
Wiesbaden, Germany; Katholisches Klinikum, Mainz, Germany;<br />
Radbourd University Nijmegen, Nijmegen, Netherlands; University<br />
Hamburg, Hamburg, Germany; German <strong>Breast</strong> Group, Neu-Isenburg,<br />
Germany; Ludwig-Maximilian-University, Munich, Germany.<br />
Treatment: Neoadjuvant Chemotherapy<br />
P1-14-01 Adding capecitabine and trastuzumab to neoadjuvant breast<br />
cancer chemotherapy - first survival analysis of the GBG/AGO<br />
intergroup-study GeparQuattro<br />
von Minckwitz G, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H,<br />
Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Blohmer<br />
J-U, Costa S-D, Jackisch C, Paepke S, Schneeweiss A, Kuemmel S,<br />
Denkert C, Mehta K, Untch M. German <strong>Breast</strong> Group, Neu-Isenburg;<br />
Louisenkrankenhaus Düsseldorf; University Erlangen; University<br />
Duesseldorf; Bethanien-Kankenhaus Frankfurt; Klinikum Landshut;<br />
Eilenriedeklinik Duesseldorf; University Kiel; University Rostock;<br />
Roteskreuzklinikum Muenchen; <strong>San</strong>kt Gertrauden Berlin; University<br />
Magdeburg; Klinikum Offenbach; Frauenklinik München; University<br />
Heidelberg; Kliniken Essen Mitte; Charite Berlin; Helios Kliniken Berlin.<br />
P1-14-02 Preoperative docetaxel (T) with or without capecitabine (X)<br />
following epirubicin, 5-fluorouracil and cyclophosphamide<br />
(FEC) in patients with operable breast cancer (OOTR N003):<br />
Results of comparative study and predictive marker analysis<br />
Toi M, Ohno S, Sato N, Masuda N, Sasano H, Takahashi F, Bando<br />
H, Iwata H, Morimoto T, Kamigaki S, Nakayama T, Murakami S,<br />
Nakamura S, Kuroi K, Aogi K, Kashiwaba M, Yamashita H, Hisamatsu<br />
K, Ito Y, Yamamoto Y, Ueno T, Fakhrejahani E, Yoshida N, Chow LWC.<br />
Organisation for Oncology and Translational Research (OOTR),<br />
Kyoto, Japan.<br />
P1-14-03 Overall survival results of a multicenter randomized phase II<br />
study in locally advanced breast cancer patients treated with<br />
or without neoadjuvant Trastuzumab for HER2 positive tumor<br />
(Remagus 02 trial)<br />
Giacchetti S, Pierga J-Y, Asselain B, Delaloge S, Brain E, Espié M,<br />
Mathieu M-C, Bertheau p, de Cremoux P, Tembo O, Marty M. Hôpital<br />
Saint Louis, Assitance Publique-Hôpitaux, Paris, France; Institut Curie,<br />
Paris, France; Institut Gustave Roussy, Villejuif, France; Institut Curie-<br />
Saint Cloud, Saint Cloud, France.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 15s <strong>Cancer</strong> Research
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P1-14-04<br />
P1-14-05<br />
P1-14-06<br />
P1-14-07<br />
P1-14-08<br />
Long- term outcome after neoadjuvant radiochemotherapy<br />
in locally advanced non-inflammatory breast cancer and<br />
predictive factors for a pathologic complete remission; results<br />
of a multi-variate analysis<br />
Matuschek C, Boelke E, Roth S, Bojar H, Audretsch W, Janni JW,<br />
Nestle-Kraemling C, Sauer R, Speer V, Budach W. Heinrich Heine<br />
University, Düsseldorf, Germany; European Institute for Molecular<br />
Oncology, Düsseldorf, Germany; Marien Hospital, Düsseldorf,<br />
Germany; Krankenhaus Gerresheim, Düsseldorf; University of<br />
Erlangen, Germany.<br />
Phase I/II Trial of primary chemotherapy with non-pegylated<br />
liposomal doxorubicin, paclitaxel and lapatinib in patients<br />
with HER2-positive, early stage breast cancer<br />
Aktas B, Kümmel S, Krocker J, Elling D, Lantzsch T, Bischoff J, Fersis<br />
N, Böhme M, Belau AK, Lampe D, Schmid P. University Hospital<br />
of Essen, Germany; Kliniken Essen Mitte, Essen, Germany; <strong>San</strong>a<br />
Klinikum Lichtenberg, Berlin, Germany; St. Barbara Krabkenhaus,<br />
Halle, Germany; University Hospital of Magdeburg, Germany;<br />
Klinikum Chemnitz, Germany; Klinik St. Marienstift, Magdeburg,<br />
Germany; University Hospital of Greifswald, Germany; Asklepios Klinik<br />
Weißenfels, Weißenfels, Germany; University of Sussex,<br />
United Kingdom.<br />
Significance of examining biomarkers of residual tumors<br />
after neoadjuvant chemotherapy using trastuzumab in<br />
combination with anthracycline and taxane in patients with<br />
primary HER2-positive breast cancer<br />
Kurozumi S, Takei H, Inoue K, Matsumoto H, Hayashi Y, Ninomiya J,<br />
Kubo K, Tsuboi M, Nagai S, Ookubo F, Oba H, Kurosumi M, Horiguchi<br />
J, Takeyoshi I. Saitama <strong>Cancer</strong> Center, Saitama, Japan; Gunma<br />
University Graduate School of Medicine, Gunma, Japan.<br />
Neoadjuvant chemotherapy and pathologic complete<br />
response in relation to the clinical response, results from a<br />
phase III study (INTENS) of the Dutch <strong>Breast</strong> <strong>Cancer</strong> Trialists’<br />
Group (BOOG)<br />
Tjan-Heijnen VCG, Vriens BE, de Vries B, van Gastel SM, Wals J, Smilde<br />
TJ, van Warmerdam LJ, van Laarhoven HW, van Spronsen DJ, Borm<br />
GF. Maastricht University Medical Centre, Maastricht, Netherlands;<br />
Comprehensive <strong>Cancer</strong> Centre, Nijmegen, Netherlands; Atrium<br />
Medical Centre, Heerlen, Netherlands; Jeroen Bosch Hospital,<br />
‘s Hertogenbosch, Netherlands; Catharina Hospital, Eindhoven,<br />
Netherlands; Radboud University Nijmegen Medical Centre,<br />
Nijmegen, Netherlands; Canisius-Wilhelmina Hospital, Nijmegen,<br />
Netherlands.<br />
A prospective multicenter randomized phase II neo-adjuvant<br />
study of 5-fluorouracil, epirubicin and cyclophosphamide<br />
(FEC) followed by docetaxel, cyclophosphamide and<br />
trastuzumab (TCH) versus TCH followed by FEC versus TCH<br />
alone, in patients (pts) with operable HER2 positive breast<br />
cancer: JBCRG-10 study<br />
Masuda N, Sato N, Higaki K, Kashiwaba M, Matsunami N, Takano T,<br />
Yamamura J, Kaneko K, Takahashi M, Ohno S, Fujisawa T, Tsuyuki<br />
S, Miyoshi Y, Ohtani S, Yamamoto Y, Bando H, Onoda T, Kawabata<br />
H, Morita S, Ueno T, Toi M. NHO Osaka National Hospital, Osaka,<br />
Japan; Niigata <strong>Cancer</strong> Center Hospital, Niigata, Japan; Hiroshima<br />
City Hospital, Hiroshima, Japan; Iwate Medical University, Morioka,<br />
Japan; Osaka Rosai Hospital, Sakai, Japan; Toranomon Hospital,<br />
Tokyo, Japan; Hokkaido <strong>Cancer</strong> Center, Sapporo, Japan; National<br />
Kyushu <strong>Cancer</strong> Center, Fukuoka, Japan; Gunma Prefectural <strong>Cancer</strong><br />
Center, Ohta, Japan; Osaka Red Cross Hospital, Osaka, Japan; Hyogo<br />
College of Medicine, Nishinomiya, Japan; Kumamoto University<br />
Hospital, Kumamoto, Japan; University of Tsukuba, Faculty of<br />
Medicine, Tsukuba, Japan; Yokohama Asahi Central General Hospital,<br />
Yokohama, Japan; Yokohama City University Graduate School of<br />
Medicine and Medical Center, Yokohama, Japan; Kyoto University,<br />
Kyoto, Japan.<br />
P1-14-09<br />
P1-14-10<br />
P1-14-11<br />
P1-14-12<br />
P1-14-13<br />
P1-14-14<br />
P1-14-15<br />
P1-14-16<br />
P1-14-17<br />
Immunohistochemical classification of intrinsic subtypes as<br />
a predictive biomarker of pathological complete response<br />
in breast cancer patients treated with preoperative<br />
chemotherapy<br />
Nagayama A, Jinno H, Takahashi M, Hayashida T, Hirose S, Kitagawa<br />
Y. School of Medicine, Keio University, Shinjuku, Tokyo, Japan.<br />
Final results of neoadjuvant trial of bevacizumab (B) and<br />
trastuzumab (T) in combination with weekly paclitaxel (P)<br />
as neoadjuvant treatment in HER2-positive breast cancer: A<br />
phase II trial (AVANTHER)<br />
Fernandez M, Calvo I, Martinez N, Herrero M, Quijano Y, Duran H,<br />
Garcia-Aranda M, Suarez A, Lopez-Rios F, Perez D, Perea S, Hidalgo<br />
M, Garcia-Estevez L. Centro Integral Oncológico Clara Campal,<br />
Madrid, Spain; Hospital Ramón y Cajal, Madrid, Spain; Hospital Costa<br />
del Sol, Marbella, Spain.<br />
Assessing Prognosis and Therapy Response in Primary<br />
Systemic Therapy of <strong>Breast</strong> <strong>Cancer</strong> with Magnetic Resonance<br />
Spectroscopy<br />
Bolan PJ, Wey A, Eberly LE, Nelson MT, Haddad TC, Yee D, Garwood<br />
M. University of Minnesota, Minneapolis, MN; Masonic <strong>Cancer</strong><br />
Center, University of Minnesota, Minneapolis, MN.<br />
Response to neoadjuvant chemotherapy and prognosis of<br />
primary breast cancer according to intrinsic subtype<br />
Kochi M, Ito M, Ohtani S, Higaki K. Hiroshima City Hospital,<br />
Hiroshima, Japan.<br />
Increased Pathologic Complete Response Rate and Reduced<br />
Tumour RNA Levels Upon Treatment of Locally Advanced<br />
<strong>Breast</strong> <strong>Cancer</strong> with Neoadjuvant Concurrent Chemotherapy<br />
and Radiation<br />
Brackstone M, Chambers A, Guo B, Vandenberg T, Potvin K, Perea F,<br />
Parissenti A. London Health Sciences Centre, London, ON, Canada;<br />
Health Sciences North, Sudbury, ON, Canada; RNA Diagnostics, Inc.,<br />
Sudbury, ON, Canada.<br />
Neoadjuvant Sunitinib (S) Administered with Weekly<br />
Paclitaxel (P)/Carboplatin(C) in Patients (Pts) with Locally<br />
Advanced Triple-Negative <strong>Breast</strong> <strong>Cancer</strong> (TNBC):<br />
Preliminary Results from a Phase I/II Trial of the Sarah<br />
Cannon Research Institute<br />
Yardley DA, Barton J, Hendricks C, Webb C, Priego V, Nimeh N,<br />
Gravenor D, Shastry M, Chirwa T, Burris HA. Sarah Cannon Research<br />
Institute, Nashville, TN; Tennessee Oncology, PLLC, Nashville, TN;<br />
National Capital Clinical Research Consortium, Bethesda, MD; Baptist<br />
Hospital East, Louisville, KY; Center for <strong>Cancer</strong> and Blood Disorders,<br />
Bethesda, MD; <strong>Cancer</strong> Center of Southwest Oklahoma Research,<br />
Lawton, OK; Family <strong>Cancer</strong> Center Foundation, Inc., Memphis, TN.<br />
Recent experience of neoadjuvant chemotherapy according<br />
to breast cancer subtype: experience from a large United<br />
Kindgom teaching hospital<br />
Rattay T, Kaushik M, Ahmed S, Shokuhi S. University Hospitals of<br />
Leicester, United Kingdom.<br />
Young age: predicts poor response rate after neoadjuvant<br />
chemotherapy in endocrine-responsive breast cancer<br />
Kim MK, Noh D-Y, Han W, Moon H-G, Ahn S-K, Kim JS, Kim T, Kim JY,<br />
Lee JW. Seoul National University Hospital, Seoul, Korea.<br />
Study of breast cancer shrinkage modes after neoadjuvant<br />
chemotherapy with whole-mount serial sections and threedimensional<br />
pathological and MRI reconstruction<br />
Wang Y-S, Zhang Z-P, Liu G, Mu D-B, Sun X-Y. Shandong <strong>Cancer</strong><br />
Hospital & Institute, Jinan, Shandong, China.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 16s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P1-14-18 Overall survival results of a multicenter randomized<br />
phase II study in locally advanced breast cancer patients<br />
treated with or without celecoxib for HER2 negative tumor<br />
(Remagus 02 trial)<br />
Giacchetti S, Pierga J-Y, Delaloge S, Asselain B, Brain E, Guinebretière<br />
JM, Che-Lehman J, Mathieu M-C, Sigal B, Marty M. Hôpital Saint<br />
Louis, Assitance Publique-Hôpitaux, Paris, France; Institut Curie, Paris,<br />
France; Institut Gustave Roussy, Villejuif, France; Institut Curie-Saint<br />
Cloud, Saint Cloud, France.<br />
P1-14-19 <strong>Breast</strong>-Conserving Surgery after Neoadjuvant Chemotherapy<br />
Is Oncologically Safe for Stage III <strong>Breast</strong> <strong>Cancer</strong> Patients<br />
Shin H-C, Han W, Moon H-G, Im S-A, Park S-J, Noh D-Y. Chung-<br />
Ang University Hospital, Seoul, Republic of Korea; Seoul National<br />
University Hospital, Seoul, Republic of Korea.<br />
P1-14-20 Withdrawn<br />
P1-14-21 High antitumoral activity of neoadjuvant chemotherapy<br />
(NCT) with weekly paclitaxel + capecitabine and trastuzumab<br />
in patients with locally advanced HER2+ breast cancer (HER2+<br />
LABC): Preliminary results<br />
Augereau P, Raro P, Verriele V, Delva R, Abadie-Lacourtoisie S,<br />
Ceban T, Paillocher N, Valo I, Maillart P, Soulie P. ICO Paul Papin,<br />
Angers, France.<br />
Treatment: Toxicities - Management<br />
P1-15-01 Patterns of granulocyte colony stimulating factor (G-CSF)<br />
use in elderly breast cancer (BC) patients receiving<br />
myelosuppressive chemotherapy<br />
Blaes AH, Chia V, Solid C, Page J, Barron RL, Choi MR, Arneson TJ.<br />
University of Minnesota, Minneapolis, MN; Amgen, Inc., Thousand<br />
Oaks, CA; Minneapolis Medical Research Foundation,<br />
Minneapolis, MN.<br />
P1-15-02 Febrile neutropenia (FN) risk assessment and granulocyte<br />
colony-stimulating factor (G-CSF) guideline adherence<br />
in patients with breast cancer – results from a German<br />
prospective multicentre observational study (PROTECT)<br />
Steffens C-C, Eschenburg H, Kurbacher C, Goehler T, Schmidt M,<br />
Eustermann H, Schaffrik M, Otremba B. MVZ für Hämatologie/<br />
Onkologie, Klinik Dr. Hancken; Praxis für Hämatologie und<br />
internistische Onkologie, Güstrow; Praxis für Gynäkologie und<br />
gynäkologische Onkologie, Medizinisches Zentrum Bonn; Praxis für<br />
Hämatologie und internistische Onkologie, Dresden; Gynäkologische<br />
Onkologie, Universitätsfrauenklinik Mainz; WiSP Wissenschaftlicher<br />
Service Pharma GmbH, Langenfeld; Amgen GmbH, München;<br />
Onkologische Praxis Oldenburg/Delmenhorst.<br />
P1-15-03 Withdrawn<br />
P1-15-04 The relationship of relative dose intensity and supportive care<br />
to febrile neutropenia rates in patients with early stage breast<br />
cancer receiving chemotherapy: a prospective cohort study of<br />
chemotherapy-associated toxicity<br />
Culakova E, Poniewierski MS, Wogu AF, Kuderer NM, Crawford J,<br />
Dale DC, Lyman GH. Duke University, Durham, NC; University of<br />
Washington, Seattle, WA.<br />
P1-15-05 GSTP1 polymorphism is associated with chemotherapy<br />
induced neuropathy<br />
Miltenburg NC, Opdam M, Winter M, van Geer M, Oosterkamp HM,<br />
Boogerd W, Linn SC. The Netherlands <strong>Cancer</strong> Institute, Amsterdam,<br />
Netherlands.<br />
P1-15-06 The impact of musculoskeletal toxicity on adherence to<br />
endocrine therapy in women with early stage breast cancer–<br />
observations in a non-trial setting<br />
Dent SF, Campbell MM, Crawley FL, Clemons MJ. The Ottawa<br />
Hospital Regional <strong>Cancer</strong> Center, Ottawa, ON, Canada.<br />
P1-15-07 Ixabepilone-associated peripheral neuropathy in<br />
metastatic breast cancer patients and its effects on the<br />
ultrastructure of neurons<br />
Jain S, Carlson K, Chuang E, Cigler T, Moore A, Donovan D, Lam C,<br />
Cobham MV, Schneider S, Ramnarain A, Carey B, Ward M, Lane M,<br />
Strickland S, Vahdat L. Weill Cornell Medical College; Rockefeller<br />
University.<br />
P1-15-08 Higher toxicity of docetaxel for obese women with early<br />
breast cancer: lean body mass is a significant predictor of<br />
chemotherapy dose intensity reduction<br />
Gouerant S, Clatot F, Modzlewski R, Chaker M, Rigal O, Veyret<br />
C, Leheurteur M. Henri Becquerel Center, Rouen, France; Rouen<br />
University Hospital, Rouen, France.<br />
P1-15-09 Multi-Institutional Evaluation of Bioimpedance<br />
Spectroscopy (BIS) in the Early Detection of <strong>Breast</strong> <strong>Cancer</strong><br />
Related Lymphedema<br />
Vicini F, Arthur D, Shah C, Anglin BV, Curcio L, Laidley AL, Beitsch<br />
P, Whitworth P, Lyden M. Michigan Healthcare Professionals/21st<br />
Century Oncology; Virginia Commonwealth University; Beaumont<br />
Health System; The Medical Center of Plano; Advanced <strong>Breast</strong> Care<br />
Specialists of Orange County; Texas <strong>Breast</strong> Specialists; Dallas Surgical<br />
Group; Nashville <strong>Breast</strong> Center; Biostat Inc.<br />
P1-15-10 Chemotherapy-Induced Neutropenia in <strong>Breast</strong> <strong>Cancer</strong><br />
Patients Receiving Sequential Anthracycline and Taxane<br />
Chemotherapy: An Institutional Experience<br />
Staudigl C, Seifert M, Tea M-K, Pfeiler G, Fink-Retter A, Fritzer N,<br />
Singer CF. Medical University of Vienna, Austria; Alps-Adria University<br />
Klagenfurt, Klagenfurt, Austria.<br />
P1-15-11 The Kampo medicine Goshajinkigan prevents docetaxelrelated<br />
peripheral neuropathy in breast cancer patients<br />
Abe H, Mori T, Kawai Y, Itoi N, Tomida K, Cho H, Kubota Y, Umeda<br />
T, Tani T. Shiga University of Medical Science Hospital, Otsu, Shiga,<br />
Japan; Shiga University of Medical Science, Otsu, Shiga, Japan.<br />
P1-15-12 Single Nucleotide Polymorphism (SNP) Bayesian networks<br />
(BNs) Predict Risk of Chemotherapy-Induced Side Effects<br />
in Patients with <strong>Breast</strong> <strong>Cancer</strong> Receiving Dose Dense (DD)<br />
Doxorubicin/Cyclophosphamide Plus Paclitaxel (AC+T)<br />
Schwartzberg LS, Sonis ST, Walker MS, Weidner SM, Alterovitz G. The<br />
West Clinic, Memphis, TN; Brigham and Women’s Hospital, Boston,<br />
MA; ACORN CRO, Memphis, TN; Inform Genomics, Boston, MA;<br />
Harvard Medical School, Boston, MA.<br />
Ongoing Trials 1: Her2<br />
OT1-1-01 A phase II study of neoadjuvant epirubicin/cyclophosphamide<br />
(EC) followed by weekly nanoparticle albumin-bound<br />
paclitaxel with or without trastuzumab for node-positive<br />
breast cancer<br />
Hirano A, Hattori A, Kamimura M, Ogura K, Kim N, Setoguchi Y,<br />
Okubo F, Inoue H, Jibiki N, Miyamoto R, Kinoshita J, Kimura K,<br />
Fujibayashi M, Shimizu T. Tokyo Women’s Medical University,<br />
Medical Center East, Tokyo, Japan; Tokyo Women’s Medical<br />
University, Yachiyo Medical Center, Yachiyo, Japan.<br />
OT1-1-02 A single-arm phase IIIb study of pertuzumab and trastuzumab<br />
with a taxane as first-line therapy for patients with HER2-<br />
positive advanced breast cancer (PERUSE)<br />
Bachelot T, Ciruelos E, Peretz-Yablonski T, Schneeweiss A, Puglisi<br />
F, Mitchell L, Dünne A, Miles D. Centre Leon Bérard, Lyon, France;<br />
Hospital Universitario 12 Octubre, Madrid, Spain; Hadassah- Hebrew<br />
University Medical Center, Jerusalem, Israel; National Center for<br />
Tumor Diseases, University-Hospital Heidelberg, Germany; University<br />
Hospital of Udine, Italy; F. Hoffmann-La Roche, Basel, Switzerland;<br />
Mount Vernon <strong>Cancer</strong> Centre, Mount Vernon Hospital, Middlesex,<br />
United Kingdom.<br />
www.aacrjournals.org<br />
17s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
OT1-1-03<br />
OT1-1-04<br />
PERSEPHONE: Duration of Trastuzumab with Chemotherapy<br />
in women with HER2 positive early breast cancer<br />
Earl HM, Cameron DA, Miles D, Wardley AM, Ogburn ERM, Vallier<br />
A-L, Loi S, Higgins HB, Hiller L, Dunn JA. University of Cambridge,<br />
Cambridge, United Kingdom; NIHR Cambridge Biomedical Research<br />
Centre, Cambridge, United Kingdom; Edinburgh University,<br />
Edinburgh, United Kingdom; Mount Vernon <strong>Cancer</strong> Centre,<br />
Middlesex, United Kingdom; The Christie Hospital, Manchester,<br />
United Kingdom; Warwick Clinical Trials Unit, University of Warwick,<br />
Coventry, United Kingdom; Cambridge <strong>Cancer</strong> Trials Centre,<br />
Cambridge.<br />
ALTERNATIVE: safety and efficacy of lapatinib (L), trastuzumab<br />
(T), or both in combination with an aromatase inhibitor<br />
(AI) for the treatment of hormone receptor-positive (HR+),<br />
human epidermal growth factor receptor 2 positive (HER2+)<br />
metastatic breast cancer<br />
Johnston S, Wroblewski S, Huang Y, Harvey C, Nagi F, Franklin N,<br />
Gradishar W. Royal Marsden NHS Foundation Trust and Institute<br />
of <strong>Cancer</strong> Research, London, United Kingdom; GlaxoSmithKline,<br />
Collegeville, PA; GlaxoSmithKline, Stockley Park, United Kingdom;<br />
Northwestern University, Chicago, IL.<br />
A Phase I pharmacokinetics trial comparing PF-05280014 and<br />
trastuzumab in healthy volunteers (REFLECTIONS B327-01)<br />
Ricart AD, Zacharchuk C, Reich SD, Meng X, Barker KB, Taylor CT,<br />
Hansson AG. Pfizer Inc., <strong>San</strong> Diego, CA; Pfizer Inc., Cambridge, MA;<br />
Pfizer Inc., New Haven, CT.<br />
A phase III randomized study of Paclitaxel and Trastuzumab<br />
versus Paclitaxel, Trastuzumab and Lapatinib in first line<br />
treatment of HER2 positive metastatic breast cancer<br />
Crown JP, Moulton B, O’Donovan N. St Vincent’s University Hospital,<br />
Elm Park, Dublin, Ireland; ICORG (All Ireland Cooperative Oncology<br />
Research Group), Dublin 4, Ireland; National Institute for Cellular<br />
Biotechnology, Dublin City University, Dublin 9, Ireland.<br />
Human epidermal growth factor receptor 2 (HER2)<br />
suppression with the addition of lapatinib to trastuzumab<br />
in HER2-positive metastatic breast cancer (LTP112515)<br />
Lin N, Danso MA, David AK, Muscato J, Rayson D, Houck, III WA,<br />
Ellis C, DeSilvio M, Garofalo A, Nagarwala Y, Winer E. Dana-Farber<br />
<strong>Cancer</strong> Institute, Boston, MA; Virginia Oncology Associates, Norfolk,<br />
VA; Augusta Oncology Associates, Augusta, GA; Missouri <strong>Cancer</strong><br />
Associates, Columbia, MO; QEII Health Sciences Centre, Halifax,<br />
NS, Canada; Virginia <strong>Cancer</strong> Specialists, PC, Winchester, VA;<br />
GlaxoSmithKline Oncology, Collegeville, PA.<br />
Clinical outcomes among ErbB2+ MBC patients treated with<br />
lapatinib-capecitabine after trastuzumab progression:<br />
Role of early switch to lapatinib (TYCO study)<br />
Abulkhair O, Uslu R, Sezgin C, Büyükberber S, Darwish T, Isikdogan<br />
A, Gumus M, Dane F, Sevinc A, Halawani H, Uncu D, Marrero N,<br />
Tobler J, Soares C, Landis S, Moraes E, Gidekel R, <strong>San</strong>tillana S,<br />
Nunez P, Cagnolati S, Rodriguez JG. Ege University Medical Faculty,<br />
Izmir, Turkey; Gazi University Medical Faculty, Ankara, Turkey; King<br />
Abdulaziz Medical City National Guard Health Affairs, Riyadh, Saudi<br />
Arabia; King Abdullah Medical City - Oncology Centre, Jeddah, Saudi<br />
Arabia; Dicle University Medical Faculty, Diyarbakir, Turkey; Kartal<br />
Training and Research Hospital, Istanbul, Turkey; Marmara University<br />
Training and Research Hospital, Istanbul, Turkey; Gaziantep<br />
University Medical Faculty, Gaziantep, Turkey; King Fahad Specialist<br />
Hospital, Dammam, Saudi Arabia; Numune Training and Research<br />
Hospital, Ankara, Turkey; Instituto Docente de Urología, Valencia,<br />
Venezuela; GlaxoSmithKline, Rio de Janeiro, Brazil; GlaxoSmithKline,<br />
Buenos Aires, Argentina; GlaxoSmithKline, Stockley Park, United<br />
Kingdom; Hospital Oncológico Padre Machado, Caracas, Venezuela;<br />
Centro Oncologico-FIDES-La Plata, Buenos Aires, Argentina.<br />
OT1-1-09<br />
OT1-1-10<br />
Opti-HER HEART: A prospective, multicenter, single-arm,<br />
phase II study to evaluate the safety of neoadjuvant liposomal<br />
doxorubicin plus paclitaxel, trastuzumab, and pertuzumab in<br />
patients with operable HER2-positive breast cancer<br />
Gavilá J, Llombart A, Guerrero A, Ruiz A, Guillem V. Fundación<br />
Instituto Valenciano de Oncología, Valencia, Spain; Hospital Arnau<br />
de Vilanova, Valencia, Spain; SOLTI <strong>Breast</strong> <strong>Cancer</strong> Research Group,<br />
Barcelona, Spain.<br />
DETECT III - A multicenter, randomized, phase III study to<br />
compare standard therapy alone versus standard therapy plus<br />
lapatinib in patients with initially HER2-negative metastatic<br />
breast cancer but with HER2-positive circulating tumor cells<br />
Melcher CA, Janni JW, Schneeweiss A, Fasching PA, Hagenbeck CD,<br />
Aktas B, Pantel K, Solomayer EF, Ortmann U, Jaeger BAS, Mueller<br />
V, Rack BK, Fehm TN. University Hospital Duesseldorf, Germany;<br />
National Center for Tumor Diseases, Heidelberg, Germany; University<br />
Hospital Erlangen; University Hospital Essen, Germany; University<br />
Medical Center Hamburg-Eppendorf, Hamburg, Germany; University<br />
Hospital Homburg, Germany; Ludwig-Maximilians-University<br />
Munich, Munich, Germany; University Hospital Hamburg-Eppendorf,<br />
Germany; University Hospital Tuebingen, Germany.<br />
TBCRC 022: Phase II Trial of Neratinib for Patients with Human<br />
Epidermal Growth Factor Receptor 2 (HER2)-Positive <strong>Breast</strong><br />
<strong>Cancer</strong> and Brain Metastases<br />
Freedman RA, Gelman RS, Wefel JS, Krop IE, Melisko ME, Ly A, Agar<br />
NYR, Connolly RM, Blackwell KL, Nabell LM, Ingle JN, Van Poznak<br />
CH, Puhalla SL, Niravath PA, Ryabin N, Wolff AC, Winer EP, Lin N.<br />
Dana-Farber <strong>Cancer</strong> Institute, Boston, MA; The University of Texas<br />
MD Anderson <strong>Cancer</strong> Center, Houston, TX; University of California,<br />
<strong>San</strong> Francisco, CA; Brigham and Women’s Hospital, Boston, MA;<br />
Johns Hopkins University, Baltimore, MD; Duke University, Durham,<br />
NC; University of Alabama, Birmingham, AL; Mayo Clinic, Rochester,<br />
MN; University of Michigan, Ann Arbor, MI; Univerity of Pittsburgh,<br />
Pittsburgh, PA; Baylor, Houston, TX,<br />
NSABP FB-7 Trial: A Phase II Randomized Clinical Trial<br />
Evaluating Neoadjuvant Therapy Regimens with Weekly<br />
Paclitaxel and Neratinib or Trastuzumab or Neratinib and<br />
Trastuzumab Followed by Doxorubicin and Cyclophosphamide<br />
with Postoperative Trastuzumab in Women with Locally<br />
Advanced HER2-Positive <strong>Breast</strong> <strong>Cancer</strong><br />
Lu J, Jacobs SA, Buyse ME, Paik S, Wolmark N. State University of New<br />
York at Stony Brook, Stony Brook, NY; National Surgical Adjuvant<br />
<strong>Breast</strong> and Bowel Project, Pittsburgh, PA.<br />
Dual blockade with Afatinib and Trastuzumab as neoadjuvant<br />
treatment for patients with locally advanced or operable<br />
breast cancer receiving taxane-anthracycline containing<br />
chemotherapy (DAFNE)-GBG70<br />
Hanusch C, Schneeweiss A, Untch M, Paepke S, Kuemmel S,<br />
Jackisch C, Huober J, Hilfrich J, Gerber B, Eidtmann H, Denkert C,<br />
Costa S-D, Blohmer J-U, Loibl S, Nekljudova V, von Minckwitz G.<br />
Rotkreuzklinikum Muenchen; University Heidelberg; Helios Klinik<br />
Berlin; Frauenklinik Muenchen; Kliniken Essen Mitte; Klinikum<br />
offenbach; University Duesseldorf; Eilenriedeklinik Düsseldorf;<br />
University Rostock; University Kiel; Charite Berlin; University<br />
Magdeburg; <strong>San</strong>kt Gertrauden Berlin; German <strong>Breast</strong> Group, Neu-<br />
Isenburg.<br />
Open-label, Phase II trial of afatinib, with or without<br />
vinorelbine, for the treatment of HER2-overexpressing<br />
inflammatory breast cancer (IBC)*<br />
Swanton C, Cromer J, On behalf of the 1200.89 trial group. CR-UK<br />
London Research Institute, London, United Kingdom; Boehringer<br />
Ingelheim, North Ryde, Australia.<br />
OT1-1-05<br />
OT1-1-06<br />
OT1-1-07<br />
OT1-1-08<br />
OT1-1-11<br />
OT1-1-12<br />
OT1-1-13<br />
OT1-1-14<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 18s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
OT1-1-15 LUX-<strong>Breast</strong> 3: Randomized Phase II trial of afatinib (BIBW<br />
2992) alone or with vinorelbine versus investigator’s choice of<br />
treatment in patients (pts) with HER2-positive breast cancer<br />
(BC) with progressive brain metastases after trastuzumab and/<br />
or lapatinib-based therapy*<br />
Joensuu H, Ould-Kaci M, On behalf of the 1200.67 trial group.<br />
Helsinki University Central Hospital, Helsinki, Finland; Boehringer<br />
Ingelheim, Paris, France.<br />
OT1-1-16 LUX-<strong>Breast</strong> 1: Randomized, Phase III trial of afatinib (BIBW<br />
2992) and vinorelbine vs. trastuzumab and vinorelbine in<br />
patients with HER2-overexpressing metastatic breast cancer<br />
(MBC) failing one prior trastuzumab treatment*<br />
Xu B, Im S-A, Huang C-S, Im Y-H, Ro J, Zhang Q, Arora R, Mehta<br />
A, Jung K, Yeh D-C, Lee S, Jassem J, Wojtukiewicz M, Chen S-C,<br />
Lahogue A, Uttenreuther-Fischer M, Hurvitz S-A, Harbeck N, Piccart-<br />
Gebhart M, On behalf of the LUX-<strong>Breast</strong> 1 study group. Chinese<br />
Academy of Medical Sciences, Beijing, China; Seoul National<br />
University Hospital, Seoul, Korea; National Taiwan University Hospital,<br />
Taipei, Taiwan; Samsung Medical Center, Seoul, Korea; National<br />
<strong>Cancer</strong> Center, Goyang, Korea; Third Affiliated Hospital of Harbin<br />
Medical University, Heilongjiang Province, China; Sujan Surgical<br />
<strong>Cancer</strong> Hospital & Amravati <strong>Cancer</strong> Foundation, Amravati, India;<br />
Central India <strong>Cancer</strong> Research Institute, Nagpur, India; Asan Medical<br />
Center, Seoul, Korea; Taichung Veterans General Hospital, Taichung,<br />
Taiwan; Severance Hospital, Seoul, Korea; Medical University, Gdansk,<br />
Poland; Medical University, Bialystok, Poland; Chang Gung Memorial<br />
Hospital - Linkou Branch, Taoyuan County, Taiwan; SCS Boehringer-<br />
Ingelheim Comm.V, Brussels, Belgium; Boehringer Ingelheim<br />
Pharma GmbH & Co. KG, Biberach, Germany; UCLA, Los Angeles,<br />
CA; University of Munich, Munich, Germany; Institut Jules Bordet,<br />
Brussels, Belgium.<br />
OT1-1-17 LUX-<strong>Breast</strong> 2: Phase II, open-label study of oral afatinib in<br />
HER2-overexpressing metastatic breast cancer (MBC) patients<br />
(pts) who progressed on prior trastuzumab and/or lapatinib*<br />
Hickish T, Mehta A, Jain M, Huang C-S, Kovalenko N, Udovitsa D,<br />
Pemberton K, Uttenreuther-Fischer M, Tseng L-M, On behalf of the<br />
LUX-<strong>Breast</strong> 2 study group. Bournemouth Hospital, Bournemouth<br />
University, Dorset, United Kingdom; Central India <strong>Cancer</strong> Research<br />
Institute, Maharashtra, India; Ruby Hall Clinic, Maharashtra, India;<br />
National Taiwan University Hospital, Taipei, Taiwan; Regional<br />
Clinical Oncology Dispensary, Stavropol, Russian Federation; GUZ<br />
Oncological Dispesary #2, Sochi, Russian Federation; Boehringer<br />
Ingelheim Limited, Bracknell, United Kingdom; Boehringer Ingelheim<br />
Pharma GmbH & Co. KG, Biberach, Germany; Taipei Veterans General<br />
Hospital, National Yang Ming University, Taipei, Taiwan.<br />
Ongoing Trials 1: Radiation Therapy<br />
OT1-2-01 NSABP B-43: A phase III clinical trial to compare trastuzumab<br />
(T) given concurrently with radiation therapy (RT) to RT alone<br />
for women with HER2+ DCIS resected by lumpectomy (Lx)<br />
Cobleigh MA, Anderson SJ, Julian TB, Siziopikou KP, Arthur DW,<br />
Rabinovitch R, Zheng P, Mamounas EP, Wolmark N. National Surgical<br />
Adjuvant <strong>Breast</strong> and Bowel Project, Pittsburgh, PA; Rush University<br />
Medical Center, Chicago, IL; University of Pittsburgh Graduate<br />
School of Public Health, Pittsburgh, PA; Allegheny General Hospital,<br />
Pittsburgh, PA; Northwestern University Feinberg School<br />
of Medicine, Chicago, IL; Virginia Commonwealth University,<br />
Richmond, VA; University of Colorado, Aurora, CO; Aultman Hospital,<br />
Canton, OH.<br />
OT1-2-02 SHARE. A French multicenter phase III trial comparing<br />
accelerated partial irradiation (APBI) versus standard or<br />
hypofractionated whole breast irradiation in low risk of local<br />
recurrence breast cancer<br />
Belkacemi Y, Bourgier C, Kramar A, Lemonier J, Auzac G, Dumas<br />
I, Lacornerie T, Mijonnet S, Mege J-P, Lartigau E. APHP; GH Henry<br />
Mondor and UPEC, Paris, Créteil, France; Institut Gustave Roussy,<br />
Villejuif, France; Oscar Lambret Center, Lille, France; UNICANCER,<br />
Paris, France.<br />
7:30 pm–9:30 pm<br />
OPEN SATELLITE EVENT presented by Research to Practice<br />
Marriott Rivercenter<br />
ONE YEAR LATER: The Practical Application of Research Advances in the<br />
Management of Early and Advanced <strong>Breast</strong> cancer<br />
Website: http://www.researchtopractice.com/Meetings/SA2012<br />
Thursday, December 6, 2012<br />
6:45 am–5:15 pm<br />
Registration<br />
Bridge Hall<br />
7:00 am–9:00 am<br />
Poster Discussion 3: Metformin/Statins<br />
Ballroom A<br />
Viewing 7:00 am<br />
Discussion 7:45 am<br />
Adrian Lee, PhD, Chair<br />
University of Pittsburgh <strong>Cancer</strong> Institute<br />
Pittsburgh, PA<br />
Michael Pollak, MD, Discussant<br />
McGill University<br />
Montreal, CANADA<br />
and<br />
Vered Stearns, MD, Discussant<br />
The Sidney Kimmel Comprehensive <strong>Cancer</strong> Center at<br />
Johns Hopkins<br />
Baltimore, MD<br />
PD03-01 Effect of metformin on apoptosis in a presurgical trial in nondiabetic<br />
patients with breast cancer<br />
Cazzaniga M, DeCensi A, Pruneri G, Puntoni M, Guerrieri-Gonzaga<br />
A, Dell’Orto P, Gentilini OD, Vingiani A, Pagani G, Puccio A, Bonanni<br />
B. European Institute of Oncology (EIO), Milan; Ospaedali Galliera,<br />
Genova; University of Milan.<br />
PD03-02 Evidence for the anti-cancer action of metformin mediated<br />
via tumor AMPK, Akt and Ki67, in a preoperative window of<br />
opportunity trial<br />
Hadad SM, Dowling RJO, Chang MC, Done SJ, Purdie CA, Jordan<br />
LB, Dewar J, Goodwin PJ, Stambolic V, Thompson AM. University<br />
of Sheffield, United Kingdom; University Health Network, Toronto,<br />
Canada; Mount Sinai Hospital, Toronto, Canada; University of<br />
Dundee, United Kingdom; Princess Margaret Hospital and Mount<br />
Sinai Hospital, Toronto, Canada.<br />
PD03-03 Pre-surgical trial of metformin in overweight and obese, multiethnic<br />
patients with newly diagnosed breast cancer<br />
Kalinsky K, Crew KD, Refice S, Wang A, Feldman SM, Taback B,<br />
Hibshoosh H, Maurer M, Hershman DL. Columbia University Medical<br />
Center, New York, NY.<br />
PD03-04 Discovery of metformin derivatives with potent antitumor<br />
activity in triple-negative breast cancer<br />
Márquez-Garbán DC, Deng G, Anderson N, Aivazyan L, Kazmi N, Hamilton<br />
N, Jung ME, Pietras RJ. UCLA, Los Angeles, CA.<br />
PD03-05 Analysis of tumour cell signaling in response to neoadjuvant<br />
metformin in women with early stage breast cancer<br />
Dowling RJO, Niraula S, Chang MC, Done SJ, Ennis M, Hood N,<br />
McCready DR, Leong W, Escallon JM, Reedijk M, Goodwin PJ,<br />
Stambolic V. Ontario <strong>Cancer</strong> Institute, University Health Network,<br />
Toronto, ON, Canada; University Health Network, Toronto, ON,<br />
Canada; Mt. Sinai Hospital, Toronto, ON, Canada; Campbell Family<br />
Institute for <strong>Breast</strong> <strong>Cancer</strong> Research and Laboratory Medicine<br />
Program, University Health Network, Toronto, ON; Campbell Family<br />
Institute for <strong>Breast</strong> <strong>Cancer</strong> Research, Princess Margaret Hospital,<br />
Toronto, ON, Canada; Applied Statistician, Markham, ON, Canada.<br />
www.aacrjournals.org<br />
19s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
PD03-06 Simvastatin radiosensitizes differentiated and stem-like breast<br />
cancer cell lines and is associated with improved local control<br />
in inflammatory breast cancer patients treated with postmastectomy<br />
radiation<br />
Lacerda L, Reddy J, Liu D, Larson R, Masuda H, Brewer T, Debeb B, Xu<br />
W, Hortobagyi GN, Buchholz TA, Ueno NT, Woodward WA. Morgan<br />
Welch Inflammatory <strong>Breast</strong> <strong>Cancer</strong> Research Program and Clinic, The<br />
University of Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
PD03-07 Statin-induced decrease in proliferation depends on HMG-CoA<br />
reductase expression in breast cancer<br />
Bjarnadottir O, Romero Q, Bendahl P-O, Rydén L, Rose C, Loman N,<br />
Uhlén M, Jirström K, Grabau D, Borgquist S. Clinical Sciences, Lund<br />
University, Lund, Sweden; School of Biotechnology, KTH - Royal<br />
Institute of Technology, Stockholm, Sweden.<br />
PD03-08 Statin use and improved survival outcome in primary<br />
inflammatory breast cancer: retrospective cohort study<br />
Brewer TM, Masuda H, Iwamoto T, Liu P, Kai K, Barnett CM,<br />
Woodward WA, Reuben JM, Yang P, Hortobagyi GN, Ueno NT. The<br />
University of Texas M.D. Anderson <strong>Cancer</strong> Center, Houston, TX;<br />
Eastern Virginia Medical School, Norfolk, VA; Okayama University<br />
Hospital, Okayama, Japan.<br />
PD03-09 Statins and breast cancer risk: A follow-up analysis of the<br />
Women’s Health Initiative Cohort<br />
Desai P, Jay A, Wu C, Cauley JA, Manson J, Peters U, Agalliu I, Abdul-<br />
Hussein M, Bock C, Budrys N, Chlebowski R, Cote M, Lane D, Luo J,<br />
Martin L, Park H, Petrucelli N, Rosenberg CA, Thomas F, Wactawski-<br />
Wende J, Simon MS. Providence Hospital Medical Center, Southfield,<br />
MI; Wayne State University, Detroit, MI; Fred Hutchinson <strong>Cancer</strong><br />
Research Center, Seattle, WA; University of Pittsburgh, PA; Harvard<br />
School of Medicine, Boston, MA; Albert Einstein College of Medicine,<br />
Bronx, NY; Lakeland Regional Medical Center, MI; Karmanos <strong>Cancer</strong><br />
Institute, Wayne State University, Detroit, MI; University of Texas<br />
Health Science Center <strong>San</strong> <strong>Antonio</strong>, TX; Los Angeles Biomedical<br />
Research Institute at Harbor-UCLA Medical Center, Torrance, CA;<br />
Stony Brook University Medical Center, Stony Brook, NY; West<br />
Virginia University, Morgantown, WV; George Washington University,<br />
Washington, DC; University of California, Irvine, CA; NorthShore<br />
University Health System, Evanston, IL; University of Tennessee<br />
Health Science Center, Memphis, TN; University at Buffalo, NY.<br />
7:00 am–9:00 am<br />
Poster Discussion 4: Local THERAPY Decision Making<br />
and DCIS<br />
Ballroom B<br />
Viewing 7:00 am<br />
Discussion 7:45 am<br />
Richard Crownover, MD, PhD, Chair<br />
UT Health Science Center<br />
<strong>San</strong> <strong>Antonio</strong>, TX<br />
John Benson, MD, PHD, MA, DM, FRCS, Discussant<br />
Addenbrooke’s Hospital<br />
Cambridge, UNITED KINGDOM<br />
and<br />
I-Tien Yeh, MD, Discussant<br />
Virginia Hospital Center<br />
Arlington, VA<br />
PD04-01 Intra-operative ultrasound in breast-conserving surgery for<br />
palpable breast cancer significantly improves both surgical<br />
accuracy and cosmetic outcome while saving costs<br />
Haloua M, Krekel N, Coupe V, van den Tol P, Meijer S. VU Medical<br />
Center, Amsterdam, Nederland, Netherlands; Alkmaar Medical<br />
Center, Alkmaar, Noord-Holland, Netherlands.<br />
PD04-02 Accelerated hypofractionated versus conventional whole<br />
breast radiotherapy for localised left-sided breast cancer: the<br />
effect on long-term cardiac morbidity<br />
Chan EK, Woods R, Virani S, Speers C, Wai ES, Nichol A, McBride ML,<br />
Tyldesley S. British Columbia <strong>Cancer</strong> Agency, Vancouver Centre;<br />
Vancouver General Hospital; British Columbia <strong>Cancer</strong> Agency,<br />
Vancouver Island Centre; British Columbia <strong>Cancer</strong> Agency.<br />
PD04-03 Is breast conservation therapy an option for young women<br />
with operable breast cancer? Local recurrence rates in young<br />
women following surgery: a single centre experience<br />
Lewis CR, Smith R, Matthews A, Choo E, Lee C. Prince of Wales<br />
<strong>Cancer</strong> Centre (POWCC), Randwick, NSW, Australia; Prince of Wales<br />
Hospital, Randwick, NSW, Australia; NHMRC Clinical Trials Unit,<br />
University of Sydney, NSW, Australia.<br />
PD04-04 What is influencing breast conservation rates in the United<br />
States? Data from the National Accreditation Program of<br />
<strong>Breast</strong> Centers<br />
Chagpar AB, Kaufman CS, Connolly J, Burgin C, Granville T,<br />
Winchester D. Yale University School of Medicine, New Haven,<br />
CT; Bellingham <strong>Breast</strong> Center; Beth Israel Deaconess, Boston, MA;<br />
National Accreditation Center for <strong>Breast</strong> Centers; Pat Nolan Center<br />
for <strong>Breast</strong> Health, Glenview, IL.<br />
PD04-05 Molecular predictors for type of recurrence following<br />
conservative treatment for DCIS<br />
Sakr RA, Andrade VP, Chandarlapaty S, Giovanni C, Giri D, Heguy A,<br />
De Brot M, Olvera N, Muhsen S, Koslow S, Van Zee KJ, Morrow M,<br />
Rosen N, King TA. Memorial Sloan-Kettering <strong>Cancer</strong> Center,<br />
New York.<br />
PD04-06 Molecular phenotypes of DCIS predict invasive and DCIS<br />
recurrence<br />
Williams KE, Barnes NLP, Cheema K, Dimopoulos N, Bundred NJ,<br />
Landberg G. The University of Manchester, Manchester, Greater<br />
Manchester, United Kingdom.<br />
PD04-07 The Ki-67 labeling index predicts the risk of recurrence of<br />
DIN patients treated with radiotherapy following breast<br />
conserving surgery<br />
Pruneri G, Lazzeroni M, Guerrieri-Gonzaga A, Botteri E, Leonardi<br />
MC, Rotmensz N, Serrano D, Varricchio C, Disalvatore L, Del Castillo<br />
A, Viale G, Bonanni B. European Institute of Oncology, Milan, Italy;<br />
European Institute of Oncology, Milan; University of Milan, School<br />
of Medicine.<br />
PD04-08 Cell cycle algorithm correlates with grade of DCIS and p53<br />
status, allows elimination of ‘intermediate grade’ disease and<br />
gives clinically meaningful information<br />
Sainsbury R, Loddo M, Proctor I, Stoeber K, Williams G, Thorat M,<br />
Cuzick J. University College London, United Kingdom; Wolfson<br />
Institute of Preventative Medicine, Queen Mary College, London,<br />
United Kingdom.<br />
7:00 am–9:00 am<br />
POSTER SESSION 2 & CONTINENTAL BREAKFAST<br />
Exhibit Halls A-B<br />
P2-01-01 Establishment and validation of circulating tumor<br />
cell-based prognostic nomograms in 497 first-line metastatic<br />
breast cancer patients<br />
Giordano A, Reuben JM, Egleston BL, Hajage D, Hortobagyi GN,<br />
Cristofanilli M, Pierga J-Y, Bidard F-C. The University of Texas MD<br />
Anderson <strong>Cancer</strong> Center, Houston, TX; Fox Chase <strong>Cancer</strong> Center,<br />
Philadelphia, PA; Institut Curie, Paris, France.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 20s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P2-01-02<br />
P2-01-03<br />
P2-01-04<br />
P2-01-05<br />
P2-01-06<br />
Circulating Tumor Cells (CTC) may Express HER2/neu in<br />
Patients With Early HER2/neu Negative <strong>Breast</strong> <strong>Cancer</strong> – Results<br />
of the German SUCCESS C Trial<br />
Jaeger BAS, Rack BK, Andergassen U, Neugebauer JK, Melcher CA,<br />
Scholz C, Hagenbeck C, Schueller K, Lorenz R, Decker T, Heinrich<br />
G, Fehm T, Schneeweiss A, Lichtenegger W, Beckmann MW,<br />
Pantel K, Sommer HL, Friese K, Janni W. Klinikum der Ludwig-<br />
Maximilians-Universitaet, Munich, Germany; Heinrich Heine<br />
University, Duesseldorf, Germany; Stat-up Statistische Beratung<br />
und Dienstleistung, Munich, Germany; Gemeinschaftspraxis Dr.<br />
Lorenz/Hecker/Wesche, Braunschweig, Germany; Studienzentrum<br />
Onkologie Ravensburg, Ravensburg, Germany; Praxis Dr. Heinrich,<br />
Fuerstenwalde, Germany; Eberhard Karls Universitaet Tuebingen,<br />
Tuebingen, Germany; National Center for Tumor Disease and<br />
Department of Gynecology and Obstetrics, University Hospital<br />
Heidelberg, Germany; Charité Medical University, Berlin, Germany;<br />
Universitaet Erlangen, Germany; University Medical Center Hamburg-<br />
Eppendorf, Hamburg, Germany.<br />
Truncated HER2 receptor in circulating tumor cells (CTCs) of<br />
early and metastatic breast cancer patients<br />
Kallergi G, Nasias D, Papadaki M, Mavroudis D, Georgoulias V, Agelaki<br />
S. University of Crete, Heraklion, Crete, Greece; University General<br />
Hospital of Heraklion, Crete, Greece.<br />
Long term independent prognostic impact of circulating<br />
tumor cells detected before neoadjuvant chemotherapy<br />
in non-metastatic breast cancer: 70 months analysis of the<br />
REMAGUS02 study<br />
Bidard F-C, Delaloge S, Giacchetti S, Brain E, de Cremoux P, Vincent-<br />
Salomon A, Marty M, Pierga J-Y. Institut Curie, France; Institut<br />
Gustave Roussy, France; Hopital Saint Louis, France.<br />
Parallel DNA and RNA profiling of EpCAM-positive cells in<br />
blood of metastatic breast cancer (MBC) patients confirm their<br />
malignant nature<br />
Magbanua MJM, Hauranieh L, Sosa EV, Pendyala P, Scott JH, Rugo<br />
HS, Park JW. University of California, <strong>San</strong> Francisco, CA.<br />
Association between Circulating Tumor Cells and Bone<br />
Turnover Markers in patients with breast cancer and bone<br />
metastases on treatment with bisphosphonates<br />
(ZOMAR study)<br />
Manso L, Barnadas A, Tusquets I, Crespo C, Gómez P, Calvo L, Ruiz<br />
M, Martínez P, Perelló A, Antón A, Codes M, Margelí M, Murias A,<br />
Salvador J, Seguí MA, De Juán A, Gavilá J, Luque M, Pérez D, Zamora<br />
P, Arizcum A, Chacón JI, Heras L, De la Piedra C. Hospital 12 de<br />
Octubre, Madrid, Spain; Hospital <strong>San</strong>ta Creu i <strong>San</strong>t Pau, Barcelona,<br />
Spain; Hospital del Mar, Barcelona, Spain; Hospital Universitario<br />
Ramón y Cajal, Madrid, Spain; Hospital Universitario Vall d’Hebrón,<br />
Barcelona, Spain; Hospital Universitario A Coruña Juan Canalejo, A<br />
Coruña, Spain; Hospital Universitario Virgen del Rocío, Sevilla, Spain;<br />
Hospital Basurto, Vizcaya, Spain; Hospital Son Dureta, Palma de<br />
Mallorca, Spain; Hospital Miguel Servet, Zaragoza, Spain; Hospital<br />
Virgen Macarena, Sevilla, Spain; Hospital Universitario Trias y Pujol,<br />
Barcelona, Spain; Hospital Universitario Insular de Gran Canaria, Gran<br />
Canaria, Spain; Hospital Nuestra Señora de Valme, Sevilla, Spain;<br />
Hospital Parc Taulí Sabadell, Barcelona, Spain; Hospital Marqués<br />
Valdecilla, <strong>San</strong>tander, Spain; Instituto Valenciano de Oncología,<br />
Valencia, Spain; Hospital General de Asturias, Oviedo, Spain; Hospital<br />
Costa del Sol, Málaga, Spain; Hospital La Paz, Madrid, Spain; Hospital<br />
Palencia Río Carrión, Palencia, Spain; Hospital Virgen de la Salud,<br />
Toledo, Spain; Hospital Cruz Roja Hospitalet del Llobregat, Barcelona,<br />
Spain; Instituto de Investigación <strong>San</strong>itaria Fundación Jiménez Díaz,<br />
Madrid, Spain<br />
P2-01-07<br />
P2-01-08<br />
P2-01-09<br />
P2-01-10<br />
P2-01-11<br />
P2-01-12<br />
P2-01-13<br />
P2-01-14<br />
Effect of first-line chemotherapy in the expression of<br />
stemness and epithelial-to-mesenchymal transition markers<br />
in circulating tumor cells of patients with metastatic<br />
breast cancer<br />
Papadaki MA, Kallergi G, Mavroudis D, Georgoulias V,<br />
Theodoropoulos PA, Agelaki S. University of Crete, Heraklion, Crete,<br />
Greece; University General Hospital of Heraklion, Crete, Greece.<br />
Different numbers and prognostic significance of circulating<br />
tumour cells in patients with metastatic breast cancer<br />
according to immunohistochemical subtypes<br />
Peeters DJ, van Dam P-J, Wuyts H, Van den Eynden GG, Jeuris K,<br />
Prové A, Rutten A, Peeters M, Pauwels P, Van Laere SJ, Hauspy J, van<br />
Dam PA, Vermeulen PB, Dirix LY. GZA Hospitals Sint-Augustinus,<br />
Antwerp, Belgium; University of Antwerp, Belgium; Catholic<br />
University of Leuven, Leuven, Vlaams-Brabant, Belgium.<br />
Tumor cell emboli in the lung and transcriptional profiles<br />
of circulating tumor cells derived from different vascular<br />
compartments in patients with metastatic breast cancer<br />
Peeters DJ, Van den Eynden GG, Rutten A, Onstenk W, Sieuwerts<br />
AM, De Laere B, van Dam PA, Peeters M, Pauwels P, Van Laere SJ,<br />
Vermeulen PB, Dirix LY. GZA Hospitals Sint-Augustinus, Antwerp,<br />
Belgium; University of Antwerp, Belgium; Erasmus University Medical<br />
Center and <strong>Cancer</strong> Genomics Center, Rotterdam, South Holland,<br />
Netherlands; Catholic University of Leuven, Leuven, Vlaams-Brabant,<br />
Belgium.<br />
Immunocytochemistry staining for estrogen and progesterone<br />
receptor in circulating tumor cells: Concordance between<br />
primary and metastatic tumors<br />
Bischoff FZ, Pham T, Wong KL, Villarin E, Xu X, Kalinsky K, Mayer JA.<br />
Biocept, Inc., <strong>San</strong> Diego, CA; Columbia University Medical Center,<br />
New York, NY.<br />
Detection and characterization of circulating and<br />
disseminated tumour cells in blood and bone marrow of<br />
breast cancer patients by two different biochemical methods<br />
Andergassen U, Rack BJ, Zebisch M, Kölbl AC, Schindlbeck C,<br />
Neugebauer J, Liesche F, Hiller Ral, Friese K, Jeschke U. Ludwig -<br />
Maximilians-University, Munich, Germany; Klinikum Traunstein,<br />
Traunstein, Germany.<br />
Circulating tumor cells and Epithelial Mesenchymal Transition<br />
in primary breast cancer patients<br />
Mego M, Karaba M, Minarik G, Benca J, Sedlackova T, Manasova D,<br />
Sieberova G, Gronesova P, Pechan J, Mardiak J, Reuben JM. Faculty of<br />
Medicine, Comenius University, Bratislava, Slovakia (Slovak Republic);<br />
National <strong>Cancer</strong> Institute, Bratislava, Slovakia (Slovak Republic);<br />
<strong>Cancer</strong> Research Institute, Bratislava, Slovakia (Slovak Republic);<br />
University of Texas, MD Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
Prognostic value of Circulating Tumor Cells count at<br />
progressive disease after first line chemotherapy metastatic<br />
breast patients in a large prospective multicenter trial<br />
including serum tumor markers (IC 2006-04 study)<br />
Pierga J-Y, Hajage D, Bachelot T, Delaloge S, Brain E, Campone M,<br />
Asselain B, Cottu PH, Dieras V, Bidard F-C. Institut Curie, Paris; Centre<br />
Léon Bérard, Lyon; Institut Gustave Roussy, Villejuif; Institut de<br />
Cancérologie de L’Ouest.<br />
Circulating tumor cells in breast cancer exhibit dynamic<br />
changes in epithelial and mesenchymal cell composition<br />
Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff<br />
SJ, Ciciliano JC, Wells MN, Shah AM, Concannon KF, Sequist LV,<br />
Brachtel E, Sgroi D, Baselga J, Ramaswamy S, Toner M, Haber DA,<br />
Maheswaran S. Massachusetts General Hospital, Harvard Medical<br />
School; Howard Hughes Medical Institute.<br />
www.aacrjournals.org<br />
21s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Detection/Diagnosis: Circulating Markers<br />
P2-02-01 Accurate identification of metastatic breast cancer using<br />
methylated gene markers in circulating free DNA in<br />
peripheral blood<br />
Sukumar S, Fackler MJ, Lopez-Bujanda Z, Teo WW, Jeter S, Umbricht<br />
C, Visvanathan K, Wolff AC. Johns Hopkins University School of<br />
Medicine, Baltimore, MD.<br />
P2-02-02 Prognostic significance of the ratio of absolute neutrophil<br />
to lymphocyte counts for breast cancer patients in<br />
neoadjuvant setting<br />
Koh YW, Lee HJ, Ahn J-H, Lee JW, Gong G. University of Ulsan<br />
College of Medicine, Asan Medical Center, Seoul, Korea; Seoul<br />
National University Bundang Hospital, Seongnam, Bundang-Gu,<br />
Kyeonggi-Do, Korea.<br />
P2-02-03 The Collagen Receptor Endo180: A Metastatic Plasma Marker<br />
in <strong>Breast</strong> <strong>Cancer</strong> Modulated by Bisphosphonate Treatment<br />
Sturge J, Caley MP, Purshouse K, Fonseca A-V, Rodriguez-Teja M,<br />
Kogianni G, Waxman J, Palmieri C. Imperial College London, United<br />
Kingdom; The University of Hull, Hull, United Kingdom.<br />
P2-02-04 The interaction between menopausal status and<br />
zoledronic acid can differentially affect serum levels of the<br />
TGFβ superfamily<br />
Wilson C, Winter MC, Holen I, Freeman JV, Evans AC, Coleman RE.<br />
University of Sheffield, United Kingdom; Sheffield Teaching Hospitals<br />
NHS Trust, Sheffield, United Kingdom.<br />
Detection/Diagnosis: Micrometastases<br />
P2-03-01 Identification of cancer stem cells (CD44+CD24-/lo) in bone<br />
marrow as a prognostic factor in early breast cancer patients<br />
Giordano A, Gao H, Cohen EN, Anfossi S, Hess KR, Krishnamurthy S,<br />
Tin S, Cristofanilli M, Hortobagyi GN, Woodward WA, Ueno NT, Lucci<br />
A, Reuben JM. The University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX; The University of Texas MD Anderson <strong>Cancer</strong> Center;<br />
Fox Chase <strong>Cancer</strong> Center.<br />
Tumor Cell and Molecular Biology: Animal Models<br />
P2-04-01 Development of mouse breast cancer models based on<br />
induced cancer stem cells (iCSC)<br />
Takamoto Y, Onishi N, Kai K, Saya H. Institute for Advanced Medical<br />
Research (IAMR), School of Medicine, Keio university, Shinjyuku-ku,<br />
Tokyo, Japan; The University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX.<br />
P2-04-02 Identification of genes associated with breast cancer<br />
micrometastatic disease in bone marrow using a<br />
human-in-mouse xenograft system<br />
Aft R, Li S, Mudalagiriyappa C, Dasgupta N, Watson M, Fleming T, Ellis<br />
M, Pillai S. Washington University, St. Louis, MO.<br />
P2-04-03 A robust transgenic mouse model to study male breast cancer<br />
Krause S, Lurvey HL, Tobin H, Ingber DE. Boston’s Children’s Hospital,<br />
Boston, MA; Wyss Institute of Biologically Inspired Engineering,<br />
Boston, MA.<br />
P2-04-04 Prolactin cooperates with loss of p53 to promote<br />
mammary tumorigenesis<br />
O’Leary KA, Sullivan R, Rugowski DE, Schuler LA. University of<br />
Wisconsin, Madison, WI.<br />
P2-04-05 Prolonged targeted overexpression of Aurora-A in mammary<br />
epithelium promotes mammary adenocarcinoma with<br />
genomic instability<br />
Treekitkarnmongkol W, Katayama H, Sen S. University of Texas M.D.<br />
Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
P2-04-06 Transgenic expression of a breast-cancer specific GATA3<br />
mutant leads to mammary hyperplasia<br />
Kenny PA, Chandiramani N. Albert Einstein College of Medicine,<br />
Bronx, NY.<br />
P2-04-07 Modeling orthotopic and metastatic progression of<br />
mammary tumors to evaluate the efficacy of TGF-β inhibitors<br />
in a pre-clinical setting<br />
Biswas T, Yang J, Zhao L, Sun L. UTHSCSA, <strong>San</strong> <strong>Antonio</strong>, TX;<br />
UCSD, CA.<br />
P2-04-08 Targeted Expression of the Human Chaperone BAG3 to the<br />
Murine Mammary Gland Dysregulates Mammary Gland<br />
Development and Differentiation By Unrestricted Expansion of<br />
Luminal Cells<br />
Virador VM, Casagrange G, Raafat A, Callahan R, Kohn E. National<br />
<strong>Cancer</strong> Institute, Bethesda, MD.<br />
Tumor Cell and Molecular Biology: Biomarkers<br />
P2-05-01 Gene expression changes associated with response to<br />
neoadjuvant chemotherapy are observed early in treatment:<br />
results from the I-SPY 1 TRIAL (CALGB 150007/150012;<br />
ACRIN 6657)<br />
Wolf DM, Yau C, Magbanua M, Boudreau A, Davis S, Haqq C, Park J,<br />
I-SPY TRIAL-1 Investigators, Esserman L, van’t Veer L. University of<br />
California, <strong>San</strong> Francisco, CA; I-SPY 1 TRIAL Institutions.<br />
P2-05-02 Clinical significance of microRNA regulator Lin28 expression in<br />
patient with early breast cancer<br />
Park S, Shin YK, Song BJ, Chae BJ, Jung SS, Choi Y-L. Seoul St. Mary’s<br />
Hospital, Catholic University School of Medicine, Seoul, Korea; Seoul<br />
National University College of Pharmacy, Seoul, Korea; Samsung<br />
Medical Center, Sungkyunkwan University School of Medicine,<br />
Seoul, Korea.<br />
P2-05-03 Mouse double minute 2 nuclear expression as a prognostic<br />
marker in patients with breast cancer<br />
Park HS, Park S, Koo JS, Cho JH, Park JM, Kim S-I, Park B-W. Yonsei<br />
University College of Medicine, Seodaemoon-gu, Seoul, Korea.<br />
P2-05-04 Differential potency of TORC1/C2 (INK/MLN-128) and pan-PI3K<br />
(GDC0941) inhibitors on breast cancer polysome composition<br />
and phosphoprotein response biomarkers<br />
Wilson-Edell KA, Yevtushenko M, Hanson I, Rogers AN, Scott GK,<br />
Benz CC. Buck Institute for Research on Aging, Novato, CA.<br />
P2-05-05 Circulating HER2 extracellular domain (ECD) predicts a poor<br />
prognosis for metastatic breast cancer patients<br />
Wang X-j, Shao X-Y, Xu X-H, Chen Z-H, Wang S, Cai J-F, Huang J,<br />
Huang P, Lou C-J, Ling Z-Q, Han MX. Zhejiang <strong>Cancer</strong> Hospital,<br />
Hangzhou, Zhejiang, China; Hangzhou Polar Gene Company,<br />
Hangzhou, Zhejiang, China.<br />
P2-05-06 Quantitative measurement of HER2 expression in breast<br />
cancers: comparison with “real world” HER2 testing in a<br />
multi-center Collaborative Biomarker Study (CBS) and<br />
correlation with clinicopathological features<br />
Yardley DA, Kaufman PA, Adams JW, Krekow L, Savin M, Lawler WE,<br />
Zrada S, Starr A, Einhorn H, Schwartzberg LS, Huang W, Weidler J, Lie<br />
Y, Paquet A, Haddad M, Anderson S, Brigino M, Bosserman L. Sarah<br />
Cannon Research Institute, Nashville, TN; Tennessee Oncology PLLC,<br />
Nashville, TN; Dartmouth Hitchcock Medical Center, Lebanon, NH;<br />
Arlington <strong>Cancer</strong> Center, Arlington, TX; Texas Oncology Bedford,<br />
Bedford, TX; Texas Oncology at Medical City Dallas 2, Dallas, TX; St.<br />
Jude Heritage Medical Group, Fullerton, CA; The Center for <strong>Cancer</strong><br />
and Hematologic Disease, Cherry Hill, NJ; Monroe Medical Associates,<br />
Harvey, IL; Swedish American Regional <strong>Cancer</strong> Center, Rockford,<br />
IL; The West Clinic, Memphis, TN; Monogram Biosciences, Inc., So.<br />
<strong>San</strong> Francisco, CA; Center for Molecular Biology and Pathology,<br />
Laboratory Corporation of America, Inc., Research Triangle Park, NC;<br />
Wilshire Oncology Medical Group, Rancho Cucamonga, CA.<br />
P2-05-07 Comparison of hormone receptor and HER-2 expression in<br />
primary breast cancers and sentinel lymph node metastases<br />
Rokutanda N, Horiguchi J, Takata D, Nagaoka R, Sato A, Tokiniwa H,<br />
Tozuka K, Uchida S, Takeyoshi I. Gunma University Graduate School<br />
of Medicine, Maebashi, Gunma, Japan.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 22s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P2-05-08<br />
P2-05-09<br />
P2-05-10<br />
P2-05-11<br />
P2-05-12<br />
P2-05-13<br />
P2-05-14<br />
P2-05-15<br />
P2-05-16<br />
P2-05-17<br />
Determination of HER2 amplification by dual-color in situ<br />
hybridization before and after neoadjuvant chemotherapy<br />
Niikura N, Kumaki N, Iwamoto T, Tsuda B, Okamura T, Yuki S, Suzuki<br />
Y, Tokuda Y. Tokai University School of Medicine, Isehara, Kanagawa,<br />
Japan; Okayama University Hospital, Okayama, Japan.<br />
Identification and validation of a miRNA signature associated<br />
with breast cancer progression<br />
Waters PS, Dwyer RM, Kerin MJ. National University of Ireland,<br />
Galway, Ireland.<br />
64<br />
Cu-DOTA-trastuzumab positron emission tomography<br />
imaging of HER2 in women with advanced breast cancer<br />
Mortimer JE, Conti P, Shan T, Carroll M, Kofi P, Colcher D, Raubitschek<br />
AA, Bading JR, Miles J. City of Hope <strong>Cancer</strong> Center/Beckman<br />
Research Institute, Duarte, CA; USC, Los Angeles, CA.<br />
Proteomic identification and in-silico verification of subtypespecific<br />
signatures in breast cancer<br />
Pavlou MP, Dimitromanolakis A, Diamandis EP. University of Toronto,<br />
ON, Canada; Mount Sinai Hospital, Toronto, ON, Canada; University<br />
Health Network, Toronto, ON, Canada.<br />
Effects of de-escalated bisphosphonate therapy on bone<br />
turnover or metastasis markers and their correlation with<br />
risk of skeletal related events – A biomarker analysis in<br />
conjunction with the REFORM study<br />
Addison CL, Zhao H, Mazzarello S, Mallick R, Amir E, Tannock I,<br />
Clemons M. Ottawa Hospital Research Institute, Ottawa, ON, Canada;<br />
Princess Margaret Hospital, Toronto, ON, Canada; The Ottawa<br />
Hospital <strong>Cancer</strong> Centre, Ottawa, ON, Canada.<br />
Correlation of conventional versus experimental biomarkers<br />
of bone turnover and metastasis behaviour with skeletal<br />
related events – A biomarker analysis in conjunction with the<br />
TRIUMPH study<br />
Addison CL, Kuchuk I, Bouganim N, Zhao H, Mazzarello S,<br />
Vandermeer L, Mallick R, Goss GD, Clemons M. Ottawa Hospital<br />
Research Institute, Ottawa, ON, Canada; The Ottawa Hospital <strong>Cancer</strong><br />
Centre, Ottawa, ON, Canada; McGill University Health Centre,<br />
Montreal, QC, Canada.<br />
Clinical significance of Lysyl oxidase-like 2 (LOXL 2) in<br />
breast cancer<br />
Ahn SG, Lee HM, Hwang SH, Lee SA, Jeong J, Lee H-E. Gangnam<br />
Severance Hospital, Yonsei University Medical College, Seoul,<br />
Republic of Korea.<br />
Assessment of Notch Signaling Pathway Components as<br />
Biomarkers for Triple Negative <strong>Breast</strong> <strong>Cancer</strong>: Comparison of<br />
Triple Negative <strong>Breast</strong> <strong>Cancer</strong> Cell Lines and Human <strong>Breast</strong><br />
<strong>Cancer</strong> Samples<br />
Zlobin A, Olsauskas-Kuprys R, Hodge S, O’Toole M, Ersahin C, Osipo<br />
C. Loyola University Chicago, Cardinal Bernardin <strong>Cancer</strong> Center,<br />
Maywood, IL.<br />
Expression of β-III tubulin, foxo 3 protein and deoxythymidine<br />
kinase in breast cancer patients receiving neoadjuvant<br />
chemotherapy<br />
Chow LWC, Loo WTY, Yip AYS, Ong EYY, Ng W-K. UNIMED Medical<br />
Institute, Hong Kong; Organisation for Oncology and Translational<br />
Research, Hong Kong; Central Hospital, Hong Kong.<br />
Correlation between cyclin D1, estrogen and progesterone<br />
receptors in invasive breast cancer after short-term treatment<br />
with tamoxifen or anastrozole<br />
Millen EC, Mattar A, Logullo AF, Nonogaki S, Soares FA, Gebrim LH.<br />
Federal University of Sao Paulo, Sao Paulo, SP, Brazil; Perola Byington<br />
Hospital, Sao Paulo, SP, Brazil; Federal University of Sao Paulo, Sao<br />
Paulo, SP; Arnaldo Vieira de Carvalho, Sao Paulo, SP, Brazil.<br />
P2-05-18 Withdrawn<br />
P2-05-19 Pathway-based analysis of breast cancer<br />
Song D, Cui M, Fan Z, Yang Y, Xue L, Zhang DY, Ye F. The First<br />
Hospital of Jilin University, Changchun, Jilin, China; The Mount Sinai<br />
Medical Center, New York, NY; Nanfang Hospital Southern Medical<br />
University, Guangzhou, China.<br />
P2-05-20 Validation and comparison of CS-IHC4 score with a nomogram<br />
based on Ki67 index, Adjuvant! Online, and St. Gallen risk<br />
stratification to predict recurrence in early Hormone Receptor<br />
(HR)-positive breast cancers<br />
Park YH, Im S-A, Cho EY, Ahn JH, Woo SY, Kim S, Keam B, Lee JE,<br />
Han W, Nam SJ, Park IA, Noh D-Y, Yang JH, Ahn JS, Im Y-H. Samsung<br />
Medical Center; Seoul National University College of Medicine.<br />
P2-05-21 Molecular subtypes of invasive breast cancers show<br />
differential expression of the proliferation marker Aurora<br />
Kinase A (AURKA)<br />
Kovatich AJ, Luo C, Chen Y, Hooke JA, Kvecher L, Rui H, Shriver CD,<br />
Mural RJ, Hu H. Windber Research Institute, Windber, PA; Walter<br />
Reed National Military Medical Center, Bethesda, MD; MDR, Global<br />
Systems LLC, Windber, PA; Thomas Jefferson University,<br />
Philadelphia, PA.<br />
P2-05-22 Preferential Activation of BP1 and c-Myc in <strong>Breast</strong> <strong>Cancer</strong> of<br />
African American Women Compared with Caucasian<br />
American Women<br />
Berg PE, Ghimbovschi S, Grizzle WE, Nguyen TH. George Washington<br />
University Medical Center, Washington, DC; Children’s National<br />
Medical Center, Washington, DC; University of Alabama at<br />
Birmingham, AL.<br />
Tumor Cell and Molecular Biology: Genomics<br />
P2-06-01 <strong>Breast</strong>-to-breast metastasis can cause hormone-receptor<br />
positive / triple negative bilateral synchronous tumors<br />
Schwab RB, Bao L, Pu M, Crain B, Dai Y, Nazareth LV, Matsui H,<br />
Wallace AM, Hasteh F, Harismendy O, Frazer KA, Parker BA, Messer<br />
K. University of California, <strong>San</strong> Diego, La Jolla, CA; Rady Children’s<br />
Hospital, Division of Genome Information Sciences, University of<br />
California, <strong>San</strong> Diego, La Jolla, CA.<br />
P2-06-02 Genomic evolution from primary breast cancers to distant<br />
metastases<br />
Hoefnagel LDC, Moelans CB, van der Groep P, van der Wall E, van<br />
Diest PJ. University Medical Center Utrecht, Netherlands.<br />
P2-06-03 Specific Transcriptional Response of Four Blockers of Estrogen<br />
Receptors on Estrogen-Modulated Genes in ZR-75-1 <strong>Breast</strong><br />
<strong>Cancer</strong> Xenografts<br />
Calvo E, Luu-The V, Martel C, Labrie F. Laval University Hospital<br />
Research Center (CRCHUL), Quebec City, QC, Canada; Laval<br />
University, Quebec City, QC, Canada; EndoCeutics Inc., Quebec City,<br />
QC, Canada.<br />
P2-06-04 Impact of genomic testing on chemotherapy utilization<br />
Riley L, Nakijima H, Balinger K, Anderson D. St. Luke’s University<br />
Health Network, Bethlehem, PA.<br />
P2-06-05 Single-cell RNA sequencing of paclitaxel-treated breast cancer<br />
cell lines to find individual cell response<br />
Vaske CJ, Lee W, Benz SC, <strong>San</strong>born JZ, Emerson BM, Pourmand N,<br />
Lopez Diaz F. Five3 Genomics, LLC, <strong>San</strong>ta Cruz, CA; University of<br />
California, <strong>San</strong>ta Cruz, CA; Salk Institute, La Jolla, CA.<br />
P2-06-06 Integrating multiple molecular profiles with pathways to learn<br />
sub-type specific interactions with PARADIGM<br />
Sedgewick AJ, Vaske CJ, Benz SC. Five3 Genomics, <strong>San</strong>ta Cruz, CA;<br />
University of Pittsburgh, PA.<br />
www.aacrjournals.org<br />
23s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P2-06-07 Exome sequencing identifies somatic mutations in basal-like<br />
breast cancer before and after neoadjuvant chemotherapy<br />
Jiang Y-Z, Yu K-D, Shao Z-M. Shanghai <strong>Cancer</strong> Center, Shanghai,<br />
Shanghai, China.<br />
Tumor Cell and Molecular Biology: Genetics - Germline Changes<br />
P2-07-01 BRCA1 regulates RHAMM function in breast cancer<br />
Fleisch MC, Yang Y, Mei Q, Sadat F, Brandi L, Iwaniuk KM, Honisch E,<br />
Maxwell CA, Niederacher D. Heinrich Heine University, Duesseldorf,<br />
Germany; University of British Columbia, Vancouver, BC, Canada.<br />
P6-07-31 Assessing germline Homologous Recombination pathway<br />
deficiency in BRCA1 mutation carriers using Single Cell<br />
Network Profiling<br />
Rosen DB, Leung LY, Louie B, Evensen E, Fields SZ, Cesano A, Shapira<br />
I, Hawtin RE. Nodality Inc, South <strong>San</strong> Francisco, CA; Monter <strong>Cancer</strong><br />
Center, North Shore Long Island Jewish Medical School, Lake<br />
Success, NY.<br />
Tumor Cell and Molecular Biology: Genetics - Somatic Changes<br />
P2-08-01 PIK3CA mutations associate with decreased Ki67 in early<br />
stage breast cancer (BC) and better outcomes in patients even<br />
among those with low Ki67 tumors<br />
Datko FM, Patil S, Kalinsky K, Asher M, Wen YH, Hedvat C, Moynahan<br />
ME. Memorial Sloan-Kettering <strong>Cancer</strong> Center; Columbia University<br />
Medical Center.<br />
P2-08-02 The large scale structure of the HER-2/neu amplicon in<br />
breast cancer<br />
Pauletti G, Anderson L, Rong H-M, Yu J, Slamon DJ. David Geffen<br />
School of Medicine, University of California, Los Angeles, CA.<br />
P2-08-03 Phosphatidylinositol-3-kinase mutations are common in<br />
lobular neoplasia<br />
Troxell ML, Ang D, Warrick A, Beadling C, Corless CL. Oregon Health<br />
& Science University, Portland, OR.<br />
P2-08-04 HER2 gene status change after taxane based chemotherapy:<br />
be aware of mis-interpretation of polyploidization! Impact for<br />
patient management<br />
Valent A, Penault-Llorca F, Cayre A, Kroemer G. Institut Gustave<br />
Roussy, Villejuif, France; Centre Jean Perrin, Clermont-Ferrand,<br />
France.<br />
Tumor Cell and Molecular Biology: Epigenetics<br />
P2-09-01 Reactivation of epigenetically silenced retinoic acid receptorbeta<br />
for therapy of breast cancer- from molecular mechanism<br />
to potential clinical applications<br />
Ordentlich P, Nguyen N, Jin K, Sadik H, Han L, Sukumar S. Syndax<br />
Pharmaceuticals; Sidney Kimmel <strong>Cancer</strong> Center, Johns Hopkins<br />
University School of Medicine.<br />
P2-09-02 Epigenetic Regulation of histone variants - a role in hormone<br />
therapy resistant breast cancer?<br />
Nayak SR, Oesterreich S, Pathiraja T. Magee Women’s Research<br />
Institute, University of Pittsburgh Medical Center, Pittsburgh, PA;<br />
Lester & Sue Smith <strong>Breast</strong> Center, Baylor College of Medicine,<br />
Houston, TX.<br />
P2-09-03 Identifying a landscape of DNA methylation-driven genes in<br />
breast cancer using MethylMix<br />
Gevaert O, Plevritis S. Stanford University.<br />
P2-09-04 DNA methylation landscapes in ER-negative breast cancer<br />
Worsham MJ, Chen KM, Chitale D, Divine G. Henry Ford Health<br />
System, Detroit, MI.<br />
P2-09-05 Screening of significantly hypermethylated genes in breast<br />
cancer using MIRA-based microarray and identifying their<br />
expression levels<br />
Lian Z-q, Wang Q, Li W-p, Zhang A-q, Wu L. <strong>Breast</strong> Disease Center,<br />
Guangdong Women and Children Hospital of Guangzhou<br />
Medical College.<br />
P2-09-06 The structure design and biological activities of inhibitory<br />
peptides, which block the interactions among polycomb<br />
repressive complex 2<br />
LI KK, Luo L, Kong X, Li L, Luo C. Rui Jin Hospital Affiliated with the<br />
Shanghai JiaoTong University School of Medicine, Shanghai, China;<br />
Shanghai Institute of Materia Medica, Chinese Academy of Sciences,<br />
Shanghai, China.<br />
Prognostic and Predictive Factors: Prognostic Factors - Clinical<br />
P2-10-01 PAM50 gene signature is prognostic for breast cancer patients<br />
treated with adjuvant anthracycline and taxane based<br />
chemotherapy<br />
Liu MC, Pitcher BN, Mardis ER, Davies SR, Snider JE, Vickery T, Reed JP,<br />
DeSchryver K, Singh B, Friedman PN, Gradishar WJ, Perez EA, Martino<br />
S, Citron ML, Norton L, Winer EP, Hudis CA, Perou CM, Ellis MJ,<br />
Barry WT. Georgetown University Lombardi Comprehensive <strong>Cancer</strong><br />
Center, Washington, DC; Duke University Medical Center, Durham,<br />
NC; Washington University, St. Louis, MO; Washington University<br />
School of Medicine, St. Louis, MO; New York University Medical<br />
Center, New York, NY; University of Chicago, IL; Robert H. Lurie<br />
Comprehensive <strong>Cancer</strong> Center, Northwestern University Feinberg<br />
School of Medicine, Chicago, IL; Mayo Clinic, Jacksonville, FL; The<br />
Angeles Clinic and Research Institute, <strong>San</strong>ta Monica, CA; Hofstra<br />
North Shore-LIJ School of Medicine, ProHEALTH Care Associates,<br />
Lake Success, NY; Memorial Sloan-Kettering <strong>Cancer</strong> Center, New<br />
York, NY; Dana Farber <strong>Cancer</strong> Institute, Harvard Medical School,<br />
Boston, MA; Lineberger Comprehensive <strong>Cancer</strong> Center, University<br />
of North Carolina at Chapel Hill, NC; Siteman <strong>Cancer</strong> Center,<br />
Washington University School of Medicine, St. Louis, MO.<br />
P2-10-02 Clinical validation of the PAM50 risk of recurrence (ROR) score<br />
for predicting residual risk of distant-recurrence (DR) after<br />
endocrine therapy in postmenopausal women with ER+ early<br />
breast cancer (EBC): An ABCSG study<br />
Gnant M, Filipits M, Mlineritsch B, Dubsky P, Jakesz R, Kwasny<br />
W, Fitzal F, Rudas M, Knauer M, Singer C, Greil R, Ferree S,<br />
Storhoff J, Cowens JW, Schaper C, Liu S, Nielsen T, On behalf of<br />
the ABCSG. Medical University of Vienna, Austria; Medizinische<br />
Universität Salzburg, Austria; A.ö. KH Wr. Neustadt, Wr. Neustadt,<br />
Austria; Hospital of the Sisters of Mercy, Linz, Austria; Nanostring<br />
Technologies, Seattle, WA; Vancouver Hospital, Vancouver, BC,<br />
Canada; MyRAQA Inc, Redwood Shores, CA; Vancouver Coastal<br />
Health, Vancouver, BC, Canada.<br />
P2-10-03 A cross-platform comparison of genomic signatures and<br />
OncotypeDx score to discover potential prognostic/predictive<br />
genes and pathways<br />
Kuderer NM, Barry WT, Geradts J, Ginsburg GS, Lyman GH, Datto<br />
M, Liotcheva V, Isner P, Veldman T, Agarwal P, Hwang S, Ready N,<br />
Marcom PK. Duke University Medical Center, Durham, NC.<br />
P2-10-04 The Mammostrat Test Is an Effective Tool To Stratify Patient<br />
Samples Previously Characterized as Intermediate by the<br />
Oncotype Dx Test<br />
Bloom KJ, Kyshtoobayeva A, Hilaire L, Gutekunst K. Clarient<br />
Diagnostic Services, Aliso Viejo, CA.<br />
P2-10-05 Continuous association of a 200-gene prognostic risk score<br />
with probability of neoadjuvant chemotherapy response and<br />
translation from fresh frozen to FFPE tissue for clinical use<br />
van Laar R, DiPaola J, Carbaugh H, Murphy T, DiRamio A, Flinchum R,<br />
Brown N, Albino T. Signal Genetics, New York, NY.<br />
P2-10-06 Multicenter I-SPY 1 TRIAL (CALGB 150007/150012): <strong>Breast</strong><br />
cancer stem cells are associated with intrinsic chemoresistance<br />
and worse survival<br />
Landis MD, Yau C, Neumeister V, Rimm DL, I-SPY 1 TRIAL<br />
Investigators, Esserman L, Chang JC. The Methodist Hospital,<br />
Houston, TX; University of California, <strong>San</strong> Francisco, CA; Yale<br />
University School of Medicine, New Haven, CT.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 24s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P2-10-07<br />
P2-10-08<br />
P2-10-09<br />
P2-10-10<br />
P2-10-11<br />
P2-10-12<br />
Stem cell marker aldehyde dehydrogenase 1 in stromal cells<br />
strongly correlates with prognosis in breast cancer<br />
Sjöström M, Hartman L, Holmdahl J, Grabau D, Malmström P, Fernö<br />
M, Niméus-Malmström E. Lund University, Lund, Sweden.<br />
Prospective comparison of Recurrence Score and different<br />
definitions of luminal subtypes by central pathology<br />
assessment of single markers in early breast cancer: results<br />
from the phase III WSG-planB Trial<br />
Gluz O, Kreipe HH, Kates RE, Christgen M, Liedtke C, Shak S,<br />
Clemens M, Salem M, Liedtke B, Aktas B, Markmann S, Uleer C,<br />
Augustin D, Thomssen C, Nitz U, Harbeck N. West German Study<br />
Group, Moenchengladbach, NRW, Germany; Ev. Bethesda Hospital,<br />
Moenchengladbach, NRW, Germany; Medizinische Hochschule<br />
Hannover, Niedersachsen, Germany; University of Muenster, Muenster,<br />
Germany; Genomic Health, Inc., Germany; Clinics Mutterhaus, Trier,<br />
Germany; University of Cologne, Germany; Ev. Hospital, Bergisch<br />
Gladbach, Germany; University of Essen, Germany; Clinics Südstadt,<br />
Rostock, Germany; Gemeinschaftspraxis Hildesheim, Hildesheim,<br />
Germany; Clinics Deggendorf, Deggendorf, Germany; University of<br />
Halle, Germany; University of Munich, Munich, Bavaria, Germany.<br />
The incidence of false negative of HER2/Neu status in primary<br />
breast cancer in the era of standardized testing: a Canadian<br />
prospective study<br />
Hanna W, Barnes PJ, Chang MC, Gilks B, Magliocco A, Rees H,<br />
Robertson S, SenGupta SK, Nofech-Mozes S. Sunnybrook Health<br />
Sciences Centre; Capital Health District Authority; Mount Sinai<br />
Hospital; Vancouver General Hospital; Tom Baker <strong>Cancer</strong> Centre;<br />
Saskatoon City Hospital; Ottawa General Hospital;<br />
Kingston General Hospital.<br />
Clinical implications of molecular heterogeneity in highly<br />
proliferative, ER-positive, HER2-negative breast cancer<br />
Bianchini G, Pusztai L, Kelly CM, Iwamoto T, Callari M, Symmans WF,<br />
Gianni L. Ospedale <strong>San</strong> Raffaele, Milan, Italy; MD Anderson <strong>Cancer</strong><br />
Center, Houston, TX; Mater Misericordiae University Hospital, Dublin,<br />
Ireland; Okayama University Hospital, Okayama, Japan; Fondazione<br />
IRCCS Istituto Nazionale dei Tumori, Milan, Italy.<br />
Prognostic performance of the EndoPredict score in nodepositive<br />
chemotherapy-treated ER+/HER2- breast cancer<br />
patients: results from the GEICAM/9906 trial<br />
Martin M, Brase JC, Ruiz-Borrego M, Krappmann K, Munarriz B, Fisch<br />
K, Ruiz A, Weber KE, Crespo C, Petry C, Rodriguez CA, Kronenwett R,<br />
Calvo L, Alba E, Carrasco E, Casas M, Caballero R, Rodriguez-Lescure<br />
A. Hospital General Universitario Gregorio Marañon, Madrid, Spain;<br />
Sividon Diagnostics GmbH, Cologne, Germany; Hospital Universitario<br />
Virgen del Rocio, Sevilla, Spain; Hospital Universitario La Fe,<br />
Valencia, Spain; Instituto Valenciano de Oncologia, Valencia, Spain;<br />
Hospital Universitario Ramon y Cajal, Madrid, Spain; Hospital Clinico<br />
Universitario de Salamanca, Salamanca, Spain; Complejo Hospitalario<br />
Universitario A Coruña, Coruña, Spain; Hospital Universitario Virgen<br />
de la Victoria, Malaga, Spain; GEICAM (Spanish <strong>Breast</strong> <strong>Cancer</strong><br />
Research Group), Madrid, Spain; Hospital General Universitario de<br />
Elche, Alicante, Spain.<br />
How well predict the 2011 St Gallen early breast cancer<br />
surrogate phenotypes metastatic survival?<br />
Vanderstichele A, Brouckaert O, Tuyls S, Amant F, Leunen K, Smeets<br />
A, Berteloot P, Van Limbergen E, Weltens C, Peeters S, Moerman<br />
P, Floris G, Paridaens R, Wildiers H, Vergote I, Christiaens M-R, Van<br />
Calster B, Neven P. University Hospitals, Leuven, Belgium.<br />
CD4 positive tumor-infiltrating lymphocytes are associated<br />
with improved prognosis in node-negative breast cancer<br />
Schmidt M, van de <strong>San</strong>dt L, Boehm D, Sicking I, Battista M, Lebrecht<br />
A, Solbach C, Koelbl H, Gehrmann M, Rahnenführer J, Hengstler JG.<br />
University Hospital, Mainz, Germany; Technical University, Dortmund,<br />
Germany; Bayer, Leverkusen, Germany; Leibniz Research Centre<br />
for Working Environment and Human Factors (IfADo), Dortmund,<br />
Germany.<br />
P2-10-14<br />
P2-10-15<br />
P2-10-16<br />
P2-10-17<br />
P2-10-18<br />
P2-10-19<br />
Triple Negative <strong>Breast</strong> <strong>Cancer</strong>: prognosis of triple-negative<br />
breast cancers and non-triple-negative breast cancers in a<br />
large registry of certified breast units<br />
Kern P, Rezai M. <strong>Breast</strong> Unit Düsseldorf Louis Hospital, Düsseldorf,<br />
Northrhine-Westfalia, Germany.<br />
Evaluation of Prognostic and Predictive Performance of <strong>Breast</strong><br />
<strong>Cancer</strong> Index and Its Components in Hormonal Receptor-<br />
Positive <strong>Breast</strong> <strong>Cancer</strong> Patients: A TransATAC Study<br />
Sgroi DC, Sestak I, Zhang Y, Erlander MG, Schnabel CA, Goss PE,<br />
Cuzick J, Dowsett M. Massachusetts General Hospital and Harvard<br />
Medical School, Boston, MA; Queen Mary University, London,<br />
United Kingdom; bioTheranostics Inc, <strong>San</strong> Diego, CA; Royal Marsden<br />
Hospital, London, United Kingdom.<br />
Quantitative HER3 protein expression and PIK3CA mutation<br />
status in matched samples from primary and metastatic breast<br />
cancer tissues and correlation with time to recurrence<br />
Sperinde J, Lara J, Michaelson R, Sun X, Conte P, Guarneri V, Barbieri<br />
E, Ali S, Leitzel K, Weidler J, Lie Y, Cook J, Haddad M, Paquet A,<br />
Winslow J, Howitt J, Hurley L, Eisenberg M, Petropoulos C, Huang<br />
W, Lipton A. Monogram Biosciences/Integrated Oncology/LabCorp,<br />
South <strong>San</strong> Francisco, CA; Saint Barnabas Medical Center, Livingston,<br />
NJ; University of Modena, Modena, Italy; Penn State/Hershey Medical<br />
Center, Hershey, PA; Lebanon VA Medical Center, Lebanon, PA;<br />
Laboratory Corporation of America, Research Triangle Park, NC.<br />
SET index predicts response to endocrine therapy rather than<br />
prognosis independently of other genomic signatures in a<br />
blinded validation study<br />
Karn T, Hatzis C, Symmans F, Pusztai L, Ruckhäberle E, Schmidt M,<br />
Müller V, Hanker L, Heinrich T, Holtrich U, Kaufmann M, Rody A.<br />
Goethe-University; Nuvera Biosciences; The University of Texas MD<br />
Anderson <strong>Cancer</strong> Center; Gutenberg-University Mainz; University<br />
Hospital Hamburg-Eppendorf; Saarland-University, Homburg.<br />
Cell Cycle Profiling – risk score (C2P-RS) based on the specific<br />
activity of CDK1 and CDK2 predicts relapse in node-negative,<br />
hormone receptor-positive breast cancer treated with<br />
endocrine therapy<br />
Kim SJ, Masuda N, Tsukamoto F, Inaji H, Akiyama F, Sonoo H,<br />
Kurebayashi J, Yoshidome K, Tsujimoto M, Takei H, Masuda S,<br />
Nakamura S, Noguchi S. Graduate School of Medicine, Osaka<br />
University, Suita, Osaka, Japan; National Hospital Organization<br />
Osaka National Hospital, Osaka, Japan; Osaka Koseinenkin Hospital,<br />
Osaka, Japan; Osaka Medical Center for <strong>Cancer</strong> & Cardiovascular<br />
Diseases, Osaka, Japan; The <strong>Cancer</strong> Institute of Japan Foundation for<br />
<strong>Cancer</strong> Research, Tokyo, Japan; Kawasaki Medical School, Kurashiki,<br />
Okayama, Japan; Osaka Police Hospital, Osaka, Japan; Saitama <strong>Cancer</strong><br />
Center, Kita-Adachi, Saitama, Japan; Nihon University School of<br />
Medicine, Tokyo, Japan; Showa University School of Medicine,<br />
Tokyo, Japan.<br />
Are the mitotic factors Mitotic Activity Index (MAI) and<br />
Phosphohistone 3 (PPH3) stronger prognostic proliferation<br />
factors than Ki67 in node-negative breast cancer?<br />
Klintman M, Strand C, Gudlaugsson E, Janssen E, Skaland I,<br />
Malmström P, Baak J, Fernö M. Clinical Sciences, Lund University<br />
and Skåne University Hospital, Lund, Sweden; Stavanger University<br />
Hospital, Stavanger, Norway; Stavanger University Hospital and the<br />
Gade Institute, University of Bergen, Stavanger, Norway.<br />
P2-10-13<br />
www.aacrjournals.org<br />
25s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P2-10-20 A tumor DNA complexity index is an independent predictor<br />
of survival in a dataset of 1950 breast cancers; a METABRIC<br />
group study<br />
Vollan HKM, Rueda OM, Børresen-Dale A-L, Aparicio S, Caldas<br />
C. Institute for <strong>Cancer</strong> Research, Oslo University Hospital, Oslo,<br />
Norway; The K.G. Jebsen Center for <strong>Breast</strong> <strong>Cancer</strong> Research,<br />
Institute for Clinical Medicine, University of Oslo, Norway; Oslo<br />
University Hospital, Oslo, Norway; Cambridge Research Institute,<br />
Cambridge, United Kingdom; University of Cambridge, United<br />
Kingdom; University of British Colombia, Vancouver, BC, Canada;<br />
British Colombia <strong>Cancer</strong> Research Center, Vancouver, BC, Canada;<br />
Cambridge Experimental <strong>Cancer</strong> Medicine Centre, Cambridge,<br />
United Kingdom; Addenbrooke’s Hospital, Cambridge University<br />
Hospital, Cambridge, United Kingdom.<br />
P2-10-21 Prognostic value of estrogen receptor status in women with<br />
synchronous or metachronous breast cancers<br />
Huo D. University of Chicago, IL.<br />
P2-10-22 Phosphorylation of Steroid Receptor Coactivator 3 (SRC3)<br />
at Ser543 is a novel independent prognostic marker in<br />
breast cancer<br />
Palmieri C, Gojis O, Rudraraju B, Abdel-Fatah TMA, Moore D, Shaw J,<br />
Green A, Ellis IO, Coombes RC, Ali S. Imperial College London, United<br />
Kingdom; Nottingham University City Hospital, Nottingham, United<br />
Kingdom; University of Leicester, United Kingdom; Nottingham<br />
University Hospitals, City Hospital Campus, Nottingham, United<br />
Kingdom.<br />
P2-10-23 Lymphovascular Invasion (LVI) and Overall Survival in<br />
Node-negative and Node-positive <strong>Breast</strong> <strong>Cancer</strong> Patients:<br />
A Meta-analysis<br />
Sahebjam S, Diaz-Padilla I, Ocana A, Seruga B, Amir E. Princess<br />
Margaret Hospital; Institute of Oncology Ljubljana.<br />
P2-10-24 Independent validation of Recurrence Online using 1,638<br />
breast cancer microarray samples<br />
Györffy B, Weltz B, Benke Z, Timar J, Sztupinszki Z, Schaefer R.<br />
Hungarian Academy of Sciences; Semmelweis University; Charité.<br />
P2-10-25 Prognostic value of relative change in tumor marker CA 27.29<br />
in early stage breast cancer – The SUCCESS trial<br />
Hepp P, Tesch H, Forstbauer H, Rezai M, Beck T, Schrader I, Kleine-<br />
Tebbe A, Hucke J, Finas D, Soeling U, Zahm D-M, Weiss E, Beckmann<br />
MW, Janni W, Rack B. University Düsseldorf; Praxis Prof. Tesch<br />
Frankfurt; Gemeinschaftspraxis Dr. Forstbauer & Dr. Ziske Troisdorf;<br />
Luisenkrankenhaus Düsseldorf; Städtisches Klinikum Rosenheim;<br />
Henriettenstiftung Krankenhaus Hannover; DRK Kliniken Berlin<br />
Köpenick; Bethesda Krankenhaus Wuppertal; Universitätsklinikum<br />
Schleswig-Holstein, Campus Lübeck; Gemeinschaftspraxis Siehl &<br />
Söling; SRH Wald-Klinikum Gera; Klinikum Sindelfingen-Böblingen;<br />
Universitätsfrauenklinik Erlangen; Universitätsfrauenklinik Munich.<br />
P2-10-26 Association between circulating tumor cells and molecular<br />
breast cancer subtypes<br />
Gang N, Haibo W, Funian L, Chen L, Xiaoyi L, Xingang W, Zhidong L.<br />
Affiliated Hospital of Medical College, Qingdao University, Qingdao,<br />
Shandong, China.<br />
P2-10-27 No Discordant Receptor Status Results among 50 Paired<br />
<strong>Breast</strong> and Axillary Metastasis Core Biopsies when Pre-analytic<br />
Variation is Controlled<br />
Miller DV, Rosenthall RE, Avent JM, Carter CC, Hansen J, Hammond<br />
MEH. Intermountain Healthcare, Salt Lake City, UT.<br />
P2-10-28<br />
P2-10-29<br />
P2-10-30<br />
P2-10-31<br />
P2-10-32<br />
P2-10-33<br />
The Prognostic Index, KiGE, Combining Proliferation,<br />
Histological Grade and Estrogen Receptor Status Challenges<br />
Gene Profiling –<br />
A Study in 1,854 Chemo-Naïve Women with N0/N1 Primary<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Strand C, Bak M, Borgquist S, Chebil G, Falck A-K, Fjällskog M-L,<br />
Grabau D, Hedenfalk I, Jirström K, Klintman M, Malmtröm P, Olsson<br />
H, Rydén L, Stål O, Bendahl P-O, Fernö M. Lund University, Division<br />
of Oncology, Skåne University Hospital, Lund, Sweden; Odense<br />
University Hospital, Odense, Denmark; Mammography, Bergaliden,<br />
Helsingborg, Sweden; Helsingborg Hospital, Helsingborg, Sweden;<br />
Uppsala University Hospital, Uppsala, Sweden; Lund University,<br />
Skåne University Hospital, Lund, Sweden; Lund University, Division of<br />
Pathology, Lund, Sweden; Skåne University Hospital, Lund, Sweden;<br />
Linköping University, County Council of Östergötland, Linköping,<br />
Sweden; Lund University, Division of Surgery, Skåne University<br />
Hospital, Lund, Sweden.<br />
Time dependent breast cancer metastasis prediction using<br />
novel biological imaging, clinico-pathological and genomic<br />
data combined with Bayesian modeling to reduce over-fitting<br />
and improve on inter-cohort reproducibility<br />
Sheeba I, Kelleher M, Lawler K, Festy F, Barber P, Shamill E, Gargi P,<br />
Weitsman G, Barrett J, Fruhwirth G, Huang L, Tullis I, Woodman N,<br />
Pinder S, Ofo E, Fernandes L, Beutler M, Ameer-Beg S, Holmberg L,<br />
Purushotham A, Fraternali F, Condeelis J, Hanby A, Gillett C, Ellis P,<br />
Vojnovic B, Coolen A, Ng T. Kings College London, Guy’s Medical<br />
School Campus, London, England, United Kingdom; King’s College<br />
London, Strand Campus, London, England, United Kingdom; Guy’s<br />
and St Thomas Foundation Trust, London, England, United Kingdom;<br />
Gray Institute for Radiation Oncology & Biology, University of Oxford,<br />
England, United Kingdom; Leeds Institute of Molecular Medicine,<br />
Leeds, England, United Kingdom.<br />
Expression of lipid metabolism genes in contralateral<br />
unaffected breast associated with estrogen receptor status of<br />
breast cancer<br />
Wang J, Scholtens D, Holko M, Ivancic D, Lee O, Hu H, Chatterton RT,<br />
Khan SA. Northwestern university, Chicago, IL.<br />
Correlation of quantitative p95HER2 and total HER2 levels<br />
with clinical outcomes in a combined analysis of two cohorts<br />
of trastuzumab-treated metastatic breast cancer patients<br />
Duchnowska R, Sperinde J, Leitzel K, Szostakiewicz B, Paquet A, Ali<br />
SM, Jankowski T, Haddad M, Fuchs E-M, Arlukowicz-Czartoryska B,<br />
Winslow J, Singer C, Wysocki PJ, Lie Y, Horvat R, Foszczynska-Kloda<br />
M, Petropoulos C, Radecka B, Litwiniuk M, Debska S, Weidler J,<br />
Huang W, Biernat W, Köstler WJ, Jassem J, Lipton A. Military Institute<br />
of Medicine, Warsaw, Poland; Monogram Biosciences/Integrated<br />
Oncology/LabCorp, South <strong>San</strong> Francisco, CA; Penn State/Hershey<br />
Medical Center, Hershey, PA; Medical University of Gdansk, Poland;<br />
Lublin Oncology Center, Lublin, Poland; Medical University of Vienna,<br />
Austria; Bialystok Oncology Center, Bialystok, Poland; Greater Poland<br />
<strong>Cancer</strong> Center, Poznan, Poland; West Pomeranian Oncology Center,<br />
Szczecin, Poland; Opole Oncology Center, Opole, Poland; Poznan<br />
University of Medical Sciences, Poznan, Poland; Regional <strong>Cancer</strong><br />
Center, Lódz, Poland.<br />
Sialyl Lewis X and inflammatory mediators in breast cancer<br />
patients: biological correlations and prognostic value<br />
Lee B-N, Arun BK, Cohen EN, Tin S, Gutierrez-Barrera AM, Miura T,<br />
Kiyokawa I, Alvarez RH, Valero V, Ueno NT, Cristofanilli M, Reuben JM.<br />
University of Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX; Nitto<br />
Boseki Co., Ltd, Tokyo, Japan; Fox Chase <strong>Cancer</strong> Center,<br />
Philadelphia, PA.<br />
Mitotic Component of Grade Can Distinguish <strong>Breast</strong> <strong>Cancer</strong><br />
Patients at Greatest Risk of Local Relapse<br />
Done SJ, Miller NA, Wei Shi W, Pintilie M, McCready DR, Liu F-F,<br />
Fyles A. University Health Network, Toronto, ON, Canada; Princess<br />
Margaret Hospital, University Health Network, Toronto, ON, Canada;<br />
University of Toronto, ON, Canada.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 26s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P2-10-34 Development and validation of ClinicoMolecular Triad<br />
Classification (CMTC), a platform for breast cancer (BC)<br />
prognostic and predictive gene signature portfolios<br />
Leong WL, Wang D-Y, Done S, McCready D. University Health<br />
Network, Toronto, ON, Canada.<br />
P2-10-35 The grade of accompanying DCIS in IDC as important<br />
prognostic factor<br />
Kim JY, Moon H-G, Han WS, Noh DY. Seoul National University<br />
Hospital, <strong>Breast</strong> <strong>Cancer</strong> Center, Seoul, Korea.<br />
P2-10-36 Analysis of biomarker expression and biological subtype<br />
in primary tumour, corresponding lymph node and distant<br />
metastasis with 5-year follow-up<br />
Falck A-K, Ferno M, Bendahl P-O, Chebil G, Olsson H, Rydén L. Clinical<br />
Sciences, Lund, Sweden.<br />
P2-10-37 Long-term prognosis of early breast cancer in a populationbased<br />
cohort with a known BRCA1/2 mutation status<br />
Nilsson MP, Werner Hartman L, Idvall I, Kristoffersson U, Olsson H,<br />
Johansson O, Borg Å, Loman N. Clinical Sciences, Lund University,<br />
Sweden; Lund University, Sweden; Landspitali University Hospital,<br />
Reykjavik, Iceland.<br />
P2-10-38 Prognostic factors uPA/PAI-1: measurement in core needle<br />
biopsies<br />
Vetter M, Landstorfer B, Lantzsch T, Buchmann J, Große R, Ruschke<br />
K, Holzhausen H-J, Thomssen C, Kantelhardt E-J. Martin-Luther<br />
University Halle-Wittenberg, Halle/Saale, Germany; St. Elisabeth & St.<br />
Barbara Hospital, Halle/Saale, Germany; Martha-Maria Hospital, Halle/<br />
Saale, Germany.<br />
P2-10-39 Does E-cadherin or N-cadherin or epithelial-mesenchymal<br />
transition have a probability of clinical implication of the<br />
prognostic marker in invasive ductal carcinoma?<br />
Lee J, Yang G, Paik SS, Chung MS. Hanyang University Medical<br />
Center, Seoul, Republic of Korea.<br />
P2-10-40 Correlation between expression of the prognostic marker<br />
Progranulin (GP88) with Oncotype Dx Recurrence Score in<br />
estrogen receptor positive breast tumors<br />
Serrero G, Koka M, Goicochea L, Tkaczuk KR, Fernandez KL, Logan<br />
LS, Tuttle K, Yue B, Ioffe OB. A&G Pharmaceutical Inc, Columbia, MD;<br />
University of Maryland Greenebaum <strong>Cancer</strong> Center, Baltimore, MD;<br />
Franklin Square Hospital, Baltimore, MD; Mercy Hospital,<br />
Baltimore, MD.<br />
P2-10-41 The prediction of invasion in ductal carcinoma in situ:<br />
developing prediction model and validation<br />
Lee SK, Kim M, Nam SJ, Lee JE, Yang J-H. Samsung Medical Center,<br />
Sungkyunkwan University School of Medicine; Konkuk University<br />
Medical Center.<br />
P2-10-42 Gene expression profiling to predict the risk of locoregional<br />
recurrence in breast cancer<br />
Drukker CA, Nijenhuis MV, Elias SG, Wesseling J, Russell NS, de<br />
Snoo F, van ‘t Veer LJ, Beitsch PD, Rutgers EJT. Netherlands<br />
<strong>Cancer</strong> Institute-Antoni van Leeuwenhoek Hospital, Amsterdam,<br />
Netherlands; University Medical Center Utrecht, Utrecht, Netherlands;<br />
Agendia Inc., Amsterdam, Netherlands; University of California <strong>San</strong><br />
Francisco, <strong>San</strong> Francisco; Dallas Surgical Group, Dallas.<br />
P2-10-43 The combination of immunohistochemistry for predicting<br />
TP53 mutation is useful prognostic marker in breast cancer<br />
Watanabe G, Ishida T, Takahasi S, Ishioka C, Watanabe M, Ohuchi N.<br />
Tohoku Univ., Sendai, Miyagi, Japan.<br />
Psychosocial, Quality of Life, and Educational Aspects: Survivorship<br />
Research<br />
P2-11-01 Effects of chemotherapy on the ovary: What you didn’t know<br />
Barton DL, Thompson SL, Senn-Reeves JN, Satele DV, Frost M. Mayo<br />
Clinic, Rochester, MN.<br />
P2-11-02<br />
P2-11-03<br />
P2-11-04<br />
P2-11-05<br />
P2-11-06<br />
P2-11-07<br />
P2-11-08<br />
P2-11-09<br />
P2-11-10<br />
P2-11-11<br />
P2-11-12<br />
Perception and practice of reproductive specialists towards<br />
fertility preservation of young breast cancer patients<br />
Shimizu C, Kato T, Tamura N, Asada Y, Hiroko B, Mizota Y, Yamamoto<br />
S, Fujiwara Y. National <strong>Cancer</strong> Center Hospital, Tokyo, Japan; Asada<br />
Lady’s Clinic, Nagoya, Aichi, Japan; University of Tsukuba, Ibaragi,<br />
Japan; National <strong>Cancer</strong> Center, Tokyo, Japan.<br />
Randomized, single blind trial comparing limited and<br />
intensive survivorship interventions following adjuvant<br />
therapy in a multiethnic cohort of breast cancer survivors<br />
Hershman DL, Greenlee H, Awad D, Kalinsky K, Maurer M, Kranwinkel<br />
G, Brooks-Brafman L, Fuentes D, Tsai W-Y, Crew KD. Columbia<br />
Univeristy Medical Center, New York, NY; Mailman School of Public<br />
Health, New York, NY.<br />
Chemotherapy Induces Neuroinflammation and Cognitive<br />
Deficits in Female Mice<br />
Jarrett BL, Lustberg MB, Hinzey A, Stuller KA, Shapiro CL, DeVries C.<br />
The Ohio State University Wexner Medical Center, Columbus, OH;<br />
The Ohio State University Comprehensive <strong>Cancer</strong> Center,<br />
Columbus, OH.<br />
Work status and financial stability during treatment for early<br />
breast cancer: a pilot study of an ethnically diverse sample<br />
Eberle CE, Min S-H, Jung S, Ramirez J, Patil S, Gany F, Blinder VS.<br />
Memorial Sloan-Kettering <strong>Cancer</strong> Center, New York, NY.<br />
Mortality among offspring of women diagnosed with breast<br />
cancer; a population based study<br />
Verkooijen HM, Ang X, Liu J, Czene K, Salim A, Hartman M.<br />
University Medical Center Utrecht, Netherlands; National University<br />
of Singapore, Singapore; Karolinska Institute, Stockholm, Sweden;<br />
National University Hospital, Singapore, Singapore.<br />
Endothelial progenitor cells as novel markers of anthracycline<br />
induced cardiac injury<br />
Lustberg MB, Ruppert AS, Carothers S, Bingman A, McCarthy B,<br />
Raman S, Das M, Kanji S, Lu J, Das H, Cinar-Akakin H, Gurcan MN,<br />
Berger MJ, Wesolowski R, Olson EM, Ramaswamy B, Mrozek E,<br />
Layman RM, Binkley P, Shapiro CL. The OSU <strong>Breast</strong> Program at<br />
Stefanie Spielman Comprehensive <strong>Breast</strong> Center; OSU.<br />
Feasibility of Enrollment into a Survivorship Care Plan Study at<br />
Initial Diagnosis<br />
Bulloch KJ, Irwin M, Chagpar A, <strong>San</strong>ft T. Yale University,<br />
New Haven, CT.<br />
Weight Change and Risk of Incident Diabetes after<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Erickson KD, Patterson RE, Natarajan L, Lindsay SP, Heath D, Caan BJ.<br />
Moores UC <strong>San</strong> Diego <strong>Cancer</strong> Center, University of California, <strong>San</strong><br />
Diego, La Jolla, CA; <strong>San</strong> Diego State University, <strong>San</strong> Diego, CA; Kaiser<br />
Permanente Northern California, Oakland, CA.<br />
Prospective memory impairment in early breast cancer<br />
survivors: Finally homing in on the real deficit?<br />
Verma S, Collins B, Song X, Bedard M, Paquet L. The Ottawa Hospital<br />
Regional <strong>Cancer</strong> Centre; The Ottawa Hospital; Carleton University.<br />
Patient Reported Outcomes after <strong>Breast</strong> <strong>Cancer</strong> Surgery and<br />
Adjuvant Therapy from a German <strong>Breast</strong> <strong>Cancer</strong> Centre<br />
Feiten S, Dünnebacke J, Heymanns J, Köppler H, Thomalla J, van<br />
Roye C, Wey D, Weide R. Institute for Health Care Research in<br />
Oncology, Koblenz, Germany; Catholic Clinical Centre Koblenz-<br />
Montabaur, Koblenz, Germany; Oncology Group Practice Koblenz,<br />
Germany.<br />
Proactive approach to risk reduction and early detection of<br />
breast cancer related lymphedema<br />
Fu MR, Guth A, Kleinman R, Cartwright F, Haber J, Axelrod D. New<br />
York University, New York, NY; NYU <strong>Cancer</strong> Center, New York, NY.<br />
www.aacrjournals.org<br />
27s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P2-11-13 The Effect of Positive Axillary Lymph Nodes on Symptoms,<br />
Physical Impairments, and Function<br />
Kesarwala AH, Pfalzer LA, O’Meara WP, Stout NL. National <strong>Cancer</strong><br />
Institute, Bethesda, MD; University of Michigan - Flint, MI; Lahey<br />
Clinic, Burlington, MA; Walter Reed National Military Medical Center,<br />
Bethesda, MD.<br />
P2-11-14 Symptoms, Physical Impairments, and Function in <strong>Breast</strong><br />
<strong>Cancer</strong> Patients with Negative Axillary Lymph Nodes<br />
Kesarwala AH, Pfalzer LA, O’Meara WP, Stout NL. National <strong>Cancer</strong><br />
Institute, Bethesda, MD; University of Michigan - Flint, MI; Lahey<br />
Clinic, Burlington, MA; Walter Reed National Military Medical Center,<br />
Bethesda, MD.<br />
P2-11-15 Development of a web-based survey tool to assess change<br />
in breast cancer (BrCa) survivor knowledge after receipt of<br />
cancer treatment summary and survivorship care plan (SCP)<br />
Custer JL, Rocque GB, Wisinski KB, Jones NR, Donohue S, Koehn TM,<br />
Champeny TL, Terhaar AR, Chen KB, Peck KA, Tun MT, Wiegmann<br />
DA, Sesto ME, Tevaarwerk AJ. University of Wisconsin, Madison, WI.<br />
P2-11-16 Cardiac Morbidity After Adjuvant Chemotherapy (CT) for Early<br />
<strong>Breast</strong> <strong>Cancer</strong> in the Community Setting<br />
Patt D, Espirito J, Turnwald B, Denduluri N, Wang Y, Lina A,<br />
Hoverman R, Neubauer M, Bosserman L, Busby L, Brooks B,<br />
Cartwright T, Sitarik M, Schnadig I, Winter W, Garey J, Ginsburg-<br />
Arlen A, Bergstrom K, Beveridge R. Pathways Task Force, US<br />
Oncology Network, McKesson Specialty Health, Austin, TX;<br />
Pathways Task Force, US Oncology Network, McKesson Specialty<br />
Health, The Woodlands, TX; Pathways Task Force, US Oncology<br />
Network, McKesson Specialty Health, Arlington, VA; US Oncology<br />
Network, McKesson Specialty Health, The Woodlands, TX; Kansas<br />
City <strong>Cancer</strong> Center, Pathways Task Force, US Oncology Network,<br />
McKesson Specialty Health, Overland Park, KS; Pathways Task<br />
Force, US Oncology Network, McKesson Specialty Health, Rancho<br />
Cucamonga, CA; Rocky Mountain <strong>Cancer</strong> Centers, Pathways Task<br />
Force, US Oncology Network, McKesson Specialty Health, Boulder,<br />
CO; Pathways Task Force, US Oncology Network, McKesson Specialty<br />
Health, Dallas, TX; Pathways Task Force, US Oncology Network,<br />
McKesson Specialty Health, Ocala, FL; Pathways Task Force, US<br />
Oncology Network, McKesson Specialty Health, Tualatin, OR;<br />
Pathways Task Force, US Oncology Network, McKesson Specialty<br />
Health, Portland, OR.<br />
P2-11-17 Pilot Study to Evaluate a Home-based Exercise and Weight<br />
Loss Intervention on Cardiopulmonary Fitness and Markers of<br />
<strong>Breast</strong> <strong>Cancer</strong> Risk in Postmenopausal <strong>Breast</strong> <strong>Cancer</strong> Survivors<br />
Burnett D, Klemp JR, Porter C, Schmitz KJ, Fabian CJ, Kluding P.<br />
University of Kansas Medical Center, Kansas City, KS; University<br />
of Kansas Hospital, Kansas City, KS; University of Pennsylvania,<br />
Philadelphia, PA.<br />
Psychosocial, Quality of Life, and Educational Aspects: Quality of Life -<br />
Supportive Care<br />
P2-12-01 Prospective Evaluation of Joint Symptoms in Postmenopausal<br />
Women Initiating Aromatase Inhibitors for Early Stage<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Crew KD, Chehayeb Makarem D, Awad D, Kalinsky K, Maurer M,<br />
Kranwinkel G, Brafman L, Fuentes D, Hershman DL. Columbia<br />
University Medical Center, New York, NY.<br />
P2-12-02 Withdrawn<br />
P2-12-03 A pilot study evaluating the benefits and feasibility of an<br />
exercise program for breast cancer patients receiving adjuvant<br />
chemotherapy<br />
Petrella TM, Laredo S, Oh P, Marzolini S, Warner E, Dent R, Verma S,<br />
Eisen A, Pritchard K, Trudeau M, Zhang L, Bjarnason G. Odette <strong>Cancer</strong><br />
Centre, Toronto, ON, Canada; Women’s College Hospital, Toronto,<br />
ON, Canada; Toronto Rehabilitation Institute, Toronto, ON, Canada;<br />
Macrostat Inc, Toronto, ON, Canada.<br />
P2-12-04 Music Therapy Reduces Radiotherapy-Induced<br />
Fatigue in Patients with <strong>Breast</strong> or Gynecological <strong>Cancer</strong>:<br />
A Randomized Trial<br />
Freitas NMA, Silva TRMA, Freitas-Junior R, Paula Junior W, Silva DJ,<br />
Machado GDP, Ribeiro MKA, Carneiro JP. Araujo Jorge Hospital/<br />
ACCG, Goiania, Goias, Brazil; Federal University of Goias, Goiania,<br />
Goias, Brazil; Instituto Integrado de Neurociencias/IINEURO, Goiania,<br />
Goias, Brazil.<br />
P2-12-05 Limited Absorption of Low Dose 10 µg Intravaginal 17-β<br />
Estradiol (Vagifem®) in Postmenopausal Women with <strong>Breast</strong><br />
<strong>Cancer</strong> on Aromatase Inhibitors<br />
Goldfarb SB, Dickler M, Dnistrian A, Patil S, Dunn L, Chang K,<br />
Berkowitz A, Tucker N, Carter J, Barakat R, Hudis C, Castiel M.<br />
Memorial Sloan-Kettering <strong>Cancer</strong> Center, New York, NY.<br />
P2-12-06 Ultra-low dose vaginal estriol and Lactobacillus acidophilus<br />
(Gynoflor®) in early breast cancer survivors on aromatase<br />
inhibitors: Pharmacokinetic, efficacy and safety results from<br />
a phase I study<br />
Neven P, Donders G, Mögele M, Lintermans A, Bellen G, Ortmann<br />
O, Buchholz S. University Hospital Gasthuisberg Leuven, Belgium;<br />
Femicare vzw, Clinical Research for Women, Tienen, Belgium;<br />
Universitätsklinikum Regensburg, Germany.<br />
P2-12-07 A review of clinical endpoints and use of quality-of-life<br />
outcomes in phase III metastatic breast cancer clinical trials<br />
Tatla R, Landaverde D, Victor C, Miles D, Verma S. University of<br />
Toronto, ON, Canada; Sunnybrook Odette <strong>Cancer</strong> Center, Toronto,<br />
ON, Canada; Dalla Lana School of Public Health, University of<br />
Toronto, ON, Canada; Mount Vernon <strong>Cancer</strong> Centre, United<br />
Kingdom.<br />
P2-12-08 Sorafenib for treatment of breast-cancer related lymphedema<br />
Zambetti M, Guidetti A, Carlo-Stella C, De Benedictis E, Tessari A,<br />
Balzarini A, Caraceni A, Gianni L, Gianni AM. IRCCS Ospedale <strong>San</strong><br />
Raffaele, Milan, Italy; Fondazione IRCCS Istituto Nazionale Tumori,<br />
Milan, Italy; Humanitas <strong>Cancer</strong> Center, IRCCS Istituto Clinico<br />
Humanitas, Rozzano, Italy.<br />
P2-12-09 A randomized controlled trial of support group intervention<br />
after breast cancer treatment: Results on sick leave, health<br />
care utilization and health economy<br />
Granstam Björneklett H, Rosenblad A, Lindemalm C, Ojutkangas<br />
M-L, Letocha H, Strang P, Bergkvist L. Centre for Clinical Research,<br />
Västerås, Västmanland, Sweden; <strong>Cancer</strong> Center Karolinska, Karolinska,<br />
Stockhoöm, Sweden; Karolinska Institutet, Stockholm, Sweden.<br />
P2-12-10 Psycho-spiritual therapy for improving the quality of life and<br />
spiritual well-being of women with breast cancer<br />
Loghmani A, Jafari N, Zamani A, Farajzadegan Z, Bahrami F, Emami<br />
H. Isfahan University of Medical Sciences, Isfahan, Islamic Republic of<br />
Iran; University of Isfahan, Islamic Republic of Iran.<br />
P2-12-11 Use of the DigniCap System To Prevent Hair Loss in Women<br />
Receiving Chemotherapy (CTX) for Stage I <strong>Breast</strong> <strong>Cancer</strong> (BC)<br />
Rugo HS, Serrurier KM, Melisko M, Glencer A, Hwang J, D’Agostino,<br />
Jr. R, Hutchens S, Esserman LJ, Melin S. University of California <strong>San</strong><br />
Francisco Helen Diller Comprehensive <strong>Cancer</strong> Center, <strong>San</strong> Francisco,<br />
CA; Wake Forest Baptist Health Medical Center, Winston-Salem, NC.<br />
P2-12-12 Efficacy and safety of scalp cooling (SC) treatment for alopecia<br />
prevention in women receiving chemotherapy (CTX) for breast<br />
cancer (BC)<br />
Serrurier KM, Melisko ME, Glencer A, Esserman LJ, Rugo HS. UCSF<br />
Helen Diller Comprehensive <strong>Cancer</strong> Center.<br />
P2-12-13 Results of randomised controlled phase II study (KBCSG02<br />
trial) of the efficiency of palonosetron, aprepitant, and<br />
dexamethasone for day 1 with or without dexamethasone on<br />
days 2 and 3<br />
Kosaka Y, Sengoku N, Kikuchi M, Nishimiya H, Enomoto T, Kuranami<br />
M, Watanabe M. Kitasato University School of Medicine, Sagamihara,<br />
Japan.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 28s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P2-12-14 Use of the MD Anderson Symptom Inventory To Screen for<br />
Depression in <strong>Breast</strong> <strong>Cancer</strong><br />
Kvale EA, Azuero CB, Azuero A, Fisch M, Ritchie C. Birmingham<br />
VA Medical Center, Birmingham, AL; University of Alabama at<br />
Birmingham, AL; University of Alabama, Tuscaloosa, AL; MD<br />
Anderson <strong>Cancer</strong> Center, Houston, TX; University of California, <strong>San</strong><br />
Francisco, CA.<br />
P2-12-15 Understanding the complex non face-to-face interventions<br />
delivered by the clinical nurse specialists in metastatic<br />
breast cancer<br />
Warren M, Mackie D, Leary A. Royal Marsden NHS Foundation Trust,<br />
Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation<br />
Trust, London, United Kingdom; Independent Healthcare Consultant<br />
and Research Analyst.<br />
Treatment: Endocrine Therapy - Adjuvant<br />
P2-13-01 Impact of Body Mass Index (BMI) on the efficacy of<br />
aromatase inhibitors to suppress estradiol serum levels<br />
in postmenopausal patients with early breast cancer: a<br />
prospective proof of principle<br />
Pfeiler G, Königsberg R, Hadji P, Fitzal F, Maroske M, Ban G, Zellinger<br />
J, Exner R, Seifert M, Singer C, Gnant M, Dubsky P. Medical University<br />
of Vienna, Austria; Applied <strong>Cancer</strong> Research – Institution for<br />
Translational Research Vienna (ACR-ITR VIEnna)/CEADDP, Austria;<br />
Universityhospital of Giessen and Marburg GmbH, Germany.<br />
P2-13-02 Effect of aspirin (ASP) or celecoxib (CC) use on outcomes<br />
in postmenopausal breast cancer patients randomized to<br />
adjuvant exemestane or anastrozole: NCIC CTG MA.27<br />
Higgins MJ, Chapman J-AW, Ingle JN, Sledge G, Budd GT, Ellis MJ,<br />
Pritchard KI, Clemons M, Badovinac Crnjevic T, Han L, Gelmon K,<br />
Rabaglio M, Elliott C, Shepherd LE, Goss PE. Massachusetts General<br />
Hospital, Boston, MA; NCIC Clinical Trials Group, Queen’s University,<br />
Kingston, ON, Canada; Mayo Clinic, Rochester, MN; Ottawa Hospital<br />
and Faculty of Medicine, University of Ottawa, ON, Canada;<br />
Vancouver Centre, BCCA, Vancouver, BC, Canada; Sunnybrook Odette<br />
<strong>Cancer</strong> Centre, Toronto, ON, Cayman Islands; Indiana University,<br />
Indianapolis, IN; Cleveland Clinic, Cleveland, OH; Washington<br />
University in St. Louis, MO; University Hospital Berne, Switzerland.<br />
P2-13-03 Prevalence of non-metastatic breast cancer patients treated<br />
with aromatase inhibitors in the United States<br />
Liede A, Hernandez RK, Pirolli M, Quigley J, Quach D. Amgen Inc.,<br />
Thousand Oaks, CA; IMS Health, Plymouth Meeting, PA.<br />
P2-13-04 Superior efficacy of anastrozole to tamoxifen as adjuvant<br />
therapy for postmenopausal patients with hormoneresponsive<br />
breast cancer. Efficacy results of long-term<br />
follow-up data from N-SAS BC 03 trial<br />
Imoto S, Osumi S, Aogi K, Hozumi Y, Mukai H, Iwata H, Yokota I,<br />
Yamaguchi T, Ohashi Y, Watanabe T, Takatsuka Y, Aihara T. School<br />
of Medicine, Kyorin University, Tokyo, Japan; National Hospital<br />
Organization Shikoku <strong>Cancer</strong> Center, Ehime, Japan; Jichi Medical<br />
University, Tochigi, Japan; National <strong>Cancer</strong> Center Hospital East,<br />
Chiba, Japan; Aichi <strong>Cancer</strong> Center Hospital, Aichi, Japan; School of<br />
Public Health, University of Tokyo, Tokyo, Japan; Tohoku University<br />
School of Medicine, Miyagi, Japan; Hamamatsu Oncology Center,<br />
Shizuoka, Japan; Kansai Rosai Hospital, Hyogo, Japan; Aihara<br />
Hospital, Osaka, Japan.<br />
P2-13-05 A pilot prospective study of adherence to aromatase inhibitor<br />
adjuvant therapy in patients with stage 1-3 breast carcinoma<br />
Heiss B, Thompson J, Nightingale G, Tait N, Kesmodel S, Bellavance<br />
E, Chumsri S, Bao T, Goloubeva O, Feigenberg S, Tkaczuk K. Marlene<br />
and Stewart Greenebaum <strong>Cancer</strong> Center, University of Maryland,<br />
Baltimore, MD; Thomas Jefferson University, Philadelphia, PA.<br />
P2-13-06 Effect of letrozole on bone and joints in collagen-induced<br />
arthritis in mice<br />
Lintermans A, Verhaeghe J, Van Bree R, Vanderschueren D,<br />
Vanderhaegen J, Braem K, Lories R, Neven P. University Hospitals<br />
Leuven, KU Leuven, Belgium; KU Leuven, Leuven, Belgium; University<br />
Hospitals Leuven, Belgium.<br />
P2-13-07 Long-term follow-up data of the side effect profile of<br />
anastrozole compared with tamoxifen in Japanese women:<br />
findings from N-SAS BC03 trial<br />
Iwata H, Ohsumi S, Aogi K, Hozumi Y, Imoto S, Mukai H, Yokota I,<br />
Yamaguchi T, Ohashi Y, Watanabe T, Takatsuka Y, Aihara T. Aichi<br />
<strong>Cancer</strong> Center Hospital, Nagoya, Aichi, Japan; NHO Shikoku <strong>Cancer</strong><br />
Center, Matsuyama, Ehime, Japan; Jichi Medical University, Tochigi,<br />
Japan; School of Medicine, Kyorin University, Tokyo, Japan; National<br />
<strong>Cancer</strong> Center Hospital East, Chiba, Japan; School of Public Health,<br />
University of Tokyo, Tokyo, Japan; Tohoku University School of<br />
Medicine, Sendai, Japan; Hamamatsu Oncology Center, Hamamatsu,<br />
Japan; Kansai Rosai Hospital, Hyogo, Japan; Aihara Hospital,<br />
Osaka, Japan.<br />
P2-13-08 Comparison of Compliance to Anti Estrogen Therapy in<br />
Patients with Early <strong>Breast</strong> <strong>Cancer</strong> followed at Tertiary Centers<br />
versus Through Family Physicians and Primary Surgeons:<br />
A Practice Review<br />
Alkhayyat SS, Younus J, Mirza FN, Stitt L. The Scarborough Hospital,<br />
Scarborough, ON, Canada; The University of Western Ontario,<br />
London, ON, Canada; Harvard University, Cambridge, MA.<br />
P2-13-09 Pharmacological impact of endoxifen in a laboratory<br />
simulation of tamoxifen therapy in postmenopausal<br />
breast cancer patients<br />
Maximov PY, McDaniel RE, Bhatta P, Brauch H, Jordan VC. Lombardi<br />
Comprehensive <strong>Cancer</strong> Center, Georgetown University Medical<br />
Center, Washington, DC; Dr. Margarete Fischer-Bosch-Institute of<br />
Clinical Pharmacology, Stuttgart, Germany.<br />
P2-13-10 Prospective randomized and multicentric evaluation<br />
of cognition in menopausal breast cancer patients<br />
receiving adjuvant hormonotherapy: a phase III study<br />
(Preliminary results)<br />
Vanlemmens L, Delbeuck X, Servent V, Mailliez A, Vanlemmens L,<br />
Lefeuvre-Plesse C, Kerbrat P, Petit T, Fournier C, Vendel Y, Clisant S,<br />
Bonneterre J, Pasquier F, Le Rhun E. Centre Mémoire de Ressource<br />
et de Recherche - CHRU Lille, Lille, France; Centre Oscar Lambret,<br />
Université Lille Nord de France, Lille, France; Centre Eugène Marquis,<br />
Rennes, France; Centre Paul Strauss, Strasbourg, France; Centre Oscar<br />
Lambret, Lille, France; CHRU, Lille, France.<br />
Treatment: Endocrine Therapy - Advanced Disease<br />
P2-14-01 Fulvestrant vs exemestane for treatment of metastatic breast<br />
cancer in patients with acquired resistance to non-steroidal<br />
aromatase inhibitors – a meta-analysis of EFECT and SoFEA<br />
(CRUKE/03/021 & CRUK/09/007)<br />
Johnston SRD, Chia S, Kilburn LS, Gradishar WJ, Cameron D, Dodwell<br />
D, Ellis P, Howell A, Im Y-H, Coombes G, Piccart M, Dowsett M,<br />
Bliss J, On behalf of the SoFEA and EFECT Investigators. The Royal<br />
Marsden Hospital NHS Foundation Trust & The Institute of <strong>Cancer</strong><br />
Research, London, United Kingdom; British Columbia <strong>Cancer</strong><br />
Agency, University of British Columbia, Vancouver, BC, Canada;<br />
The Institute of <strong>Cancer</strong> Research, Sutton, Surrey, United Kingdom;<br />
Robert H. Lurie Comprehensive <strong>Cancer</strong> Center, Feinberg School of<br />
Medicine, Northwestern University, Chicago, IL; Christie Hospital NHS<br />
Trust, Manchester, United Kingdom; Edinburgh <strong>Cancer</strong> Research<br />
Centre, University of Edinburgh and NHS Lothian, Edinburgh,<br />
United Kingdom; Leeds Teaching Hospitals NHS Trust, St. James’s<br />
University Hospital, Leeds, United Kingdom; Guy’s and St Thomas’s<br />
NHS Foundation Trust, London, United Kingdom; Samsung Medical<br />
Center, Seoul, Korea; Jules Bordet Institute, Brussels, Belgium; The<br />
Royal Marsden NHS Foundation Trust, London, United Kingdom.<br />
www.aacrjournals.org<br />
29s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P2-14-02 Preclinical Evaluation of Enzalutamide in <strong>Breast</strong> <strong>Cancer</strong> Models<br />
Cochrane DR, Bernales S, Jacobsen BM, D’Amato NC, Guerrero J,<br />
Gómez F, Protter AA, Elias AD, Richer JK. University of Colorado<br />
Anschutz Medical Campus, Aurora, CO; Medivation Inc., <strong>San</strong><br />
Francisco, CA; Fundación Ciencia & Vida, <strong>San</strong>tiago, Chile.<br />
P2-14-03 “Ethinylestradiol” is beneficial for postmenopausal<br />
advanced breast cancer patients heavily pre-treated with<br />
endocrine agents<br />
Iwase H, Yamamoto Y, Murakami K-I, Yamamoto-Ibusuki M, Tomita S,<br />
Omoto Y. Kumamoto University, Kumamoto, Japan.<br />
P2-14-04 A Phase Ib Dose Escalation Trial of RO4929097 (A γ-secretase<br />
inhibitor) in Combination with Exemestane in Patients with<br />
ER + Metastatic <strong>Breast</strong> <strong>Cancer</strong><br />
Means-Powell JA, Minton SE, Mayer IA, Abramson VG, Ismail-Khan<br />
R, Arteaga CL, Ayers DA, <strong>San</strong>ders MS, Lush RM, Miele L. Vanderbilt-<br />
Ingram <strong>Cancer</strong> Center, Nashville, TN; Moffit <strong>Cancer</strong> Center, Tampa,<br />
FL; University of Mississippi Health Care <strong>Cancer</strong> Institute, Jackson, MS.<br />
P2-14-05 A phase II study of combined fulvestrant and RAD001<br />
(everolimus) in metastatic estrogen receptor (ER) positive<br />
breast cancer after aromatase inhibitor (AI) failure<br />
Croley JJ, Black EP, Romond E, Chambers M, Waynick S, Slone<br />
S, Waynick C, Stevens M, Weiss HL, Massarweh SA. University of<br />
Kentucky and Markey <strong>Cancer</strong> Center, Lexington, KY.<br />
P2-14-06 A phase II trial of low dose estradiol in postmenopausal<br />
women with advanced breast cancer and acquired resistance<br />
to an aromatase inhibitor<br />
Howell SJ, Seif MW, Armstrong AC, Cope J, Wilson G, Welch RS,<br />
Misra V, Ryder D, Blowers E, Palmieri C, Wardley AM. University of<br />
Manchester, United Kingdom; The Christie NHS Foundation Trust,<br />
Manchester, United Kingdom; Imperial College, London, United<br />
Kingdom.<br />
P2-14-07 Evaluation of Aromatase Inhibitor failure and total healthcare<br />
expenditures among post-menopausal women with<br />
metastatic ER+/HER2- breast cancer in the US<br />
Namjoshi M, Landsman-Blumberg P, Thomson E, Chu BC. Novartis<br />
Pharmaceuticals Corporation, East Hanover, NJ; Thomson Reuters,<br />
Washington, DC.<br />
P2-14-08 The Pilot Trial of Intermittent Exemestane Therapy for<br />
Metastatic <strong>Breast</strong> <strong>Cancer</strong><br />
Luu T, Frankel PH, Somlo G, Wong C, Leong L, Mortimer JE, Hurria<br />
A, Koczywas M, Chao J, Chow W, Chung C, Chen S. City of Hope,<br />
Duarte, CA; Angeles Clinic & Research Institute, <strong>San</strong>ta Monica, CA.<br />
Treatment: Patient Resources<br />
P2-15-01 An efficient resource to accelerate research into the cause and<br />
prevention of breast cancer: the Love/Avon Army of Women<br />
Love SM. Dr. Susan Love Research Foundation, <strong>San</strong>ta Monica, CA.<br />
P2-15-02 The Efficacy of Recruitment and Retention Strategies for<br />
Research Subjects in an Early Phase Investigator-Initiated<br />
<strong>Breast</strong> <strong>Cancer</strong> Trial<br />
Reichow J, Higgins D, Parker S, Childs J, Disis ML, Salazar LG.<br />
University of Washington, Seattle, WA.<br />
Treatment: Tissue and Data Banks<br />
P2-16-01 Prospective <strong>Breast</strong> <strong>Cancer</strong> Quality Evaluation Application<br />
Developed for Native Android Tablet and Web Browser for<br />
Improving Mutltidisciplinary <strong>Breast</strong> <strong>Cancer</strong> Care<br />
Grobmyer SR, Raum N, Sposato V. University of Florida, Gainesville,<br />
FL; University of Florida, Gaineville, FL.<br />
P2-16-02 A web-based data management system for a multicenter<br />
international breast cancer oriented blood, tissue, and data<br />
biobank<br />
Margossian AL, Saadjian H, Mira A, Contreras A, Rimawi MF,<br />
Margossian ML, Scheurer M, Osborne K, Gutierrez C. <strong>Breast</strong> Center,<br />
Buenos Aires, Argentina; Dan Duncan <strong>Cancer</strong> Center/Smith <strong>Breast</strong><br />
Center, Baylor College of Medicine, Houston, TX.<br />
P2-16-03 Creation of a ‘state-of-the-art’ breast cancer data and biobank<br />
in Argentina<br />
Margossian AL, Gutierrez C, Saadjian H, May M, Ohanessian R,<br />
Bacigalupo S, Baravalle S, Margossian J, Osborne KC, Scheurer ME.<br />
<strong>Breast</strong> Center, Buenos Aires, Argentina; Dan Duncan <strong>Cancer</strong> Center/<br />
Smith <strong>Breast</strong> Center, Baylor College of Medicine, Houston, TX.<br />
P2-16-04 Attitudes of metastatic breast cancer patients towards<br />
research biopsies<br />
Seah DS, Scott SM, Najita J, Openshaw T, Krag KJ, Frank E, Sohl J,<br />
Stadler ZK, Garrett M, Winer EP, Come S, Lin NU. Dana-Farber <strong>Cancer</strong><br />
Institute, Boston, MA; Beth Isreal Deaconness Medical Center, Boston,<br />
MA; <strong>Cancer</strong> Care of Maine, Brewer, ME; Mass General North Shore<br />
<strong>Cancer</strong> Center, Danvers, MA; Memorial Sloan-Kettering <strong>Cancer</strong><br />
Center, New York, NY.<br />
9:00 am–9:30 am<br />
PLENARY LECTURE 2<br />
Exhibit Hall D<br />
Estrogen Receptor Cistrome: Implications for<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Jason S. Carroll, PhD<br />
<strong>Cancer</strong> Research UK, University of Cambridge<br />
Cambridge, UNITED KINGDOM<br />
9:30 am–11:30 am<br />
GENERAL SESSION 3<br />
Exhibit Hall D<br />
Moderator: <strong>San</strong>dra M. Swain, MD<br />
Washington Hospital Center<br />
Washington, DC<br />
9:30 S3-1. Neoadjuvant chemotherapy in the very young 35 years of<br />
age or younger<br />
Loibl S, Jackisch C, Gade S, Untch M, Paepke S, Kuemmel S, Schneeweiss<br />
A, Jackisch C, Huober J, Hilfrich J, Hanusch C, Gerber B, Eidtmann<br />
H, Denkert C, Costa S-D, Blohmer J-U, Nekljudova V, Mehta K, von<br />
Minckwitz G. German <strong>Breast</strong> Group, Neu-Isenburg; Klinikum Offenbach;<br />
Helios Kliniken Berlin; University Muenchen; Kliniken Essen Mitte;<br />
University Heidelberg; Uni Duesseldorf; Eilenriedeklinik Duesseldorf;<br />
Rotkreuzklinikum Muenchen; University Rostock; University Kiel; Charite<br />
Berlin; University Magdeburg; <strong>San</strong>kt Gertrauden Berlin.<br />
9:45 S3-2. Chemotherapy prolongs survival for isolated local<br />
or regional recurrence of breast cancer: The CALOR trial<br />
(Chemotherapy as Adjuvant for Locally Recurrent breast cancer;<br />
IBCSG 27-02, NSABP B-37, BIG 1-02)<br />
Aebi S, Gelber S, Lang I, Anderson SJ, Robidoux A, Martin M, Nortier JWR,<br />
Mamounas EP, Geyer Jr. CE, Maibach R, Gelber RD, Wolmark N, Wapnir<br />
I. International <strong>Breast</strong> <strong>Cancer</strong> Study Group, Bern, Switzerland; National<br />
Surgical Adjuvant <strong>Breast</strong> and Bowel Project, Pittsburgh, PA; <strong>Breast</strong><br />
International Group, Brussels, Belgium.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 30s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
10:00 S3-3. The UK TACT2 Trial: comparison of standard vs accelerated<br />
epirubicin in patients requiring chemotherapy for early breast<br />
cancer (EBC) (CRUK/05/019)<br />
Cameron D, Barrett-Lee P, Canney P, Banerji J, Bartlett J, Bloomfield<br />
D, Bowden S, Brunt M, Earl H, Ellis P, Fletcher M, Morden JP, Robinson<br />
A, Sergenson N, Stein R, Velikova G, Verrill M, Wardley A, Coleman R,<br />
Bliss JM. Edinburgh <strong>Cancer</strong> Research Centre, University of Edinburgh,<br />
United Kingdom; Velindre NHS Trust <strong>Cancer</strong> Centre, Cardiff, United<br />
Kingdom; Beatson West of Scotland <strong>Cancer</strong> Centre, Glasgow, United<br />
Kingdom; The Institute of <strong>Cancer</strong> Research, Sutton, United Kingdom;<br />
Ontario Institute for <strong>Cancer</strong> Research, Toronto, Canada; Brighton &<br />
Sussex University Hospitals, Brighton, United Kingdom; University of<br />
Birmingham, United Kingdom; University Hospital of North Staffordshire,<br />
Stoke-on-Trent, United Kingdom; University of Cambridge and NIHR<br />
Cambridge Biomedical Research Centre, Cambridge, United Kingdom;<br />
Guys Hospital & King College, London, United Kingdom; Leeds Institute<br />
of Molecular Medicine, Leeds, United Kingdom; Southend University<br />
Hospital, Southend, United Kingdom; Information Services Division NHS<br />
National Services Scotland, Edinburgh, United Kingdom; UCL Hospitals,<br />
London, United Kingdom; Northern Centre For <strong>Cancer</strong> Care, Newcastle<br />
upon Tyne, United Kingdom; The Christie Hospital, Manchester, United<br />
Kingdom; Weston Park Hospital, Sheffield, United Kingdom.<br />
10:15 S3-4. Ten year follow-up analysis of intense dose-dense adjuvant<br />
ETC (epirubicin (E), paclitaxel (T) and cyclophosphamide<br />
(C)) confirms superior DFS and OS benefit in comparison to<br />
conventional dosed chemotherapy in high-risk breast cancer<br />
patients with ≥ 4 positive lymph nodes<br />
Moebus V, Schneeweiss A, du Bois A, Lueck H-J, Eustermann H,<br />
Kuhn W, Kurbacher C, Nitz U, Kreienberg R, Jackisch C, Huober J,<br />
Thomssen C, Untch M. Klinikum Frankfurt Höchst, Frankfurt, Germany;<br />
University of Heidelberg, Germany; Klinikum Essen Mitte, Essen,<br />
Germany; Gynäkologisch-Onkologische Praxis, Hannover, Germany;<br />
WiSP Research Institute, Langenfeld, Germany; University of Bonn,<br />
Germany; Medizinisches Zentrum Bonn-Friedensplatz, Bonn, Germany;<br />
Ev. Krankenhaus Bethesda, Mönchengladbach, Germany; University of<br />
Ulm, Germany; Klinikum Offenbach, Offenbach, Germany; University<br />
of Duesseldorf, Germany; University of Halle, Germany; Helios Klinikum<br />
Berlin-Buch, Berlin, Germany.<br />
10:30 S3-5. Myelodysplatic syndrome and/or acute myelogenous<br />
leukemia (MDS and/or AML) after a breast cancer diagnosis: the<br />
National Comprehensive <strong>Cancer</strong> Network (NCCN) experience<br />
Karp JE, Blackford A, Visvanathan K, Rugo HS, Moy B, Goldstein LJ,<br />
Stockerl-Goldstein K, Neumayer L, Langbaum TS, Hughes ME, Weeks JC,<br />
Wolff AC. Johns Hopkins Kimmel <strong>Cancer</strong> Center; University of California<br />
<strong>San</strong> Francisco; Massachusetts General Hospital; Fox Chase <strong>Cancer</strong> Center;<br />
Washington University School of Medicine; University of Utah School of<br />
Medicine; Dana Farber <strong>Cancer</strong> Institute.<br />
10:45 S3-6. Profiling of triple-negative breast cancers after neoadjuvant<br />
chemotherapy identifies targetable molecular alterations in the<br />
treatment-refractory residual disease<br />
Balko JM, Wang K, <strong>San</strong>ders ME, Kuba MG, Pinto JA, Doimi F, Gomez H,<br />
Palmer G, Cronin MT, Miller VA, Yelensky R, Stephens PJ, Arteaga CL.<br />
Vanderbilt University, Nashville, TN; Foundation Medicine, Cambridge,<br />
MA; Oncosalud, Lima, Peru; Instituto Nacional de Enfermedades<br />
Neoplásicas, Lima, Peru.<br />
11:00 S3-7. Treatment with histone deacetylase inhibitors creates<br />
’BRCAness’ and sensitizes human triple negative breast cancer<br />
cells to PARP inhibitors and cisplatin<br />
Bhalla KN, Rao R, Sharma P, Das Gupta S, Chauhan L, Stecklein S, Fiskus S.<br />
University of Kansas <strong>Cancer</strong> Center, Kansas City, KS.<br />
11:15 S3-8. Identification of novel synthetic-lethal targets for MYCdriven<br />
triple-negative breast cancer<br />
Goga A, Samson S, Horiuchi D. UCSF, <strong>San</strong> Francisco, CA.<br />
11:30 am–12:00 pm<br />
AACR Outstanding Investigator Award for<br />
<strong>Breast</strong> <strong>Cancer</strong> Research, funded by Susan G. Komen for<br />
the Cure ®<br />
Exhibit Hall D<br />
<strong>Breast</strong> Tumor Evolution: Drivers and Clinical Relevance<br />
Kornelia Polyak, MD, PhD<br />
Dana-Farber <strong>Cancer</strong> Institute<br />
Boston, MA<br />
12:00 pm–1:35 pm<br />
LUNCH<br />
12:30 pm–1:35 pm<br />
CASE DISCUSSION 1<br />
Ballroom A<br />
Moderator: Mothaffar Rimawi, MD<br />
Baylor College of Medicine<br />
Houston, TX<br />
Panelists:<br />
Elisabeth Burgess<br />
<strong>Breast</strong> <strong>Cancer</strong> Aotearoa Coalition<br />
Auckland, NEW ZEALAND<br />
Michael Gnant, MD<br />
Medical University of Vienna<br />
Vienna, AUSTRIA<br />
Minetta Liu, MD<br />
Mayo Clinic<br />
Rochester, MN<br />
Eric P. Winer, MD<br />
Dana-Farber <strong>Cancer</strong> Institute<br />
Boston, MA<br />
Richard Zellars, MD<br />
Johns Hopkins University School of Medicine<br />
Baltimore, MD<br />
12:30 pm–1:35 pm<br />
Basic Science Forum<br />
Ballroom B<br />
Epigenetics in <strong>Breast</strong> <strong>Cancer</strong><br />
Moderator: Nancy E. Davidson, MD<br />
University of Pittsburgh <strong>Cancer</strong> Institute,<br />
Pittsburgh, PA<br />
Estrogen-mediated epigenetic gene silencing in luminal<br />
cancers<br />
Tim Hui-Ming Huang, PhD<br />
UT Health Science Center <strong>San</strong> <strong>Antonio</strong><br />
<strong>San</strong> <strong>Antonio</strong>, TX<br />
translational implications of epigenetic gene regulation<br />
Stephen B. Baylin, MD<br />
Johns Hopkins University School of Medicine<br />
Baltimore, MD<br />
1:45 pm–3:15 pm<br />
MINI-SYMPOSIUM 2<br />
Exhibit Hall D<br />
<strong>Breast</strong> Density: Mechanisms and Clinical Implications<br />
Moderator: Melissa Bondy, PhD<br />
Baylor College of Medicine<br />
Houston, TX<br />
Genetics and epidemiology<br />
Celine M. Vachon, PhD<br />
Mayo Clinic College of Medicine<br />
Rochester, MN<br />
www.aacrjournals.org<br />
31s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Clinical<br />
Norman Boyd, MD, DSC<br />
Ontario <strong>Cancer</strong> Institute<br />
Toronto, CANADA<br />
Biological basis of breast density and cancer risk<br />
Thea D. Tlsty, PhD<br />
University of California, <strong>San</strong> Francisco<br />
<strong>San</strong> Francisco, CA<br />
3:15 pm–5:00 pm<br />
GENERAL SESSION 4<br />
Exhibit Hall D<br />
Moderator: Matthew Goetz, MD<br />
Mayo Clinic College of Medicine<br />
Rochester, MN<br />
3:15 S4-1. The UK START (Standardisation of <strong>Breast</strong> Radiotherapy)<br />
Trials: 10-Year follow-up results<br />
Haviland JS, Agrawal R, Aird E, Barrett J, Barrett-Lee P, Brown J, Dewar J,<br />
Dobbs J, Hopwood P, Hoskin P, Lawton P, Magee B, Mills J, Morgan D,<br />
Owen R, Simmons S, Sydenham M, Venables K, Bliss JM, Yarnold JR, on<br />
behalf of the START Trialists. The Institute of <strong>Cancer</strong> Research, Sutton,<br />
United Kingdom; Shrewsbury and Telford Hospital NHS Trust, United<br />
Kingdom; Mount Vernon Hospital, Northwood, United Kingdom; Royal<br />
Berkshire NHS Foundation Trust, Reading, United Kingdom; Velindre<br />
Hospital NHS Trust, Cardiff, United Kingdom; previously University of<br />
Bristol, now Eli Lilly & Company, United Kingdom; formerly Ninewells<br />
Hospital, Dundee, United Kingdom; formerly Guys and St Thomas’<br />
NHS Trust, London, United Kingdom; Nottingham City Hospital, United<br />
Kingdom; formerly The Christie NHS Foundation Trust, Manchester,<br />
United Kingdom; formerly Nottingham University Hospital NHS Trust,<br />
United Kingdom; formerly Cheltenham General Hospital, United<br />
Kingdom; The Institute of <strong>Cancer</strong> Research and Royal Marsden NHS<br />
Foundation Trust, Sutton, United Kingdom.<br />
3:30 S4-2. Targeted intraoperative radiotherapy for early breast cancer:<br />
TARGIT-A trial- updated analysis of local recurrence and first<br />
analysis of survival<br />
Vaidya JS, Wenz F, Bulsara M, Joseph D, Tobias JS, Keshtgar M, Flyger<br />
H, Massarut S, Alvarado M, Saunders C, Eiermann W, Metaxas M,<br />
Sperk E, Sutterlin M, Brown D, Esserman L, Roncadin M, Thompson<br />
A, Dewar JA, Holtveg H, Pigorsch S, Falzon M, Harris E, Matthews A,<br />
Brew-Graves C, Potyka I, Corica T, Williams NR, Baum M. University<br />
College London, London, United Kingdom; University Medical Centre<br />
Mannheim, University of Heidelberg, Heidelberg, Germany; University of<br />
Notre Dame, Fremantle, Australia; Sir Charles Gairdner Hospital, Perth,<br />
Australia; University College Hospital, London, United Kingdom; Royal<br />
Free Hospital, London, United Kingdom; University of Copenhagen,<br />
Copenhagen, Denmark; Centro di Riferimento Oncologia, Aviano, Italy;<br />
University of California, <strong>San</strong> Francisco, CA; University of Western Australia,<br />
Perth, WA, Australia; Red Cross Hospital, Munich, Germany; Ninewells<br />
Hospital, Dundee, United Kingdom; Technical University of Munich,<br />
Munich, Germany; University College London Hospitals, London, United<br />
Kingdom; National <strong>Cancer</strong> Research Institute and Independent <strong>Cancer</strong><br />
Patient’s, Voice, United Kingdom; Moffit <strong>Cancer</strong> Centre , Tampa, FL.<br />
3:45 S4-3. The EndoPredict score identifies late distant metastases in<br />
ER+/HER2- breast cancer patients<br />
Dubsky P, Brase JC, Fisch K, Jakesz R, Singer CF, Greil R, Dietze O, Weber<br />
KE, Petry C, Kronenwett R, Rudas M, Knauer M, Gnant M, Filipits M.<br />
Medical University Vienna, Austria; Sividon Diagnostics GmbH, Cologne,<br />
Germany; Paracelsus Private Medical University, Salzburg, Austria; Sisters<br />
of Charity Hospital, Linz, Austria.<br />
4:00 S4-4. Independent validation of Genomic Grade in the<br />
BIG 1-98 study<br />
Sotiriou C, Ignatiadis M, Desmedt C, Azim Jr. HA, Veys I, Larsimont D,<br />
Lyng M, Viale G, Leyland-Jones B, Ditzel H, Giobbie-Hurder A, Regan M,<br />
Piccart M, Michiels S. Universite Libre de Bruxelles; Institut Jules Bordet;<br />
University of Southern Denmark; University of Milan; Edith <strong>San</strong>ford<br />
Research; Harvard Medical School.<br />
4:15 S4-5. Ki67 levels in pretherapeutic core biopsies as predictive and<br />
prognostic parameters in the neoadjuvant GeparTrio trial<br />
Denkert C. Blohmer JU, Müller BM, Eidtmann H, Eiermann W, Gerber<br />
B, Tesch H, Hilfrich J, Huober J, Fehm T, Barinoff J, Jackisch C, Prinzler<br />
J, Rüdiger T, Budczies J, Erbstößer E, Loibl S, von Minckwitz G. Charite<br />
University Hospital, Berlin, Germany; <strong>San</strong>kt Gertrauden Krankenhaus,<br />
Berlin, Germany; Christian-Albrechts Universität zu Kiel, Kiel, Germany;<br />
Rotkreuzklinikum, München, Germany; Universitätsfrauenklinik Rostock,<br />
Germany; Bethanien Krankenhaus, Frankfurt, Germany; Eilenriede Klinik,<br />
Hannover, Germany; University of Düsseldorf, Germany; Universitäts<br />
Frauenklinik, Tübingen, Germany; Kliniken Essen Mitte, Essen, Germany;<br />
Klinikum Offenbach, Offenbach, Germany; Klinikum Karlsruhe, Karlsruhe,<br />
Germany; Klinikum St. Salvator, Halberstadt, Germany; German <strong>Breast</strong><br />
Group, Neu-Isenburg, Germany.<br />
4:30 S4-6. An international Ki67 reproducibility study<br />
Nielsen TO, Polley M-YC, Leung SCY, Mastropasqua MG, Zabaglo LA,<br />
Bartlett JMS, Viale G, McShane LM, Hayes DF, Dowsett M, on behalf of<br />
the International Ki67 in <strong>Breast</strong> <strong>Cancer</strong> Working Group of the BIG-NABCG<br />
collaboration. University of British Columbia, Vancouver, BC, Canada;<br />
National <strong>Cancer</strong> Institute, Bethesda, MD; European Institute of Oncology,<br />
Milan, Italy; The Institute of <strong>Cancer</strong> Research, London, United Kingdom;<br />
Ontario Institute for <strong>Cancer</strong> Research, Toronto, ON, Canada; University of<br />
Michigan Comprehensive <strong>Cancer</strong> Center, Ann Arbor, MI; Royal Marsden<br />
Hospital, London, United Kingdom; <strong>Breast</strong> International Group-North<br />
American <strong>Breast</strong> <strong>Cancer</strong> Group Collaboration.<br />
4:45 S4-7. Discussion<br />
W. Fraser Symmans, MD, MD Anderson <strong>Cancer</strong> Center, Houston, TX<br />
5:00 pm–7:00 pm<br />
Poster Discussion 5: Clinical Sequencing<br />
Ballroom A<br />
Viewing 5:00 pm<br />
Discussion 5:15 pm<br />
Charles Perou, PhD, Chair<br />
University of North Carolina<br />
Chapel Hill, NC<br />
Katherine Hoadley, PhD, Discussant<br />
University of North Carolina<br />
Chapel Hill, NC<br />
and<br />
Christine Desmedt, PhD, Discussant<br />
Jules Bordet Institute<br />
Bruxelles, BELGIUM<br />
PD05-01 Next generation genomic sequencing (NGS) identifies<br />
molecular targets in inflammatory breast cancer (IBC)<br />
Cristofanilli M, Alpaugh KR, Ross J, Binghman C, Wu H, Stephens<br />
P, Lipson D, Palmer G. Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA;<br />
Foundation Medicine, Cambridge, MA.<br />
PD05-02 Novel mutations in lobular carcinoma in situ (LCIS) as<br />
uncovered by targeted parallel sequencing<br />
De Brot M, Andrade VP, Morrogh M, Berger MF, Won HH, Koslow<br />
Mautner S, Qin L-X, Giri DD, Olvera N, Sakr RA, King TA. Memorial<br />
Sloan-Kettering <strong>Cancer</strong> Center, New York, NY.<br />
PD05-03 What is the appropriate sample (s) on which to perform<br />
sequencing for mutational analysis to guide the selection of<br />
targeted therapy?<br />
Alpaugh RK, Bingham C, Fittipaldi P, Banzi M, Palmer G, Cristofanilli<br />
M. Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA; Silicon Biosystems,<br />
Spa, Bologna, Italy; Foundation Medicine, Cambridge, MA.<br />
PD05-04 Targeted resequencing in oncogenetics : developing a new<br />
approach for molecular diagnostics<br />
Sevenet N, Lafon D, Dupiot-Chiron J, Hubert C, Jones N, Debled M,<br />
Tunon de Lara C, Longy M, Bonnet F. Institut Bergonie, Bordeaux,<br />
France; Centre de Génomique Foncionnelle de Bordeaux, Bordeaux,<br />
France; Institut Bergonie & Universite Bordeaux Segalen, Bordeaux,<br />
France.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 32s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
PD05-05 RNA-seq identifies unique transcriptomic changes after brief<br />
exposure to preoperative nab-paclitaxel (N), bevacizumab<br />
(B) or trastuzumab (T) and reveals down-regulation of TGF-β<br />
signaling associated with response to bevacizumab<br />
Varadan V, Kamalakaran S, Janevski A, Banerjee N, Lezon-Geyda<br />
K, Miskimen K, Bossuyt V, Abu-Khalaf M, Sikov W, Dimitrova N,<br />
Harris LN. Philips Research North America, Briarcliff Manor, NY; Yale<br />
University School of Medicine, New Haven, CT; Yale Comprehensive<br />
<strong>Cancer</strong> Center, New Haven, CT; Yale University School of Medicine,<br />
Yale Comprehensive <strong>Cancer</strong> Center, New Haven, CT; Warren Alpert<br />
Medical School of Brown University, New Haven, CT; Seidman <strong>Cancer</strong><br />
Center, Cleveland, OH.<br />
PD05-06 Next-generation RNA-sequencing of triple negative breast<br />
cancer compared to donated microdissected normal<br />
epithelium and adjacent normal tissues<br />
Radovich M, Atale R, Clare SE, Sledge GW, Schneider BP. Indiana<br />
University School of Medicine, Indianapolis, IN.<br />
PD05-07 Detection of fusion transcripts among 100 breast cancer<br />
samples by next generation sequencing<br />
Kim J, Han W, Moon H-G, Ahn SK, In Y-H, Kim S, Lee H-S, Lee JW,<br />
Kim JY, Kim T, Kim MK, Noh D-Y. Seoul National University Hospital,<br />
Seoul, Korea; <strong>Cancer</strong> Research institute, Seoul National University,<br />
Seoul, Korea; i-Pharm (Information Center for Bio-pharmacological<br />
Network) IBBI (Integrated Bioscience and Biotechnology Institute)<br />
Advanced Institute of Convergence Technology, Seoul National<br />
University, Seoul, Korea; Seoul National University, Seoul, Korea;<br />
Macrogen Inc., Seoul, Korea.<br />
PD05-08 Genomic characterisation of invasive breast cancers with<br />
heterogeneous HER2 gene amplification<br />
Ng CKY, Gauthier A, Mackay A, Lambros MBK, Rodrigues DN, Arnoud<br />
L, Lacroix-Triki M, Penault-Llorca F, Baranzelli MC, Sastre-Garau<br />
X, Lord CJ, Zvelebil M, Mitsopoulos C, Ashworth A, Natrajan R,<br />
Weigelt B, Delattre O, Cottu P, Reis-Filho JS, Vincent-Salomon A. The<br />
Breakthrough <strong>Breast</strong> <strong>Cancer</strong> Research Centre, The Institute of <strong>Cancer</strong><br />
Research, London, United Kingdom; Institut Curie, Paris, France; CRB<br />
Ferdinand Cabanne, Centre Georges François Leclerc, Dijon, France;<br />
Institut Claudius Regaud, Toulouse, France; Centre Jean Perrin,<br />
Clermont-Ferrand, France; Centre Oscar Lambret, Lille, France.<br />
PD05-09 Whole-genome progression of breast cancer from early<br />
neoplasia to invasive carcinoma<br />
West RB, Kashef-Haghighi D, Newburger D, Weng Z, Brunner A, Salari<br />
R, Guo X, Troxell M, Zhu S, Varma S, Sidow A, Batzoglou S. Stanford<br />
University, Stanford, CA; Oregon Health & Science University,<br />
Portland, OR.<br />
5:00 pm–7:00 pm<br />
Poster Discussion 6: Ki67<br />
Ballroom B<br />
Viewing 5:00 pm<br />
Discussion 5:15 pm<br />
Peter Ravdin, MD, Chair<br />
UT Health Science Center<br />
<strong>San</strong> <strong>Antonio</strong>, TX<br />
Rinat Yerushalmi, MD, Discussant<br />
Davidoff Center<br />
Petach Tikva, ISRAEL<br />
and<br />
Allen M. Gown, MD, Discussant<br />
PhenoPath Labs PLLC<br />
Seattle, WA<br />
PD06-01 Automated computational Ki67 scoring in the GeparTrio<br />
breast cancer study cohort<br />
Klauschen F, Wienert S, Blohmer J-U, Mueller BM, Eiermann W,<br />
Gerber B, Tesch H, Hilfrich J, Huober J, Fehm T, Barinoff J, Jackisch<br />
C, Erbstoesser E, Loibl S, Denkert C, von Minckwitz G. Charite<br />
Universitaetsmedizin Berlin, Berlin, Germany; <strong>San</strong>kt Getrauden<br />
Hospital, Berlin, Germany; University of Munich, Munich, Germany;<br />
Klinikum Suedstadt Rostock, Rostock, Germany; Onkologisches<br />
Zentrum am Bethanien-Kankenhaus, Frankfurt, Germany; Ellenriede<br />
Hospital, Hannover, Germany; University Duesseldorf, Germany;<br />
University of Tuebingen, Germany; Kliniken Essen Mitte, Essen,<br />
Germany; Kliniken Offenbach, Offenbach, Germany; Salvator Hospital,<br />
Germany; German <strong>Breast</strong> Group, Neu-Isenburg, Germany.<br />
PD06-02 Standardized assessment of Ki-67 using virtual slides and<br />
automated analyzer for breast cancer patients: Comparison of<br />
automated and central/local pathology assessment<br />
Mizuno Y, Yamada J, Abe H, Natori T, Sato K. Tokyo-West Tokushukai<br />
Hospital, Tokyo, Japan; SRL, Inc., Tokyo, Japan.<br />
PD06-03 Development of a highly reproducible clinical test for Ki67<br />
using AQUA technology<br />
Murphy DA, Pacia E, Beruti S, Lamoureux J, Dabbas B, Diver J,<br />
Christiansen J. Genoptix Medical Laboratory, Carlsbad, CA.<br />
PD06-04 St. Gallen 2011 clinicopathological subtyping of breast cancer:<br />
impact of different proliferation assessment methods<br />
Focke CM, Gläser D, Finsterbusch K, Decker T. Bonhoeffer Medical<br />
Center, Neubrandenburg, Germany.<br />
PD06-05 St. Gallen 2011 clinico-pathological subtypes of breast cancer:<br />
concordance of core biopsies and related surgical specimens<br />
Decker T, Focke CM. Bonhoeffer Medical Center, Neubrandenburg,<br />
Germany.<br />
PD06-06 Relationship between molecular subtype and change in Ki-67<br />
in the placebo arms of window of opportunity trials<br />
Pruneri G, Gandini S, Guerrieri-Gonzaga A, Serrano D, Cazzaniga<br />
M, Lazzeroni M, Puntoni M, Toesca A, Caldarella P, Johansson H,<br />
Bonanni B, DeCensi A. European Institute of Oncology, Milan,<br />
Italy; Galliera Hospital, Genoa, Italy; University of Milan, School of<br />
Medicine, Milan, Italy.<br />
PD06-07 Evaluation of an optimal cut-off point for the Ki-67 index<br />
as a prognostic factor in primary breast cancer<br />
Tashima R, Nishimur R. Kumamoto Municipal Hospital,<br />
Kumamoto, Japan.<br />
PD06-08 Strong prognostic concordance between Ki67 and binary, but<br />
not multi-level gene expression signatures<br />
Tobin NP, Lindström LS, Carlson JW, Bergh J, Wennmalm K.<br />
Karolinska Institutet and University Hospital, Stockholm, Sweden.<br />
5:00 pm–7:00 pm<br />
POSTER SESSION 3 & RECEPTION<br />
Exhibit Halls A–B<br />
Detection/Diagnosis: <strong>Breast</strong> Imaging - Mammography<br />
P3-01-01 Insulin, Insulin-like Growth Factor-1 and cycling estrogen<br />
predict premenopausal mammographic density<br />
Frydenberg H, Flote VG, Iversen A, Finstad SE, Furberg A-S, Fagerland<br />
M, Wist EA, Schlichting E, Ellison PT, McTiernan A, Ursin G, Thune<br />
I. Oslo University Hospital, Oslo, Norway; University of Tromsø,<br />
Norway; Harvard University, Cambridge, MA; Fred Hutchinson <strong>Cancer</strong><br />
Research Center, Seattle, WA; The Norwegian <strong>Cancer</strong> Registry,<br />
Oslo, Norway.<br />
P3-01-02 Correlation of Mammographic breast density and tumor<br />
characteristics in Korean breast cancer patients<br />
Cho JY, Ahn SH, Lee JW, Yu JH, Koh BS, Kim HJ, Lee JW, Son BH,<br />
Gong G-y, Kim HH. College of Medicine, University of Ulsan, Asan<br />
Medical Center, Seoul, Republic of Korea.<br />
www.aacrjournals.org<br />
33s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P3-01-03 <strong>Breast</strong> density profile in a prospective large breast cancer<br />
screening program in South Brazil<br />
Caleffi M, Zignani J, Clarissa A, Ademar BJ, Ribeiro R, Dakir DF. Núcleo<br />
Mama Porto Alegre, Hospital Moinhos de Vento, Porto Alegre,<br />
RS, Brazil.<br />
P3-01-04 Surgical management of mammographic microcalcification is<br />
improved by full field digital mammography (FFDM)<br />
Bundred SM, Zhou J, Hurley E, Wilson M, Morris J, Bundred NJ.<br />
University Hospital of South Manchester; University of Manchester.<br />
P3-01-05 The Role of Mammographic Calcification in the Neo-adjuvant<br />
Therapy of <strong>Breast</strong> <strong>Cancer</strong> Imaging Evaluation<br />
Li JJ, Chen CM, Di GH, Wu J, Lu JS, Shao Z-M. Shanghai <strong>Cancer</strong><br />
Center and <strong>Cancer</strong> Institute, Shanghai, China.<br />
P3-01-06 Ultrasound as single mode of imaging may miss significant<br />
pathology in symptomatic women aged 35-39<br />
Baker EL, Masudi T, Waterworth A. Calderdale and Huddersfield NHS<br />
Foundation Trust, Huddersfield, West Yorkshire, United Kingdom.<br />
P3-01-07 Estimated risk of radiation-induced breast cancer from<br />
mammographic screening<br />
Freitas-Junior R, Correa RS, Peixoto J-E, Ferreira RS, Tanaka RMN.<br />
Federal University of Goias, Goiania, Goias, Brazil; Comissão Nacional<br />
de Energia Nuclear, Goiania, Goias, Brazil; National <strong>Cancer</strong> Institute<br />
of Brazil, Rio de Janeiro, RJ, Brazil; Superintendência de Vigilância em<br />
Saúde do Estado de Goias, Goiania, Goias, Brazil.<br />
P3-01-08 Mammographic density and estrogen receptor α gene<br />
polymorphism in Javanese ethnic women<br />
Choridah L, Aryandono T, Faisal A, Sadewa AH, Purnomosari D.<br />
Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, DIY,<br />
Indonesia; Faculty of Medicine, Universitas Gadjah Mada.<br />
Detection/Diagnosis: Screening<br />
P3-02-01 Mammographic Screening: Good Prognosis Tumor Biology in<br />
Screen-detected <strong>Breast</strong> <strong>Cancer</strong>s<br />
Drukker CA, Schmidt MK, Rutgers EJT, Cardoso F, Kerlikowske<br />
K, Esserman LJ, Slaets L, Bogaerts J, van’t Veer LJ. Netherlands<br />
<strong>Cancer</strong> Institute-Antoni van Leeuwenhoek Hospital, Amsterdam,<br />
Netherlands; Champalimaud <strong>Cancer</strong> Centre, Lisbon, Portugal;<br />
University of California, <strong>San</strong> Francisco; EORTC, Brussels, Belgium;<br />
Agendia NV, Amsterdam, Netherlands.<br />
P3-02-02 Use of contrast-enhanced computed tomography in clinical<br />
staging of asymptomatic breast cancer patients to detect<br />
asymptomatic distant metastases<br />
Tanaka S, Sato N, Fujioka H, Takahashi Y, Kimura K, Iwamoto M,<br />
Uchiyama K. Osaka Medical College, Takatsuki City, Osaka, Japan.<br />
P3-02-03 Increased risk of breast cancer in women with falsepositive<br />
screening test: can it be entirely explained by<br />
misclassification?<br />
von Euler-Chelpin M, Kuchiki M, Vejborg I. University of Copenhagen,<br />
Denmark; University Hospital Copenhagen, Denmark.<br />
P3-02-04 Screen detected HER2 positive breast cancer within the<br />
West of London <strong>Breast</strong> Screening population:Incidence,<br />
Management and Outcome<br />
O’Cathail S, White A, Brindley JH, Hadjiminas D, Xynos Y, Cleator<br />
S, Hogben K, Palmieri C. Imperial College Healthcare NHS Trust,<br />
London, United Kingdom.<br />
P3-02-05 Subtypes of screen-detected invasive breast cancer and<br />
symptomatic invasive breast cancer and their impact on<br />
survival<br />
Kobayashi N, Hikichi M, Miyajima S, Utsumi T. Fujita Health University,<br />
Toyoake, Aichi, Japan.<br />
P3-02-06<br />
P3-02-07<br />
P3-02-08<br />
P3-02-09<br />
P3-02-10<br />
P3-02-11<br />
P3-02-12<br />
P3-02-13<br />
Survival impact of early detection of recurrence after surgery<br />
in early breast cancer patients<br />
Hojo T, Tamura K, Masuda N, Inoue K, Kinoshita T, Fujisawa T, Hara<br />
F, Saji S, Asaga S, Anan K, Yamamoto N, Wada N, Takahashi M,<br />
Nakagami K, Kuroi K, Iwata H. National <strong>Cancer</strong> Center Hospital,<br />
Tokyo, Japan; Osaka National Hospital, Osaka, Japan; Saitama <strong>Cancer</strong><br />
Center, Saitama, Japan; Gunma Prefectural <strong>Cancer</strong> Center, Gunma,<br />
Japan; Shikoku <strong>Cancer</strong> Center, Shikoku, Japan; Kyoto University<br />
Graduate School of Medicine, Kyoto, Japan; Kitakyushu Municipal<br />
Medical Center, Kitakyushu, Japan; Chiba <strong>Cancer</strong> Center, Chiba,<br />
Japan; National <strong>Cancer</strong> Center Hospital East, Chiba, Japan; Hokkaido<br />
<strong>Cancer</strong> Center, Hokkaido, Japan; Shizuoka General Hospital, Shizuoka,<br />
Japan; Tokyo Metropolitan <strong>Cancer</strong> and Infectious diseases Center<br />
Komagome Hospital, Tokyo, Japan; Aichi <strong>Cancer</strong> Center Hospital,<br />
Nagoya, Aichi, Japan.<br />
Rates of <strong>Cancer</strong> Detection and Abnormal Results among<br />
Clients Recruited for Mammography through Outreach and<br />
Education Supported by the Avon <strong>Breast</strong> Health Outreach<br />
Program<br />
Hurlbert M, Rose J, Opdyke KM, Gates-Ferris K. Cicatelli Associates<br />
Inc. (CAI), New York, NY; Avon Foundation for Women, New York, NY.<br />
Is repetition of the contralateral mammogram of patients<br />
referred from breast cancer screening for unilateral findings<br />
necessary?<br />
Castro C, Schipper R-J, van Roozendaal L, van Goethem M, Lobbes<br />
M, Smidt M. Maastricht University Medical Center, Maastricht,<br />
Netherlands; Antwerp University Hospital, Antwerp, Belgium.<br />
Cost-effectiveness of screening with additional MRI for<br />
women with familial risk for breast cancer without a genetic<br />
predisposition<br />
Saadatmand S, Heijnsdijk EA, Rutgers EJ, Hoogerbrugge N,<br />
Oosterwijk JC, Tollenaar RA, Hooning M, Obdeijn I-M, de Koning<br />
HJ, Tilanus-Linthorst MM. Erasmus Medical Center, Rotterdam,<br />
Netherlands; The Netherlands <strong>Cancer</strong> Institute, Antoni van<br />
Leeuwenhoek Hospital, Amsterdam, Netherlands; Radboud<br />
University Medical Center, Nijmegen, Netherlands; University Medical<br />
Center Groningen, Netherlands; Leiden University Medical Center,<br />
Leiden, Netherlands; Erasmus Medical Center, Netherlands.<br />
Implementation and uptake of a provincial, population-based,<br />
organized breast screening program for high risk women in<br />
Ontario: The Ontario breast screening program (OBSP) high<br />
risk program<br />
Eisen A, Carroll J, Chiarelli AM, Horgan M, Meschino W, Rabeneck L,<br />
Shumak R, Warner E. Sunnybrook Health Sciences Centre, Toronto,<br />
ON, Canada; University of Toronto, ON, Canada; Mount Sinai Hospital,<br />
Toronto, ON, Canada; <strong>Cancer</strong> Care Ontario, Toronto, ON, Canada;<br />
North York General Hospital, Toronto, ON, Canada.<br />
Screening Magnetic Resonance Imaging (MRI) of the breast<br />
in women at increased lifetime risk for breast cancer: A<br />
retrospective single institution study<br />
Ehsani S, Strigel R, Pettke E, Wilke L, Szalkucki L, Tevaarwerk AJ,<br />
Wisinski KB. University of Wisconsin Carbone <strong>Cancer</strong> Center,<br />
Madison, WI.<br />
The Cost of Mammography Screening in the United States by<br />
Screening Policy<br />
Thorsen CM, Eklund M, Ozanne EM, Esserman LJ. University of<br />
California, <strong>San</strong> Francisco, CA; Karolinska Institute, Stockholm,<br />
Sweden.<br />
Analysis of infrastructure for mammography screening in the<br />
State of Goias, Brazil, 2010<br />
Freitas-Junior R, Correa RS, Peixoto J-E, Rodrigues DCN, Rahal RMS.<br />
Federal University of Goias, Goiania, Goias, Brazil; Comissão Nacional<br />
de Energia Nuclear, Goiania, Goias, Brazil; National <strong>Cancer</strong> Institute of<br />
Brazil, Rio de Janeiro, RJ, Brazil.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 34s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P3-02-14 Integrated program for breast cancer control: Partial<br />
presentation of the results obtained in the first 24 months<br />
of operation<br />
Blanco EC, Borges MM, Pinotti M, Gennari MB, Ribeiro IM,<br />
Nascimento CCP, <strong>San</strong>tos LFG, Sahium RC. Oswaldo Cruz Alemão<br />
Hospital, São Paulo, Brazil.<br />
Detection/Diagnosis: Radiology - Tumor Monitoring<br />
P3-03-01 3D mapping of total choline in human breast cancer using<br />
high-speed MR spectroscopic imaging at 3T: initial experience<br />
during neoadjuvant therapy<br />
Posse S, Zhang T, Royce M, Dayao Z, Lopez S, Sillerud L, Casey L,<br />
Eberhardt S, Lomo L, Rajput A, Russell J, Lee S-j, Bolan P. University<br />
of New Mexico School of Medicine and UNM <strong>Cancer</strong> Center,<br />
Albuquerque, NM; New Mexico <strong>Cancer</strong> Center, Albuquerque, NM;<br />
University of Minnesota, Minneapolis, MN.<br />
P3-03-02 The metastatic rate of IMLN, when IMLN metastasis is<br />
suspected with PET CT<br />
Lee J-H, Son G-T, Choi J-E, Kang S-H, Lee S-J. Yeungnam University<br />
College of Medicine, Daegu, Republic of Korea.<br />
P3-03-03 A tri-modality imaging assessment algorithm to evaluate<br />
neoadjuvant therapy response in patients with operable<br />
breast cancer<br />
Umphrey H, Bernreuter W, Bland K, Carpenter J, Falkson C, Forero A,<br />
Keene K, Krontiras H, Meredith R, Urist M, De Los <strong>San</strong>tos J. University<br />
of Alabama at Birmingham, AL.<br />
Tumor Cell and Molecular Biology: Molecular Profiles<br />
P3-04-01 Protein pathway activation mapping of the I-SPY 1 biopsy<br />
specimens identifies new network focused drug targets for<br />
patients with triple negative tumors<br />
Wulfkuhle JD, Wolf D, Gallagher RI, Yau C, Calvert V, Espina V, Illi J,<br />
Wu Q, Boe M, Yan Y, I-SPY TRIAL-1 Investigators, Liotta LA, van’t Veer<br />
L, Esserman L, Petricoin EF. George Mason University, Manassas, VA;<br />
University of California, <strong>San</strong> Francisco, CA; Genentech, South <strong>San</strong><br />
Francisco, CA.<br />
P3-04-02 Protein pathway activation mapping of I-SPY 1 biopsy<br />
specimens identifies new network focused drug targets for<br />
patients with HR+/HER2- tumors<br />
Wulfkuhle JD, Yau C, Gallagher RI, Wolf D, Calvert V, Espina V, Illi J,<br />
Wu Q, Boe M, Yan Y, I-SPY TRIAL-1 Investigators, Liotta LA, van’t Veer<br />
L, Esserman L, Petricoin EF. George Mason University, Manassas, VA;<br />
University of California, <strong>San</strong> Francisco, CA; Genentech, South <strong>San</strong><br />
Francisco, CA.<br />
P3-04-03 A seven-gene profile predicting benefit of postmastectomy<br />
radiotherapy independently of nodal status in high risk breast<br />
cancer<br />
Tramm T, Mohammed H, Myhre S, Alsner J, Børresen-Dale A-L,<br />
Sørlie T, Frigessi A, Overgaard J. Aarhus University Hospital, Aarhus,<br />
Denmark; Oslo University Hospital, Radiumhospitalet, Oslo, Norway;<br />
University Oslo, Norway.<br />
P3-04-04 Identification of a ‘BRCAness’ signature in triple negative<br />
breast cancer by Comparative Genomic Hybridization<br />
Toffoli S, Bar I, Abdulsater F, Delrée P, Hilbert P, Cavallin F, Moreau F,<br />
Clark J, Lacroix-Triki M, Campone M, Martin A-L, Roché H, Machiels<br />
J-P, Carrasco J, Canon J-L. Institute of Pathology and Genetics,<br />
Gosselies, Belgium; MDxHealth, Liège, Belgium; Institut Claudius<br />
Regaud, Toulouse, France; Institut de Cancérologie de l’Ouest-René<br />
Gauducheau, Saint-Herblain - Nantes, France; UNICANCER, Paris,<br />
France; Cliniques Universitaires Saint-Luc, Brussels, Belgium; Grand<br />
Hôpital de Charleroi (GHdC), Charleroi, Belgium.<br />
P3-04-05 Kinomic and phospho-proteomic analysis of breast cancer<br />
stem-like cells<br />
Leth-Larsen R, Christensen AG, Ehmsen S, Moeller M, Palmisano<br />
G, Larsen MR, Ditzel HJ. University of Southern Denmark, Odense,<br />
Denmark; Odense University Hospital, Odense, Denmark.<br />
P3-04-06 Higher gene expression of CSPG4 in the basal-like subtype of<br />
invasive breast cancer and its negative association with lymph<br />
node metastasis<br />
Luo C, Iida J, Chen Y, Dorchak J, Kovatich AJ, Mural RJ, Hu H, Shriver<br />
CD. Windber Research Institute, Windber, PA; Walter Reed National<br />
Military Medical Center, Bethesda, MD; MDR, Global Systems LLC,<br />
Windber, PA.<br />
P3-04-07 Comparison of breast tumors with HER2 amplification and<br />
polysomy 17<br />
Field LA, Deyarmin B, Ellsworth RE, Shriver CD. Windber Research<br />
Institute, Windber, PA; Henry M. Jackson Foundation for the<br />
Advancement of Military Medicine, Windber, PA; Walter Reed<br />
National Military Medical Center, Bethesda, MD.<br />
P3-04-08 Expression of hormone-responsive genes in benign breast<br />
tissue varies with menstrual cycle phase and menopausal<br />
status<br />
Hu H, Wang J, Lee O, Shidfar A, Iyer S, Ivancic D, Chatterton RT,<br />
Stearns V, Sukumar S, Khan SA. Northwestern University, Chicago, IL;<br />
Johns Hopkins University School of Medicine.<br />
P3-04-09 Withdrawn<br />
P3-04-10 Comparison between RNA-Seq and Affymetrix gene<br />
expression data<br />
Fumagalli D, Haibe-Kains B, Michiels S, Brown DN, Gacquer D, Majjaj<br />
S, Salgado R, Larsimont D, Detour V, Piccart M, Sotiriou C, Desmedt<br />
C. Institut Jules Bordet, Brussels, Belgium; Institut de Recherches<br />
Cliniques de Montréal, Montréal, QC, Canada; Université Libre de<br />
Bruxelles, Campus Erasme, Brussels, Belgium.<br />
P3-04-11 Systemic treatment decision making for patients with stage I<br />
and II, hormone receptor positive, her2/neu negative breast<br />
cancer<br />
Zhu X, Graham N, Paquet L, Dent S, Song X. University of Ottawa, ON,<br />
Canada; The Ottawa Hospital <strong>Cancer</strong> Centre, Ottawa, ON, Canada;<br />
Carleton University, Ottawa, ON, Canada.<br />
P3-04-12 <strong>Breast</strong>Mark: An integrated approach to mining publically<br />
available Transcriptomic Datasets relating to <strong>Breast</strong> <strong>Cancer</strong><br />
Outcome<br />
Madden S, Gaule P, Clarke C, Aherne ST, O’Donovan N, Clynes M,<br />
Crown J, Gallagher WM. Molecular Therapeutics for <strong>Cancer</strong> Ireland,<br />
National Institute for Cellular Biotechnology, Dublin City University,<br />
Dublin 9, Ireland; University College Dublin, Dublin 9, Ireland.<br />
Tumor Cell and Molecular Biology: Tumor Heterogeneity/Molecular<br />
Subclassification<br />
P3-05-01 Molecular subtyping improves stratification of patients into<br />
diagnostically more meaningful risk groups<br />
Cristofanilli M, Turk M, Kaul K, Weaver J, Wesseling J, Stork-Sloots L,<br />
de Snoo F, Yao K. Fox Chase <strong>Cancer</strong> Center; NorthShore University<br />
HealthSystem; Netherlands <strong>Cancer</strong> Institute; Agendia NV.<br />
P3-05-02 Pathological assessment of discordant cases for molecular<br />
(BluePrint and MammaPrint) versus clinical subtypes for<br />
breast cancer among 621 patients from the EORTC 10041/BIG<br />
3-04 (MINDACT) trial<br />
Viale G, Slaets L, de Snoo F, van’t Veer L, Rutgers E, Piccart M,<br />
Bogaerts J, van den Akker J, Stork-Sloots L, Engelen K, Russo L,<br />
Dell’Orto P, Cardoso F. European Institute of Oncology; European<br />
Organisation for Research and Treatment of <strong>Cancer</strong>; Agendia NV;<br />
Netherlands <strong>Cancer</strong> Institute; Jules Bordet Institute; Champalimaud<br />
<strong>Cancer</strong> Center.<br />
www.aacrjournals.org<br />
35s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P3-05-03<br />
P3-05-04<br />
P3-05-05<br />
P3-05-06<br />
P3-05-07<br />
P3-05-08<br />
P3-05-09<br />
Characterization of PIK3CA mutations in lobular breast cancer<br />
Desmedt C, Metzger O, Fumagalli D, Brown D, Singhal S, Vincent<br />
D, Adnet P-Y, Smeets D, Bertucci F, Galant C, Salgado R, Veys I,<br />
Saini K, Pruneri G, Krop I, Winer E, Michiels S, Piccart M, Lambrechts<br />
D, Larsimont D, Viale G, Sotiriou C. Institut Jules Bordet, Brussels,<br />
Belgium; Dana-Farber <strong>Cancer</strong> Institute, Boston; Vesalius Research<br />
Centre, VIB, Leuven, Belgium; Institut Paoli Calmettes, Marseille,<br />
France; Université Catholique de Louvain, Brussels, Belgium;<br />
European Institute of Oncology, University of Milan, Milan, Italy.<br />
Intra-tumor heterogeneity as a predictor of therapy response<br />
in HER2 positive breast cancer<br />
Rye IH, Helland Å, Sætersdal A, Naume B, Almendro V, Polyak K,<br />
Børessen-Dale A-L, Russnes HG. Institute for <strong>Cancer</strong> Research, Oslo,<br />
Norway; Oslo University Hospital, Oslo, Norway; University of Oslo,<br />
Oslo, Norway; Dana-Farber <strong>Cancer</strong> Institute and Harvard Medical<br />
School, Boston, MA; Hospital Clínic, Barcelona, Spain.<br />
HER2 Expression and Gene copy analysis by<br />
Immunofluorescence and Fluorescence in situ Hybridization,<br />
on a Single formalin-fixed paraffin-embedded tissue section<br />
Ha T, Seppo A, Ginty F, Kenny K, Henderson D, Kyshtoobayeva A,<br />
Gerdes M, Larriera A, Liu X, Corwin A, Zingelewicz S, Lazare M, Jun<br />
N, Kyshtoobayeva A, Chow C, Al-Kofahi Y, Hollman D, Bloom K. GE<br />
Global Research, Niskayuna, NY; Clarient Diagnostics Services, Aliso<br />
Viejo, CA.<br />
Automated analysis of Her2 FISH using combined<br />
Immunofluorescence and FISH signals<br />
Seppo A, Al-Kofahi Y, Padfield D, Ha T, Jun N, Kyshtoobayeva A,<br />
Kaanumalle L, Corwin A, Henderson D, Kamath V, McCulloch C,<br />
Hollman D, Bloom KJ. GE Global Research, Niskayuna, NY; Clarient<br />
Diagnostics Services, Aliso Viejo, CA.<br />
Poor prognosis early breast cancer: pathological<br />
characteristics of the Unicancer-PACS08 trial including<br />
patients treated with docetaxel or ixabepilone in adjuvant<br />
setting<br />
Lacroix-Triki M, Delrée P, Filleron T, Penault-Llorca F, Bor C, Mery<br />
E, Maisongrosse V, Génin P, Jacquemier J, Reyre J, Caveriviere P,<br />
Quintyn-Ranty M-L, Escourrou G, Mesleard C, Lemonnier J, Martin<br />
A-L, Campone M. Institut Claudius Regaud, Toulouse, France; Institut<br />
de Pathologie et de Génétique, Gosselies, Belgium; Centre Jean<br />
Perrin, Clermont-Ferrand, France; Centre Francois Baclesse, Caen,<br />
France; Centre Alexis Vautrin, Vandoeuvre les Nancy, France; Institut<br />
Paoli Calmettes, Marseille, France; Laboratoire Anatomie et de<br />
Cytologie des Feuillants, Toulouse, France; CHU Rangueil, Toulouse,<br />
France; R&D Unicancer, Paris, France; ICO Centre René Gauducheau,<br />
Saint Herblain, France.<br />
Analysis of the expression of claudin-3, -4, -7 and E-cadherin<br />
in breast cancer: are they surrogates for the claudin-low<br />
subtype?<br />
Tokes A-M, Szasz AM, Kovács AK, Juhasz E, Nemeth Z, Baranyai Z,<br />
Madaras L, Kulka J. Semmelweis University, Budapest, Hungary;<br />
Uzsoki Memorial Hospital, Budapest, Hungary.<br />
The role of TGF-beta receptor type 3 in breast cancer<br />
progression<br />
Jovanovic B, Ashby WJ, Zijlstra A, Pietenpol JA, Moses HL. Vanderbilt<br />
University, Nashville, TN.<br />
Prognostic and Predictive Factors: Response Predictions - Biomarkers and<br />
Other Factors<br />
P3-06-01 Hotspot mutations in PIK3CA are predictive for treatment<br />
outcome on aromatase inhibitors but not for tamoxifen<br />
Ramirez Ardila DE, Helmijr JC, Lurkin I, Look M, Ruigrok-Ritstier K,<br />
Simon I, Van Laere S, Sweep F, Span P, Linn S, Foekens J, Sleijfer<br />
S, Berns EMJJ, Jansen MPHM. Erasmus MC - Daniel den Hoed,<br />
Rotterdam, Zuid Holland, Netherlands; Agendia BV, Amsterdam,<br />
Netherlands; Antwerp University/Oncology Centre, GZA Hospitals<br />
St-Augustinus, Antwerp, Belgium; Radboud University Nijmegen<br />
Medical Center, Nijmegen, Netherlands; Netherlands <strong>Cancer</strong><br />
Institute, Amsterdam, Netherlands.<br />
P3-06-02 Genetic polymorphisms from genome-wide association study<br />
associated with the metabolic and cell proliferation pathways<br />
affect the time to distant metastases of hormone receptorpositive<br />
and Her2-negative early breast cancer<br />
Huang C-S, Kuo S-H, Yang S-Y, Lien H-C, Lin C-H, Lu Y-S, Cheng A-L,<br />
Chang K-J. National Taiwan University Hospital and National Taiwan<br />
University College of Medicine, Taipei, Taiwan; College of Public<br />
Health, National Taiwan University, Taipei, Taiwan.<br />
P3-06-03 Association between PAM50 breast cancer intrinsic subtypes<br />
and effect of gemcitabine in advanced breast cancer patients<br />
Jørgensen CLT, Nielsen TO, Bjerre KD, Liu S, Wallden B, Balslev E,<br />
Nielsen DL, Ejlertsen B. Herlev University Hospital, Herlev, Denmark;<br />
Danish <strong>Breast</strong> <strong>Cancer</strong> Cooperative Group, Copenhagen, Denmark;<br />
University of British Columbia, Vancouver, BC, Canada; NanoString<br />
Technologies, Seattle, WA.<br />
P3-06-04 Role of pMAPkinase, pAKT, p27 & IGF-IR as predictive<br />
markers of response to trastuzumab in patients with HER2-<br />
positive invasive breast cancer treated with neoadjuvant<br />
chemotherapy ± trastuzumab in the REMAGUS02 trial<br />
Mathieu MC, Goubar A, Sigal B, Bertheau P, Guinebretière JM, André<br />
F, Pierga JY, Delaloge S, Giacchetti S, Brain E, Marty M. Institut<br />
Gustave Roussy - INSERM U981, Villejuif, France; Institut Curie, Paris,<br />
France; Hopital Saint-Louis, Paris, France.<br />
P3-06-05 Expression of SPARC in human breast cancer and its predictive<br />
value in the GeparTrio neoadjuvant trial<br />
Untch M, Prinzler J, Fasching P, Müller BM, Gade S, Meinhold-<br />
Heerlein I, Huober J, Karn T, Liedtke C, Loibl S, Müller V, Rack B,<br />
Schem C, Darb-Esfahani S, von Minckwitz G, Denkert C. Helios<br />
Klinikum Berlin-Buch, Germany; Charité Universitätsmedizin<br />
Berlin, Germany; Universitätsklinikum Erlangen, Germany; German<br />
<strong>Breast</strong> Group, Germany; Universitätsklinikum Aachen, Germany;<br />
Universitätsklinikum Düsseldorf, Germany; Universitätsklinikum<br />
Frankfurt am Main, Germany; Universitätsklinikum Münster,<br />
Germany; Universitätsklinikum Hamburg-Eppendorf, Germany;<br />
Universitätsklinikum München; Universitätsklinikum Schleswig-<br />
Holstein, Germany.<br />
P3-06-06 Lactate dehydrogenase B in breast cancer contributes to<br />
glycolytic phenotype and predicts response to neoadjuvant<br />
chemotherapy<br />
Dennison JB, Molina JR, Mitra S, Gonzalez-Angulo AM, Brown RE,<br />
Mills GB. MD Anderson <strong>Cancer</strong> Center, Houston, TX; University of<br />
Texas Health Science Center, Houston, TX.<br />
P3-06-07 Ki67 as a Predictive Marker of Response to Neoadjuvant<br />
Chemotherapy in Patients with Early-Stage <strong>Breast</strong> <strong>Cancer</strong><br />
(ESBC): A Systematic Review and Evidence Summary<br />
Lyman GH, Culakova E, Poniewierski MS, Wogu AF, Barry W, Ginsburg<br />
GS, Marcom PK, Ready N, Abernethy A, Geradts J, Hwang S, Kuderer<br />
NM. Duke University.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 36s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P3-06-08<br />
P3-06-09<br />
P3-06-10<br />
P3-06-11<br />
P3-06-12<br />
P3-06-13<br />
Ki-67 mRNA as a predictor for response to neoadjuvant<br />
chemotherapy in primary breast cancer<br />
Marme F, Schneeweiss A, Aigner J, Eidt S, Altevogt P, Sinn P,<br />
Wirtz RM. National Center for Tumor Diseases, University-Hospital<br />
Heidelberg, Germany; Institut of Pathologie at the St.-Elisabeth-<br />
Hospital, Cologne, Germany; German <strong>Cancer</strong> Research Center,<br />
Heidelberg, Germany; University of Heidelberg, Germany;<br />
STRATIFYER MolecularPathology GmbH, Cologne, Germany.<br />
Test of association between Ki67 index of early breast<br />
cancer and local relapse after adjuvant hypofractionated<br />
radiotherapy<br />
Rodrigues DN, Somaiah N, Daley F, Davies S, Rakha E, A’Hern R,<br />
Haviland J, Sydenham M, Owen R, Reis-Filho J, Yarnold JR. Institute<br />
of <strong>Cancer</strong> Research, London, United Kingdom; The Royal Marsden<br />
NHS Foundation Trust, Sutton, Surrey, United Kingdom; Institute<br />
of <strong>Cancer</strong> Research, Sutton, Surrey, United Kingdom; University<br />
of Nottingham and Nottingham University Hospitals NHS Trust,<br />
Nottingham, United Kingdom; Cheltenham General Hospital,<br />
Cheltenham, United Kingdom.<br />
Pretreatment Vitamin D Levels and Response to Neoadjuvant<br />
Chemotherapy in the I-SPY 1 TRIAL<br />
Clark AS, Chen J, Kapoor S, Esserman LJ, DeMichele A, I-SPY TRIAL-1<br />
Investigators. Abramson <strong>Cancer</strong> Center, Philadelphia, PA; Perelman<br />
School of Medicine at the University of Pennsylvania, Philadelphia,<br />
PA; Center for Clinical Epidemiology and Biostatistics, Philadelphia,<br />
PA; Helen Diller Family Comprehensive <strong>Cancer</strong> Center, <strong>San</strong> Francisco,<br />
CA; UCSF/Mount Zion Medical Center, <strong>San</strong> Francisco, CA; I-SPY1<br />
TRIAL Investigators.<br />
Response and long-term outcomes after neo-adjuvant<br />
chemotherapy: Pooled dataset of patients stratified by<br />
molecular subtyping using MammaPrint and BluePrint<br />
Glück S, Peeters J, Stork-Sloots L, Somlo G, van’t Veer L, de Snoo<br />
F. University of Miami, Sylvester Comprehensive <strong>Cancer</strong> Center;<br />
Agendia NV; City of Hope; University of California, <strong>San</strong> Francisco.<br />
Effect of TOP2A and cMYC gene copy number on outcome in<br />
a Phase II trial of adjuvant TC (Docetaxel/Cyclophosphamide)<br />
plus trastuzumab (HER TC) in HER2-positive early stage breast<br />
cancer<br />
Jones S, Collea R, Paul D, Sedlacek S, Favret A, Gore I, Lindquist<br />
DL, Holmes FA, Allison MAK, Steinberg MS, Stokoe C, Portillo<br />
RM, Crockett M, Wang Y, Lina A, Robert NJ, O’Shaughnessy J. US<br />
Oncology Research, McKesson Specialty Health, The Woodlands,<br />
TX; Texas Oncology, Baylor-Sammons <strong>Cancer</strong> Center, Dallas, TX;<br />
New York Oncology Hematology, Albany, NY; Rocky Mountain<br />
<strong>Cancer</strong> Center, Denver, CO; Virginia <strong>Cancer</strong> Specialists, Fairfax, VA;<br />
Birmingham Hematology and Oncology, Birmingham, AL; Arizona<br />
Oncology Associates, Sedona, AZ; Texas Oncology-Texas Memorial<br />
City, Houston, TX; Comprehensive <strong>Cancer</strong> Center, Henderson, NV;<br />
Virginia Oncology Associates, Virginia Beach, VA; Texas Oncology -<br />
Plano East, Plano, TX; Texas Oncology - El Paso West, El Paso, TX.<br />
Expression of Phosphorylated Activating Transcription factor<br />
2 (ATF2) is associated with sensitivity to endocrine therapy in<br />
breast cancer<br />
Palmieri C, Rudraraju B, Abdel-Fatah TMA, Moore DA, Shaw J, Green<br />
A, Ellis IO, Coombes RC, Simak A. Imperial College London, United<br />
Kingdom; Nottingham University City Hospital, Nottingham, United<br />
Kingdom; University of Leicester, United Kingdom.<br />
Identification of Prognosis-Relevant Subgroups in Patients<br />
with Chemoresistant Triple Negative <strong>Breast</strong> <strong>Cancer</strong><br />
Yu K-D, Zhu R, Zhan M, Shao Z-M, Yang W, Symmans WF, Rodriguez<br />
AA, Makris A, Wong ST, Chang JC. Shanghai <strong>Cancer</strong> Center and<br />
<strong>Cancer</strong> Institute of Fudan University, Shanghai, China; The Methodist<br />
Hospital, Houston, TX; The University of Texas MD Anderson <strong>Cancer</strong><br />
Center, Houston, TX; Mount Vernon <strong>Cancer</strong> Centre, United Kingdom;<br />
The Methodist Hospital Research Institute, Houston, TX.<br />
P3-06-15<br />
P3-06-16<br />
P3-06-17<br />
P3-06-18<br />
P3-06-19<br />
P3-06-20<br />
P3-06-21<br />
P3-06-22<br />
Baseline CD4/CD8 tumor infiltrating lymphocytes (TIL) ratio<br />
predicts pathologic response to neoadjuvant chemotherapy<br />
(NC) in breast cancer<br />
García-Martínez E, Luengo Gil G, Chaves Benito A, García García T,<br />
Vicente Conesa AM, Zafra Poves M, García Garre E, Vicente García V,<br />
Ayala de la Peña F. University Hospital Morales Meseguer, Murcia,<br />
Spain; Centro de Hemodonación Regional, Murcia, Spain.<br />
Predictive biomarker of pathologic complete response to<br />
neoadjuvant chemotherapy in triple negative breast cancer<br />
Kim T, Han W, Moon H-G, Noh D-Y. Seoul National University College<br />
of Medicine, Seoul, Korea.<br />
Withdrawn<br />
Increase of serum androgen and its metabolites in<br />
postmenopausal primary breast cancer patients with disease<br />
progression during neo-adjuvant exemestane treatment;<br />
JFMC 34-0601 TR<br />
Takada M, Saji S, Honma N, Masuda N, Yamamoto Y, Kuroi K,<br />
Yamashita H, Ohno S, Aogi K, Ueno T, Toi M. Graduate School<br />
of Medicine, Kyoto University, Kyoto, Japan; Tokyo Metropolitan<br />
Institute of Gerontology, Tokyo, Japan; Osaka National Hospital,<br />
Osaka, Japan; Kumamoto University Hospital, Kumamoto, Japan;<br />
Tokyo Metropolitan <strong>Cancer</strong> and Infectious Diseases Center,<br />
Komagome Hospital, Tokyo, Japan; Hokkaido University, Sapporo,<br />
Japan; National Hospital Organization Kyushu <strong>Cancer</strong> Center,<br />
Fukuoka, Japan; National Hospital Organization Shikoku <strong>Cancer</strong><br />
Center, Ehime, Japan.<br />
Ki-67 mRNA as a predictor for response to neoadjuvant<br />
chemotherapy in primary breast cancer<br />
Aigner J, Schneeweiss A, Marme F, Eidt S, Altevogt P, Sinn P, Wirtz R.<br />
National Center for Tumor Diseases, University-Hospital Heidelberg,<br />
Germany; Institut of Pathology at the St.-Elisabeth-Hospital, Cologne,<br />
Germany; German <strong>Cancer</strong> Research Center, Heidelberg, Germany;<br />
University of Heidelberg, Germany; STRATIFYER MolecularPathology<br />
GmbH, Cologne, Germany.<br />
Is it possible to predict the efficacy of a combination of<br />
Panitumumab plus FEC 100 followed by docetaxel (T) for<br />
patients with triple negative breast cancer (TNBC)? Final<br />
biomarker results from a phase II neoadjuvant trial<br />
Nabholtz J-M, Dauplat M-M, Abrial C, Weber B, Mouret-Reynier M-A,<br />
Gligorov J, Tredan O, Vanlemmens L, Petit T, Guiu S, Jouannaud C,<br />
Tubiana-Mathieu N, Kwiatkowski F, Cayre A, Uhrhammer N, Privat<br />
M, Desrichard A, Chollet P, Chalabi N, Penault-Llorca F. Centre Jean<br />
Perrin, Clermont-Ferrand, France; Centre Alexis Vautrin, Vandoeuvre<br />
les Nancy, France; Hôpital Tenon, Paris, France; Centre Leon Berard,<br />
Lyon, France; Centre Oscar Lambret, Lille, France; Centre Paul Strauss,<br />
Strasbourg, France; Centre Georges François Leclerc, Dijon, France;<br />
Institut Jean Godinot, Reims, France; CHU Dupuytren, Limoges,<br />
France.<br />
Unique Molecular Subtypes of Triple Negative <strong>Breast</strong><br />
Carcinomas by Routine IHC: Implications for Treatment and<br />
Prognosis<br />
Ashfaq R, Wright B, Russell K, Voss A. Caris Life Sciences, Phoenix, AZ.<br />
Mechanisms behind trastuzumab resistance as neoadjuvant<br />
therapy in HER2-positive operable breast cancer<br />
Jinno H, Sato T, Hayashida T, Takahashi M, Hirose S, Kitagawa Y. Keio<br />
University School of Medicine, Shinjuku, Tokyo, Japan.<br />
Predicting response to neoadjuvant letrozole<br />
Larionov A, Turnbull A, Sims A, Renshaw L, Kay C, Harrison D, Dixon<br />
JM. University of Edinburgh, Scotland, United Kingdom.<br />
Early activation of IFN/STAT signaling in tumor cells of patientderived<br />
triple negative breast cancer xenografts predicts<br />
tumor sensitivity to chemotherapy<br />
Legrier M-E, Yvonnet V, Beurdeley A, Stephant G, Le Ven E, Banis S,<br />
Lassalle M, Deas O, Cairo S, Judde J-G. Xentech, Evry, Ile de France,<br />
France.<br />
P3-06-14<br />
P3-06-23<br />
P3-06-24<br />
www.aacrjournals.org<br />
37s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P3-06-25<br />
P3-06-26<br />
P3-06-27<br />
P3-06-28<br />
P3-06-29<br />
P3-06-30<br />
P3-06-31<br />
P3-06-32<br />
P3-06-33<br />
P3-06-34<br />
PTEN mRNA positivity using in situ measurements is<br />
associated with better outcome in Tamoxifen treated breast<br />
cancer patients<br />
Schalper KA, Li K, Rimm DL. Yale School of Medicine, New Haven, CT.<br />
Serum anti-p53 antibody titers predict pathological response<br />
to preoperative chemotherapy in women with HER2 positive<br />
or triple negative breast cancer<br />
Yoshiyama T, Nakamura Y, Igawa A, Saruwatari A, Shigechi T, Ueda N,<br />
Kuba S, Ishida M, Nishimura S, Nishiyama K, Ohno S. National Kyushu<br />
<strong>Cancer</strong> Center, Fukuoka, Japan.<br />
Dynamic tomographic optical breast imaging (TOBI) to<br />
monitor response to neoadjuvant therapy in breast cancer<br />
Carp SA, Wanyo CM, Specht M, Schapira L, Moy B, Finkelstein DM,<br />
Boas DA, Isakoff SJ. Massachusetts General Hospital, Charlestown,<br />
MA; Massachusetts General Hospital, Boston, MA.<br />
Use of the MiCK drug-induced apoptosis assay improves<br />
clinical outcomes in recurrent breast cancer (BRCA)<br />
Bosserman L, Rogers K, Davidson D, Whitworth P, Karimi M,<br />
Upadhyaya G, Rutledge J, Hallquist A, Perree M, Presant C. Wilshire<br />
Oncology Medical Group-US Oncology; Nashville Oncology<br />
Associates; Tennessee Plateau Oncology; Nashville <strong>Breast</strong> Center;<br />
Data Vision; DiaTech Life Sciences.<br />
Change of circulating tumor cells before and after<br />
neoadjuvant chemotherapy in patients with primary<br />
breast cancer<br />
Horiguchi J, Takata D, Rokutanda N, Nagaoka R, Tokiniwa H, Tozuka<br />
K, Sato A, Kikuchi M, Oyama T, Takeyoshi I. Gunma University<br />
Hospital, Maebashi, Gunma, Japan.<br />
Predictors of Pathologic Complete Response to Chemotherapy<br />
and Antiangiotherapy in <strong>Breast</strong> <strong>Cancer</strong><br />
Makhoul I, Griffin RJ, Dhakal I, Raj V, Hennings L, Kadlubar SA.<br />
University of Arkansas for Medical Sciences, Little Rock, AR.<br />
Etirinotecan pegol in patients with metastatic breast cancer<br />
(mBC): Modeling CA27.29 response and its correlation with<br />
tumor response<br />
Chia YL, Hoch U, Hannah A, Eldon MA. Nektar Therapeutics, <strong>San</strong><br />
Francisco, CA.<br />
Topoisomerase 1 gene copy aberration is a frequent finding in<br />
clinical breast cancer samples<br />
Stenvang J, Smid M, Nielsen S, Balslev E, Timmermans M, Rømer M,<br />
Nygaard S, Christensen I, Nielsen D, Foekens J, Brünner N, Martens<br />
J. University of Copenhagen, Denmark; Erasmus University Medical<br />
Center/Daniel den Hoed <strong>Cancer</strong> Center, Rotterdam, Netherlands;<br />
Herlev University Hospital, Copenhagen, Denmark; Copenhagen<br />
Biocenter, Rigshospitalet, Copenhagen, Denmark.<br />
Effect of trastuzumab-based therapy on serum activin A levels<br />
in metastatic breast cancer<br />
Zubritsky LM, Ali SM, Leitzel K, Koestler W, Fuchs E-M, Costa L, Knight<br />
R, Laadem A, Sherman ML, Lipton A. Penn State Hershey Medical<br />
Center, Hershey, PA; Lebanon VA Medical Center, Lebanon, PA;<br />
Medical University of Vienna, Austria; <strong>San</strong>ta Maria Hospital, Lisbon,<br />
Portugal; Celgene Corp., Summit, NJ; Acceleron Pharma, Cambridge,<br />
MA.<br />
Plasma (p) VEGF-A and VEGFR-2 biomarker (BM) results from<br />
the BEATRICE phase III trial of bevacizumab (BEV) in triplenegative<br />
early breast cancer (BC)<br />
Carmeliet P, Pallaud C, Deurloo RJ, Bubuteishvili-Pacaud L, Henschel<br />
V, Dent R, Bell R, Mackey J, Scherer SJ, Cameron D. Vesalius<br />
Research Center, Leuven, Belgium; F. Hoffmann-La Roche Ltd, Basel,<br />
Switzerland; Genentech, Inc., South <strong>San</strong> Francisco; University of<br />
Edinburgh and <strong>Cancer</strong> Services, NHS Lothian, Edinburgh, United<br />
Kingdom; Sunnybrook Health Sciences Center and University of<br />
Toronto, Toronto, ON, Canada; National <strong>Cancer</strong> Center, Singapore,<br />
Singapore; Andrew Love <strong>Cancer</strong> Centre, Geelong, Australia; Cross<br />
Center Institute, Edmonton, Canada.<br />
P3-06-35 Topoisomerase 1 gene copy aberrations in 52 human breast<br />
cancer cell lines and association to gene expression<br />
Stenvang J, Smid M, Nielsen S, Timmermans M, Rømer M, Nielsen<br />
D, Foekens J, Brünner N, Martens J. University of Copenhagen,<br />
Denmark; Erasmus University Medical Center/Daniel den Hoed<br />
<strong>Cancer</strong> Center, Rotterdam, Netherlands; Herlev University Hospital,<br />
Copenhagen, Denmark.<br />
Epidemiology, Risk, and Prevention: Epidemiology - Population Studies<br />
P3-07-01 Withdrawn<br />
P3-07-02 Time-trends in survival in young women with breast cancer in<br />
a SEER population-based study<br />
Ademuyiwa FO, Groman A, Hong C-C, Kumar S, Levine EG, Miller A,<br />
Ambrosone CB. Roswell Park <strong>Cancer</strong> Institute.<br />
P3-07-03 The impact of Carcinoma in situ of the breast and family<br />
history on risk of subsequent breast cancer events and<br />
mortality-a population based study from Sweden<br />
Sackey H, Hui M, Czene K, Edgren G, Frisell J, Hartman M. Karolinska<br />
Institutet, Stockholm, Sweden; Saw Swee Hock School of Public<br />
Health, National University of Singapore, Singapore; Harvard School<br />
of Public Health, Boston; National University Hospital, Singapore.<br />
P3-07-04 Cigarette smoking and postmenopausal breast cancer risk:<br />
results from the NIH-AARP Diet and Health Study<br />
Nyante SJ, Gierach GL, Dallal CM, Park Y, Hollenbeck AR, Brinton LA.<br />
National <strong>Cancer</strong> Institute, Rockville, MD; AARP, Washington, DC.<br />
P3-07-05 Bisphosphonate use after primary breast cancer and risk of<br />
contralateral breast cancer using pharmacy data<br />
Kwan M, Habel L, Song J, Weltzien E, Chung J, Sun Y, Fletcher<br />
S, Haque R. Division of Research, Kaiser Permanente Northern<br />
California; Kaiser Permanente Southern California; Harvard Medical<br />
School.<br />
P3-07-06 Initial treatment and survival among elderly breast<br />
cancer patients with positive estrogen receptor status by<br />
progesterone receptor status and stage: an analysis of US<br />
national registry data 2000-2009<br />
Lang K, Huang H, Namjoshi M, Federico V, Menzin J. Boston Health<br />
Economics, Waltham, MA; Novartis Pharmaceuticals Corporation,<br />
East Hanover, NJ.<br />
P3-07-07 Incidence and survival among breast cancer patients in the<br />
United States by race and stage diagnosis: an analysis of<br />
national registry data 2000-2009<br />
Lang K, Huang H, Namjoshi M, Federico V, Menzin J. Boston Health<br />
Economics, Waltham, MA; Novartis Pharmaceuticals Corporation,<br />
East Hanover, NJ.<br />
P3-07-08 Recent trends in the characteristics of patients with distant<br />
stage breast cancer in the United States Surveillance,<br />
Epidemiology and End Stage Disease (SEER) program<br />
Li J, Dalvi T, Pawaskar M, Tsai K, Caspard H, Fryzek J. Medimmune,<br />
Gaithersburg, MD; Epistat Institute, Gaithersburg, MD.<br />
P3-07-09 Prevalence and effects of off-label use of chemotherapeutic<br />
agents in elderly breast cancer patients: estimates from<br />
Surveillance, Epidemiology and End Results-Medicare data<br />
Eaton AA, Sima CS, Panageas KS. Memorial Sloan-Kettering <strong>Cancer</strong><br />
Center, New York, NY.<br />
P3-07-10 Effect of lifestyle and single nucleotide polymorphisms on<br />
breast cancer risk: A case-control study in Japanese women<br />
Mizoo T, Taira N, Nishiyama K, Nogami T, Iwamoto T, Motoki T, Shien<br />
T, Matuoka J, Doihara H, Ishihara S, Kawai N, Kawasaki K, Ishibe<br />
Y, Ogasawara Y. Okayama Medical University, Okayama, Japan;<br />
Okayama Saiseikai General Hospital, Okayama, Japan; Okayama<br />
Rousai Hospital, Okayama, Japan; Kagawa Prefectural <strong>Cancer</strong><br />
Detection Center, Takamatsu, Kagawa, Japan; Mizushima Kyodo<br />
Hospital, Kurashiki, Okayama, Japan; Kagawa Prefectural Central<br />
Hospital, Takamatsu, Kagawa, Japan.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 38s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P3-07-11 Retrospective database review of outcomes in invasive lobular<br />
carcinoma and invasive ductal carcinoma of the breast<br />
Shih Y-C, Dillon P. University of Virginia, Charlottesville, VA.<br />
P3-07-12 Risk Factors for <strong>Breast</strong> <strong>Cancer</strong> in Women Served in Odete<br />
Valadares Maternity, Belo Horizonte-MG<br />
Sediyama CMNO, Peluzio MCG, Abranches MV. Universidade Federal<br />
de Viçosa, Viçosa, MG, Brazil.<br />
P3-07-13 Importance of socioeconomic status in relation to breast<br />
cancer risk and prognostic factors in Argentina<br />
Croce MV, Demichelis SO, Cermignani L, Zwenger A, Segal-Eiras<br />
A, Giacomi N. Faculty of Medical Sciences, UNLP, La Plata, Buenos<br />
Aires, Argentina.<br />
P3-07-14 Initial treatment and survival among elderly breast cancer<br />
patients in the United States by estrogen receptor status and<br />
cancer stage at diagnosis: an analysis of national registry data<br />
2000-2009<br />
Lang K, Huang H, Namjoshi M, Federico V, Menzin J. Boston Health<br />
Economics, Waltham, MA; Novartis Pharmaceuticals Corporation,<br />
East Hanover, NJ.<br />
Epidemiology, Risk, and Prevention: Epidemiology - Genetic and Molecular<br />
P3-08-01 The prospective risk of ovarian cancer in 1433 women in a<br />
breast cancer family history clinic: no increased risk in families<br />
testing negative for BRCA1 and BRCA2<br />
Evans DGR, Ingham SL, Sahin S, Buchan I, Warwick J, O’Hara C,<br />
Moran A, Howell A. St Mary’s Hospital, Manchester, United Kingdom;<br />
Wythenshawe Hospital, Manchester, United Kingdom; The University<br />
of Manchester, Manchester, United Kingdom; Imperial College<br />
London, United Kingdom; North West <strong>Cancer</strong> Intelligence Service,<br />
NHS Foundation Trust, Manchester, United Kingdom; Christie<br />
Hospital, Manchester, United Kingdom.<br />
P3-08-02 Common variants at 10p14 and 1p11.2 display heterogeneity<br />
in breast cancer associations by E-cadherin tumor tissue<br />
expression in two independent datasets<br />
Horne HN, Sherman ME, Garcia-Closas M, Pharoah PD, Blows FM,<br />
Yang XR, Lissowska J, Brinton LA, Chanock SJ, Figueroa JD. National<br />
<strong>Cancer</strong> Institute, Rockville, MD; The Institute of <strong>Cancer</strong> Research,<br />
Sutton, Surrey, United Kingdom; University of Cambridge, United<br />
Kingdom; M. Sklodowska-Curie Memorial <strong>Cancer</strong> Center and Institute<br />
of Oncology, Warsaw, Poland.<br />
P3-08-03 Urinary levels of prostaglandin E 2<br />
metabolite and<br />
postmenopausal breast cancer<br />
Kim S, Taylor JA, <strong>San</strong>dler DP. Georgia Health Sciences University,<br />
Augusta, GA; National Institute of Environmental Health Sciences,<br />
Research Triangle Park, NC.<br />
P3-08-04 Impact of CYP3A variation on estrone levels and breast<br />
cancer risk<br />
Ross GM, Johnson N, Orr N, Walker K, Gibson L, Folkerd E, Haynes B,<br />
Palles C, Coupland B, Shoemaker M, Jones M, Broderick P, Sawyer<br />
E, Kerin M, Tomlinson I, Zvelebil M, Chilcott-Burns S, Tomczyk<br />
K, Simpson G, Williamson J, Hillier S, Houlston R, Swerdlow A,<br />
Ashworth A, Dowsett M, Peto J, dos <strong>San</strong>tos I, Fletcher O. Royal<br />
Marsden Hospital, London, United Kingdom; Breakthrough <strong>Breast</strong><br />
<strong>Cancer</strong>, Institute of <strong>Cancer</strong> Research, London, United Kingdom;<br />
London School of Hygiene and Tropical Medicine, United Kingdom;<br />
Wellcome Trust Centre for Human Genetics, Oxford, United<br />
Kingdom; Biomedical Research Centre, Guys, United Kingdom;<br />
Edinburgh University, United Kingdom; University Hospital, Galway,<br />
Ireland.<br />
P3-08-05 Copy number variation and risk of chemotherapy-related<br />
infection<br />
Abraham JE, Rueda OM, Chin S-F, Guo Q, Harrington P, Earl HM,<br />
Pharoah PD, Caldas C. Strangeway’s Research Laboratory, University<br />
of Cambridge, Cambridgeshire, United Kingdom; University of<br />
Cambridge NHS Foundation Hospitals, Cambridge, Cambridgeshire,<br />
United Kingdom; <strong>Cancer</strong> Research UK Cambridge Research Institute,<br />
Li Ka Shing Centre, Cambridge, Cambridgeshire, United Kingdom.<br />
P3-08-06 Triple Negative <strong>Breast</strong> <strong>Cancer</strong> and BRCA Status: Implications<br />
for Genetic Counseling<br />
Haque R, Alvarado M, Ahmed SA, Shi JM, Chung JWL, Avila CC,<br />
Zheng CX, Tiller GE. Kaiser Permanente Southern California,<br />
Pasadena, CA.<br />
P3-08-07 HER2 positive breast carcinomas: trend in evolution between<br />
1998 and 2008 and relationship with clinico-pathological<br />
characteristics in a population based study<br />
Beltjens F, Bertaut A, Pigeonnat S, Pouget N, Guiu S, Poillot M-L,<br />
Charon-Barra C, Coudert B, Dabakuyo S, Fumoleau P, Arveux P,<br />
Arnould L. Centre GF Leclerc, Dijon, France.<br />
P3-08-08 Vitamin D status at breast cancer diagnosis: correlation with<br />
patient and tumor characteristics<br />
Berger N, Klein P, Boolbol SK, Gillego A, Estabrook A, Malamud<br />
S, Chadha M, Boachie-Adjei K, Shao T. Lutheran Medical Center,<br />
Brooklyn, NY; Beth Israel Medical Center, Continuum <strong>Cancer</strong> Centers<br />
of New York, New York, NY; St. Luke’s-Roosevelt Hospital center,<br />
Continuum <strong>Cancer</strong> Centers of New York, New York, NY.<br />
P3-08-09 Clinical and Pathological Characteristics of <strong>Breast</strong> <strong>Cancer</strong> in<br />
Women with Neurofibromatosis Type 1<br />
Yap Y-S, Wong J, Chan M, Yong W-S, Ong K-W, Lo S-K, Ngeow J,<br />
Tan B, Madhukumar P, Tan M-H, Ang P, Teh B-T, Tan P-H, Lee AS-G.<br />
National <strong>Cancer</strong> Centre Singapore; Singapore General Hospital.<br />
Epidemiology, Risk, and Prevention: Ethnic/Racial Aspects<br />
P3-09-01 Odds of the triple negative subtype and survival of stages 1-3<br />
breast cancer: Variation by race/ethnicity<br />
Parise C, Caggiano V. Sutter Institute for Medical Research,<br />
Sacramento, CA.<br />
P3-09-02 The HER2 –positive subtypes by stage and race/ethnicity<br />
Caggiano V, Parise C. Sutter Institute for Medical Research,<br />
Sacramento, CA.<br />
P3-09-03 <strong>Breast</strong> cancer subtype distribution among HapMap classified<br />
ethnic groups<br />
Luo C, Chen Y, Shriver CD, Hu H, Mural RJ. Windber Research<br />
Institute, Windber, PA; Walter Reed National Military Medical Center,<br />
Bethesda, MD.<br />
P3-09-04 The associations between body mass index and breast cancer<br />
intrinsic subtypes in Japanese women<br />
Kimura K, Tanaka S, Iwamoto M, Uchiyama K. Osaka Medical College,<br />
Takatsuki City, Osaka, Japan.<br />
P3-09-05 The role of breast size in detection of breast cancer in<br />
asian women<br />
Lee S, <strong>San</strong>dhu H, Zheng Y. Holy Name Medical Center.<br />
Treatment: Inflammatory <strong>Breast</strong> <strong>Cancer</strong><br />
P3-10-01 Epidemiological risk factors and normal breast tissue markers<br />
in inflammatory breast cancer<br />
Atkinson RL, Sexton KR, Ueno NT, El-Zein R, Brewster AM,<br />
Krishnamurthy SA, Woodward WA. University of Texas MD Anderson<br />
<strong>Cancer</strong> Center, Houston, TX; Dan L Duncan <strong>Cancer</strong> Center, Baylor<br />
College of Medicine, Houston, TX.<br />
P3-10-02 Modulation of mRNA and miRNAs by the novel histone<br />
deacetylase inhibitor, CG-1521 disrupts cytokinesis in<br />
SUM149PT inflammatory breast cancer cells<br />
Chatterjee N, Tenniswood MPR. University at Albany, Rensselaer, NY.<br />
www.aacrjournals.org<br />
39s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P3-10-03 Bartonella henselae Infection Detected in Patients with<br />
Inflammatory <strong>Breast</strong> <strong>Cancer</strong><br />
Fernandez SV, Aburto L, Maggi R, Breitschwerdt EB, Cristofanilli M.<br />
Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA; North Caroline State<br />
University, Raleigh, NC.<br />
P3-10-04 Regulation of inflammatory breast cancer cell invasion<br />
through Akt1/PKBα phosphorylation of RhoC GTPase<br />
Lehman HL, Van Laere SJ, van Golen CM, Vermeulen PB, Dirix LY, van<br />
Golen KL. The University of Delaware, Newark, DE; Sint Augustine<br />
Hospital, Antwerp, Belgium; Catholic University, Leuven, Belgium;<br />
Delaware State University, Dover, DE.<br />
P3-10-05 Response to neoadjuvant systemic therapy (NST) in<br />
inflammatory breast cancer (IBC) according to estrogen<br />
receptor (ER) and HER2 expression<br />
Masuda H, Iwamoto T, Brewer T, Hsu L, Kai K, Woodward WA,<br />
Reuben JM, Valero V, Alvarez RH, Willey J, Hortobagyi GN, Ueno NT.<br />
Morgan Welch Inflammatory <strong>Breast</strong> <strong>Cancer</strong> Research Program and<br />
Clinic, The University of Texas MD Anderson <strong>Cancer</strong> Center, Houston,<br />
TX; The University of Texas MD Anderson <strong>Cancer</strong> Center, Houston,<br />
TX; Okayama University Hospital, Okayama, Japan.<br />
P3-10-06 Patterns of failure in patients with inflammatory breast<br />
cancer: the case for aggressive local/regional treatment<br />
Warren LE, Regan MM, Nakhlis F, Yeh ED, Jacene HA, Hirshfield-<br />
Bartek J, Overmoyer BA, Bellon JR. Harvard Medical School, Boston,<br />
MA; Dana Farber <strong>Cancer</strong> Institute, Harvard Medical School,<br />
Boston, MA.<br />
P3-10-07 Lymph node status and survival in inflammatory breast cancer<br />
Sieffert MR, Pedersen RC, Tereffe W, Cui H, Woods RR, Viscusi RK,<br />
LeBeau-Grasso L, Lang JE. University of Arizona College of Medicine,<br />
Tucson, AZ; University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX; University of Arizona <strong>Cancer</strong> Center, Tucson, AZ;<br />
University of Arizona Health Sciences Center, Tucson, AZ; University<br />
of Southern California Norris Comprehensive <strong>Cancer</strong> Center, Los<br />
Angeles, CA.<br />
P3-10-08 A new in vitro method of growing and studying inflammatory<br />
breast cancer emboli<br />
Lehman HL, Daasner EJ, Vermeulen PB, Dirix LY, Van Laere S, van<br />
Golen KL. The University of Delaware, Newark, DE; Sint Augustine<br />
Hospital, Antwerp, Belgium; Catholic University, Leuven, Belgium.<br />
P3-10-09 Peptide-based molecular targeting of inflammatory<br />
breast cancer<br />
Eckhardt BL, Miao RY, Cao Y, Driessen WH, Krishnamurthy S,<br />
Arap W, Ueno N, Anderson RL, Pasqualini R. The University of Texas<br />
at MD Anderson <strong>Cancer</strong> Center, Houston, TX; Stanford University<br />
School of Medicine; Trescowthick Research Laboratories, Peter<br />
MacCallum <strong>Cancer</strong> Center; The University of Texas at MD Anderson<br />
<strong>Cancer</strong> Center.<br />
P3-10-10 Status of anaplastic lymphoma kinase (ALK) gene in<br />
inflammatory breast carcinoma<br />
Krishnamurthy S, Woodward W, Reuben JM, Tepperberg J, Ogura<br />
D, Niwa S, Ueno NT. MD Anderson <strong>Cancer</strong> Center, Houston, TX;<br />
LabCorp, Durham, NC; Link Genomics, Toyoka, Japan<br />
Treatment: Male <strong>Breast</strong> <strong>Cancer</strong><br />
P3-11-01 Matched-pair analysis of patients with male and female<br />
breast cancer<br />
Kim M, Lee SK, Choi M-Y, Kim S, Kim J, Jung SP, Bae SY, Kil WH, Lee<br />
JE, Nam SJ. Samsung Medical Center, Sungkyunkwan University<br />
School of Medicine, Seoul, Republic of Korea.<br />
P3-11-02 Male breast cancer: A comparison between BRCA mutation<br />
carriers and non-carriers in Hong Kong, Southern China<br />
Kwong A, Chau WW, Wong CHN, Law FBF, Ng EKO, Suen DTK, Kurian<br />
AW, West DW, Ford JM, Ma ESK. University of Hong Kong, Pokfulam,<br />
Hong Kong; Hong Kong Hereditary <strong>Breast</strong> <strong>Cancer</strong> Family Registry,<br />
Happy Valley, Hong Kong; Stanford University School of Medicine,<br />
Stanford, CA; Hong Kong <strong>San</strong>itorium & Hospital, Happy Valley,<br />
Hong Kong.<br />
P3-11-03 Treatment outcomes for early stage male breast cancer: a<br />
single centre retrospective case-control study<br />
Kwong A, Visram H, Graham N, Balchin K, Petrcich W, Dent S. The<br />
Ottawa Hospital, Ottawa, ON, Canada; Ottawa Hospital Research<br />
Institute, Ottawa, ON, Canada.<br />
P3-11-04 Male breast cancer: Overall survival in a single institution<br />
Bello MA, Bergmann A, Costa CRA, Pinto RR, Millen EC,<br />
Thuler LCS, Bender PFM. Brazilian National <strong>Cancer</strong> Institute,<br />
Rio de Janeiro, Brazil.<br />
Treatment: Brain Metastases<br />
P3-12-01 Serum biomarkers identification using quantitative<br />
proteomics in patients (pts) with untreated brain metastases<br />
from HER2-positive breast cancer receiving capecitabine (C)<br />
and lapatinib (L) (UNICANCER LANDsCAPE trial)<br />
Gonçalves A, Camoin L, Ben Younès I, Romieu G, Campone M, Diéras<br />
V, Cropet C, Mahier Aït-Oukhatar C, Dalenc F, Le Rhun E, Labbe-<br />
Devilliers C, Borg J-P, Bachelot T. Institut Paoli Calmettes, Marseille,<br />
France; Université de la Méditerranée, Marseille, France; Centre Val<br />
d’Aurelle, Montpellier, France; Institut de Cancérologie de l’Ouest,<br />
Nantes, France; Institut Curie, Paris, France; Centre Léon Bérard, Lyon,<br />
France; Unicancer, Paris, France; Institut Claudius Regaud, Toulouse,<br />
France; Centre Oscar Lambret, Lille, France.<br />
P3-12-02 The impact of estrogen receptor status on treatment<br />
outcomes following gamma knife radiosurgery for brain<br />
metastases of primary breast cancer<br />
Cupelo EC, Aridgides PD, Bogart JA, Hahn SS, Shapiro AJ. SUNY<br />
Upstate Medical University, Syracuse, NY.<br />
P3-12-03 Combined targeting of HER2 and VEGFR2 for effective<br />
treatment of HER2-amplified breast cancer brain metastases<br />
Kodack DP, Chung E, Yamashita H, Incio J, Peters A, Song Y, Ager E,<br />
Huang Y, Farrar C, Lussiez A, Goel S, Snuderl M, Kamoun W, Hiddingh<br />
L, Tannous BA, Fukumura D, Engelman JA, Jain RK. Massachusetts<br />
General Hospital, Boston, MA.<br />
P3-12-04 A phase 2, multi-center, open label study evaluating the<br />
efficacy and safety of GRN1005 alone or in combination with<br />
trastuzumab in patients with brain metastases from breast<br />
cancer<br />
Lin NU, Schwartzberg LS, Kesari S, Yardley DA, Verma S, Anders CK,<br />
Shih T, Shen Y, Miller K. UC <strong>San</strong> Diego, La Jolla, CA; Indiana University<br />
Melvin and Bren Simon <strong>Cancer</strong> Center, Indianapolis, IN; Sunnybrook<br />
Odette <strong>Cancer</strong> Centre, Toronto, ON, Canada; Dana-Farber <strong>Cancer</strong><br />
Institute, Boston, MA; The West Clinic, Memphis, TN; Geron, Menlo<br />
Park, CA; University of North Carolina at Chapel Hill, NC; Sarah<br />
Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC.,<br />
Nashville, TN.<br />
P3-12-05 Clinical features and outcomes of leptomeningeal metastasis<br />
in patients with breast cancer: a single center experience<br />
Jo J-C, Kang MJ, Ahn J-H, Jung KH, Kim JE, Gong G, Kim HH, Ahn SD,<br />
Kim SS, Son BH, Ahn SH, Kim S-B. Asan Medical Center, University of<br />
Ulsan College of Medicine, Seoul, Korea.<br />
P3-12-06 Clinicopathological Analysis of <strong>Breast</strong> <strong>Cancer</strong> Patients with<br />
Brain Metastases<br />
Ushio A, Sawaki M, Fujita T, Hattori M, Kondo N, Horio A, Gondou N,<br />
Iwata H. Aichi <strong>Cancer</strong> Center, Japan.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 40s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P3-12-07 Voyagers and their aids: The role of interactions between<br />
tumor and endothelial cells in brain metastasis<br />
Shah KN, Faridi JS. University of the Pacific, Stockton, CA.<br />
P3-12-08 Incidence, predictive factors and outcome of brain metastases<br />
(BM) in a single institution cohort of breast cancer patients<br />
Perelló A, Alarcon J, Garcias C, Duran J, Colom B, Clemente G, Avella<br />
A, Canet R, Torrecabota J, Rifa J. Hospital Universitari Son Espases,<br />
Palma, Balearic Islands, Spain.<br />
P3-12-09 The risk of brain metastases according to expression<br />
of selected immunohistochemical markers in primary<br />
breast cancers<br />
Sosinska-Mielcarek K, Winczura P, Duchnowska R, Badzio A,<br />
Majewska H, Lakomy J, Peksa R, Pieczynska B, Radecka B, Debska<br />
S, Zok J, Rogowski W, Strzelecka M, Kulma-Kreft M, Blaszczyk<br />
P, Litwiniuk M, Jesien-Lewandowicz E, Rutkowski T, Jaworska-<br />
Jankowska M, Adamowicz K, Foszczynska-Kloda M, Biernat W,<br />
Jassem J. Regional Oncology Center, Gdansk, Poland; Medical<br />
University of Gdansk, Poland; Military Institute of Medicine, Warsaw,<br />
Poland; Regional Oncology Center in Opole, Opole, Poland; Medical<br />
University of Lódz, Poland; Warmia and Masuria Oncology Center,<br />
Olsztyn, Poland; PCK Marine Hospital, Gdynia, Poland; Oncology<br />
Center in Bydgoszcz, Poland; Medical University of Poznan, Poland;<br />
Maria Sklodowska-Curie Memorial <strong>Cancer</strong> Center and Institute of<br />
Oncology, Gliwice, Poland; Regional Hospital in Wroclaw, Wroclaw,<br />
Poland; Pomeranian Oncology Center, Szczecin, Poland.<br />
P3-12-10 Age, breast cancer subtype approximation and the risk of the<br />
development of brain metastasis in breast cancer patients<br />
Hung M-H, Liu C-Y, Chao T-C, Wang Y-L, Tsai Y-F, King K-L, Chiu J-H,<br />
Shiau C-Y, Shyr Y-M, Tzeng C-H, Tseng L-M. Taipei Veterans General<br />
Hospital, Taipei, Taiwan; National Yang-Ming University,<br />
Taipei, Taiwan.<br />
P3-12-11 Clinical outcome in patients with surgically resected brain<br />
metastases from breast cancer: prognostic considerations<br />
regarding molecular status and established prognostic<br />
classification systems<br />
Tabouret E, Metellus P, Tallet A, Figarella-Branger D, Charaffe-Jauffret<br />
E, Viens P, Gonçalves A. Institut Paoli Calmettes, Marseille, France;<br />
APHM, Marseille, France; Insitut Paoli-Calmettes, Marseille, France.<br />
P3-12-12 Chemotherapy and targeted therapy after whole-brain<br />
radiotherapy may improve survival in RPA class II/III patients<br />
with brain metastases from breast cancer<br />
Zhang Q, Chen J, Cai G, Yang Z, Chen J. Fudan University Shanghai<br />
<strong>Cancer</strong> Center, Shanghai, China.<br />
Treatment: Bone Metastases<br />
P3-13-01 Prospective study of treatment pattern, effectiveness, and<br />
safety of zoledronic acid (ZOL) therapy beyond 24 months:<br />
subgroup analysis of patients (pts) with metastatic bone<br />
disease (MBD) from breast cancer (BC)<br />
Van den Wyngaert T, Delforge M, Doyen C, Duck L, Wouters K,<br />
Delabaye I, Wouters C, Wildiers H. Antwerp University Hospital;<br />
University Hospitals Leuven; C.H.U. Mont – Godinne; Clinique<br />
St-Pierre; Novartis Pharmaceuticals.<br />
P3-13-02 Safety and Efficacy of Zoledronic Acid Beyond 24 Months in<br />
<strong>Breast</strong> <strong>Cancer</strong> Patients<br />
Suzuki Y, Saito Y, Ogiya R, Oshitanai R, Terao M, Terada M, Morioka T,<br />
Tsuda B, Niikura N, Okamura T, Tokuda Y. Tokai University School of<br />
Medicine, Isehara, Kanagawa, Japan.<br />
P3-13-03 Molecular factors associated with bone metastases in breast<br />
cancer patients<br />
Winczura P, Sosinska-Mielcarek K, Duchnowska R, Badzio A, Lakomy<br />
J, Majewska H, Peksa R, Pieczynska B, Radecka B, Debska S, Zok J,<br />
Rogowski W, Strzelecka M, Kulma-Kreft M, Blaszczyk P, Litwiniuk<br />
M, Jesien-Lewandowicz E, Rutkowski T, Jaworska-Jankowska M,<br />
Adamowicz K, Foszczynska-Kloda M, Biernat W, Jassem J. Medical<br />
University of Gdansk, Poland; Regional Oncology Center, Gdansk,<br />
Poland; Regional Oncology Center, Opole, Poland; Military Institute<br />
of Medicine, Warsaw, Poland; Medical University of Lódz, Poland;<br />
Warmia and Masuria Oncology Center, Olsztyn, Poland; Maritime<br />
Hospital, Gdynia, Poland; Oncology Center, Bydgoszcz, Poland;<br />
Maria Sklodowska-Curie Memorial <strong>Cancer</strong> Center and Institute of<br />
Oncology, Gliwice, Poland; Regional Hospital in Wroclaw, Poland;<br />
West Pomeranian Oncology Center, Szczecin, Poland.<br />
P3-13-04 Skeletal related Events and Bone Metastasis Patients with<br />
<strong>Breast</strong> <strong>Cancer</strong> in Japan. A Retrospective Study<br />
Yamashiro H, Takada M, Imai S, Yamauch A, Tsuyuki S, Inamoto<br />
T, Matsutani Y, Sakata S, Wada Y, Okamura R, Harada T, Tanaka F,<br />
Moriguchi Y, Kato H, Higashide S, Kan N, Yoshibayashi H, Suwa<br />
H, Okino T, Nakayama I, Ichinose Y, Yamagami K, Hashimoto T,<br />
Nakatani E, Nagata Y, Kudo Y, Toi M. National Hospital Organization<br />
KURE Medical Center, Kure, Hiroshima, Japan; Graduate School<br />
of Medicine, Kyoto University, Kyoto, Japan; Kurashiki Central<br />
Hospital, Kurashiki, Okayama, Japan; Kitano Hospital (The Tazuke<br />
Kofukai Medical Research Institute), Osaka, Japan; Osaka Red Cross<br />
Hospital, Osaka, Japan; Tenri Hospital, Tenri, Nara, Japan; National<br />
Hospital Organization Kyoto Medical Center, Kyoto, Japan; National<br />
Hospital Organization Himeji Medical Center, Himeji, Hyogo, Japan;<br />
Yamatotakada Municipal Hospital, Yamatotakada, Nara, Japan;<br />
Osaka Saiseikai Noe Hospital, Osaka, Japan; Fukui Red Cross Hospital,<br />
Fukui, Japan; Kyoto City Hospital, Kyoto, Japan; Nagahama City<br />
Hospital, Nagahama, Shiga, Japan; Kan Norimichi Clinic, Kyoto,<br />
Japan; Japanese Red Cross Society Wakayama Medical Center,<br />
Wakayama, Wakayama, Japan; Hyogo Prefectural Tsukaguchi<br />
Hospital, Amagasaki, Hyogo, Japan; Kouga Public Hospital, Kouga,<br />
Shiga, Japan; Kyoto Min-iren Chuo Hospital, Kyoto, Japan; Takatsuki<br />
Red Cross Hospital, Takatsuki, Osaka, Japan; Shinko Hospital, Kobe,<br />
Hyogo, Japan; Hashimoto Clinic, Kobe, Hyogo, Japan; Translational<br />
Research Informatics Center, Foundation for Biomedical Research<br />
and Innovation, Kobe, Hyogo, Japan; Kobe City Medical Center<br />
General Hospital, Kobe, Hyogo, Japan.<br />
P3-13-05 Evaluating efficacy of de-escalated bisphosphonate therapy<br />
in metastatic breast cancer patients at low-risk of skeletal<br />
related events. TRIUMPH: A pragmatic multicentre trial<br />
Bouganim N, Vandermeer L, Kuchuk I, Dent S, Hopkins S, Song X,<br />
Robbins D, Spencer P, Mazzarello S, Hilton JF, Amir E, Dranitsaris G,<br />
Addison C, Mallick R, Clemons MJ. McGill University Health Center,<br />
Montreal, QC, Canada; Ottawa Hospital <strong>Cancer</strong> Center, Ottawa,<br />
ON, Canada; Princess Margaret Hospital and University of Toronto,<br />
Toronto, ON, Canada; Health Economics and Biostatistics Consultant,<br />
Toronto, ON, Canada; The Ottawa Hospital Research Institute,<br />
Ottawa, ON.<br />
P3-13-06 Osteocytic Connexin 43 Hemichannels in Prevention of<br />
Bone Metastasis<br />
Zhou JZ, Jiang JX. University of Texas Health Science Center,<br />
<strong>San</strong> <strong>Antonio</strong>, TX.<br />
Treatment: DCIS/LCIS<br />
P3-14-01 Molecular definition of the transition of ductal carcinoma in<br />
situ (DCIS) to invasive ductal carcinoma (IDC)<br />
Colavito S, Stepansky A, Madan A, Harris LN, Hicks J, Bossuyt V, Rimm<br />
D, Lannin D, Stern DF. Yale University, New Haven, CT; Cold Spring<br />
Harbor Laboratory, Cold Spring Harbor, NY; Case Western Reserve<br />
University, Cleveland, OH.<br />
www.aacrjournals.org<br />
41s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P3-14-02<br />
Withdrawn<br />
P3-14-03 Differences in pathological and biological factors between<br />
DCIS, DCIS with microinvasion (DCIS-MI) and DCIS with<br />
concomitant invasive ductal carcinoma (DCIS-IDC)<br />
MacGrogan G, Baranzelli MC, Picquenot JM, Penault-Llorca F,<br />
Mathieu MC, Tas P, Fermeaux V, Mery E, Sagan C, Blanc-Fournier C,<br />
Brabencova E, Arnould L, Jacquemier J, Ettore F, Velasco V, Gonzalves<br />
B, Brouste V, Tunon de Lara C. Institut Bergonié, Bordeaux, France;<br />
Centre Oscar Lambret, Lille, France; Centre Henri Becquerel, Rouen,<br />
France; Centre Jean Perrin, Clermont-Ferrand, France; Institut<br />
Gustave Roussy, Villejuif, France; Centre Eugène Marquis, Rennes,<br />
France; CHU de Limoges, Limoges, France; Institut Claudius Regaud,<br />
Toulouse, France; Centre René Gauducheau, Saint Herblain, France;<br />
Centre François Baclesse, Caen, France; Institut Jean Godinot, Reims,<br />
France; Centre Georges François Leclerc, Dijon, France; Institut Paoli<br />
Calmettes, Marseille, France; Centre Antoigne Lacassagne, Nice,<br />
France.<br />
P3-14-04 Symptomatic DCIS is a risk factor for invasion and should be<br />
managed accordingly<br />
Dimopoulos N, Williams K, Kirwan CC, Johnson R, Howe M, Bundred<br />
NJ. University Hospital of South Manchester.<br />
P3-14-05 Recurrence in Patients Diagnosed with Ductal Carcinoma In<br />
Situ: Predictors and Prognostic Significance<br />
Sue GR, Killelea B, Horowitz NR, Lannin DR, Chagpar AB. Yale<br />
University School of Medicine, New Haven, CT.<br />
P3-14-06 The Utility of Margin Index To Predict Residual DCIS Following<br />
<strong>Breast</strong> Conserving Surgery<br />
Aneja S, Lannin DR, Killelea B, Horowitz NR, Chagpar AB. Yale<br />
University School of Medicine, New Haven, CT.<br />
Ongoing Trials 2: Surgery/Nodes<br />
OT2-1-01 Feasibility of sentinel node detection after neoadjuvant<br />
chemotherapy for patient with proved axillary lymph node<br />
involvement: the French prospective multiinstitutional GANEA<br />
2 ongoing trial<br />
Classe J-M, Bordes V, Gimbergues P, Tunon de Lara C, Faure C,<br />
Belichard C, Houpeau J-L, Raro P, Dupré P-F, Houvenaeghel G,<br />
Barranger E, Marchal F, Deblay P, Rouanet P, Lefebvre C, Bourcier C,<br />
Alran S. Institut de <strong>Cancer</strong>ologie de l’Ouest, Nantes Saint Herblain,<br />
France; Centre Jean Perrin, Clermont-Ferrand, France; Institut<br />
Bergonié, Bordeaux, France; Centre Leon Berard, Lyon, France;<br />
Centre Huguenin, Saint Cloud, France; Centre Oscar Lambret, Lille,<br />
France; Centre Hospitalier Universitaire Morvan, Brest, France; Paoli<br />
Calmettes, Marseille, France; CHU Lariboisière, Paris, France; Centre<br />
Alexis Vautrin, Nancy, France; Centre
December 4–8, 2012<br />
Program Schedule<br />
OT2-2-05 A prospective, randomised multi-centre phase II study<br />
evaluating the adjuvant, neoadjuvant or palliative treatment<br />
with tamoxifen +/- GnRH analogue versus aromatase inhibitor<br />
+ GnRH analogue in male breast cancer patients (GBG-54<br />
MALE)<br />
Linder M, von Minckwitz G, Kamischke A, Rudlowski C, Eggemann<br />
H, Nekljudova V, Loibl S. German <strong>Breast</strong> Group, Neu-Isenburg;<br />
Kinderwunschzentrum Münster, Germany; Universitätsfrauenklinik<br />
Bonn; Universitätsfrauenklinik Magdeburg.<br />
Ongoing Trials 2: Targeted Agents<br />
OT2-3-01 Phase Ib pilot study to evaluate reparixin in combination with<br />
chemotherapy with weekly paclitaxel in patients with HER-2<br />
negative metastatic breast cancer (MBC)<br />
Schott AF, Wicha M, Cristofanilli M, Ruffini P, McCanna S, Reuben<br />
JM, Goldstein LJ. University of Michigan, Ann Arbor, MI; Fox Chase<br />
<strong>Cancer</strong> Center, Philadelphia, PA; Dompé s.p.a., Milano, Italy; MD<br />
Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
OT2-3-02 Phase Ib/II study of an oral PI3K/mTOR inhibitor plus letrozole<br />
compared with letrozole (L) in pre-operative setting in<br />
patients with Estrogen Receptor-positive, HER2-negative early<br />
breast cancer (BC): Phase Ib preliminary data<br />
Canon JL, Bergh J, Saura C, Oliveira M, Houk B, Millham R, Barton<br />
J, Dowsett M, Giorgetti C. Grand Hopital de Charleroi, Charleroi,<br />
Belgium; Karolinska Institutet and University Hospital, Stockholm,<br />
Sweden; Vall d’Hebron University Hospital, Vall d’Hebron Institute of<br />
Oncology (VHIO), Barcelona, Spain; Pfizer Oncology, La Jolla; Pfizer<br />
Oncology, Groton; Pfizer Biotechnology Unit & Oncology Clinical<br />
Research, <strong>San</strong> Diego; Royal Marsden Hospital, London, United<br />
Kingdom; Pfizer Oncology, Milan, Italy.<br />
OT2-3-03 Denosumab versus placebo as adjuvant treatment for<br />
women with early-stage breast cancer at high risk of<br />
disease recurrence (D-CARE): An international, randomized,<br />
double-blind, placebo-controlled phase 3 clinical trial<br />
Goss PE, Barrios CH, Chan A, Finkelstein DM, Iwata H, Martin M, Braun<br />
A, Ke C, Maniar T, Coleman RE. Massachusetts General Hospital,<br />
Boston, MA; PUCRS School of Medicine, Porto Alegre, Brazil; <strong>Breast</strong><br />
<strong>Cancer</strong> Research Centre, Perth, WA, Australia; Aichi <strong>Cancer</strong> Center,<br />
Nagoya, Chikusa-ku, Japan; Hospital Gregorio Maranon, Madrid,<br />
Spain; Amgen Inc., Thousand Oaks, CA; CR-UK/YCR Sheffield <strong>Cancer</strong><br />
Research Centre, Sheffield, United Kingdom.<br />
OT2-3-04 A pilot phase II study to evaluate the impact of denosumab<br />
on disseminated tumor cells (DTC) in patients with early stage<br />
breast cancer (ESBC)<br />
Li J, Rugo HS. University of California, <strong>San</strong> Francisco, CA.<br />
OT2-3-05 AVASTEM: a phase II randomized trial evaluating anticancer<br />
stem cell activity of pre-operative bevacizumab and<br />
chemotherapy in breast cancer<br />
Gonçalves A, Pierga J-Y, Brain E, Tarpin C, Cure H, Esterni B, Boyer-<br />
Chammard A, Bertucci F, Jalaguier A, Houvenaeghel G, Viens P,<br />
Charaffe-Jauffret E, Extra J-M. Institut Paoli Calmettes, Marseille,<br />
France; Institut Curie-Centre René Huguenin, Paris, France; Institut<br />
Jean Godinot, Reims, France.<br />
OT2-3-06 A phase II, non-randomized, multicenter, exploratory trial<br />
of single agent BKM120 in patients with triple-negative<br />
metastatic breast cancer<br />
Saura C, Lin N, Ciruelos E, Maurer M, Lluch A, Gavilé J, Winer E,<br />
Baselga J, Rodón J. Vall d’Hebron University Hospital, Barcelona,<br />
Spain; Dana-Farber <strong>Cancer</strong> Institute, Boston, MA; Hospital 12 de<br />
Octubre, Madrid, Spain; Columbia University Medical Center,<br />
New York; Hospital Clínico de Valencia, Valencia, Spain; Instituto<br />
Valenciano de Oncología, Valencia, Spain; Massachusetts General<br />
Hospital, Boston; SOLTI <strong>Breast</strong> <strong>Cancer</strong> Research Group,<br />
Barcelona, Spain.<br />
OT2-3-07<br />
OT2-3-08<br />
OT2-3-09<br />
OT2-3-10<br />
OT2-3-11<br />
A randomized, phase 2 study of the poly (ADP-ribose)<br />
polymerase (PARP) inhibitor veliparib (ABT-888) in<br />
combination with temozolomide (TMZ) or in combination<br />
with carboplatin (C) and paclitaxel (P) versus placebo plus C/P<br />
in subjects with BRCA1 or BRACA2 mutation and metastatic<br />
breast cancer<br />
Isakoff SJ, Pulhalla S, Shepherd SP, Falotico N, Kaufman B, Friedlander<br />
M, Robson M, Domchek S, Garber J, McKeegan E, Chyla B, Qian J,<br />
Giranda VL. Massachusetts General Hospital, Boston, MA; University<br />
of Pittsburgh, PA; Abbott, Abbott Park, IL, Virgin Islands, British;<br />
Sheba Medical Center, Israel; Prince of Wales Hospital, Sydney,<br />
Australia; Memorial Sloan-Kettering <strong>Cancer</strong> Center, New York, NY;<br />
University of Pennsylvania, Philadelphia, PA; Dana Farber <strong>Cancer</strong><br />
Institute, Boston, MA.<br />
Phase III randomized study of the oral pan-PI3K inhibitor<br />
BKM120 with fulvestrant in postmenopausal women with<br />
HR+/HER2– locally advanced or metastatic breast cancer,<br />
treated with aromatase inhibitor, and progressed on or after<br />
mTOR inhibitor-based treatment – BELLE-3<br />
Di Leo A, Germa C, Weber D, Di Tomaso E, Dharan B, Massacesi C,<br />
Hirawat S. <strong>San</strong>dro Pitigliani Hospital of Prato, Prato, Italy; Novartis<br />
Oncology, Paris, France; Novartis Institutes for BioMedical Research,<br />
Inc., Cambridge, MA; Novartis Pharmaceuticals Corporation, East<br />
Hanover, NJ.<br />
Phase III randomized study of the oral pan-PI3K inhibitor<br />
BKM120 with fulvestrant in postmenopausal women with<br />
HR+/HER2– locally advanced or metastatic breast cancer<br />
resistant to aromatase inhibitor – BELLE-2<br />
Baselga J, Campone M, Cortes J, Iwata H, de Laurentiis M, Jonat W,<br />
Di Tomaso E, Hachemi S, Goteti S, Germa C, Massacesi C, Arteaga<br />
C. Massachusetts General Hospital, Boston, MA; Centre René<br />
Gauducheau, Nantes, France; Vall d’Hebron Institute Oncology,<br />
Barcelona, Spain; Aichi <strong>Cancer</strong> Center Hospital, Nagoya, Aichi, Japan;<br />
Università degli Studi di Napoli Federico II, Naples, Italy; Christian-<br />
Albrechts-Universität zu Kiel, Kiel, Germany; Novartis Institutes for<br />
BioMedical Research, Inc., Cambridge, MA; Novartis Oncology, Paris,<br />
France; Novartis Pharmaceuticals Corporation, East Hanover, NJ;<br />
Vanderbilt-Ingram <strong>Cancer</strong> Center, Nashville, TN.<br />
Phase II study of panitumumab, nab-paclitaxel, and<br />
carboplatin for patients with primary inflammatory breast<br />
cancer (IBC) without HER2 overexpression<br />
Willey JS, Alvarez RH, Valero V, Lara JM, Parker CA, Hortobagyi GN,<br />
Ueno NT. Morgan Welch Inflammatory <strong>Breast</strong> <strong>Cancer</strong> Research<br />
Program and Clinic, The University of Texas MD Anderson <strong>Cancer</strong><br />
Center, Houston, TX; University of TX, MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX.<br />
Tivozanib in combination with paclitaxel vs placebo with<br />
paclitaxel in patients with locally advanced or metastatic<br />
triple-negative breast cancer<br />
Mayer EL, Miller K, O’Shaughnessy J, Dickler M, Vogel C, Leyland-<br />
Jones B, Steelman L, Robinson M, Kuriyama N, Agarwal S. <strong>Breast</strong><br />
Oncology Center, Dana-Farber <strong>Cancer</strong> Institute, Boston, MA; Indiana<br />
University Melvin and Bren Simon <strong>Cancer</strong> Center, Indianapolis, IN;<br />
Baylor-Charles A. Sammons <strong>Cancer</strong> Center, Texas Oncology and US<br />
Oncology, Dallas, TX; Memorial Sloan-Kettering <strong>Cancer</strong> Center, New<br />
York, NY; Sylvester Comprehensive <strong>Cancer</strong> Center, Miami, FL; <strong>San</strong>ford<br />
Research/USD, Sioux Falls, SD; AVEO Oncology, Cambridge, MA.<br />
7:30 pm–10:00 pm<br />
OPEN SATELLITE EVENT presented by Clinical Care Options<br />
Marriott Rivercenter<br />
HER2-Positive <strong>Breast</strong> <strong>Cancer</strong>: Applying the Latest Developments to<br />
Clinical Practice<br />
WEBSITE: http://clinicaloptions.com/HER2Positive<br />
www.aacrjournals.org<br />
43s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
7:30 pm–10:00 pm<br />
OPEN SATELLITE EVENT presented by Clinical Care Options<br />
Marriott Rivercenter<br />
Practical Answers to Your Clinical Challenges: Optimal Use of Bone-<br />
Modifying Agents in <strong>Breast</strong> <strong>Cancer</strong><br />
WEBSITE: http://clinicaloptions.com/BoneHealth<strong>Breast</strong><strong>Cancer</strong><br />
Friday, December 7, 2012<br />
6:45 am–5:15 pm<br />
Registration<br />
Bridge Hall<br />
7:00 am–9:00 am<br />
Poster Discussion 7: Neoadjuvant Endocrine Therapy &<br />
Bisphosphonates<br />
Ballroom A<br />
Viewing 7:00 am<br />
Discussion 7:45 am<br />
Ruth O’Regan, MD, Chair and Discussant<br />
Emory University School of Medicine<br />
Atlanta, GA<br />
and<br />
Ingrid Mayer, MD, MSCI, Discussant<br />
Vanderbilt University Medical Center<br />
Nashville, TN<br />
PD07-01 Z1031B neoadjuvant aromatase inhibitor trial: A Phase 2 study<br />
of triage to chemotherapy based on 2 to 4 week Ki67 level<br />
>10%<br />
Ellis MJ, Suman V, McCall L, Luo R, Hoog J, Brink A, Watson M, Ma C,<br />
Unzeitig G, Pluard T, Whitworth P, Babiera G, Guenther M, Dayao Z,<br />
Leitch M, Ota D, Olson J, Hunt K, Allred C. Siteman <strong>Cancer</strong> Center,<br />
Washington University, St Louis, MO; Mayo Clinic; Duke University;<br />
Doctor’s Hospital of Laredo; Nashville <strong>Breast</strong> Center; MD Anderson<br />
<strong>Cancer</strong> Center; St. Elizabeth Med Ctr Southwest; Univ of New Mexico;<br />
UT Southwestern; University of Maryland Medical Center.<br />
PD07-02 Anticancer activity of letrozole plus zoledronic acid as<br />
neoadjuvant therapy for postmenopausal patients with breast<br />
cancer: FEMZONE trial results<br />
Fasching PA, Jud SM, Hauschild M, Kümmel S, Schütte M, Warm M,<br />
Hanf V, Muth M, Baier M, Schulz-Wendtland R, Beckmann MW, Lux<br />
MP. Erlangen University Hospital, Friedrich Alexander University of<br />
Erlangen Nuremberg, Erlangen, Germany; Frauenklinik Rheinfelden,<br />
Rheinfelden, Germany; Frauenklinik, Klinikum Essen-Mitte, Essen,<br />
Germany; Essen University Hospital, Essen, Germany; Cologne<br />
University Hospital, Cologne, Germany; Kliniken der Stadt Köln<br />
Holweide, Cologne, Germany; Klinikum Fuerth, Fuerth, Germany;<br />
Novartis Pharma GmbH, Nuremberg, Germany; Erlangen University<br />
Hospital, Friedrich Alexander University of Erlangen–Nuremberg,<br />
Erlangen, Germany.<br />
PD07-03 Increased pathologic complete response rate after a long term<br />
neoadjuvant letrozole treatment in postmenopausal estrogen<br />
and/or progesterone receptor-positive breast cancer<br />
Allevi G, Strina C, Andreis D, Zanoni V, Bazzola L, Bonardi S, Foroni C,<br />
Milani M, Cappelletti MR, Generali D, Berruti A, Bottini A. A.O. Istituti<br />
Ospitalieri di Cremona, Cremona, Italy; A.O.U. <strong>San</strong> Luigi Gonzaga di<br />
Orbassano, Orbassano, TO, Italy.<br />
PD07-04<br />
PD07-05<br />
PD07-06<br />
PD07-07<br />
PD07-08<br />
A randomized phase II neoadjuvant trial evaluating<br />
anastrozole and fulvestrant efficiency for post-menopausal<br />
ER-positive, HER2-negative breast cancer patients: first results<br />
of the UNICANCER CARMINA 02 French trial<br />
Lerebours F, Bourgier C, Alran S, Mouret-Reynier M-A, Venat Bouvet<br />
L, Kerbrat P, Salmon R, Mijonnet S, Becette V, Trassard M, Spyratos F,<br />
Lebas N, Martin A-L, Lemonnier J, Mouret-Fourme E. Institut Curie,<br />
Saint Cloud, France; Institut Gustave Roussy, Villejuif, France; Institut<br />
Curie, Paris, France; Centre Jean Perrin, Clermont-Ferrand, France;<br />
CHU, Limoges, France; Centre Eugene Marquis, Rennes, France; R&D<br />
Unicancer, Paris, France.<br />
A randomized controlled trial comparing zoledronic acid plus<br />
chemotherapy with chemotherapy alone as a neoadjuvant<br />
treatment in patients with HER2-negative primary breast<br />
cancer<br />
Hasegawa Y, Kohno N, Horiguchi J, Miura D, Ishikawa T, Hayashi<br />
M, Takao S, Kim SJ, Tanino H, Miyashita M, Konishi M, Shigeoka<br />
Y, Yamagami K, Akazawa K. Hirosaki Municipal Hospital, Hirosaki,<br />
Aomori, Japan; Tokyo Medical University Hospital, Tokyo, Japan;<br />
Gunma University Hospital, Maebashi, Gunma, Japan; Toranomon<br />
Hospital, Tokyo, Japan; Yokohama City University Medical Center,<br />
Yokohama, Kanagawa, Japan; Tokyo Medical University Hachioji<br />
Medical Center, Hachioji, Tokyo, Japan; Hyogo <strong>Cancer</strong> Center, Akashi,<br />
Hyogo, Japan; Osaka University Hospital, Suita, Osaka, Japan; Naga<br />
Municipal Hospital, Kinokawa, Wakayama, Japan; Konan Hospital,<br />
Kobe, Hyogo, Japan; Hyogo Prefectural Nishinomiya Hospital,<br />
Nishinomiya, Hyogo, Japan; Yodogawa Christian Hospital, Osaka,<br />
Japan; Shinko Hospital, Kobe, Hyogo, Japan; Niigata University<br />
Medical and Dental Hospital, Niigata, Japan.<br />
NEO-ZOTAC: Toxicity data of a phase III randomized trial with<br />
NEOadjuvant chemotherapy (TAC) with or without ZOledronic<br />
acid (ZA) for patients with HER2-negative large resectable or<br />
locally advanced breast cancer (BC)<br />
van de Ven S, Liefers G-j, Putter H, van Warmerdam LJ, Kessels LW,<br />
Dercksen W, Pepels MJ, Maartense E, van Laarhoven HWM, Vriens B,<br />
Smit VTHBM, Wasser MNJM, Meershoek-Klein Kranenbarg EM, van<br />
Leeuwen-Stok E, van de Velde CJH, Nortier JWR, Kroep JR. Leiden<br />
University Medical Center (LUMC), Leiden, Netherlands; Catharina<br />
Hospital, Eindhoven, Netherlands; Deventer Hospital, Deventer,<br />
Netherlands.<br />
Prediction of antiproliferative response to lapatinib by HER3 in<br />
an exploratory analysis of HER2-non-amplified (HER2-) breast<br />
cancer in the MAPLE presurgical study (CRUK E/06/039)<br />
Dowsett M, Leary A, Evans A, A’Hern R, Bliss J, Sahoo R, Detre S,<br />
Hills M, Haynes B, Harper-Wynne C, Bundred N, Coombes G, Smith<br />
IE, Johnston S. Royal Marsden Hospital, London, United Kingdom;<br />
Institut Gustave Roussy, Paris, France; Poole Hospital, Poole, Dorset,<br />
United Kingdom; Institute of <strong>Cancer</strong> Research, London, United<br />
Kingdom; Kent Oncology Centre, Maidstone, Kent, United Kingdom;<br />
University Hospital of South Manchester NHS Trust, Manchester,<br />
United Kingdom.<br />
Zoledronic acid specifically inhibits development of bone<br />
metastases in the post-menopausal setting – evidence from<br />
an in vivo breast cancer model<br />
Holen I, Wang N, Reeves KJ, Fowles AM, Croucher PI, Eaton CL,<br />
Ottewell PD. University of Sheffield, United Kingdom.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 44s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
PD07-09 Zoledronate versus ibandronate comparative evaluation<br />
(ZICE) trial - first results of a UK NCRI 1,405 patient phase<br />
III trial comparing oral ibandronate versus intravenous<br />
zoledronate in the treatment of breast cancer patients with<br />
bone metastases<br />
Barrett-Lee PJ, Casbard A, Abraham J, Grieve R, Wheatley D,<br />
Simmons P, Coleman R, Hood K, Griffiths G, Murray N. Velindre<br />
NHS Trust, Cardiff, Wales, United Kingdom; Cardiff University School<br />
of Medicine, Cardiff, Wales, United Kingdom; University Hospital,<br />
Coventry, England, United Kingdom; Royal Cornwall Hospital,<br />
Truro, England, United Kingdom; University Hospital, Southampton,<br />
England, United Kingdom; Weston Park Hospital, Sheffield, England,<br />
United Kingdom; Royal Adelaide Hospital, Adelaid, South Australia,<br />
Australia.<br />
7:00 am–9:00 am<br />
Poster Discussion 8: Disparities<br />
Ballroom B<br />
Viewing 7:00 am<br />
Discussion 7:45 am<br />
Patricia Ganz, MD, Chair<br />
UCLA Jonsson Comprehensive <strong>Cancer</strong> Center<br />
Los Angeles, CA<br />
Dawn Hershman, MD, Discussant<br />
Columbia University Medical Center<br />
New York, NY<br />
and<br />
Amelie Ramirez, DRPH, MPH, DO, Discussant<br />
UT Health Science Center<br />
<strong>San</strong> <strong>Antonio</strong>, TX<br />
PD08-01 Utilization of Oncotype DX in an inner-city population:<br />
Race or place?<br />
Guth AA, Fineberg S, Fei K, Franco R, Bickell N. NYU School of<br />
Medicine, New York, NY; Montefiore Medical Center, Bronx, NY;<br />
Mount Sinai School of Medicine, New York, NY.<br />
PD08-02 Disparities in the utilization of reconstruction after<br />
mastectomy: The California Teachers Study<br />
Kruper L, Xu XX, Bernstein L, Henderson K. City of Hope <strong>Cancer</strong><br />
Center, Duarte, CA.<br />
PD08-03 Barriers to breast reconstructive surgery in an underprivileged<br />
community: Does income really matter?<br />
Zelek LH, Festa A, Barbeau E, Morere J-F. Assistance Publique<br />
Hôpitaux de Paris, CHU Avicenne, Bobigny, France; Oncologie 93,<br />
Bobigny, France.<br />
PD08-04 Factors which affect surgical management in an underinsured,<br />
county hospital population<br />
Komenaka IK, Olsen L, Klemens AE, Hsu C-H, Nodora J, Martinez ME,<br />
Thompson PA, Bouton M. Maricopa Medical Center, Phoenix, AZ;<br />
University of Arizona, Tucson, AZ; Moores <strong>Cancer</strong> Center, University<br />
of California, <strong>San</strong> Diego, CA.<br />
PD08-05 Spanning the continuum to assess, serve and navigate Latinas<br />
with breast cancer: A tale of six projects<br />
Ramirez AG, Holden AE, Gallion K, <strong>San</strong>Miguel SA, Munoz E, Penedo<br />
FJ, Perez-Stable EJ, Talavera GG, Carrillo JE, Fernandez ME. University<br />
of Texas Health Science Center at <strong>San</strong> <strong>Antonio</strong>, TX; Redes en Accion:<br />
The National Latino <strong>Cancer</strong> Research Network, The University of<br />
Texas Health Science Center at <strong>San</strong> <strong>Antonio</strong>, <strong>San</strong> <strong>Antonio</strong>, TX.<br />
PD08-06 Significant clinical impact of recurrent BRCA1<br />
and BRCA2 (BRCA) mutations in Mexico<br />
Villarreal-Garza C, Herrera LA, Herzog J, Port D, Mohar A, Perez-<br />
Plasencia C, Clague J, Alvarez RMa, <strong>San</strong>tibanez M, Blazer KR,<br />
Weitzel JN. Instituto Nacional de <strong>Cancer</strong>ologia, Mexico City, Mexico<br />
DF, Mexico; Instituto Nacional de <strong>Cancer</strong>ologia – Instituto de<br />
Investigaciones Biomedicas, UNAM, Mexico City, Mexico DF, Mexico;<br />
City of Hope, Duarte, CA.<br />
7:00 am–9:00 am<br />
POSTER SESSION 4 & Continental Breakfast<br />
Exhibit Halls A–B<br />
Detection/Diagnosis: <strong>Breast</strong> Imaging - MRI<br />
P4-01-01 Integrating dynamic magnetic resonance imaging and gene<br />
expression profiling reveals novel therapeutic targets in<br />
locally advanced breast cancer<br />
Hughes NP, Mehta S, Winchester L, Han C, Buffa FM, Adams RF,<br />
Harris AL. Stanford University, Stanford, CA; University of Oxford,<br />
United Kingdom; Churchill Hospital, Oxford, United Kingdom.<br />
P4-01-02 Association of DCE-MRI texture features with molecular<br />
phenotypes and neoadjuvant therapy response in<br />
breast cancer<br />
Banerjee N, Maity S, Varadan V, Janevski A, Kamalakaran S, Sikov W,<br />
Abu-Khalaf M, Bossuyt V, Lannin D, Harris L, Cornfeld D, Dimitrova N.<br />
Philips Research North America; Yale Comprehensive <strong>Cancer</strong> Center;<br />
Warren Alpert Medical School of Brown University; Yale-New Haven<br />
Hospital; Yale <strong>Breast</strong> <strong>Cancer</strong> Program; Seidman <strong>Cancer</strong> Center.<br />
P4-01-03 Quantitative DCE-MRI to predict the response of primary<br />
breast cancer to neoadjuvant therapy<br />
Li X, Arlinghaus LR, Chakravarthy AB, Abramson RG, Abramson VG,<br />
Farley J, Ayers GD, Mayer IA, Kelley MC, Meszoely IM, Means-Powell J,<br />
Grau AM, <strong>San</strong>ders ME, Yankeelov TE. Vanderbilt University.<br />
P4-01-04 MRI enhancement in stromal tissue surrounding breast<br />
tumors: Association with RFS following neoadjuvant<br />
chemotherapy<br />
Jones EF, Sinha SP, Newitt D, Klifa C, Kornak J, Park CC, Hylton NM.<br />
University of California, <strong>San</strong> Francisco, CA.<br />
P4-01-05 Utility of Preoperative Routine MRI and PET/CT in <strong>Breast</strong><br />
<strong>Cancer</strong> Staging vs. Surgical Staging<br />
Higaki K, Kochi M, Ito M, Otani S. Hiroshima City Hospital,<br />
Hiroshima, Japan.<br />
P4-01-06 Evaluation of 3D T2-weighted <strong>Breast</strong> MRI<br />
Moran CJ, Hargreaves BA, Saranathan M, Daniel BL. Stanford<br />
University, Stanford, CA.<br />
P4-01-07 The Relationship of <strong>Breast</strong> Density in Mammography and<br />
Magnetic Resonance (MR) Imaging in a High Risk Population<br />
Chun J, Refinetti AP, Schnabel F, Leite AP, Price A, Billig J, Schwartz S,<br />
Moy L. NYU Langone Medical Center, New York, NY.<br />
P4-01-08 Effect of bilateral salpingo-oophorectomy on breast MRI<br />
fibroglandular volume and background parenchymal<br />
enhancement for BRCA 1/2 mutation carriers<br />
DeLeo, III MJ, Domchek S, Kontos D, Conant E, Weinstein S. Hospital<br />
of the University of Pennsylvania, Philadelphia, PA.<br />
P4-01-09 Screening breast magnetic resonance imaging (MRI) in earlystage<br />
breast cancer survivors<br />
Dowton AA, Meyer ME, Ruddy KJ, Yeh ED, Partridge AH. Dana-Farber<br />
<strong>Cancer</strong> Institute, Boston, MA; Brigham & Women’s Hospital,<br />
Boston, MA.<br />
P4-01-10 High-resolution diffusion weighted imaging for the separation<br />
of benign from malignant BI-RADS 4/5 lesions found on breast<br />
MRI at 3 Tesla<br />
Wisner DJ, Rogers N, Deshpande VS, Newitt DN, Laub GA, Porter<br />
DA, Joe BN, Hylton NM. University of California, <strong>San</strong> Francisco, CA;<br />
Siemens Medical Solutions, USA, Inc, <strong>San</strong> Francisco, CA; Siemens<br />
Medical Solutions, Erlangen, Germany.<br />
P4-01-11 Clinical Findings and Outcomes from MRI Staging of <strong>Breast</strong><br />
<strong>Cancer</strong> in a Diverse Population<br />
Raghavendra A, Ji L, Ricker C, Tang S, Church TD, Larsen L, Sheth<br />
P, Sposto R, Sener S, Tripathy D. University of Southern California<br />
Keck School of Medicine, Los Angeles, CA; Los Angeles County and<br />
University of Southern California (LAC+USC) Healthcare Network,<br />
Los Angeles, CA; USC Norris Comprehensive <strong>Cancer</strong> Center,<br />
Los Angeles, CA.<br />
www.aacrjournals.org<br />
45s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-01-12 Compliance with Recommended Follow-Up after MRI-<br />
Guided Core Needle Biopsy of Suspicious <strong>Breast</strong> Lesions: A<br />
Retrospective Study<br />
Thompson MO, Lipson JA, Daniel BL, Harrigal CL, Mullarkey PJ, Ikeda<br />
DM. Stanford University School of Medicine, Stanford, CA.<br />
P4-01-13 Practice patterns of MRI utilization for breast cancer treatment<br />
within the University of California system as part of the<br />
Athena initiative<br />
Tokin CA, Ojeda H, Mayadev JS, Hylton NM, Fowble BL, Rugo HS,<br />
Hwang S, Hurvitz S, Wells C, Blair SL. University of California, <strong>San</strong><br />
Diego; University of California, Davis; University of California, <strong>San</strong><br />
Francisco; Duke University; University of California, Los Angeles.<br />
P4-01-14 Can MRI predict the response to neoadjuvant chemotherapy<br />
in breast cancer accurately?<br />
Fatayer H, Kim B, Dall B, Sharma N, Manuel D, Shabaan A, Perren<br />
T, Velikova G, Horgan K, Lansdown M. Leeds General Infirmary; St<br />
James‘s University Hospital.<br />
P4-01-15 Impact of Preoperative MRI on the Surgical Treatment of<br />
<strong>Breast</strong> <strong>Cancer</strong>: A SEER-Medicare Analysis<br />
Thorsen CM, Weiss JE, Kerlikowske K, Ozanne EM, Buist DS, Hubbard<br />
RA, Tosteson AN, Henderson LM, Virnig BA, Goodrich ME, Onega<br />
TL. University of California, <strong>San</strong> Francisco, CA; Dartmouth Medical<br />
School, Lebanon, NH; University of Washington, Seattle, WA;<br />
University of North Carolina, Chapel Hill, NC; University of Minnesota,<br />
Minneapolis, MN.<br />
P4-01-16 Withdrawn<br />
P4-01-17 Ductolobular breast carcinoma and the role of preoperative<br />
magnetic resonance imaging<br />
Postma EL, El Sharouni MA, Verkooijen HM, Witkamp AJ, van den<br />
Bosch MA, van Hillegersberg R, van Diest PJ. UMC Utrecht, Utrecht,<br />
Utrecht, Netherlands.<br />
Detection/Diagnosis: Molecular, Functional, and Novel Imaging<br />
P4-02-01 18F-FDG PET/CT for the assessment of locoregional lymph<br />
node involvement and radiotherapy indication in stage II-III<br />
breast cancer treated with neoadjuvant chemotherapy<br />
Koolen BB, Valdés Olmos RA, Vogel WV, Vrancken Peeters M-JTFD,<br />
Rodenhuis S, Rutgers EJT, Elkhuizen PHM. Netherlands <strong>Cancer</strong><br />
Institute - Antoni van Leeuwenhoek Hospital, Amsterdam,<br />
Netherlands.<br />
P4-02-02 Comparison of 18F-FDG PET-CT and 11C-MET PET-CT for<br />
assessment of response to neoadjuvant chemotherapy in<br />
locally advanced breast carcinoma<br />
Dinesh A, Ramteke VK, Chander J, Tripathi M, Mahajan S. Maulana<br />
Azad Medical College, New Delhi, Delhi, India; Institute of Nuclear<br />
Medicine & Allied Sciences, New Delhi, Delhi, India.<br />
P4-02-03 FDG PET/CT for early monitoring of response to neoadjuvant<br />
chemotherapy in breast cancer patients<br />
Andrade W, Soares F, Lima E, Maciel MdS, Toledo C, Iyeyasu H, Cruz<br />
M, Fanelli M. A. C. Camargo <strong>Cancer</strong> Hospital, São Paulo, SP, Brazil.<br />
P4-02-04 Tissue oxyhemoglobin dynamics measured with functional<br />
optical imaging immediately after starting chemotherapy<br />
correlates with markers of cellular proliferation and<br />
inflammation in a rat breast tumor model<br />
Ueda S, Roblyer D, Cerussi A, Saeki T, Tromberg B. Beckman Laser<br />
Institute, University of California, Irvine, Irvine, CA; Saitama Medical<br />
University, Hidaka, Saitama, Japan.<br />
P4-02-05 A novel 64Cu-liposomal PET agent (MM-DX-929) predicts<br />
response to liposomal chemotherapeutics in preclinical breast<br />
cancer models<br />
Lee H, Zheng J, Gaddy D, Kirpotin D, Dunne M, Drummond D, Allen<br />
C, Jaffray D, Hendriks B, Wickham T. Merrimack Pharmaceuticals,<br />
Boston, MA; Princess Margaret Hospital, University Health Network,<br />
Toronto, ON, Canada; Leslie Dan Faculty of Pharmacy, University of<br />
Toronto, ON, Canada.<br />
P4-02-06 Molecular imaging with trastuzumab and pertuzumab<br />
of HER2-positive breast cancer in mice: a step towards<br />
personalized medicine<br />
Collin B, Oudot A, Vrigneaud J-M, Moreau M, Raguin O, Duchamp<br />
O, Tizon X, Denat F, Varoqueaux N, Brunotte F, Fumoleau P.<br />
Centre Georges François Leclerc, Dijon, France; Institut de Chimie<br />
Moléculaire de l’université de Bourgogne, Dijon, France; Oncodesign,<br />
Dijon, France; Roche France, Boulogne Billancourt, France.<br />
P4-02-07 Early Optical Tomography Changes Predict <strong>Breast</strong> <strong>Cancer</strong><br />
Response to Neoadjuvant Chemotherapy<br />
Lim EA, Gunther JE, Flexman M, Kim HK, Hibshoosh H, Kalinsky K,<br />
Crew K, Maurer M, Taback B, Feldman S, Brown M, Refice S, Alvarez-<br />
Cid M, Hielscher A, Hershman DL. Columbia University Medical<br />
Center, New York, NY; Columbia University, New York, NY; Herbert<br />
Irving Comprehensive <strong>Cancer</strong> Center, New York, NY; Mailman School<br />
of Public Health, New York, NY.<br />
P4-02-08 Quantitative Characterization of 3D Vasculature Spatial<br />
Patterns Within Tumor Microenvironment of <strong>Breast</strong> <strong>Cancer</strong><br />
Stem Cells<br />
Zhan M, Li F, Zhu Y, Ma J, Landua J, Wei W, Vadakkan T, Zhang M,<br />
Dickinson M, Lewis M, Rosen J, Wong S. NCI Center for Modeling<br />
<strong>Cancer</strong> Development, The Methodist Hospital, Houston, TX; Baylor<br />
College of Medicine, Houston, TX.<br />
P4-02-09 Molecular <strong>Breast</strong> Imaging: the sensitivity of breastspecific<br />
gamma imaging (BSGI) as a diagnostic adjunct to<br />
mammography and ultrasound in a triple assessment protocol<br />
Weigert JM, Kieper DA, Stern LH, Böhm-Vélez M. Mandell and Blau<br />
MDs PC, New Britain, CT; Hampton University, Hampton, VA; Thomas<br />
Jefferson University, Methodist Division, Philadelphia, PA; Weinstein<br />
Imaging Associates, Pittsburgh, PA.<br />
P4-02-10 Molecular <strong>Breast</strong> Imaging: A multicenter clinical registry to<br />
compare breast-specific gamma imaging (BSGI) and breast<br />
MRI in the detection of breast carcinoma<br />
Weigert JM, Kieper DA, Stern LH, Böhm-Vélez M. Hampton<br />
University, Hampton, VA; Thomas Jefferson University, Methodist<br />
Division, Philadelphia, PA; Mandell and Blau MDs PC, New Britain, CT;<br />
Weinstein Imaging Associates, Pittsburgh, PA.<br />
Detection/Diagnosis: <strong>Breast</strong> Imaging - Other Methods<br />
P4-03-01 Distance of breast cancer from the skin influence axillary<br />
nodal metastasis<br />
Kim EJ, Chae BJ, Song BJ, Kwak HY, Chang EY, Kim SH, Jung SS. Seoul<br />
St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic<br />
of Korea.<br />
P4-03-02 Automatic BI-RADS Diagnosis of <strong>Breast</strong> Lesions by<br />
CAD(computer-aid diagnosis)<br />
Kuo W-H, Chuang S-C, Yang S-H, Chen C-N, Chen A, Chang K-J.<br />
National Taiwan University Hospital and National Taiwan University<br />
College of Medicine, Taipei, Taiwan; Graduate Institute of Industrial<br />
Engineering, National Taiwan University, Taipei, Taiwan.<br />
P4-03-03 Feasibility study of a new volume navigation system-guided<br />
breast biopsy method for incidental enhancing lesions<br />
detected by breast contrast-enhanced magnetic resonance<br />
imaging<br />
Takahashi M, Jinno H, Hayashida T, Nemoto M, Tanimoto A, Kitagawa<br />
Y. Keio University School of Medicine, Tokyo, Japan.<br />
P4-03-04 The potential use of Optical Coherence Tomography for<br />
intraoperative breast tumour margin width estimation<br />
Wilson BC, Akens MK, Niu CJ. University Health Network, Ontario<br />
<strong>Cancer</strong> Institute, Toronto, ON, Canada; Tornado Medical System,<br />
Toronto, ON, Canada.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 46s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P4-03-05 The Clinical Trial of New Optical Mammography<br />
Ogura H, Yoshimoto K, Nasu H, Hosokawa Y, Matsunuma R, Ide<br />
Y, Yamaki E, Yamashita D, Suzuki T, Oda M, Ueda Y, Yamashita Y,<br />
Sakahara H. Hamamatsu University School of Medicine, Hamamatsu,<br />
Shizuoka, Japan; Hamamatsu Photonics K.K., Hamamatsu,<br />
Shizuoka, Japan.<br />
P4-03-06 Non-invasive classification of microcalcifications by the use of<br />
X-ray phase contrast mammography as a novel tool in breast<br />
diagnostics<br />
Hauser N, Wang Z, Kubik-Huch RA, Singer G, Trippel M, Roessl E, Hohl<br />
MK, Stampanoni M. Interdisciplinary <strong>Breast</strong> Center Kantonsspital<br />
Baden, Baden, Switzerland; Paul Scherrer Institut, Villigen, Switzerland;<br />
Kantonsspital Baden, Baden, Switzerland; Philips Research<br />
Laboratories, Hamburg, Germany.<br />
P4-03-07 Angiogenic effect of bevacizumab and paclitaxel in<br />
metastatic breast cancer: evaluation by contrast-enhanced<br />
ultrasonography using Sonazoid®<br />
Ito T, Mizuno H, Iiboshi Y, Yamamura N, Fujii H, Hitora T, Fujii R,<br />
Ohashi T, Nakagawa T, Izukura M. Rinku General Medical Center,<br />
Izumisano, Osaka, Japan.<br />
P4-03-08 A new real-time image fusion technique, a coordinated<br />
sonography and MRI using magnetic position tracking system,<br />
improves the sonographic identification of enhancing lesions<br />
in breast MRI<br />
Nakano S, Fujii K, Yoshida M, Kousaka J, Mouri Y, Fukutomi T,<br />
Ishiguchi T. Aichi Medical University, Nakakute, Aichi, Japan.<br />
P4-03-09 A comparison of MRI, PET-CT, and ultrasonography for<br />
evaluation of tumor response to neoadjuvant chemo-therapy<br />
in patients with locally advanced breast cancer<br />
Boothe DL, Stessin A, Nagar H, Hayes MK. Weill Cornell Medical<br />
College, New York, NY.<br />
P4-03-10 Sonographic-pathological correlation in contrast-enhanced<br />
ultrasonography in the diagnosis of breast cancers<br />
Kato K, Miyamoto Y, Kamio M, Nogi H, Imawari Y, Mimoto R, Toriumi<br />
Y, Nakata N, Takeyama H, Uchida K. The Jikei University School of<br />
Medicine, Tokyo, Japan.<br />
P4-03-11 SUVmax of FDG-PET/CT Is Associated with Chemotherapy<br />
Response Assay Test Results and Prognostic Factors in <strong>Breast</strong><br />
<strong>Cancer</strong> Patients<br />
Lee A, Chang J, Bang B, Lee J, Han D, Min S, Yun C, Kim BS, Lim W,<br />
Paik N, Moon B-I. Ewha Womans University Hospital, Seoul, Republic<br />
of Korea.<br />
P4-03-12 Diagnostic value and clinical significance of integrin αvβ3 in<br />
breast mass<br />
Xu Z, Song Y, Sun L, Sun G, Ma Q, Gao S, Wang K. China-Japan<br />
Union Hospital of JiLin University, JiLin Province <strong>Breast</strong> Diseases<br />
Institute, Changchun, Jilin, China; China-Japan Union Hospital of JiLin<br />
University, Changchun, Jilin, China.<br />
Tumor Cell and Molecular Biology: Immunology and Preclinical<br />
Immunotherapy<br />
P4-04-01 Combination of intratumoral CpG with systemic anti-OX40 and<br />
anti-CTLA4 mAbs eradicates established triple negative breast<br />
tumors in mice<br />
Li J, Tandon V, Levy R, Esserman L, Campbell M. University of<br />
California, <strong>San</strong> Francisco, CA; Stanford University, Stanford, CA.<br />
P4-04-02 Tumor-initiated peripheral myeloid cell expansion is reversed<br />
by radiation therapy<br />
Gough MJ, Savage T, Bahjat KS, Redmond W, Bambina S, Kasiewicz M,<br />
Cottam B, Newell P, Crittenden MR. Earle A. Chiles Research Institute,<br />
Providence <strong>Cancer</strong> Center, Portland, OR; Providence <strong>Cancer</strong> Center,<br />
Portland, OR; The Oregon Clinic, Portland, OR.<br />
P4-04-03 Monocytic immature myeloid cells permit tumor immune<br />
evasion during postpartum involution<br />
Schedin P, Martinson H, Callihan E, Jindal S, Borges V. University of<br />
Colorado, Aurora, CO.<br />
P4-04-04 Immunohistochemical analysis of <strong>Cancer</strong> Testis antigens and<br />
Topoisomerase 2-alpha expression in triple negative breast<br />
carcinomas: a retrospective study<br />
Juretic A, Mrklic I, Spagnoli GC, Pogorelic Z, Tomic S. Zagreb<br />
University Hospital Centre, Zagreb, Croatia; Split University Hospital<br />
Centre, Split, Croatia; University of Basel, Switzerland.<br />
P4-04-05 Listeria monocytogenes-based bivalent Lm-LLO immunotherapy<br />
for the treatment of HER2/neu positive and triple negative<br />
breast cancer and its impact on immunosuppression<br />
Wallecha A, Ramos K, Malinina I, Singh R. Advaxis Inc, Princeton, NJ.<br />
P4-04-06 Young women’s breast cancer is characterized by increased<br />
immune suppression through circulating myeloid derived<br />
supressor cells<br />
Borges VF, Ramirez O, Borakove M, Manthey E, Diamond JR, Elias AD,<br />
Finlayson C, Kounalakis N, Jordan K. University of Colorado Denver,<br />
Aurora, CO; University of Colorado <strong>Cancer</strong> Center, Aurora, CO.<br />
P4-04-07 Tartrate-resistant Acid Phosphatase (TRAcP)-Expressed Tumor-<br />
Associated Macrophages Promote <strong>Breast</strong> <strong>Cancer</strong> Progression<br />
Dai M-S, Wu C-C, Chang P-Y, Ho C-L, Hsieh Y-F, Lo K-Y, Kao W-Y,<br />
Chao T-Y, Yu J-C. Tri-Service General Hospital, Taipei, Taiwan; Taipei<br />
Medical University, Taipei, Taiwan.<br />
P4-04-08 A Potential non-viral vector to transfect dendritic cell and<br />
thereby MHC-Class I antigen presentation might be a potential<br />
use in carcinoma<br />
Shaheen S, Akita H, Souichirou I, Miura N, Harashima H. Hokkaido<br />
University, Sapporo, Hokkaido, Japan.<br />
Tumor Cell and Molecular Biology: Gene Therapy<br />
P4-05-01 Oncolytic Herpes Simplex Virus Vector G47Δ Effectively Targets<br />
<strong>Breast</strong> <strong>Cancer</strong> Stem Cells<br />
Liu R, Zeng W, Hu P, Wu J, Li J, Wang J, Lei L. The Third Affiliated<br />
Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China;<br />
The Sichuan Province <strong>Cancer</strong> Hospital, Chengdu, Sichuan, China.<br />
Tumor Cell and Molecular Biology: Novel/Emerging Therapeutic Targets<br />
P4-06-01 JAK2/STAT3 activity in inflammatory breast cancer supports<br />
the investigation of JAK2 therapeutic targeting<br />
Overmoyer BA, Almendro V, Shu S, Peluffo G, Park SY, Nakhlis F,<br />
Bellon JR, Yeh ED, Jacene HA, Hirshfield-Bartek J, Polyak K. Dana<br />
Farber <strong>Cancer</strong> Institute, Harvard Medical School, Boston, MA; Seoul<br />
National University, Seoul, Korea.<br />
P4-06-02 Identification of novel G-protein coupled receptor targets in<br />
HER2-positive breast cancer<br />
Yadav P, Bhat RR, Chayanam S, Christiny PI, Nanda S, Hu H, Creighton<br />
C, Osborne CK, Schiff R, Trivedi MV. University of Houston, TX; Lester<br />
& Sue Smith <strong>Breast</strong> Center, Dan Duncan <strong>Cancer</strong> Center, Houston, TX;<br />
Baylor College of Medicine, Houston, TX.<br />
P4-06-03 Zinc Finger Nuclease Genome Engineering Reveals Multiple<br />
Functions of Secretory Leukocyte Peptidase Inhibitor in<br />
Regulating Pleuripotency of <strong>Cancer</strong> Stem Cells in Inflammatory<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Robertson FM, Hibbs S, Boley KM, Chu K, Ye Z, Wright MC, Liu H, Luo<br />
AZ, Cristofanilli M, Wemhoff G. The University of Texas MD Anderson<br />
<strong>Cancer</strong> Center, Houston, TX; Sigma-Aldrich, St. Louis, MO; Fox Chase<br />
<strong>Cancer</strong> Center, Philadelphia, PA.<br />
P4-06-04 Gamma-secretase inhibitors suppress the activation of NFκB<br />
and the expression of TNFα, IL-6 and IL-8 in triple negative<br />
breast cancer cells<br />
Gu J-W, King J, Makey KL, Chinchar E, Gibson J, Miele L. University of<br />
Mississippi Medical Center, Jackson, MS.<br />
www.aacrjournals.org<br />
47s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-06-05 NF-κB Upregulates β1-integrin via Increased Transcriptional<br />
Activity in Three-dimensional Culture: a Mechanism by which<br />
Malignant <strong>Breast</strong> Cells Acquire Radioresistance<br />
Ahmed KM, Zhang H, Park CC. Lawrence Berkeley National<br />
Laboratory, Berkeley, CA; University of California, <strong>San</strong> Francisco, CA.<br />
P4-06-06 RNAi screen of the breast cancer genome identifies KIF14 and<br />
TLN1 as genes that modulate chemosensitivity in breast cancer<br />
Singel SM, Cornelius C, Batten K, Fasciani G, Wright WE, Lum L, Shay<br />
JW. University of Texas Southwestern, Dallas, TX.<br />
P4-06-07 Moved to Poster Session 6, Saturday, December 8<br />
7:00 AM - 8:30 AM<br />
P4-06-08 Clinical utility of functional analysis of FGFR kinase family for<br />
selecting patients who may benefit from FGFR inhibitors<br />
Hoe N, Zhou J, Kuy C, Jin K, Srikrishnan R, Soundararajan A, Ma Y, Liu<br />
X, Singh S. Prometheus Labs, <strong>San</strong> Diego, CA.<br />
P4-06-09 Cell surface receptor CDCP1 as a potential marker of triple<br />
negative breast cancers progression<br />
Campiglio M, Sasso M, Bianchi F, De Cecco L, Turdo F, Triulzi T, Orlandi<br />
R, Morelli D, Aiello P, Ghirelli C, Agresti R, Tagliabue E. Fondazione<br />
IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Fondazione IRCCS<br />
Istituto Nazionale dei Tumori.<br />
P4-06-10 Epigenetic silencing of glutamine synthetase (Glul) defines<br />
glutamine depletion therapy<br />
Cavicchioli F, Shia A, O’Leary K, Haley V, Crook TR, Thompson AM,<br />
Lackner M, Lo Nigro C, Schmid P. Brighton and Sussex Medical<br />
School, University of Sussex, Brighton, United Kingdom; Ninewells<br />
Hospital, University of Dundee, United Kingdom; Genentech, Inc., <strong>San</strong><br />
Francisco; S. Croce General Hospital, Cuneo, Italy.<br />
P4-06-11 Expression of genes spanning a breast cancer susceptibility<br />
locus on 6q25.1 is modulated by epigenetic modification<br />
Dunbier AK, White J, Van Huffel S. University of Otago, Dunedin,<br />
Otago, New Zealand.<br />
P4-06-12 Monoclonal antibodies against nicastrin for the treatment of<br />
breast cancer: in vitro and in vivo characterisation and function<br />
Filipovic A, Lombardo Y, Deonarain M, Giamas G, Cordingley H,<br />
Tralau-Stewart C, Coombes RC. Imperial College London, United<br />
Kingdom.<br />
P4-06-13 Effects of Statin on triple-negative breast cancer (TNBC) with<br />
Ets-1 overexpression<br />
Lee S, Jung HH, Park YH, Ahn JS, Im Y-H. Samsung Medical Center.<br />
P4-06-14 CD146-suppresses breast tumor invasion via a novel<br />
transcription target TIMPv<br />
Shanmuganathan S, AbdElmageed Z, Fernando A, Gaur R, Ramkumar<br />
A, Bhat S, Gupta I, Muzumdar S, Hakkim L., Ouhtit A. Sultan Qaboos<br />
University, Al-Khod, Seeb, Oman.<br />
P4-06-15 Mifepristone modifies the tumor microenvironment increasing<br />
the therapeutic efficiency of low doses of Doxorubicin<br />
liposomes or paclitaxel-albumin nanoparticles in a murine<br />
model of breast cancer<br />
Sequeira GR, Vanzulli SI, Lamb CA, Rojas PA, Lanari C. Instituto de<br />
Biología y Medicina Experimental, Ciudad Autónoma de Buenos Aires,<br />
Argentina; Academia Nacional de Medicina, Ciudad Autónoma de<br />
Buenos Aires, Argentina.<br />
P4-06-16 TGF-β2, A Novel Target of CD44-Promoted <strong>Breast</strong> <strong>Cancer</strong><br />
Invasion<br />
Gupta I, Madani S, Abdraboh M, Al Riyami H, Muzumdar S,<br />
AbdElmageed Z, Shanmuganathan S, Bhat S, Ramkumar A, Hakkim<br />
L, Ouhtit A. College of Medicine and Health Sciences, Sultan Qaboos<br />
University, Muscat, Al Khuwd, Oman.<br />
P4-06-17<br />
P4-06-18<br />
P4-06-19<br />
Antitumor activity of the novel mithramycin analog EC8042 in<br />
triple negative breast cancer<br />
Pandiella A, Montero JC, Cuenca D, Re-Louhau F, Nuñez LE, Moris<br />
F, Ocana A. Salamanca <strong>Cancer</strong> Research Center, Salamanca, Spain;<br />
Translational Research Unit, Albacete University Hospital, Albacete,<br />
Spain; Entrechem SL, Oviedo, Spain.<br />
Targeting basal-like breast cancer through downstream<br />
effectors of oncogene cooperation<br />
McMurray HR, Walters EA, Heyer DM, Candelaria PV, Wang S, Grose<br />
VA, Llop JR, Zhang Y. University of Rochester Medical Center,<br />
Rochester, NY.<br />
Astemizole and calcitriol: A novel targeted therapeutic strategy<br />
for breast cancer<br />
García J, García R, Villanueva O, <strong>San</strong>tos N, Barrera D, Avila E, Ordaz D,<br />
Halhali A, Camacho J, Larrea F, Díaz L. Instituto Nacional de Ciencias<br />
Médicas y Nutrición Salvador Zubirán, México, DF, Mexico; Centro de<br />
Investigación y de Estudios Avanzados del I.P.N., México, DF, Mexico.<br />
Tumor Cell and Molecular Biology: New Drugs and Mechanisms<br />
P4-07-01 The Class I Selective PI3K Inhibitor GDC-0941 Enhances the<br />
Efficacy of Docetaxel in Human <strong>Breast</strong> <strong>Cancer</strong> Models by<br />
Increasing the Rate of Apoptosis<br />
Wallin JJ, Guan J, Prior WW, Lee LB, Ross L, Belmont LD, Koeppen<br />
H, Belvin M, Sampath D, Friedman LS. Genentech, Inc., South <strong>San</strong><br />
Francisco, CA.<br />
P4-07-02 Withdrawn<br />
P4-07-03 Rapamycin and Dalotuzumab in combination inhibit parental<br />
and endocrine resistant breast cancer cells<br />
Beckwith H, Fettig-Anderson L, Yueh N, Douglas Y. University of<br />
Minnesota, Minneapolis, MN.<br />
P4-07-04 Methioninase cell-cycle synchronization potentiates<br />
chemotherapy for breast cancer<br />
Yano S, Li S, Han Q, Tan Y, Fujiwara T, Hoffman RM. Anti<strong>Cancer</strong> Inc.,<br />
<strong>San</strong> Diego, CA; Okayama University Graduate School of Medicine and<br />
Dentistry, Okayama, Japan; University of California, <strong>San</strong> Diego, CA.<br />
P4-07-05 MEDI3379, an antibody against HER3, is active in HER2-driven<br />
human breast tumor models<br />
Xiao Z, Rothstein R, Carrasco R, Wetzel L, Kinneer K, Chen H, Tice D,<br />
Hollingsworth R, Steiner P. MedImmune, LLC, Gaithersburg, MD.<br />
Tumor Cell and Molecular Biology: Drug Resistance<br />
P4-08-01 PI3K/mTOR inhibition overcomes in vitro and in<br />
vivo trastuzumab resistance independent of feedback<br />
activation of pAKT<br />
O’Brien NA, McDonald K, Tong L, Von Euw E, Conklin D, Kalous O,<br />
Di Tomaso E, Schnell C, Linnartz R, Hurvitz SA, Finn RS, Hirawat<br />
S, Slamon DJ. UCLA, Los Angeles, CA; Novartis Pharmaceuticals,<br />
Cambridge, MA; Novartis Pharmaceuticals, Basel, Switzerland.<br />
P4-08-02<br />
P4-08-03<br />
P4-08-04<br />
Reactivation of oncogenic signaling through mTOR inhibitorsinduced<br />
feedback adaptations<br />
Rodrik-Outmezguine V, Chandarlapaty S, Poulikakos P, Scaltriti M,<br />
Baselga J, Rosen N. MSKCC, New York, NY; MGH, Charlestown, MA.<br />
The impact of the heregulin-HER receptor signaling axis on<br />
response to HER tyrosine kinase inhibitors<br />
Gwin WR, Liu L, Zhao S, Xia W, Spector NL. Duke University, Durham,<br />
NC.<br />
Abcc10 status affects proliferation, metastases and tumor<br />
sensitivity<br />
Domanitskaya N, Paulose C, Jacobs J, Foster K, Hopper-Borge E. Fox<br />
Chase <strong>Cancer</strong> Center, Philadelphia, PA.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 48s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P4-08-05 Basement membrane localized tumor cells are protected from<br />
HER2-targeted therapy in vivo<br />
Zoeller JJ, Bronson RT, Gilmer TM, Selfors LM, Lu Y, Apple SK, Press<br />
MF, Hurvitz SA, Slamon DJ, Mills GB, Brugge JS. Harvard Medical<br />
School, Boston, MA; GlaxoSmithKline, Research Triangle Park, NC; UT<br />
MD Anderson <strong>Cancer</strong> Center, Houston, TX; University of California, Los<br />
Angeles, CA; University of Southern California, Los Angeles, CA.<br />
P4-08-06 Notch-dependent Regulation of Novel Genes Associated with<br />
Trastuzumab Resistance<br />
Osipo C, Baumgartner A, Zlobin A, O’Toole M. Loyola University<br />
Chicago, Maywood, IL.<br />
P4-08-07 Novel insight into the tumor “flare” phenomenon and lapatinib<br />
resistance<br />
Piede JA, Zhao S, Liu L, Lyerly HK, Osada T, Wang T, Xia W, Spector N.<br />
Duke University Medical Center, Durham, NC.<br />
P4-08-08 HOXC10, a homeobox protein overexpressed in breast cancer,<br />
modulates the response to chemotherapy treatment<br />
Sadik H, Nguyen N, Panday H, Kumar R, Pandita T, Sukumar S. Sidney<br />
Kimmel Comprehensive <strong>Cancer</strong> Center at Johns Hopkins, Baltimore,<br />
MD; UT Southwestern Medical Center, Dallas, TX.<br />
P4-08-09 Targeting Thyroid Receptor β in Estrogen Receptor Negative<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Gu G, Covington K, Rechoum Y, O’Malley B, Mangelsdorf D, Minna<br />
J, Webb P, Fuqua S. Baylor College of Medicine, Houston, TX; UT<br />
Southwestern Medical Center; The Methodist Hospital Research<br />
Institute.<br />
P4-08-10 Systematic expression analysis of the genes related to drugresistance<br />
in isogenic docetaxel- and adriamycin-resistant<br />
breast cancer cell lines<br />
Tang J, Li W, Zhong S, Xu J, Zhao J. Jiangsu <strong>Cancer</strong> Hospital, Nanjing,<br />
Jiangsu, China; Jiangsu <strong>Cancer</strong> Hospital, Nanjing, Jiangsu, China.<br />
Prognostic and Predictive Factors: Prognostic Factors - Preclinical<br />
P4-09-01 Retrospective evaluation of precision of gene-expressionbased<br />
signatures of prognosis and tumor biology in replicate<br />
surgical biospecimens from patients with breast cancer<br />
Barry WT, Marcom PK, Geradts J, Datto MB. Duke University Medical<br />
Center, Durham, NC.<br />
P4-09-02 A robust signature of long-term clinical outcome in breast<br />
cancer<br />
Boudreau A, Elias SG, Yau C, Wolf DM, van’t Veer LJ. University of<br />
California, <strong>San</strong> Francisco; Netherlands <strong>Cancer</strong> Institute.<br />
P4-09-03 Withdrawn<br />
P4-09-04 Gene expression profile that predict outcome of Tamoxifentreated<br />
estrogen receptor-positive, high-risk, primary breast<br />
cancer patients: a DBCG study<br />
Lyng MB, Lænkholm A-V, Tan Q, Vach W, Gravgaard KH, Knoop<br />
A, Ditzel HJ. University of Southern Denmark, Odense, Denmark;<br />
Slagelse Hospital, Slagelse, Denmark; Odense University Hospital,<br />
Odense, Denmark; University Medical Center Freiburg, Germany.<br />
P4-09-05 Microarray anlyses of breast cancers identify CH25H, a<br />
cholesterol gene, as a potential marker and target for late<br />
metastatic reccurences<br />
Saghatchian M, Mittempergher L, Michiels S, Wolf D, Canisius<br />
SV, Dessen P, Delaloge S, Lazar V, Benz SC, Roepman P, Glas AM,<br />
Tursz T, Bernards R, van’t Veer LJ. The Netherlands <strong>Cancer</strong> Institute,<br />
Amsterdam, Netherlands; Institut Jules Bordet, Brussels, Belgium;<br />
UCSF Helen Diller Family Comprehensive <strong>Cancer</strong> Center, <strong>San</strong><br />
Francisco; Institut Gustave Roussy, Villejuif, France; University of<br />
California, <strong>San</strong>ta Cruz; Agendia, Amsterdam, Netherlands.<br />
P4-09-06 miR-187 is an independent prognostic factor in lymph nodepositive<br />
breast cancer patients<br />
O’Connor DP, Mulrane L, Brennan DJ, Madden S, Gremel G, McGee<br />
SF, McNally S, Martin FM, Crown JP, Jirstrom K, Higgins DG, Gallagher<br />
W. UCD Conway Institute, Dublin, Ireland; Molecular Therapeutics for<br />
<strong>Cancer</strong> Ireland, Dublin City University, Dublin, Ireland; St Vincent’s<br />
University Hospital, Dublin, Ireland; Lund University, Lund, Sweden.<br />
P4-09-07 ING1 Expression Measured by AQUA can be an Independent<br />
Prognostic Marker in <strong>Breast</strong> <strong>Cancer</strong><br />
Thakur S, Klimowicz A, Pohorelic B, Dean M, Konno M, Bose P,<br />
Magliocco A, Riabowol K. University of Calgary, AB, Canada; Tom Baker<br />
<strong>Cancer</strong> Center, Calgary, AB, Canada.<br />
P4-09-08 HOXB9, a gene promoting tumor angiogenesis and<br />
proliferation, is significantly associated with poor clincal<br />
outcomes in ER-positive breast cancer patients<br />
Seki H, Hayashida T, Jinno H, Takahashi M, Suzuki K, Kaneda M, Hara<br />
H, Osaku M, Asanuma F, Yamada Y, Mukai M, Kitagawa Y. Kitasato<br />
University Kitasato Institute Hospital, Tokyo, Japan; Keio University<br />
School of Medicine, Tokyo, Japan; Keio University School of Medicine,<br />
Japan.<br />
P4-09-09 Circulating HER2 extracellular domain (ECD) levels are<br />
associated with progression-free survival in metastatic breast<br />
cancer patients<br />
Wang X-j, Shao X-Y, Chen Z-H, Ye W-w, Qin J, Zhang Y-m, Zheng Y-b,<br />
Yu X-y, Lei L, Ling Z-Q, Feng J-g, Han MX. Zhejiang <strong>Cancer</strong> Hospital,<br />
Hangzhou, Zhejiang, China; Hangzhou Polar Gene Company,<br />
Hangzhou, Zhejiang, China.<br />
P4-09-10 Prospective Analysis of Fatty Acid Synthase (FASN) in <strong>Breast</strong><br />
<strong>Cancer</strong> Tissue of Early-Stage <strong>Breast</strong> <strong>Cancer</strong> Patients<br />
Puig T, Blancafort A, Casoliva G, Oliveras G, Casas M, Buxo M, Saiz E,<br />
Viñas G, Dorca J, Porta R. University of Girona and Girona Biomedical<br />
Research Institute (IDIBGi), Girona, Spain; Assistència <strong>San</strong>itària<br />
Institute, Girona, Spain; Catalan Institute of Oncology, Girona, Spain;<br />
Dr. Josep Trueta Hospital, Girona, Spain; Dr. Josep Trueta Hospital and<br />
Girona Biomedical Research Institute (IDIBGi), Girona, Spain; Health<br />
Inequalities Research Group - Employment Conditions Knowledge<br />
Network (GREDS-EMCONET), Universitat Pompeu Fabra, Barcelona,<br />
Spain; Dr. Josep Trueta Hospitaland Girona Biomedical Research<br />
Institute (IDIBGi), Girona, Spain.<br />
P4-09-11 Fatty Acid Synthase (FASN) expression in Triple-Negative<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Viñas G, Oliveras G, Perez-Bueno F, Giro A, Blancafort A, Puig-Vives<br />
M, Marcos-Gragera R, Dorca J, Brunet J, Puig T. Catalan Institute of<br />
Oncology and Girona Biomedical Research Institute (IDIBGi), Girona,<br />
Spain; University of Girona and Biomedical Research Institute (IDIBGi),<br />
Girona, Spain; Dr. Josep Trueta Hospital and Catalan Institute of<br />
Health (ICS), Girona, Spain; Catalan Institute of Oncology, Girona,<br />
Spain; University of Girona, Spain.<br />
P4-09-12 TIMP-4 – Prognostic Marker and Treatment Target for Triple-<br />
Negative <strong>Breast</strong> <strong>Cancer</strong>s<br />
Wallon UM, Sabol JL, Gilman PB, Zemba-Palko V, DuHadaway JB,<br />
Ciocca RM, Ali ZA, Carp NZ, Choy NS, Wojciechowski BS, Prendergast<br />
GC. Lankenau Medical Center, Wynnewood, PA.<br />
Epidemiology, Risk, and Prevention: Familial <strong>Breast</strong> <strong>Cancer</strong> - Molecular<br />
Genetics<br />
P4-10-01 Edgetic perturbation of BRCT-mediated interactions caused by<br />
the BRCA1 H1686Q sequence variant<br />
De Nicolo A, Pathania S, Parisini E, Joukov V. Dana-Farber <strong>Cancer</strong><br />
Institute, Boston, MA; Harvard Medical School, Boston, MA; Italian<br />
Institute of Technology, Milan, Italy.<br />
www.aacrjournals.org<br />
49s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-10-02 Targeted resequencing of BRCA1 and BRCA2 in inherited<br />
breast cancer<br />
Wong MW, Li S, Wilkins M, Avery-Kiejda KA, Bowden NA, Scott RJ.<br />
University of Newcastle, NSW, Australia; University of New South<br />
Wales, Sydney, NSW, Australia; Hunter Area Pathology Service (HAPS),<br />
Newcastle, NSW, Australia.<br />
Epidemiology, Risk, and Prevention: Familial <strong>Breast</strong> <strong>Cancer</strong> - Genetic<br />
Testing<br />
P4-11-01 Rapid genetic counseling and testing in newly diagnosed<br />
breast cancer patients, findings from an RCT<br />
Wevers MR, Ausems MG, Bleiker EM, Rutgers EJ, Witkamp AJ, Hahn<br />
DE, Brouwer T, Kuenen MA, van der <strong>San</strong>den-Melis J, van der Luijt RB,<br />
Hogervorst FB, van Dalen T, Theunissen EB, van Ooijen B, de Roos<br />
MA, Borgstein PJ, Vrouenraets BC, Huisman JJ, Bouma WH, Rijna H,<br />
Vente JP, Valdimarsdottir H, Verhoef S, Aaronson NK. Netherlands<br />
<strong>Cancer</strong> Institute - Antoni van Leeuwenhoek Hospital, Amsterdam,<br />
Netherlands; University Medical Center, Utrecht, Netherlands;<br />
Diakonessen Hospital, Utrecht, Netherlands; St. Antonius Hospital,<br />
Nieuwegein, Netherlands; Meander Medical Center, Amersfoort,<br />
Netherlands; Rivierenland Hospital, Tiel, Netherlands; Onze Lieve<br />
Vrouwe Gasthuis, Amsterdam, Netherlands; St. Lucas Andreas<br />
Hospital, Amsterdam, Netherlands; Tergooi Hospitals, Blaricum,<br />
Netherlands; Gelre Hospitals, Apeldoorn, Netherlands; Kennemer<br />
Gasthuis, Haarlem, Netherlands; Zuwe Hofpoort Hospital, Woerden,<br />
Netherlands; Mount Sinai School of Medicine, New York.<br />
P4-11-02 Novel BRCA1 and BRCA2 genomic rearrangements in Southern<br />
Chinese breast/ovarian cancer patients<br />
Kwong A, Ng EKO, Law FBF, Wa A, Wong CLP, Wong CHN, Kurian AW,<br />
West DW, Ford JM, Ma ESK. University of Hong Kong, Pokfulam, Hong<br />
Kong; Hong Kong <strong>San</strong>itorium & Hospital, Happy Valley, Hong Kong;<br />
Hong Kong Hereditary <strong>Breast</strong> <strong>Cancer</strong> Family Registry, Happy Valley,<br />
Hong Kong; Stanford University School of Medicine, Stanford, CA.<br />
P4-11-03 Single nucleotide polymorphism testing for breast cancer risk<br />
assessment: patient trust and willingness to pay<br />
Howe R, Omer Z, Hanoch Y, Miron-Shatz T, Thorsen C, Ozanne EM.<br />
Universiy of California <strong>San</strong> Francisco, CA; Massachusetts General<br />
Hospital, Boston, MA; Plymouth University, United Kingdom; Ono<br />
Academic College, Israel.<br />
P4-11-04 A Structured Genetic Risk Evaluation and Testing Program in<br />
the Community Oncology Practice Increases Identification of<br />
Individuals at Risk for BRCA Mutations<br />
Langer L, Clark L, Gress J, Patt D, Denduluri N, Wang Y, Andersen J,<br />
Solti M, Wheeler A, Delamelena T, Smith, II JW, <strong>San</strong>dbach J. Compass<br />
Oncology, Portland, OR; Texas Oncology, Austin, TX; Virginia <strong>Cancer</strong><br />
Specialists, Arlington, VA; McKesson Specialty Health/The US<br />
Oncology Network, The Woodlands, TX.<br />
P4-11-05 Optimal age to start preventive measures in women with<br />
BRCA1/2 mutations or high familial breast cancer risk<br />
Tilanus-Linthorst MMA, Lingsma H, Evans GD, Kaas R, Manders P,<br />
Hooning MJ, van Asperen CJ, Thompson D, Eeles R, Oosterwijk<br />
JC, Leach MO, Steyerberg EJ. Erasmus University MC, Rotterdam,<br />
Netherlands; Erasmus University MC, Netherlands; University of<br />
Manchester, United Kingdom; NKI/AVL, Amsterdam, Netherlands;<br />
UMC St Radboud, Netherlands; Leiden University Medical Centre,<br />
Netherlands; Centre for <strong>Cancer</strong> Genetic Epidemiology, Cambridge,<br />
United Kingdom; Royal Marsden NHS Foundation, United Kingdom;<br />
University Medical Centre Groningen, Netherlands; Institute of <strong>Cancer</strong><br />
Research, Royal Marsden, Sutton, United Kingdom.<br />
P4-11-06 Automatic referral to genetic counseling for identification<br />
of BRCA1/2 mutations: a pilot program at Norton <strong>Cancer</strong><br />
Institute, Louisville, KY<br />
Lewis AL, Alabek ML, Dreher C, Goldberg JM, Brooks SE. Norton<br />
Healthcare, Louisville, KY.<br />
Epidemiology, Risk, and Prevention: Risk Factors and Modeling<br />
P4-12-01 A nomogram based on clinical, imaging and histological data<br />
to predict the risk of upgrades to malignancy at surgery in<br />
biopsy-diagnosed premalignant lesions of the breast<br />
Uzan C, Mazouni C, Balleyguier C, Mathieu M-C, Ferchiou M, Delaloge<br />
S. Institut Gustave Roussy, Villejuif, France.<br />
P4-12-02 Serum 25-hydroxyvitamin D3 is associated with decreased risk<br />
of postmenopausal breast cancer in whites: the Multiethnic<br />
Cohort Study<br />
Kim Y, Franke AA, Shvetsov YB, Wilkens LR, Lurie G, Cooney RV,<br />
Maskarinec G, Hernandez BY, Le Marchand L, Henderson B, Kolonel<br />
LN, Goodman MT. University of Hawai’i <strong>Cancer</strong> Center; University of<br />
Hawaii; Keck School of Medicine, University of Southern California.<br />
P4-12-03 Towards a risk prediction model for breast cancer that utilizes<br />
breast tissue risk features<br />
Pankratz VS, Degnim AC, Visscher DW, Frank RD, Vierkant RA, Ghosh<br />
K, Aziza N, Vachon CM, Frost M, Radisky DC, Hartmann LC. Mayo<br />
Clinic, Rochester, MN; Mayo Clinic, Jacksonville, FL.<br />
P4-12-04 Association of single-strand breaks (SSBs) in normal breast<br />
DNA with estimates of breast cancer risk<br />
Chatterton RT, Sahadevan M, Heinz RE, Sukumar S, Stearns V, Fackler<br />
MJ, Lee O, Sivaraman I, Kenney K, Khan SA. Northwestern University<br />
Feinberg School of Medicine, Chicago, IL; Johns Hopkins School of<br />
Medicine, Baltimore, MD.<br />
P4-12-05 Enrichment of aldosterone synthase (CYP11B2) gene C-allele<br />
carriers in women at high risk in the OncoVue® polyfactorial<br />
risk model<br />
Jupe ER, Pugh TW, Knowlton NS, DeFreese DC. InterGenetics<br />
Incorporated, Oklahoma City, OK; NSK Statistical Solutions, Choctaw,<br />
OK.<br />
P4-12-06 A mammographic density prediction model using<br />
environmental factors, endogenous hormones and growth<br />
factors in Japanese women<br />
Yoshimoto N, Nishiyama T, Toyama T, Takahashi S, Shiraki N, Sugiura<br />
H, Endo Y, Iwasa M, Asano T, Fujii Y, Yamashita H. Nagoya City<br />
University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.<br />
P4-12-07 Diabetes Increases the Risk of <strong>Breast</strong> <strong>Cancer</strong><br />
Hardefeldt PJ, Edirimanne S, Eslick GD. University of Sydney, NSW,<br />
Australia; Nepean Hospital, University of Sydney, Penrith, NSW,<br />
Australia.<br />
Epidemiology, Risk, and Prevention: Epidemiology, Risk, and Prevention -<br />
Other<br />
P4-13-01 Racial Disparities in the Incidence of Dose-limiting<br />
Chemotherapy Induced Peripheral Neuropathy<br />
Speck RM, Sammel MD, Farrar JT, Hennessy S, Mao JJ, Stineman<br />
MG, DeMichele A. Perelman School of Medicine, University of<br />
Pennsylvania.<br />
P4-13-02 Comparing data quality of client intake forms by interview<br />
mode: results of a pilot study on the use of audio computerassisted<br />
self-interview (ACASI) in the Avon <strong>Breast</strong> Health<br />
Outreach Program<br />
Hallum-Montes R, Senter L, D’Souza R, Hurlbert M, Gates-Ferris K,<br />
Anastario M. CAI Global, New York, NY; Avon Foundation for Women,<br />
New York, NY; New York University, New York, NY.<br />
P4-13-03 Hormone replacement therapy, is there an increased risk of in<br />
situ breast cancer? Data from a French cohort<br />
Coussy F, Giacchetti S, Hamy A-S, Porcher R, Cuvier C, Lalloum M,<br />
de Roquancourt A, Albiter M, Espié M. Hôpital St Louis, Paris, France;<br />
Assistance Publique-Hôpitaux de Paris, Hôpital St Louis, Paris, France.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 50s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P4-13-04 Estrogen and Avoidance of Invasive <strong>Breast</strong> <strong>Cancer</strong>, Coronary<br />
Heart Disease and All-cause Mortality. Public Health Impact of<br />
Estrogen Guidelines for Women entering Menopause<br />
Ragaz J, Wilson K, Shakeraneh S, Budlovsky J, Wong H. University of<br />
British Columbia, Vancouver, BC, Canada; British Columbia <strong>Cancer</strong><br />
Agency, Victoria, BC, Canada.<br />
P4-13-05 The gap between perceptions of risk and actual risk for<br />
breast cancer<br />
Kaplan CP, Lopez M, Tice J, Pasick R, Kerlikowske K, Chen A, Karliner L.<br />
University of California, <strong>San</strong> Francisco, CA.<br />
P4-13-06 Association of Age, Obesity and Incident <strong>Breast</strong> <strong>Cancer</strong><br />
Phenotypes<br />
Scheri R, Power S, Marks J, Seewaldt V, Marcom K, Hwang S. Duke<br />
University Medical Center, Durham, NC.<br />
P4-13-07 Meta-analysis of epidemiological studies of Insulin Glargine<br />
and <strong>Breast</strong> <strong>Cancer</strong> Risk<br />
Boyle P, Koechlin A, Boniol M, Bota M, Robertson C, Rosenstock J,<br />
Bolli GB. International Prevention Research Institute, Lyon, France;<br />
University of Strathclyde, Glasgow, United Kingdom; Dallas Diabetes<br />
and Endocrine Center, Dallas; University of Perugia, Italy.<br />
P4-13-08 Diabetes, Related Factors and <strong>Breast</strong> <strong>Cancer</strong> Risk<br />
Boyle P, Boniol M, Koechlin A, Bota M, Robertson C, Leroith D,<br />
Rosenstock J, Bolli GB, Autier P. International Prevention Research<br />
Institute, Lyon, France; University of Strathclyde, Glasgow, United<br />
Kingdom; Mt. Sinai, New York; Dallas Diabetes and Endocrine Center,<br />
Dallas; University of Perugia, Italy.<br />
P4-13-09 The effect of weight change on breast adipose and<br />
dense tissue<br />
Graffy HJ, Harvie MN, Warren RM, Boggis CR, Astley SM, Evans<br />
GD, Adams JE, Howell A. University Hospital of South Manchester,<br />
Manchester, United Kingdom; Addenbrooke’s Hospital, Cambridge,<br />
United Kingdom; University of Manchester, United Kingdom; Central<br />
Manchester University Hospitals NHS Foundation Trust, Manchester,<br />
United Kingdom.<br />
P4-13-10 Do BRCA1 and BRCA2 mutation carriers have an earlier natural<br />
menopause than their non-carrier relatives: A study from the<br />
Kathleen Cuningham Foundation Consortium For Research<br />
Into Familial <strong>Breast</strong> <strong>Cancer</strong> (kConFab)<br />
Collins IM, Milne RL, McLachlan SA, Friedlander M, Birch KE,<br />
Weideman PC, Hopper JL, Phillips K-A. Peter MacCallum <strong>Cancer</strong><br />
Centre, Melbourne, Australia; University of Melbourne, Australia; St<br />
Vincent’s Hospital, Melbourne, VIC, Australia; Prince of Wales <strong>Cancer</strong><br />
Centre, Sydney, Australia<br />
P4-13-11 Prognostic factors in young breast cancer patients over time –<br />
a 40 year longitudinal analysis<br />
Hagenbeck C, Muschler B, Jaeger BAS, Jueckstock J, Andergassen<br />
U, Katzorke N, Hepp P, Melcher CA, Janni JW, Rack BK. Heinrich<br />
Heine University, Duesseldorf, Germany; Freising Hospital, Freising,<br />
Germany; Ludwig-Maximilians-University, Munich, Germany.<br />
P4-13-12 Identifying women at increased risk for breast cancer using the<br />
electronic health record in an integrated health system<br />
Leader JB, Bengier A, Darer J, Stark A, Vogel VG. Geisinger Health<br />
System, Danville, PA; Geisinger Health System, Lewisburg, PA.<br />
P4-13-13 Risk Assessment and Personalized Decision Support: The<br />
University of California Athena <strong>Breast</strong> Health Network<br />
Ozanne EM, Crawford B, Petruse A, Madlensky L, Weiss L, Hogarth M,<br />
Wenger N, Goodman D, Park H, Anton-Culver H, Yasmeen S, Howell<br />
L, Ojeda H, Parker BA, Kaplan C, van’t Veer L, Esserman L, Naeim A.<br />
University of California, <strong>San</strong> Francisco, CA; University of California, Los<br />
Angeles, CA; University of California, <strong>San</strong> Diego, CA; Athena Program<br />
Management Office, <strong>San</strong> Francisco, CA; University of California, Davis,<br />
CA; University of California, Irvine, CA.<br />
P4-13-14 Lung cancer after treatment of breast cancer: retrospective<br />
study from Curie Institut<br />
Sebbagh S, Cosquer M, Kirova YM, Livartowski A. Institut Curie, Paris,<br />
France.<br />
Treatment: Surgery<br />
P4-14-01 Incidence rate of nipple areolar complex ischemia after nipple<br />
sparing mastectomy. Analysis of the American Society of<br />
<strong>Breast</strong> Surgeons Nipple Sparing Mastectomy Registry<br />
Mitchell SD, Willey SC, Feldman SM, Beitsch PD, Unzeitig GW,<br />
Manasseh DME, Neumayer LA, Laidley AL, Grutman SB, Habal N,<br />
Busch-Devereaux E, Dupont EL, Ashikari AY. White Plains Hospital<br />
Medical Center, White Plains, NY; Georgetown, Washington, DC;<br />
Columbia University College of Physicians & Surgeons, New York,<br />
NY; Dallas <strong>Breast</strong> Center, Dallas, TX; Laredo <strong>Breast</strong> Care, Laredo, TX;<br />
Maimonides Medical Center, Brooklyn, NY; University of Utah, Salt<br />
Lake City, UT; Texas <strong>Breast</strong> Specialists, Texas Oncology, Dallas, TX;<br />
American Society of <strong>Breast</strong> Surgeons, Columbia, MD; Carolina <strong>Breast</strong><br />
& Oncologic Surgery, Greenville, NC; <strong>Breast</strong> Surgery Associates,<br />
Greenlawn, NY; Watson Clinic, Lakeland, FL; Ashikari <strong>Breast</strong> Center,<br />
Dobbs Ferry, NY.<br />
P4-14-02 National Trends and Indications for Nipple-Sparing<br />
Mastectomy: An Analysis Using the Surveillance, Epidemiology,<br />
and End Results (SEER) Database<br />
Agarwal S, Agarwal S, Agarwal J. Wayne State University, Detroit, MI;<br />
University of Michigan, Ann Arbor, MI; University of Utah, Salt Lake<br />
City, UT.<br />
P4-14-03 Nipple-sparing mastectomy and intra-operative nipple biopsy:<br />
To freeze or not to freeze?<br />
Guth AA, Blechman K, Samra F, Shapiro R, Axelrod D, Choi M, Karp N,<br />
Alperovich M. NYU School of Medicine, New York, NY.<br />
P4-14-04 Total skin-sparing mastectomy in BRCA mutation carriers<br />
Warren Peled A, Hwang ES, Ewing CA, Alvarado M, Esserman LJ.<br />
University of California, <strong>San</strong> Francisco; Duke University Medical<br />
Center.<br />
P4-14-05 Skin sparing mastectomy – thorough breast tissue removal<br />
leads to a low local recurrence rate of breast cancer<br />
Paily AJ, Drabble EH. Derriford Hopsital, Plymouth, Devon, United<br />
Kingdom.<br />
P4-14-06 Withdrawn<br />
P4-14-07 Impact of preservation of the intercostobrachial nerve during<br />
axillary dissection on sensory change and health-related<br />
quality of life two years after breast cancer surgery<br />
Taira N, Shimozuma K, Ohsumi S, Kuroi K, Shiroiwa T, Watanabe T,<br />
Saito M. Okayama University Hospital, Okayama, Japan; Ritsumeikan<br />
University, Japan; National Shikoku <strong>Cancer</strong> Center, Japan; Tokyo<br />
Metropolitan <strong>Cancer</strong> and Infectious Diseases Center Komagome<br />
Hospital, Japan; Teikyo University, Japan; Sendai Medical Center,<br />
Japan; Juntendo University, Japan.<br />
P4-14-08 Intraoperative ultrasound guidance for excision of nonpalpable<br />
breast cancer<br />
Barentsz MW, van Dalen T, Gobardhan PD, Bongers V, Perre CI,<br />
Pijnappel RM, van den Bosch MA, Verkooijen HM. University Medical<br />
Center Utrecht, Netherlands; Diakonessenhuis, Utrecht, Netherlands;<br />
Amphia Hospital, Breda, Netherlands.<br />
P4-14-09 Feasibility of liposuction for treatment of arm lymphedema<br />
from breast cancer<br />
Doren EL, Smith PD, Sun W, Lacevic M, Fulp W, Reid R, Laronga C.<br />
University of South Florida, Tampa, FL; Moffitt <strong>Cancer</strong> Center,<br />
Tampa, FL.<br />
P4-14-10 Atypical Ductal Hyperplasia diagnosed on directional vacuumassisted<br />
biopsy: is surgical excision mandatory?<br />
Chauvet M-P, Rivaux G, Farre I, Houpeau J-L, Giard S, Ceugnart L.<br />
Centre Oscar Lambret, Lille, France.<br />
www.aacrjournals.org<br />
51s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-14-11 Risk reducing mastectomy for women with high personal<br />
breast cancer risk<br />
Onyekwelu O, Shetty G, Baildam A. Nightingale & Genesis <strong>Breast</strong><br />
<strong>Cancer</strong> Prevention Centre, University Hospital of South Manchester,<br />
Wythenshawe, Manchester, United Kingdom; St. Bartholomew’s<br />
Hospital (Bart’s), West Smithfield, London, United Kingdom.<br />
P4-14-12 Evaluation of the effect of pasireotide LAR administration in<br />
the lymphocele prevention after mastectomy with axillary<br />
lymph node dissection for breast cancer: results of a phase 2<br />
randomized study<br />
Chereau E, Uzan C, Zohar S, Bezu C, Mazouni C, Ballester M, Gouy<br />
S, Rimareix F, Garbay J-R, Darai E, Uzan S, Rouzier R. Tenon, APHP,<br />
UPMC - Paris 6, Paris, France; Institut Gustave Roussy, Villejuif, France;<br />
Hopital Saint-Louis, APHP, U444-INSERM, Paris 7, Paris, France.<br />
P4-14-13 Therapeutic mammaplasty does not cause a delay in the<br />
delivery of chemotherapy in high risk breast cancer patients<br />
Khan J, Barrett S, Stallard S, Forte C, Weiler-Mithoff E, Reid I, Winter<br />
A, Doughty J, Romics L. Victoria Infirmary, Glasgow, United Kingdom;<br />
Beatson West of Scotland <strong>Cancer</strong> Centre, Glasgow, United Kingdom;<br />
Western Infirmary, Glasgow, United Kingdom; Royal Infirmary,<br />
Glasgow, United Kingdom.<br />
P4-14-14 Phyllodes tumour of the breast: A retrospective analysis of<br />
87 cases<br />
Walter HS, Esmail F, Krupa J, Ahmed SI. Leicester Royal Infirmary,<br />
Leicester, United Kingdom; Glenfield Hospital, Leicester, United<br />
Kingdom.<br />
Treatment: <strong>Breast</strong> Conservation<br />
P4-15-01 Second conservative treatment for ipsilateral breast tumor<br />
recurrence: GEC-ESTRO <strong>Breast</strong> WG study<br />
Hannoun-Levi J-M, Resch A, Gal J, Niehoff P, Loessl K, Kovács G, Van<br />
Limbergen E, Polgar C. Antoine Lacassagne <strong>Cancer</strong> Center, University<br />
of Nice-Sophia, Nice, France; Medical University, General Hospital<br />
of Vienna, Austria; Antoine Lacassagne <strong>Cancer</strong> Center, Nice, France;<br />
University Erlangen-Nuremberg, Erlangen, Germany; University<br />
Hospital Bernes, Switzerland; University Hospital Schleswig-Holstein<br />
Campus Lübeck, Germany; University Hospital Gasthuisberg, Leuven,<br />
Belgium; National Institute of Oncology, Budapest, Hungary.<br />
P4-15-02 Timing of infectious complications following breast<br />
conserving therapy with catheter-based accelerated partial<br />
breast irradiation<br />
Haynes AB, Bloom ES, Bedrosian I, Kuerer HM, Hwang RF, Caudle AS,<br />
Hunt KK, Graviss L, Chemaly RF, Tereffe W, Shaitelman SF, Babiera GV.<br />
University of Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
P4-15-03 Patterns of relapse following re-irradiation of the breast using<br />
partial breast brachytherapy (PBB)<br />
Chadha M, Boachie-Adjei K, Boolbol SK, Kirstein L, Osborne MP, Tarter<br />
P, Harrison LB. Beth Israel Medical Center, New York, NY.<br />
P4-15-04 Impact of awake breast cancer surgery on postoperative<br />
lymphocyte responses<br />
Vanni G, De Felice V, Buonomo C, Esser A, Petrella G, Buonomo OC.<br />
Tor Vergata University, Rome, Italy.<br />
P4-15-05 Long-term outcome of breast cancer patients treated with<br />
radiofrequency ablation<br />
Earashi M, Noguchi M, Motoyoshi A, Komiya H, Fujii H. Yatsuo General<br />
Hospital, Toyama, Japan; Kanazawa Medical University Hospital,<br />
Uchinada-Daigaku, Ishikawa, Japan.<br />
Treatment: Radiotherapy<br />
P4-16-01 Accelerated hypofractionated whole breast radiotherapy<br />
for localized breast cancer: the effect of a boost on patient<br />
reported long-term cosmetic outcome<br />
Chan EK, Tabarsi N, Tyldesley S, Khan M, Woods R, Speers C, Weir L.<br />
British Columbia <strong>Cancer</strong> Agency, Vancouver Centre, Vancouver, BC,<br />
Canada; University of British Columbia, Vancouver, BC, Canada.<br />
P4-16-02<br />
P4-16-03<br />
P4-16-04<br />
P4-16-05<br />
P4-16-06<br />
P4-16-07<br />
P4-16-08<br />
P4-16-09<br />
P4-16-10<br />
A survival benefit from locoregional radiotherapy for<br />
node-positive and CMF treated breast cancer is most<br />
significant in Luminal A tumors<br />
Voduc D, Cheang MCU, Tyldesley S, Chia S, Gelmon K, Speers C,<br />
Nielsen TO. BC <strong>Cancer</strong> Agency, Vancouver, BC, Canada; University of<br />
British Columbia, Vancouver, BC, Canada.<br />
Patterns of failure after accelerated partial breast irradiation<br />
by consensus panel group: A pooled analysis of William<br />
Beaumont Hospital and the American Society of <strong>Breast</strong><br />
Surgeons Trial data<br />
Wilkinson JB, Beitsch PD, Arthur D, Shah C, Haffty BG, Wazer D, Keisch<br />
M, Shaitelman SF, Lyden M, Chen PY, Vicini FA. Oakland University<br />
William Beaumont School of Medicine, Royal Oak, MI; Dallas Surgical<br />
Group, Dallas, TX; Massey <strong>Cancer</strong> Center, Virginia Commonwealth<br />
University, Richmond, VA; Washington University School of Medicine,<br />
St. Louis, MO; <strong>Cancer</strong> Institute of New Jersey, Robert Wood Johnson<br />
Medical School, Camden, NJ; Tufts Medical Center and Rhode Island<br />
Hospital/Brown University, Boston, MA; <strong>Cancer</strong> Healthcare Associates,<br />
Miami, FL; University of Texas M.D. Anderson <strong>Cancer</strong> Center, Houston,<br />
TX; Biostat International, Inc., Tampa, FL; Michigan Healthcare<br />
Professionals/21st Century Oncology, Farmington Hills, MI.<br />
Outcome of stage II/III breast cancer treated with neoadjuvant<br />
versus adjuvant radiotherapy in British Columbia<br />
Lohmann AE, Voduc D, Speers C, Chia S. British Columbia <strong>Cancer</strong><br />
Agency, Vancouver, BC, Canada.<br />
Benefit from Postoperative Radiotherapy for N1 <strong>Breast</strong> <strong>Cancer</strong><br />
Tsai Y-CS, Cheng H-CS, Yu B-L, Horng C-F, Chen C-M, Jian J-MJ, Chu<br />
N-M, Tsou M-H, Liu M-C, Huang AT. Koo Foundation Sun Yat-Sen<br />
<strong>Cancer</strong> Center, Taipei, Taiwan; Duke University Medical Center,<br />
Durham, NC.<br />
Radiotherapy to the Primary Tumor Is Associated with<br />
Improved Survival in Stage IV <strong>Breast</strong> <strong>Cancer</strong><br />
Morgan SC, Caudrelier J-M, Clemons MJ. University of Ottawa, ON,<br />
Canada; The Ottawa Hospital <strong>Cancer</strong> Centre, Ottawa, ON, Canada.<br />
Selective use of post-mastectomy radiation therapy in the<br />
neoadjuvant setting<br />
Warren Peled A, Wang F, Stover AC, Rugo HS, Melisko ME, Park JW,<br />
Alvarado M, Ewing CA, Esserman LJ, Fowble B, Hwang ES. University<br />
of California, <strong>San</strong> Francisco; Duke University Medical Center.<br />
Intraoperative electron radiotherapy in early stage breast<br />
cancer. A single-institution experience<br />
Dall’Oglio S, Maluta S, Marciai N, Gabbani M, Franchini Z, Pietrarota P,<br />
Meliadò G, Guariglia S, Cavedon C. University Hospital, Verona, Italy.<br />
Dosimetric feasibility and acute toxicity in a prospective trial<br />
of ultra-short course accelerated partial breast irradiation<br />
(APBI) using a multi-lumen balloon brachytherapy device<br />
Khan AJ, Vicini FA, Brown S, Haffty BG, Kearney T, Dale R, Arthur<br />
DW. <strong>Cancer</strong> Institute of New Jersey, New Brunswick, NJ; Michigan<br />
Healthcare Professionals, Farmington Hills, MI; Wellstar Kennestone<br />
Hospital, Marietta, GA; Imperial College London, United Kingdom;<br />
Virginia Commonwealth University, Massey <strong>Cancer</strong> Center,<br />
Richmond, VA<br />
Positive sentinel lymph nodes (SLNs) without axillary<br />
dissection in breast cancer: the tangent fields of irradiation<br />
may not allow optimal coverage and dose distribution in<br />
level I and II of the axilla<br />
Qiong P, Khodari W, Bigorie V, Bosc R, Dao TH, Totobenazara J-L,<br />
Assaf E, Caillet P, Diana C, Lagrange J-L, Calitchi E, Belkacemi Y.<br />
APHP GH Henri Mondor et Université de Paris-Est, Créteil, France;<br />
APHP GH Henri Mondor, Créteil, France; Association of Radiotherapy<br />
and Oncology of the Mediterranean Area, France; French <strong>Breast</strong><br />
Intergroup, France.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 52s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P4-16-11 Impact of receptor status on prognosis among<br />
breast cancer patients with brain metastases treated with<br />
Cyberknife radiosurgery<br />
Fasola CE, Gibbs IC, Soltys SG, Horst KC. Stanford <strong>Cancer</strong> Center,<br />
Stanford, CA.<br />
P4-16-12 Outcomes of low-risk Ductal Carcinoma in situ in South East<br />
Asian women treated with breast conservation surgery<br />
Wong FY, Wang FQ, Chen JJ, Tan CH, Tan PH. National <strong>Cancer</strong> Centre<br />
Singapore; Singapore General Hospital, Singapore, Singapore.<br />
P4-16-13 Relationship between coverage of axillary lymph nodes, with<br />
tangential breast irradiation, and body mass index<br />
Inokuchi M, Furukawa H, Fujimura T, Ohta T, Ohashi S, Takanaka T.<br />
Kanazawa University Hospital, Kanazawa, Ishikawa, Japan.<br />
P4-16-14 Salvage Radiotherapy and Cisplatin for Triple Negative <strong>Breast</strong><br />
<strong>Cancer</strong>: A Multi-Centre Study<br />
Lee JW, Brackstone M, Gandhi S, Arce Salinas C, Dinniwell R.<br />
University of Toronto, ON, Canada; London Regional <strong>Cancer</strong> Program,<br />
London, ON, Canada; Princess Margaret Hospital, University of<br />
Toronto, ON, Canada.<br />
P4-16-15 Improvement of accuracy and consistency in delineating the<br />
breast lumpectomy cavity using surgical clips<br />
Atrchian S, Sadeghi P, Cwajna W, Helyer L, Rheaume D, Nolan<br />
M, Rutledge R, Calverley V, Bennett S, Ago T, Robar J. Dalhousie<br />
University, Halifax, NS, Canada.<br />
Treatment: Reconstruction<br />
P4-17-01 The effect of body mass index on breast reconstruction<br />
outcomes<br />
Lopez JJ, Laronga C, Doren EL, Sun W, Fulp WJ, Smith PD. University<br />
of South Florida, Tampa, FL; H. Lee Moffitt <strong>Cancer</strong> Center, Tampa, FL.<br />
P4-17-02 Radiation therapy and expander-implant breast<br />
reconstruction: an analysis of timing and comparison of<br />
complications<br />
Lentz RB, Higgins SA, Matthew MK, Kwei SL. Yale University School of<br />
Medicine, New Haven, CT.<br />
P4-17-03 Towards the standardisation of outcome reporting in<br />
reconstructive breast surgery: Initial results of the BRAVO<br />
(<strong>Breast</strong> Reconstruction and Valid Outcome) Study–A<br />
multicentre consensus process to develop a core outcome set<br />
for reconstructive breast surgery<br />
Potter S, Ward J, Cawthorn S, Holcombe C, Warr R, Wilson S, Tillett<br />
R, Weiler-Mithoff E, Winters Z, Barker J, Oates C, Harcourt D, Brookes<br />
S, Blazeby J. University of Bristol, United Kingdom; North Bristol NHS<br />
Trust, Bristol, United Kingdom; Linda McCartney <strong>Breast</strong> Centre, Royal<br />
Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool,<br />
United Kingdom; NHS Greater Glasgow and Clyde, Glasgow, United<br />
Kingdom; University of the West of England, Bristol, United Kingdom.<br />
P4-17-04 BRECONDA: Development and acceptability of an interactive<br />
decisional support tool for women considering breast<br />
reconstruction<br />
Sherman KA, Harcourt D, Lam T, Boyages J. Macquarie University,<br />
Sydney, NSW, Australia; Westmead Hospital, University of Sydney,<br />
Westmead, NSW, Australia; University of the West of England, Bristol,<br />
United Kingdom.<br />
P4-17-05 Withdrawn<br />
P4-17-06 The use of specialist nurse-led clinics in preparation for<br />
reconstructive breast surgery<br />
Affan AM, Ali RA, Morton-Gittens JA, Perry A, Harry A, O’Donoghue<br />
JM, Rampaul R. St James Medical Complex, St James, POS, Trinidad<br />
and Tobago; Royal Victoria Infirmary, Newcastle-upon-Tyne, London,<br />
United Kingdom.<br />
P4-17-07 Reconstructive Outcomes of Nipple-Sparing Mastectomy: A<br />
Five Year Experience<br />
Guth AA, Blechman K, Samra F, Shapiro R, Axelrod D, Choi M, Karp N,<br />
Alperovich M. NYU School of Medicine, New York, NY.<br />
P4-17-08 Tissue Expander/Implant <strong>Breast</strong> Reconstruction with and<br />
without Postmastectomy Radiation: Predictive Factors for<br />
Complications<br />
Nguyen SKA, Oxley P, Rastegar R, Joffres M, Kwan W. British Columbia<br />
<strong>Cancer</strong> Agency, Fraser Valley <strong>Cancer</strong> Centre; University of British<br />
Columbia; Simon Fraser University.<br />
P4-17-09 Efficacy and safety of lipomodelling and adipose tissue derived<br />
degenerative stem cells(ADRC) for breast reconstruction –<br />
Medium term follow up<br />
Noor L, Bhaskar P, Hennessy C. University Hospital of North Tees,<br />
Cleveland, United Kingdom.<br />
9:00 am–9:30 am<br />
PLENARY LECTURE 3<br />
Exhibit Hall D<br />
<strong>Breast</strong> Radiotherapy: Fractionation and Other Fashions<br />
John Yarnold, MD<br />
Institute of <strong>Cancer</strong> Research<br />
Sutton, UNITED KINGDOM<br />
9:30 am–11:30 am<br />
GENERAL SESSION 5<br />
Exhibit Hall D<br />
Moderator: George W. Sledge, Jr., MD<br />
Indiana University Simon <strong>Cancer</strong> Center<br />
Indianapolis, IN<br />
9:30 S5-1. Biomarker analyses in CLEOPATRA: A phase III, placebocontrolled<br />
study of pertuzumab in HER2-positive, first-line<br />
metastatic breast cancer (MBC)<br />
Baselga J, Cortés J, Im S-A, Clark E, Kiermaier A, Ross G, Swain SM.<br />
Massachusetts General Hospital <strong>Cancer</strong> Center and Harvard Medical<br />
School, Boston, MA; Vall d’Hebron University Hospital, Barcelona,<br />
Spain; Seoul National University College of Medicine, Seoul, Korea; Roche<br />
Products Limited, Welwyn, United Kingdom; F. Hoffmann-La Roche<br />
Limited, Basel, Switzerland; MedStar Washington Hospital Center,<br />
Washington, DC.<br />
9:45 S5-2. HERA TRIAL: 2 years versus 1 year of trastuzumab after<br />
adjuvant chemotherapy in women with HER2-positive early breast<br />
cancer at 8 years of median follow up<br />
Goldhirsch A, Piccart-Gebhart MJ, Procter M, de Azambuja E, Weber HA,<br />
Untch M, Smith I, Gianni L, Jackisch C, Cameron D, Bell R, Dowsett M,<br />
Gelber RD, Leyland-Jones B, Baselga J, on behalf of the HERA Study Team<br />
NA. European Institute of Oncology, Milan, Italy; BrEAST Data Centre, Jules<br />
Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium; Frontier<br />
Science (Scotland) Ltd, Kincraig, Kingussie, United Kingdom; F Hoffmann-<br />
La Roche, Basel, Switzerland; Helios Klinikum Berlin-Buch, Akademisches<br />
LK der Universität Charité, Berlin, Germany; Royal Marsden Hospital and<br />
Institute of <strong>Cancer</strong> Research, London, United Kingdom; <strong>San</strong> Raffaele<br />
Institute, Milan, Italy; Klinikum Offenbach, Offenbach, Germany; University<br />
of Edinburgh, Western General Hospital, Edinburgh, United Kingdom;<br />
Geelong Hospital, Geelong, Australia; The Royal Marsden NHS Trust,<br />
London, United Kingdom; Dana-Farber <strong>Cancer</strong> Institute, Boston, MA;<br />
<strong>San</strong>ford Research, Sioux Falls, SD; Massachusetts General Hospital <strong>Cancer</strong><br />
Center, Boston, MA.<br />
www.aacrjournals.org<br />
53s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
10:00 S5-3. PHARE Trial results of subset analysis comparing 6 to 12<br />
months of trastuzumab in adjuvant early breast cancer<br />
Pivot X, Romieu G, Bonnefoi H, Pierga J-Y, Kerbrat P, Guastalla J-P,<br />
Lortholary A, Espié M, Fumoleau P, Khayat D, Pauporte I, Kramar A.<br />
University Hospital J. Minjoz, Besancon, France; Anti <strong>Cancer</strong> Center Val<br />
d’Aurelle, Montpellier, France; Anti <strong>Cancer</strong> Center Bergonie, Bordeaux,<br />
France; Curie Institute, Paris, France; Anti <strong>Cancer</strong> Center Eugene Marquis,<br />
Rennes, France; Anti <strong>Cancer</strong> Center Leon Berard, Lyon, France; Catherine<br />
de Sienne Center, Nantes, France; University Hospital St Louis, Paris,<br />
France; Anti <strong>Cancer</strong> Center Georges Francois Leclerc, Dijon, France;<br />
University Hospital Pitie Salpetriere, Paris, France; French National <strong>Cancer</strong><br />
Institut (INCa), France; Centre Oscar Lambret, Lille, France.<br />
10:15 S5-4. EGFR expression measured by quantitative<br />
immunofluorescense is associated with decreased benefit from<br />
trastuzumab in the adjuvant setting in the NCCTG (Alliance)<br />
N9831 trial<br />
Rimm D, Ballman KV, Cheng H, Vassilakopoulou M, Chen B, Gralow J,<br />
Hudis C, Davidson NE, Psyrri A, Fountzilas G, Perez EA. Yale University<br />
School of Medicine, New Haven, CT; Mayo Clinic, Rochester, MN; Seattle<br />
<strong>Cancer</strong> Care Alliance, Seattle, WA; Memorial Sloan-Kettering <strong>Cancer</strong><br />
Center, New York, NY; University of Pittsburgh <strong>Cancer</strong> Institute, Pittsburgh,<br />
PA; “Papageorgiou” Hospital, Aristotle University of Thessaloniki School<br />
of Medicine, Thessaloniki, Macedonia, Greece; Attikon University Hospital,<br />
Athens, Greece; Mayo Clinic, Jacksonville, FL.<br />
10:30 S5-5. Trastuzumab plus adjuvant chemotherapy for HER2-positive<br />
breast cancer: Final planned joint analysis of overall survival (OS)<br />
from NSABP B-31 and NCCTG N9831<br />
Romond E, Suman VJ, Jeong J-H, Sledge, Jr. GW, Geyer Jr. CE, Martino S,<br />
Rastogi P, Gralow J, Swain SM, Winer E, Colon-Otero G, Hudis C, Paik S,<br />
Davidson N, Mamounas EP, Zujewski JA, Wolmark N, Perez EA. National<br />
Surgical Adjuvant <strong>Breast</strong> and Bowel Project (NSABP) Operations and<br />
Biostatistical Centers; University of Kentucky; Mayo Clinic; University of<br />
Pittsburgh Graduate School of Public Health; IU Simon <strong>Cancer</strong> Center;<br />
University of Texas Southwestern Medical Center; The Angeles Clinic and<br />
Research Institute; University of Pittsburgh <strong>Cancer</strong> Institute; University of<br />
Washington; Medstar Washington Hospital Center; Dana-Farber <strong>Cancer</strong><br />
Institute; Memorial Sloan-Kettering <strong>Cancer</strong> Center; Aultman Hospital;<br />
<strong>Cancer</strong> Therapy Evaluation Program, National <strong>Cancer</strong> Institute, National<br />
Institutes of Health, D.H.H.S; Allegheny <strong>Cancer</strong> Center Allegheny General<br />
Hospital.<br />
10:45 S5-6. Activating HER2 mutations in HER2 gene amplification<br />
negative breast cancers<br />
Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, Monsey<br />
J, Li S, Ding L, Mardis ER, Ellis MJ. Washington University School of<br />
Medicine, St. Louis, MO.<br />
11:00 S5-7. Combined blockade of PI3K/AKT and EGFR/HER3 enhances<br />
anti-tumor activity in triple negative breast cancer<br />
Tao J, Ip P, Auricchio N, Juric D, Yu M, Shyamala M, Kim P, Singh S,<br />
Hazra S, Haber D, Scaltriti M, Baselga J. Massachusetts General Hospital;<br />
Prometheus Lab.<br />
11:15 S5-8. Parallel upregulation of Bcl2 and estrogen receptor<br />
(ER) expression in HER2+ breast cancer patients treated with<br />
neoadjuvant lapatinib<br />
Giuliano M, Wang YC, Gutierrez C, Rimawi MF, Chang JC, Wang T,<br />
Hilsenbeck SG, Trivedi MV, Chamness GC, Osborne CK, Schiff R. Lester &<br />
Sue Smith <strong>Breast</strong> Center, Baylor College of Medicine, Houston, TX; Baylor<br />
College of Medicine, Houston, TX; The Methodist Hospital Research<br />
Institute, Houston, TX; University of Houston, Houston, TX.<br />
11:30 am–12:00 pm<br />
AACR Distinguished Lectureship in <strong>Breast</strong> <strong>Cancer</strong><br />
Research<br />
Exhibit Hall D<br />
Genes and the Microenvironment: The Twosome of Gene<br />
Expression and <strong>Breast</strong> <strong>Cancer</strong><br />
Mina J. Bissell, PhD<br />
Lawrence Berkeley National Laboratory<br />
Berkeley, CA<br />
12:00 pm–1:35 pm<br />
LUNCH<br />
12:30 pm–1:35 pm<br />
CASE DISCUSSION 2<br />
Ballroom A<br />
Moderator: Mothaffar Rimawi, MD<br />
Baylor College of Medicine<br />
Houston, TX<br />
Panelists:<br />
Dian Corneliussen-James<br />
METAvivor Research and Support<br />
Annapolis, MD<br />
Jennifer De Los <strong>San</strong>tos, MD<br />
University of Alabama at Birmingham<br />
Birmingham, AL<br />
Tari King, MD<br />
Memorial Sloan-Kettering <strong>Cancer</strong> Center<br />
New York, NY<br />
Hope Rugo, MD<br />
University of California <strong>San</strong> Francisco<br />
<strong>San</strong> Francisco, CA<br />
George W. Sledge, Jr., MD<br />
Indiana University Simon <strong>Cancer</strong> Center<br />
Indianapolis, IN<br />
12:30 pm–1:35 pm<br />
Basic Science Forum<br />
Ballroom B<br />
Molecular Imaging of <strong>Breast</strong> <strong>Cancer</strong>: Visualizing In Vivo <strong>Breast</strong><br />
<strong>Cancer</strong> Biology<br />
Moderator: David A. Mankoff, MD, PhD<br />
University of Pennsylvania Health System – PENN Medicine<br />
Philadelphia, PA<br />
Molecular imaging to characterize breast cancer models<br />
Lewis A. Chodosh, MD, PhD<br />
Perelman School of Medicine<br />
University of Pennsylvania<br />
Philadelphia, PA<br />
Molecular imaging for breast cancer patients<br />
David A. Mankoff, MD, PhD<br />
University of Pennsylvania Health System - PENN Medicine<br />
Philadelphia, PA<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 54s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
1:45 pm–3:15 pm<br />
MINI-SYMPOSIUM 3<br />
Exhibit Hall D<br />
Snp’s - Germline Polymorphisms in <strong>Breast</strong> <strong>Cancer</strong> Susceptibility<br />
and Treatment Toxicity<br />
Moderator: Laura J. van ’t Veer, PhD<br />
University of California, <strong>San</strong> Francisco<br />
<strong>San</strong> Francisco, CA<br />
Germline polymorphisms and susceptibility to breast cancer<br />
Douglas Easton, PhD<br />
University of Cambridge<br />
Cambridge, UNITED KINGDOM<br />
Exploring germline variability as predictors for therapyinduced<br />
toxicity<br />
Bryan P. Schneider, MD, PhD<br />
Indiana University School of Medicine<br />
Indianapolis, IN<br />
Identifying the real promise of genomic medicine<br />
James P. Evans, MD, PhD<br />
University of North Carolina at Chapel Hill<br />
Chapel Hill, NC<br />
3:15 pm–5:00 pm<br />
GENERAL SESSION 6<br />
Exhibit Hall D<br />
Moderator: Suzanne Fuqua, PhD<br />
Baylor College of Medicine<br />
Houston, TX<br />
3:15 S6-1. Exploration of isoform switching and mutation expression in<br />
breast cancer by mRNA-sequencing analysis<br />
Hoadley KA, Parker JS, Wilkerson MD, Mose LE, Jefferys SR, Soloway MG,<br />
Turman YJ, Auman JT, Hayes DN, Perou CM. Lineberger Comprehensive<br />
<strong>Cancer</strong> Center, University of North Carolina at Chapel Hill, NC; University<br />
of North Carolina at Chapel Hill, Chapel Hill, NC.<br />
3:30 S6-2. Characterization of different foci of multifocal breast cancer<br />
using genomic, transcriptomic and epigenomic data<br />
Desmedt C, Nik-Zainal S, Fumagalli D, Rothé F, Singhal S, Majjaj S, Brown<br />
D, Dedeurwaerder S, Defrance M, Maetens M, Adnet P-Y, Vincent D,<br />
Salgado R, Fuks F, Piccart M, Larsimont D, Campbell P, Sotiriou C. Institut<br />
Jules Bordet, Brussels, Belgium; Wellcome Trust <strong>San</strong>ger Institute, Hinxton,<br />
United Kingdom; Université Libre de Bruxelles, Brussels, Belgium.<br />
3:45 S6-3. Neurocognitive impact in adjuvant chemotherapy for breast<br />
cancer linked to fatigue: A prospective functional MRI study<br />
Cimprich B, Hayes DF, Askren MK, Jung MS, Berman MG, Ossher L,<br />
Therrien B, Reuter-Lorenz PA, Zhang M, Peltier S, Noll DC. University of<br />
Michigan, Ann Arbor, MI; University of Washington, Seattle, WA; Rotman<br />
Research Institute at Baycrest, University of Toronto, Canada.<br />
4:00 S6-4. Vitamin D, but not bone turnover markers, predict relapse in<br />
women with early breast cancer: An AZURE translational study<br />
Coleman RE, Rathbone EJ, Marshall HC, Wilson C, Brown JE, Gossiel F,<br />
Gregory WM, Cameron D, Bell R. University of Leeds, United Kingdom;<br />
University of Sheffield, United Kingdom; University of Edinburgh, United<br />
Kingdom; Andrew Love <strong>Cancer</strong> Centre, Geelong, Australia.<br />
4:15 S6-5. Primary results of BEATRICE, a randomized phase III trial<br />
evaluating adjuvant bevacizumab-containing therapy in<br />
triple-negative breast cancer<br />
Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, Steger G, Suter<br />
T, Toi M, Parmar M, Bubuteishvili-Pacaud L, Henschel V, Laeufle R, Bell R.<br />
University of Edinburgh and <strong>Cancer</strong> Services, NHS Lothian, Edinburgh,<br />
United Kingdom; University of Leeds, United Kingdom; Sunnybrook<br />
Health Sciences Center and University of Toronto, Toronto, ON, Canada;<br />
Klinikum Offenbach, Offenbach, Germany; Cross Center Institute,<br />
Edmonton, Canada; University Hospital Jean Minjoz, Besançon, France;<br />
Medical University of Vienna, Austria; Bern University Hospital, Inselspital,<br />
Switzerland; Kyoto University, Kyoto, Japan; MRC Clinical Trials Unit,<br />
London, United Kingdom; F. Hoffmann-La Roche Ltd., Basel, Switzerland;<br />
Andrew Love <strong>Cancer</strong> Centre, Geelong, Australia; National <strong>Cancer</strong> Center,<br />
Singapore, Singapore.<br />
4:30 S6-6. A Phase III, open-label, randomized, multicenter study of<br />
eribulin mesylate versus capecitabine in patients with locally<br />
advanced or metastatic breast cancer previously treated with<br />
anthracyclines and taxanes<br />
Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Wanders J, Olivo<br />
MS, He Y, Dutcus CE, Cortes. Norris Cotton <strong>Cancer</strong> Center, Dartmouth-<br />
Hitchcock Medical Center, Lebanon, NH; Jules Bordet Institute, Brussels,<br />
Belgium; Leeds Institute of Molecular Medicine and St James’s Institute<br />
of Oncology, Leeds, United Kingdom; University of Montreal, Montreal,<br />
Canada; Mayo Medical Clinic, Jacksonville, FL; Eisai Ltd., Hatfield, United<br />
Kingdom; Eisai Inc., Woodcliff Lake, NJ; Vall D’Hebron University Hospital,<br />
Barcelona, Spain.<br />
4:45 S6-7. Adaptive immune system and immune checkpoints are<br />
associated with response to pertuzumab (P) and trastuzumab (H)<br />
in the NeoSphere study<br />
Gianni L, Bianchini G, Valagussa P, Belousov A, Thomas M, Ross G, Pusztai<br />
L. <strong>San</strong> Raffaele Hospital - Scientific Institute, Milano, Italy; Fondazione<br />
Michelangelo, Milano, Italy; Roche Diagnostics GmbH, Penzberg,<br />
Germany; Roche Products Limited, Welwyn, United Kingdom; Yale School<br />
of Medicine, New Haven, CT.<br />
5:00 pm–7:00 pm<br />
Poster Discussion 9: DNA Repair<br />
Ballroom A<br />
Viewing 5:00 pm<br />
Discussion 5:15 pm<br />
Daniel Silver, MD, PhD, Chair and Discussant<br />
Dana-Farber <strong>Cancer</strong> Institute<br />
Boston, MA<br />
Shridar Ganesan, MD, PhD, Discussant<br />
The <strong>Cancer</strong> Institute of New Jersey<br />
New Brunswick, NJ<br />
PD09-01 BRCA1 inactivation induces NF-κB in human breast cancer cells<br />
and in murine and human mammary glands<br />
Sau A, Arnaout A, Pratt C. University of Ottawa, ON, Canada; Ottawa<br />
Hospital, Ottawa, ON, Canada.<br />
PD09-02 BRCA1 insufficiency is predictive of superior survival in<br />
patients with triple negative breast cancer treated with<br />
platinum based chemotherapy<br />
Sharma P, Stecklein S, Kimler BF, Klemp JR, Khan QJ, Fabian CJ, Tawfik<br />
OW, Connor CS, McGinness MK, Mammen JMW, Jensen RA. University<br />
of Kansas Medical Center, Westwood, KS; University of Kansas Medical<br />
Center, Kansas City, KS.<br />
www.aacrjournals.org<br />
55s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
PD09-03<br />
PD09-04<br />
PD09-05<br />
PD09-06<br />
PD09-07<br />
PD09-08<br />
PD09-09<br />
PD09-10<br />
Impact of BRCA1/2 mutation status in TBCRC009: A multicenter<br />
phase II study of cisplatin or carboplatin for metastatic triple<br />
negative breast cancer<br />
Isakoff SJ, Goss PE, Mayer EL, Traina T, Carey LA, Krag KJ, Liu MC,<br />
Rugo H, Stearns V, Come S, Finkelstein D, Hartman A-R, Garber JE,<br />
Ryan PD, Winer EP, Ellisen LW. Massachusetts General Hospital,<br />
Boston, MA; Dana-Farber <strong>Cancer</strong> Institute, Boston, MA; Memorial<br />
Sloan-Kettering <strong>Cancer</strong> Center, New York, NY; University of North<br />
Carolina Lineberger Comprehensive <strong>Cancer</strong> Center, Chapel Hill, NC;<br />
Mass General/North Shore <strong>Cancer</strong> Ctr, Danvers, MA; Georgetown<br />
Lombardi Comprehensive <strong>Cancer</strong> Center, Washington, DC; University<br />
of California, <strong>San</strong> Francisco Helen Diller Family Comprehensive<br />
<strong>Cancer</strong> Center, <strong>San</strong> Francisco, CA; Sidney Kimmel Comprehensive<br />
<strong>Cancer</strong> Center at Johns Hopkins University, Baltimore, MD; Beth Israel<br />
Deaconess Medical Center, Boston, MA; Myriad Genetics, Salt Lake<br />
City, UT; Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA.<br />
Homologous Recombination Deficiency (HRD) score predicts<br />
pathologic response following neoadjuvant platinum-based<br />
therapy in triple-negative and BRCA1/2 mutation-associated<br />
breast cancer (BC)<br />
Telli ML, Jensen KC, Abkevich V, Hartman A-R, Vinayak S, Lanchbury<br />
J, Gutin A, Timms K, Ford JM. Stanford University School of Medicine,<br />
Stanford, CA; Myriad Genetics, Salt Lake City, UT.<br />
Single nucleotide polymorphism of XRCC1 which participates<br />
in DNA repair mechanism predicts clinical outcome in<br />
relapsed or metastatic breast cancer patients treated with<br />
S1 and oxaliplatin chemotherapy: Results from multicenter<br />
prospective study (TORCH_KCSG BR07-03)<br />
Im S-A, Oh D-Y, Keam B, Lee KS, Ahn J-H, Sohn J, Ahn JS, Kim JH,<br />
Lee MH, Lee KE, Kim HJ, Lee K-H, Han SW, Kim S-Y, Kim SB, Im Y-H,<br />
Ro J, Park H-S. Seoul National University Hospital, Seoul, Korea;<br />
National <strong>Cancer</strong> Center, Goyang, Korea; Asan Medical Center, Seoul,<br />
Korea; Yonsei University College of Medicine, Severance Hospital,<br />
Seoul, Korea; Samsung Medical Center, Seoul, Korea; Seoul National<br />
University Bundang Hospital, Seongnam, Korea; Inha University<br />
Hospital, Incheon, Korea; Ewha Womans University Medical Center,<br />
Seoul, Korea; Hallym University Sacred Heart Hospital, Anyang, Korea;<br />
Kyung-Hee University Hospital, Seoul, Korea; Soon Chun Hyang<br />
University Hospital, Seoul, Korea.<br />
Two phase I trials exploring different dosing schedules<br />
of carboplatin (C), paclitaxel (P), and the poly-ADP-ribose<br />
polymerase (PARP) inhibitor, veliparib (ABT-888) (V) with<br />
activity in triple negative breast cancer (TNBC)<br />
Puhalla SL, Appleman LJ, Beumer JH, Tawbi H, Stoller RG, Owonikoko<br />
TK, Ramalingam SS, Belani CP, Brufsky AM, Abraham J, Shepherd SP,<br />
Giranda V, Chen AP, Chu E. University of Pittsburgh <strong>Cancer</strong> Institute,<br />
Pittsburgh, PA; Winship <strong>Cancer</strong> Institute of Emory University, Atlanta,<br />
GA; West Virginia University <strong>Cancer</strong> Center, Morgantown, WV; Penn<br />
State Hershey <strong>Cancer</strong> Institute, Hershey, PA; National <strong>Cancer</strong> Institute,<br />
Bethesda, MD; Abbott Laboratories, Abbott Park, IL.<br />
Therapeutic potential of targeting ATM-PELP1-p53 axis in<br />
triple negative breast cancer<br />
Krishnan SR, Nair BC, Sareddy GR, Mann M, Roy SS, Vadlamudi RK.<br />
UTHSCSA, <strong>San</strong> <strong>Antonio</strong>, TX.<br />
The potential role of TLK2 as a therapeutic target in<br />
breast cancer<br />
Kim J-A, Cao X, Tan Y, Schiff R, Wang X. Lester & Sue Smith <strong>Breast</strong><br />
Center, Baylor College of Medicine, Houston, TX.<br />
The Akt inhibitor MK-2206 is an effective radio-sensitizer of<br />
p53 deficient triple negative breast cancer (TNBC) cells<br />
Connolly EP, Sun Y, Chao KC, Hei TK. Columbia University,<br />
New York, NY.<br />
DNA damage and repair in mammary gland development<br />
Kass EM, Helgadottir H, Moynahan ME, Jasin M. Memorial Sloan-<br />
Kettering <strong>Cancer</strong> Center, New York, NY.<br />
5:00 pm–7:00 pm<br />
Poster Discussion 10: Prognostic/Predictive<br />
Ballroom B<br />
Viewing 5:00 pm<br />
Discussion 5:15 pm<br />
Matthew Goetz, MD, Chair<br />
Mayo Clinic College of Medicine<br />
Rochester, MN<br />
Dennis C. Sgroi, MD, Discussant<br />
Massachusetts General Hospital<br />
Charlestown, MA<br />
and<br />
Hiltrud Brauch, PhD, Discussant<br />
Dr. Margarete Fischer-Bosch –<br />
Institute of Clinical Pharmacology<br />
Stuttgart, GERMANY<br />
PD10-01 Rescheduled as S1-10<br />
PD10-02 Metabolic syndrome and recurrence within the 21-gene<br />
recurrence score assay risk categories in lymph node negative<br />
breast cancer<br />
Lakhani A, Guo R, Duan X, Ersahin C, Gaynor ER, Godellas C, Kay C, Lo<br />
SS, Mai H, Perez C, Albain K, Robinson P. Loyola University Medical<br />
Center, Maywood, IL.<br />
PD10-03 Predictive value of a proliferation score (MS) in<br />
postmenopausal women with endocrine-responsive breast<br />
cancer: results from International <strong>Breast</strong> <strong>Cancer</strong> Study Group<br />
(IBCSG) Trial IX<br />
Sninsky J, Wang A, Gray K, Lagier R, Christopherson C, Rowland C,<br />
Chang M, Kammler R, Viale G, Kwok S, Regan M, Leyland-Jones B.<br />
Celera, Alameda, CA; Dana-Farber <strong>Cancer</strong> Institute, Boston, MA;<br />
IBCSG Coordinating Center, Berne, Switzerland; European Institute of<br />
Oncology, Milan, Italy; <strong>San</strong>ford Research, Sioux Falls, SD.<br />
PD10-04 Predictive genomic markers to chemotherapy and adjuvant<br />
trastuzumab via whole genome expression DASL profiling in the<br />
N9831 adjuvant study<br />
Perez EA, Eckel-Passow JE, Ballman KV, Anderson SK, Thompson<br />
EA, Asmann YW, Jen J, Dueck AC, Lingle WL, Sledge GW, Winer EP,<br />
Gralow J, Jenkins RB, Reinholz MM. Mayo Clinic, Jacksonville, FL; Mayo<br />
Clinic, Rochester, MN; Mayo Clinic, Scottsdale, AZ; Indiana University<br />
Simon <strong>Cancer</strong> Center, Indianapolis, IN; Dana Farber <strong>Cancer</strong> Institute,<br />
Boston, MA; Seattle <strong>Cancer</strong> Care Alliance, Seattle, WA; Ventana<br />
Medical Systems, Inc., Tuscon, AZ.<br />
PD10-05 HLA-DQA1*02:01/DRB1*07:01 as a biomarker for lapatinibinduced<br />
hepatotoxicity: prospective confirmation in a large<br />
randomised clinical trial (TEACH, EGF105485)<br />
Spraggs CF, Schaid DJ, Parham LR, McDonnell SK, Briley LP, King<br />
KS, Rappold E, Goss PE. GlaxoSmithKline, Stevenage, Hertfordshire,<br />
United Kingdom; GlaxoSmithKline, Raleigh, NC; Mayo Clinic,<br />
Rochester, MN; GlaxoSmithKline, Collegeville, PA; Massachussets<br />
General Hospital, Boston, MA.<br />
PD10-06 CXCL13 mRNA predicts docetaxel benefit in triple<br />
negative tumors<br />
Wirtz RM, Leinonen M, Bono P, Isola J, Kellokumpu-Lehtinen P-L,<br />
Kataja V, Turpeenniemi-Hujanen T, Jyrkkiö S, Eidt S, Schmidt M,<br />
Joensuu H. STRATIFYER Molecular Pathology GmbH, Cologne,<br />
Germany; Pharma, Turku, Finland; Helsinki University Central Hospital<br />
and University of Helsinki, Helsinki, Finland; University of Tampere and<br />
Tampere University Hospital, Finland; Tampere University Hospital,<br />
Tampere, Finland; Kuopio University Hospital, Kuopio, Finland; Oulu<br />
University Hospital, Oulu, Finland; Turku University Hospital, Turku,<br />
Finland; Institute of Pathology at the St-Elisabeth-Hospital, Cologne,<br />
Germany; University Hospital Mainz, Germany.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 56s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
PD10-07 Patients carrying CYP2C8*3 are at increased risk of<br />
paclitaxel-induced neuropathy<br />
Hertz DL, Dees EC, Roy S, Motsinger-Reif AA, Drobish A, Clark LS,<br />
McLeod HL, Carey LA. University of North Carolina at Chapel Hill,<br />
NC; Lineberger Comprehensive <strong>Cancer</strong> Center, University of North<br />
Carolina at Chapel Hill, NC; North Carolina State University, Raleigh,<br />
NC; Gentris Corp., Morrisville, NC.<br />
PD10-08 Venlafaxine inhibits the CYP2D6 mediated metabolic<br />
activation of tamoxifen: Results of a prospective multicenter<br />
study: (NCT00667121)<br />
Goetz MP, Suman V, Henry NL, Reid J, Safgren S, Kosel M, Kuffel M,<br />
Sideras K, Flockhart D, Stearns V, Denduluri N, Irvin WJ, Ames M. Mayo<br />
Clinic, Rochester, MN; University of Michigan, Ann Arbor, MI; Indiana<br />
University, Indianapolis, IN; Johns Hopkins, Baltimore, MD; Fairfax-<br />
Northern Virginia Hematology-Oncology, Arlington, VA; University of<br />
North Carolina, Chapel Hill, NC.<br />
PD10-09 CYP2D6 and adjuvant tamoxifen: Impact on outcome in<br />
pre- but not postmenopausal breast cancer patients<br />
Margolin S, Lindh J, Thorén L, Xie H, Koukel L, Dahl M-L, Eliasson<br />
E. Karolinska Institutet, Stockholm, Sweden; Karolinska University<br />
Hospital, Stockholm, Sweden; Karolinska Institutet, Karolinska<br />
University Hospital Huddinge, Stockholm, Sweden.<br />
5:00 pm–7:00 pm<br />
POSTER SESSION 5 & RECEPTION<br />
Exhibit Halls A-B<br />
Detection/Diagnosis: Diagnostic Pathology<br />
P5-01-01 Predicting OncoDX Recurrence Scores with<br />
Immunohistochemical Markers<br />
Bradshaw SH, Gravel DH, Song X, Marginean EC, Robertson SJ. The<br />
Ottawa Hospital, Ottawa, ON, Canada.<br />
P5-01-02 Inter-observer concordance of Ki-67 labeling index in breast<br />
cancer: Japan <strong>Breast</strong> <strong>Cancer</strong> Research Group (JBCRG) Ki-67<br />
Ring Study<br />
Ueno T, Mikami Y, Yoshimura K, Tsuda H, Kurosumi M, Masuda S,<br />
Horii R, Toi M, Sasano H. Kyoto University Hospital, Kyoto, Japan;<br />
National <strong>Cancer</strong> Center Hospital, Tokyo, Japan; Saitama <strong>Cancer</strong><br />
Center, Saitama, Japan; Nihon University School of Medicine, Tokyo,<br />
Japan; The <strong>Cancer</strong> Institute Hospital of the Japanese Foundation for<br />
<strong>Cancer</strong> Research, Tokyo, Japan; Tohoku University School of Medicine,<br />
Sendai, Japan.<br />
P5-01-03 Discordant Estrogen and Progesterone Receptor Status in<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Hefti MM, Hu R, Knoblauch N, Collins L, Tamimi RM, Beck AH. Beth<br />
Israel Deaconess Medical Center, Boston, MA; Brigham and Women’s<br />
Hospital, Boston, MA.<br />
P5-01-04 Clinico-pathological features of low-grade triple negative early<br />
breast cancers<br />
Nourieh M, Furhmann L, Feron J-G, Caly M, Diéras V, Sastre-Garau X,<br />
Chavrier P, Vincent-Salomon A. Institut Curie, Paris, France.<br />
P5-01-05 Could C-myc amplification replace Cahan’s criteria to<br />
discriminate secondary from primary angiosarcoma<br />
of the breast?<br />
Laé M, Hamel F, Hadj-Hamou S, Malfoy B, Kirova YM. Institut Curie,<br />
Paris, France.<br />
P5-01-06 Differences in FGF1 and FGFR2 expression in BRCA1-<br />
associated, BRCA2-associated, and sporadic breast carcinomas<br />
Vos S, van der Wall E, van Diest PJ, van der Groep P. University<br />
Medical Center Utrecht, Netherlands.<br />
P5-01-07 Fibroadenomatoid changes are more prevalent in<br />
middle-aged women and have a positive association with<br />
invasive breast cancer<br />
Chen Y, Bekhash A, Kovatich AJ, Hooke JA, Kvecher L, Mitchell EP, Rui<br />
H, Mural RJ, Shriver CD, Hu H. Windber Research Institute, Windber,<br />
PA; Walter Reed National Military Medical Center, Bethesda, MD;<br />
MDR, Global Systems LLC, Windber, PA; Thomas Jefferson University,<br />
Philadelphia, PA.<br />
P5-01-08 Complex fibroadenoma is not an independent risk marker for<br />
breast cancer<br />
Nassar A, Visscher DW, Degnim AC, Frank RD, Vierkant RA, Hartmann<br />
LC, Frost MH, Ghosh K. Mayo Clinic, Rochester, MN.<br />
P5-01-09 Identification of Molecular Apocrine Triple Negative <strong>Breast</strong><br />
<strong>Cancer</strong> Using a Novel 2-Gene Assay and Comparison with<br />
Androgen Receptor Protein Expression and Gene Expression<br />
Profiling by DASL<br />
Alvarez J, Schaffer M, Karkera J, Martinez G, Gaffney D, Bell K, Sharp M,<br />
Wong J, Hertzog B, Ricci D, Platero S. Janssen Pharmaceuticals.<br />
P5-01-10 Clinical-pathological features and outcomes of Invasive lobular<br />
(ILC) vs Invasive ductal (IDC) breast cancer (BC): a monoinstitutional<br />
series<br />
Ferro A, Eccher C, Triolo R, Caldara A, Di Pasquale MC, Russo LM, De<br />
Carli NL, Cuorvo LV, Barbareschi M, Gasperetti F, Berlanda G, Pellegrini<br />
M, Moroso S, Galligioni E. S Chiara Hospital, Trento, Italy; FBK,<br />
Trento, Italy.<br />
P5-01-11 Same-day diagnosis’ of women suspected of breast cancer:<br />
success rate and impact on diagnostic quality and patients’<br />
anxiety levels<br />
Barentsz MW, Wessels H, van Diest PJ, Pijnappel RM, van der Pol CC,<br />
Witkamp AJ, van den Bosch MA, Verkooijen HM. University Medical<br />
Center Utrecht.<br />
P5-01-12 Over- and Undergrading of <strong>Breast</strong> <strong>Cancer</strong> on Core Biopsies in<br />
Comparison to Surgical Specimens<br />
Decker T, Focke CM, Gläser D, Finsterbusch K. Bonhoeffer Medical<br />
Center, Neubrandenburg, Germany.<br />
P5-01-13 Flat Epithelial Atypia: Management and outcome in three<br />
Dutch teaching hospitals<br />
Ghuijs PM, de Vries B, Strobbe LJA, van Deurzen CHM, Heuts<br />
EM, Keymeulen KBMI, Lobbes MBI, Wauters CAP, Van de Vijver<br />
KKBT, Smidt ML. Maastricht University Medical Centre, Maastricht,<br />
Netherlands; Canisius-Wilhelmina Hospital, Nijmegen, Netherlands;<br />
Erasmus Medical Centre, Rotterdam, Netherlands.<br />
P5-01-14 Discrepancy between routine and expert pathologists in<br />
histological assessment of early stage non palpable breast<br />
cancer and its impact on loco regional and systemic treatment<br />
Postma EL, Verkooijen HM, van Diest PJ, Willems SM, van den Bosch<br />
MA, van Hillegersberg R. UMC Utrecht.<br />
P5-01-15 Anti-ER monoclonal antibody SP1 seems more sensitive in the<br />
identification of ER alpha positive breast cancer cases than<br />
anti-ER monoclonal antibody 1D5<br />
Madeira KP, Daltoé RD, Sirtoli GM, Rezende LCD, Carvalho AA, Silva IV,<br />
Rangel LBA. Universidade Federal do Espírito <strong>San</strong>to, Vitória, ES, Brazil.<br />
P5-01-16 Value of ultrasonography appearance of breast mass in<br />
prediction of histologic type<br />
Xu Z, Sun L, Yang H, Song Y, Sun G. JiLin Province <strong>Breast</strong> Dieases<br />
Institue, Changchun, JiLin, China.<br />
Detection/Diagnosis: Detection/Diagnosis - Other<br />
P5-02-01 Discrepancy between CT and FDG-PET/CT in the staging of<br />
patients with inflammatory breast cancer: Implications for<br />
radiation therapy treatment planning<br />
Jacene H, DiPiro P, Bellon J, Nakhlis F, Hirshfield-Bartek J, Yeh E,<br />
Overmoyer B. Dana-Farber <strong>Cancer</strong> Institute, Harvard Medical School,<br />
Boston, MA.<br />
www.aacrjournals.org<br />
57s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-02-02 Factors influencing time to seeking medical advice and<br />
start of treatment in breast cancer (BC) patients – an<br />
International survey<br />
Jassem J, Ozmen V, Bacanu F, Drobniene M, Eglitis J, Kahan Z,<br />
Lakshmaiah K, Mardiak J, Pienkowski T, Semiglazova T, Stamatovic<br />
L, Timcheva C, Vasovics S, Vrbanec D, Zaborek P. Medical University<br />
of Gdansk, Poland; University of Istanbul, Turkey; Sf Maria Hospital,<br />
Bucharest, Romania; Institute of Oncology, Vilnius University, Vilnus,<br />
Lithuania; Riga East University Hospital, Riga, Latvia; University of<br />
Szeged, Hungary; Kidwai Memorial Institute of Oncology, Bangaluru,<br />
India; National <strong>Cancer</strong> Institute and Medical School of Comenius<br />
University, Bratislava, Slovakia (Slovak Republic); Medical Center<br />
of Postgraduate Education, ECZ, Otwock, Poland; Petrov Research<br />
Institute of Oncology, St. Petersburg, Russian Federation; Institute<br />
of Oncology and Radiology, Belgrade, Serbia; Chemiotherapy Clinic,<br />
Sofia, Bulgaria; Zagreb University Hospital Center, Zagreb, Croatia;<br />
Warsaw School of Economics, Warsaw, Poland.<br />
P5-02-03 Large-scale genomic instability consistently identifies BRCA1/2<br />
inactivation in breast cancers<br />
Stern M-H, Popova T, Manié E, Dubois T, Sigal-Zafrani B, Bollet M,<br />
Sastre-Garau X, Vincent-Salomon A, Houdayer C, Stoppa-Lyonnet D.<br />
Institut Curie, Paris, France.<br />
Tumor Cell and Molecular Biology: Stem/Progenitor Cells<br />
P5-03-01 <strong>Cancer</strong> stem cells predict engraftment and poor prognosis of<br />
primary breast tumors<br />
Charaffe-Jauffret E, Ginestier C, Bertucci F, Cabaud O, Wicinski J,<br />
Finetti p, Josselin E, Adelaide J, Nguyen T-T, Monville F, Jacquemier J,<br />
Thomassin-Piana J, Pinna G, Jalaguier A, Lambaudie E, Houvenaeghel<br />
G, Xerri l, Harel-bellan A, Chaffanet M, Viens P, Birnbaum D. CRCM-<br />
IPC; CEA.<br />
P5-03-02 Targeting mRNA Translation To Enhance the Radiosensitivity<br />
of Inflammatory <strong>Breast</strong> <strong>Cancer</strong> Stem Cells<br />
Silvera D, Connolly EP, Volta V, Arju R, Venuto T, Schneider RJ. NYU<br />
School of Medicine, New York, NY; NYU <strong>Cancer</strong> Institute, NYU School<br />
of Medicine, New York, NY; Columbia University College of Physicians<br />
and Surgeons, New York, NY.<br />
P5-03-03 Antitumor Activity and <strong>Cancer</strong> Stem Cells Effect of Cetuximab<br />
in Combination with Ixabepilone in Triple Negative <strong>Breast</strong><br />
<strong>Cancer</strong>s (TNBC)<br />
Tanei T, Rodriguez AA, Dobrolecki L, Choi DS, Landis M, Chang JC.<br />
The Methodist Hospital Research Institute and Weill Cornell Medical<br />
School, Houston, TX.<br />
P5-03-04 Effect of aging on the function and transformation of murine<br />
mammary stem cells<br />
Bandyopadhyay A, Dong Q, Wang D, Gao H, Wu A, Yeh I-T, Sun L.<br />
University of Texas Health Science Center, <strong>San</strong> <strong>Antonio</strong>, TX; Virginia<br />
Hospital Center, Arlington, VA.<br />
P5-03-05 Histone deacetylase (HDAC)-inhibitor mediated<br />
reprogramming drives cancer cells to the pentose phosphate<br />
metabolic pathway<br />
Debeb BG, Larson RA, Lacerda L, Xu W, Smith DL, Ueno NT, Reuben<br />
JM, Gilcrease M, Krishnamurthy S, Buchholz TA, Woodward WA. MD<br />
Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
P5-03-06 Bisphenol A and mammary stem cells: implications in breast<br />
cancer susceptibility<br />
Dong Q, Wang D, Gao H, Bandyopadhyay A, Wu A, Yeh I-T, Huang<br />
C, Sun L. University of Texas Health Science Center at <strong>San</strong> <strong>Antonio</strong>,<br />
TX; Wenzhou Medical College, Wenzhou, Zhejiang, China; Virginia<br />
Hospital Center, Arlington, VA.<br />
P5-03-07 Targeting Hedgehog pathway to reverse chemoresistance in<br />
breast cancer stem cells<br />
Mañu A, Fresquet V, Mena M, Sánchez S, Espinós J, Fernandez<br />
Hidalgo OA, Fernández-Zapico M, Knutson KL, Martínez-Climent JA,<br />
<strong>San</strong>tisteban M. Clinic University of Navarra, Pamplona, Navarra, Spain;<br />
Foundation for Applied Medical Research, Pamplona, Navarra, Spain;<br />
Mayo Clinic, Rochester, MN.<br />
P5-03-08 A fluorescence STAT3 reporter preferentially expressed in<br />
human breast cancer tumor-initiating cells<br />
Wei W, Tweardy D, Zhang M, Roarty K, Rosen J, Lewis M. Lester and<br />
Sue Smith <strong>Breast</strong> Center, Baylor College of Medicine, Houston, TX.<br />
P5-03-09 Receptor Activator of Nuclear Factor Kappa B (RANK) as a<br />
potential therapeutic target in triple-negative breast cancer<br />
Reyes ME, Masuda H, Zhang D, Reuben JM, Woodward W, Darnay BG,<br />
Hortobagyi GN, Ueno NT. MD Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
P5-03-10 HIF-1alpha knockout radiosensitizes select Inflammatory<br />
<strong>Breast</strong> <strong>Cancer</strong> cells through reduction of stem-like cancer cells<br />
Xu W, Debeb BG, Smith DL, Li JL, Ueno NT, Alvarez de Lacerda LC,<br />
Larson RA, Schwba LP, Seagroves TN, Woodward WA. MD Anderson<br />
<strong>Cancer</strong> Center, Houston, TX; U of Tennessee Health Science Center,<br />
Memphis, TN.<br />
P5-03-11 Possible role for cancer stem cells: results from a pilot<br />
neoadjuvant trial of HER-2 positive breast cancer patients<br />
treated with a combination of (Nab)-paclitaxel and lapatinib<br />
Siziopikou KP, Gradishar WJ, Kaklamani VG. Northwestern University<br />
Feinberg School of Medicine, Chicago, IL.<br />
P5-03-12 Targeting breast cancer stem cells using the autophagy<br />
inhibitor N-Acetyl cysteine<br />
Dave B, Granados S, Mitra S, Chang JC. Methodist Hostpital Research<br />
Institute, Houston, TX.<br />
P5-03-13 Detection of tumor initiating cells (TIC) among the peripherally<br />
circulating epithelial tumor cells from patients with breast<br />
cancer<br />
Pachmann K, Zimon D, Pizon M, Carl S, Rabenstein C, Camara O,<br />
Pachmann U. University Hospital Jena, Germany; Transfusion Center,<br />
Bayreuth, Germany.<br />
P5-03-14 Expression of ALDH1 in metastasizing axillary lymphnodes in<br />
breast cancer<br />
Shi A, Dong Y, Bi L, Xu N, Fan Z, Li S, Yang H, Li Y. First Hospital of<br />
Bethune Medical College, Jilin University, Changchun, Jilin, China;<br />
Lester & Sue Smith <strong>Breast</strong> Center, Baylor College of Medicine,<br />
Houston, TX.<br />
Tumor Cell and Molecular Biology: Epithelial-Mesenchymal Transition<br />
P5-04-01 Expression of epithelial-mesenchymal transition (EMT)-<br />
related markers in primary tumors and matched lymph node<br />
metastases in breast cancer patients<br />
Zaczek AJ, Ahrends T, Markiewicz A, Seroczynska B, Szade J, Welnicka-<br />
Jaskiewicz M, Jassem J. Intercollegiate Faculty of Biotechnology,<br />
University of Gdansk and Medical University of Gdansk, Gdansk,<br />
Poland; Medical University of Gdansk, Pomorskie, Poland.<br />
P5-04-02 DYRK2 regulates breast cancer invasion via Snail/E-cadherin<br />
pathway<br />
Mimoto R, Imawari Y, Kamio M, Kato K, Nogi H, Toriumi Y, Takeyama<br />
H, Yoshida K, Uchida K. The Jikei University School of Medicine,<br />
Tokyo, Japan.<br />
P5-04-03 Epithelial-mesenchymal transition is associated with in situ to<br />
invasive transition of basal-like breast cancer<br />
Park SY, Choi Y, Kim EJ, Lee HE, Lee HJ, Kang E, Kim S-W. Seoul<br />
National University College of Medicine, Seoul, Republic of Korea;<br />
Seoul National University Bundang Hospital, Seongnam,<br />
Republic of Korea.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 58s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P5-04-04 Significance of PELP1/HDAC2/microRNA-200 regulatory<br />
network in EMT and metastasis of breast cancer<br />
Roy SS, Gonugunta VK, Bandyopadhyay AM, Rao M, Goodall G, Sun<br />
L, Tekmal RR, Vadlamudi RK. UTHSCSA, <strong>San</strong> <strong>Antonio</strong>, TX; Centre for<br />
<strong>Cancer</strong> Biology, Adelaide, Australia.<br />
P5-04-05 E-Cadherin Is Required for In Vivo Growth of Inflammatory<br />
<strong>Breast</strong> <strong>Cancer</strong>: Importance of Mesenchymal-Epithelial<br />
Transition (MET) and Role of HIF1α<br />
Chu K, Boley KM, Cristofanilli M, Robertson FM. The University of<br />
Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX; Fox Chase <strong>Cancer</strong><br />
Center, Philadelphia, PA.<br />
P5-04-06 Soluble factors from activated immune cells induce epithelial<br />
mesenchymal transition in inflammatory breast cancer cells<br />
Cohen EN, Gao H, Anfossi S, Giordano A, Tin S, Wu Q, Lee B-N, Luthra<br />
R, Krishnamurthy S, Hortobagyi GN, Ueno NT, Woodward WA, Reuben<br />
JM. The University of Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX;<br />
The University of Texas at Houston Health Science Center, Houston,<br />
TX; The Morgan Welch Inflammatory <strong>Breast</strong> <strong>Cancer</strong> Research Program<br />
and Clinic, The University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX.<br />
P5-04-07 Epithelial-mesenchymal transition phenotype in breast<br />
cancers is associated with clinicopathologic factors indicating<br />
aggressive biologic behavior and poor clinical outcome<br />
Bae YK, Kim A, Choi JE, Kang SH, Lee SJ. Yeungnam University College<br />
of Medicine, Daegu, Korea.<br />
P5-04-08 Identifying and characterizing human kinases for novel<br />
regulators of epithelial-mesenchymal transition in breast<br />
cancer cells<br />
Li L, Azizian N, Li W. Brown Foundation Institute of Molecular<br />
Medicine, University of Texas Health Science Center at Houston, TX.<br />
P5-04-09 Squamous Cell Carcinoma Antigen 1 (SCCA1) Upregulation<br />
Causes Epithelial to Mesenchymal Transition (EMT) and<br />
Promotes Mammary Tumorigenesis<br />
Sheshadri N, Ullman E, Catanzaro J, Chen E, Zong W-X. Stony Brook<br />
University, Stony Brook, NY.<br />
Tumor Cell and Molecular Biology: Systems Biology of <strong>Breast</strong> <strong>Cancer</strong><br />
P5-05-01 Catalogued phospho-sensing peptides identifying active,<br />
oncogenic kinase signatures<br />
Mori M, Chen Z, Boudreau A, van’t Veer L, Coppé J-P. University of<br />
California, <strong>San</strong> Francisco, CA; Kinogea Inc., Shanghai, China; Lawrence<br />
Berkeley National Laboratory, Berkeley, CA.<br />
P5-05-02 The role of cellular heterogeneity on the therapeutic response<br />
of breast cancer: Clinical insights from a hybrid multiscale<br />
computational model<br />
Powathil GG, Thompson A, Chaplain MAJ. University of Dundee,<br />
Scotland, United Kingdom; Dundee <strong>Cancer</strong> Centre, University of<br />
Dundee, Scotland, United Kingdom.<br />
P5-05-03 The 5p12 breast cancer susceptibility locus is associated with<br />
MRPS30 expression in estrogen receptor - positive tumors<br />
Quigley DA, Van Loo P, Alnæs GG, Tost J, Zelenika D, Balmain A,<br />
Børresen-Dale A-L, Kristensen VN. Institute for <strong>Cancer</strong> Research, Oslo<br />
University Hospital, Oslo, Norway; Wellcome Trust <strong>San</strong>ger Institute,<br />
Hinxton, United Kingdom; Helen Diller Family Comprehensive <strong>Cancer</strong><br />
Center, University of California, <strong>San</strong> Francisco, CA; CEA - Institut de<br />
Génomique, Evry, France.<br />
P5-05-04 Intraductal delivery of RNAi-based therapeutics to gene targets<br />
identified through computational systems modeling<br />
Brock A, Krause S, Li H, Kowalski M, Collins J, Ingber D. Wyss Institute,<br />
Harvard University, Boston, MA; Boston Children’s Hospital,<br />
Boston, MA.<br />
P5-05-05 Computational modeling of breast cancer growth and spread:<br />
the role of matrix degrading enzymes<br />
Deakin NE, Thompson AM, Chaplain MAJ. University of Dundee,<br />
United Kingdom; Dundee <strong>Cancer</strong> Centre, University of Dundee,<br />
United Kingdom.<br />
P5-05-06 Spatio-temporal computational modeling of the p53-Mdm2<br />
pathway<br />
Sturrock M, Thompson AM, Chaplain MAJ. University of Dundee,<br />
United Kingdom; Dundee <strong>Cancer</strong> Centre, University of Dundee,<br />
United Kingdom.<br />
Tumor Cell and Molecular Biology: Cell Cycle Regulation<br />
P5-06-01 Active pak6 induces aneuploidy in breast cancer cells<br />
Paul BA, Lu ML. University of Miami Miller School of Medicine, Miami,<br />
FL; Florida Atlantic University, Boca Raton, FL.<br />
P5-06-02 The Role of <strong>Breast</strong> Tumor Kinase (Brk) in Cell Cycle Control<br />
Nimnual AS, Chan E. Stony Brook University, Stony Brook, NY.<br />
Tumor Cell and Molecular Biology: Cellular Mechanisms<br />
P5-07-01 Defining the mechanism of breast cancer growth by<br />
chemokine receptor CXCR7 and Epidermal Growth Factor<br />
Receptor coupling interaction<br />
Salazar N, Muñoz D, Singh RK, Lokeshwar BL. University of Miami<br />
Miller School of Medicine, Miami, FL; Miami VA Medical Center,<br />
Miami, FL; Dow Corning Inc., Midland, MI.<br />
P5-07-02 Analysis of a novel synergistic relationship between the FK506<br />
binding protein FKBP52 and beta catenin in androgen receptor<br />
signaling pathways<br />
Storer CL, Olivares K, Fletterick RJ, Webb P, Cox MB. The University<br />
of Texas at El Paso, El Paso, TX; The University of California, <strong>San</strong><br />
Francisco, CA; The Methodist Hospital Research Institute, Houston, TX.<br />
P5-07-03 Gallotannins and Gallic acid From Mango Fruit (Mangifera<br />
Indica L) Suppress <strong>Breast</strong> <strong>Cancer</strong> Tumor Growth by Targeting<br />
Phosphatidylinositol3-kinase (PI3K)-Akt-NF-kB Pathway and<br />
Associated microRNAs<br />
Banerjee N, Kim H, Krenek K, Talcott S, Talcott SM. Texas A&M<br />
University, College Station, TX.<br />
P5-07-04 Aurora kinase regulates PKC-mediated MMP-9 expression and<br />
invasion in MCF-7 breast cancer cells<br />
Kim JS, Noh EM, Lee YR, Hwang B-M, Jung SH, Youn HJ, Lee SJ.<br />
Institute for Medical Sciences Chonbuk National University Medical<br />
School, Jeonju, Republic of Korea; Chonbuk National University<br />
Medical School, Jeonju, Republic of Korea; School of Dentistry,<br />
Wonkwang University, Iksan, Republic of Korea; College of Phamacy,<br />
Ewha Womans University, Seoul, Republic of Korea.<br />
P5-07-05 Insulin-like growth factor binding protein-3 is a key<br />
component of the breast cancer cell response to DNAdamaging<br />
therapy<br />
Baxter RC, Lin MZ, Marzec KA, Martin JL. University of Sydney,<br />
Sydney, NSW, Australia.<br />
P5-07-06 Triple negative receptor status is associated with low DNA<br />
repair capacity in women with breast cancer<br />
Matta J, Ortiz C, Vargas W, Echenique M, <strong>San</strong>chez F, Ramirez E,<br />
Torres A, Ortiz J, Bolaños G, Gonzalez J, Laboy J, Barnes R, <strong>San</strong>tiago S,<br />
Romero A, Martinez R, Alvarez-Garriga C, Bayona M. Ponce School<br />
of Medicine and Health Sciences, Ponce, Puerto Rico; Auxilio Mutuo<br />
Hospital, <strong>San</strong> Juan, Puerto Rico; Ponce School of Medicine and Health<br />
Sciences and Damas Hospital, Ponce, Puerto Rico; Private Office,<br />
Ponce, Puerto Rico; Ponce School of Medicine and Health Sciences<br />
and Private Practice, Ponce, Puerto Rico; Ponce School of Medicine<br />
and Health Sciences and <strong>San</strong> Lucas Hospital, Ponce, Puerto Rico;<br />
Ponce School of Medicine and Health Sciences, Ponce, Puerto Rico;<br />
Dr. Pila Hospital, Ponce, Puerto Rico; Food and Drug Administration,<br />
Silver Spring, MD.<br />
Tumor Cell and Molecular Biology: Telomeres/Telomerase<br />
P5-08-01 Investigating the role of BRCA1 in sensitivity to GRN163L, a<br />
telomerase template antagonist<br />
Phipps EA, Gryaznov SM, Herbert B-S. Indiana University School of<br />
Medicine, Indianapolis, IN; Geron Corporation, Menlo Park, CA.<br />
www.aacrjournals.org<br />
59s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Tumor Cell and Molecular Biology: Apoptosis and Senescence<br />
P5-09-01 Evaluation of BCL2 sequence variant in Iranian women patients<br />
with <strong>Breast</strong> cancer<br />
Motahari B, Ghaffarpour M, Javadi GH, Houshmand M. Science and<br />
Research branch, Islamic Azad University, Tehran, Islamic Republic<br />
of Iran; National Institute of Genetic Engineering and Biotechnology,<br />
Tehran, Islamic Republic of Iran; Iranian Research Organization for<br />
Science and Technology, Tehran, Islamic Republic of Iran; Special<br />
Medical Center, Tehran, Islamic Republic of Iran.<br />
Tumor Cell and Molecular Biology: MicroRNAs<br />
P5-10-01 MicroRNAs -181 and -135a modulate tumour<br />
infiltrating immune cell programs in distinct molecular breast<br />
cancer subtypes<br />
Paladini L, Truglia M, Arcangeli A, De Mattos Aruda L, Bianchini G,<br />
Iwamoto T, Bottai G, Pusztai L, Calin GA, Di Leo A, <strong>San</strong>tarpia L. Istituto<br />
Toscano Tumori, Prato, Italy; Istituto Toscano Tumori - Hospital of<br />
Prato, Prato, Italy; University of Florence, Italy; Vall d’Hebron Institute<br />
of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain;<br />
Fondazione Centro <strong>San</strong> Raffaele del Monte Tabor, Milan, Italy;<br />
Okayama University Hospital, Okayama, Japan; The University of Texas<br />
M.D. Anderson <strong>Cancer</strong> Center, Houston.<br />
P5-10-02 High serum levels of miR-19a are associated with poor<br />
outcome in metastatic inflammatory breast cancer<br />
Anfossi S, Giordano A, Cohen EN, Gao H, Woodward W, Ueno NT,<br />
Valero V, Alvarez RH, Hortobagyi GN, Lee B-N, Cristofanilli M, Reuben<br />
JM. The University of Texas MD Anderson <strong>Cancer</strong> Center; Morgan<br />
Welch Inflammatory <strong>Breast</strong> <strong>Cancer</strong> Research Program and Clinic,<br />
The University of Texas MD Anderson <strong>Cancer</strong> Center; Fox Chase<br />
<strong>Cancer</strong> Center.<br />
P5-10-03 OncomiR-569 deregulates p53 pathway and initiate<br />
breast oncogenesis<br />
Chaluvally-Raghavan P, Zhang F, Pradeep S, Hee-Dong H, Lu Y,<br />
Borresen-Dale A-L, Flores ER, Sood AK, Mills GB. MD Anderson <strong>Cancer</strong><br />
Centre, Houston, TX; Institute for <strong>Cancer</strong> Research, Oslo University<br />
Hospital, Oslo, Oslo, Norway.<br />
P5-10-04 Metformin mediated upregulation of microRNA-193 triggers<br />
apoptosis by decreasing fatty acid synthase<br />
Cochrane DR, Wahdan-Alaswad RS, Edgerton SM, Terrell KL, Spoelstra<br />
NS, Thor AD, Anderson SM, Richer JK. University of Colorado Denver<br />
School of Medicine, Aurora, CO.<br />
P5-10-05 Novel Mechanisms of Metformin Action in TN <strong>Breast</strong> <strong>Cancer</strong>:<br />
Upregulation of miRNA 141 and 192, Are Associated with a<br />
Decrease in Targets GRB2 and MSN Involved in Signaling and<br />
Motility Respectively<br />
Edgerton SM, Richer JK, Fan Z, Spoelstra NS, Wahdan-Alsawad RS,<br />
Arnadottir SS, Thor AD. University of Colorado Denver School of<br />
Medicine, Aurora, CO; Aarhus University, Aarhus, Denmark.<br />
P5-10-06 A functional role for miR-150 in breast cancer<br />
D’Amato NC, Gu H, Lee M, Heinz R, Spoelstra NS, Jean A, Cochrane<br />
DR, Richer JK. University of Colorado Anschutz Medical Campus,<br />
Aurora, CO.<br />
P5-10-07 Luminal A breast cancer: identification of novel circulating<br />
miRNA biomarkers<br />
McDermott AM, Miller N, Ball G, Sweeney KJ, Kerin MJ. National<br />
University of Ireland, Galway, Galway, Ireland; Nottingham Trent<br />
University, Nottingham, United Kingdom.<br />
P5-10-08 Hyperactive MAPK signaling alters expression of miR-221/222<br />
and miR-30 families, which impacts multiple pathways and<br />
contributes to breast cancer aggressiveness and progression<br />
Miller P, El-Ashry D. University of Miami, FL.<br />
P5-10-09 Prediction of Trastuzumab treatment response for<br />
HER2-positive breast cancer by microRNA profiling<br />
Sato F, Wang Z, Ueno T, Myomoto A, Takizawa S, Masuda N, Mikami<br />
Y, Shimizu K, Tsujimoto G, Toi M. Graduate School of Medicine,<br />
Kyoto University, Kyoto, Japan; Toray Industry, Kamakura, Kanagawa,<br />
Japan; Kyoto University Hospital, Kyoto, Japan; Graduate School of<br />
Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.<br />
P5-10-10 The miR-34a is down-regulated in breast cancer and breast<br />
stem cells and a potential to eradicating breast cancer via a<br />
systemic delivery of a VISA –miR-34a nanoparticle system<br />
Xie X, Li L, Xie X, Wei W, Kong Y, Wu M, Yang L, Gao J, Xiao X, Tang<br />
J, Xie Z, Wang X, Liu P, Li X, Guo J. Sun Yat-Sen University <strong>Cancer</strong><br />
Center, Guangzhou, China.<br />
P5-10-11 Clinical significance of microRNA expression as a prognostic<br />
factor in early N+ breast cancer (BC)<br />
Ciruelos EM, de Velasco GA, Castañeda C, Rodriguez-Peralto JL,<br />
Gamez A, Sepúlveda JM, Cortés-Funes H, Castellano DE, Fresno JA.<br />
Hospital Universitario 12 de Octubre, Madrid, Spain; Instituto de<br />
Enfermedades Neoplásicas, Lima, Peru; Hospital Universitario La Paz,<br />
Madrid, Spain.<br />
P5-10-12 Differences in microRNA expression patterns in breast cancer<br />
and triple negative tumors<br />
Romero-Cordoba SL, Rebollar-Vega RG, Quintanar-Jurado V,<br />
Rodriguez-Cuevas S, Bautista-Pina V, Maffuz-Aziz A, Hidalgo-Miranda<br />
A. National Institute of Genomic Medicine, Mexico; Instituto de<br />
Enfermedades de la Mama FUCAM, Mexico.<br />
P5-10-13 Pre-surgical plasma microRNA pattern defines a biologically<br />
distinct triple negative breast cancer (TNBC) occuring in black<br />
(B) compared to white (W) women<br />
Shapira I, Lee A, Oswald M, Taioli E, Bradley T, Barginear M, Mason C,<br />
Keogh M, Budman D. Monter <strong>Cancer</strong> Center, Hofstra North Shore LIJ<br />
School of Medicine, Lake Success, NY; Hofstra North Shore LIJ School<br />
of Medicine, Manhasset, NY.<br />
P5-10-14 MicroRNAs as biomarkers and therapeutic adjuvants for the<br />
prognosis and treatment of drug-resistant breast cancers<br />
Chang Y-F, Panneerdoss S, Zoghi B, Pertsemlidis A, Rao M. Greehey<br />
Children’s <strong>Cancer</strong> Research Institute, University of Texas Health<br />
Science Center at <strong>San</strong> <strong>Antonio</strong>, TX; UT Health Science Center at <strong>San</strong><br />
<strong>Antonio</strong>, TX.<br />
P5-10-15 Genetic variants located in beta2 adrenergic receptor gene<br />
(ADRB2) and miRNA let-7 binding site alter breast cancer<br />
susceptibility: a case control analysis<br />
Du Y, Lu J. Shanghai <strong>Cancer</strong> Center, Fudan University, Shanghai,<br />
China; Shanghai Medical College, Fudan University, Shanghai, China.<br />
P5-10-16 miRNAs as novel therapeutic adjuvants for the prognosis and<br />
treatment of triple negative breast cancers<br />
Zoghi B, Chang Y-F, Subbarayalu P, Plyler JR, Rao M. University of<br />
Texas Health Science Center at <strong>San</strong> <strong>Antonio</strong>, TX; Greehey Children’s<br />
<strong>Cancer</strong> Research Institute, University of Texas Health Science Center<br />
at <strong>San</strong> <strong>Antonio</strong>.<br />
P5-10-17 Radiotherapy-induced miR expression influences the<br />
formation of local recurrence in breast cancer<br />
Fabris L, Berton S, Massarut S, D’Andrea S, Roncadin M, Perin T,<br />
Calin G, Belletti B, Baldassarre G. CRO, National <strong>Cancer</strong> Institute; MD<br />
Anderson <strong>Cancer</strong> Center.<br />
Psychosocial, Quality of Life, and Educational Aspects: Advocacy<br />
P5-11-01 Extending breast conservation choices for women with<br />
breast cancer<br />
Egbeare DM, Chan HY. Cheltenham General Hospital, Cheltenham,<br />
Gloucestershire, United Kingdom.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 60s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P5-11-02 <strong>Breast</strong> <strong>Cancer</strong> Radiation Therapy and the Risk of Developing<br />
Bronchiolitis Obliterans Organizing Pneumonia (BOOP):<br />
Communication of BOOP Risk by <strong>Breast</strong> <strong>Cancer</strong> Information<br />
Websites and General Medical Information Websites<br />
Kelly EM. Kelly Consulting, Smithtown, NY.<br />
Psychosocial, Quality of Life, and Educational Aspects: Education<br />
P5-12-01 Are web-based resources the breast? An evaluation of the<br />
quality of online resources for breast cancer patients<br />
Nguyen S, Regehr G, Brar B, Lin J, Ingledew P. British Columbia<br />
<strong>Cancer</strong> Centre, Fraser Valley <strong>Cancer</strong> Centre, Surrey, BC, Canada;<br />
Centre for Health Education Scholarship, Vancouver, BC, Canada;<br />
UBC, Vancouver, BC, Canada.<br />
P5-12-02 Tangled in the <strong>Breast</strong> <strong>Cancer</strong> Web: An Evaluation of the<br />
Usage of Web-based Information Resources by <strong>Breast</strong><br />
<strong>Cancer</strong> Patients<br />
Nguyen SKA, Ingledew P. British Columbia <strong>Cancer</strong> Agency, FVCC,<br />
Surrey, BC, Canada.<br />
P5-12-03 Developing the ePromotora: Increasing Promotora’s Access to<br />
<strong>Breast</strong> <strong>Cancer</strong> Electronic Resources<br />
Lopez AM, Ryan J, Valencia A, El-Khayat Y, Nunez A. University of<br />
Arizona, Tucson, AZ.<br />
Psychosocial, Quality of Life, and Educational Aspects: Doctor-Patient<br />
Communication<br />
P5-13-01 Does empowering patients improve accrual to<br />
breast cancer trials?<br />
Arnaout A, Kuchuk I, Bouganim N, Verma S, Clemons M. Ottawa<br />
Hospital, Ottawa, ON, Canada; Mcgill University and Segal <strong>Cancer</strong><br />
Centre, Jewish General Hospital, Montreal, QC, Canada.<br />
P5-13-02 Decision making from multidisciplinary team meetings to<br />
bedside: factors predicting for physicians’ and breast cancer<br />
patients’ acceptance of clinical trials proposed by MTMs<br />
Deneuve J, Mazouni C, Arnedos M, Prenois F, Saghatchian M, André<br />
F, Bourrgier C, Delaloge S. Institut Gustave Roussy, Villejuif, France.<br />
P5-13-03 <strong>Breast</strong> cancer risk assessment for underserved minority<br />
women in primary care: patient and provider perspectives<br />
Hoskins KF, Anderson EE, Tejedo S, Stolley M, VandeWydeven K,<br />
Korah V, Moreno L, Rojas M, Carillo A, Caseras M, Awolala Y, Calhoun<br />
E, Campbell R, Warnecke R. The University of Illinois Hospital and<br />
Health Sciences System, Chicago, IL; The University of Illinois at<br />
Chicago School of Public Health, Chicago, IL; OSF Saint Anthony<br />
Medical Center, Rockford, IL; Loyola University Medical Center,<br />
Maywood, IL; Chicago Family Health Center, Chicago, IL.<br />
Psychosocial, Quality of Life, and Educational Aspects: Disparities and<br />
Barriers to Care<br />
P5-14-01 Withdrawn<br />
P5-14-02 Women’s responses to changes in US Preventive Services Task<br />
Force mammography screening guidelines: results from focus<br />
groups among ethnically diverse women<br />
Bluethmann SM, Allen JD, Hernandez C, Opdyke KM, Gates-Ferris K,<br />
Hurlbert M, Harden E. University of Texas School of Public Health;<br />
Dana Farber <strong>Cancer</strong> Institute; Avon Foundation for <strong>Breast</strong> <strong>Cancer</strong><br />
Crusade; Cicatelli and Associates.<br />
P5-14-03 <strong>Breast</strong> cancer screening and follow-up of abnormal<br />
mammogram results: A population-based study comparing<br />
results from an urban university cancer center to a national<br />
database<br />
Mitchell EP, Avery TP, Jaslow RC, Berger AC, Lee SY, Vaughan-Briggs<br />
C, Bonat J. Thomas Jefferson University, Philadelphia, PA.<br />
P5-14-04 Alleviate the pain in the system: Using process improvement<br />
and systems design tools to strive for a high quality breast<br />
healthcare system in the District of Columbia metro area<br />
Brousseau MK, Graham L, Kaye P, Nolan T, Moraras N. Primary Care<br />
Coalition of Montgomery County, Maryland, Silver Spring, MD;<br />
Regional Primary Care Coalition, Washington, DC; Associates in<br />
Process Improvement, Silver Spring, MD.<br />
P5-14-05 Compliance with radiation therapy in breast cancer patients in<br />
Southeastern Kentucky<br />
Elsoueidi R, Adane E, Dignan M. Appalachian Regional Healthcare,<br />
Hazard, KY; University of Kentucky, Lexington, KY.<br />
P5-14-06 Analysis of test-therapy concordance for biomarkers uPA and<br />
PAI-1 in primary breast cancer in clinical hospital routine:<br />
Results of a prospective multi-center study at Certified <strong>Breast</strong><br />
<strong>Cancer</strong>s in Germany<br />
Jacobs VR, Augustin D, Wischnik A, Kiechle M, Hoess C, Steinkohl O,<br />
Rack B, Kapitza T, Krase P. Paracelsus Medical University, Salzburg,<br />
Austria; Klinikum Deggendorf, Deggendorf; Klinikum Augsburg,<br />
Augsburg, Germany; Technical University Munich (TUM), Germany;<br />
Cooperative <strong>Breast</strong> Center Ebersberg-Rosenheim. Kreisklinikum<br />
Ebersberg, Ebersberg, Germany; Klinikum Dritter Orden, Munich,<br />
Germany; Ludwig-Maximilian-University (LMU), Munich, Germany;<br />
Top-Expertise, Germering/Munich, Germany; AOK Bayern, Munich.<br />
Psychosocial, Quality of Life, and Educational Aspects: Cost-Effectiveness<br />
P5-15-01 Cost-effectiveness of gene expression profiling for ductal<br />
carcinoma in-situ (Oncotype DCIS Score)<br />
Alvarado MD, Harrison BL, Solin LJ, Ozanne EM. University of<br />
California, <strong>San</strong> Francisco, CA; Albert Einstein Medical Center,<br />
Philadelphia, PA.<br />
P5-15-02 The benefit of targeted therapeutics in medical oncology since<br />
the development of trastuzumab<br />
Conter HJ, Conter D, Wolff RA, Valero V, Zwelling L. University of<br />
Texas M.D. Anderson <strong>Cancer</strong> Center, Houston, TX; Huron College,<br />
London, ON, Canada.<br />
P5-15-03 Cost-effectiveness of ‘radioguided occult lesion localization’<br />
(ROLL) versus ‘wire-guided localization’ (WGL) in breast<br />
conserving surgery for non-palpable breast cancer: results<br />
from a randomized controlled multicentre trial<br />
Postma EL, Koffijberg E, Verkooijen HM, Witkamp AJ, van den Bosch<br />
MA, van Hillegersberg R. UMC Utrecht; Julius Center Utrecht.<br />
P5-15-04 CTX and CTX-related direct medication costs saved by testing<br />
biomarkers uPA and PAI-1 in primary breast cancer: Results of<br />
a prospective multi-center study at Certified <strong>Breast</strong> Centers<br />
in Germany<br />
Jacobs VR, Augustin D, Wischnik A, Kiechle M, Hoess C, Steinkohl O,<br />
Rack B, Kapitza T, Krase P. Paracelsus Medical University, Salzburg,<br />
Austria; Klinikum Deggendorf, Deggendorf, Germany; Klinikum<br />
Augsburg, Augsburg, Germany; Technical University Munich<br />
(TUM), Germany; Cooperative <strong>Breast</strong> Center Ebersberg-Rosenheim.<br />
Kreisklinikum Ebersberg, Ebersberg, Germany; Klinikum Dritter<br />
Orden, Munich, Germany; Ludwig-Maximilian-University (LMU),<br />
Munich, Germany; Top Expertise, Germering/Munich, Germany; AOK<br />
Bayern, Munich, Germany.<br />
P5-15-05 Budget impact analysis of everolimus for estrogen receptor<br />
positive, human epidermal growth factor receptor-2 negative<br />
metastatic breast cancer patients in the United States<br />
Xie J, Diener M, De G, Yang H, Wu EQ, Namjoshi M. Analysis Group,<br />
Inc., New York, NY; Analysis Group, Inc., Boston, MA; Novartis<br />
Pharmaceuticals Corporation, East Hanover, NJ.<br />
www.aacrjournals.org<br />
61s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-15-06 Societal economics of the 21-gene Recurrence Score® in<br />
estrogen-receptor-positive early-stage breast cancer in Japan<br />
Yamauchi H, Nakagawa C, Yamashige S, Takei H, Yagata H, Yoshida<br />
A, Hayashi N, Hornberger J, Yu T, Chien R, Chao C, Yoshizawa C,<br />
Nakamura S. St. Luke’s International Hospital, Chu-o-ku, Tokyo,<br />
Japan; Hitotsubashi University, Tokyo, Japan; Saitama <strong>Cancer</strong> Center,<br />
Saitama, Japan; Cedar Associates LLC, Menlo Park, CA; Stanford<br />
University School of Medicine, Stanford, CA; Mailman School of<br />
Public Health, Columbia University, New York, NY; Genomic Health,<br />
Inc., Redwood City, CA; Showa University, Tokyo, Japan.<br />
P5-15-07 Time savings with trastuzumab subcutaneous (SC) injection<br />
vs. trastuzumab intravenous (IV) infusion: First results from a<br />
Time-and-Motion study (T&M)<br />
de Cock E, Tao S, Alexa U, Pivot X, Knoop A. United Biosource<br />
Corporation, Barcelona, Spain; United Biosource Corporation,<br />
Montreal, Canada; F Hoffmann-La Roche Ltd, Basel, Switzerland;<br />
CHU Jean Minjoz, Besancon, France; Odense University Hospital,<br />
Odense, Denmark.<br />
Treatment: Immunotherapy<br />
P5-16-01 Survival advantage in patients with metastatic breast cancer<br />
receiving endocrine therapy plus Sialyl Tn-KLH vaccine: post<br />
hoc analysis of a large randomized trial<br />
Ibrahim NK, Murray JL, Zhou D, Mittendorf EA, Sample D, Tautchin<br />
M, Miles D. University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX; Biomira, Inc., AB, Canada; Mount Vernon <strong>Cancer</strong> Center,<br />
Northwood, Middlesex, United Kingdom.<br />
P5-16-02 Final Results of the Phase I/II Trials of the E75 Adjuvant<br />
<strong>Breast</strong> <strong>Cancer</strong> Vaccine<br />
Vreeland TJ, Clifton GT, Hale DF, Sears AK, Patil R, Holmes JP, Ponniah<br />
S, Mittendorf EA, Peoples GE. <strong>San</strong> <strong>Antonio</strong> Military Medical Center,<br />
<strong>San</strong> <strong>Antonio</strong>, TX; Joyce Murtha <strong>Breast</strong> Care Center, Windber, PA;<br />
Redwood Regional Medical Group, <strong>San</strong>ta Rosa Memorial Hospital,<br />
<strong>San</strong>ta Rosa, CA; Uniformed Services University of Health Sciences,<br />
Bethesda, MD; MD Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
P5-16-03 Phase II study of autologous dendritic cell vaccination in<br />
patients with HER2 negative breast cancer combined with<br />
neoadjuvant chemotherapy<br />
Castillo A, Salgado E, Inoges S, Arevalo E, Castañon E, López Díaz<br />
de Cerio A, Sola JJ, Pina L, Nuñez J, Rodriguez-Spiteri N, Espinós<br />
J, Aramendia JM, Fernandez Hidalgo OA, <strong>San</strong>tisteban M. Clínica<br />
Universidad de Navarra, Pamplona, Navarra, Spain; Complejo<br />
Hospitalario de Navarra, Pamplona, Navarra, Spain; Universidad de<br />
Navarra, Pamplona, Navarra, Spain; Clínica Universidad de Navarra.<br />
P5-16-04 A phase I study of a DNA plasmid based vaccine encoding<br />
the HER-2/neu intracellular domain in subjects with HER2+<br />
breast cancer<br />
Salazar LG, Slota M, Higgens D, Coveler A, Dang Y, Childs J, Bates N,<br />
Guthrie K, Waisman J, Disis ML. University of Washington, Seattle,<br />
WA; BREASTLINK, Hawthorne, CA.<br />
P5-16-05 The combination of trastuzumab and HER2-directed peptide<br />
vaccines is safe in HER2-expressing breast cancer patients<br />
Hale DF, Vreeland TJ, Perez SA, Berry JS, Ardavanis A, Trappey<br />
AF, Tzonis P, Sears AK, Clifton GT, Shumway NM, Papamichail<br />
M, Ponniah S, Peoples GE, Mittendorf EA. Brooke Army Medical<br />
Center, <strong>San</strong> <strong>Antonio</strong>, TX; <strong>Cancer</strong> Immunology and Immunotherapy<br />
Center, Athens, Greece; MD Anderson <strong>Cancer</strong> Center, Houston, TX;<br />
Uniformed Services University of the Health Sciences, Bethesda, MD.<br />
P5-16-06 A phase 2 randomized trial of docetaxel (DOC) alone or<br />
in combination with therapeutic cancer vaccine, CEA-,<br />
MUC-1-TRICOM (PANVAC)<br />
Heery CR, Ibrahim NK, Mohebtash M, Madan RA, Arlen PM, Bilusic M,<br />
Kim JW, Singh NK, Hodge S, McMahon S, Steinberg SM, Hodge JW,<br />
Schlom J, Gulley JL. National <strong>Cancer</strong> Institute.<br />
Treatment: Antiangiogenic Therapy<br />
P5-17-01 Bevacizumab (B) in the adjuvant treatment of breast cancer -<br />
first toxicity results from Eastern Cooperative Oncology Group<br />
trial E5103<br />
Miller KD, O’Neill A, Dang C, Northfelt D, Gradishar W, Sledge GW.<br />
Indiana University Melvin and Bren Simon <strong>Cancer</strong> Center; Dana<br />
Farber <strong>Cancer</strong> Institute; Memorial Sloan Kettering <strong>Cancer</strong> Center;<br />
Mayo Clinic; Northwestern University.<br />
P5-17-02 Withdrawn<br />
P5-17-03 Quality of life (QoL) results from the TURANDOT trial<br />
comparing two bevacizumab (BEV)-containing regimens<br />
as first-line treatment for HER2-negative metastatic breast<br />
cancer (mBC)<br />
Láng I, Inbar MJ, Kahan Z, Greil R, Beslija S, Stemmer SM, Kaufman<br />
B, Ahlers S, Brodowicz T, Zielinski C. National Institute of Oncology,<br />
Budapest, Hungary; Tel Aviv Sourasky Medical Centre, Tel Aviv,<br />
Israel; University of Szeged, Hungary; Paracelsus Medical University,<br />
Salzburg, Austria; Institute of Oncology, Sarajevo, Bosnia and<br />
Herzegowina; Rabin Medical Center, Petah-Tikva, Israel; Sheba<br />
Medical Center, Ramat Gan, Israel; IST GmbH Mannheim, Mannheim,<br />
Germany; Medical University of Vienna and Central European<br />
Cooperative Oncology Group (CECOG), Vienna, Austria.<br />
P5-17-04 Management of Antiangiogenics’ Renovascular Safety in<br />
breast cancer. Subgroup and intermediate results of the<br />
MARS Study<br />
Launay-Vacher V, Janus N, Daniel C, Rey J-B, Ray-Coquard I, Gligorov<br />
J, Spano J-P, Thery J-C, Jouannaud C, Goldwasser F, Mir O, Morere<br />
J-F, Oudard S, Azizi M, Dorent R, Deray G, Beuzeboc P. Institut Curie,<br />
Paris, France; Hôpital de la Pitié-Salpêtrière, Paris, France; Institut Jean<br />
Godinot, Reims, France; Centre Léon Bérard, Lyon, France; Hôpital<br />
Tenon, Paris, France; Hôpital Cochin, Paris, France; Hôpital Avicenne,<br />
Bobigny, France; Hôpital Européen Georges Pompidou, Paris, France.<br />
P5-17-05 Sorafenib plus Ixabepilone as First-Line Treatment for<br />
Patients with HER2-Negative Metastatic <strong>Breast</strong> <strong>Cancer</strong>:<br />
Preliminary Results of the Phase II Trial of the Sarah Cannon<br />
Research Institute<br />
Yardley DA, Barton, Jr. J, Dickson N, Shipley D, Drosick DR, Hendricks<br />
C, Inhorn RC, Shastry M, Finney L, Burris HA. Tennessee Oncology,<br />
PLLC, Nashville, TN; Sarah Cannon Research Institute, Nashville,<br />
TN; National Capital Clinical Research Consortium, Bethesda, MD;<br />
Oncology Hematology Care, Cincinnati, OH; Mercy Hospital,<br />
Portland, ME.<br />
P5-17-06 The deficient eNOS c.894G>T genotype is not associated with<br />
increased severity of hypertension and proteinuria in breast<br />
cancer patients receiving bevacizumab<br />
Del Re M, Ferrarini I, Fontana A, <strong>San</strong>toro M, Bona E, Del Re I, Stasi<br />
I, Bertolini I, Laurà F, Landucci E, Salvadori B, Falcone A, Danesi R.<br />
University Hospital, Pisa, Italy.<br />
P5-17-07 Influence of bevacizumab on local-regional recurrence in<br />
triple negative breast cancer<br />
Prendergast BM, De Los <strong>San</strong>tos JF, Barrett OC, Forero A, Falkson<br />
CI, Urist MM, Krontiras H, Bland KI, Meredith RF, Keene KS, You Z,<br />
Carpenter JT. University of Alabama Birmingham, AL.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 62s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
Treatment: HER2-Targeted Therapy<br />
P5-18-01 Pertuzumab (P) in combination with trastuzumab (T) and<br />
docetaxel (D) in elderly patients with HER2-positive metastatic<br />
breast cancer in the CLEOPATRA study<br />
Miles D, Baselga J, Amadori D, Sunpaweravong P, Semiglazov V,<br />
Knott A, Clark E, Ross G, Swain SM. Mount Vernon <strong>Cancer</strong> Centre,<br />
Middlesex, United Kingdom; Massachusetts General Hospital <strong>Cancer</strong><br />
Center and Harvard Medical School, Boston, MA; Istituto Scientifico<br />
Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy;<br />
Songklanagarind Hospital, Prince of Songkla University, Hat Yai,<br />
Thailand; NN Petrov Research Institute of Oncology, St Petersburg,<br />
Russian Federation; Roche Products Limited, Welwyn, United<br />
Kingdom; MedStar Washington Hospital Center, Washington, DC.<br />
P5-18-02 Selective Crossover in Randomized Trials of Adjuvant<br />
Trastuzumab for <strong>Breast</strong> <strong>Cancer</strong>: Coping with Success<br />
Regan MM, Dafni U, Karlis D, Goldhirsch A, Untch M, Smith I, Gianni<br />
L, Jackisch C, de Azambuja E, Heinzmann D, Cameron D, Bell R,<br />
Dowsett M, Baselga J, Leyland-Jones B, Piccart-Gebhart MJ, Gelber<br />
RD, On behalf of the HERA Study Team. Dana-Farber <strong>Cancer</strong> Institute,<br />
Boston, MA; University of Athens and Frontier Science Foundation-<br />
Hellas, Athens, Greece; Institut Jules Bordet, Universite Libre de<br />
Bruxelles, Brussels, Belgium; Helios Klinikum Berlin Buch, Berlin,<br />
Germany; Royal Marsden Hospital and Institute of <strong>Cancer</strong> Research,<br />
London, United Kingdom; <strong>San</strong> Raffaele Institute, Milan, Italy; Western<br />
General Hospital and University of Edinburgh, United Kingdom;<br />
The Royal Marsden NHS Trust, London, United Kingdom; European<br />
Institute of Oncology, Milan, Italy; Athens University of Economics,<br />
Athens, Greece; Massachusetts General Hospital, Boston, MA; F.<br />
Hoffmann-La Roche, Basel, Switzerland; <strong>San</strong>ford Research, Sioux Falls,<br />
SD; The Andrew Love <strong>Cancer</strong> Centre, The Geelong Hospital, Geelong,<br />
Australia; Klinikum Offenbach, Offenbach, Germany.<br />
P5-18-03 Clinicopathological features among patients with HER2-<br />
positive breast cancer with prolonged response to<br />
trastuzumab based therapy<br />
Vaz-Luis I, Seah D, Olson E, Metzger O, Wagle N, Sohl J, Litsas G,<br />
Burstein H, Krop I, Winer E, Lin NU. Dana Farber <strong>Cancer</strong> Institute,<br />
Boston, MA; Ohio State University.<br />
P5-18-04 Tolerability and efficacy of targeting both mTOR and HER2<br />
signaling in trastuzumab-refractory HER2+ metastatic<br />
breast cancer<br />
Gajria D, King T, Pannu H, Sakr R, Modi S, Drullinsky P, Syldor A, Patil<br />
S, Seidman A, Norton L, Rosen N, Hudis C, Chandarlapaty S. Memorial<br />
Sloan-Kettering <strong>Cancer</strong> Center, New York, NY.<br />
P5-18-05 Interim Results from a Phase 1b/2a Study of Trastuzumab<br />
Emtansine and Docetaxel, With and Without Pertuzumab, in<br />
Patients With HER2-Positive Locally Advanced or Metastatic<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Martin M, García-Sáenz JÁ, Dewar JA, Albanell J, Limentani<br />
SA, Strasak A, Patre M, Branle F, Fumoleau P. Hospital General<br />
Universitario Gregorio Marañón; Hospital <strong>San</strong> Carlos; Ninewells<br />
Hospital; Hospital del Mar; Levine <strong>Cancer</strong> Institute; F. Hoffmann-La<br />
Roche Limited; Centre Georges François Leclerc.<br />
P5-18-06 Trastuzumab emtansine in HER2-positive metastatic breast<br />
cancer: pooled safety analysis from seven studies<br />
Diéras V, Harbeck N, Budd GT, Greenson JK, Guardino E, Samant<br />
M, Chernyukhin N, Smitt M, Krop IE. Institut Curie; <strong>Breast</strong> Center,<br />
University of Munich; Cleveland Clinic, Lerner College of Medicine;<br />
University of Michigan; Genentech, Inc.; Dana-Farber <strong>Cancer</strong> Institute.<br />
P5-18-07 Completed SN33 Trial: 60 month follow-up of Early Stage<br />
Node Positive HER2 Negative patients with NeuVax (E75)<br />
and sargramostim<br />
Mazanet R, Schwartz MW, Ramadan D, Lavin PT. Galena Biopharma,<br />
Lake Oswego, OR; Aptiv Solutions, Southborough, MA.<br />
P5-18-08<br />
P5-18-09<br />
P5-18-10<br />
P5-18-11<br />
P5-18-12<br />
P5-18-13<br />
P5-18-14<br />
P5-18-15<br />
P5-18-16<br />
Identification of ErbB2 function in the heart: implication for<br />
anti-ErbB2 therapy in breast cancer<br />
Perry M-C, Eichner LJ, Dufour CR, Muller WJ, Giguère V. Rosalind<br />
and Morris Goodman <strong>Cancer</strong> Research Centre, McGill University,<br />
Montréal, QC, Canada; McGill University, Montréal, QC, Canada.<br />
A Phase I Study of MM-302, a HER2-targeted Liposomal<br />
Doxorubicin, in Patients with Advanced, HER2- Positive<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Wickham T, Futch K. Merrimack Pharmaceuticals.<br />
Chemotherapy can enhance trastuzumab-mediated ADCC<br />
Tagliabue E, Sfondrini L, Regondi V, Casalini P, Pupa SM, Sommariva<br />
M, Balsari A, Triulzi T. Fondazione IRCCS Istituto Nazionale dei Tumori;<br />
Università degli Studi di Milano.<br />
Pharmacokinetics and exposure-efficacy relationship of<br />
trastuzumab emtansine in EMILIA, a phase 3 study of<br />
trastuzumab emtansine vs capecitabine and lapatinib in HER2-<br />
positive locally advanced or metastatic breast cancer<br />
Wang B, Jin J, Wada R, Fang L, Saad O, Olsen S, Althaus B, Swain<br />
S, Untch M, Girish S. Genentech, Inc.; Quantitative Solutions;<br />
Washington Hospital Center; HELIOS Hospital Berlin-Buch.<br />
Comparison of treatment patterns and outcomes in metastatic<br />
breast cancer patients initiated on trastuzumab vs. lapatinib; a<br />
retrospective analysis<br />
Gauthier G, Guérin A, Styles AL, Wu EQ, Masaquel A, Brammer MG,<br />
Lalla D. Analysis Group Inc., Boston, MA; Genentech, Inc., South <strong>San</strong><br />
Francisco, CA.<br />
Inhibiting telomerase to reverse trastuzumab (T) resistance in<br />
HER2+ breast cancer<br />
Miller KD, Steding CE, Prasad N, Rojas LA, Herbert B-S. Indiana<br />
University Melvin and Bren Simon <strong>Cancer</strong> Center.<br />
Cardiac monitoring during adjuvant trastuzumab therapy for<br />
breast cancer<br />
Ng D, Ferrusi I, Khong H, Earle C, Trudeau M, Marshall D, Leighl N.<br />
University of Toronto, ON, Canada; McMaster University, Hamilton,<br />
ON, Canada; University of Calgary, AB, Canada; Ontario Institute for<br />
<strong>Cancer</strong> Research, Toronto, ON, Canada.<br />
Molecular effects of lapatinib in HER2 positive ductal<br />
carcinoma in situ (DCIS)<br />
Estevez LG, Suarez A, Calvo I, Garcia E, Miro C, Durán H, Quijano<br />
Y, Perea S, Herrero M, Lopez-Rios F, Hidalgo M. Centro Integral<br />
Oncologico Clara Campal, Madrid, Spain.<br />
A Multicenter Phase 2 Study (JO22997) Evaluating the<br />
Efficacy and Safety of Trastuzumab Emtansine in Japanese<br />
Patients With Heavily Pretreated HER2-Positive Metastatic<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Masuda N, Ito Y, Takao S, Doihara H, Rai Y, Horiguchi J, Kohno N,<br />
Fujiwara Y, Tokuda Y, Watanabe J, Iwata H, Ishiguro H, Miyoshi Y,<br />
Matsubara M, Kashiwaba M. NHO Osaka National Hospital, Osaka,<br />
Japan; The <strong>Cancer</strong> Institute Hospital of JFCR, Tokyo, Japan; Hyogo<br />
<strong>Cancer</strong> Center, Akashi, Japan; Okayama University Hospital, Okayama,<br />
Japan; Sagara Hospital, Kagoshima, Japan; Gunma University,<br />
Maebashi, Japan; Tokyo Medical University, Tokyo, Japan; National<br />
<strong>Cancer</strong> Center Central Hospital, Tokyo, Japan; Tokai University,<br />
Isehara, Japan; Shizuoka <strong>Cancer</strong> Center, Sunto-gun, Japan; Aichi<br />
<strong>Cancer</strong> Center, Nagoya, Japan; Kyoto University, Kyoto, Japan; Hyogo<br />
College of Medicine, Nishinomiya, Japan; Chugai Pharmaceutical<br />
Co.,Ltd., Tokyo, Japan; Iwate Medical University, Morioka, Japan.<br />
www.aacrjournals.org<br />
63s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-18-17 Impact of compliance with National Comprehensive <strong>Cancer</strong><br />
Network guidelines on adjuvant trastuzumab administration<br />
for patients with HER2-positive breast cancer<br />
Mullins DN, Maly J, Abdel-Rasoul M, Shapiro CL, Olson EM.<br />
Comprehensive <strong>Cancer</strong> Center, The Ohio State University Wexner<br />
Medical Center, Arthur G. James <strong>Cancer</strong> Hospital and Richard J.<br />
Solove Research Institute, Columbus, OH; The Ohio State University<br />
Wexner Medical Center, Columbus, OH; The Ohio State University,<br />
Columbus, OH.<br />
P5-18-18 Lapatinib versus trastuzumab, or both, added to preoperative<br />
chemotherapy for breast cancer: A meta-analysis of<br />
randomized evidence<br />
Valachis A, Nearchou A, Lind P. University of Uppsala, Sweden;<br />
Mälarsjukhuset, Eskilstuna, Sweden; Karolinska Institute,<br />
Stockholm, Sweden.<br />
P5-18-19 The 2006 Adjuvant Trastuzumab Convention in Belgium: 5<br />
years later<br />
Vanderhaegen J, Paridaens R, Piccart M, Lalami Y, Machiels J-P, Louis<br />
E, Borms M, Mebis J, Dirix L, Lintermans A, Brouckaert O, Neven P.<br />
University Hospital Leuven, Belgium; University Hospital Leuven/<br />
Catholic University Leuven, Belgium; Institut Jules Bordet, Brussels,<br />
Belgium; Cliniques Universitaires St-Luc, Brussels, Belgium; CHU de<br />
Liège, Liege, Belgium; AZ Groeninge, Kortrijk, Belgium; Limburgs<br />
Oncologisch Centrum, Limburg, Belgium; St Augustinus Hospital,<br />
Wilrijk, Belgium.<br />
P5-18-20 Phase II study of pertuzumab, trastuzumab, and weekly<br />
paclitaxel in patients with metastatic HER2-overexpressing<br />
metastatic breast cancer<br />
Datko F, D’Andrea G, Dickler M, Theodoulou M, Goldfarb S, Lake D,<br />
Fornier M, Modi S, Sklarin N, Comen E, Fasano J, Gajria D, Drullinsky<br />
P, Gilewski T, Murphy C, Syldor A, Lau A, Hamilton N, Patil S, Liu J,<br />
Chandarlapaty S, Hudis C, Dang C. Memorial Sloan-Kettering <strong>Cancer</strong><br />
Center, New York, NY; Bon Secours Hospital, Cork, Ireland.<br />
P5-18-21 A Phase II randomized trial of lapatinib with either vinorelbine<br />
or capecitabine as first- and second-line therapy for ErbB2-<br />
overexpressing metastatic breast cancer (MBC)<br />
Janni W, Sarosiek T, Pikiel J, Karaszewska B, Staroslawska E, Salat<br />
C, Caglevic C, Potemski P, Brain E, Briggs K, de Silvio M, Sapunar F,<br />
Papadimitriou C. Klinikum der Heinrich-Heine-Universität Düsseldorf,<br />
Düsseldorf, Germany; Centrum Medyczne Ostrobramska, NZOZ<br />
Magodent, Warsaw, Poland; Wojewodzkie Centrum Onkologii,<br />
Centrum Badan Klinicznych, Gdansk, Poland; Przychodnia Lekarska<br />
NZOZ “KOMED”, Konin, Poland; Centrum Onkologii Ziemii Lubelskiej,<br />
Lublin, Poland; Hämato-Onkologische Gemeinschaftspraxis, München,<br />
Germany; Mariano <strong>San</strong>chez Fontecilla, Las Condes, Chile; Wojewodzki<br />
Szpital Specjalistyczny, Kopernika, Poland; Institut Curie - Hôpital René<br />
Huguenin, Saint-Cloud, France; GlaxoSmithKline Oncology, Uxbridge,<br />
Middlesex, United Kingdom; GlaxoSmithKline Oncology, Collegeville,<br />
PA; Therapeutic Clinic, General Hospital of Athens, Greece.<br />
P5-18-22 Long-term survival of patients with HER2 metastatic breast<br />
cancer treated by targeted therapies<br />
Fiteni F, Villanueva C, Bazan F, Chaigneau L, Cals L, Dobi E,<br />
Montcuquet P, Nerich V, Limat S, Pivot X. Besançon University<br />
Hospital, Besançon, Doubs, France.<br />
P5-18-23 The prognosis of T1a, T1b N0 M0, HER2+ patients in Korea<br />
Lee JW, Moon H-G, Han W, Noh D-Y. Seoul National University<br />
Hospital, Seoul, Korea.<br />
P5-18-24 Population pharmacokinetics of trastuzumab emtansine, a<br />
HER2-targeted antibody-drug conjugate, in patients with<br />
HER2-positive metastatic breast cancer: clinical implications of<br />
the effect of various covariates<br />
Lu D, Girish S, Gao Y, Wang B, Yi J-H, Guardino E, Samant M,<br />
Cobleigh M, Rimawi M, Conte P, Jin J. Genentech, Inc.; Quantitative<br />
Solutions; Rush University Medical Center; Baylor College of<br />
Medicine; University of Modena and Reggio Emilia.<br />
P5-18-25 Bispecific Fynomer-antibody fusion proteins targeting two<br />
epitopes on HER2<br />
Grabulovski D, Brack S, Toller I, Mourlane F, Bertschinger J. Covagen<br />
AG, Zurich-Schlieren, Switzerland.<br />
P5-18-26 Confirmatory overall survival (OS) analysis of CLEOPATRA: a<br />
randomized, double-blind, placebo-controlled Phase III study<br />
with pertuzumab (P), trastuzumab (T), and docetaxel (D) in<br />
patients (pts) with HER2-positive first-line (1L) metastatic<br />
breast cancer (MBC)<br />
Swain SM, Kim S-B, Cortes J, Ro J, Semiglazov V, Campone M,<br />
Ciruelos E, Ferrero J-M, Schneeweiss A, Knott A, Clark E, Ross G,<br />
Benyunes MC, Baselga J. MedStar Washington Hospital Center,<br />
Washington; Asan Medical Center, University of Ulsan College of<br />
Medicine, Seoul, Korea; Vall d’Hebron University Hospital, Barcelona,<br />
Spain; National <strong>Cancer</strong> Center, Goyang, Korea; NN Petrov Research<br />
Institute of Oncology, St Petersburg, Russian Federation; Centre<br />
René Gauducheau, Saint-Herblain (Nantes), France; Hospital 12 De<br />
Octubre, Madrid, Spain; Centre Antoine Lacassagne, Nice, France;<br />
University Hospital Heidelberg, Heidelberg, Germany; Roche<br />
Products Limited, Welwyn, United Kingdom; Genentech, South<br />
<strong>San</strong> Francisco; Massachusetts General Hospital <strong>Cancer</strong> Center and<br />
Harvard Medical School, Boston.<br />
Treatment: Signal Transduction Inhibitors<br />
P5-19-01 Targeting the HER3-phosphatidyl inositol-3 kinase pathway in<br />
breast cancers<br />
Cook RS, Morrison MM, Arteaga CL, Perou CM. Vanderbilt University,<br />
Nashville, TN; University of North Carolina.<br />
P5-19-02 Selective PI3K and dual PI3K/mTOR inhibitors enhance the<br />
efficacy of endocrine therapies in breast cancer models<br />
Friedman L, Ross LB, Wallin J, Guan J, Prior WW, Wu E, Nannini M,<br />
Sampath D. Genentech, Inc., South <strong>San</strong> Francisco, CA.<br />
P5-19-03 Olaparib plus carboplatin in combination with vandetanib<br />
inhibited the growth of BRCA-wt triple negative breast tumors<br />
in mice: Outside BRCA-box<br />
Dey N, Sun Y, De P, Leyland-Jones B. <strong>San</strong>ford Research/USD,<br />
Sioux Falls, SD.<br />
Treatment: Targeted Therapy - Advanced Disease<br />
P5-20-01 A randomized double-blind phase II study of the<br />
combination of oral WX-671 plus capecitabine vs.<br />
capecitabine monotherapy in first-line HER2- negative<br />
metastatic breast cancer (MBC)<br />
Goldstein LJ, Oliveria CT, Heinrich B, Stemmer SM, Mala C, Selder<br />
S, Bevan P, Harbeck N. Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA;<br />
Instituto Brasilerio Controle <strong>Cancer</strong>, Sao Paulo, Brazil; Hamatologisch-<br />
Onkologische-Praxis Augsburg, Augsburg, Germany; Rabin Medical<br />
Center, Petah Tikva, Israel; Wilex, Munich, Germany; Univeristy of<br />
Munich, Munich, Germany.<br />
P5-20-02 Predictors of long-term survival in a large cohort of patients<br />
with HER2-positive (HER2+) metastatic breast cancer (MBC)<br />
Chavez Mac Gregor M, Lei X, Giordano SH, Valero V, Esteva F,<br />
Mittendorf EA, Gonzalez-Angulo AM, Hortobagyi GN. University of<br />
Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
P5-20-03 A phase 2, double-blind, randomized, placebo-controlled,<br />
dose-finding study of sotatercept for the treatment of<br />
patients with chemotherapy-induced anemia and metastatic<br />
breast cancer<br />
Auerbach M, Osborne CRC, Klesczewski K, Laadem A, Sherman<br />
ML, Bianca R. Auerbach Hematology/Oncology, Baltimore, MD;<br />
Texas Oncology, P.A., Sammons <strong>Cancer</strong> Center, Dallas, TX; Celgene<br />
Corporation, Summit, NJ; Acceleron Pharma, Cambridge, MA.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 64s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P5-20-04<br />
P5-20-05<br />
P5-20-06<br />
P5-20-07<br />
P5-20-08<br />
P5-20-09<br />
P5-20-10<br />
P5-20-11<br />
Eribulin mesylate + trastuzumab as first-line therapy for<br />
locally recurrent or metastatic HER2-positive breast cancer:<br />
results from a phase 2, multicenter, single-arm study<br />
Vahdat L, Schwartzberg L, Wilks S, Rege J, Liao J, Cox D,<br />
O’Shaughnessy J. Weill Cornell Medical College, New York, NY; The<br />
West Clinic, Memphis, TN; <strong>Cancer</strong> Care Centers of South Texas, <strong>San</strong><br />
<strong>Antonio</strong>, TX; Eisai Inc, Woodcliff Lake, NJ; Texas Oncology-Baylor<br />
Charles A. Sammons <strong>Cancer</strong> Center, Dallas, TX.<br />
A Phase 2 trial of RAD 001 and Carboplatin in patients with<br />
triple negative metastatic breast cancer<br />
Singh JC, Volm M, Novik Y, Speyer J, Adams S, Omene CO, Meyers<br />
M, Smith JA, Schneider R, Formenti S, Goldberg JD, Li X, Davis S,<br />
Beardslee B, Tiersten A. New York University, New York, NY.<br />
RAD001 (Everolimus) in combination with Letrozole in the<br />
treatment of postmenopausal women with estrogen receptor<br />
positive Metastatic <strong>Breast</strong> cancer after failure of hormonal<br />
therapy – a phase II study<br />
Safra T, Kaufman B, Ben Baruch N, Kadouri-Sonenfeld L, Nisenbaum<br />
B, Greenberg J, Ryvo L, Yerushalmi R, Evron E. Tel Aviv Sourasky MC,<br />
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Sheba<br />
Medical Center, Ramat Gan, Israel; Kaplan Medical Center, Rehovot,<br />
Israel; Hadassah Ein Karem Medical Center, Jerusalem, Israel; Meir<br />
Kfar Saba Medical Center, Kfar Saba, Israel; Rabin Medical Center<br />
Belinson Campus, Petach Tikva, Israel; Assaf Harofeh Medical Center,<br />
Assaf Harofeh, Israel.<br />
Phase II Trial of Dasatinib in Combination With Weekly<br />
Paclitaxel for Patients with Metastatic <strong>Breast</strong> Carcinoma<br />
Morris PG, Lake D, McArthur HL, Gilewski T, Dang C, Chaim J, Patl S,<br />
Lim K, Norton L, Hudis CA, Fornier MN. Memorial Sloan-Kettering<br />
<strong>Cancer</strong> Center, New York.<br />
Phase II trial of ixabepilone (Ixa) and dasatinib (D) for<br />
treatment of metastatic breast cancer (MBC)<br />
Schwartzberg LS, Tauer KW, Schnell FM, Hermann R, Rubin P,<br />
Christianson D, Weinstein P, Epperson A, Walker M. The West Clinic,<br />
Memphis, TN; Central Georgia <strong>Cancer</strong> Care, Macon, GA; Northwest<br />
Georgia Oncology Centers, Marietta, GA; Cone Health <strong>Cancer</strong> Center,<br />
Greensboro, NC; Hematology Oncology Centers of the Northern<br />
Rockies, Billings, MT; Hematology Oncology PC, Stamford, CT; ACORN<br />
Research, LLC, Memphis, TN.<br />
Tumor mutational analysis and therapy outcomes for<br />
patients (pts) with metastatic/unresectable locally advanced<br />
myoepithelial/metaplastic breast cancer treated with PI3K<br />
targeted therapy<br />
Moulder S, Wheler J, Albarracin C, Gilcrease M, Falchook G, Naing<br />
A, Hong D, Fu S, Piha-Paul S, Tsimberidou A, Janku F, Kurzrock R.<br />
University of Texas, MD Anderson <strong>Cancer</strong> Center.<br />
Panitumumab, Gemcitabine and Carboplatin in Triple-<br />
Negative Metastatic <strong>Breast</strong> <strong>Cancer</strong>: Preliminary Results of a<br />
Phase II Trial of the Sarah Cannon Research Institute<br />
Yardley DA, Ward P, Handricks C, Daniel B, Harwin W, Kannarkat<br />
G, Saez R, Shastry M, Chirwa T, Peacock N. Sarah Cannon Research<br />
Institute, Nashville, TN; Oncology Hematology Care, Cincinnati,<br />
OH; National Capital Clinical Research Consortium, Bethesda, MD;<br />
Chattanooga Oncology and Hematology Associates, Chattanooga,<br />
TN; Florida <strong>Cancer</strong> Specialists, Ft. Myers, FL; Peninsula <strong>Cancer</strong><br />
Institute, Newport News, VA; Texas Health Physician Group,<br />
Arlington, TX; Tennessee Oncolcogy, PLLC, Nashville, TN.<br />
Bevacizumab in metastatic breast cancer: a retrospective<br />
matched-pair analysis<br />
Gampenrieder SP, Romeder F, Muß C, Pircher M, Ressler S,<br />
Rinnerthaler G, Bartsch R, Sattlberger C, Mlineritsch B, Greil R.<br />
Paracelsus Medical University, Salzburg, Austria; Comprehensive<br />
<strong>Cancer</strong> Center Vienna, Medical University of Vienna, Austria; Hospital<br />
of Vöcklabruck, Vöcklabruck, Austria.<br />
P5-20-12 Aromatase inhibitor failure: predictors and time to first<br />
failure among women with metastatic ER+/HER2- breast<br />
cancer in the US<br />
Thomson E, Namjoshi M, Landsman-Blumberg P, Chu BC. Thomson<br />
Reuters, Washington, DC; Novartis Pharmaceuticals Corporation, East<br />
Hanover, NJ.<br />
P5-20-13 Preliminary report of a phase I/II study of entinostat (IND#NSC<br />
706995, /M275) and lapatinib (IND#NSC 727989) in patients<br />
with HER2-positive metastatic breast cancer in whom<br />
trastuzumab has failed<br />
Ueno NT, Jackson SA, Alvarez RH, Willey JS, Hortobagyi GN,<br />
Angulo-Gonzalez AM, Giordano SH, Booser DJ, Valero V. Morgan<br />
Welch Inflammatory <strong>Breast</strong> <strong>Cancer</strong> Research Program and Clinic,<br />
The University of Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX;<br />
University of Texas, MD Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
Treatment: Targeted Therapy - Adjuvant<br />
P5-21-01 pT1a,bpN0M0 breast cancer: clinicopathological<br />
characteristics and their impact on treatment decision. Central<br />
review of the prospective ODISSEE cohort<br />
Lacroix-Triki M, Radosevic-Robin N, Louis B, Roche-Comet I,<br />
Soubeyrand M-S, Bourgeois H, Chauvet M-P, Fourrier-Réglat A,<br />
Gligorov J, Peyrat J-P, Dalenc F, Belkacemi Y, Penault-Llorca F. Institut<br />
Claudius Regaud, Toulouse, France; Centre Jean Perrin, Clermont-<br />
Ferrand, France; Laboratoire d’Anatomie et Cytologie Pathologiques,<br />
Strasbourg, France; Institut Histo-Cyto-Pathologie, Le Bouscat,<br />
France; Cabinet CY-PATH, Villeurbanne, France; Clinique Victor Hugo,<br />
Le Mans, France; Centre Oscar Lambret, Lyon, France; Université<br />
Victor Segalen, Bordeaux, France; Hôpital Tenon, Paris, France; CHU<br />
Henri Mondor-UPEC, Créteil, France.<br />
P5-21-02 Hormone receptor status and endocrine therapy in a<br />
prospective observation study on trastuzumab (Herceptin®)<br />
in the adjuvant treatment of breast cancer<br />
Dall P, Friedrichs K, Petersen V, Hinke A, Brucker C, Schmidt P,<br />
von der Assen A, Jungberg P, Bohnsteen B. Städtisches Klinikum,<br />
Lüneburg, Germany; Krankenhaus Jerusalem, Mammazentrum,<br />
Hamburg, Germany; Praxis, Heidenheim, Germany; WiSP, Biostatistik,<br />
Langenfeld, Germany; Klinikum Nürnberg, Brustzentrum, Nürnberg,<br />
Germany; Praxis, Neunkirchen, Germany; Franziskus-Hospital<br />
Harderberg, Georgsmarienhütte, Germany; Praxis, Chemnitz,<br />
Germany; Praxis, Dessau-Rosslau, Germany.<br />
P5-21-03 Concurrent loco-regional radiotherapy and trastuzumab in<br />
early-stage breast cancer: Long term results of prospective<br />
single-institution study<br />
Jacob J, Belin L, Pierga J-Y, Vincent-Salomon A, Dendale R, Beuzeboc<br />
P, Cottu P-H, Campana F, Fourquet A, Kirova YM. Institut Curie,<br />
Paris, France.<br />
P5-21-04 Real-world use and effectiveness of adjuvant trastuzumab in<br />
2665 consecutive breast cancer patients<br />
Tjan-Heijnen VCG, Seferina SC, Lobbezoo DJA, Voogd AC, Dercksen<br />
MW, van den Berkmortel F, van Kampen RJW, van de Wouw<br />
AJ, Joore MA, Borm GF. Maastricht University Medical Centre,<br />
Maastricht, Limburg, Netherlands; GROW-School for Oncology<br />
and Developmental Biology, Maastricht University Medical Centre,<br />
Maastricht, Limburg, Netherlands; Máxima Medical Centre,<br />
Veldhoven, Brabant, Netherlands; Atrium Medical Centre Parkstad,<br />
Heerlen, Limburg, Netherlands; Orbis Medical Center, Sittard-Geleen,<br />
Limburg, Netherlands; VieCuri Medical Centre, Venlo, Limburg,<br />
Netherlands; Radboud University Medical Center, Nijmegen,<br />
Gelderland, Netherlands.<br />
www.aacrjournals.org<br />
65s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Ongoing Trials 3: Immunotherapy<br />
OT3-1-01 A pilot study of single-dose ipilimumab and/or cryoablation<br />
in women with early-stage breast cancer scheduled for<br />
mastectomy<br />
Diab A, McArthur HL, Solomon S, Comstock C, Maybody M, Sacchini<br />
V, Durack J, Gucalp A, Yuan J, Patil S, Thorne A, Sung J, Kotin A,<br />
Morris E, Brogi E, Morrow M, Wolchok J, Allison J, Hudis C, Norton L.<br />
Memorial Sloan-Kettering <strong>Cancer</strong> Center, New York, NY.<br />
OT3-1-02 Phase II randomized study of combination immunotherapy<br />
with or without Polysaccharide Krestin (PSK®) concurrently<br />
with a HER2 ICD peptide-based vaccine and trastuzumab in<br />
patients with stage IV breast cancer<br />
Childs JS, Higgins DM, Parker S, Reichow J, Lu H, Standish L, Disis ML,<br />
Salazar LG. University of Washington, Seattle, WA; Bastyr University,<br />
Kenmore, WA.<br />
Ongoing Trials 3: Survivorship<br />
OT3-2-01 Influence of strength and endurance training on selected<br />
physical and psychological parameters and on immune<br />
system, metabolism and circulating tumor cells during<br />
adjuvant chemotherapy<br />
Mundhenke C, Weisser B, Keller L, <strong>San</strong>ders L, Summa B, Duerkop J,<br />
Schmidt T, Jonat W. University of Kiel, SH, Germany; Institute of Sport<br />
Science, University of Kiel, SH, Germany; Comprehensive <strong>Cancer</strong><br />
Center North, Kiel, SH, Germany.<br />
OT3-2-02 The PREDICT Study ( Prospective, Randomized Early Detection<br />
and Intervention after <strong>Breast</strong> <strong>Cancer</strong>-Treatment, for women at<br />
risk of lymphedema)<br />
Taghian AG, Skolny MN, O’Toole J, Miller CL, Jammallo LS, Specht<br />
MC. Massachusetts General Hospital, Boston, MA.<br />
Ongoing Trials 3: Chemotherapy<br />
OT3-3-01 Eniluracil + 5-fluorouracil + leucovorin (EFL) vs. capecitabine<br />
phase 2 trial for metastatic breast cancer<br />
Rivera E, Chang JC, Semiglazov V, Gorbunova V, Manikhas A,<br />
Krasnozhon D, Kirby G, Spector T. Banner MD Anderson <strong>Cancer</strong><br />
Center, Gilbert, AZ; The Methodist Hospital Research Institute,<br />
Houston, TX; Road Clinical Hospital of the Russian Railways, St.<br />
Petersburg, Russian Federation; Russian Oncological Research<br />
Center n.s.Blokhin RAMS, Moscow, Russian Federation; City Clinical<br />
Oncology Center, St. Petersburg, Russian Federation; Institution<br />
Leningrad Regional Oncology Center, Leningrad Region, Russian<br />
Federation; Adherex Technologies, Inc., Research Triangle Park, NC.<br />
OT3-3-02 ADAPT - Adjuvant Dynamic marker-Adjusted Personalized<br />
Therapy trial optimizing risk assessment and therapy response<br />
prediction in early breast cancer<br />
Gluz O, Hofmann D, Kates RE, Harbeck N, Nitz U. West German Study<br />
Group, Moenchengladbach, NRW, Germany; Ev. Bethesda Hospital,<br />
Moenchengladbach, NRW, Germany; University Clinic Großhadern,<br />
Munich, Bavaria, Germany.<br />
OT3-3-03 Withdrawn<br />
OT3-3-04 ALOPREV : first cooling scalp trial for prevention of persisting<br />
alopecia after docetaxel for early breast cancer patients<br />
Bourgeois H, Soulié P, Lucas B, Mercier Blas A, Zannetti A, Delecroix<br />
V, L’haridon T, Blot E, Delaloge S, Grudé F. Clinique Victor Hugo, Le<br />
Mans, France; Observatoire dédié au <strong>Cancer</strong> Bretagne Pays de Loire,<br />
Angers, France; Institut de Cancérologie de l’Ouest, Angers Nantes,<br />
France; CHRU Morvan, Brest, France; CHP, Saint Grégoire, France;<br />
CHD, Cholet, France; Pôle Hospitalier Mutualiste, Saint Nazaire,<br />
France; CHD, La Roche sur Yon, France; Centre Hospitalier Bretagne<br />
Atlantique, Vannes, France; Clinique Océane, Centre Saint Yves,<br />
Vannes, France; Institut Gustave Roussy, Villejuif, France.<br />
OT3-3-05<br />
OT3-3-06<br />
OT3-3-07<br />
OT3-3-08<br />
OT3-3-09<br />
Neurotoxicity characterization phase II randomized study<br />
of nab-paclitaxel versus conventional paclitaxel as first-line<br />
therapy of metastatic HER2-negative breast cancer.<br />
An ONSOCUR Study Group<br />
Ciruelos E, Bueno C, Cantos B, Carrión R, Echarri M, Enrech S, García<br />
Saenz JA, Guerra JA, Lara MA, Martínez N, Rodríguez-Antona<br />
C, Domínguez-González C, <strong>San</strong>z JL, Baquero J, Cortés-Funes H,<br />
Sepúlveda JM. Hospital 12 de Octubre, Madrid, Spain; Hospital<br />
Universitario Ramón y Cajal, Madrid, Spain; Hospital Universitario<br />
del Sureste, Arganda del Rey (Madrid), Spain; Hospital Universitario<br />
Clínico <strong>San</strong> Carlos, Madrid, Spain; Hospital Universitario Severo<br />
Ochoa, Leganés (Madrid), Spain; Hospital Universitario Puerta<br />
de Hierro Majadahonda, Majadahonda (Madrid), Spain; Hospital<br />
Universitario Infanta Cristina, Parla (Madrid), Spain; Hospital<br />
Universitario Infanta Leonor, Madrid, Spain; Hospital Universitario de<br />
Getafe, Getafe (Madrid), Spain; Hospital Universitario de Fuenlabrada,<br />
Fuenlabrada (Madrid), Spain; APICES, Madrid, Spain; Celgene, Madrid,<br />
Spain; Centro Nacional de Investigaciones Oncologicas,<br />
Madrid, Spain.<br />
NeoEribulin: A Phase II, non-randomized, open-label, singlearm,<br />
multicenter, exploratory pharmacogenomic study of<br />
single agent eribulin as neoadjuvant treatment for operable<br />
Stage I-II HER2 non-overexpressing breast cancer<br />
Prat A, Llombart A, de la Peña L, Di Cosimo S, Ortega V, Rubio I,<br />
Muñoz E, Harbeck N, Cortés J. Vall d’Hebron University Hospital,<br />
Barcelona, Spain; Hospital Arnau de Vilanova, Valencia, Spain; SOLTI<br />
<strong>Breast</strong> <strong>Cancer</strong> Research Group, Barcelona, Spain; Istituto Nazionale<br />
dei Tumori, Milan, Italy; Brustzentrum am Klinikum der Universität<br />
München, Munich, Germany.<br />
Neoadjuvant bevacizumab with weekly nanoparticle<br />
albumin bound (nab)-paclitaxel plus carboplatin followed by<br />
doxorubicin plus cyclophosphamide (AC) for triple negative<br />
breast cancer<br />
Snider JN, Allen JW, Young R, Schwartzberg L, Javed Y, Jahanzeb<br />
M, Sachdev JC. University of Tennessee, Memphis, TN; The West<br />
Clinic, Memphis, TN; The Center for <strong>Cancer</strong> and Blood Disorders, Fort<br />
Worth, TX.<br />
Eribulin/Cyclophosphamide versus Docetaxel/<br />
Cyclophosphamide as Neoadjuvant Therapy in Locally<br />
Advanced HER2-Negative <strong>Breast</strong> <strong>Cancer</strong>: A Randomized Phase<br />
II Trial of the Sarah Cannon Research Institute<br />
Yardley DA, Hainsworth JD, Shastry M, Finney L, Burris HA. Tennessee<br />
Oncology, PLLC, Nashville, TN; Sarah Cannon Research Institute,<br />
Nashville, TN.<br />
ARTemis trial - randomised trial with neo-adjuvant<br />
chemotherapy for patients with early breast cancer<br />
Earl HM, Blenkinsop C, Grybowicz L, Vallier A-L, Cameron DA,<br />
Bartlett JMS, Murray N, Caldas C, Thomas J, Dunn JA, Higgins HB,<br />
Hiller L, Hayward L. University of Cambridge, United Kingdom;<br />
NIHR Cambridge Biomedical Research Centre, Cambridge, United<br />
Kingdom; University of Warwick, Coventry, United Kingdom;<br />
Cambridge University Hospitals NHS Foundation Trust, Cambridge,<br />
United Kingdom; Edinburgh University, Edinburgh, United Kingdom;<br />
University of Edinburgh, United Kingdom; Royal Adelaide Hospital,<br />
Adelaide, SA, Australia; <strong>Cancer</strong> Research UK Cambridge Research<br />
Institute, Cambridge, United Kingdom; Western General Hospital,<br />
Edinburgh, United Kingdom.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 66s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
OT3-3-10 ASTER 70s: Benefit of adjuvant chemotherapy for oestrogen<br />
receptor-positive HER2-negative breast carcinoma in women<br />
over 70 according to Genomic Grade. A French UNICANCER<br />
Geriatric Oncology Group (GERICO) and <strong>Breast</strong> Group (UCBG)<br />
multicentre phase III trial<br />
Brain E, Baffert S, Bonnefoi HR, Cottu P, Girre V, Lacroix-Triki M,<br />
Latouche A, Leger-Falandry C, Peyro Saint Paul HP, Rollot F, Romieux<br />
G, Servent V, Orsini C, Bonnetain F. Institut Curie, Saint-Cloud, France;<br />
Institut Curie, Paris, France; Institut Bergonié, Bordeaux, France;<br />
Centre Hospitalier La Roche sur Yon, La Roche sur Yon, France;<br />
Institut Claudius Regaud, Toulouse, France; CNAM, Paris, France;<br />
Centre Hospitalier Lyon Sud, Lyon, France; Ipsogen SA, Marseille,<br />
France; Centre Val d’Aurelle, Montpellier, France; Centre Oscar<br />
Lambret, Lille, France; R&D Unicancer, Paris, France; Centre Georges<br />
François Leclerc, Dijon, France.<br />
OT3-3-11 A randomized phase III trial comparing nanoparticle-based<br />
paclitaxel with solvent-based paclitaxel as part of neoadjuvant<br />
chemotherapy for patients with early breast cancer<br />
(GeparSepto) GBG 69<br />
Untch M, Jackisch C, Blohmer J-U, Costa S-D, Denkert C, Eidtmann H,<br />
Gerber B, Hanusch C, Hilfrich J, Huober J, Kuemmel S, Schneeweiss<br />
A, Paepke S, Loibl S, Nekljudova V, von Minckwitz G. Helios Kliniken<br />
Berlin; Klinikum Offenbach; <strong>San</strong>kt-Gertrauden Berlin; University<br />
Magdeburg; Charite Berlin; University Kiel; University Rostock;<br />
Rotkreuzklinikum Muenchen; Eilenriedeklinik Dueseldorf; University<br />
Duesseldorf; Kliniken Essen Mitte; Frauenklinik Muenchen; German<br />
<strong>Breast</strong> Group, Neu-Isenburg.<br />
Ongoing Trials 3: Response Prediction<br />
OT3-4-01 PROMIS: Prospective Registry Of MammaPrint in breast cancer<br />
patients with an Intermediate recurrence Score<br />
Soliman H, Untch S, Stork-Sloots L. Moffitt <strong>Cancer</strong> Center; Agendia<br />
Inc; Agendia NV.<br />
OT3-4-02 MINT I: Multi-Institutional Neo-adjuvant Therapy,<br />
MammaPrint Project I<br />
Cox C, Blumencranz P, Reintgen D, Saez R, Howard N, Gibson J,<br />
Stork-Sloots L, Glück S. University of South Florida; Morton Plant<br />
Hospital; Florida Hospital North Pinellas; Plano <strong>Cancer</strong> Institute;<br />
Agendia Inc; Agendia NV; Miller School of Medicine,<br />
University of Miami.<br />
OT3-4-03 Prospective neo-adjuvant registry trial linking MammaPrint,<br />
subtyping and treatment response: Neo-adjuvant <strong>Breast</strong><br />
Registry – Symphony Trial (NBRST)<br />
Whitworth P, Gittleman M, Akbari S, Nguyen B, Baron P, Rotkiss M,<br />
Beatty J, Gibson J, Stork-Sloots L, de Snoo F, Beitsch P. Nashville<br />
<strong>Breast</strong> Center; <strong>Breast</strong> Care Specialists; Virginia Hospital Center;<br />
Todd <strong>Cancer</strong> Institute, Long Beach Memorial Medical Center;<br />
<strong>Cancer</strong> Specialists of Charleston; Northern Indiana <strong>Cancer</strong> Research<br />
Consortium; The <strong>Breast</strong> Place Charleston; Agendia Inc; Agendia NV;<br />
Dallas Surgical Group.<br />
OT3-4-04 InVite: an observational pilot study evaluating the feasibility<br />
of genome-wide association studies using self-reported data<br />
from patients with metastatic breast cancer treated with<br />
bevacizumab<br />
Leyland-Jones B, Faoro L, Barnholt K, Kiefer A, Yager S, Yi J, Turner B,<br />
Keane A, Wang L, Eriksson N, Milián ML, O’Neill V. Genentech, Inc.;<br />
23andMe; <strong>San</strong>ford Research/USD.<br />
OT3-4-05 Use of early CIRculating tumor CElls count changes to guide<br />
the use of chemotherapy in advanced metastatic breast cancer<br />
patients: the CirCe01 randomized trial<br />
Bidard F-C, Asselain B, Baffert S, Brain E, Campone M, Delaloge S,<br />
Bachelot T, Tubiana-Mathieu N, Pelissier S, Pierga J-Y. Institut Curie;<br />
Institut de Cancérologie de l’Ouest; Institut Gustave Roussy, Villejuif;<br />
Centre Léon Bérard, Lyon; CHU Limoges.<br />
OT3-4-06<br />
Circulating tumor cells to guide the choice between<br />
chemotherapy and hormone therapy as first line treatment for<br />
hormone receptors positive metastatic breast cancer patients:<br />
the STIC CTC METABREAST trial<br />
Bidard F-C, Baffert S, Hajage D, Brain E, Armanet S, Simondi C, Mignot<br />
L, Asselain B, Tresca P, Pierga J-Y. Institut Curie, France.<br />
Saturday, December 8, 2012<br />
6:45 am–9:00 am<br />
Registration<br />
Bridge Hall<br />
7:00 am–8:30 am<br />
POSTER SESSION 6 & continental breakfast<br />
Exhibit Hall C<br />
Tumor Cell and Molecular Biology: Metabolism and <strong>Breast</strong> <strong>Cancer</strong><br />
P6-01-01 Metastatic and non-metastatic isogenic breast cancer cells<br />
lines show different metabolic signatures in response to<br />
intermittent hypoxia and transient glutamine/glucose<br />
deprivation<br />
Simoes RV, Ackerstaff E, Serganova I, Kruchevsky N, Sukenick G,<br />
Blasberg R, Koutcher JA. Memorial Sloan-Kettering <strong>Cancer</strong> Center,<br />
New York, NY; Cornell University, New York, NY.<br />
P6-01-02 Adipose tissue from breast cancer patients with the metabolic<br />
syndrome promotes proliferation and invasion of tumor cells<br />
and influences expression of genes involved in carcinogenesis<br />
McGarrigle SA, Carroll PA, Healy LA, Boyle T, Pidgeon GP, Kennedy<br />
MJ, Connolly EM. Trinity College Dublin and St. James’s Hospital,<br />
Dublin, Ireland.<br />
P6-01-03 Decreasing the metastatic potential in Triple Negative <strong>Breast</strong><br />
<strong>Cancer</strong> through the miR-17 cluster<br />
Jin L, Simone B, <strong>San</strong>o Y, Lim M, Zhao S, Savage JE, Baserga<br />
R, Camphausen K, Simone NL. Thomas Jefferson University,<br />
Philadelphia, PA; National <strong>Cancer</strong> Institute, Bethesda, MD.<br />
P6-01-04 DDB2 a new regulator of metabolism and cell death in human<br />
breast tumor cells<br />
Klotz R, Besancenot V, Brunner E, Becuwe P, Grandemange S.<br />
Université de Lorraine, Vandoeuvre les Nancy, France.<br />
P6-01-05 Enhancement of 18 F-FDG uptake and glycolysis by epidermal<br />
growth factor via PI3K activation in T47D breast cancer cells<br />
Lee EJ, Park JW, Cung Q, Jung K-H, Lee JH, Paik J-Y, Lee K-H.<br />
Samsung Medical Center, Sungkyunkwan University School of<br />
Medicine, Seoul, Korea.<br />
Tumor Cell and Molecular Biology: Microenvironment - Stromal-Epithelial<br />
Interactions<br />
P6-02-01 Apoptotic cell clearance lies at the interface of post-lactational<br />
involution and breast cancer<br />
Cook RS, Stanford JC, Earp S. Vanderbilt University; University of<br />
North Carolina.<br />
P6-02-02 Altered matrix homeostasis regulates estrogen biosynthesis in<br />
adipose tissue<br />
Ghosh S, Ashcraft K, Li R. UT Health Science Center at<br />
<strong>San</strong> <strong>Antonio</strong>, TX.<br />
P6-02-03 Mouse Models Of <strong>Breast</strong> <strong>Cancer</strong> Identify Oncogene-Specific<br />
Stroma Associated With Human <strong>Breast</strong> <strong>Cancer</strong> Molecular<br />
Subtypes<br />
Saleh SM, Laferriere J, Cory S, Souleimanova M, Zacksenhaus E,<br />
Muller W, Hallett M, Park M. McGill University, Montreal, QC, Canada;<br />
Toronto General Hospital, Toronto, ON, Canada.<br />
www.aacrjournals.org<br />
67s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P6-02-04 TMEM (Tumor MicroEnvironment of Metastasis) in human<br />
breast cancer is a blood vessel associated intravasation<br />
microenvironment unrelated to lymphatics<br />
Ginter PS, Robinson BD, D’Alfonso TM, Oktay MH, Gertler FB, Rohan<br />
TE, Condeelis JS, Jones JG. Weill Cornell Medical College, New York,<br />
NY; Albert Einstein College of Medicine, Bronx, NY; Massachusetts<br />
Institute of Technology, Cambridge, MA.<br />
P6-02-05 A novel culturing 3-D model to evaluate the role of tumor<br />
microenvironment in IBC<br />
Dong X, Franco-Barraza J, Mu Z, Alpaugh RK, Cristofanilli M,<br />
Cukierman E. Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA.<br />
P6-02-06 A 3D tri-culture model of normal mammary gland. A tool for<br />
breast cancer initiation studies<br />
Nash CE, Holliday DL, Mavria G, Tomlinson DC, Hanby AM, Speirs V.<br />
Leeds Institute of Molecular Medicine, The University of Leeds, Leeds,<br />
West Yorkshire, United Kingdom.<br />
P6-02-07 In vitro 3D Model of <strong>Breast</strong> Tumor Stroma<br />
Jaganathan H, Mitra S, Dave B, Godin B. The Methodist Hospital<br />
Research Institute, Houston, TX.<br />
P6-02-08 Molecular drivers of adipogenotoxicosis in breast tumorassociated<br />
adipose<br />
Ellsworth RE, Field LA, van Laar R, Deyarmin B, Hooke JA, Shriver CD.<br />
Windber Research Institute, Windber, PA; Signal Genetics, New York,<br />
NY; Walter Reed National Military Medical Center, Bethesda, MD;<br />
Henry M. Jackson Foundation, Windber, PA.<br />
P6-02-09 Role of HGF in obesity-associated tumorigenesis: C3(1)-Tag<br />
mice as a model for human basal-like breast cancer<br />
Sundaram S, Freemerman AJ, Hamilton J, McNaughton K, Galanko<br />
JA, Darr DB, Perou CM, Troester MA, Makowski L. University of North<br />
Carolina at Chapel Hill, Chapel Hill, NC.<br />
Tumor Cell and Molecular Biology: Mammary Development and<br />
Differentiation<br />
P6-03-01 Molecular Dissection of <strong>Breast</strong> Luminal Cell Transcription<br />
Factor Networks<br />
Bargiacchi FG, Earp HS, Perou CM. University of North Carolina<br />
Chapel Hill, NC.<br />
Tumor Cell and Molecular Biology: Endocrine Therapy and Resistance<br />
P6-04-01 Global analysis of breast cancer metastasis suggests<br />
cellular reprogramming is central to the endocrine resistant<br />
phenotype<br />
Bolger JC, McCartan D, Walsh CA, Hao Y, Hughes E, Byrne C, Hill ADK,<br />
O’Gaora P, Young LS. Royal College of Surgeons in Ireland, Dublin 2,<br />
Ireland; University College Dublin, Ireland.<br />
P6-04-02 Final progression-free survival analysis of BOLERO-2: a phase<br />
III trial of everolimus for postmenopausal women with<br />
advanced breast cancer<br />
Piccart M, Baselga J, Noguchi S, Burris H, Gnant M, Hortobagyi G,<br />
Mukhopadhyay P, Taran T, Sahmoud T, Rugo H. Institut Jules Bordet,<br />
Université Libre de Bruxelles, Brussels, Belgium; Massachusetts<br />
General Hospital <strong>Cancer</strong> Center and Harvard Medical School, Boston,<br />
MA; Osaka University, Osaka, Japan; Sarah Cannon Research Institute,<br />
Nashville, TN; Comprehensive <strong>Cancer</strong> Center, Medical University<br />
of Vienna, Vienna, Austria; The University of Texas MD Anderson<br />
<strong>Cancer</strong> Center, Houston, TX; Novartis Pharmaceuticals Corporation,<br />
East Hanover, NJ; University of California, <strong>San</strong> Francisco Helen Diller<br />
Family Comprehensive <strong>Cancer</strong> Center, UCSF, <strong>San</strong> Francisco, CA.<br />
P6-04-03<br />
P6-04-04<br />
P6-04-05<br />
P6-04-06<br />
P6-04-07<br />
P6-04-08<br />
P6-04-09<br />
P6-04-10<br />
P6-04-11<br />
Changes in breast tumor metabolism and estradiol<br />
binding as measured by FES PET in patients treated with<br />
the histone deacetylace inhibitor vorinostat and aromatase<br />
inhibitor therapy<br />
Linden HM, Kurland BF, Specht JM, Vijayakrishn GK, Gralow JR,<br />
Peterson LM, Schubert EK, Link JM, David MA, Eary JF, Krohn<br />
KA. University of Washington, Seattle, WA; Fred Hutchinson<br />
<strong>Cancer</strong> Research Center, Seattle, WA; University of Pennsylvania,<br />
Philadelphia, PA.<br />
Upregulation of the androgen agonist prosaposin in<br />
aromatase inhibitor resistant breast cancer; mediation by the<br />
developmental protein HOXC11<br />
McIlroy M, Hao Y, Bane FT, Young L, O’Gaora P. Royal College<br />
of Surgeons in Ireland, Dublin, Ireland; University College<br />
Dublin, Ireland.<br />
Tamoxifen dose escalation based on endoxifen level:<br />
a prospective trial with genotyping, phenotyping and<br />
pharmacokinetics over 4 months<br />
Zaman K, Dahmane E, Perey L, Bodmer A, Anchisi S, Wolfer A,<br />
Galmiche M, Stravodimou A, Buclin T, Eap C, Decosterd L, Csajka<br />
C, Leyvraz S. University Hospital CHUV, Lausanne, Switzerland;<br />
Ensemble Hospitalier de la Côte, Morges, Switzerland; University<br />
Hospital CHUV, University of Geneva, Lausanne, Switzerland;<br />
University Hospital, Geneva, Switzerland; Hôpital Cantonal, Sion,<br />
Switzerland.<br />
Inverse regulation of Neuregulin1 and HER-3 during<br />
treatment with aromatase inhibitors of estrogen receptorpositive<br />
breast cancer<br />
Flågeng MH, Larionov A, Geisler J, Dixon JM, Lønning PE, Mellgren<br />
G. Haukeland University Hospital, Bergen, Norway; University<br />
of Edinburgh, United Kingdom; Akershus University Hospital,<br />
Lørenskog, Norway; University of Bergen, Norway.<br />
Significance and therapeutic potential of PELP1-mTOR axis in<br />
breast cancer progression and therapy resistance<br />
Gonugunta VK, Cortez V, Sareddy GR, Roy SS, Zhang H, Tekmal<br />
RR, Vadlamudi RK. UTHSCSA, <strong>San</strong> <strong>Antonio</strong>, TX; Shantou University<br />
Medical College, Shantou, China.<br />
FOXA1 expression: regulated by EZH2 and associated with<br />
favorable outcome to tamoxifen in advanced breast cancer<br />
Reijm EA, Helmijr JCA, Soler CMJ, Beekman R, Gerritse FL, Pragervan<br />
der Smissen WJC, Ruigrok-Ritstier K, van IJcken WFJ, Stevens<br />
MG, Smid M, Look MP, Meijer ME, Sieuwerts AM, Sleijfer S, Foekens<br />
JA, Berns EMJJ, Jansen MPHM. Erasmus MC - Daniel den Hoed,<br />
Rotterdam, Netherlands; Erasmus MC, Rotterdam, Netherlands.<br />
Lack of response to aromatase inhibitors involves<br />
distinct mechanisms<br />
Turnbull AK, Larionov AA, Renshaw L, Kay C, Sims AH, Dixon JM.<br />
University of Edinburgh, United Kingdom.<br />
Comprehensive gene and protein assessment of the role<br />
of Her2 in the response to neoadjuvant Letrozole suggests<br />
patients without amplification may also benefit from anti-<br />
Her2 treatment<br />
Webber V, Turnbull AK, Larionov AA, Sims AH, Harrison D, Renshaw<br />
L, Dixon JM. Melville Trust for Care and Cure of <strong>Cancer</strong>, Edinburgh;<br />
Western General Hospital, Edinburgh.<br />
Combination of PI3K-AKT-mTOR and MEK-ERK pathway<br />
inhibitors overcome acquired resistance to letrozole in ER+<br />
breast cancer models<br />
De P, Sun Y, Friedman LS, Chen S, Dey N, Leyland-Jones B. <strong>San</strong>ford<br />
Research/USD, Sioux Falls, SD; Genentech, Inc., South <strong>San</strong> Francisco,<br />
CA; Beckman Research Institute of the City of Hope, Duarte, CA.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 68s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P6-04-12<br />
P6-04-13<br />
P6-04-14<br />
P6-04-15<br />
P6-04-16<br />
P6-04-17<br />
P6-04-18<br />
P6-04-19<br />
P6-04-20<br />
P6-04-21<br />
P6-04-22<br />
P6-04-23<br />
Novel selective estrogen receptors degraders regress tumors<br />
in pre-clinical models of endocrine-resistant breast cancer<br />
Hager JH, Darimont B, Joseph J, Govek S, Grillot K, Aparicio A,<br />
Bischoff E, Kahraman M, Kaufman J, Lai A, Lee K-J, Lu N, Nagasawa J,<br />
Prudente R, Qian J, Sensintaffar J, Shao G, Heyman R, Rix P, Smith ND.<br />
Aragon Pharmaceuticals, <strong>San</strong> Diego, CA.<br />
HOXB7 functions as a co-activator of estrogen receptor in<br />
the development of tamoxifen resistance<br />
Jin K, Teo WW, Yoshida T, Park S, Sukumar S. Johns Hopkins<br />
University School of Medicine, Baltimore, MD.<br />
Targeting the PI3K/mTOR pathway in patient-derived<br />
xenograft models of endocrine resistant luminal breast cancer<br />
Cottu PH, Bagarre T, Assayag F, Bièche I, Chateau-Joubert S, Fontaine<br />
J-J, Decaudin D, Slimane K, Vincent-Salomon A, Marangoni E.<br />
Institut Curie, Paris, France; Institut Curie, Saint-Cloud, France; Ecole<br />
Veterinaire d’Alfort, Maisons-Alfort, France; Novartis Pharma, Rueil<br />
Malmaison, France.<br />
The involvement of LMTK3 in endocrine resistance is mediated<br />
via multiple signaling pathways<br />
Giamas G, Xu Y, Filipovic A, Grothey A, Coombes CR, Stebbing J.<br />
Imperial College, London, United Kingdom.<br />
The role of RIP140 and FOXA1 in breast cancer endocrine<br />
sensitivity and resistance<br />
Harada-Shoji N, Coombes RC, Lam EW-F. Imperial College London,<br />
United Kingdom.<br />
The androgen metabolite-dependent growth in hormone<br />
receptor positive breast cancer as a novel aromatase inhibitorresistance<br />
mechanism<br />
Hanamura T, Niwa T, Nishikawa S, Konno H, Ghono T, Kobayashi Y,<br />
Kurosumi M, Takei H, Yamaguchi Y, Ito K-I, Hayashi S-I. Graduate<br />
School of Medicine, Tohoku University, Sendai, Japan; Shinshu<br />
University School of Medicine, Matsumoto, Japan; Saitama <strong>Cancer</strong><br />
Center, Saitama, Japan.<br />
Evaluation of the molecular mechanisms behind fulvestrant<br />
resistant breast cancer<br />
Kirkegaard T, Hansen SK, Reiter BE, Sorensen BS, Lykkesfeldt AE.<br />
Danish <strong>Cancer</strong> Society Research Center, Copenhagen, Denmark;<br />
Aarhus University Hospital, Aarhus, Denmark.<br />
Neutralizing antibody to human GP88 (progranulin) restores<br />
sensitivity to tamoxifen and inhibits breast tumor growth in<br />
mouse xenografts<br />
Serrero G, Dong J, Hayashi J. A&G Pharmaceutical Inc, Columbia, MD.<br />
Endocrine resistance in invasive lobular carcinoma cells<br />
parallels unique estrogen-mediated gene expression<br />
Sikora MJ, Luthra S, Chandran UR, Dabbs DJ, Welm AL, Oesterreich S.<br />
University of Pittsburgh <strong>Cancer</strong> Institute, Pittsburgh, PA; University of<br />
Pittsburgh, PA; Magee-Womens Hospital, Pittsburgh, PA; University<br />
of Utah Huntsman <strong>Cancer</strong> Institute, Salt Lake City, UT.<br />
AIB1 expression specifically predicts breast cancer patient<br />
response to aromatase inhibitor therapy<br />
Vareslija D, O’Hara J, Tibbitts P, McBryan J, Hao Y, Hill A, Young L.<br />
Royal College of Surgeons Ireland, Dublin, Ireland.<br />
Regulation of Notch localization by endocrine therapy<br />
in Estrogen Receptor positive breast cancer cells: Clinical<br />
implications for endocrine resistance<br />
Espinoza I, Caskey M, Baker RC, Miele L. University of Mississippi,<br />
Jackson, MS.<br />
Targeting of endocrine therapy resistance through combined<br />
mTOR and histone deacetylase inhibition<br />
Ordentlich P, Flechsig S, Hoffmann J. Syndax Pharmaceuticals,<br />
Waltham, MA; EPO-GmbH Berlin, Berlin, Germany.<br />
P6-04-24 Overexpression of protein kinase C alpha differentially<br />
activates transcription factors in T47D breast cancer cells<br />
in the presence of 17β-estradiol both in the 2D and 3D<br />
environments<br />
Pham TND, Asztalos S, Weiss MS, Shea LD, Tonetti DA. University of<br />
Illinois at Chicago, IL; Northwestern University, Evanston, IL.<br />
P6-04-25 Genomic Deregulation and Therapeutic Role of Nemo-like<br />
Kinase in Luminal B <strong>Breast</strong> <strong>Cancer</strong><br />
Cao X, Qin L, Kim J-A, Tan Y, Wang X, Schiff R. Lester & Sue Smith<br />
<strong>Breast</strong> Center, Baylor College of Medicine, Houston, TX.<br />
P6-04-26 Tamoxifen may block estrogen induced secretion of certain<br />
cytokines to interrupt tumor associated macrophage<br />
infiltration in breast cancer<br />
Ding J, Chen CM, Jin W, Shao Z, Wu J. <strong>Breast</strong> <strong>Cancer</strong> Institute, Fudan<br />
University Shanghai <strong>Cancer</strong> Center, Shanghai, China; Shanghai<br />
Medical College, Fudan University, Shanghai, China.<br />
P6-04-27 EBAG9 immunoreactivity is a potential prognostic factor<br />
for poor outcome of breast cancer patients with adjuvant<br />
tamoxifen therapy<br />
Shigekawa T, Ijichi N, Ikeda K, Miyazaki T, Horie-Inoue K, Shimizu C,<br />
Saji S, Aogi K, Tsuda H, Osaki A, Saeki T, Inoue S. Research Center for<br />
Genomic Medicine, Saitama Medical University; International Medical<br />
Center, Saitama Medical University; Tokyo Metropolitan <strong>Cancer</strong> and<br />
Infectious Disease Center, Komagome Hospital; National <strong>Cancer</strong><br />
Center Hospital; Graduate School of Medicine, Kyoto University;<br />
National Shikoku <strong>Cancer</strong> Center; Graduate School of Medicine, The<br />
University of Tokyo.<br />
P6-04-28 Changes in BAG-1 expression level affect the Tamoxifeninduced<br />
apoptosis and Gefitinib-induced apoptosis in<br />
breast cancer cells<br />
Lu S, Zhuang X, Liu H. Tianjin Medical University <strong>Cancer</strong> Institute<br />
and Hospital, Tianjin, China; Tianjin Medical University, Minstry of<br />
Education, Tianjin, China.<br />
P6-04-29 Vitamin D induces expression of estrogen receptor and<br />
restores endocrine therapy response in estrogen receptornegative<br />
breast cancer<br />
<strong>San</strong>tos N, Diaz L, Ordaz D, Garcia J, Barrera D, Avila E, Halhali A,<br />
Medina H, Camacho J, Larrea F, Garcia R. Instituto Nacional de<br />
Ciencias Médicas y Nutrición Salvador Zubirán, México, DF, Mexico;<br />
Centro de Investigación y de Estudios Avanzados del I.P.N., México,<br />
DF, Mexico.<br />
P6-04-30 COUP-TFII suppresses NFκB activation in endocrine-resistant<br />
breast cancer cells<br />
Litchfield LM, Klinge CM. University of Louisville School of Medicine,<br />
Louisville, KY.<br />
Tumor Cell and Molecular Biology: Hormonal Factors and Receptors<br />
P6-05-01 Evaluation of the prognostic significance of androgen<br />
receptor (AR) expression in relation to ER expression in<br />
breast cancer (BC)<br />
Gucalp A, Datko FM, Patil S, Hedvat CV, Kalinsky K, Hudis CA, Traina<br />
TA, Moynahan ME. Memorial Sloan-Kettering <strong>Cancer</strong> Center;<br />
Columbia University Medical Center.<br />
P6-05-02 Endocrine biomarkers in response to AR-inhibition with<br />
bicalutamide for the treatment of AR(+), ER/PR(-) metastatic<br />
breast cancer (MBC) (TBCRC011)<br />
Gucalp A, Tolaney S, Isakoff SJ, Ingle J, Liu MC, Carey L, Blackwell<br />
KL, Rugo H, Nabell L, Forero A, Stearns V, Momen L, Gonzalez J,<br />
Akhtar A, Giri DD, Patil S, Feigin KN, Hudis CA, Traina TA. Memorial<br />
Sloan-Kettering <strong>Cancer</strong> Center; Dana Farber/Harvard <strong>Cancer</strong> Center;<br />
Mayo Clinic <strong>Cancer</strong> Center; Lombardi Comprehensive <strong>Cancer</strong> Center<br />
at Georgetown University; University of North Carolina Lineberger<br />
<strong>Cancer</strong> Center; University of California <strong>San</strong> Francisco Comprehensive<br />
<strong>Cancer</strong> Center; Duke University Medical <strong>Cancer</strong> Center; University<br />
of Alabama Comprehensive <strong>Cancer</strong> Center; The Sidney Kimmel<br />
Comprehensive <strong>Cancer</strong> Center at Johns Hopkins University.<br />
www.aacrjournals.org<br />
69s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P6-05-03<br />
P6-05-04<br />
P6-05-05<br />
P6-05-06<br />
P6-05-07<br />
P6-05-08<br />
P6-05-09<br />
P6-05-10<br />
P6-05-11<br />
P6-05-12<br />
P6-05-13<br />
Targeted inhibition of recurrent PIK3CA mutations<br />
synergizes with bicalutamide in AR-expressing triple negative<br />
breast cancer<br />
Lehmann BD, Bauer JA, Schafer JM, Tang L, Pendleton CS, <strong>San</strong>ders<br />
ME, Pietenpol JA. Vanderbilt, Nashville, TN.<br />
Expression of the Androgen Receptor in triple negative<br />
tumors and its modulation by receptor tyrosine kinases and<br />
downstream pathways<br />
Cuenca D, Montero JC, Morales JC, Prat A, Pandiella A, Ocana A.<br />
Albacete University Hospital, Albacete, Spain; <strong>Cancer</strong> Research<br />
Center, CIC-CSIC, Salamanca, Spain; Lineberger <strong>Cancer</strong> Center,<br />
University of North Carolina.<br />
Triple receptor comparison between primary breast cancer<br />
and metachronous or synchronous liver metastasis<br />
Tuyls S, Brouckaert O, Vanderstichele A, Vanderhaegen J, Amant<br />
F, Leunen K, Smeets A, Berteloot P, Van Limbergen E, Weltens C,<br />
Peeters S, Vanbeckevoort D, Floris G, Moerman P, Paridaens R,<br />
Wildiers H, Vergote I, Christiaens M-R, Neven P. University Hospitals<br />
Leuven, Belgium.<br />
Serum estradiol levels in postmenopausal ER+/PR- breast<br />
cancer are lower than those in postmenopausal ER+/PR+<br />
Yamamoto Y, Ibusuki M, Goto H, Murakami K, Iwase H. Kumamoto<br />
University Hospital, Kumamoto, Japan.<br />
Amplified in breast cancer 1 and ankyrin repeat containing<br />
cofactor 1 mediate estrogen induced repression of the<br />
ErbB2 oncogene<br />
Garee JP, Riegel AT. Georgetown University, Washington, DC.<br />
Significant heterogeneity in ERalpha and PR receptor status in<br />
different distant breast cancer metastases of the same patient<br />
Hoefnagel LDC, van der Groep P, Broers JE, van der Wall E, van Diest<br />
PJ. UMC Utrecht, Utrecht, Netherlands.<br />
Unravelling the global effect of estrogen on breast cancer cell<br />
proteome using quantitative proteomics<br />
Pavlou MP, Drabovich AP, Dimitromanolakis A, Diamandis EP.<br />
University of Toronto, ON, Canada; Mount Sinai Hospital, Toronto,<br />
ON, Canada; University Health Network, Toronto, ON, Canada;<br />
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto,<br />
ON, Canada.<br />
Progestins exert divergent growth effects and regulate<br />
tumor-unique gene cohorts in patient derived breast cancer<br />
xenografts<br />
Sartorius CA, Finlay-Schultz J, Li C, Rosen RB, Hendricks P, Wisell J,<br />
Finlayson C, Elias A, Kabos P. University of Colorado Denver Anschutz<br />
Medical Campus, Aurora, CO.<br />
Leptin and Leptin receptor expression in human breast cancer<br />
Wazir U, Al Sarakbi W, Jiang WG, Mokbel K. The London <strong>Breast</strong><br />
Institute, The Princess Grace Hospital, London, United Kingdom;<br />
Cardiff University-Peking University Oncology Joint Institute, Cardiff,<br />
United Kingdom.<br />
Lack of Frequent Estrogen Receptor Mutation in Primary<br />
<strong>Breast</strong> Tumors<br />
Oesterreich S, Kitchens C, Gavin P, Wu C-C, Riehle K, Coarfa C,<br />
Edwards D, Schiff R, Milosavljevic A, Lee A. University of Pittsburgh<br />
<strong>Cancer</strong> Institute, Pittsburgh, PA; Baylor College of Medicine, Houston,<br />
TX; NSABP, Pittsburgh, PA.<br />
ESR1 gene amplification in breast cancer: influence of RNAse<br />
treatment on FISH results<br />
Moelans CB, Holst F, Hellwinkel O, Simon R, van Diest PJ. University<br />
Medical Center Utrecht, Netherlands; University Medical Center<br />
Hamburg Eppendorf, Hamburg, Germany.<br />
P6-05-14 Estrogen-induced genes in ductal carcinoma in situ(DCIS):<br />
their comparison with invasive ductal carcinoma<br />
Ebata A, Suzuki T, Takagi K, Miki Y, Onodera Y, Nakamura Y, Fujishima<br />
F, Ishida K, Watanabe M, Tamaki K, Ishida T, Ohuchi N, Sasano H.<br />
Tohoku University Graduate School of Medicine, Sendai, Miyagi,<br />
Japan; Tohoku University Hospital, Sendai, Miyagi, Japan.<br />
P6-05-15 Glucocorticoids has diverse effect on the tumorigenicity<br />
in estrogen receptor positive and estrogen receptor<br />
negative cancer cells<br />
Gao M, Yeh L-C, Chang C-P, Cheng A-L, Lu Y-S. National Taiwan<br />
University Hospital, Taipei, Taiwan.<br />
Tumor Cell and Molecular Biology: Tumor Cell and<br />
Molecular Biology - Other<br />
P6-06-01 Lobular involution reduces breast cancer risk through<br />
downregulation of invasive and proliferative cellular<br />
processes<br />
Radisky DC, Visscher DW, Stallings-Mann ML, Frost MH, Allers TM,<br />
Degnim AC, Hartmann LC. Mayo Clinic, Jacksonville, FL; Mayo Clinic,<br />
Rochester, MN.<br />
P6-06-02 Characterization of an exosome-associated apoptosisinducing<br />
activity produced by triple negative<br />
breast cancer cells<br />
Georgoulia NE, Iliopoulos D, Mitchison TJ. Harvard Medical School,<br />
Boston, MA; Dana Farber <strong>Cancer</strong> Institute, Boston, MA.<br />
P6-06-03 Caveolin-1: A potential mediator of RhoC GTPase driven<br />
Inflammatory breast cancer cell invasion<br />
Joglekar M, van Golen K. University of Delaware, Newark, Delaware.<br />
P6-06-04 Withdrawn<br />
P6-06-05 Down-regulation of the circadian factor Period 2 by<br />
the oncogenic E3 ligase Mdm2: Relevance of circadian<br />
components for cell cycle progression<br />
Liu J, Gotoh T, Vila-Caballer M, <strong>San</strong>tos CS, Yang J, Finkielstein CV.<br />
Virginia Tech, Blacksburg, VA.<br />
P6-06-06 The therapeutic potential and hazard of exposure to Cerbera<br />
odollam leaf extracts<br />
Chung F, Chan K, Lim YY, Li B. Monash University Sunway Campus,<br />
Subang Jaya, Selangor, Malaysia; Taylor’s University, Subang Jaya,<br />
Selangor, Malaysia.<br />
Prognostic and Predictive Factors: Prognostic and<br />
Predictive Factors - Other<br />
P6-07-01 Withdrawn<br />
P6-07-02 Prediction of oncotype DX® recurrence score using pathology<br />
generated equations<br />
Bhargava R, Klein ME, Shuai Y, Brufsky AM, Puhalla SL, Jankowitz<br />
R, Dabbs DJ. Magee-Womens Hospital of UPMC, Pittsburgh, PA;<br />
University of Wisconsin-Madison School of Medicine and Public<br />
Health, Madison, WI; University of Pittsburgh <strong>Cancer</strong> Institute,<br />
Pittsburgh, PA.<br />
P6-07-03 Risk classification of Early Stage <strong>Breast</strong> <strong>Cancer</strong> as Assessed by<br />
MammaPrint and Oncotype DX Genomic Assays<br />
Clough KB, Poulet B, Jamshidian F, Butler S, Svedman C, Levy E.<br />
L’Institut du Sein-Paris <strong>Breast</strong> Centre, Paris, Ile de France, France;<br />
Genomic Health, Inc., Redwood City, CA.<br />
P6-07-04 Evaluation of Adjuvant! Online for primary operable grade 2<br />
breast cancers with 10-year follow-up<br />
Van Calster B, Brouckaert O, Wildiers H, Christiaens M-R,<br />
Weltens C, Paridaens R, Van Limbergen E, Neven P. On behalf of<br />
Multidisciplinary <strong>Breast</strong> Centre, UZ Leuven.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 70s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P6-07-05<br />
P6-07-06<br />
P6-07-07<br />
P6-07-08<br />
P6-07-09<br />
P6-07-10<br />
P6-07-11<br />
Prognosis of 368 women with primary breast cancer during<br />
pregnancy: results from an international collaborative trial<br />
Amant F, von Minckwitz G, Han SN, Bontenbal M, Ring A, Giermek<br />
J, Fehm T, Wildiers H, Linn SC, Schlehe B, Neven P, Westenend<br />
PJ, Müller V, Van Calsteren K, Rack B, Nekljudova V, Harbeck N,<br />
Lenhard M, Witteveen PO, Kaufmann M, Van Calster B, Loibl S.<br />
Leuven <strong>Cancer</strong> Institute, University Hospitals Leuven, KU Leuven,<br />
Belgium; German <strong>Breast</strong> Group, Neu-Isenburg, Germany; BOOG<br />
Study Center, Amsterdam, Netherlands; Royal Sussex County<br />
Hospital, Brighton, United Kingdom; Institute in Warsaw <strong>Breast</strong><br />
<strong>Cancer</strong> and Reconstructive Surgery Clinic, Warsaw, Poland; University<br />
Women Hospital, Tübingen, Germany; University Women Hospital<br />
Heidelberg, Germany; University Medical Center Hamburg-<br />
Eppendorf, Hamburg, Germany; University Hospitals Leuven, KU<br />
Leuven, Belgium; Ludwigs Maximilian University, Frauenklinik<br />
Innenstadt, München, Germany; University Women Hospital<br />
Cologne, Germany; Klinik und Poliklinik für Frauenheilkunde und<br />
Geburtshilfe Klinikum der Universität München, Grosshadern,<br />
Germany; University Medical Center Utrecht, Netherlands; J.W.<br />
Goethe University, Frankfurt, Germany.<br />
Patterns of locoregional failure in the CALOR (Chemotheraphy<br />
as Adjuvant for Locally Recurrent <strong>Breast</strong> <strong>Cancer</strong>) Trial<br />
Wapnir IL, Gelber S, Lang I, Anderson SJ, Robidoux A, Martin M,<br />
Nortier JWR, Mamounas EP, Geyer CE, Maibach R, Gelber RD,<br />
Wolmark N, Aebi S. National Surgical Adjuvant <strong>Breast</strong> and Bowel<br />
Project (NSABP) Operations and Biostatistical Centers; Stanford<br />
University Medical School of Medicine; International <strong>Breast</strong><br />
<strong>Cancer</strong> Study Group; National Institute of Oncology; University of<br />
Pittsburgh Graduate School of Public Health; Centre Hospitalier de<br />
l’Université de Montréal; Hospital General Universitario Gregorio<br />
Marañón; Leiden University Medical Center, Leiden, Netherlands;<br />
Aultman Hospital; University of Texas Southwestern Medical Center;<br />
Allegheny <strong>Cancer</strong> Center at Allegheny General Hospital.<br />
Withdrawn<br />
Associations between lifestyle parameters and prognostic<br />
factors used for stratifying for adjuvant treatment in<br />
breast cancer<br />
Guldberg TL, Christensen S, Ravnsbaek A, Zachariae B, Jensen AB.<br />
Aarhus University Hospital, Aarhus, Denmark.<br />
Identification of Trophinin associated protein (TROAP) as a<br />
novel biological marker in breast cancer (BC): Co-expression of<br />
TROAP and TOPO2A predicts response of anthracycline based<br />
chemotherapy (ATC-CT)<br />
Abdel-Fatah TMA, Balls G, Miles AK, Moseley P, Green A, Rees R, Ellis<br />
IO, Chan SYT. Nottinigham City Hospital NHS Trust; The Van Geest<br />
<strong>Cancer</strong> Research Center, Nottingham Trent University; University of<br />
Nottingham.<br />
Luminal A vs. Basal-like <strong>Breast</strong> <strong>Cancer</strong>: time dependent<br />
changes in the risk of relapse in the absence of treatment<br />
Cheang MCU, Parker J, DeSchryver K, Snider J, Walsh T, Davies S,<br />
Prat A, Vickery T, Reed J, Zehnbauer B, Leung S, Voduc D, Nielsen<br />
T, Mardis E, Bernard P, Perou C, Ellis M. University of North Carolina<br />
at Chapel Hill, NC; University of British Columbia, Vancouver, BC,<br />
Canada; Washington University School of Medicine;<br />
University of Utah.<br />
Is the prognosis of lymphotropic invasive micropapillary<br />
carcinoma worse than invasive ductal carcinoma?: A<br />
population-based study of 645 patients<br />
Chen AC, Paulino AC, Schwartz MR, Rodriguez AA, Bass BL, Chang<br />
JC, Teh BS. Baylor College of Medicine, Houston, TX; The Methodist<br />
Hospital, Houston, TX.<br />
P6-07-12<br />
P6-07-13<br />
P6-07-14<br />
P6-07-15<br />
P6-07-16<br />
P6-07-17<br />
P6-07-18<br />
Akt2 expression is associated with good long-term prognosis<br />
in estrogen receptor positive breast cancer<br />
Fohlin H, Pérez-Tenorio G, Fornander T, Skoog L, Nordenskjöld B,<br />
Carstensen J, Stål O. Regional <strong>Cancer</strong> Center, Southeast Sweden,<br />
Linköping, Sweden; Faculty of Health Sciences, Linköping University,<br />
Linköping, Sweden; Karolinska University Hospital, Karolinska<br />
Institute, Stockholm, Sweden; Linköping University, Linköping,<br />
Sweden.<br />
Local relapse and survival<br />
Harland R, Prathap P, Lionaki A, Mahmood N. Royal Albert Edward<br />
Infirmary, Wigan, United Kingdom; Euxton Hall Hospital, Chorley,<br />
United Kingdom.<br />
Mutational and transcriptomic characterization of breast<br />
cancer (BC) arising in young patients (pts) and during<br />
pregnancy and their associations with long-term outcome<br />
Azim Jr HA, Peccatori FA, Loi S, Lambrechts D, Majjaj S, Renne<br />
G, Desmedt C, Rotmensz N, Michiels S, Dell’Orto P, Ignatiadis M,<br />
Goldhirsch A, Piccart M, Viale G, Sotiriou C. Universite Libre de<br />
Bruxelles, Brussels, Belgium; Institut Jules Bordet, Brussels, Belgium;<br />
European Institute of Oncology, Milan, Italy; University of Leuven,<br />
Belgium.<br />
The effect of taxanes in ER+ early breast cancer is likely to be<br />
mitigated by chromosomal instability<br />
A’Hern RP, Bliss JM, Szallasi Z, Johnston S, Roylance R, Swanton C.<br />
The Institute of <strong>Cancer</strong> Research, Sutton, United Kingdom; Technical<br />
University of Denmark, Lyngby, Denmark; Barts and The Royal<br />
London Hospital, London, United Kingdom; <strong>Cancer</strong> Research UK<br />
London Research Institute, London, United Kingdom; Royal Marsden<br />
NHS Foundation Trust and The Institute of <strong>Cancer</strong> Research, London,<br />
United Kingdom.<br />
Evaluation of circulating tumor cell as a marker of prognosis<br />
and efficacy in a randomized phase III study in HER2 negative<br />
metastatic breast cancer patients treated with capecitabine<br />
and docetaxel: JO21095 study<br />
Masuda N, Yamamoto D, Sato N, Sagara Y, Yamamoto Y, Saito M,<br />
Iwata H, Oura S, Watanabe J, Kuroi K. National Hospital Organization<br />
Osaka National Hospital, Osaka, Japan; Kansai Medical University<br />
Hirakata Hospital, Hirakata, Osaka, Japan; Niigata <strong>Cancer</strong> Center<br />
Hospital, Niigata, Japan; Sagara Hospital, Kagoshima, Japan;<br />
Kumamoto University Hospital, Kumamoto, Japan; Juntendo<br />
University Hospital, Bunkyo, Tokyo, Japan; Aichi <strong>Cancer</strong> Center<br />
Hospital, Nagoya, Aichi, Japan; Wakayama Medical University,<br />
Wakayama, Wakayama, Japan; Shizuoka <strong>Cancer</strong> Center, Nagaizumicho,<br />
Suntou-gun, Shizuoka, Japan; Tokyo Metropolitan <strong>Cancer</strong> and<br />
Infectious Diseases Center Komagome Hospital, Bunkyo,<br />
Tokyo, Japan.<br />
Proteomic screening of FFPE tissue identifies FKBP4 as an<br />
independent prognostic factor in hormone receptor positive<br />
breast cancers<br />
Hu J, Pohorelic B, Konno M, Price JT, Morris D, Krizman D, Magliocco<br />
AM, Klimowicz AC. Alberta Health Services, Calgary, AB, Canada;<br />
University of Calgary, AB, Canada; Monash University, Clayton, VIC,<br />
Australia; OncoPlex Diagnostics, Rockville, MD; H. Lee Moffitt <strong>Cancer</strong><br />
Center & Research Institute, Tampa, FL.<br />
Identification of Sperm Associated Antigen 5 (SPAG5) as a<br />
novel biological and predictive biomarker in <strong>Breast</strong> cancer<br />
Abdel-Fatah TMA, Ball G, Miles AK, Moseley P, Green A, Rees B, Ellis<br />
IO, Chan SYT. Nottingham City Hospital NHS Trust, Nottingham;<br />
The John van Geest <strong>Cancer</strong> Research Centre, Nottingham Trent<br />
University; University of Nottingham.<br />
www.aacrjournals.org<br />
71s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P6-07-19<br />
P6-07-20<br />
P6-07-21<br />
P6-07-22<br />
P6-07-23<br />
P6-07-24<br />
P6-07-25<br />
P6-07-26<br />
P6-07-27<br />
P6-07-28<br />
Prognostic relevance of PR and detection mode in Luminal<br />
Her-2 negative breast cancer<br />
Brouckaert O, Van Calster B, Paridaens R, Wildiers H, Van Limbergen<br />
E, Weltens C, Christiaens M-R, Neven P. On behalf of Multidisciplinary<br />
<strong>Breast</strong> Centre.<br />
Variables measured at Central Nervous System (CNS) relapse,<br />
but not Immunophenotype, identify groups of breast cancer<br />
patients with shorter post CNS-relapse survival<br />
Gómez HL, Pinto JA, Schwarz JL, Vigil CE, Vallejos CS. Instituto<br />
Nacional de Enfermedades Neoplásicas, Lima, Peru; Oncosalud,<br />
Lima, Peru.<br />
Signs and symptoms at central nervous system (CNS) relapse<br />
in breast cancer patients with Leptomeningeal carcinomatosis<br />
related with shorter survival after recurrence<br />
Gomez HL, Schwarz LJ, Vásquez J, Neciosup SP, Pinto JA, Vidaurre<br />
T, Ferreyros G, Vallejos CS. Instituto Nacional de Enfermedades<br />
Neoplásicas, Peru; Oncosalud, Peru.<br />
Association between SPARC mRNA expression, prognosis and<br />
response to neoadjuvant chemotherapy in early breast cancer<br />
(BC): a pooled in-silico analysis<br />
Azim Jr HA, Singhal S, Michiels S, Ignatiadis M, Djazouli K, Fumagalli<br />
D, Desmedt C, Piccart M, Sotiriou C. Universite Libre de Bruxelles,<br />
Brussels, Belgium; Institut Jules Bordet, Brussels, Belgium;<br />
Celgene International.<br />
Proportion of invasive micropapillary carcinoma lesion and<br />
primary breast cancer prognosis<br />
Takei J, Nakayama K, Yagata H, Hayashi N, Yoshida A, Ohde S, Suzuki<br />
K, Nakamura S, Yamauchi H. St. Luke’s International Hospital, Tokyo,<br />
Japan; Showa University School of Medicine, Tokyo, Japan.<br />
Prognostic Tools in Early <strong>Breast</strong> <strong>Cancer</strong>: Predicting benefit of<br />
adjuvant chemotherapy<br />
Parkes EE, Davidson C, James CR, Hanna GG. Northern Ireland <strong>Cancer</strong><br />
Centre, Belfast City Hospital, Belfast, United Kingdom; Queen’s<br />
University of Belfast, United Kingdom.<br />
Annexin expression and survival outcomes in women with<br />
breast cancer<br />
Dawood S, Gonzalez-Angulo AM, Liu S, Chen H, Li Y, Albarracin CT.<br />
MD Anderson <strong>Cancer</strong> Center, Houston, TX; Dubai Hospital, United<br />
Arab Emirates.<br />
Prognostic significance of the maximal value of the baseline<br />
standardized uptake value on fluorine 18 fluorodeoxyglucose<br />
positron emission tomography /computed tomography for<br />
predicting pathologic malignancy of operable breast cancer<br />
with neoadjuvant chemotherapy<br />
Kadoya T, Akimoto E, Emi A, Shigematsu H, Masumoto N, Okada M.<br />
Hiroshima University, Hiroshima, Japan.<br />
Body mass index and survival after breast cancer diagnosis<br />
in Japanese women<br />
Kawai M, Minami Y, Nishino Y, Ohuchi N, Kakugawa Y. Tohoku<br />
University Graduate School of Medicine, Sendai, Miyagi, Japan;<br />
Miyagi <strong>Cancer</strong> Center Research Institute, Natori, Miyagi, Japan;<br />
Miyagi <strong>Cancer</strong> Center Hospital, Natori, Miyagi, Japan.<br />
Assessment of T stage in the multiple breast carcinomas<br />
Gong G, Jo J-H, Lee HJ, Kang J. University of Ulsan College of<br />
Medicine, Asan Medical Center, Republic of Korea; University of<br />
Ulsan College of Medicine, Gangneung Asan Hospital, Republic<br />
of Korea; Seoul National University Bundang Hospital, Republic of<br />
Korea; Haeundae Paik Hospital, Inje University College of Medicine,<br />
Republic of Korea.<br />
P6-07-29 Independent prognostic value of age depends on breast<br />
cancer subtype<br />
Brouckaert O, Salihi R, Laenen A, Vanderhaegen J, Amant F, Leunen<br />
K, Smeets A, Berteloot P, Van Limbergen E, Weltens C, Moerman<br />
P, Peeters S, Paridaens R, Floris G, Wildiers H, Vergote I, Christiaens<br />
M-R, Neven P. UZ Leuven; Interuniversity Centre for Biostatistics and<br />
Statistical Bioinformatics.<br />
P6-07-30 The clinical significance of pathologic complete response<br />
using different definitions after neoadjuvant chemotherapy in<br />
HER2 positive breast cancer patients according to hormonal<br />
receptor status<br />
Tanioka M, Hirokaga K, Kitao A, Matsumoto K, Yoshida S, Miki M,<br />
Maekawa Y, Takao S, Negoro S. Hyogo <strong>Cancer</strong> Center, Akashi, Japan.<br />
P6-07-31 Moved to Poster Session 2, Thursday, December 6 7:00 AM -<br />
9:00 AM<br />
P6-07-32 Prognosis of metastatic breast cancer subtypes: the hormone<br />
receptor/HER2 positive subtype is associated with the most<br />
favorable outcome<br />
Tjan-Heijnen VCG, Lobbezoo DJA, van Kampen RJW, Voogd AC,<br />
Dercksen MW, van den Berkmortel F, Smilde TJ, van de Wouw<br />
AJ, Peters FPJ, van Riel JMGH, Peters NAJB, Borm GF. Maastricht<br />
University Medical Center, Maastricht, Netherlands; Maxima<br />
Medical Center, Eindhoven, Netherlands; Atrium Medical Center<br />
Parkstad, Heerlen, Netherlands; Jeroen Bosch Hospital, Den Bosch,<br />
Netherlands; Viecuri Medical Center, Venlo, Netherlands; Orbis<br />
Medical Center, Sittard, Netherlands; St Elisabeth Hospital, Tilburg,<br />
Netherlands; St Jans Hospital, Weert, Netherlands; Radboud<br />
University Medical Center, Nijmegen, Netherlands.<br />
P6-07-33 A clinicopathologic analysis of 45 patients with metaplastic<br />
breast cancer<br />
Verma S, Cimino-Mathews A, Figueroa Magalhaes MC, Zhang Z,<br />
Stearns V, Connolly RM. Sidney Kimmel Comprehensive <strong>Cancer</strong><br />
Center at Johns Hopkins, Baltimore, MD; St. Agnes Hospital,<br />
Baltimore, MD; Johns Hopkins Hospital, Baltimore, MD.<br />
P6-07-34 Disease-related outcomes with adjuvant chemotherapy in<br />
HER2 positive or triple negative T1a/bN0 breast cancers<br />
Shao T, Olszewski AJ, Boolbol SK, Migdady Y, Boachie-Adjei K, Sakr<br />
BJ, Klein P, Sikov W. Beth Israel Medical Center, Continuum <strong>Cancer</strong><br />
Centers of New York, New York, NY; The Warren Alpert Medical<br />
School of Brown University, Providence, RI.<br />
P6-07-35 Dragonfly Effect or Ironic Paradox: Prognostic Implication of<br />
Postsurgical Drain in <strong>Breast</strong> <strong>Cancer</strong> Patients<br />
Yin W, Lin Y, Shen Z, Shao Z-M, Lu J. Fudan University Shanghai<br />
<strong>Cancer</strong> Center, Shanghai, China.<br />
P6-07-36 A Prognostic Model For Triple-Negative <strong>Breast</strong> <strong>Cancer</strong> Patients<br />
Based On Node Status, Cathpesin-D And Ki-67<br />
Huang L, Liu Yb, Chen S, Zhou Rj, Liu Y, Shao Z-M. Fudan University<br />
Shanghai <strong>Cancer</strong> Hospital, Shanghai, China.<br />
P6-07-37 Impact of body mass index on recurrence risk in patients with<br />
ductal carcinoma in situ<br />
Klepczyk LC, Meredith RF, De Los <strong>San</strong>tos JF, Li Y, Keene KS. University<br />
of Alabama at Birmingham, AL.<br />
P6-07-38 The Value of Progesterone Receptor in Predicting the<br />
Recurrence Score for Hormone-Receptor–Positive Invasive<br />
<strong>Breast</strong> <strong>Cancer</strong> Patients<br />
Onoda T, Yamauchi H, Yagata H, Hayashi N, Yoshida A, Nakamura<br />
S. St Luke’s International Hospital, Tokyo, Japan; Showa University,<br />
Tokyo, Japan; Yokohama Asahi Central General Hospital,<br />
Kanagawa, Japan.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 72s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P6-07-39 Prognostic Value of Body Mass Index in Japanese <strong>Breast</strong><br />
<strong>Cancer</strong> Patients: A Collaborative Study by the Kobe <strong>Breast</strong><br />
<strong>Cancer</strong> Oncology Group and Hokkaido <strong>Cancer</strong> Center<br />
Shigeoka Y, Watanabe K, Takahashi M, Hirokaga K, Takao S, Miyashita<br />
M, Wakita K, Miyoshi Y, Okuno T, Kohno S, Kishimoto M, Kokufu I.<br />
Yodogawa Christian Hospital, Osaka, Japan; Hokkaido <strong>Cancer</strong> Center,<br />
Sapporo, Japan; Hyogo <strong>Cancer</strong> Center, Akashi, Japan; Konan Hospital,<br />
Kobe, Japan; Chayamachi <strong>Breast</strong> Clinic, Osaka, Japan; Hyogo College<br />
of Medicine, Nishinomiya, Japan; Kobe Urban <strong>Breast</strong> Clinic, Kobe,<br />
Japan; Kobe University, Kobe, Japan; Meiwa Hospital, Nishinomiya,<br />
Japan; Kokufu <strong>Breast</strong> Clinic, Takarazuka, Japan.<br />
P6-07-40 Initial Neutrophil-to-Lymphocyte ratio in primary<br />
breast cancer patients: a simple and useful biomarker as<br />
prognostic factor<br />
Han A, Noh H, Lee J. Yonsei University Wonju Medical School, Wonju,<br />
Gangwon, Republic of Korea.<br />
P6-07-41 Sub classification of early stage hormone positive (HP) Her-2<br />
negative breast cancer (BC) by immunohistochemistry (IHC)<br />
into intrinsic subtypes (IS) and their correlation with Oncotype<br />
Recurrence Score (RS)<br />
Mahesh S, Lane J, Ravichandran P. Summa Health Systems,<br />
Akron, OH.<br />
P6-07-42 Patients with Nipple-areola Paget’s Disease and Underlying<br />
Invasive <strong>Breast</strong> Carcinoma had a Very Poor Survival: a Matched<br />
Cohort Study<br />
Ling H, Xu X-L, Liu Z-B, Shao Z-M. Fudan University Shanghai <strong>Cancer</strong><br />
Center, Shanghai, China.<br />
P6-07-43 The Maximum Standardized Uptake Value of 18 F-FDG to<br />
Prognosticate Prognosis of Hormone-Receptor Positive<br />
Metastatic <strong>Breast</strong> <strong>Cancer</strong><br />
Hu X-C, Zhang (co-first author) J, Jia Z, Ragaz J, Zhang Y-J, Zhou M,<br />
Zhang Y-P. Fudan University Shanghai <strong>Cancer</strong> Center, Shanghai,<br />
China; School of Population and Public Health; University of British<br />
Columbia, Vancouver, Canada.<br />
P6-07-44 Overall survival and the prognostic factors among women<br />
with infiltrating lobular carcinoma of the breast in National<br />
<strong>Cancer</strong> Institute of Brazil<br />
Bello MA, Monteiro SO, Lima DT, Gomes DO, Thuler LCS, Carmo PAO,<br />
Carvalho RM, Pinto RR, Bergmann A. Instituto Nacional de Câncer,<br />
Rio de Janeiro, RJ, Brazil.<br />
P6-07-45 Molecular Morphology Based Genomic Signatures of<br />
Moderate Complexity Predict Pathologic Complete Response<br />
in HER2 Molecular <strong>Breast</strong> Carcinoma Class Patients Treated<br />
with Trastuzumab-based Preoperative Therapy<br />
Tubbs RR, Portier BP, Morrison L, Wang Z, Minca E, Lanigan C,<br />
Budd T. Cleveland Clinic, Cleveland, OH; Ventana Medical Systems,<br />
Tucson, AZ; Cleveland Clinic Tausig <strong>Cancer</strong> Center, Cleveland, OH.<br />
Psychosocial, Quality of Life, and Educational Aspects:<br />
Psychosocial Aspects<br />
P6-08-01 Perceptions of breast cancer risk, psychological adjustment<br />
and behaviors in adolescent girls at high-risk and populationrisk<br />
for breast cancer<br />
Bradbury AR, Patrick-Miller L, Egleston B, Schwartz L, Tuchman L,<br />
Moore C, Rauch P, <strong>San</strong>ds C, Shorter R, Rowan B, Malhotra S, van<br />
Decker S, Schmidheiser H, Sicilia P, Bealin L, Daly M. University<br />
of Pennsylvania, Philadelphia, PA; University of Chicago, IL; Fox<br />
Chase <strong>Cancer</strong> Center, Philadelphia, PA; The Children’s Hospital of<br />
Philadelphia, Philadelphia, PA; Children’s National Medical Center,<br />
Washington, DC; Massachusetts General Hospital, Boston, MA.<br />
P6-08-02 Do personal, familial or counseling factors influence the<br />
choice for prophylactic mastectomy and/or bilateral salpingooöphorectomy<br />
of female BRCA mutation carriers?<br />
Caanen BA, Gielen M, GomezGarcia EB, Kruitwagen RF, Keymeulen<br />
KB, Ter Haar-van Eck SA, Schenk K, Helderman-van den Enden<br />
A. Maastricht University Medical Centre, GROW School for<br />
Oncology and Developmental Biology, Maastricht Medical Centre,<br />
Maastricht, Netherlands; NUTRIM School for Nutrition, Toxicology<br />
and Metaboloism, University of Birmingham, Birmingham, United<br />
Kingdom; Maxima Medical Centre, Eindhoven, Netherlands.<br />
P6-08-03 Informational needs and psychosocial assessment of patients<br />
in their first year after metastatic breast cancer diagnosis<br />
Seah DS, Lin NU, Curley C, Winer E, Partridge A. Dana-Farber <strong>Cancer</strong><br />
Institution, Boston, MA.<br />
P6-08-04 The Impact of a <strong>Breast</strong> <strong>Cancer</strong> Diagnosis in Young Women on<br />
their Relationship with their Mothers<br />
Ali A, Fergus K, Wright F, Pritchard K, Kiss A, Warner E. Sunnybrook<br />
Health Sciences Centre, Odette <strong>Cancer</strong> Centre, University of Toronto,<br />
Toronto.<br />
P6-08-05 Changes in Cognitive Function in Older Women With<br />
<strong>Breast</strong> <strong>Cancer</strong> Treated with Standard Chemotherapy and<br />
Capecitabine within CALGB 49907<br />
Freedman RA, Pitcher B, Keating NL, Barry WT, Ballman KV, Kornblith<br />
A, Mandelblatt J, Kimmick GG, Hurria A, Winer EP, Hudis CA, Cohen<br />
HJ, Muss HB. Dana-Farber <strong>Cancer</strong> Institute, Boston, MA; Duke<br />
University Medical Center, Durham, NC; Harvard Medical School,<br />
Boston, MA; Mayo Clinic, Rochester, MN; Georgetown University,<br />
Washington, DC; City of Hope, Duarte, CA; Memorial Sloan-Kettering,<br />
New York, NY; University of North Carolina, Chapel Hill, NC.<br />
P6-08-06 Use of an NIH PROMIS® instrument to identify predictors<br />
of fatigue in breast cancer patients receiving adjuvant<br />
chemotherapy<br />
Cohen J, Junghaenel DU, Schneider S, Mahler L, Stone A, Broderick J.<br />
Stony Brook University, Stony Brook, NY.<br />
P6-08-07 Quality of life of women with breast cancer: A Middle East<br />
perspective<br />
Jassim GA, Whitford DL. Royal College of Surgeons in Ireland-Medical<br />
University of Bahrain, Busaiteen, Bahrain.<br />
P6-08-08 Three months of adjuvant hormone therapy does not increase<br />
fatigue or cognitive failure: results of a prospective early stage<br />
breast cancer trial<br />
Kennedy D, Lower EE. Oncology Hematology Consultants,<br />
Cincinnati, OH.<br />
P6-08-09 Overcoming <strong>Breast</strong> <strong>Cancer</strong>: The Importance of Connecting<br />
with Fellow Survivors<br />
Geoghegan C, Whitman B. Y-ME National <strong>Breast</strong> <strong>Cancer</strong><br />
Organization, Chicago, IL; Whitman Insight Strategies, New York, NY.<br />
P6-08-10 <strong>Cancer</strong> as self: a novel assessment of patient identity as it<br />
relates to a cancer diagnosis<br />
Horst KC, Fero KE, Haimovitz K, Dweck CS. Stanford University,<br />
Stanford, CA.<br />
Psychosocial, Quality of Life and Educational Aspects: Psychosocial,<br />
QOL and Educational Aspects-Other<br />
P6-09-01 Investigating the effectiveness of a psycho-educational<br />
behavioral intervention for cancer-related cognitive<br />
dysfunction in women with breast and gynecological cancer:<br />
Knowledge, self-efficacy, and behavioral change<br />
Bernstein LJ, Dissanayake D, Tirona KM, Nyhof-Young JM, Catton<br />
PA. Princess Margaret Hospital, Toronto, ON, Canada; University of<br />
Toronto, ON, Canada.<br />
www.aacrjournals.org<br />
73s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P6-09-02<br />
P6-09-03<br />
P6-09-04<br />
P6-09-05<br />
P6-09-06<br />
P6-09-07<br />
P6-09-08<br />
P6-09-09<br />
P6-09-10<br />
P6-09-11<br />
Pre-treatment cognitive function (CF) in women with locally<br />
advanced breast cancer (LABC) and in healthy controls<br />
Bernstein LJ, Seruga B, Pond G, Tirona KM, Dodd A, Tannock IF.<br />
Princess Margaret Hospital, Toronto, ON, Canada; University of<br />
Toronto; Institute of Oncology Ljubljana, Slovenia; McMaster<br />
University, Hamilton, ON, Canada.<br />
Fatigue after breast cancer may be related to conditions other<br />
than the cancer. The impact of comorbidity is essential<br />
Reidunsdatter RJ, Hjermstad M, Oldervoll L, Lundgren S. HiST/NTNU,<br />
Trondheim, Norway; HIST, Trondheim, Norway; NTNU, Trondheim,<br />
Norway; Oslo University Hospital, Oslo, Norway; Røros Rehabilitation,<br />
Røros, Norway; St. Olav University Hospital, Trondheim, Norway.<br />
The Association of Low Level Arm Volume Increases<br />
with Lymphedema Symptoms Following Treatment for<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Skolny MN, Miller CL, Shenouda M, Jammallo LS, O’Toole J,<br />
Niemierko A, Taghian AG. Massachusetts General Hospital,<br />
Boston, MA.<br />
Women’s perceptions of lymphedema risk management:<br />
Psychological factors do matter<br />
Sherman KA, Roussi P, Miller SM. Macquarie University, Sydney, NSW,<br />
Australia; Aristotle University, Thessaloniki, Greece; Fox Chase <strong>Cancer</strong><br />
Center, Philadelphia, PA.<br />
Family Members’ Burden in Patients with Metastatic and Early<br />
Stage <strong>Breast</strong> <strong>Cancer</strong><br />
Wan Y, Gao X, Mehta S, Zhang Z, Faria C, Schwartzberg L. Pharmerit<br />
North America; Eisai, Inc.; The West Clinic.<br />
Impact of comprehensive geriatric assessment on treatment<br />
decision and follow-up in older breast cancer patients<br />
Kenis C, Decoster L, Bode H, Bastin J, Lobelle J-P, Milisen K, van<br />
Puyvelde K, Paridaens R, Neven P, Fontaine C, de Grève J, Flamaing J,<br />
Wildiers H. University Hospitals Leuven; University Hospitals Brussels;<br />
Consult in Statistics, Beernem; Catholic University Leuven.<br />
COMPliance and Arthralgia in Clinical Therapy:<br />
The COMPACT trial, assessing the incidence of arthralgia,<br />
therapy costs and compliance within the first year of adjuvant<br />
anastrozole therapy<br />
Harbeck N, Blettner M, Bolten WW, Hindenburg H-J, Jackisch C,<br />
Klein P, König K, Kreienberg R, Rief W, Wallwiener D, Zaun S, Hadji P.<br />
University of Munich, Germany; University of Mainz, Germany; Klaus-<br />
Miehlke-Hospital for Rheumatology, Wiesbaden, Germany; Head<br />
of BNGO e.V., Germany; Hospital for Gynecology and Obstetrics,<br />
Offenbach, Germany; d.s.h. Statistical Services, Rohrbach, Germany;<br />
Gynecological Society Germany e.V., Germany; University Women’s<br />
Hospital, Ulm, Germany; Outpatient Clinic for Psychotherapy,<br />
Philipps-University, Marburg, Germany; University Women’s Hospital,<br />
Tübingen, Germany; AstraZeneca GmbH, Wedel, Germany; Women’s<br />
Hospital Phillips-University, Marburg, Germany.<br />
Perceptions of marginalization in those affected by advanced<br />
breast cancer<br />
Ahmed I, Harvey A, Amsellem M. <strong>Cancer</strong> Support Community,<br />
Washington, DC.<br />
Informational needs among women considering breast<br />
reconstruction post-mastectomy<br />
Ahmed I, Harvey A, Amsellem M. <strong>Cancer</strong> Support Community,<br />
Washington, DC.<br />
Examining patient treatment choices involving efficacy,<br />
toxicity, and cost tradeoffs in the metastatic breast cancer<br />
setting<br />
White CB, Smith ML, Abidoye O, Lalla D. Carol B. White & Associates;<br />
Research Advocacy Network; Genentech, Inc.<br />
Treatment: Novel Targets and Targeted Agents<br />
P6-10-01 A randomized phase 2 study of the antibody-drug conjugate<br />
CDX-011 in advanced GPNMB-overexpressing breast cancer:<br />
The EMERGE study<br />
Yardley DA, Weaver R, Melisko ME, Saleh MN, Arena FP, Forero A,<br />
Cigler T, Stopeck A, Citron D, Oliff I, Bechhold R, Loutfi R, Garcia A,<br />
Crowley E, Green J, Yellin MJ, Davis TA, Vahdat LT. Florida <strong>Cancer</strong><br />
Specialists, Tampa, FL; University of California, <strong>San</strong> Francisco Helen<br />
Diller Family Comprehensive <strong>Cancer</strong> Center, <strong>San</strong> Francisco, CA; Sarah<br />
Cannon Research Institute/Tennessee Oncology, PLLC, Nashville,<br />
TN; Georgia <strong>Cancer</strong> Specialists PC, <strong>San</strong>dy Springs, GA; Arena Onc<br />
Assoc PC, Lake Success, NY; Bium Inc, Birmingham, AL; Weill Cornell<br />
Medical College, New York, NY; Celldex Therapeutics, Inc., Needham,<br />
MA; Arizona <strong>Cancer</strong> Center at the University of Arizona, Tucson,<br />
AZ; <strong>Cancer</strong> Treatment Centers of America/Midwestern Regional<br />
Medical Center, Zion, IL; Orchard Healthcare Research Inc., Skokie,<br />
IL; Oncology Hematology Care, Cincinnati, OH; Henry Ford Health<br />
System, Detroit, MI; USC/Norris Comprehensive <strong>Cancer</strong> Center, Los<br />
Angeles, CA.<br />
P6-10-02 MLN8237 (alisertib), an investigational Aurora A<br />
Kinase inhibitor, in patients with breast cancer:<br />
Emerging phase 2 results<br />
Alvarez RH, DeMichele A, Mailliez A, Benaim E, Fingert H,<br />
Schusterbauer C, Zhang B, Melichar B. The University of Texas<br />
MD Anderson <strong>Cancer</strong> Center, Houston, TX; Abramson <strong>Cancer</strong><br />
Center, Philadelphia, PA; Centre Oscar Lambret, Lille, Cedex 59,<br />
France; Millennium Pharmaceuticals, Inc., Cambridge, MA; Fakultní<br />
nemocnice Olomouc - Onkologická klinika, Olomouc, Czech<br />
Republic.<br />
p6-10-03 The PKC inhibitor PKC412 antagonizes breast cancer cell<br />
growth and enhances tamoxifen sensitivity<br />
Shou J, Chew SA, Mitsiades N, Kumar V, Fu X, Chamness G, Osborne<br />
K, Schiff R. Lester & Sue Smith <strong>Breast</strong> Center, Baylor College of<br />
Medicine, Houston, TX; Baylor College of Medicine, Houston, TX; Dan<br />
L Duncan <strong>Cancer</strong> Center, Baylor College of Medicine, Houston, TX.<br />
P6-10-04 The Presence of Anaplastic Lymphoma Kinase Recapitulates<br />
Formation of <strong>Breast</strong> Tumor Emboli with Encircling<br />
Lymphovasculogenesis<br />
Liu H, Chu K, Ochoa AE, Ye Z, Zhang X, Jin J, Wright MC, Barsky SH,<br />
Cristofanilli M, Robertson FM. The University of Texas MD Anderson<br />
<strong>Cancer</strong> Center, Houston, TX; University of Nevada School of<br />
Medicine, Reno, NV; Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA.<br />
P6-10-05 SU2C Phase 1b Trial of Dual PI3K/ mTOR Inhibitor BEZ235 with<br />
Letrozole in ER+/HER2- Metastatic <strong>Breast</strong> <strong>Cancer</strong> (MBC)<br />
Mayer IA, Abramson VG, Balko JM, Isakoff SJ, Forero A, Kuba MG,<br />
<strong>San</strong>ders ME, Li Y, Winer E, Arteaga CL. Vanderbilt-Ingram <strong>Cancer</strong><br />
Center, Nashville, TN; Massachussets General Hospital, Boston, MD;<br />
University of Alabama at Birmingham, AL; MD Anderson <strong>Cancer</strong><br />
Center, Houston, TX; Dana-Farber <strong>Cancer</strong> Institute, Boston, MD.<br />
P6-10-06 Rational combination therapy against triple-negative<br />
breast cancer<br />
Al-Ejeh F, Miranda M, Simpson PT, Chenevix-Trench G, Lakhani SR,<br />
Khanna KK. Queensland Institute of Medical Research, Brisbane,<br />
QLD, Australia; The University of Queensland, Brisbane,<br />
QLD, Australia.<br />
P6-10-07 Phase I study of BYL719, an alpha-specific PI3K inhibitor,<br />
in patients with PIK3CA mutant advanced solid tumors:<br />
preliminary efficacy and safety in patients with PIK3CA mutant<br />
ER-positive (ER+) metastatic breast cancer (MBC)<br />
Juric D, Argiles G, Burris HA, Gonzalez-Angulo AM, Saura C, Quadt<br />
C, Douglas M, Demanse D, De Buck S, Baselga J. M.assachussetts<br />
General Hospital <strong>Cancer</strong> Center, Boston, MA; Vall d’Hebron University<br />
Hospital, Barcelona, Spain; Sarah Cannon Research Institute,<br />
Nashville, TN; M.D. Anderson <strong>Cancer</strong> Center, Houston, TX; Novartis<br />
Pharma Corporation, East Hanover, NJ; Novartis Pharma AG,<br />
Basel, Switzerland.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 74s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
P4-06-07 Isoform specific antibodies against the fibroblast growth<br />
factor receptor 2 have predictive and therapeutic implications<br />
in the treatment of human breast cancers<br />
Ettyreddy AR, Somarelli J, Bitting R, Armstrong A, Garcia Blanco MA.<br />
Duke University, Durham, NC.<br />
Treatment: New Drugs and Treatment Strategies<br />
P6-11-01 Intermittent High Dose Proton Pump Inhibitor Improves<br />
Progression Free Survival as Compared to Standard<br />
Chemotherapy in the First Line Treatment of Patients with<br />
Metastatic <strong>Breast</strong> <strong>Cancer</strong><br />
Hu X, Wang B, Sun S, Chiesi A, Wang J, Zhang J, Fais S. Fudan<br />
University Shanghai <strong>Cancer</strong> Center, Shanghai, China; National<br />
Institute of Health, Roma, Italy.<br />
P6-11-02 Inhibition of mTOR and Fatty Acid Synthase (FASN) overcome<br />
acquired resistance to Trastuzumab, Lapatinib and both in<br />
HER2+ breast cancer<br />
Puig T, Blancafort A, Giro A, Viqueira A, Viñas G, Massaguer A,<br />
Carrion-Salip D, Bolos MV, Urruticoechea A, Oliveras G. University<br />
of Girona and Girona Biomedical Research Institute (IDIBGi), Girona,<br />
Spain; Catalan Institute of Oncology (ICO) and Girona Biomedical<br />
Research Institute (IDIBGi), Girona, Spain; Pfizer, Madrid, Spain;<br />
University of Girona, Spain; Catalan Institute of Oncology (ICO),<br />
Hospitalet de Llobregat, Barcelona, Spain.<br />
P6-11-03 Site-Specific, Concomitant Delivery of Rapamycin and<br />
Paclitaxel in <strong>Breast</strong> <strong>Cancer</strong>: Consequent Synergistic<br />
Efficacy Enhancement<br />
Blanco E, <strong>San</strong>gai T, Hsiao A, Ruiz-Esparza GU, Ferrari M, Meric-<br />
Bernstam F. The Methodist Hospital Research Institute, Houston, TX;<br />
The University of Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
P6-11-04 Targeting the tumor microenvironment: tetrathiomolybdate<br />
decreases circulating endothelial progenitor cells in women<br />
with breast cancer at high risk of relapse<br />
Jain S, Kornhauser N, Lam C, Ward MM, Chuang E, Cigler T, Moore<br />
A, Donovan D, Cobham MV, Schneider S, Hurtado Rua SM, Lane ME,<br />
Mittal V, Vahdat LT. Weill Cornell Medical College.<br />
P6-11-05 Novel sorafenib-derivatives induce apoptosis in breast cancer<br />
cells through STAT3 inhibition<br />
Liu C-Y, Tseng L-M, Chang K-C, Chu P-Y, Su J-C, Shiau C-W, Chen K-F.<br />
Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming<br />
University, Taipei, Taiwan; St. Martin De Porres Hospital, Chia-Yi,<br />
Taiwan; National Taiwan University Hospital, Taipei, Taiwan.<br />
P6-11-06 A phase Ib study of LCL161, an oral inhibitor of apoptosis (IAP)<br />
antagonist, in combination with weekly paclitaxel in patients<br />
with advanced solid tumors<br />
Dienstmann R, Vidal L, Dees EC, Chia S, Mayer EL, Porter D, Baney<br />
T, Dhuria S, Sen SK, Firestone B, Papoutsakis D, Cameron S, Infante<br />
JR. Vall d’Hebron University Hospital, Barcelona, Spain; Hospital<br />
Clinic i Provincial, Barcelona, Spain; University of North Carolina<br />
Lineberger Comprehensive <strong>Cancer</strong> Center, Chapel Hill, NC;<br />
British Columbia <strong>Cancer</strong> Agency, University of British Columbia,<br />
Vancouver, BC, Canada; Dana-Farber <strong>Cancer</strong> Institute, Boston, MA;<br />
Novartis Pharmaceuticals Corporation, Cambridge, MA; Novartis<br />
Pharmaceuticals Corporation, Florham Park, NJ; Sarah Canon<br />
Research Institute, Nashville, TN.<br />
P6-11-07 The <strong>Cancer</strong> Stem Cell-Targeting Wnt Inhibitor VS-507 Reduces<br />
<strong>Breast</strong> <strong>Cancer</strong> Growth and Metastasis<br />
Ring JE, Kolev VN, Padval MV, Keegan M, Vidal CM, Neill AA, Shapiro<br />
IM, Pachter JA, Xu Q. Verastem, Inc., Cambridge, MA.<br />
P6-11-08 A multicenter, open-label Ph IB/II study of BEZ235, an oral<br />
dual PI3K/mTOR inhibitor, in combination with paclitaxel in<br />
patients with HER2-negative, locally advanced or metastatic<br />
breast cancer<br />
Campone M, Fumoleau P, Gil-Martin M, Isambert N, Beck JT, Becerra<br />
C, Shtivelband M, Duval V, di Tomaso E, Roussou P, Urban P,<br />
Urruticoechea A. Centre René Gauducheau, Nantes, France; Centre<br />
Georges François Leclerc, Dijon, France; Institut Català d’Oncologia,<br />
Barcelona, Spain; Highlands Oncology Group, Fayetteville, AR; Baylor<br />
University Medical Center, Dallas, TX; Ironwood <strong>Cancer</strong> and Research<br />
Centers, Chandler, AZ; Novartis Pharma AG, Basel, Switzerland;<br />
Novartis Institutes for BioMedical Research, Inc., Cambridge, MA.<br />
P6-11-09 FAK Inhibitor VS-4718 Attenuates <strong>Breast</strong> <strong>Cancer</strong> Stem Cell<br />
Function In Vitro and In Vivo<br />
Kolev VN, Vidal CM, Shapiro IM, Pavdal M, Keegan M, Xu Q, Pachter<br />
JA. Verastem, Cambridge, MA.<br />
P6-11-10 IBL2001: Phase I/II study of a novel dose-dense schedule of<br />
oral indibulin for the treatment of metastastic breast cancer<br />
Traina TA, Hudis C, Seidman A, Gajria D, Gonzalez J, Anthony SP,<br />
Smith DA, Chandler JC, Jac J, Youssoufian H, Korth CC, Barrett JA,<br />
Sun L, Norton L. Memorial Sloan-Kettering <strong>Cancer</strong> Center, New<br />
York, NY; Evergreen Hematology and Oncology, Spokane, WA;<br />
Compass Oncology, Vancouver, WA; The West Clinic, Memphis, TN;<br />
US Oncology Research, Woodlands, TX; ZIOPHARM Oncology, Inc.,<br />
Boston, MA; Harmon Hill Consulting, New York, NY.<br />
P6-11-11 Multistage Delivery of Paclitaxel: Increased Drug Stability<br />
and Sustained Release Results in Enhanced Efficacy in<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Blanco E, <strong>San</strong>gai T, Hsiao A, Ferrati S, Bai L, Liu X, Meric-Bernstam F,<br />
Ferrari M. The Methodist Hospital Research Institute, Houston, TX;<br />
The University of Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX.<br />
P6-11-12 Nanoparticle-enhanced chemotherapeutics delivery in<br />
drug-resistant triple-negative breast cancer<br />
van de Ven AL, Landis MD, Paskett LA, Meyn A, Frieboes HB, Chang<br />
JC, Ferrari M. The Methodist Hospital Research Institute, Houston, TX;<br />
University of Louisville, KY.<br />
P6-11-13 In vitro antineoplastic evaluation of rationally designed<br />
naphthoquinone-derived drugs in triple-negative<br />
breast cancer cell line<br />
Madeira KP, Daltoé RD, Herlinger AL, Guimarães IS, Allochio Filho JF,<br />
Teixeira SF, Valadão IC, Greco S, Rangel LBA. Federal University of<br />
Espirito <strong>San</strong>to, Brazil.<br />
P6-11-14 Post-hoc safety and tolerability assessment in patients<br />
receiving palliative radiation during treatment with eribulin<br />
mesylate for metastatic breast cancer<br />
Yardley DA, Vahdat L, Rege J, Cortés J, Wanders J, Twelves C. Sarah<br />
Cannon Research Institute, Nashville, TN; Weill Cornell Medical<br />
College, New York, NY; Eisai Inc, Woodcliff Lake, NJ; Vall d’Hebron<br />
University Hospital, Barcelona, Spain; European Knowledge Center,<br />
Eisai Ltd., Hatfield, Hertfordshire, United Kingdom; St James<br />
University Hospital, Leeds, United Kingdom.<br />
Treatment: Adjuvant Therapy - Other<br />
P6-12-01 Adjuvant treatment in breast cancer patients aged 70<br />
years or older during three years. A systematic review of<br />
patients charts<br />
Nätterdal T, Klint L, Holmberg E, Gunnarsdottír KA, Linderholm BK.<br />
Institution of Medical Sciences, Sahlgrenska University Hospital,<br />
Gothenburg, Sweden; Sahlgrenska University Hospital, Gothenburg,<br />
Sweden; Karolinska Institute Science Park, Stockholm, Sweden.<br />
P6-12-02 Use of cytochrome P450 interacting medications in the setting<br />
of adjuvant therapy for breast cancer<br />
Njiaju UO, Kolesar JM, Johnston SA, Eickhoff JC, Osterby KR, Poggi<br />
LE, Tevaarwerk AJ, Millholland RJ, Oliver KA, Heideman JL, Wisinski<br />
KB. University of Wisconsin-Madison, WI; University of Wisconsin-<br />
Madison; University of Wisconsin Hospitals and Clinics.<br />
www.aacrjournals.org<br />
75s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P6-12-03 Effects of high dose of bisphosphonate therapy on bone<br />
microarchitecture of the peripheral skeleton in women with<br />
early stage breast cancer<br />
Shao T, Shane ES, McMahon D, Crew KD, Kalinsky K, Maurer M,<br />
Brown M, Gralow JR, Hershman DL. Beth Israel Medical Center,<br />
Continuum <strong>Cancer</strong> Centers of New York, New York, NY; Columbia<br />
University Medical Center, New York, NY; University of Washington/<br />
Seattle <strong>Cancer</strong> Care Alliance, Seattle, WA.<br />
Treatment: Therapy for Advanced Disease - Other<br />
P6-13-01 Lyso-thermosensitive liposomal doxorubicin + local<br />
hyperthermia for radiation-pretreated chest wall recurrence<br />
Formenti S, Rugo H, Myerson R, Diederich C, Straube W, O’Conner B,<br />
Matzkowitz AJ, Goodman RL, Muggia F. New York University <strong>Cancer</strong><br />
Institute, New York, NY; UC <strong>San</strong> Francisco, <strong>San</strong> Francisco, CA; Siteman<br />
<strong>Cancer</strong> Center, Saint Louis, MO; Rhode Island Hospital, Providence,<br />
RI; New Hope <strong>Cancer</strong> Center, Hudson, FL; Saint Barnabas Medical<br />
Center, Livingston, NJ.<br />
P6-13-02 Overcoming therapy resistance of metastatic breast cancer by<br />
enhanced tumor delivery of polymeric doxorubicin<br />
Shen H, Xu R, Mai J, Huang Y, Ferrari M. The Methodist Hospital<br />
Research Institute, Houston, TX.<br />
P6-13-03 Symptomatic bone marrow involvement (BMinv) in breast<br />
cancer (BC): Clinical presentation, treatment and prognosis<br />
according to BC subtype and Zoledronic acid (ZA) use.<br />
A single institution review<br />
Torrejon-Castro D, Zamora E, <strong>San</strong>chez-Olle G, Balmaña J, Gomez<br />
P, Saura C, Perez-Garcia J, Muñoz-Cousuelo E, Vidal M, Ortega V,<br />
Oliveira M, De Mattos L, Cortes J, Bellet M. Vall d´Hebron University<br />
Hospital, Barcelona, Spain.<br />
Treatment: Treatment - Other<br />
P6-14-01 Estrogen/progestogen use after <strong>Breast</strong> <strong>Cancer</strong> – a long-term<br />
follow-up of the Stockholm randomized trial<br />
Fahlén MC, Fornander T, Johansson H, Rutqvist L-E, Wilking N, von<br />
Schoultz E. Capio St Görans Hospital, Stockholm, Sweden; Karolinska<br />
Institutet, Stockholm, Sweden.<br />
P6-14-02 Withdrawn<br />
P6-14-03 Statin and aspirin use is not associated with a reduced risk of<br />
VTE’s in breast cancer patients<br />
Shai A, Rennert HS, Ballan Haj M, Lavie O, Steiner M, Rennert G. Lin<br />
Medical Center, Haifa, Israel; Carmel Lady Davis Medical Center,<br />
Haifa, Israel.<br />
P6-14-04 Rosehip extracts prevent triple negative breast cancer<br />
cell proliferation by regulating the phosphorylation of<br />
p70S6 Kinase<br />
Coburn TL, Cagle PD, Shofoluwe AI, Martin PM. North Carolina<br />
Agricultural and Technical State University, Greensboro, NC.<br />
P6-14-05 Impact of breast cancer CME: Physician practice pattern,<br />
knowledge, and competence assessments<br />
Haas M, Heintz A, Stacy T. Educational Concepts Group, LLC,<br />
Atlanta, GA.<br />
8:30 am–9:00 am<br />
PLENARY LECTURE 4<br />
Exhibit Hall D<br />
1st International Consensus Guidelines Conference for Advanced<br />
<strong>Breast</strong> <strong>Cancer</strong> – ABC1<br />
Fatima Cardoso, MD<br />
Champalimaud <strong>Cancer</strong> Centre<br />
Lisbon, PORTUGAL<br />
9:00 am–11:00 am<br />
THE YEAR IN REVIEW<br />
Exhibit Hall D<br />
Moderator: C. Kent Osborne, MD<br />
Baylor College of Medicine<br />
Houston, TX<br />
Advances in basic breast cancer research<br />
Jeffrey M. Rosen, PhD<br />
Baylor College of Medicine<br />
Houston, TX<br />
Discoveries in translational breast cancer research<br />
in 2012<br />
Douglas Yee, MD<br />
University of Minnesota<br />
Minneapolis, MN<br />
Adjuvant and neoadjuvant<br />
Kathy D. Miller, MD<br />
Indiana University School of Medicine<br />
Indianapolis, IN<br />
New therapies in 2012 for advanced disease –<br />
where do they all fit in<br />
Stephen Johnston, MA, PhD, FRCP<br />
Royal Marsden Hospital<br />
London, UNITED KINGDOM<br />
11:00 am<br />
ADJOURNMENT<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012 76s <strong>Cancer</strong> Research
December 4–8, 2012<br />
Program Schedule<br />
www.aacrjournals.org 77s <strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
ES1-1<br />
Molecular Profiling for In Situ Carcinoma of the <strong>Breast</strong><br />
Solin LJ. Albert Einstein Medical Center, Philadelphia, PA<br />
The management of in situ carcinoma of the breast represents a clinical<br />
dilemma. Such a non-invasive lesion places the patient at risk for<br />
subsequent development of an invasive lesion, and various treatments<br />
have been shown to reduce this risk. However, most patients are<br />
asymptomatic at initial presentation, and standard treatments are<br />
associated with the risk of side effects. It can be difficult for the<br />
individual patient to find the most appropriate balance between<br />
the risks and benefits of adding treatment. Although many patients<br />
elect for all treatments to minimize risk of progression regardless<br />
of potential side effects, other patients elect against treatment, often<br />
because of the potential risk of associated side effects.<br />
Standard approaches to managing the patient with in situ disease have<br />
employed various clinical and pathologic characteristics to assess<br />
and stratify risk. Models for determining risk have used a number<br />
of clinical and pathologic characteristics, including patient age,<br />
lesion size, and grade. Ductal carcinoma in situ (DCIS) and lobular<br />
carcinoma in situ (LCIS) have different risk profiles. For example,<br />
LCIS is well known to have subsequent risk that is more frequently<br />
bilateral than DCIS.<br />
Prospective randomized clinical trials for DCIS have demonstrated<br />
a substantial reduction in the risk of recurrence associated with<br />
adding radiation treatment and tamoxifen after lumpectomy. Five<br />
randomized DCIS trials have shown that adding radiation treatment<br />
after lumpectomy lowers the risk of local recurrence and invasive<br />
local recurrence in the ipsilateral breast by approximately 50%. Two<br />
randomized DCIS trials have demonstrated that adding tamoxifen<br />
reduces the risk of all breast cancer events (combined ipsilateral plus<br />
contralateral) by approximately 30-40%. No survival benefit has been<br />
shown for adding either radiation or tamoxifen. For LCIS, hormonal<br />
treatment has been shown to reduce subsequent risk.<br />
More recent efforts have focused on the value of molecular markers<br />
to individualize and tailor risk profiling for the individual patient.<br />
Using such molecular risk profiling, adding treatment can be selected<br />
for higher risk patients, and omitting treatment can be chosen for<br />
lower risk patients. To be clinically useful, molecular profiling<br />
should demonstrate value beyond that seen using standard clinical<br />
and pathologic factors. While current efforts have focused on using<br />
molecular profiling as a prognostic factor, future efforts will evaluate<br />
molecular profiling as a predictive factor.<br />
ES1-2<br />
The Practical Use of Molecular Profiling: The View of a Medical<br />
Oncologist<br />
Wolff AC. Johns Hopkins Kimmel Comprehensive <strong>Cancer</strong> Center<br />
Adjuvant therapy changed the natural of early stage breast cancer.<br />
Starting in the 1970s, randomized trials have shown a survival<br />
benefit from adjuvant chemotherapy in operable, node-pos disease.<br />
Since 1985, the Oxford Overview led the rapid adoption of adjuvant<br />
chemotherapy (for ER-neg disease) and tamoxifen (for ER-pos<br />
disease), and this trend accelerated after the 1988 NCI Clinical Alert<br />
on adjuvant chemotherapy in node-neg disease. However, this was<br />
not without controversy. In 1990, an NIH Consensus Development<br />
Conference concluded that “… some degree of improvement (from<br />
adjuvant therapy) may be so small that they are outweighed by the<br />
disadvantages of therapy.” Soon, adjuvant chemotherapy also became<br />
a standard in ER-pos, node-neg disease.<br />
Starting in the mid 1990s, data began to suggest that not all patients<br />
with ER-pos disease benefitted from chemotherapy. Decision<br />
algorithms based on routine clinicopathologic factors (eg, TNM,<br />
grade, ER, and HER2) proved quite useful for decision-making for<br />
the average patient. But by the early 2000s, new molecular tools to<br />
stratify recurrence risk (prognosis) and likelihood of benefit from<br />
chemotherapy (prediction) became available in clinical practice to<br />
further individualize clinical decisions. Prospective-retrospective<br />
studies tested the prognostic/predictive utility of Oncotype DX.<br />
Soon, it became clear that it and routine clinicopathologic parameters<br />
offered independent prognostic utility in ER-pos disease. The TailoRx<br />
(node-neg) and RxPONDER (node-pos) trials are now prospectively<br />
testing Oncotype DX to guide the decision to add chemotherapy to<br />
endocrine therapy in patients with a lower/intermediate recurrence<br />
score. Mammaprint became the first FDA-cleared IVDMIA assay, and<br />
the MINDACT study directly addresses this predictive utility question<br />
by having randomized patients with a discordant result (compared to<br />
Adjuvant! Online) also receive chemotherapy or not.<br />
Patients with HER2-pos disease are offered HER2-directed therapy<br />
plus chemotherapy. Consequently, a clinical decision gap exists in<br />
triple-neg disease (TNBC), which affects 50,000 women just in the<br />
US each year. Decision algorithms for them are exclusively based on<br />
clinicopathological factors like TNM, grade, and HER2, as molecular<br />
assays like Oncotype DX and MammaPrint have no role in this setting.<br />
New molecular assays based on DNA methylation, immune markers,<br />
or other gene expression signatures are under development. In the<br />
meantime, adjuvant chemotherapy is routinely offered to all TNBC<br />
patients with at least T1b tumors, despite the fact that most patients<br />
with ER-neg, node-neg disease remain disease-free long-term when<br />
treated with just locoregional therapy.<br />
Various studies examined clinical decisions based on standard<br />
clinicopathologic parameters alone or with knowledge of molecular<br />
assay results. However, data beyond costs of care are needed to<br />
assess their independent and complementary role to improve the<br />
most important clinical outcome to patients (i.e., survival). Until then,<br />
access to accurate routine clinicopathologic markers for all patients<br />
worldwide remains critical to ensure the most optimal outcome to all<br />
patients in high and low income countries.<br />
ES2-2<br />
Triple Negative <strong>Breast</strong> <strong>Cancer</strong>: Subtypes, Molecular Targets, and<br />
Therapeutic Approaches<br />
Pietenpol JA. Vanderbilt-Ingram <strong>Cancer</strong> Center; Vanderbilt<br />
University School of Medicine, Nashville, TN<br />
The term “triple negative breast cancer” (TNBC) is used to classify<br />
10%-20% of all breast cancers that lack estrogen receptor (ER)<br />
and progesterone receptor expression as well as amplification of<br />
the human epidermal growth factor receptor 2 (HER2) 1 . Disease<br />
heterogeneity and the absence of well-defined molecular targets<br />
have made treatment of TNBC challenging. To make significant<br />
clinical advances for TNBC patients, integrative and comprehensive<br />
genomic and molecular analyses of TNBC are required to understand<br />
the complexity of the disease as well as to allow identification<br />
of homogeneous subsets and ‘driver pathways’ that can then be<br />
therapeutically targeted. In response to this need, we compiled<br />
an extensive number of TNBC gene expression (GE) profiles and<br />
initiated molecular subtyping of the disease 2 . We identified two basallike<br />
TNBC subtypes with cell cycle and DDR GE signatures (BL1<br />
and BL2); two mesenchymal subtypes with high expression of genes<br />
involved in differentiation and growth factor pathways (M and MSL);<br />
an immunomodulatory (IM) type; and a luminal subtype driven by<br />
androgen signaling (LAR). Differential GE was used to designate 25<br />
TNBC cell line models representative of these subtypes. Predicted<br />
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‘driver’ signaling pathways were pharmacologically targeted in these<br />
preclinical models as proof of concept that analysis of distinct GE<br />
signatures can inform therapy selection. Representative BL1 and BL2<br />
subtype cell lines preferentially respond to cisplatin. Mesenchymal,<br />
basal, and luminal subtype lines with aberrations in PI3K signaling<br />
have the greatest sensitivity, in general, to phosphatidylinositol<br />
3-kinase (PI3K) inhibitors. The LAR subtype cell lines express<br />
AR and are uniquely sensitive to bicalutamide (AR antagonist).<br />
We have also developed “TNBCtype,” a web-based subtyping tool<br />
for candidate TNBC tumor samples using our GE metadata and<br />
classification methods 3 . The approaches used and data generated<br />
have value for biomarker selection, drug discovery, and clinical trial<br />
design that will enable alignment of TNBC patients to appropriate<br />
targeted therapies.<br />
1. Dent, R., Trudeau, M., Pritchard, K.I., Hanna, W.M., Kahn, H.K.,<br />
Sawka, C.A., Lickley, L.A., Rawlinson, E., Sun, P., and Narod, S.A.<br />
(2007). Triple-negative breast cancer: clinical features and patterns<br />
of recurrence. Clin <strong>Cancer</strong> Res 13, 4429-4434.<br />
2. Lehmann, B.D., Bauer, J.A., Chen, X., <strong>San</strong>ders, M.E., Chakravarthy,<br />
A.B., Shyr, Y., and Pietenpol, J.A. (2011). Identification of human<br />
triple-negative breast cancer subtypes and preclinical models for<br />
selection of targeted therapies. J Clin Invest. 121: 2750-67.<br />
3. Chen, X., Li, J., Gray, W.H., Lehmann, B.D., Bauer, J.A., Shyr, Y.,<br />
and Pietenpol, J.A. (2012). TNBCtype: A Subtyping Tool for Triple-<br />
Negative <strong>Breast</strong> <strong>Cancer</strong>. <strong>Cancer</strong> informatics 11, 147-156.<br />
ES2-3<br />
The Clonal and Mutational Composition of Triple Negative<br />
<strong>Breast</strong> <strong>Cancer</strong>s<br />
Aparicio S. University of British Columbia<br />
The notion that cancers are mosaics, composed of clones of cells<br />
has been fundamental to cancer biology for several decades.<br />
Clonal evolution may underpin clinical features of cancer, such as<br />
emergence of treatment resistance, the heterogeneous responses of<br />
metastatic disease within individual patients and divergence between<br />
primary and metastatic disease. Spatial and temporal variation<br />
in clonal composition poses significant challenges for diagnostic<br />
sampling and disease monitoring. We have recently developed next<br />
generation sequencing approaches to these questions and applied<br />
them to the understanding of mutational and clonal composition<br />
of primary triple negative breast cancers (TNBC). The notion that<br />
triple negative breast cancers form a distinct disease entity is already<br />
strongly challenged by expression analysis and small scale mutational<br />
analysis. Our results show that both the mutational composition and<br />
clonal structure of primary triple negative breast cancers is in fact a<br />
complete spectrum, exploding the notion of TNBC (currently defined),<br />
as a distinct disease. Clonal analysis suggests a means by which the<br />
genetic complexity might be reduced by following patient evolution<br />
over time and space. I will discuss the specific implications of the<br />
mutational and transcriptome landscapes of TNBC in relation to<br />
possible disease biologies.<br />
ES3-1<br />
Early Phase Trials – What Are They For?<br />
Hilsenbeck SG. Baylor College of Medicine, Houston, TX<br />
Early in drug development, there are lots of things we need to learn<br />
about new agents or new combinations of agents in order to make<br />
‘good’ decisions about whether and how to proceed. The landscape<br />
of clinical trials is changing, with greater focus on targeted therapies<br />
and biomarker defined patient populations. Trial design, as we will<br />
hear in this session, must adapt to these new challenges. However,<br />
fundamentals still apply. We still need to demonstrate that drugs are<br />
safe and effective. As an introduction to the session, we will review<br />
the basic steps in drug development, especially early development,<br />
and the basic questions that must be answered at each step, in order<br />
to develop evidence for safety and efficacy.<br />
ES3-2<br />
Clinical Trial Designs for New Therapies: What Agents Should<br />
We Study?<br />
DeMichele A. University of Pennsylvania Perelman School of<br />
Medicine, Philadelphia, PA<br />
Biologically-targeted, novel agents hold great promise in breast<br />
cancer, but require adjustments to traditional study design, conduct<br />
and patient selection to be tested safely, effectively and economically.<br />
Key questions to be address in this talk include: Is the drug safe?<br />
Is it hitting the target? Can we identify the “right” patients to test?<br />
In what setting do we test it? Toxicities of these agents move wellbeyond<br />
traditional myelosuppression and fatigue, encompassing<br />
almost every organ system and requiring changes in monitoring<br />
and management to assure safety. Dosing and assessment strategies<br />
must be aimed at optimally modulating target and assessing whether<br />
hitting the target has the desired effect on the natural history of the<br />
disease. The concurrent development of predictive biomarkers is<br />
necessary to select appropriate study subjects, which may be limited<br />
to a relatively small subset of patients with the disease. Finally,<br />
selecting the best therapeutic setting (treatment naïve, refractory,<br />
acquired resistance) can greatly impact the performance of the agent<br />
and requires knowledge of cancer biological evolution through the<br />
metastatic process.<br />
ES3-3<br />
Clinical Trial Designs for New Therapies: What Endpoints<br />
Should We Use?<br />
Hudis CA. Memorial Sloan-Kettering <strong>Cancer</strong> Center, New York, NY;<br />
Weill Cornell Medical College, New York, NY<br />
The selection of endpoints is critical to the interpretation of clinical<br />
trials results. In early phase clinical trials investigators seek evidence<br />
of activity, then predictors of clinical benefit, and in most randomized<br />
trials, accepted surrogates of meaningful benefit. At one extreme we<br />
may seek improvements in overall survival while in another we may<br />
be satisfied simply with evidence of tumor stabilization or changes in<br />
circulating biomarkers. In between these extremes are intermediate<br />
and composite endpoints including “partial responses”, “clinical<br />
benefit rate”, and those that are time-dependent endpoints such as<br />
disease-free or progression free survival. Many of the discussions and<br />
disagreements we hear in the context of drug development, benefit,<br />
and approval can be linked to a fundamental lack of agreement on the<br />
value and meaning of many of these endpoints. Activity of a given<br />
novel agent may, or may not, persuade some investigators, clinicians,<br />
and patients, that it is a worthwhile addition to our treatment options.<br />
On the other hand, a small but statistically significant improvement<br />
in overall survival in advanced cancer may, or may not, convince this<br />
same audience that the tested treatment is worthy of approval and use.<br />
Again, the intermediate endpoints may be unreliable or only weak<br />
predictors of more profound benefits. We will review and explore<br />
these issues considering not only the endpoints themselves but also<br />
their meaning in specific clinical settings and the impact of endpoint<br />
selection on further drug development.<br />
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ES3-4<br />
Clinical Trial Designs for New Therapies: When Should We<br />
Randomize?<br />
Hunsberger S. National <strong>Cancer</strong> Institute<br />
There is a tension in clinical trial study design between the desire to<br />
keep the number of patients in a study small (so that as few patients<br />
as possible are exposed to potentially harmful agents, resources are<br />
minimized, and an answer is obtained as early as possible) and how<br />
much certainty is needed in the conclusion of the study. Different<br />
phases of drug development require different levels of certainty.<br />
Single arm studies require fewer patients than randomized studies<br />
but an observed improvement in the study defined endpoint in<br />
a single arm study may be observed for reasons unrelated to the<br />
experimental treatment. In randomized studies factors (known and<br />
unknown) that influence the endpoint of interest should be balanced<br />
between groups therefore any improvement in the endpoint of interest<br />
can be attributed to the experimental agent. In this talk I discuss<br />
circumstances that would be appropriate to perform single arms<br />
studies and circumstances that require randomized studies.<br />
ES4-1<br />
Navigating the Obstacles and Risks of Survivorship: <strong>Breast</strong><br />
<strong>Cancer</strong> Sexuality: Issues and Answers<br />
Krychman M. The Southern California Center for Sexual Health and<br />
Survivorship, Newport Beach, CA; University of California Irvine,<br />
Irvine, CA; University of Southern California, Los Angeles, CA<br />
The sexual consequences of breast cancer and its treatments are well<br />
known. Sexual difficulties include alteration in hormonal levels,<br />
changes in sexual organs and anatomy, vaginal and vulvar dryness,<br />
changes in libido, increased latency to orgasm and decreased intensity<br />
of orgasmic response. Changes in body image, sexual self-esteem and<br />
relationship dynamic tension may present as survivorship challenges<br />
for the breast cancer patient and her partner. Severe vulvo vaginal<br />
and clitoral atrophy as a result of chemotherapy and/or adjuvant<br />
hormone therapy, and loss of libido secondary to dyspareunia are<br />
widespread. Cytostatic medications that are prescribed for long-term<br />
use (aromatase inhibitors) can impact bone health, sexual functioning/<br />
satisfaction and overall quality of life. Many women on aromatase<br />
inhibitors have severe complaints of vulvar and vaginal atrophy.<br />
Sexual dysfunction is common for breast cancer population and<br />
limited acceptable treatments are available. Minimally absorbed local<br />
vaginal estrogen use in this population remains controversial and a<br />
hotly debated controversial topic. More data should be forthcoming.<br />
There are multiple new innovative treatments in the research pipeline<br />
for female sexual dysfunction. DHEA intravaginal suppositories,<br />
Flibanserin and Bremelanotide (PT 141) remain promising although<br />
they have not been adequately studied in the breast cancer population.<br />
Ospemifene a novel estrogen agonist/ antagonist has demonstrated<br />
a strong estrogenic effect on the vaginal epithelium during a three<br />
month trial period and did not stimulate the endometrium; however,<br />
the medication did mildly aggravate hot flashes (this did not lead<br />
to drug discontinuation). Although not studied in breast cancer<br />
patients, pivotal Phase 3 data confirmed effectiveness of ospemifene<br />
as effective treatment for vulvovaginal atrophy. In a recent article<br />
in Menopause, Ospemifene and 4-hydroxyospemifene effectively<br />
prevented and treat breast cancer in Mtag.TG Transgenic Mouse.<br />
Testosterone use remains off label and is not FDA approved, yet it<br />
is widely used in the non cancer population. New emerging safety<br />
data will be presented. Vaginal moisturizers, lubricants and dilators in<br />
association with genito pelvic floor therapy and intravaginal valium<br />
suppositories can be considered front line treatment for atrophy,<br />
dyspareunia and hypertonic vaginismus. New innovative data on non<br />
hormonal management of hot flashes is and important initial step in<br />
the overall management of the breast cancer patient who is suffering<br />
from sexual dysfunction.<br />
A multi model treatment paradigm will be presented which will<br />
include pharmacologic, nonpharmacologic, and psychosocial<br />
interventions.<br />
ES4-2<br />
Cognitive Changes and <strong>Breast</strong> <strong>Cancer</strong> Treatments<br />
Ganz PA. University of California, Los Angeles<br />
Cognitive difficulties after cancer treatment are among the most<br />
feared outcomes voiced by patients who are approaching the start of<br />
chemotherapy. This phenomenon, sometimes referred to as “chemo<br />
brain” or “chemo fog,” is quite common during the acute course of<br />
chemotherapy treatment. This may result from direct antieneoplastic<br />
drug toxicity, use of premedications and anxiolytics to prevent nausea<br />
and vomiting, as well as the expected anxiety, depression, and sleep<br />
deprivation that accompanies a new diagnosis of cancer and initiation<br />
of treatment. For most patients, this fog clears after the completion of<br />
acute treatments, and as with many physical symptoms, resolves in<br />
the following months. However, 15-25% of post-treatment patients,<br />
cognitive complaints persist long after treatment ends. Reports of<br />
difficulty concentrating, remembering recent events, multi-tasking,<br />
and paying attention are frequent in such patients. For those used to<br />
carrying on demanding executive function activities prior to cancer<br />
treatment, this can lead to substantial disruption in work and home<br />
life. Most of the studies conducted to date with early stage breast<br />
cancer have not accounted for the impact of adjuvant endocrine<br />
therapy alone or added to adjuvant chemotherapy. This presentation<br />
will review emerging data regarding self-reported cognitive<br />
complaints, neuropsychological testing, and brain imaging as they<br />
related to adjuvant therapies for breast cancer. In addition, some of<br />
the developing information about potential mechanisms associated<br />
with this late effect will be discussed.<br />
ES4-3<br />
Risk of Developing Second Primary <strong>Breast</strong> <strong>Cancer</strong> among<br />
Survivors of <strong>Breast</strong> <strong>Cancer</strong><br />
Bernstein JL. Memorial Sloan-Kettering <strong>Cancer</strong> Center, New York, NY<br />
Of the nearly 226,870 US women expected to develop breast cancer in<br />
2012 and the over 3 million breast cancer survivors currently residing<br />
in the US, five to ten percent will develop a subsequent primary in the<br />
contralateral breast (CBC) (www.cancer.org). This risk of developing<br />
CBC is higher than the overall risk of breast cancer in the general<br />
population. The rising incidence of breast cancer, coupled with an<br />
improved survival potential after cancer diagnosis has placed an<br />
increased number of women at risk for CBC, yet the epidemiology is<br />
poorly understood. Despite common genetics and exposures shared<br />
by both breasts, only a fraction of women who survive their first<br />
primary will develop a second primary in the contralateral breast.<br />
Epidemiologic studies have identified factors associated with an<br />
increased risk of developing CBC, including family history of breast<br />
cancer, early age at diagnosis, hormonal factors, reproductive history,<br />
body-mass index, and tumor characteristics of the first primary e.g.,<br />
lobular histology, stage and estrogen receptor (ER) status. The risk of<br />
developing CBC has also been associated with mutations of specific<br />
genes including BRCA1, BRCA2, and CHEK2. Importantly, the<br />
treatment a woman receives for her first primary breast cancer can<br />
also influence her risk of developing CBC; chemotherapy, hormonal<br />
therapies and tamoxifen significantly reduces the risk of developing<br />
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CBC while the radiation received to the contralateral breast during<br />
radiotherapy increases the risk of CBC. Despite the number of<br />
established risk factors for increased CBC risk, their combined effect<br />
accounts for only a small portion of the CBCs that develop each year.<br />
It is unclear whether, and to what extent, genetic factors and radiation,<br />
individually or via interaction, contribute to the development of CBC.<br />
This talk will review the state of the field.<br />
ES5-3<br />
Investigating <strong>Breast</strong> <strong>Cancer</strong> with Single-Cell Sequencing<br />
Navin NE. UT MD Anderson <strong>Cancer</strong> Center, Houston, TX<br />
Tumors evolve from single cells. As they evolve, they acquire complex<br />
somatic mutations and diversify, forming distinct subpopulations of<br />
cells. This intratumor heterogeneity confounds basic research and<br />
clinical practice because tools do not exist to resolve it. Standard<br />
genomic methods are limited to reporting an average signal from a<br />
complex population of cells, because they require a large amount of<br />
input material. These bulk methods may mask population diversity<br />
and rare cells in the tumor - that may be the most malignant. To<br />
address this limitation my laboratory has developed single-cell<br />
sequencing tools to delineate intratumor heterogeneity and investigate<br />
mutational evolution in human cancers. We developed a method to<br />
profile genomic copy number in single cells and used this method to<br />
study genome evolution in triple-negative (ER-/PR-/Her2-) breast<br />
tumors (Navin et al., 2011 Nature) which revealed a punctuated<br />
model for copy number evolution. Recently, we have extended this<br />
method to obtain whole-genome, high-coverage sequencing data<br />
from single human tumor cells. From this data we can detect the full<br />
spectrum of genomic mutations, including point mutations, indels and<br />
microdeletions in single human cells. We applied this method to study<br />
clonal diversity in an estrogen-receptor-positive breast carcinoma<br />
and sequenced four single cells in addition to a population sample.<br />
In the population we detected only 36 coding mutations. However,<br />
our whole-genome single-cell sequencing data revealed hundreds of<br />
additional coding mutations, suggesting extensive clonal diversity<br />
in the tumor. Our data from this tumor support a mutator phenotype<br />
model for tumor progression, in which cancer is driven by elevating<br />
the rate of random mutations. Our studies show that a wealth of<br />
information can be obtained from studying single cancer cells, data<br />
that could not be obtained by analyzing the tumor en masse. We expect<br />
single-cell sequencing to have major clinical applications in early<br />
detection, analyzing scarce tissue samples and monitoring residual<br />
disease in patients with cancer.<br />
ES6-1<br />
Sentinel Node Biopsy in <strong>Breast</strong> <strong>Cancer</strong>: Before or after<br />
Neoadjuvant Chemotherapy?<br />
Mamounas EP. Aultman Hospital<br />
Neoadjuvant chemotherapy (NC) was originally used to render<br />
inoperable breast cancer (BC) patients to operable candidates. Its use<br />
subsequently expanded to operable BC patients requiring mastectomy<br />
to convert them to candidates for breast conserving surgery. NC has<br />
also been shown to downstage axillary lymph nodes in up to 40-50%<br />
of patients. This observation, coupled with the development and<br />
validation of sentinel node biopsy (SNB) in patients with operable BC<br />
provided yet another potential advantage for the use of neoadjuvant<br />
over adjuvant chemotherapy, i.e. the potential to decrease the extent<br />
and morbidity of axillary surgery.<br />
Several small, single-institution studies have examined the efficacy<br />
of lymphatic mapping and the accuracy of SNB after NC with<br />
significant variability in the rate of SN identification and in the rate<br />
of false negative SN. Nonetheless, when these studies are examined<br />
collectively or when larger, multi-center data sets are analyzed, SNB<br />
after NC appears to have somewha lower rate of SN identification but<br />
similar rate of false negative SN compared to SNB before systemic<br />
therapy. This also appears to be the case even in patients who have<br />
documented involvement of the axillary nodes before NC. Results<br />
of two prospective studies on this subject (ACOSOG 1071 and<br />
SENTINA) will be presented at the 2012 SABCS.<br />
Some have proposed that candidates for NC should have SNB<br />
performed before NC rather than after. They argue that this approach<br />
obtains information on the status of the SN without the potential<br />
confounding effects of NC and SN negative patients can avoid axillary<br />
dissection. Although this approach may be useful in patients who will<br />
not need adjuvant/neoadjuvant chemotherapy if the SN is negative,<br />
it is not generally useful for the majority of candidates for NC. SNB<br />
before NC commits patients to two surgical procedures whether the<br />
SN is negative or positive and this approach does not take advantage<br />
of the down-staging effect of NC on the axillary nodes.<br />
Knowledge of the pathologic SN status before NC does not seem to<br />
help in deciding which NC regimen to use or whether to use additional<br />
adjuvant chemotherapy after surgery. Furthermore, the prognostic<br />
significance of negative axillary nodes after NC and prior positive<br />
SNB is dubious since node negativity in this setting may reflect<br />
axillary nodal down-staging or just the prior removal of all positive<br />
nodes by SNB. Lastly, it has been argued that knowing whether the<br />
axillary nodes are involved before NC may provide useful information<br />
regarding the need for postoperative XRT to regional lymph nodes<br />
or the chest wall (after mastectomy). Recent results on the rates and<br />
patterns of loco-regional recurrence (LRR) from two NSABP NC<br />
trials (B-18 and B-27) have shown that achievement of pathologic<br />
complete response (pCR) in the breast with histologically negative<br />
axillary nodes at surgery is an independent predictor of LRR and that<br />
LRR rates are low for patients who are clinically node positive before<br />
NC but histologically node-negative after NC, particularly if they<br />
have pCR in the breast. Thus, based on this data the value of knowing<br />
the pathologic status of the SN(s) before NC is further diminished.<br />
ES6-2<br />
Evolving Trends in Implant <strong>Breast</strong> Reconstruction<br />
Pusic A. Memorial Sloan-Kettering <strong>Cancer</strong> Center, New York, NY<br />
For women undergoing mastectomy, implant breast reconstruction<br />
is increasingly common. Over the past 5 years, new trends in<br />
implant reconstruction have been evolving. The use of ‘nextgeneration’<br />
silicone implants, acellular dermal matrices and fat<br />
grafting have expanded the range of options available to patients.<br />
In addition, for women undergoing both skin-sparing and nipplesparing<br />
mastectomies, there is growing experience with single-stage<br />
implant reconstruction (i.e. implant placement directly at the time of<br />
mastectomy without use of a tissue expander). Finally, indications<br />
for post-mastectomy radiation continue to increase and this has<br />
important implications for long-term patient satisfaction with implant<br />
reconstruction.<br />
ES7-2<br />
Tumor Dormancy from an Experimental Biologist’s Perspective<br />
Chambers AF. London Regional <strong>Cancer</strong> Program, London, ON,<br />
Canada<br />
Survival from breast cancer has improved steadily over the past<br />
decades. However, most breast cancer deaths are due to metastasis,<br />
and considerably less progress has been made against metastatic<br />
disease. We still know remarkably little about preventing or delaying<br />
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metastatic recurrence or effectively treating the cancer if it does recur.<br />
Making breast cancer treatment even more challenging is the fact<br />
that breast cancer patients may appear to be cured of their disease,<br />
only to have it return later. These recurrences can happen even<br />
decades after apparently successful primary treatment. This creates<br />
years of uncertainty for breast cancer patients, who do not know if<br />
they have been cured or if the cancer will return, and makes clinical<br />
management difficult.<br />
We have used experimental models, both in vitro and in vivo, to<br />
try to understand the process of breast cancer metastasis. We have<br />
found that a population of cancer cells can remain as dormant<br />
cells, and have shown that these cells can resist being killed by<br />
cytotoxic chemotherapy that successfully kills actively diving<br />
cells. Experimental studies raise questions that must be addressed<br />
clinically. For example, what is the prevalence of dormant cells in<br />
breast cancer patients – are they common or rare? Are there factors<br />
inherent to the cancer cells that influence the likelihood of dormant<br />
cells persisting and subsequently re-awakening? Conversely, are there<br />
host microenvironmental factors, such as diet, exercise or stress, that<br />
can influence whether dormant cells persist and re-awaken? This<br />
information will be important in learning better how to prevent, delay<br />
and treat metastatic breast cancer.<br />
ES8-1<br />
Inflammation and <strong>Breast</strong> <strong>Cancer</strong><br />
Condeelis J. Albert Einstein College of Medicine<br />
Mechanism-based insights into prognosis and treatment of breast<br />
cancer derived from high resolution multiphoton imaging<br />
John Condeelis, Thomas Rohan, Maja Oktay - Einstein, New York;<br />
Tony Ng – King’s College London, UK;<br />
Seema Agarwal, David Rimm – Yale, New Haven;<br />
Brian Robinson, Joan Jones – Weill Cornell Medical Center, New York<br />
Frank Gertler MIT, Boston.<br />
Multi-photon microscopy allows the observation of tumor cell<br />
behavior at single cell resolution in vivo and has demonstrated<br />
that invasive and migratory tumor cells in mammary tumors form<br />
migratory streams and intravasate only when associated with<br />
macrophages. This analysis demonstrates that tumor cell streaming<br />
and intravasation are cell autonomous behaviors that are the direct<br />
result of the tumor cell -macrophage interaction.<br />
The in vivo invasion assay was developed to collect these streaming<br />
and intravasation competent tumor cells from primary tumors in vivo.<br />
Collection of these cells was coupled to expression profiling to reveal<br />
the genes expressed by tumor cells during streaming and intravasation<br />
in rat, mouse and human breast tumors (the Invasion Signature).<br />
The invasion, adhesion and motility pathways identified in the<br />
Invasion Signature converge on the RhoC/Cofilin/Mena pathway<br />
identifying it as a master regulator of chemotaxis, streaming and<br />
intravasation of breast tumor cells in vivo. Using prognostic markers<br />
derived from the RhoC/Cofilin/Mena pathway, anatomical landmarks<br />
have been developed for use with breast cancer patients. One of these,<br />
composed of the tumor cell-macrophage intravasation complex, is<br />
called TMEM (Tumor MicroEnvironment for Metastasis) in human<br />
breast tumors. TMEM density in histology sections of breast tumor<br />
tissue has been found to predict metastatic risk.<br />
The potential for tumor cell/macrophage pairing, steaming and TMEM<br />
assembly can be detected in breast tumors by the relative expression<br />
of isoforms of Mena-INV (enhancer) and Mena11a (suppressor of<br />
migration and dissemination, referred to as the MenaCalc test). Two<br />
retrospective studies with breast cancer tissue from patients with<br />
known recurrence and survival outcome have demonstrated the use,<br />
for prediction of metastatic risk, of the MenaCalc test and the TMEM<br />
test in resected breast tumor tissue.<br />
A CofilinxP-Cofilin test, also derived from the RhoC/Cofilin/Mena<br />
pathway of the human Invasion Signature, is showing promise as<br />
a predictor of disease-free survival. The Cofilin part of the RhoC/<br />
Mena/Cofilin pathway is associated with the overall activity of a<br />
biologically relevant sub-network of proteins (centered around four<br />
seed proteins ezrin/radixin/moesin/cofilin) in the cancer proteome<br />
that control membrane-cytoskeletal linkage and tumor cell motility.<br />
CofilinxP-Cofilin co-localization intensity was the most biologically<br />
significant variable measured among these others in predicting<br />
survival in a large retrospective trial of breast cancer patients. The<br />
value of this test derives from the fact that it is independent of antiestrogen<br />
(hormonal) treatment and chemotherapy.<br />
In summary, multi-photon imaging in deep tissue locations in live<br />
animals in real time has revealed molecular mechanisms associated<br />
with complex cancer cell behavior during metastatic dissemination<br />
leading directly to new markers of metastatic risk and survival.<br />
ES8-2<br />
<strong>Breast</strong> <strong>Cancer</strong> Stroma: A Predictor of Clinical Outcome and<br />
Tumour Heterogeneity<br />
Bertos N, Finak G, Lesurf R, Saleh SM, Zhao H, Souleimanova M,<br />
Meterrisian S, Omeroglu A, Hallett M, Park M. McGill University,<br />
Montreal, QC, Canada<br />
<strong>Breast</strong> cancer heterogeneity is one of the principal obstacles both<br />
to predicting outcome and to determining an effective course of<br />
treatment for this disease. Individual cases demonstrate heterogeneity<br />
at multiple levels, including those parameters assessed by studies of<br />
gene expression, chromosomal aberrations, and classical and immunopathology.<br />
Although genomic technologies have been used to gain a<br />
better understanding of the impact of gene expression heterogeneity<br />
on breast cancer outcome by identifying gene expression signatures<br />
associated with clinical outcome, histopathological breast cancer<br />
subtypes, and a variety of cancer--related pathways and processes,<br />
relatively little is known about the effects of heterogeneity in the<br />
tumor microenvironment. We have addressed changes in stroma by<br />
analyzing changes in gene expression in stromal tissue associated<br />
with breast tumors when compared to normal breast tissue. We have<br />
integrated gene expression data from laser capture microdissected<br />
breast tumor stroma with matched normal stroma. Using this approach<br />
we have identified that the microenvironment of a breast tumor can<br />
be classified into one of six distinct molecular phenotypes exhibiting<br />
distinct biological functions and carrying prognostic information<br />
independent of existing therapeutic biomarkers and tumor subtypes.<br />
A trained predictor of 23 genes was developed and contains new<br />
information to stratify breast cancer subtypes. This is independent of<br />
clinical parameters and published predictors of outcome and identifies<br />
patients with poor outcome in multiple breast cancer expression data<br />
generated using using whole tissue. The stromal predictor selects<br />
poor outcome patients from multiple clinical subtypes of breast<br />
cancer and contains genes representing distinct biological features,<br />
including differential immune response, angiogenic response, as<br />
well as a hypoxic response. Elements of this signature are present in<br />
murine models of breast cancer. These results highlight the complex<br />
relationship between the tumor and its microenvironment, and<br />
underline the role that the stroma plays in tumor progression.<br />
These results demonstrate an important role for the tumor<br />
microenvironment in defining breast cancer heterogeneity, with a<br />
consequent impact upon clinical outcome. Novel therapies could be<br />
targeted at the processes that define the stroma classes, suggesting new<br />
avenues for the development of individualized treatment regimens.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
82s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Invited Speakers<br />
ES9-1<br />
Adjuvant Treatment of HER2 Positive <strong>Breast</strong> <strong>Cancer</strong>: The Next<br />
Installment<br />
Pietenpol JA. Vanderbilt-Ingram <strong>Cancer</strong> Center; Vanderbilt<br />
University School of Medicine, Nashville, TN<br />
The treatment of HER2 positive breast cancer radically changed in<br />
2005; at ASCO that year adjuvant trials reported that the addition of<br />
trastuzumab consistently showed a major improvement in progression<br />
free survival in the treatment of early breast cancer that was HER2<br />
positive. A benefit was seen when trastuzumab was given either<br />
concurrently with chemotherapy or sequentially. The trials generally<br />
studied one year of trastuzumab although data from Finland showed<br />
a benefit for 3 months of treatment. Additional, yet to be reported<br />
studies, have explored durations of 6 months and 2 years. Initially<br />
there was concern about cardio toxicity and the potential for significant<br />
long-term harm, but the rate of cardio toxicity remains low and<br />
usually is seen early in the treatment. To further improve outcomes,<br />
new agents have been studied in the neo and adjuvant settings. The<br />
large ALTTO study randomized patients to either chemotherapy with<br />
either a year of trastuzumab, a year of lapatinib (the TKI inhibitor<br />
with efficacy in the metastatic arena), the combination of both agents<br />
or sequential use of each agent. The lapatinib monotherapy arm was<br />
shown to be inferior in an interim analysis and discontinued. Final<br />
data is pending although extrapolating from the NEOALTTO study,<br />
one may expect heightened activity from dual blockade. The BETH<br />
study added bevacizumab to trastuzumab in a 2-arm study trying to<br />
combat angiogenesis with HER2 blockade; this study has not reported.<br />
Although the same combination studied in the AVEREL study in the<br />
advanced setting did not show a benefit, this may not be the case in<br />
earlier disease and we need to wait for data. Dual blockade with two<br />
antiHER2 agents has been beneficial in the advanced setting and this<br />
has led to the APHINITY study, which is comparing chemotherapy<br />
with standard trastuzumab or trastuzumab with another antiHER2<br />
antibody, pertuzumab. This study is accruing well and will provide<br />
evidence for whether dual blockade with two antibodies is of benefit.<br />
It will also provide some clinical trial data for small tumors, as these<br />
are eligible for enrollment in this trial. Other new agents, including<br />
TDM 1, are being taken into the neoadjuvant setting and will be in<br />
adjuvant trials soon. Subcutaneous trastuzumab may provide easier<br />
treatment for women over their year of adjuvant therapy. A big<br />
question is whether all HER2 tumors are the same or whether we can<br />
begin tailoring treatment according to molecular features. Are there<br />
some cancers that will be cured with a short course of chemotherapy<br />
and trastuzumab while others may need multiple antiHER2 agents<br />
combined to acquire the same result? With the collection of tumor<br />
samples we can hopefully begin to further understand this. Tailored<br />
treatment has the potential to decrease toxicity and improve quality of<br />
life issues, provide more rational use of costly resources, and finally<br />
develop more intensive therapy for resistant tumors thus improving<br />
outcomes overall.<br />
PL-1<br />
Hormones and the <strong>Breast</strong>: Local and Environmental Interactions<br />
Brisken C, Rajaram R, Ayyannan A, Beleut M, Yalcin O. Ecole<br />
Polytechnique Fédérale de Lausanne (EPFL); ISREC/SV; EPFL;<br />
Izmir Institute of Technology<br />
A woman’s reproductive history affects her risk to get breast cancer.<br />
In particular, the number of menstrual cycles she experiences<br />
correlates with risk. We use tissue recombination experiments and<br />
different mouse mutant models to discern the roles of the ovarian<br />
hormones estrogens and progesterone act in the mammary gland.<br />
While estrogens drive pubertal development, progesterone is the<br />
major driver of proliferation in the adult mammary epithelium. Both<br />
steroids rely strongly on paracrine signaling to elicit cell proliferation<br />
and other biological effects.<br />
Perinatal exposure to environmentally relevant concentrations of<br />
a high production volume chemical, bisphenol A, that is detected<br />
in human due to exposure through consumer products, results<br />
in persistent changes in the mammary gland. The cell number is<br />
increased in in adult females as is the response to progesterone.<br />
ML-1<br />
William l. McGuire Memorial Lecture: Neoadjuvant Systemic<br />
Therapy: Promising Experimental Model, or Improved Standard<br />
of Care?<br />
Hortobagyi GN. UT MD Anderson <strong>Cancer</strong> Center, Houston, TX<br />
Neoadjuvant chemotherapy (NACT) was developed to improve the<br />
management of largely inoperable breast cancers (BC), including<br />
inflammatory BC. In the early 1970s, despite heroic efforts combining<br />
radical surgical resection with high doses of radiotherapy, local failure<br />
rate remained between 20% and 50% and 5-year overall survival (OS)<br />
rates rarely approached 20%. With the introduction of anthracyclinecontaining<br />
combination chemotherapy regimens, most large primary<br />
tumors responded to chemotherapy, with greater than 50% reductions<br />
in almost 90% of patients. Clinical complete remissions (CR) were<br />
reported in about 10% of such large tumors. These results were<br />
obtained when adjuvant chemotherapy was in its earliest clinical<br />
evaluation. Our group at the MD Anderson <strong>Cancer</strong> Center and others<br />
pioneered multidisciplinary strategies consisting of NACT, followed<br />
by surgery and radiotherapy. Such strategies rapidly became the<br />
standard of care for locally advanced BC and inflammatory BC,<br />
improving local control rates to >80%, and 5-year OS rates to >30%.<br />
In the early 1980s, we described the concept of pathological CR (pCR)<br />
and its correlation with favorable long-term OS. We also described<br />
the clinical and pathological correlates of pCR: thus, most pCRs were<br />
observed in patients with estrogen receptor (ER)-negative, high grade<br />
and highly proliferative tumors. pCRs were rarely observed when<br />
tumors had the opposite characteristics. Achieving major clinical<br />
responses expanded breast conserving surgery to patients with large,<br />
even locally advanced BC. Additional advantages to these strategies<br />
included the ability to monitor response to NACT, both clinically<br />
and through serial biopsies, thus documenting the biological effects<br />
of systemic treatments. By 1990, the first neoadjuvant endocrine<br />
therapies were introduced in patients with ER-positive BC, who were<br />
largely refractory to NACT. With the initial steps in high throughput<br />
genomic assays, our group focused on the development of prognostic,<br />
and later predictive profiles based on gene expression. These research<br />
directions rapidly established the importance of molecular subtypes.<br />
The old paradigm, based on a monolithic concept of BC was rapidly<br />
displaced by the 4-5 main molecular (and biomarker defined) BC<br />
subtypes. In little over 10 years, selection of standard treatment<br />
became dependent on four clinical biomarkers, while novel, RNA,<br />
DNA and protein based profiles became rapidly established in our<br />
diagnostic toolbox. Our field is rapidly evolving toward baseline<br />
identification of molecular anomalies that might serve as targets for<br />
novel, targeted agents (antibodies, kinase inhibitors, etc.). The proof<br />
of concept was trastuzumab and other HER-2-directed agents. Drug<br />
development is rapidly moving from advanced, refractory metastatic<br />
BC to the neoadjuvant setting, where modest size clinical trials<br />
promise to accelerate clinical assessment of new drugs, delivering<br />
them to the patients most likely to benefit from them. Neoadjuvant<br />
systemic therapy is at least equivalent to adjuvant systemic therapy<br />
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<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
and provides practical and scientific advantages that make it preferable<br />
in many subsets of BC. It is a new standard of care while continuing<br />
to serve as an excellent research tool.<br />
CS1-1<br />
Treatment on the Edges: Discordance between Stage and Biology<br />
Albain KS. Loyola University Chicago Stritch School of Medicine<br />
This Clinical Science Forum addresses one of the mort vexing issues<br />
that faces a clinician when guiding patients in adjuvant therapy<br />
decisions – what to do for treatment “on the edges”? That is, when<br />
there is discordance between stage/risk of relapse and biology, which<br />
should most influence the choice of therapy? The first presentation<br />
will address bad stage or high risk disease but “good” biology, and the<br />
second talk will consider good stage/traditionally lower risk disease<br />
but a “bad” biologic profile. This abstract provides an overview of<br />
the first scenario.<br />
Historically, in the era predating knowledge about biologic subtypes<br />
and without systemic adjuvant therapy, surgical series reported<br />
probable cures in patients with large and even locally advanced<br />
tumors, as well as in a subset with positive nodes. This data base<br />
serves as a backdrop for more modern series in which there is a wide<br />
range of long-term survival potential for patients with tumors that have<br />
adverse prognostic features. Currently, it is considered standard of<br />
care to offer systemic adjuvant chemotherapy, endocrine therapy and/<br />
or HER2 targeted treatments to all such patients – with the particular<br />
therapeutic choice based on tumor biology. In particular, it is not wise<br />
to withhold therapy in these higher risk (“bad stage”) scenarios when<br />
the disease is triple negative or HER2-positive.<br />
However, across the luminal subtypes, there is great variation in<br />
outcome even when tumors are large and/.or nodes are positive.<br />
Some of these patients will require only endocrine therapy despite<br />
the high risk status, whereas others need more creative therapeutic<br />
therapies to circumvent multi-pathway drivers of tumor growth<br />
and progression. Subsets defined by high levels of expression of<br />
the estrogen receptor and low proliferation have a better outcome<br />
and often are cured with endocrine therapy alone. Refinement of<br />
prediction of which groups may do very well with this approach<br />
alone has been possible with the advent of multigene assays such as<br />
the 21 gene Recurrence score or the 70 gene assay. In fact, it can be<br />
argued that many patients in the high risk (“bad stage”) breast cancer<br />
group are over-treated with chemotherapy. For example, in SWOG<br />
S8814, a study in postmenopausal, ER+, node positive disease, the<br />
10 year breast cancer specific survival was over 90% in those with<br />
a low 21 gene RS assay and this outcome did not vary whether the<br />
adjuvant treatment was tamoxifen alone or anthracycline-based<br />
therapy followed by tamoxifen. Similar findings were reported for<br />
higher risk, node-negative patients in NSABP B20. The current status<br />
of the three large prospective studies designed to validate and refine<br />
prediction of chemotherapy benefit will be updated (TAILORx,<br />
RxPONDER and MINDACT).<br />
Finally, there is the other group of patients with high risk (“bad stage”)<br />
ER-positive disease whose risk remains high with tumor biology<br />
relatively resistant to standard chemotherapy and insufficient efficacy<br />
of the endocrine therapy. In this group, optimizing inhibition of cross<br />
talk with other pathways that take over driving tumor growth - despite<br />
the endocrine therapy blockade - is mandatory. Only then can “bad<br />
stage” be turned into an excellent outcome.<br />
CS1-2<br />
Small Tumor – Aggressive Biology: When They Collide!<br />
Piccart MJ, Azim Jr HA. Institut Jules Bordet, Brussels, Belgium<br />
Historically, tumor stage was the main stay in determining the<br />
prognosis and the need for adjuvant therapy in patients with operable<br />
breast cancer (BC). Patients with a tumor size < 1cm (pT1a, b)<br />
and negative nodal involvement (pN0) were regarded to have very<br />
favorable prognosis. This in turn was reflected in the way these<br />
patients were managed. Since a decade or more, it became obvious<br />
that BC is not a single disease, but a group of molecularly distinct<br />
subtypes. The appreciation of the biological diversity of BC subtypes<br />
has urged the question on the relevance of tumor stage in the decisionmaking,<br />
nowadays. In other words, should patients with early-stage<br />
disease continue to receive “milder” or even no systemic therapy<br />
being historically known to have favorable prognosis, even if they<br />
are of aggressive nature?<br />
Evidence in this regards mainly rely on retrospective data as these<br />
patients are often excluded from randomized trials. Data based on<br />
analyzing untreated cohorts have shown that the 5-year relapse-free<br />
survival of patients with pT1a, b pN0 disease is rather favorable, in<br />
the range of 90%. However, obvious differences in outcome were<br />
observed according to BC subtype. Patients with ER-positive disease<br />
often have an even more favorable outcome reaching up to 95%<br />
unlike those with HER2 and t tumors in which 5-year RFS ranges<br />
around 75-80%. This calls for integrating biological information in<br />
managing these patients.<br />
Patients with ER-positive disease are composed of at least two<br />
subtypes, luminal-A and luminal-B.; the latter being more aggressive.<br />
It is unlikely that this differs in patients with pN0 disease. This was<br />
demonstrated by the Mammaprint®, which separate pT1a, b patients<br />
into two distinct groups with different outcome.<br />
Few data suggested that the addition of trastuzumab particularly<br />
in patients with pT1b is worthwhile. This is further endorsed by<br />
guidelines like NCCN and St Gallen. However, it is important to note<br />
that the exact magnitude of benefit of trastuzumab in these patients<br />
is unknown. It is plausible to assume that the relative risk reduction<br />
on relapse will be similar to that in patients with more advanced<br />
tumors, which is in the range of 50%. On the basis that these patients<br />
have an absolute risk of relapse in the range of 20-25%, it appears<br />
reasonable to consider trastuzumab, particularly in patients with pT1b,<br />
which were shown to experience more BC-related events compared<br />
to patients with pT1a.<br />
A similar argument exists on the added value of chemotherapy for<br />
patients with TN disease. Based on the recent EBCTCG overview,<br />
the relative risk reduction on the risk of relapse by administering<br />
chemotherapy does not exceed 30%. Acknowledging the absolute<br />
risk of relapse of the pT1a, b pN0 patients, the absolute benefit from<br />
offering chemotherapy appears to be modest; especially for those<br />
with pT1a.<br />
Hence, the appreciation of BC heterogeneity on the molecular level is<br />
vital and should be considered in managing patients with very small<br />
tumors. As these patients have “relatively” low risk of relapse, it is<br />
important to consider absolute risk reductions that are foreseen by the<br />
addition of chemotherapy ± trastuzumab. This would help refining<br />
management strategies and hence improve counseling of patients<br />
diagnosed with these relatively indolent, yet challenging tumors.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
84s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Invited Speakers<br />
BS1-1<br />
Essential Role for Wnt Signaling in Metastatic Colonization<br />
Huelsken J. EPFL (Swiss Federal Institute of Technology Lausanne),<br />
Lausanne, Switzerland<br />
Metastatic growth in distant organs is the major cause of cancer<br />
mortality. Formation of metastasis is a multi-step process with several<br />
rate-limiting steps: while dissemination of tumour cells appears to<br />
be an early and frequent event, successful initiation of metastatic<br />
growth, a process termed metastatic colonization, is rather inefficient<br />
and accomplished only by a minority of cancer cells that reach distant<br />
sites. We now identify two key mechanisms essential for the initiation<br />
of metastasis: first, a small population of cancer stem cells that are<br />
critical for metastatic colonization, i.e. the initial expansion of cancer<br />
cells at the secondary site. Second, we find stromal niche signals to<br />
be crucial for this process. This niche is required to promote Wnt<br />
signaling in infiltrating cancer stem cells and thereby this pathway<br />
plays an essential role in metastatic colonization. We suggest that<br />
interfering with this stromal support may represent a novel treatment<br />
strategy against metastatic disease.<br />
BS1-2<br />
Reactive Stroma as Therapeutic Targets in <strong>Breast</strong> <strong>Cancer</strong> Bone<br />
Metastasis<br />
Kang Y. Princeton University, Princeton, NJ<br />
Metastasis represents the most devastating stage of cancer<br />
progression. Bone metastasis is a frequent occurrence in breast cancer,<br />
affecting more than 70% of late stage cancer patients. Discovering<br />
bone metastasis genes that are clinically relevant and functionally<br />
important are critical for the development of novel therapeutics<br />
for high-risk breast cancer patients. We apply a multidisciplinary<br />
approach to analyze the molecular basis of breast cancer bone<br />
metastasis, combining functional genomics tools with animal models<br />
and clinical analysis of cancer metastasis. Candidate bone metastasis<br />
genes were identified from gene expression profiling of highly bone<br />
metastatic cells derived after in vivo selection in animal models.<br />
Functional characterization of these genes revealed their novel role<br />
in mediating tumor-stromal interactions essential for the formation of<br />
osteolytic bone metastasis. We discovered a novel metalloproteaseinitiated,<br />
EGFR-dependent paracrine signaling cascade among tumor<br />
cells, osteoblasts and osteoclasts that promotes the maturation of<br />
bone-degrading osteoclasts and formation of osteolytic lesions. Using<br />
in vivo imaging technology, we showed that TGFbis released from<br />
bone matrix upon bone destruction, and signals to breast cancer to<br />
further enhance their malignancy in developing bone metastasis. We<br />
furthered identified Jagged1 as a TGFb target genes in tumor cells that<br />
engaged bone stromal cells through the activation of Notch signaling<br />
to provide a positive feedback to promote tumor growth and to activate<br />
osteoclast differentiation. More recently, we identified osteoclastderived<br />
miRNAs as biomarkers and therapeutic targets of osteolytic<br />
bone metastasis. Importantly, pharmaceutical inhibitors against<br />
EGFR, TGFb and Notch signaling pathways and miRNAs blocking<br />
osteoclast differentiation significantly reduce the development of<br />
bone metastasis, suggesting novel avenues for clinical management<br />
of skeletal complications of breast cancer.<br />
MS1-1<br />
Targeting PI3K<br />
Cantley L. Beth Israel Deaconess Medical Center<br />
Targeting PI3K<br />
Lewis C. Cantley<br />
Beth Israel Deaconess Medical Center and Harvard Medical School,<br />
Boston, MA USA<br />
Phosphoinositide 3-Kinase (PI3K) is a central enzyme in a signaling<br />
pathway that mediates cellular responses to growth factors. The<br />
signaling pathway downstream of PI3K is highly conserved from<br />
worms and flies to humans and genetic analysis of the pathway<br />
has revealed a conserved role in regulating glucose metabolism<br />
and cell growth. Mutational events that lead to hyperactivation of<br />
the PI3K pathway result in hamartoma syndromes and cancers.<br />
Activating mutations in PIK3CA, encoding the p110alpha catalytic<br />
subunit of PI3K (PIK3CA) or inactivating mutations in PTEN, a<br />
phosphoinositide 3-phosphatases that reverses the effects of PI3K,<br />
are among the most common events in solid tumors, especially breast<br />
cancers. Drugs that target PI3K are in clinical trials for a variety of<br />
cancers. It is likely that PI3K pathway inhibitors will need to be<br />
combined with other drugs to be broadly effective. We have employed<br />
genetically engineered mouse models that develop cancers due to<br />
mutations in genes in the PI3K pathway and are using these models<br />
to explore the efficacy of PI3K pathway inhibitors as single agents or<br />
in combination with other drugs. We are also interrogating the role of<br />
PI3K in the growth and survival of Brca1/p53 mutant breast cancers.<br />
The role of PI3K inhibitors for treating cancers in these mouse models<br />
and in human trials will be discussed.<br />
MS1-3<br />
Clinical Development of mTOR Inhibitors in <strong>Breast</strong> <strong>Cancer</strong><br />
André F. Gustave Roussy Institute<br />
mTOR is a serine/threonine kinase involved in cancer cell metabolism<br />
and protein synthesis. mTOR induces phosphorylation of estrogen<br />
receptor and resistance to endocrine therapy in preclinical models.<br />
Based on this rationale, clinical trials have evaluated whether first<br />
generation of mTOR inhibitors could reverse resistance to endocrine<br />
therapy. Two randomized trials, including one registration trial,<br />
have reported that everolimus improves progression-free survival<br />
in patients resistant to non-steroidal aromatase inhibitors. These<br />
data are consistent with a phase II randomized trial performed in<br />
the neoadjuvant setting. One large phase III trial performed with<br />
temsirolimus failed, mainly due to dose intensity of the drug and<br />
patient population. Overall, these finding suggest that rapalogs could<br />
reverse resistance to endocrine therapy. These data open several<br />
avenues in the field of breast cancer.<br />
First, two trials are starting that evaluate the efficacy of everolimus in<br />
the adjuvant setting. These trials evaluate everolimus either frontline<br />
or after 2-3 years of endocrine therapy.<br />
Second, rapalogs are being tested in other breast cancer subtypes<br />
including Her2-overexpressing breast cancers and triple negative<br />
breast cancers. Indeed, mTOR has been shown to be involved<br />
in trastuzumab resistance in preclinical studies. Early trials have<br />
suggested that mTOR inhibition could reverse trastuzumab resistance.<br />
mTOR inhibitors have also been shown to synergize with cisplatin in<br />
preclinical models, and this combination is currently being evaluated<br />
in a phase II randomized trial.<br />
Finally, several mechanisms of resistance to rapalogs have been<br />
identified. This includes positive feedback loops and lack of optimal<br />
bioactivity on p4EBP1. Rapalogs indeed mediate activating feedback<br />
loops that in turn induce a paradoxical activation of kinase pathways.<br />
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<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Based on this observation, several trials have started that evaluate the<br />
combination between Rapalogs and IGF1R inhibitors. Preliminary<br />
results from phase I trial suggest that this combination is active in<br />
ER+/highly proliferative disease. Although they induce optimal<br />
inhibition of pS6K, several studies have reported that rapalogs could<br />
be suboptimal to inhibit p4EBP1, a protein downstream of mTORC1.<br />
4EBP1 is involved in protein synthesis. Second generation mTOR<br />
inhibitors (mTORC1/C2 inhibitors) present an increased bioactivity<br />
on 4EBP1, in addition to avoid mTORC2-mediated feedback loop.<br />
This second generation mTOR inhibitor is being tested in early<br />
phase trials.<br />
Overall, rapalogs have opened the path for the development of mTOR<br />
inhibitors in the field of breast cancer. This will further improve<br />
outcome by exploring new indications and by developing strategies<br />
to reverse resistance. Finally, the development of mTOR inhibitors<br />
will dramatically increase our knowledge on the role of metabolism<br />
and protein translation in cancer progression.<br />
BL-1<br />
Brinker Award Lecture: How Does HER2 Contribute to <strong>Breast</strong><br />
<strong>Cancer</strong> Progression?<br />
Yarden Y. Weizmann Institute, Rehovot, Israel<br />
HER2 (also called NEU and ERBB2), a receptor tyrosine kinase<br />
frequently overexpressed in breast cancer, is one of the most<br />
oncogenic kinases of the human kinome. Multiple mechanisms<br />
contribute to the transforming potential of HER2. Although HER2 is<br />
structurally similar to the receptors for EGF (EGFR) and neuregulins<br />
(ERBB3 and ERBB4), the cytoplasm-facing kinase domain of HER2<br />
is characterized by relatively high basal activity, and unlike the<br />
ectodomains of EGFR and ERBB3/ERBB4, HER2?s extracellular<br />
part cannot bind any known growth factor with high affinity.<br />
Nevertheless, HER2 acts as the preferred partner of the other three<br />
receptors, and the heterodimers it forms display not only high kinase<br />
activity but also increased binding affinity toward a broad spectrum of<br />
growth factors. In addition, HER2-containing heterodimers typically<br />
interact with a relatively wide set of cytoplasmic effector proteins,<br />
such as the phosphoinositol 3-kinase and SHC, which recruits the<br />
mitogen-activated protein kinase pathway. The collective outcome<br />
of these functional features translates to prolonged and enhanced<br />
signaling capacity.<br />
One way to comprehend HER2 is offered by the evolutionary<br />
history of the family of receptor tyrosine kinases. Accordingly, HER2<br />
and EGFR share a common precursor, but genome duplications<br />
denied a growth factor from HER2, and in parallel inactivated<br />
the catalytic function of ERBB3, to achieve a layered signaling<br />
network, whose autonomy and steady state are maintained by a<br />
dense web of feedback regulatory loops. In line with this scenario,<br />
HER2 cannot signal in isolation, but requires an activating growth<br />
factor receptor. Once recruited, HER2 enables evasion of negative<br />
feedback regulation, such as receptor ubiquitination and intracellular<br />
degradation: Unlike homodimers of EGFRs, which are targeted<br />
to lysosomes for degradation, HER2-containing heterodimers are<br />
targeted to a recycling pathway that replenishes the surface pool of<br />
HER2 molecules and further prolongs signaling.<br />
In-depth understanding of HER2?s oncogenic functions<br />
holds promise for therapy of a fraction of breast cancer patients. For<br />
example, the relatively high basal activation of the kinase domain<br />
means that HER2 relies on a chaperone called HSP90, hence blocking<br />
HSP90 might retard HER2-overexpressing tumors. Likewise, it is<br />
predictable that agents able to block either recycling of HER2 or its<br />
ability to form heterodimers, would curtail tumor growth.<br />
BL-2<br />
Brinker Award Lecture: Older Women and <strong>Breast</strong> <strong>Cancer</strong>:<br />
Challenges and Opportunities<br />
Muss HB. University of North Carolina, Chapel Hill, NC; , Chapel<br />
Hill, NC<br />
In the United States and other developed nations breast cancer<br />
incidence and mortality rates rise dramatically with increasing age.<br />
This fact, coupled with the aging of the U.S population is leading to<br />
a tsunami of older women with breast cancer. Most oncologists lack<br />
training in geriatrics and the frequent comorbidities in older patients<br />
along with a new diagnosis of breast cancer makes treatment selection<br />
challenging. Little data from clinical trials are available to guide<br />
physicians in treatment selection and a paucity of geriatricians makes<br />
it difficult to develop comprehensive treatment plans for many older<br />
patients. Newer tools that are validated, fast, and user-friendly are now<br />
available to help busy clinicians do meaningful geriatric assessments<br />
which are necessary for evaluating the medical, functional, cognitive,<br />
psychological, and social status of older patients. Such tools can<br />
be used to accurately estimate survival in older patients and more<br />
recently to predict chemotherapy related toxicity. For older patients,<br />
maintenance of independent living and cognitive function are their<br />
major goals and such preferences must be taken into consideration<br />
when planning treatment. Older women, like younger women, are<br />
interested in body image and when possible should be offered breast<br />
preservation with lumpectomy and radiation. In some older women<br />
treated with lumpectomy and adjuvant endocrine therapy for small<br />
tumors that are hormone-receptor positive and lower grade, breast<br />
radiation may be omitted with only a small increase in the risk of<br />
in-breast recurrence. The majority of older patients with early stage<br />
breast cancer have hormone receptor positive, HER-2 negative breast<br />
cancers and are excellent candidates for endocrine therapy. The<br />
major issue in these patients is defining the potential added value<br />
of chemotherapy. Elders with HER-2 positive tumors may be good<br />
candidates for chemotherapy and trastuzumab, while for many with<br />
“triple-negative” lesions, chemotherapy is the option of choice. Older<br />
patients with metastatic breast cancer whose tumors have progressed<br />
after endocrine therapy can be considered for palliative chemotherapy<br />
and many single agent regimens are well tolerated in this setting. In<br />
these patients, making sure they are offered “structured” palliative<br />
care as part of their treatment program is integral to maximizing<br />
quality of life and possibly even prolonging survival. Lastly, eligible<br />
elders should be offered clinical trials participation. Although getting<br />
elders on trials remains a challenge, it’s essential we work diligently<br />
on recruitment so as to obtain meaningful data on outcomes and<br />
toxicities of newer treatment regimens. Opportunities for trials of all<br />
types abound, not only for testing new treatments, but for defining<br />
interventions that minimize toxicity and loss of function. All of us<br />
in oncology will need to learn how to care for older cancer patients<br />
to provide them with optimal treatment.<br />
PL-2<br />
Estrogen Receptor Cistrome: Implications for <strong>Breast</strong> <strong>Cancer</strong><br />
Carroll JS. <strong>Cancer</strong> Research UK; University of Cambridge<br />
Estrogen Receptor (ER) is the defining feature of luminal breast<br />
cancers, where is functions as a transcription factor. The traditional<br />
view of ER getting recruited to promoters of target genes is too<br />
simplistic. The recent discovery of ER-DNA interaction regions from<br />
ER+ breast cancer cell lines has revealed that ER rarely associates<br />
with promoter regions of target genes and instead associates with<br />
enhancer elements significant distances from the target genes. The<br />
genomic mapping of ER binding events also revealed the enrichment<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
86s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Invited Speakers<br />
of DNA motifs for Forkhead factors. The Forkhead protein FOXA1<br />
(HNF3α) was subsequently shown to bind to ∼half of the ER binding<br />
events in the genome and was required for ER to maintain interaction<br />
with DNA. We have extended on these findings to map ER binding<br />
events in primary breast cancers and distant metastases. We find<br />
context dependent ER cis-regulatory elements (cistromes) that give<br />
insight into underlying transcriptional networks. These differential<br />
ER binding profiles correlate with clinical response in ER+ breast<br />
cancers. We experimentally explore the binding dynamics between<br />
drug sensitive and resistant contexts and identify properties that<br />
govern ER binding differences. These data suggest that ER-DNA<br />
interactions are dynamic and can be modulated by changes in FOXA1.<br />
We are currently exploring mechanisms that mediate FOXA1-DNA<br />
interactions, in order to better understand ER transcriptional activity<br />
in breast cancer biology.<br />
MS2-1<br />
Genetics and Epidemiology of Mammographic <strong>Breast</strong> Density<br />
Vachon CMM. Mayo Clinic College of Medicine<br />
Differences in the relative amounts of fat, connective and epithelial<br />
tissues in the breast lead to variations in mammographic appearance.<br />
<strong>Breast</strong> density is a measure that reflects this variation in tissue<br />
composition and is most commonly assessed as the absolute amount<br />
or proportion of the mammogram comprised of fibroglandular or<br />
non-fatty tissue. <strong>Breast</strong> density has been characterized using both<br />
qualitative and quantitative estimates. The most widely used clinical<br />
density measure is the American College of Radiology’s <strong>Breast</strong><br />
Imaging Reporting and Data System (BI-RADS) four-category<br />
tissue composition measure. Quantitative estimates include userassisted<br />
thresholding methods, and more recently, automated area and<br />
volumetric density measures. Increased breast density is common,<br />
with 26-32% of women in the general population having dense tissue<br />
occupying over half of their breast. <strong>Breast</strong> density has been shown to<br />
be a strong risk factor for breast cancer at any age of mammography,<br />
in both Caucasian and non-Caucasian populations, and years prior to<br />
the breast cancer. Women with over 50% of their breast comprised of<br />
dense tissue have a 3-5 fold increased risk of breast cancer relative<br />
to those with low or no density. Further, up to one third of all breast<br />
cancers are found in women with density over 50%.<br />
<strong>Breast</strong> density decreases with age, with the greatest declines seen<br />
between ages 45-55. This decline has been hypothesized to reflect<br />
the reduction of hormones and involution of the breast tissue with<br />
onset of menopause. Several risk factors demonstrate associations<br />
with percentage breast density that are consistent with their breast<br />
cancer associations, suggesting these factors may potentially affect<br />
breast cancer risk through their influence on breast density. Positive<br />
associations are seen between breast density and nulliparity, late<br />
age at first birth, never having breast fed, postmenopausal hormone<br />
use (particularly combination therapy), and alcohol intake. Inverse<br />
associations are seen with tamoxifen use as well as body mass index<br />
(BMI), but BMI and breast density have been shown to be independent<br />
risk factors for breast cancer, and likely act through different pathways<br />
on risk. Taken together, the epidemiologic risk factors account for<br />
only 20 - 30% of the variation in breast density in the population.<br />
Genetics also contribute to the variability in breast density. Twin and<br />
family studies have shown that percentage breast density is highly<br />
heritable, and that inherited factors explain between 30-60% of the<br />
variance. Some of these genetic factors are shared between breast<br />
density and breast cancer. Of the established breast cancer loci, single<br />
nucleotide polymorphisms in LSP1, ZNF365, ESR1 and RAD51L1,<br />
are also associated with breast density. Additional genetic loci for<br />
breast density (including a variant at 12q24) have been validated<br />
in large consortia. However, the loci identified to date together<br />
account for less than 5% of the variance in breast density. Identifying<br />
additional genetic loci for breast density will not only help inform the<br />
biology of breast density but also contribute to understanding breast<br />
cancer and risk prediction efforts.<br />
MS2-2<br />
<strong>Breast</strong> Density: Clinical Implications<br />
Boyd NF. Ontario <strong>Cancer</strong> Institute, Toronto, ON, Canada<br />
Potential clinical applications of mammographic density include:<br />
1) the prediction of outcome of breast disease, 2) mammographic<br />
screening, 3) research and practice of cancer prevention, and 4)<br />
improved prediction of risk in individuals.<br />
1) <strong>Breast</strong> cancer characteristics and clinical outcomes. Extensive<br />
percent mammographic density (PMD) is associated with increased<br />
risks for the development of most of the histological non-obligate<br />
precursors of breast cancer, including ductal carcinoma in situ (DCIS),<br />
atypical hyperplasia, hyperplasia without atypia, and columnar cell<br />
lesions (CLLs). PMD is associated with an increased risk of both<br />
ER+ and ER- tumors, and with larger tumors of higher histological<br />
grade. Risk of contralateral second breast cancer is also increased by<br />
extensive PMD. However, among women with breast cancer, risk<br />
of death from the disease does not appear to be increased by PMD.<br />
2) Mammographic screening. Women with extensive PMD are<br />
both at higher risk of breast cancer and at greater risk that cancer<br />
will not be detected by mammography. This heterogeneity is not<br />
currently recognized in the design of screening programs. Women<br />
with extensive PMD, might benefit from screening more often than<br />
once every 2 to 3 years and with modalities such as MR or UST in<br />
addition to mammography. Conversely, for women with radiolucent<br />
breast tissue and a negative screening mammogram, in whom risk is<br />
lower and detection easier, re-screening less frequently than every<br />
2 to 3 years with mammography might be safe. Research into these<br />
issues is required.<br />
3) <strong>Breast</strong> cancer prevention trials. Unlike most other risk factors for<br />
breast cancer, PMD can be changed), suggesting that it might be used<br />
as a surrogate marker in clinical trials of breast cancer prevention.<br />
Clinical trials of breast cancer prevention require large numbers of<br />
subjects and long periods of observation and thus are expensive.<br />
Smaller, shorter, and less expensive trials of prevention strategies<br />
would be possible if there were a surrogate marker that allow the<br />
identification of interventions that would reduce breast cancer<br />
incidence. To be used as a surrogate for breast cancer, a biomarker<br />
such as PMD should meet the following criteria: (a) the marker should<br />
be associated with risk of breast cancer, (b) the marker should be<br />
changed by the intervention, and (c) the change in the marker should<br />
mediate the effect of the intervention on breast cancer risk. The extent<br />
to which these criteria can currently be met will be discussed.<br />
4) Improved risk prediction. PMD is inversely associated with age,<br />
while breast cancer incidence increases with age. We used data from<br />
3250 healthy women aged 15-80 to estimate cumulative breast density<br />
(CBD) in the population, which increases with age, and compared this<br />
with age-specific incidence of breast cancer in Canada. Log CBD and<br />
log breast cancer incidence had a linear association (r=0.98; p=6.0<br />
E-9) that was unchanged by adjustment for log age (r= 0.97; p=8.0 E<br />
-7). Log CBD alone was a better predictor of age-specific log breast<br />
cancer incidence (r2=0.97) than age alone (r2=0.88). The observed<br />
strong association between CBD and breast cancer incidence suggest<br />
that the factors responsible for CBD may be causally related to the<br />
age-specific incidence of breast cancer.<br />
www.aacrjournals.org 87s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
PL-3<br />
<strong>Breast</strong> Radiotherapy: Fractionation and Other Fashions<br />
Yarnold J. Institute of <strong>Cancer</strong> Research & Royal Marsden NHS<br />
Foundation Trust, Sutton, United Kingdom<br />
Hypofractionation, defined as the use of fraction sizes >2.0 Gy,<br />
requires a reduction in the total dose delivered in 1.8 - 2.0 Gy<br />
fractions that takes account of the greater effect per Gy of larger<br />
fractional doses. Generations of radiation oncologists have been<br />
taught that small (≤2.0 Gy) daily fractions are always gentler on the<br />
dose-limiting healthy tissues than on the cancer, thereby optimising<br />
clinical benefit. This relationship applies at many tumour sites, but<br />
breast cancer is different. Well-designed randomised trials involving<br />
>7000 women confirm that there are no advantages to using ≤2.0<br />
Gy fractions, which spare breast cancer as much as the normal<br />
tissues. The limits of hypofractionation for whole breast/chest wall<br />
radiotherapy are under evaluation in the UK FAST Forward trial,<br />
testing 2 dose levels of a 5-fraction regimen given in 1 week against<br />
the 3-week UK standard. Hypofractionation can also be employed to<br />
match dose intensity more effectively to the spatial pattern of tumour<br />
relapse by modulating fraction size across the breast in preference<br />
to fraction number, an approach under test in the UK IMPORT<br />
HIGH trial. In marked contrast to conservative attitudes towards<br />
whole breast hypofractionation, there has been a dash to accelerated<br />
hypofractionation schedules among practitioners of partial breast<br />
radiotherapy.<br />
The mean fractionation sensitivity of breast cancer, expressed as an<br />
α/β value, is approximately 3 Gy. The distribution around this point<br />
estimate could be wide or narrow; we don’t know. The fractionation<br />
sensitivities of early responding normal tissues and cancers are<br />
postulated to reflect the responses of a limited number of target<br />
stem cell populations. Late-responding normal tissues are more<br />
complex in that multiple parenchymal and stromal cell lineages and<br />
interactions need to be considered. Despite potential complexity, a<br />
strong association between the proliferative indices of normal tissue<br />
parenchymal cells and fractionation sensitivity support the notion that<br />
the latter has a cellular basis, justifying a focus on classical cellular<br />
recovery and DNA double strand break (DSB) repair. Differences<br />
between healthy and malignant tissues in how they handle DSB are<br />
but one of several potential modulators of fractionation sensitivity.<br />
The processes are likely to be strongly affected by mutational and<br />
epigenetic alternations in tumours, but they foretell a future when<br />
predictive biomarkers replace historical dogma in determining<br />
fractionation regimens for cancer patients.<br />
BS3-2<br />
Molecular Imaging of <strong>Breast</strong> <strong>Cancer</strong>: Visualizing In Vivo <strong>Breast</strong><br />
<strong>Cancer</strong> Biology<br />
Mankoff DA, Chodosh LA. Perelman School of Medicine, University<br />
of Pennsylvania, Philadelphia, PA<br />
The ability to measure biochemical and molecular processes underlies<br />
progress in breast cancer biology and treatment. These assays have<br />
traditionally been performed by analysis of cell culture or tissue<br />
samples. More recently, functional and molecular imaging allows<br />
in vivo assay of biochemistry and molecular biology that is highly<br />
complementary to tissue-based assay. Molecular imaging can serve<br />
and number of roles, from characterization of pre-clinical models, to<br />
testing the ability of novel drugs to interact with their intended targets,<br />
to characterizing entire burden of disease for patients with breast<br />
cancer, to helping direct therapeutic choices and assign their efficacy.<br />
This talk will review basic principals of molecular imaging, with an<br />
emphasis on those methods of greatest translational potential. The<br />
session will discuss the use of pre-clinical models of breast disease to<br />
help test and validate new molecular imaging methods, and in turn,<br />
the use of molecular imaging to characterize the disease process in<br />
the animal models. The session will then review the current state of<br />
molecular imaging in breast cancer patients, including methods in<br />
routine clinical use, those undergoing advanced clinical trials, and<br />
those in early-phase testing.<br />
The session is designed for a broad audience, ranging from breast<br />
cancer translational scientists to practicing physicians caring for<br />
breast cancer patients.<br />
References<br />
1. Vernon AE, Bakewell SJ, Chodosh LA. Deciphering the molecular<br />
basis of breast cancer metastasis with mouse models. Rev Endocr<br />
Metab Disord. 2007 Sep;8(3):199-213.<br />
2. Mankoff DA. Molecular imaging as a tool for translating breast<br />
cancer science. <strong>Breast</strong> <strong>Cancer</strong> Res. 2008;10 Suppl 1:S3.<br />
3. Specht JM, Mankoff DA. Advances in molecular imaging for breast<br />
cancer detection and characterization. <strong>Breast</strong> <strong>Cancer</strong> Res. 2012 Mar<br />
16;14(2):206.<br />
MS3-3<br />
Navigating the Genome: Quandaries and Approaches to Dealing<br />
with Genomic Information<br />
Evans JP. University of North Carolina at Chapel Hill, Chapel Hill,<br />
NC<br />
Recent technological advances have made large-scale DNA<br />
sequencing, including whole genome sequencing, a practical reality.<br />
The ability to sequence tumor genomes as well as the germ-line<br />
genome of individuals holds considerable promise for the practice<br />
of oncology. Broad assessment of cancer risk in individuals,<br />
identification of those at extreme risk for cancer who might benefit<br />
from specific interventions and pharmacogenomic guidance regarding<br />
therapy are possible benefits of assessing an individual’s genome.<br />
Likewise, analysis of genomic information in tumors is poised to<br />
begin helping to guide highly specific treatment of cancer in an<br />
increasingly individualized manner.<br />
However, as the field of oncology begins to use genomic queries to<br />
assess patient risk, characterize disease and guide treatment, many<br />
challenges must be addressed. Purely technical issues include the<br />
suboptimal accuracy of current platforms for massively parallel<br />
sequencing, tumor heterogeneity and difficulties interpreting genomic<br />
risk information in a clinically relevant manner. Systemic challenges<br />
include how to interpret, store and present massive amounts of<br />
genomic data in the currently highly fragmented (and limited)<br />
electronic medical record. Finally, in the process of genome-scale<br />
sequencing vast numbers of incidental results are inevitably generated,<br />
which may have important ramifications for patients and providers<br />
but may be unwelcome. Such ethical, legal and social implications<br />
of whole genome sequencing raise significant questions about patient<br />
autonomy, the physician’s duty to warn and the laboratory’s duty to<br />
report a wide variety of highly heterogeneous genomic findings. In<br />
this presentation some of these salient issues and possible solutions<br />
will be explored.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
88s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 1<br />
S1-1<br />
Relative effectiveness of letrozole compared with tamoxifen for<br />
patients with lobular carcinoma in the BIG 1-98 trial.<br />
Metzger O, Giobbie-Hurder A, Mallon E, Viale G, Winer E,<br />
Thürlimann B, Gelber RD, Colleoni M, Ejlertsen B, Bonnefoi H,<br />
Coates AS, Goldhirsch A, Gusterson B. BIG 1-98 Collaborative<br />
Group, International <strong>Breast</strong> <strong>Cancer</strong> Study Group<br />
Background: Invasive lobular carcinoma (ILC) is mostly hormone<br />
receptor-positive (ER+) and associated with higher risk of late<br />
relapse (> 5 years after diagnosis) when compared to invasive ductal<br />
carcinoma (IDC). In this analysis we investigate the magnitude of<br />
benefit of endocrine treatment (tamoxifen [tam] or letrozole [let])<br />
and the patterns of relapse over time in patients with ILC (classical<br />
subtype) or IDC enrolled in the monotherapy arms of BIG 1-98 study<br />
(12-year update).<br />
Material and methods: BIG 1-98 was a randomized, phase III study<br />
that compared five years of tam or let (monotherapy arms), or their<br />
sequences in post-menopausal women with ER+ early BC. There were<br />
4922 patients enrolled in the monotherapy arms of BIG 1-98. This<br />
analysis includes patients who had centrally-reviewed histology data<br />
(n = 4080) and classified as IDC and ILC (n = 3660). Centrally-defined<br />
ER, PgR, Ki-67 were used to defined ER+ subtypes (n = 2923). ER+<br />
subtypes were defined as Luminal A (ER+ and/or PR+ HER2- and<br />
Ki6799% TAM). With mean 7.1 woman-years<br />
follow-up (30,000 w-y in years 5-9, 16,000 in years 10-14, 2000 later),<br />
1328 recurrences were reported (900 in years 5-9, 379 in years 10-14).<br />
Recurrence was significantly lower with10 than 5 years TAM (Table:<br />
logrank 2p=0.002, rate ratio (RR)=0.90 se 0.06 in years 5-9 and 0.75<br />
se 0.08 in years 10+). So were both BCM (2p=0.01, RR=0.97 se 0.10<br />
in years 5-9 and 0.71 se 0.09 in years 10+) and all-cause mortality<br />
(2p=0.01, with no increase in non-BCM). Proportional risk reductions<br />
were homogeneous by country, age and stage. Kaplan-Meier risks<br />
in years 5-14 (K-M) were: recurrence 21.4 vs 25.1%, BCM 12.2 vs<br />
15.0%. Uterine cancer K-Ms in those randomized at age 50+ were:<br />
incidence 2.6 vs 1.6% (2p=0.08), mortality 0.2 vs 0.2%. In premenopausal<br />
women (where AIs are not an alternative to TAM) there<br />
was no apparent excess of uterine cancer.<br />
Discussion: Compared with just 5 years TAM, continuing TAM to<br />
year 10 safely protects further against recurrence and, particularly<br />
during the second decade, BCM. Combining results from ATLAS<br />
and the EBCTCG meta-analyses of 5 years TAM vs none (both had<br />
∼80% compliance), in a hypothetical trial of 10 vs 0 years TAM with<br />
∼80% compliance, 15-year BCM would be reduced by at least onethird.<br />
Hence, full compliance with 10 years TAM would yield even<br />
greater benefit (Table). Further follow-up of ATLAS will assess more<br />
reliably the apparently substantial mortality reduction in the second<br />
decade after diagnosis.<br />
ER+ disease: RR [95% CI] by time period from diagnosis for 5v0 years TAM in EBCTCG<br />
(n=10645, 80% complied); 10v5 years TAM in ATLAS (n=6846, ∼80% complied); and 10v0 years<br />
TAM (hypothetical)<br />
Time from<br />
diagnosis<br />
EBCTCG 5v0y<br />
TAM: ∼80%<br />
comply<br />
Product of trial RRs:<br />
ATLAS 10v5y TAM:<br />
effect of 10v0 y TAM<br />
∼80% comply<br />
if ∼80% comply<br />
RR for effect of<br />
10v0 y TAM if all<br />
comply**<br />
Recurrence<br />
0-4y 0.53[0.48-0.57]¢ 1 0.53[0.48-0.57]¢ 0.41<br />
5-9y 0.68[0.60-0.78]¢ 0.90[0.78-1.02] 0.61[0.51-0.73]¢ 0.52<br />
10+ 0.94[0.79-1.12] 0.75[0.62-0.90]* 0.70[0.54-0.91]* 0.63<br />
BCM<br />
0-4y 0.71[0.62-0.80]¢ 1 0.71 [0.62-0.81]¢ 0.64<br />
5-9y 0.66[0.58-0.75]¢ 0.97[0.79-1.18] 0.64 [0.50-0.82]† 0.55<br />
10+ 0.73[0.62-0.86]† 0.71[0.58-0.88]§ 0.52 [0.40-0.68]¢ 0.40<br />
**Estimated gain if all comply=1.25x gain if ∼80% comply. *2p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
S1-3<br />
DISCUSSANT<br />
William E. Barlow, PhD; SWOG Statistical Center; Fred Hutchinson<br />
<strong>Cancer</strong> Research Center; Seattle WA<br />
S1-4<br />
Final analysis of overall survival for the Phase III CONFIRM<br />
trial: fulvestrant 500 mg versus 250 mg<br />
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN,<br />
Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR,<br />
Pendergrass K, Garnett S, Rukazenkov Y, Martin M. Hospital of<br />
Prato, Prato, Italy; Centre Hospitalier Universitaire Sart Tilman,<br />
Liège, Belgium; First Faculty of Medicine of Charles University,<br />
Prague, Czech Republic; Instituto Nacional del Cáncer, <strong>San</strong>tiago,<br />
Chile; Dnipropetrovsk Municipal Clinical Hospital, Dnipropetrovsk,<br />
Ukraine; Republican Clinical Oncological Center, Kazan, Russian<br />
Federation; AZ Klina, Brasschaat, Belgium; Hospital Nossa Senhora<br />
da Conceição, Porto Alegre, Brazil; Medical Radiological Science<br />
Center, Obninsk, Russian Federation; Russian <strong>Cancer</strong> Research<br />
Centre, Moscow, Russian Federation; Kansas City <strong>Cancer</strong> Center,<br />
Kansas City; AstraZeneca Pharmaceuticals, Macclesfield, United<br />
Kingdom; Hospital Universitario Gregorio Maranon, Madrid, Spain<br />
Background<br />
The COmparisoN of Faslodex In Recurrent or Metastatic breast<br />
cancer (CONFIRM) trial (NCT00099437) compared fulvestrant 500<br />
mg with fulvestrant 250 mg in postmenopausal women with locally<br />
advanced or metastatic estrogen receptor (ER)-positive breast cancer<br />
who had recurred or progressed following prior endocrine therapy.<br />
Fulvestrant 500 mg was associated with a statistically significant<br />
increase in progression-free survival compared with fulvestrant 250<br />
mg (Di Leo A et al. J Clin Oncol 2010; 28: 4594-4600). At the time of<br />
the primary analysis approximately 50% of patients had died. Median<br />
overall survival was 25.1 months and 22.8 months for fulvestrant 500<br />
mg and 250 mg, respectively (hazard ratio [HR] 0.84; 95% confidence<br />
interval [CI] 0.69, 1.03; p=0.091). A follow-up analysis of overall<br />
survival was subsequently planned for when 75% of patients had died<br />
and the results are presented here.<br />
Methods<br />
CONFIRM was a randomized, double-blind, parallel-group,<br />
multicenter, Phase III study. Patients were randomized 1:1 to either<br />
fulvestrant 500 mg (500 mg i.m. on Days 0, 14 and 28 and every 28<br />
days thereafter) or fulvestrant 250 mg (250 mg i.m. every 28 days).<br />
After the primary analysis, patients on fulvestrant 250 mg were<br />
permitted to switch to 500 mg and all patients were followed up<br />
for overall survival, regardless of treatment discontinuation, unless<br />
consent was withdrawn. Overall survival was analyzed using an<br />
unadjusted log-rank test. No adjustments were made for multiplicity.<br />
Serious adverse events (SAEs) were also reported.<br />
Results<br />
In total, 736 women (median age 61.0 years) were randomized<br />
between February 2005 and August 2007 from 128 centers in 17<br />
countries (fulvestrant 500 mg: n=362; fulvestrant 250 mg: n=374).<br />
At time of follow-up analysis, 63 (9.0%) patients were lost to followup,<br />
16 (2.2%) patients had withdrawn consent, 103 (14.0%) patients<br />
were still ongoing (21 [2.9%] on treatment and 82 [11.1%] not on<br />
treatment), and 554 (75.3%) patients had died. Eight (2.1%) patients<br />
crossed over from fulvestrant 250 mg to 500 mg. Median overall<br />
survival was 26.4 months for fulvestrant 500 mg and 22.3 months for<br />
fulvestrant 250 mg (HR 0.81; 95% CI, 0.69, 0.96; nominal p=0.016).<br />
During the treatment period, a total of 32 (8.9%) patients had at<br />
least one SAE in the fulvestrant 500 mg and 25 (6.7%) patients in<br />
the fulvestrant 250 mg groups, and SAEs that were causally related<br />
to study treatment were reported for 6 (1.7%) and 3 (0.8%) patients,<br />
respectively. SAEs with an outcome of death were reported for 5<br />
(1.4%) and 6 (1.6%) patients, respectively, during the treatment<br />
period. Overall, there were no clinically important differences in the<br />
profiles of SAEs between the treatment groups and no clustering of<br />
SAEs could be detected in either treatment group.<br />
Conclusions<br />
Overall survival data from CONFIRM demonstrate that, in patients<br />
with locally advanced or metastatic ER positive breast cancer,<br />
fulvestrant 500 mg is associated with a clinically relevant 4.1 month<br />
difference in median overall survival and 19% reduction in risk of<br />
death compared with fulvestrant 250 mg. There were no new safety<br />
concerns associated with the use of fulvestrant 500 mg.<br />
S1-5<br />
PIK3CA mutations are linked to PgR expression: a Tamoxifen<br />
Exemestane Adjuvant Multinational (TEAM) pathology study.<br />
Sabine VS, Crozier C, Drake C, Piper T, van de Velde CJH, Hasenburg<br />
A, Kieback DG, Markopoulos C, Dirix L, Seynaeve C, Rea D, Bartlett<br />
JMS. Ontario Institute for <strong>Cancer</strong> Research, Toronto, ON, Canada;<br />
University of Edinburgh <strong>Cancer</strong> Research Centre, Institute of Genetics<br />
& Molecular Medicine, Edinburgh, Scotland, United Kingdom;<br />
Leiden University Medical Center, Leiden, Netherlands; University<br />
Hospital, Freiburg, Germany; Elblandklinikum, Riesa, Germany;<br />
Athens University Medical School, Athens, Greece; St. Augustinus<br />
Hospital, Antwerp, Belgium; Erasmus Medical Center-Daniel den<br />
Hoed, Rotterdam, United Kingdom; University of Birmingham,<br />
Birmingham, United Kingdom<br />
Background: PIK3CA is mutated in about 26% of breast cancers<br />
(BC) and is the most frequently mutated gene in (BC). Almost 95% of<br />
mutations occur in exons 9 (E9) or 20 (E20). PIK3CA mutations may<br />
be associated with increased survival in endocrine-treated patients;<br />
however the impact of mutations in E9 vs E20 is not clear. We assessed<br />
10 common PIK3CA mutations (95% of all mutations), in ER-positive<br />
(+ve) samples from the TEAM pathology study (n=∼4500), and<br />
determined the impact of PIK3CA mutations on survival. We report<br />
an interim analysis of 1969 TEAM cases.<br />
Methods: DNA was extracted from formalin-fixed paraffin embedded<br />
sections. Mutational analyses were performed on 25 mutations<br />
in 6 genes (PIK3CAx10, Akt1x1, KRASx5, HRASx3, NRASx2 &<br />
BRAFx4), using Sequenom MassArray.<br />
Results: Mutations were found in PIK3CA: 37.5%; Akt1: 3.3%;<br />
KRAS: 0.3%; and BRAF: 0.1% of cases. No mutations were found<br />
in HRAS or NRAS (n=1969). 90% of PIK3CA mutations were<br />
located in E9 and E20. Outcome data was available for 1958/1969<br />
patients. Patients whose tumours contained any PIK3CA mutations<br />
(n=739) were at lower risk of distant metastasis, Hazard ratio=0.86<br />
(0.67 – 1.11), when compared to those without PIK3CA mutations<br />
(n=1219); although this difference was not statistically significant<br />
(Cox Regression; p=0.24). PIK3CA mutations were significantly<br />
more frequent in HER2-negative (-ve) (39%) than in HER2+ve<br />
samples (25%) (p=0.001), without evidence that PIK3CA mutations<br />
differentially impacted outcome in HER2+ve vs HER2-ve patients.<br />
A positive correlation was demonstrated between PIK3CA mutations<br />
and PgR Allred score (p=0.002) but not ER Allred score (p=0.37).<br />
With increasing PgR Allred score increase there is an increased<br />
frequency of mutations in E20 but not E9 (Table 1).<br />
Discussion: This study indicates a higher percentage of PIK3CA<br />
mutations in ER+ve BC samples than previously demonstrated, either<br />
for BC as a whole or for ER+ve cases, suggesting that in ER+ve early<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
90s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 1<br />
BC, PIK3CA mutations are more common than previously reported.<br />
Furthermore, increased PIK3CA mutation frequency is significantly<br />
associated with increasing PgR Allred score and this appears solely<br />
due to increased numbers of patients with E20 mutations further<br />
complicating the analysis of the impact of PIK3CA mutations in BC.<br />
This may explain current uncertainty regarding the impact of PIK3CA<br />
mutations in E9 vs E20 with respect to clinical outcome. Whilst we<br />
were unable to show a significant impact on outcome in patients<br />
whose tumours contained PIK3CA mutations, we believe the complex<br />
relationship between PgR expression (good prognosis indicator) and<br />
PI3K mutations requires further exploration in the full dataset using<br />
interaction techniques adjusting for the impact of PgR on outcome.<br />
Mutational analysis and correlation with clinical outcome data for<br />
the remaining ∼2500 DNA samples, along with the existing data for<br />
1969 patients, will be presented.<br />
PIK3CA mutation:<br />
PgR Allred<br />
score<br />
# cases All 10 Exon9 Exon20 Others<br />
0 - 4 503 30% 14% 13% 3%<br />
5 & 6 502 38% 16% 20% 2%<br />
7 & 8 878 42% 14% 22% 5%<br />
Table 1: Analysis of 10 common PIK3CA mutations in TEAM pathology study by PgR Allred score.<br />
S1-6<br />
Results of a randomized phase 2 study of PD 0332991, a cyclindependent<br />
kinase (CDK) 4/6 inhibitor, in combination with<br />
letrozole vs letrozole alone for first-line treatment of ER+/HER2-<br />
advanced breast cancer (BC)<br />
Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl<br />
J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL,<br />
Breazna A, Kim ST, Randolph S, Slamon DJ. University of California,<br />
Los Angeles, Los Angeles, CA; Irish Cooperative Oncology Research<br />
Group, Dublin, Ireland; Orszagos Onkologiai Intezet, Budapest,<br />
Hungary; Szent Margit Korhaz, Budapest, Hungary; Dnipropetrovsk<br />
City Multiple-Discipline Clinical Hospital, Ukraine; Municipal<br />
Treatment-and-Prophylactic Institution “Donetsk City Oncological<br />
Dispensary”, Ukraine; Technical University of Munich, Germany;<br />
Comprehensive Blood and <strong>Cancer</strong> Center, Bakersfield, CA; Petz<br />
Aladar Megyei Oktato Korhaz, Gyor, Hungary; University Hospital<br />
Mainz, Mainz, Germany; Lviv State Oncologic Regional Treatment<br />
and Diagnostic Center, Ukraine; Comprehensive <strong>Cancer</strong> Centers<br />
of Nevada, Henderson, NV; Kyiv City Clinical Oncology Center,<br />
Ukraine; Pfizer Oncology, New York, NY; Pfizer Oncology, <strong>San</strong><br />
Diego, CA<br />
Background: PD 0332991, a selective inhibitor of CDK 4/6, prevents<br />
cellular DNA synthesis by blocking cell cycle progression. Preclinical<br />
studies in a BC cell line panel identified the luminal ER subtype,<br />
elevated expression of cyclin D1 and Rb protein, and reduced p16<br />
expression as being associated with sensitivity to PD 0332991 (Finn<br />
et al. 2009). Synergistic activity was also observed in vitro when<br />
combined with tamoxifen. After determination of the recommended<br />
phase 2 dose in combination with letrozole (letrozole 2.5 mg QD<br />
plus PD 0332991 125 mg QD on Schedule 3/1), a randomized phase<br />
2 study comparing letrozole alone (L) to letrozole plus PD 0332991<br />
(L+P) was initiated.<br />
Methods: The phase 2 portion of the study was designed as a twopart<br />
study; Part 1 enrolled post- menopausal women with ER+/<br />
HER2- advanced BC; Part 2 in addition to ER+/HER2- as eligibility<br />
criteria, screened for CCND1 amplification and/or loss of p16 by<br />
FISH. The primary endpoint is progression-free survival (PFS);<br />
secondary endpoints include response rate, overall survival, safety,<br />
and correlative biomarker studies. In both parts, post-menopausal<br />
women with ER+/HER2- advanced BC were randomized 1:1 to<br />
receive letrozole either with or without PD 0332991. Pts continue<br />
on assigned study treatment until disease progression, unacceptable<br />
toxicity, or consent withdrawal, and are followed for tumor<br />
assessments every 2 months.<br />
Results: 66 pts were randomized in Part 1 and 99 pts in Part 2.<br />
Preliminary results from Part 1 of this study have been previously<br />
reported (IMPAKT <strong>Breast</strong> <strong>Cancer</strong> Conference, <strong>Abstract</strong> #292,<br />
Finn et al. May 2012) demonstrating a significant improvement in<br />
median PFS in the L+P vs. L arm (HR=0.35; 95% CI, 0.17 to 0.72;<br />
p=0.006). With the additional 99 pts randomized in Part 2 (N=165),<br />
the statistically significant improvement in median PFS (26.2 vs. 7.5<br />
months, respectively) continues to be observed with a HR=0.32 (95%<br />
CI, 0.19 to 0.56) with p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
The primary objective was to compare progression-free survival<br />
(PFS) between treatment arms. Secondary objectives were overall<br />
survival, time to treatment failure, overall response rate, response<br />
duration, clinical benefit rate, and safety. In total, 344 patients (172<br />
in each treatment arm) were needed to detect a hazard ratio of 0.69<br />
(corresponding to a median PFS of 9 months in the ET arm and 13<br />
months in the ET+B arm) with α=0.05 and β=0.2. With an expected<br />
drop-out rate of 10%, 378 patients were to be included. The efficacy<br />
analysis is pre-planned after 270 events.<br />
Results: From 11/2007 to 8/2011, 380 patients were randomized in<br />
Spain and Germany to ET (n= 189) or ET+B (n=191), 342 patients<br />
received letrozole and 38 fulvestrant. Baseline characteristics were<br />
well balanced. Median age was 65 years (38-86) and 72% of patients<br />
had ECOG PS 0. Twelve patients (4%) entered the trial with locally<br />
advanced disease, 65% had measurable lesions, 63% had bone<br />
and 45% visceral metastasis. 76% of patients had both hormone<br />
receptor positive. 44% had adjuvant chemotherapy and 51% adjuvant<br />
endocrine therapy from which 36% of patients received adjuvant AI.<br />
Full safety data will be presented at ESMO this year. The main side<br />
effects (any grade, per patient, ET+B vs ET) were anemia 76% vs<br />
44%, p
December 4-8, 2012 <strong>Abstract</strong>s: General Session 1<br />
χ2: 7.97, p=0.005) versus RS (LR-χ2: 0.51, p=0.5) and IHC4 (LR-χ2:<br />
1.63, p=0.2). Similar comparative results of BCI, RS and IHC4 for<br />
late recurrence were observed for the other clinical endpoints.<br />
Discussion: This is the first large-scale clinical study to compare<br />
several multi-gene signatures for their prognostic strength to quantify<br />
late residual risk of recurrence after endocrine therapy. BCI, unlike<br />
IHC4 and RS, is a significant prognostic factor for late recurrence and<br />
enables the assessment of individual recurrence risk for ER+ patients<br />
recurrence-free after 5 years of endocrine therapy.<br />
S1-10<br />
Association between the 21-gene recurrence score (RS) and benefit<br />
from adjuvant paclitaxel (Pac) in node-positive (N+), ER-positive<br />
breast cancer patients (pts): Results from NSABP B-28<br />
Mamounas EP, Tang G, Paik S, Baehner FL, Liu Q, Jeong J-H, Kim<br />
S-R, Butler SM, Jamshidian F, Cherbavaz DB, Sing AP, Shak S,<br />
Julian TB, Lembersky BC, Wickerham DL, Costantino JP, Wolmark<br />
N. National Surgical Adjuvant <strong>Breast</strong> and Bowel Project Operations<br />
and Biostatistical Centers; Aultman Hospital; Graduate School<br />
of Public Health, University of Pittsburgh; Genomic Health, Inc.;<br />
Allegheny <strong>Cancer</strong> Center at Allegheny General Hospital; University<br />
of Pittsburgh <strong>Cancer</strong> Institute<br />
Background: The RS result predicts outcome in N- and N+, ER+<br />
pts treated with adjuvant endocrine therapy. RS also predicts benefit<br />
from adjuvant chemotherapy (CT) and pts with a high RS result<br />
receive most of the benefit. We evaluated the association between<br />
RS and paclitaxel (Pac) benefit in N+, ER+ pts from NSABP B-28.<br />
Methods: B-28 compared 4 cycles of doxorubicin/cyclophosphamide<br />
(AC) vs. AC followed by Pac x 4 (AC→Pac). Pts ≥50 yrs and those
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
the breast and lymph nodes (ypT0ypN0 or ypT0/isypN0) was better<br />
associated with improved EFS and OS compared to eradication of<br />
tumor from the breast alone (ypT0/is). Patients who achieved a pCR<br />
(ypT0/isypN0) had an improved EFS (HR=0.48) and OS (HR=0.36)<br />
compared to those who did not. pCR was uncommon in patients with<br />
low-grade hormone receptor-positive (HR+) tumors (7%) and more<br />
common in the following tumor subtypes: high-grade HR+ (16%),<br />
triple negative (34%), HR+ /HER2+ (30%), and hormone receptornegative<br />
(HR-)/HER2+ (50%). Patients with more aggressive tumor<br />
subtypes who achieved pCR had greater EFS compared to patients<br />
who did not achieve pCR as follows: HR+ high grade (HR=0.27),<br />
HR+ /HER2+ (HR=0.58), HR- /HER2+ (HR=0.25), and triple<br />
negative (HR=0.24). A trial level analysis on the relationship between<br />
pCR effect size and EFS did not show a correlation. Conclusions:<br />
Individual patients who attain a pCR, defined as either ypT0ypN0 or<br />
ypT0/isypN0, have a more favorable long-term outcome. The data<br />
show comparable EFS or OS regardless of the presence or absence<br />
of DCIS. For consistency, a standard pCR definition (ypT0ypN0 or<br />
ypT0/isypN0) should be used in future trials. Impact of pCR effect<br />
is limited to patients with HR+/grade 3, HR-/HER2-, and HER2+<br />
tumors. This meta-analysis did not establish the magnitude of increase<br />
in pCR rate needed to predict the superiority of one regimen over<br />
another in terms of EFS or OS. This may be due to low pCR rates<br />
and the heterogeneity of the patient population included in this<br />
meta-analysis. The absolute magnitude of improvement in pCR<br />
rate needed to impact long-term outcome may be greater than the<br />
observed difference in these trials and may vary according to breast<br />
cancer subtype.<br />
S2-1<br />
The role of sentinel lymph node surgery in patients presenting<br />
with node positive breast cancer (T0-T4, N1-2) who receive<br />
neoadjuvant chemotherapy – results from the ACOSOG Z1071<br />
trial<br />
Boughey JC, Suman VJ, Mittendorf EA, Ahrendt GM, Wilke LG,<br />
Taback B, Leitch AM, Flippo-Morton TS, Byrd DR, Ollila DW,<br />
Julian TB, McLaughlin SA, McCall L, Symmans WF, Le-Petross HT,<br />
Haffty BG, Buchholz TA, Hunt KK. Mayo Clinic, Rochester, MN; MD<br />
Anderson <strong>Cancer</strong> Center, Houston, TX; Magee-Womens Surgical<br />
Associates, Pittsburgh, PA; University of Wisconsin-Madison, WI;<br />
Columbia University Medical Center, New York, NY; University<br />
of Texas Southwestern Medical Center, Dallas, TX; Carolinas<br />
Medical Center, Charlotte, NC; University of Washington Medical<br />
Center, Seattle, WA; University of North Carolina - Chapel Hill,<br />
NC; Allegheny General Hospital, Pittsburgh, PA; Mayo Clinic,<br />
Jacksonville, FL; Duke University Medical Center, Durham, NC;<br />
The <strong>Cancer</strong> Institute of New Jersey, New Brunswick, NJ<br />
Background:<br />
The utility of sentinel lymph node (SLN) surgery after neoadjuvant<br />
chemotherapy (NAC) in patients presenting with node-positive<br />
breast cancer has not been determined. The American College of<br />
Surgeons Oncology Group (ACOSOG) Z0171 trial was designed<br />
to evaluate SLN surgery after NAC in women presenting with node<br />
positive disease.<br />
Methods:<br />
ACOSOG Z1071 enrolled women with clinical T0-4, N1-2, M0 breast<br />
cancer receiving NAC. At the time of surgery, all patients were to<br />
undergo SLN surgery followed by axillary lymph node dissection<br />
(ALND). The primary endpoint was false negative rate (FNR) in<br />
women with cN1 disease with 2 or more SLNs reviewed. Positive<br />
SLNs were defined as metastases >0.2mm on H&E. The protocol<br />
encouraged dual tracer technique. A Bayesian study design with a<br />
non-informative prior was chosen to assess whether the probability<br />
that the SLN surgery FNR is greater than 10%.<br />
Results:<br />
From July 2009 to July 2011, 756 patients were enrolled from 136<br />
institutions. Fifteen women were ineligible and 33 withdrew. Of 708<br />
evaluable pts (668 cN1, 40 cN2), 643 had a SLN identified and an<br />
ALND (607 cN1, with indeterminate SLN results in 2); 52 pts (48<br />
cN1) had no SLN identified and had ALND; 11 underwent ALND<br />
only (all cN1), and 2 pts had SLN only (both cN1).<br />
In patients with SLN and ALND, the SLN identification rate was<br />
92.5% (92.7% in cN1, 90% in cN2). SLN correctly identified nodal<br />
status in 84% of the 695 pts [258 of pathologically node negative<br />
and 327 of pathologically node positive; cN1: 83.8% (549/655),<br />
cN2: 90.0% (36/40)].<br />
Of the 643 pts with a SLN identified there was a complete pathologic<br />
response in 40.3% (40.3 % for cN1 and 50% for cN2). Of the pts<br />
with a positive SLN, the SLN was the only site of disease in 40%.<br />
For pts with cN1 disease with 2+ SLNs identified with residual nodal<br />
disease, the SLN FNR was 12.8%. In pts with dual tracer technique<br />
the FNR was 11.1%. There were no FN results among pts with cN2<br />
disease with 2+ SLNs reviewed.<br />
Of the 40 pts with a false negative SLN of the 528 cN1 patients with<br />
2+ SLNs examined, the number of positive nodes at ALND was 1<br />
(50.0%); 2 (25%); 3 (10.0%) and 4-9 (15.0%).<br />
FN rates in pts with at least 2 SLNs examined<br />
N1 pts<br />
N1 & N2 pts<br />
FN rate 12.8% 12.2%<br />
Tracer<br />
Blue dye only 2/11 (18.8%) 2/13 (15.4%)<br />
Radiolabeled colloid only 10/50 (20.0%) 10/51 (19.6%)<br />
Both blue and radiolabeled<br />
colloid<br />
28/252 (11.1%) 28/263 (10.7%)<br />
Number of SLN reviewed<br />
2 19/91 (20.9%) 19/97 (19.6%)<br />
3 7/80 (8.8%) 7/84 (8.3%)<br />
4+ 14/142 (9.9%) 14/146 (9.6%)<br />
Clinical T stage<br />
T0/T1 6/40 (15.0%) 6/40 (15.0%)<br />
T2 27/187 (14.4%) 27/192 (14.1%)<br />
T3 6/75 (8.0%) 6/81(7.4%)<br />
T4 1/11 (9.1%) 1/14 (7.1%)<br />
Conclusions:<br />
NAC resulted in eradication of lymph node disease in 40% of node<br />
positive breast cancer patients. SLN surgery after NAC in node<br />
positive breast cancer pts correctly identified nodal status in 84% of<br />
all patients and was associated with a FNR of 12.8%.<br />
The FNR of SLN is higher than the prespecified study endpoint of<br />
10%. Further analysis of factors associated with FNR such as clinical<br />
response, histological findings and axillary ultrasound findings is<br />
warranted prior to widespread use of SLN in these patients.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
94s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 2<br />
S2-2<br />
Sentinel Lymph Node Biopsy Before or After Neoadjuvant<br />
Chemotherapy - Final Results from the Prospective German,<br />
multiinstitutional SENTINA-Trial -<br />
Kuehn T, Bauerfeind IGP, Fehm T, Fleige B, Helms G, Lebeau A,<br />
Liedtke C, von Minckwitz G, Nekljudova V, Schrenk P, Staebler A,<br />
Untch M. Klinikum Esslingen, Esslingen, Baden Wuerttemberg,<br />
Germany; Klinikum Landshut, Landshut, Bayern, Germany;<br />
Universitaetsfrauenklinik Tuebingen, Baden Wuerttemberg, Germany;<br />
Helios Klinikum Berlin-Buch, Berlin, Germany; University Medical<br />
Center Hamburg-Eppendorf, Hamburg, Germany; University<br />
Medical Center Muenster, Nordrhein-Westfalen, Germany; German<br />
<strong>Breast</strong> Group, Neu-Isenburg, Hessen, Germany; AKH-LFKK Linz,<br />
Austria; University Medical Center Tuebingen, Baden Wuerttemberg,<br />
Germany<br />
Background: The optimal timing for sentinel lymph node biopsy<br />
(SLNB) in the neoadjuvant setting is still unclear. Evidence for both,<br />
feasibility (detection rate, DR) and accuracy (false negative rate,<br />
FNR) of SLNB before and after primary systemic treatment (PST) is<br />
restricted to monocentric and/or retrospective trials. The success rates<br />
for SLNB are particularly unclear for patients who are downstaged<br />
from a cN1 to a ycN0 status.<br />
Material and Methods: The German SENTINA (SENTInel<br />
NeoAdjuvant) trial is a 4-arm prospective multicenter cohort<br />
study designed to evaluate a specific algorithm for the timing of a<br />
standardized SLNB procedure in patients, who undergo PST and<br />
to provide reliable data for the DR and FNR in different settings.<br />
Patients were categorized into four treatment arms according to the<br />
clinical axillary staging before and after chemotherapy. Patients with<br />
a cN0 status underwent SLNB prior to PST and were categorized<br />
as arm A and B: If the SLN was histologically negative no further<br />
axillary surgery was performed after PST (arm A), whereas in case<br />
of histologically positive SLN status, a second SLNB and axillary<br />
dissection (AD) was performed after PST (arm B). Patients with a<br />
cN1 status prior to PST underwent no axillary surgery prior to PST<br />
and were stratified as arm C and D: If patients converted to cN0 after<br />
PST, SLNB and AD were performed (arm C); patients presenting with<br />
cN1 status after PST underwent classical AD (arm D).<br />
Results: 1737 eligible patients from 103 institutions entered the trial.<br />
From these 662 patients were classified as arm A, 360 pts as arm B,<br />
592 pts as arm C and 123 pts as arm D.<br />
The DR for SLNB was 1013/1022 (99.1%) before PST (arms A and<br />
B), 474/592 (80.1%) in Arm C (after PST), and 219/360 (60.8%) in<br />
arm B (after prior SLNB and PST) (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
S3-1<br />
Neoadjuvant Chemotherapy in the very young 35 years of age<br />
or younger<br />
Loibl S, Jackisch C, Gade S, Untch M, Paepke S, Kuemmel S,<br />
Schneeweiss A, Jackisch C, Huober J, Hilfrich J, Hanusch C, Gerber<br />
B, Eidtmann H, Denkert C, Costa S-D, Blohmer J-U, Nekljudova V,<br />
Mehta K, von Minckwitz G. German <strong>Breast</strong> Group, Neu-Isenburg;<br />
Klinikum Offenbach; Helios Kliniken Berlin; University Muenchen;<br />
Kliniken Essen Mitte; University Heidelberg; Uni Duesseldorf;<br />
Eilenriedeklinik Duessldorf; Rotkreuzklinikum Muenchen; University<br />
Rostock; University Kiel; Charite Berlin; University Magdeburg;<br />
<strong>San</strong>kt Gertrauden Berlin<br />
Background: In young women the course of breast cancer (BC) tends<br />
to be more aggressive. In several trials young age at diagnosis was<br />
an independent predictive factor for pathological complete response<br />
(pCR) after neoadjuvant chemotherapy. Here we investigate especially<br />
the rare entity of very young women at age 35 years or younger.<br />
Methods: 8949 patients from 8 neoadjuvant German studies with<br />
operable or locally advanced, non-metastatic breast cancer and<br />
follow-up were included (for details see von Minckwitz G et al,<br />
BCRT 2010 and NEJM 2012). A subgroup of 704 patients of age<br />
35 years or younger was analyzed. All patients with endocrine<br />
responsive disease received adjuvant endocrine therapy according to<br />
institutional standard. We compared pathological complete remission<br />
rate (pCR) defined as ypT0, ypN0 and disease free survival rate (DFS)<br />
of this very young group with older patients in total and in different<br />
histopathological subgroups (as defined previously by von Minckwitz<br />
J Clin Oncol 2012).<br />
Results: From 8949/6561 had known ER, PR, HER2 and grading.<br />
There were less Luminal A and more TNBC in the very young women<br />
compared to the one >35 years of age: Luminal A: 131 (21%) vs.<br />
2251 (27%); Luminal B HER2-: 50 (8%) vs. 783 (10%); Luminal B<br />
HER2+: 103 (17%) vs. 989 (14%); HER2+/HR-: 72 (11%) vs. 739<br />
(10%); TNBC: 164 (26%) vs. 1415 (19%).<br />
The pCR rate was significantly higher in the very young than in the<br />
group older than 35 years (23.6% vs. 15.7.%; p
December 4-8, 2012 <strong>Abstract</strong>s: General Session 3<br />
S3-3<br />
The UK TACT2 Trial: comparison of standard vs accelerated<br />
epirubicin in patients requiring chemotherapy for early breast<br />
cancer (EBC) (CRUK/05/019)<br />
Cameron D, Barrett-Lee P, Canney P, Banerji J, Bartlett J, Bloomfield<br />
D, Bowden S, Brunt M, Earl H, Ellis P, Fletcher M, Morden JP,<br />
Robinson A, Sergenson N, Stein R, Velikova G, Verrill M, Wardley<br />
A, Coleman R, Bliss JM. Edinburgh <strong>Cancer</strong> Research Centre,<br />
University of Edinburgh, United Kingdom; Velindre NHS Trust<br />
<strong>Cancer</strong> Centre, Cardiff, United Kingdom; Beatson West of Scotland<br />
<strong>Cancer</strong> Centre, Glasgow; The Institute of <strong>Cancer</strong> Research, Sutton,<br />
United Kingdom; Ontario Institute for <strong>Cancer</strong> Research, Toronto,<br />
Canada; Brighton & Sussex University Hospitals, Brighton, United<br />
Kingdom; University of Birmingham, United Kingdom; University<br />
Hospital of North Staffordshire, Stoke-on-Trent, United Kingdom;<br />
University of Cambridge and NIHR Cambridge Biomedical Research<br />
Centre, Cambridge, United Kingdom; Guys Hospital & King<br />
College, London, United Kingdom; Leeds Institute of Molecular<br />
Medicine, Leeds, United Kingdom; Southend University Hospital,<br />
Southend, United Kingdom; Information Services Division, NHS<br />
National Services Scotland, Edinburgh, United Kingdom; UCL<br />
Hospitals, London, United Kingdom; Northern Centre for <strong>Cancer</strong><br />
Care, Newcastle upon Tyne, United Kingdom; The Christie Hospital,<br />
Manchester, United Kingdom; Weston Park Hospital, Sheffield,<br />
United Kingdom<br />
Introduction: TACT2, a multicentre randomized phase III trial in<br />
patients with node +ve or high risk node -ve invasive EBC with<br />
E-CMF as control (Poole NEJM 2006), tests two hypotheses in a 2x2<br />
factorial design: A) accelerated epirubicin (aE) improves outcomes<br />
compared to standard epirubicin (E) (CALGB9741 Citron JCO 2003);<br />
and B) capecitabine (X) gives similar efficacy but preferential sideeffect<br />
profile to CMF. Here we focus on the impact of accelerating<br />
epirubicin treatment on patient outcome. Tolerability and toxicity of<br />
this regimen have already been presented (Cameron 2010, SABCS);<br />
33/4391 pts did not start chemotherapy. 4261 (97%) completed the<br />
initial 4 cycles (E 2143 (96%), aE 2118 (98%)) with RDI >85% for<br />
E 2061 (93%) and aE 1985 (91%). Serious CTCAE toxicity was less<br />
common with aE compared with E, however patients report poorer<br />
global QL, fatigue & role function which does not appear to be<br />
explained by impact on daily activities due to individual side-effects.<br />
Patients & Methods: Between December 2005 and December 2008,<br />
4391 patients (4371 women, 20 men) were randomized to receive<br />
either E (100mg/m 2 x 4) q3wk or aE (100mg/m 2 x 4 plus pegfilgrastim,<br />
6mg d2) q2wk followed by classical CMF q4wk x 4 or X (2500mg/<br />
m 2 /day x 14) q3wk x 4. Other adjuvant treatment was delivered<br />
according to local practice (HER2+ve – sequential trastuzumab<br />
for 1 year from June 2006; ER/PgR+ve - endocrine therapy for 5<br />
years). Tumor blocks were collected prospectively to enable central<br />
biomarker testing. Median age of patients was 52 years (IQR 46-59).<br />
53% patients had node +ve disease; 59% had tumors >2cm; 57% were<br />
grade 3. According to local assessment, of 4366 patients where both<br />
ER and HER2 status were known, 60% had ER+ve/HER2-ve tumors,<br />
19% HER2+ve, 21% ER-ve/HER2-ve. Primary endpoint was time to<br />
recurrence (TTR), defined as time to loco-regional or distant relapse,<br />
or breast cancer-death. Secondary endpoints included disease-free<br />
survival (DFS), overall survival (OS), tolerability of regimens and<br />
quality of life. TACT2 has over 90% power to detect a clinically<br />
meaningful 4% difference in TTR between standard and accelerated<br />
epirubicin schedules (from 80% to 84% at 5 years). Survival estimates<br />
will be compared using stratified log-rank tests and Cox regression.<br />
Results: At 1 st June 2012, median follow up was 49 months<br />
(interquartile range: 46-60) with 553 TTR events reported. The<br />
Independent Data Monitoring Committee consider these data<br />
sufficiently mature for presentation of analyses relating to the<br />
accelerated epirubicin hypothesis. A further data snapshot, after query<br />
resolution, for the main analysis will be taken in Q3 2012. Data to be<br />
presented, by treatment group, include TTR, DFS, OS, late toxicity<br />
and pre-planned subgroup analyses according to ER, PgR and HER2<br />
status and Ki67 levels.<br />
Discussion: TACT2 will provide a definitive analysis to confirm or<br />
refute benefits previously reported for accelerating anthracycline<br />
chemotherapy in early breast cancer including, via pre-planned<br />
subgroup analyses, exploration of the potential benefits in phenotypic<br />
subtypes.<br />
S3-4<br />
Ten year follow-up analysis of intense dose-dense adjuvant<br />
ETC (epirubicin (E), paclitaxel (T) and cyclophosphamide<br />
(C) ) confirms superior DFS and OS benefit in comparison to<br />
conventional dosed chemotherapy in high-risk breast cancer<br />
patients with ≥ 4 positive lymph nodes.<br />
Moebus V, Schneeweiss A, du Bois A, Lueck H-J, Eustermann H,<br />
Kuhn W, Kurbacher C, Nitz U, Kreienberg R, Jackisch C, Huober<br />
J, Thomssen C, Untch M. Klinikum Frankfurt Höchst, Frankfurt,<br />
Germany; University of Heidelberg, Germany; Klinikum Essen Mitte,<br />
Essen, Germany; Gynäkologisch-Onkologische Praxis, Hannover,<br />
Germany; WiSP Research Institute, Langenfeld, Germany; University<br />
of Bonn, Germany; Medizinisches Zentrum Bonn-Friedensplatz, Bonn,<br />
Germany; Ev. Krankenhaus Bethesda, Mönchengladbach, Germany;<br />
University of Ulm, Germany; Klinikum Offenbach, Offenbach,<br />
Germany; University of Duesseldorf, Germany; University of Halle,<br />
Germany; Helios Klinikum Berlin-Buch, Berlin, Germany<br />
Background: The 5-year analysis of adjuvant chemotherapy with<br />
intense dose-dense (IDD) ETC had shown a significant improved<br />
DFS (HR 0.72; p < 0.001) and OS (HR 0.76; p=0.29) in comparison<br />
with conventional dosed chemotherapy (J Clin Oncol 28: 2874-2880,<br />
2010). In contrast to other dose-dense trials the ETC regimen is dosedense<br />
and dose-intensified. Long-term results are essential to evaluate<br />
the impact of dose-dense chemotherapy in the adjuvant treatment of<br />
breast cancer patients (pts). We now report the final analysis of DFS,<br />
OS, and long-term safety including the application of epoetin alfa<br />
after 10 years of follow-up.<br />
Patients and Methods:<br />
A multi-center phase-III trial of the German AGO <strong>Breast</strong> Study<br />
Group recruited 1284 pts from 12/98 until 4/03. Pts below 65<br />
years of age were eligible if at least 4 axillary lymph nodes were<br />
infiltrated. In the experimental arm, pts were assigned to receive<br />
three courses each of epirubicin (150 mg/m 2 ), paclitaxel (225 mg/<br />
m 2 ) and cyclophosphamide (2500 mg/m 2 ) at 2-week intervals (q2w)<br />
(ETC) with G-CSF support (5µg/kg/SC day 3-10). In the standard<br />
arm 4 courses of conventional dosed epirubicin/cyclophosphamide<br />
(90/600 mg/m 2 ) followed by 4 courses of paclitaxel (175 mg/<br />
m 2 ) were given (EC→T). All cycles were administered in 3-week<br />
intervals without growth factor support. A second randomization ±<br />
epoetin alfa was performed in the IDD-ETC arm only (150IU/kg/sc<br />
three times weekly) to reduce the number of red blood cells (RBC’s)<br />
transfusion and to evaluate the impact of epoetin alfa on DFS and<br />
OS in the adjuvant setting.<br />
Results:<br />
58% and 42% of the pts presented with 4-9 and ≥ 10 positive nodes<br />
with a median number of 8 involved nodes. The median age was 51<br />
years and median follow-up was 122 months. We observed 604 DFS<br />
events (282 with IDD ETC; 322 with EC→T) (p=0.00014, one-sided;<br />
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HR 0.74; 95% CI, 0.63 to 0.87). IDD ETC improved DFS irrespective<br />
of nodal status, HER2 and ER status. 446 pts. have died (201 events<br />
in the IDD ETC arm vs. 245 events in the standard arm). 10 year OS<br />
rates were 69% with IDD ETC and 59% with EC→ T (p=0.0007;<br />
two-sided; HR, 0.72; 95% CI, 0.60-0.87). Nine cases of acute myeloid<br />
leukemia or myelodysplastic syndrome occurred in the IDD ETC arm<br />
vs. two cases in the standard arm. 28% of pts in the IDD ETC arm<br />
vs. 13% in the IDD ETC arm plus epoetin alfa (p
December 4-8, 2012 <strong>Abstract</strong>s: General Session 3<br />
common. Sporadic growth factor receptor amplifications occurred<br />
in EGFR, KIT, PDGFRA, PDGFRB, MET, FGFR1, FGFR2, and<br />
IGF1R. NGS identified 7 patients with ERBB2 gene amplification<br />
in the RD which was confirmed by FISH in both the pre- and posttreatment<br />
tissue, suggesting NGS could assist in the identification of<br />
ERBB2-overexpressing tumors misclassified at the time of diagnosis.<br />
In general, the gene amplifications identified by NGS corresponded<br />
to enhanced gene expression levels. Amplifications of MYC were<br />
independently associated with poor recurrence-free survival (RFS)<br />
and overall survival (OS). An interaction effect on survival was<br />
observed between MEK activation (assayed by a gene expression<br />
signature) and MYC amplification, suggesting cooperation between<br />
these pathways. Alterations in DNA repair also identified a subgroup<br />
with poor RFS and OS. In contrast, high post-NAC Ki67 score did<br />
not predict poor RFS or OS in this predominantly TNBC cohort.<br />
Conclusions: The diversity of lesions in residual TNBCs after NAC<br />
underscores the need for powerful and broad molecular approaches<br />
to identify actionable molecular alterations and, in turn, better inform<br />
personalized therapy of this aggressive disease. Incorporation of this<br />
platform into clinical studies and eventually standards of care should<br />
aid in the prioritization of patients with RD after NAC into rational<br />
adjuvant studies.<br />
S3-7<br />
Treatment with Histone Deacetylase Inhibitors Creates<br />
‘BRCAness’ and Sensitizes Human Triple Negative <strong>Breast</strong> <strong>Cancer</strong><br />
Cells to PARP Inhibitors and Cisplatin<br />
Bhalla KN, Rao R, Sharma P, Das Gupta S, Chauhan L, Stecklein<br />
S, Fiskus W. University of Kansas <strong>Cancer</strong> Center, Kansas City, KS<br />
DNA damage induces DNA damage response (DDR), which regulates<br />
cell cycle transit, DNA repair and apoptosis. During DDR, stability<br />
and activity of ATR and CHK1 is essential for the cell cycle arrest<br />
and subsequent DNA repair through homologous recombination<br />
(HR) in which BRCA1 protein is involved. We have previously<br />
reported that ATR, CHK1 and BRCA1 are hsp90 client proteins<br />
and treatment with hsp90 inhibitor sensitizes cancer cells to DNA<br />
damage. We have also previously shown that treatment with pan-<br />
HDAC inhibitors, including vorinostat (VS) and panobinostat (PS),<br />
induces hyperacetylation of hsp90, thereby inhibiting its chaperone<br />
function. In the present studies we determined that treatment with VS<br />
or PS induced hyper-acetylation and inhibition of chaperone function<br />
of nuclear hsp90, leading to proteasomal degradation and depletion<br />
of ATR, CHK1 and BRCA1. This led to inhibition of DDR and DNA<br />
repair following ionizing radiation (IR) through destabilization of<br />
ATR-CHK1 and BRCA1 proteins. Based on this, we hypothesized that<br />
treatment with VS or PS would create ‘BRCAness’ in breast cancer<br />
cells. Specific siRNA-mediated knockdown of HDAC3 but not of<br />
HDAC1 or HDAC2 also induced hyper-acetylation of the nuclear<br />
hsp90 and depletion of ATR and CHK1, indicating that among the<br />
class I HDACs, HDAC3 is the deacetylase for the nuclear hsp90. We<br />
next determined whether, by depleting DDR proteins and BRCA1<br />
and inducing ‘BRCAness’, treatment with VS would sensitize the<br />
triple negative breast cancer (TNBC) SUM59PT, MB-231 and<br />
HCC1937 cells to the PARP inhibitor ABT888 (veliparib). Indeed,<br />
combined treatment with VS or PS with ABT888 (10 to 20 µM) for<br />
48 hours synergistically induced apoptosis (Combination indices by<br />
isobologram analysis being < 1.0) of TNBC cells with (HCC1937)<br />
or without BRCA1 mutation (MB-231 and SUM159PT cells). As<br />
compared to treatment with each agent alone, co-treatment with VS<br />
and ABT888 also induced significantly more DNA strand breaks,<br />
as demonstrated by higher γ-H2AX levels. Combined treatment<br />
also induced markedly greater tail moment, as determined by the<br />
Comet assay that evaluates the SYBR green-stained DNA tails by<br />
fluorescent microscopy. Co-treatment with VS and ABT888 also<br />
induced more BH3 domain-only pro-death protein BIM, while<br />
knock-down of BIM by shRNA significantly reduced the apoptosis<br />
induced by co-treatment with VS and ABT888. It is noteworthy that<br />
treatment with VS also sensitized the TNBC cells to cisplatin (2.0<br />
to 10 µM)-induced apoptosis. Moreover, co-treatment with VS and<br />
ciplatin synergistically induced apoptosis of TNBC cells (CIs < 1.0).<br />
These findings indicate that treatment with pan-HDAC inhibitors VS<br />
or PS creates BRCAness, and in combination with a PARP inhibitor<br />
or cisplatin synergistically induces apoptosis in human TNBC cells.<br />
These findings support a compelling rationale to confirm whether<br />
the combination of VS or PS with ABT888 and cisplatin would be a<br />
highly active treatment in the in vivo models of human TNBC cells,<br />
irrespective of their expression of mutant BRCA1.<br />
S3-8<br />
Identification of Novel Synthetic-Lethal Targets for MYC-Driven<br />
Triple-Negative <strong>Breast</strong> <strong>Cancer</strong><br />
Goga A, Samson S, Horiuchi D. UCSF, <strong>San</strong> Francisco, CA; UCSF<br />
Currently, the greatest clinical challenge in treating breast cancer<br />
occurs in those patients whose tumors lack expression of the estrogen<br />
and progesterone receptors and the HER2 oncoprotein. No targeted<br />
agents currently exist against this aggressive type of receptor ‘triple<br />
negative’ breast cancer that disproportionately affects young African<br />
American women and also a substantial number of white American<br />
women. We have discovered that triple-negative tumors frequently<br />
express high levels of the MYC proto-oncogene. We sought to identify<br />
new “synthetic-lethal” strategies to selectively kill triple-negative<br />
breast tumors with MYC overexpression. Synthetic lethality arises<br />
when a combination of mutations in two or more genes leads to<br />
cell death, whereas a mutation in only one of these genes has little<br />
effect. Using this strategy, we can take advantage of the elevated<br />
MYC signaling in triple-negative tumors to selectively kill them,<br />
while sparing normal tissues in which MYC is expressed at much<br />
lower levels.<br />
RESULTS: We performed a shRNA synthetic-lethal screen to identify<br />
new molecules, such as cell cycle kinases, which when inhibited can<br />
preferentially kill triple-negative breast tumor cells. The unbiased<br />
shRNA-based screening approach was performed in human mammary<br />
epithelial cells (HMECs) that have inducible MYC over-expression.<br />
A high-throughput screen of ∼2000 shRNAs, that target the human<br />
kinome (∼ 600 kinases) was performed, and identified 13 kinases<br />
whose inhibition by >1 shRNAs gave rise to >50% inhibition of<br />
cell growth. Two of the kinases identified in our screen, ARK5 and<br />
GSK3A, were also recently identified by other studies and shown to<br />
have a synthetic-lethal interaction with MYC. These results validated<br />
our ability to identify synthetic-lethal targets. We are currently<br />
characterizing and validating the 11 novel targets identified in this<br />
screen, using human cancer cell lines as well as mouse cancer models<br />
to determine the impact of inhibiting these targets on triple-negative<br />
breast cancer development and proliferation. Additional syntheticlethal<br />
interactions with MYC over-expression in triple-negative breast<br />
cancers will be presented.<br />
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S4-1<br />
The UK START (Standardisation of <strong>Breast</strong> Radiotherapy) Trials:<br />
10-year follow-up results<br />
Haviland JS, Agrawal R, Aird E, Barrett J, Barrett-Lee P, Brown J,<br />
Dewar J, Dobbs J, Hopwood P, Hoskin P, Lawton P, Magee B, Mills<br />
J, Morgan D, Owen R, Simmons S, Sydenham M, Venables K, Bliss<br />
JM, Yarnold JR, On Behalf of the START Trialists. The Institute of<br />
<strong>Cancer</strong> Research, Sutton, United Kingdom; Shrewsbury and Telford<br />
Hospital NHS Trust, United Kingdom; Mount Vernon Hospital,<br />
Northwood, United Kingdom; Royal Berkshire NHS Foundation Trust,<br />
Reading, United Kingdom; Velindre Hospital NHS Trust, Cardiff,<br />
United Kingdom; previously University of Bristol, now Eli Lilly &<br />
Company, United Kingdom; Formerly Ninewells Hospital, Dundee,<br />
United Kingdom; Formerly Guys and St Thomas’ NHS Trust, London,<br />
United Kingdom; Nottingham City Hospital, United Kingdom;<br />
Formerly The Christie NHS Foundation Trust, Manchester, United<br />
Kingdom; Formerly Nottingham University Hospital NHS Trust,<br />
United Kingdom; Formerly Cheltenham General Hospital, United<br />
Kingdom; The Institute of <strong>Cancer</strong> Research and Royal Marsden NHS<br />
Foundation Trust, Sutton, United Kingdom<br />
Background International standard adjuvant radiotherapy regimens<br />
following primary surgery for early breast cancer have historically<br />
delivered a high total dose (50Gy) in 25 small daily doses (fractions)<br />
over 5 weeks, however randomised trials, including START, indicate<br />
that a lower total dose delivered in fewer, larger fractions (Fr) is likely<br />
to be at least as safe and effective (START Trialists’ Group, Lancet<br />
2008 & Lancet Oncol 2008). With patients remaining at risk of local<br />
relapse for many years, information on long-term outcomes is needed<br />
to provide confidence in clinical practice. Here, we report 10-year<br />
follow-up of the UK START Trials testing 13- and 15-Fr regimens<br />
in terms of local cancer control and late adverse effects.<br />
Methods Between 1999 and 2002, 4451 women with completely<br />
excised invasive breast cancer (T1-3, N0-1, M0) were randomised<br />
after primary surgery to comparisons of 50Gy in 25Fr over 5 weeks<br />
vs 41·6Gy or 39Gy in 13Fr over 5 weeks (START A), or 50Gy in<br />
25Fr over 5 weeks vs 40Gy in 15Fr over 3 weeks (START B). Women<br />
were eligible if aged over 18 years and did not have an immediate<br />
surgical reconstruction. Protocol-specified principal endpoints were<br />
local-regional (LR) tumour relapse and late normal tissue effects.<br />
Analysis was by intention to treat.<br />
Findings Median follow-up in survivors is now 9.3 years in START A<br />
and 9.9 years in START B, with 139 LR relapses in START A and 95<br />
in START B. In START A, the 10-year rate of LR relapse was 7.4%<br />
(95%CI 5.5-10.0) after 50Gy, 6.3% (95%CI 4.7-8.5) after 41·6Gy and<br />
8.8% (95%CI 6.7-11.4) after 39Gy. In START B, the 10-year rate of<br />
LR relapse was 5.5% (95%CI 4.2-7.2) after 50Gy and 4.3% (95%CI<br />
3.2-5.9) after 40Gy. Clinician assessments suggested lower 10-year<br />
rates of any moderate/marked late normal tissue effects after 39Gy<br />
(43.9%; 95%CI 39.3-48.7) and similar rates after 41.6Gy (49.5%;<br />
95%CI 44.9-54.3) compared with 50Gy (50.4%; 95%CI 45.8-55.3)<br />
in START A and lower rates after 40Gy in START B (37.9%; 95%CI<br />
34.5-41.5) compared with 50Gy (45.3%; 95%CI 41.7-49.0). From a<br />
planned meta-analysis of START A and the START pilot trial (Owen<br />
et al, Lancet Oncol 2006), the adjusted estimate of α/β value for<br />
tumour control was 3.5Gy (95% CI 1.2-5.7) and for late change in<br />
photographic breast appearance was 3.1Gy (95% CI 2.0-4.2).<br />
Interpretation Long-term follow-up confirms that breast cancer<br />
and the surrounding dose-limiting healthy tissues respond similarly<br />
to radiotherapy fraction size and thus that appropriately-dosed<br />
hypofractionated radiotherapy is safe and effective in treatment of<br />
patients with early breast cancer. 41·6Gy in 13Fr and 40Gy in 15Fr<br />
each appear comparable to 50Gy in 25Fr in terms of local-regional<br />
tumour control and late normal tissue effects. These results support<br />
the continued use of 40Gy in 15Fr as standard of care (UK NICE<br />
Guidance 2009) for women requiring adjuvant radiotherapy for early<br />
breast cancer.<br />
S4-2<br />
Targeted intraoperative radiotherapy for early breast cancer:<br />
TARGIT-A trial- updated analysis of local recurrence and first<br />
analysis of survival<br />
Vaidya JS, Wenz F, Bulsara M, Joseph D, Tobias JS, Keshtgar M,<br />
Flyger H, Massarut S, Alvarado M, Saunders C, Eiermann W,<br />
Metaxas M, Sperk E, Sutterlin M, Brown D, Esserman L, Roncadin<br />
M, Thompson A, Dewar JA, Holtveg H, Pigorsch S, Falzon M, Harris<br />
E, Matthews A, Brew-Graves C, Potyka I, Corica T, Williams NR,<br />
Baum M. University College London, London, United Kingdom;<br />
University Medical Centre Mannheim, University of Heidelberg,<br />
Heidelberg, Germany; University of Notre Dame, Fremantle,<br />
Australia; Sir Charles Gairdner Hospital, Perth, Australia; University<br />
College Hospital, London, United Kingdom; Royal Free Hospital,<br />
London, United Kingdom; University of Copenhagen, Copenhagen,<br />
Denmark; Centro di Riferimento Oncologia, Aviano, Italy; University<br />
of California, <strong>San</strong> Francisco, CA; University of Western Australia,<br />
Perth, WA, Australia; Red Cross Hospital, Munich, Germany;<br />
Ninewells Hospital, Dundee, United Kingdom; Technical University<br />
of Munich, Munich, Germany; University College London Hospitals,<br />
London, United Kingdom; National <strong>Cancer</strong> Research Institute and<br />
Independent <strong>Cancer</strong> Patients’ Voice, United Kingdom; Moffit <strong>Cancer</strong><br />
Centre<br />
Background TARGIT-A, an international phase 3 randomised trial<br />
(Lancet 2010;376:91-102) compared outcomes in patients undergoing<br />
breast conserving surgery followed by either whole breast external<br />
beam radiotherapy (EBRT) over several weeks, or a risk-adaptive<br />
approach using single dose targeted intra-operative radiotherapy<br />
(TARGIT). Risk-adaptive approach meant that if the final pathology<br />
report demonstrated unpredicted pre-specified adverse features, then<br />
EBRT was to be added to TARGIT.<br />
Method 3451 women aged 45 years or older with invasive ductal<br />
carcinoma were enrolled from 33 centres in 10 countries between<br />
2000 and 2012.<br />
Randomisation to TARGIT or EBRT arm was done either before<br />
lumpectomy (pre-pathology) or after lumpectomy (postpathology).<br />
If allocated to TARGIT, patients in the pre-pathology group received<br />
it immediately after surgical excision under the same anaesthesia;<br />
patients in the post-pathology group received it as a subsequent<br />
procedure. We pre-specified that analysis would be performed<br />
overall as the primary analysis and for these groups separately as<br />
a secondary analysis. The primary outcome was ipsilateral within<br />
breast recurrence (IBR) with an absolute non-inferiority margin of<br />
2.5% at 5 years and secondary outcome was survival. We performed<br />
exploratory analyses for loco-regional recurrence, ‘all recurrence’<br />
(ipsilateral or contralateral breast, axilla or distant), distant recurrence,<br />
and causes of death.<br />
Results 1721 patients were randomly allocated to receive TARGIT<br />
and 1730 to EBRT. 1010 patients have a minimum 4 years follow up<br />
and 611 patients have minimum 5 years follow up. Primary events<br />
have increased from 13 to 34 since 2010.<br />
For the primary outcome of ipsilateral breast recurrence, the absolute<br />
difference at 5-years was 2.0%, which was higher with TARGIT<br />
and reached the conventional levels of statistical significance<br />
(p=0.042), but was within the pre-specified non-inferiority margin;<br />
in prepathology the absolute difference in 5-year IBR was 1%; in<br />
postpathology it was 3.7%.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
100s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 4<br />
For the secondary outcome, there was a non-significant trend for<br />
improved overall survival with TARGIT (HR = 0.70(0.46-1.07)) due<br />
to fewer non-breast cancer deaths (17 vs. 35, HR 0.47 (0.26-0.84)).<br />
Cardiovascular deaths were 1 vs. 10 and deaths from cancers other<br />
than breast were 7 vs.16.<br />
Ipsilateral breast<br />
recurrenc(IBR)<br />
Events<br />
5-year cumulative risk (95%CI)<br />
TARGIT EBRT<br />
23 11<br />
HR (95% CI)<br />
3.3%(2.1-5.1) 1.3% (0.7-2.5) 2.07 (1.01-4.25)<br />
All recurrence (ipsilateral and<br />
contralateral breast, axilla 69 48<br />
and distant)<br />
8.2%(6.3-10.6) 5.7%(4.1-7.8) 1.44(0.99-2.08)<br />
Death 37 51<br />
3.9%(2.7-5.8) 5.3%(3.9-7.3) 0.70(0.46-1.07)<br />
Conclusion The risk-adapted approach using single dose TARGIT<br />
has a slightly higher local recurrence rate than EBRT for the<br />
primary endpoint of IBR, but was within the preset non-inferiority<br />
boundary, with the prepathology apparently performing better than<br />
the postpathology stratum. In addition there was a trend for improved<br />
overall survival in the TARGIT arm due to fewer non-breast cancer<br />
deaths.<br />
S4-3<br />
The EndoPredict score identifies late distant metastases in ER+/<br />
HER2- breast cancer patients<br />
Dubsky P, Brase JC, Fisch K, Jakesz R, Singer CF, Greil R, Dietze O,<br />
Weber KE, Petry C, Kronenwett R, Rudas M, Knauer M, Gnant M,<br />
Filipits M. Medical University Vienna, Austria; Sividon Diagnostics<br />
GmbH, Cologne, Germany; Paracelsus Private Medical University,<br />
Salzburg, Austria; Sisters of Charity Hospital, Linz, Austria; Medical<br />
University of Vienna, Austria<br />
Background:<br />
ER+/HER2- negative (ER+) breast cancers have a proclivity for late<br />
recurrence. A first step to an improved adjuvant treatment of late<br />
metastasis is to identify women at risk and understand the underlying<br />
biology. Several prognostic multigene tests have been developed for<br />
ER+ breast cancer patients. Some of these tests have been validated<br />
to predict early recurrence events. However, few gene expression<br />
assays have been shown to predict late metastases.<br />
Here, we assess whether the prognostic EndoPredict (EP) score,<br />
which incorporates both the expression levels of proliferative - and<br />
ESR1-related genes, can be used to identify late relapse events in<br />
ER+ breast cancer patients.<br />
Methods:<br />
Patients included in this study participated in the ABCSG-6<br />
(tamoxifen-only arm) or ABCSG-8 phase III adjuvant trial and<br />
received either tamoxifen for 5 years or tamoxifen for 2 years followed<br />
by anastrozole for 3 years. All 1702 ER+/HER2- breast cancer patients<br />
were retrospectively assigned into risk categories based on the EP and<br />
on common clinical parameters. The primary endpoint was distant<br />
metastasis. Ongoing collection of follow-up events allowed estimation<br />
of metastasis rates using the Kaplan–Meier method in an early and late<br />
time cohort: 0-5 years/early recurrence and 5-10 years/late recurrence.<br />
Results:<br />
49% of all patients were classified as low-risk according to the EP<br />
score. Kaplan Meier analysis demonstrated that the EP low-risk<br />
group had a significantly improved clinical outcome in the first (0-5<br />
years; p < 0.0001) and second time interval (5-10 years; p = 0.002).<br />
Nodal metastasis was also significantly associated with the clinical<br />
outcome in both time intervals, with node-positive tumors showing<br />
a considerably higher rate of late recurrence events. In contrast,<br />
Ki67 levels and grading were not significantly associated with late<br />
metastasis. Multivariate analysis showed that EP was an independent<br />
prognostic parameter after adjustment for age, grade, lymph node<br />
status, tumor size and Ki67 in both the first and second time interval.<br />
The EPclin – a combination of the EP and the clinical risk factors nodal<br />
status and tumor size – showed the best performance in predicting late<br />
relapse events. Exploratory analyses of proliferative - versus ESR-1<br />
related genes as contributors to early and late distant metastases show<br />
differential effects.<br />
Conclusions:<br />
The EndoPredict test identified a subgroup of patients that have a low<br />
likelihood of developing late metastases. The eight genes contained<br />
in the test provide complimentary prognostic information to clinicopathologic<br />
parameters. Both the expression of proliferative - and<br />
ESR1-related genes contributes to the underlying biology of late<br />
distant metastases.<br />
S4-4<br />
Independent validation of Genomic Grade in the BIG 1-98 study<br />
Sotiriou C, Ignatiadis M, Desmedt C, Azim Jr HA, Veys I, Larsimont<br />
D, Lyng M, Viale G, Leyland-Jones B, Ditzel H, Giobbie-Hurder<br />
A, Regan M, Piccart M, Michiels S. Universite Libre de Bruxelles;<br />
Institut Jules Bordet; University of Southern Denmark; University of<br />
Milan; Edith <strong>San</strong>ford Research; Harvard Medical School<br />
Background: We have reported that a 97-gene signature, the Genomic<br />
Grade Index (GGI) can separate histological grade (HG) 2 breast<br />
tumors into low vs high GGI tumors with different outcomes. We<br />
have also developed a quantitative reverse transcriptase polymerase<br />
chain reaction (qRT-PCR) tool including 6 reporter and 3 control<br />
genes that can reliably evaluate Genomic Grade (GG) in paraffin<br />
embedded tumors.<br />
Methods: We evaluated the qRT-PCR GG in women treated with either<br />
tamoxifen or letrozole monotherapy in the <strong>Breast</strong> International Group<br />
(BIG) 1-98 study with 8.1 year median follow-up. The association<br />
between continuous GG and distant recurrence-free interval (DRFI)<br />
was evaluated in Cox regression models stratified for the 2 vs 4<br />
arm randomization option, chemotherapy and hormonotherapy use,<br />
with and without adjustment for clinicopathological characteristics.<br />
Estrogen, progesterone receptor (ER, PR), Ki67 and HG were<br />
centrally reviewed. The clinicopathological model included age and<br />
log2 tumor size, ER and PR as continuous variables, nodal status (N0<br />
vs 1-3 vs >3), HG (1 vs 2 vs 3) and HER2 (negative vs positive).<br />
Similar analyses were performed for log2 Ki67 as continuous<br />
variable. Added prognostic value was assessed using the likelihood<br />
ratio statistic.<br />
Results: We obtained GG in 883 (62%) of 1428 samples. Non<br />
evaluable results were due to pre-analytical issues or technical failure.<br />
Among the 883 patients, 521 (59%) had N0 disease, 435 (49%) were<br />
treated with tamoxifen and 84 (10%) had distant recurrences. The<br />
GG classified 502 patients with HG2 tumors as either GG1 (N=202,<br />
40%), equivocal (N=220, 44%) or GG3 (N=80, 16%). In univariate<br />
analysis, increasing GG and Ki67 were significantly associated with<br />
lower DRFI (Table). When the 773 N0/1-3 patients were analyzed<br />
based on HG, the Kaplan-Meier estimate for 10-year DRFI was 98%<br />
(95% confidence intervals 96-100%) for the 123 HG1, 92% (88-95%)<br />
for the 456 HG2 and 84% (78-90%) for the 194 HG3 patients. In the<br />
N0/1-3 population, 10 year DRFI based on GG was 95% (96-100%)<br />
for the 290 GG1, 92% (89-95%) for the 309 GG equivocal and 84%<br />
(77-90%) for the 178 GG3 patients. Interestingly, when the 456 HG2<br />
and N0/1-3 patients were analyzed based on GG, the 10-year DRFI<br />
was 95% (92-100%) for the 185 HG2/GG1 patients, 92% (88-96%)<br />
for the 202 HG2/GG equivocal patients, 86% (76-96%) for the 69<br />
www.aacrjournals.org 101s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
HG2/GG3 patients. In all patients either GG or Ki67 as continuous<br />
variable significantly improved the clinicopathological model in<br />
predicting distant recurrence (Table).<br />
Conclusion: Either Genomic Grade or centrally reviewed Ki67<br />
provides independent prognostic information for risk of distant<br />
recurrence beyond clinicopathological characteristics in patients<br />
treated with endocrine therapy.<br />
Table: Univariate and multivariate analysis for DRFI including either GG or Ki67 alone or together<br />
with the clinicopathological model<br />
Degrees of<br />
Model Comparison Patients Chi-square<br />
Freedom P Concordance Index<br />
(95% CI)<br />
GG vs null 883 21.7 1 3.2E-06 0.66 (0.6-0.71)<br />
Ki67 vs null 862 16.9 1 4.0E-05 0.65 (0.6-0.71)<br />
Clinicopathological model + GG<br />
848<br />
vs Clinicopathological model<br />
4.6 1 0.03 0.76 (0.71-0.8)<br />
Clinicopathological model +<br />
Ki67 vs Clinicopathological 833 5.4 1 0.02 0.76 (0.71-0.81)<br />
model<br />
Concordance index of clinicopathological model alone is equal to 0.75 (0.7-0.8)<br />
S4-5<br />
Ki67 levels in pretherapeutic core biopsies as predictive and<br />
prognostic parameters in the neoadjuvant GeparTrio trial<br />
Denkert C, Blohmer JU, Müller BM, Eidtmann H, Eiermann W,<br />
Gerber B, Tesch H, Hilfrich J, Huober J, Fehm T, Barinoff J, Jackisch<br />
C, Prinzler J, Rüdiger T, Budczies J, Erbstoesser E, Loibl S, von<br />
Minckwitz G. Charite University Hospital, Berlin, Germany; <strong>San</strong>kt<br />
Gertrauden Krankenhaus, Berlin, Germany; Christian-Albrechts<br />
Universität zu Kiel, Kiel, Germany; Rotkreuzklinikum, München,<br />
Germany; Universitätsfrauenklinik Rostock, Germany; Bethanien<br />
Krankenhaus, Frankfurt, Germany; Eilenriede Klinik, Hannover,<br />
Germany; University of Düsseldorf, Germany; Universitäts<br />
Frauenklinik, Tübingen, Germany; Kliniken Essen Mitte, Essen,<br />
Germany; Klinikum Offenbach, Offenbach, Germany; Klinikum<br />
Karlsruhe, Karlsruhe, Germany; Klinikum St. Salvator, Halberstadt,<br />
Germany; German <strong>Breast</strong> Group, Neu-Isenburg, Germany<br />
Background: Ki67 has been suggested as a marker for definition of<br />
luminal A and luminal B tumors by the 2011 St. Gallen consensus<br />
panel. However, the cutoffs for Ki67 are still under debate. In<br />
particular, it is not clear if one single cutoff is useful for prognostic<br />
and predictive information in the different molecular subtypes. It is an<br />
advantage of the neoadjuvant approach that predictive and prognostic<br />
outcome measurements can be separated in the same cohort. In<br />
this study, we evaluated a large cohort of core biopsies from the<br />
neoadjuvant GeparTrio trial to investigate the impact of pretherapeutic<br />
Ki67 levels as a predictive marker for response to neoadjuvant<br />
chemotherapy as well as a prognostic marker for progression-free<br />
and overall survival. The analysis was stratified for hormone-receptor<br />
positive and negative tumors as well as HER2 status.<br />
Methods: A total of 1166 pretherapeutic core biopsies from<br />
the neoadjuvant Gepartrio trial were evaluated for Ki67 by<br />
immunohistochemistry, a total of 200 cells were counted in each<br />
sample. Ki67 cutoffs were evaluated using web-based software<br />
Cutoff Finder (http://molpath.charite.de/cutoff/). The details of the<br />
GeparTrio study design have been described before (von Minckwitz,<br />
JNCI 2008). We compared pCR rate as well as the overall and disease<br />
free survival in the complete cohort as well as subgroups of patients<br />
based on hormone receptor and HER2 expression.<br />
Results: Using Ki67 as a continuous parameter, a wide range of<br />
cutoffs between 10% and 80% for Ki67 were predictive for pCR.<br />
For DFS and OS, a wide range of cutoffs between 10% and 45% was<br />
significant. For further analysis, the three groups of Ki67 0-15% vs.<br />
Ki67 15.1%-35% vs. Ki67 >35 were defined and were compared for<br />
different outcome parameters. The pCR rates in these three groups<br />
of Ki67 expression were 4.2%, 12.9% and 29.0% (p35%) as a reasonable approach for further<br />
standardization of this marker.<br />
S4-6<br />
An international Ki67 reproducibility study<br />
Nielsen TO, Polley M-YC, Leung SCY, Mastropasqua MG, Zabaglo<br />
LA, Bartlett JMS, Viale G, McShane LM, Hayes DF, Dowsett M, On<br />
Behalf of the International Ki67 in <strong>Breast</strong> <strong>Cancer</strong> Working Group<br />
of the BIG-NABCG collaboration. University of British Columbia,<br />
Vancouver, BC, Canada; National <strong>Cancer</strong> Institute, Bethesda,<br />
MD; European Institute of Oncology, Milan, Italy; The Institute of<br />
<strong>Cancer</strong> Research, London, United Kingdom; Ontario Institute for<br />
<strong>Cancer</strong> Research, Toronto, ON, Canada; University of Michigan<br />
Comprehensive <strong>Cancer</strong> Center, Ann Arbor, MI; Royal Marsden<br />
Hospital, London, United Kingdom; <strong>Breast</strong> International Group-<br />
North American <strong>Breast</strong> <strong>Cancer</strong> Group Collaboration<br />
Introduction: In breast cancer, immunohistochemical assessment of<br />
the cell proliferation marker Ki67 is of interest for potential use in<br />
clinical management (e.g. prognosis, prediction of treatment response,<br />
monitoring the effect of neoadjuvant therapy). However, lack of<br />
consistency across labs has limited the value of Ki67. A working group<br />
was assembled to devise a strategy to harmonize Ki67 analysis and<br />
scoring and to identify procedures to improve concordance (Dowsett<br />
et al. JNCI,’11). As a result, we have conducted an international Ki67<br />
reproducibility study.<br />
Methods: Step 1: 100 breast cancer cases arranged into 1 mm core<br />
tissue microarrays (TMAs) were centrally stained using MIB-1<br />
antibody. Eight labs scored Ki67 as the percentage of positively<br />
stained invasive tumor cells using their own local method. Six labs<br />
repeated scoring of 50 cases on the same TMA 3 times. Ki67 data<br />
were log2-transformed to approximate a normal distribution. Pairwise<br />
intra-lab and inter-lab concordance was displayed using Bland-<br />
Altman plots. Sources of variation (e.g. patient and lab) were analyzed<br />
using two-way crossed random effects models with quantification of<br />
reproducibility via intraclass correlation coefficient (ICC; range of<br />
0-1, 1 = highest agreement).<br />
Step 2: A web-based scoring calibration interface was created to<br />
mitigate systematic differences in Ki67 interpretation observed in<br />
Step 1. Digital images of TMA cores from 9 “training” and 9 “test”<br />
cases representing a range of Ki67 values were assembled onto the<br />
web-based interface. An initial set of observers yielding consistent<br />
scores using a standardized scoring method served as reference labs.<br />
Detailed instructions for the standardized method were provided<br />
to 8 other labs, who were asked to score the cases and learn from<br />
discrepancies observed via the web tool. Statistical criteria for passing<br />
were pre-specified.<br />
Results: In Step 1, intra-lab reproducibility was high (ICC = 0.94).<br />
Inter-lab reproducibility was only moderate (ICC = 0.71). Absolute<br />
mean Ki67 values across the series ranged from 7% to 24%.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
102s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 5<br />
Contributing to inter-lab discordance were tumor region selection,<br />
formal counting of nuclei versus visual estimation, and subjective<br />
assessment of staining positivity. Labs using formal counting methods<br />
gave more consistent results than those using visual estimation. The<br />
calibration exercise (Step 2) helped to improve consistency: all 8 labs<br />
passed the training exercise, 4 at first attempt and 4 after 1-2 rounds<br />
of retraining. When the same 8 labs scored the 9 test calibration cases,<br />
3 passed on first attempt. Although overall concordance improved,<br />
discrepancies for cases with low Ki67 were largely responsible for<br />
the failure of the remaining 5 labs to pass the testing.<br />
Conclusions: Absolute values and cutpoints for Ki67, and associated<br />
clinical decisions, cannot be transferred between laboratories without<br />
careful standardization of scoring methodology. Our calibration<br />
training tool offers an initial process to improve inter-lab concordance,<br />
but further studies are required to establish what concordance can be<br />
achieved in practice. A large subsequent study will assess whether a<br />
pre-specified target of success (ICC = 0.9) can be achieved on glass<br />
slides after training with the web-based calibration tools developed<br />
as part of this study<br />
S4-7<br />
DISCUSSANT<br />
W. Fraser Symmans, MD, Department of Pathology, MD Anderson<br />
<strong>Cancer</strong> Center, Houston, TX<br />
S5-1<br />
Biomarker analyses in CLEOPATRA: A phase III, placebocontrolled<br />
study of pertuzumab in HER2-positive, first-line<br />
metastatic breast cancer (MBC)<br />
Baselga J, Cortés J, Im S-A, Clark E, Kiermaier A, Ross G, Swain SM.<br />
Massachusetts General Hospital <strong>Cancer</strong> Center and Harvard Medical<br />
School, Boston, MA; Vall d’Hebron University Hospital, Barcelona,<br />
Spain; Seoul National University College of Medicine, Seoul, Korea;<br />
Roche Products Limited, Welwyn, United Kingdom; F. Hoffmann-La<br />
Roche Limited, Basel, Switzerland; MedStar Washington Hospital<br />
Center, Washington, DC<br />
Background<br />
The anti-HER2 humanized monoclonal antibodies trastuzumab (T)<br />
and pertuzumab (P) have complementary mechanisms of action.<br />
CLEOPATRA showed that P+T+docetaxel (D) significantly improved<br />
progression-free survival (PFS) compared with placebo (Pla)+T+D<br />
in the first-line treatment of HER2-positive MBC (HR=0.62, 95%<br />
CI 0.51–0.75; p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Materials and Methods: HERA (BIG 01-01) is an international,<br />
multicenter, phase III randomized trial involving 5102 women<br />
with HER2-positive EBC. Pts were randomized, after completion<br />
of primary therapy [surgery, chemotherapy and radiotherapy as<br />
indicated], to T every 3 weeks for 1 yr, 2 years (yrs), or observation.<br />
This landmark efficacy analysis compares the outcome of pts<br />
randomized to either 2 yrs or 1 yr of T who were disease-free at 1 yr<br />
after randomization (N=1553 for 2 yrs, and N=1552 for 1 yr). The<br />
primary endpoint is DFS and secondary endpoints are OS and time to<br />
distant recurrence (TTDR). Updated efficacy analyses of the T arms<br />
vs. observation at 8-yrs of median follow-up (FU) are also presented.<br />
Results: On 12 April 2012 HERA reached the target number of 725<br />
DFS events needed for 80% power to detect a true hazard ratio (HR)<br />
of 0.80 for the comparison of 2 yrs vs. 1 yr of T. The unadjusted HR<br />
for an event in the 2-yr vs. 1-yr T arms was 0.99 (95% CI 0.85-1.14;<br />
P=0.86). OS in the two arms was comparable [HR=1.05 (95% CI<br />
0.86-1.28; P=0.63)]. TTDR results were similar. The primary cardiac<br />
endpoint* was comparable (1.0% vs. 0.8% for 2-yr and 1-yr arms,<br />
respectively), but the secondary cardiac endpoint** was higher in<br />
the 2-yr arm (7.2% vs. 4.1%). Importantly, the durable benefit in<br />
DFS and OS for both 1 yr and 2 yrs of T compared with observation<br />
remains stable at 8 yrs of median FU. Subgroup analyses including<br />
by hormone receptor status will be available for the meeting.<br />
Conclusions: These results confirm that 1 yr of adjuvant T remains<br />
the standard of care for HER2-positive EBC pts. It is also reassuring<br />
that the significant improvement in DFS and OS persists over time<br />
and that the incidence of cardiac endpoints remains low at a median<br />
FU of 8 yrs.<br />
* NYHA class III or IV, confirmed by a cardiologist, and LVEF <<br />
50% and ≥ 10% below baseline, OR cardiac death.<br />
** LVEF < 50% and ≥ 10% below baseline confirmed by repeat<br />
assessment, excluding patients with a primary cardiac endpoint.<br />
S5-3<br />
PHARE Trial results of subset analysis comparing 6 to 12 months<br />
of trastuzumab in adjuvant early breast cancer<br />
Pivot X, Romieu G, Bonnefoi H, Pierga J-Y, Kerbrat P, Guastalla J-P,<br />
Lortholary A, Espié M, Fumoleau P, Khayat D, Pauporte I, Kramar A.<br />
University Hospital J. Minjoz, Besancon, France; Anti <strong>Cancer</strong> Center<br />
Val d’Aurelle, Montpellier, France; Anti <strong>Cancer</strong> Center Bergonie,<br />
Bordeaux, France; Curie Institute, Paris, France; Anti <strong>Cancer</strong><br />
Center Eugene Marquis, Rennes, France; Anti <strong>Cancer</strong> Center Leon<br />
Berard, Lyon, France; Catherine de Sienne Center, Nantes, France;<br />
University Hospital St Louis, Paris, France; Anti <strong>Cancer</strong> Center<br />
Georges Francois Leclerc, Dijon, France; University Hospital Pitie<br />
Salpetriere, Paris, France; French National <strong>Cancer</strong> Institut (INCa),<br />
France; Centre Oscar Lambret, Lille, France<br />
Background: Since 2005, One year trastuzumab (T) treatment has<br />
been providing survival benefit to patients with early breast cancer<br />
and HER2 overexpression. However, the optimal duration of T<br />
has been debatable due to concerns for cardiac toxicity and results<br />
from the FinHer trial which showed that 9 weeks of T provided a<br />
similar magnitude of benefit than the 1-year treatment. The French<br />
National <strong>Cancer</strong> Institute (INCa) initiated an academic randomised<br />
non-inferiority trial aiming to compare a shorter T exposure of 6<br />
months versus the standard 12 months. This trial, named PHARE<br />
for ‘Protocol for Herceptin® as Adjuvant therapy with Reduced<br />
Exposure’ [NCT00381901] was approved byan independent ethics<br />
committee with regularly planned IDMC meetings.<br />
Patients and methods: Patients with HER2 + early breast cancer<br />
who received at least 4 cycles of (neo)-adjuvant chemotherapy<br />
were eligible. Randomization 1:1 using a minimisation algorithm<br />
was stratified on concomitant or sequential T administration with<br />
chemotherapy, oestrogen receptors (ER) status and center. The<br />
primary objective was to compare disease free survival (DFS). Overall<br />
survival (OS) and cardiac toxicity were investigated as secondary<br />
aims. An absolute loss of 2% in DFS in the experimental arm was<br />
defined as the non-inferiority margin (1.15 in relative terms) and<br />
required 3400 patients with alpha=0.05 and 80% power.<br />
Results: Between 5/2006 and 7/2010, 3382 patients were randomized<br />
to 6 or 12 months of T following the IDMC recommendation for<br />
accrual interruption and extended follow-up. Disease and treatment<br />
characteristics were well balanced between the 2 arms: median age<br />
55 years (range 21 - 86), median tumour size 20 mm (0 - 270), node<br />
involvement 45%, SBR grade III 56%, ER positive 58%, radiotherapy<br />
88%; concomitant T administration 58%, anthracyclin and taxane<br />
containing chemotherapy 73%. The data-base was locked on July<br />
30 th , 2012. The 95% HR confidence interval was ranged between 1.09<br />
- 1.66 for DFS between the 2 arms and it included the pre-specified<br />
non-inferiority margins of 1.15. Thus the results were inconclusive<br />
regarding the non-inferiority (p = 0.14). A subset analysis based on<br />
stratification factors will be presented at SABCS.<br />
S5-4<br />
EGFR expression measured by quantitative immunofluorescense<br />
is associated with decreased benefit from trastuzumab in the<br />
adjuvant setting in the NCCTG (Alliance) N9831 trial.<br />
Rimm D, Ballman KV, Cheng H, Vassilakopoulou M, Chen B,<br />
Gralow J, Hudis C, Davidson NE, Psyrri A, Fountzilas G, Perez<br />
EA. Yale University School of Medicine, New Haven, CT; Mayo<br />
Clinic, Rochester, MN; Seattle <strong>Cancer</strong> Care Alliance, Seattle, WA;<br />
Memorial Sloan-Kettering <strong>Cancer</strong> Center, New York, NY; University<br />
of Pittsburgh <strong>Cancer</strong> Institute, Pittsburgh, PA; “Papageorgiou”<br />
Hospital, Aristotle University of Thessaloniki School of Medicine,<br />
Thessaloniki, Macedonia, Greece; Attikon University Hospital,<br />
Athens, Greece; Mayo Clinic, Jacksonville, FL<br />
Background: Epidermal Growth Factor Receptor (EGFR, HER1) is<br />
known to heterodimerize with HER2 and may impact the effectiveness<br />
of trastuzumab. Historically, EGFR has been difficult to measure;<br />
thus there is no evidence regarding its effects on trastuzumab<br />
clinical therapy. Here we use a new, standardized, quantitative<br />
immunofluorescence assay and a novel EGFR antibody to evaluate<br />
the correlation between EGFR expression and clinical outcome in a<br />
cohort from the North Central <strong>Cancer</strong> Treatment Group (NCCTG,<br />
Alliance) N9831 trial.<br />
Methods: Of the 3505 women in the N9831 trial, tissue microarrays<br />
were constructed that allowed analysis of 1,444 patients randomly<br />
assigned to receive chemotherapy alone (Arm A), sequential<br />
trastuzumab after chemotherapy (Arm B) or concurrent trastuzumab<br />
with chemotherapy (Arm C). Fluorescence-based, standardized<br />
measurement of EGFR was done using the rabbit monoclonal EGFR<br />
antibody D38B1 on the AQUA platform (HistoRx). EGFR expression<br />
levels were analyzed as a continuous variable and dichotomized using<br />
recursive partitioning to define an optimal cut point. The cut point<br />
was validated on an independent retrospective cohort comprised<br />
of 130 patients with HER2-positive metastatic breast cancer who<br />
received trastuzumab.<br />
Results: EGFR assessed as a continuous variable shows an<br />
association with disease free survival (DFS) in Arm C (p=0.002) but<br />
not in Arms A or B. Dichotomizing EGFR expression shows that<br />
high level expression is associated with worse outcome (HR=2.2;<br />
95% CI 1.33-3.59, p=0.002) in arm C. Five year DFS within the low<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
104s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 5<br />
level EGFR expression group was 71%, 74% and 90% for Arms A,<br />
B and C, respectively (log-rank p-value=0.02) and within the high<br />
level EGFR expression (n= 213) group was 62%, 76% and 74%<br />
respectively (log-rank p-value 0.22). As validation, the same cut-point<br />
was used to define high EGFR expression in a retrospective metastatic<br />
breast cancer cohort. The median progression free survival difference<br />
between EGFR high group and EGFR low group was 6.1 months<br />
(p=0.0063) and the hazard ratio of high EGFR was 1.92 (p=0.0073).<br />
Conclusions: High expression of EGFR by the AQUA platform<br />
appears to be associated with decreased benefit from adjuvant<br />
concurrent (not sequential) trastuzumab and shorter PFS in the<br />
metastatic setting. The biological underpinning for these observations<br />
is being considered. Since there are other treatment options for HER2-<br />
driven tumors, this marker, once validated, could help select patients<br />
for alternative or additive therapy.<br />
S5-5<br />
Trastuzumab plus adjuvant chemotherapy for HER2-positive<br />
breast cancer: Final planned joint analysis of overall survival<br />
(OS) from NSABP B-31 and NCCTG N9831<br />
Romond E, Suman VJ, Jeong J-H, Sledge, Jr. GW, Geyer, Jr. CE,<br />
Martino S, Rastogi P, Gralow J, Swain SM, Winer E, Colon-Otero G,<br />
Hudis C, Paik S, Davidson N, Mamounas EP, Zujewski JA, Wolmark<br />
N, Perez EA. National Surgical Adjuvant <strong>Breast</strong> and Bowel Project<br />
(NSABP) Operations and Biostatistical Centers; University of<br />
Kentucky; Mayo Clinic; University of Pittsburgh Graduate School<br />
of Public Health; IU Simon <strong>Cancer</strong> Center; University of Texas<br />
Southwestern Medical Center; The Angeles Clinic and Research<br />
Institute; University of Pittsburgh <strong>Cancer</strong> Institute; University of<br />
Washington; Medstar Washington Hospital Center; Dana-Farber<br />
<strong>Cancer</strong> Institute; Memorial Sloan-Kettering <strong>Cancer</strong> Center; Aultman<br />
Hospital; <strong>Cancer</strong> Therapy Evaluation Program, National <strong>Cancer</strong><br />
Institute, National Institutes of Health, D.H.H.S; Allegheny <strong>Cancer</strong><br />
Center Allegheny General Hospital<br />
Background: Preplanned combined analysis of the National Surgical<br />
Adjuvant <strong>Breast</strong> and Bowel Project (NSABP) B-31 trial and North<br />
Central <strong>Cancer</strong> Treatment Group (NCCTG) (Alliance) N9831 Trial<br />
compared adjuvant chemotherapy with or without trastuzumab in<br />
women with HER2-positive breast cancer. The initial results were<br />
reported in 2005 and updated in early 2011<br />
Methods: 4045 patients with HER2-positive operable breast cancer<br />
were enrolled to receive doxorubicin plus cyclophosphamide followed<br />
by paclitaxel with or without trastuzumab in both trials. The definitive<br />
analysis for OS will occur when 710 events have been reported.<br />
Results: Median time on study is 8 years. The required number of<br />
events have occurred for the definitive analysis for OS to be conducted<br />
by the end of September 2012. Updated analyses of disease free<br />
survival and related subgroups will also be presented.<br />
Supported by NCI grants U10-CA-12027, -69651, -37377, -69974,<br />
-44066, U24-CA-114732, CA25224; <strong>Breast</strong> <strong>Cancer</strong> Research<br />
Foundation; Genentech 35-03<br />
S5-6<br />
Activating HER2 mutations in HER2 gene amplification negative<br />
breast cancers.<br />
Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC,<br />
Monsey J, Li S, Ding L, Mardis ER, Ellis MJ. Washington University<br />
School of Medicine, St. Louis, MO<br />
Background: <strong>Breast</strong> cancer genome sequencing projects, performed<br />
by the genome sequencing centers in the U.S., Canada, and the U.K.,<br />
are elucidating the somatic mutations and other genomic alterations<br />
that occur in human breast cancer. These studies recently identified<br />
somatic HER2 mutations in breast cancers lacking HER2 gene<br />
amplification.<br />
Results: Compilation of data from seven sequencing studies<br />
documented 22 patients with somatic HER2 mutations. These<br />
mutations clustered in three regions. The first cluster was at amino<br />
acid (aa) 309-310 (exon 8), located in the extracellular domain. These<br />
aa residues form part of the HER2 dimerization interface. The second<br />
cluster was at aa 755-781, located in the kinase domain (exons 19-20).<br />
This was the most common location for HER2 mutations, with 17 out<br />
of 22 patients having somatic mutations here. The third region was at<br />
aa 835-896, also in the kinase domain (exons 21-22). Using multiple<br />
experimental approaches (cell line experiments, in vitro kinase<br />
assays, protein structure modeling, and xenograft experiments), we<br />
tested seven of these HER2 mutations and showed that 4 of them are<br />
activating mutations that are sensitive to lapatinib and trastuzumab.<br />
Another 2 mutations were found to be lapatinib resistant and we<br />
determined their sensitivity to neratinib, canertinib, and gefitinib.<br />
Conclusions: These findings biologically validate somatic HER2<br />
mutations as good targets for breast cancer treatment, but the<br />
appropriate choice of targeted drug is dependent on the precise<br />
mutation present. This study is among the first to functionally<br />
characterize mutations identified by breast cancer genome sequencing.<br />
A prospective, multi-institutional clinical trial has been launched to<br />
screen for HER2 mutation positive patients and determine the clinical<br />
outcome of treatment with HER2 targeted drugs.<br />
S5-7<br />
Combined Blockade of PI3K/AKT and EGFR/HER3 Enhances<br />
Anti-Tumor Activity in Triple Negative <strong>Breast</strong> <strong>Cancer</strong><br />
Tao J, Ip P, Auricchio N, Juric D, Yu M, Shyamala M, Kim P, Singh<br />
S, Hazra S, Haber D, Scaltriti M, Baselga J. Massachusetts General<br />
Hospital; Prometheus Lab<br />
Background: Up to 60% of triple negative breast cancers (TNBCs)<br />
express high levels of EGFR (HER1). Moreover, TNBCs are<br />
associated with increased frequency of phosphatase and tension<br />
homologue (PTEN) loss of function, leading to hyperactivation of<br />
the phosphoinositide 3-kinase (PI3K)/AKT pathway. This provides<br />
the rationale for using PI3K/AKT inhibitors in this subset of patients.<br />
However, compensatory expression of receptor tyrosine kinases<br />
(RTKs) such as HER3 may limit efficacy of PI3K/AKT inhibitors.<br />
Therefore, we hypothesize that combined targeting of both HER<br />
family receptors and the PI3K/AKT pathway will result in superior<br />
antitumor activity compared to single agent blockade in TNBC.<br />
Materials and Methods: TNBC cell lines MDA-MB-231, MDA-<br />
MB-468, HCC70, HCC1143 and HCC1937 were treated with<br />
MEHD7945A, a dual-action antibody that targets both EGFR and<br />
HER3, AKT inhibitor GDC0068, and pan-PI3K inhibitor GDC0941.<br />
Cell viability was measured by CellTiter-Glo and Crystal Violet. Both<br />
cell line- and patient-derived xenograft models of TNBC were grown<br />
subcutaneously in Nu/Nu mice and then treated with MEHD7945A,<br />
GDC0068, GDC0941, or the combination of MEHD7945A with<br />
either GDC0068 or GDC0941. Tumor size and histology were<br />
examined. Circulating tumor cells (CTCs) were isolated from murine<br />
peripheral blood by Herring Bone CTC chip. Protein expression was<br />
measured by Western blot, Reverse Phase Protein Analysis (RPPA),<br />
and immunohistochemistry.<br />
Results: GDC0068 and GDC0941 treatment resulted in variable<br />
inhibition of cell viability, with IC50s ranging from 170 nM to<br />
>1 µM across all TNBC cell lines. Under full-serum (10% FBS)<br />
conditions, MEHD7945A led to a very mild decrease in cell viability<br />
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in vitro. Combination treatments were modestly more effective than<br />
monotherapy in vitro. In vivo, MEHD7945, GDC0941 and GDC0068<br />
showed variable delay in tumor growth whereas combination of<br />
MEHD7945A with either GDC0068 or GDC0941 was superior to<br />
single agent treatment. While untreated tumors increased over 14<br />
fold in size, tumor growth of MEHD7945, GDC0941 and GDC0068<br />
treated xenografts reached 6, 4 and 2.5 fold increase respectively.<br />
However, both combination arms prevented tumor growth, with<br />
complete responses achieved in 1/9 mice in each of the combination<br />
cohorts. Of note, all the treatments (up to 9 weeks of therapeutic<br />
exposure) were well tolerated. Analysis of treated tumors reveals<br />
potent inhibition of the PI3K/AKT pathway, with decreased levels<br />
phospho-PRAS40, and phospho-S6, as well as decreased expression<br />
of total EGFR and HER3. Circulating tumor cells are being used as<br />
surrogate markers of pathway inhibition.<br />
Conclusions: Combined therapy with MEHD7945A and either<br />
GDC0068 or GDC0941 was superior to monotherapy in preclinical<br />
models of TNBC. We observed significantly greater effect with the<br />
combination treatment in vivo compared to in vitro. We are currently<br />
exploring whether expression/activation of the HER receptors<br />
following PI3K/Akt blockade are accentuated in vivo. Additionally,<br />
this may be the first mouse model enabling CTC collection from<br />
subcutaneous xenografts, allowing for real-time pharmacodynamic<br />
investigation. These findings provide the rationale for combined<br />
targeting of PI3K/AKT and EGFR/HER3 in triple negative breast<br />
cancers.<br />
S5-8<br />
Parallel upregulation of Bcl2 and estrogen receptor (ER)<br />
expression in HER2+ breast cancer patients treated with<br />
neoadjuvant lapatinib.<br />
Giuliano M, Wang YC, Gutierrez C, Rimawi MF, Chang JC, Wang<br />
T, Hilsenbeck SG, Trivedi MV, Chamness GC, Osborne CK, Schiff<br />
R. Lester & Sue Smith <strong>Breast</strong> Center, Baylor College of Medicine,<br />
Houston, TX; Baylor College of Medicine, Houston, TX; The<br />
Methodist Hospital Research Institute, Houston, TX; University of<br />
Houston, TX<br />
Background: We previously showed in HER2+ models of breast<br />
cancer (BC) that potent inhibition of the HER receptor layer can<br />
lead to re-expression of estrogen receptor (ER) or activation of the<br />
ER pathway. Consequently, the anti-apoptotic ER gene product<br />
Bcl2 is upregulated, resulting in enhanced tumor cell survival and<br />
treatment resistance. In this study, we investigated whether Bcl2 and<br />
ER expression levels are simultaneously increased by neoadjuvant<br />
treatment with the dual HER1/2 tyrosine kinase inhibitor lapatinib<br />
in HER2+ BC patients.<br />
Methods: In a neoadjuvant phase II clinical trial 49 HER2+ BC<br />
patients were treated with lapatinib as a single agent for 6 weeks,<br />
followed by trastuzumab/docetaxel for 12 weeks before surgery.<br />
Tumor specimens were prospectively collected at different timepoints<br />
during lapatinib treatment (baseline, and weeks 2 and 4).<br />
Bcl2, ER, progesterone receptor (PR), total (t) and phosphorylated<br />
(p)-HER2, and Ki67 were assessed by immunohistochemistry.<br />
Spearman correlation was used to evaluate the association among the<br />
biomarkers at baseline, and the correlation of their changes over time.<br />
Fisher’s Exact test and non-parametric Wilcoxon rank sum test were<br />
used respectively to determine if the frequency and the magnitude<br />
of Bcl2 expression changes were associated with baseline ER status.<br />
Results: 35/49 HER2+ tumor specimens (71%) were available for<br />
baseline evaluation of Bcl2 and ER. Of those, 12 (34%) were ERpositive<br />
(Allred score ≥ 3) and 23 (66%) ER-negative. Baseline Bcl2<br />
expression correlated positively with ER (r=.75; p
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
were performed using supervised and unsupervised methods. A<br />
bias in isoform quantitation was first identified that correlated with<br />
RNA Integrity Score (i.e. RIN). When this bias was accounted<br />
for, unsupervised methods identified 9 genes that demonstrated<br />
significant isoform switching that was independent of subtype.<br />
Supervised analysis of basal-like versus luminal tumors identified<br />
30 genes showing isoform switching including CD44, CTNND1 and<br />
RAD51L1; most of these unique isoform switches also correlated<br />
with the expression of many other genes that did not show isoform<br />
changes. Additional analyses are being performed including 1)<br />
identification of genes expressing more than one isoform, but which<br />
do not change dramatically in abundance across samples, and 2)<br />
correlations of genomic DNA somatic mutations with the mRNA-seq<br />
based mutation detection.<br />
Conclusions: Appropriate processing of mRNA-sequencing data<br />
yields unparalleled information in isoform level abundance and<br />
robust expression signatures. The modest isoform switching observed<br />
here segregated samples into distinct groups of common switching<br />
events, most of which correlated with subtype. The additional data<br />
types provided by mRNA-seq including isoform identification, fusion<br />
gene detection, and mutation information, extend the capabilities of<br />
expression analyses and may provide new data of clinical utility.<br />
S6-2<br />
Characterization of different foci of multifocal breast cancer using<br />
genomic, transcriptomic and epigenomic data<br />
Desmedt C, Nik-Zainal S, Fumagalli D, Rothé F, Singhal S, Majjaj<br />
S, Brown D, Dedeurwaerder S, Defrance M, Maetens M, Adnet P-Y,<br />
Vincent D, Salgado R, Fuks F, Piccart M, Larsimont D, Campbell<br />
P, Sotiriou C. Institut Jules Bordet, Brussels, Belgium; Wellcome<br />
Trust <strong>San</strong>ger Institute, Hinxton, United Kingdom; Université Libre<br />
de Bruxelles, Brussels, Belgium<br />
Background: A significant proportion of breast cancer (BC) patients<br />
(pts) develop multiple synchronous unilateral breast tumors, also<br />
referred to as multifocal BC (MBC), which represent a diagnostic<br />
and therapeutic challenge. Here, we aimed first to better define the<br />
incidence of MBCs and then to compare different foci from ductal<br />
MBCs in a global analysis using genomic, transcriptomic and<br />
epigenomic data.<br />
Methods: The incidence of MBCs was sought via a systematic query<br />
of all pathology reports between 2000 and 2010 within the Institut<br />
Bordet. The biological characterization of MBCs focused on 5 ductal<br />
MBCs for which the foci did not differ in terms of grade, hormonal<br />
receptors and HER2 status, since this is the case for the majority of<br />
MBCs. It involved the identification of somatic rearrangements (Rs),<br />
transcriptomic and epigenomic profiling in 2 foci from each pt, via<br />
low-coverage whole genome sequencing, HG133 Plus 2.0 Chips and<br />
Infinium Methylation 450K arrays respectively. Genomic Rs were<br />
validated using an orthogonal sequencing platform.<br />
Results: MBC is a frequent finding since it concerns 24% (1410/5811)<br />
of primary BCs. When investigating the genomics of the 5 MBCs,<br />
we observed that the number of Rs varied in each pt, with 3 pts<br />
having few ( 100Rs with a<br />
particular tandem-duplication phenotype. All pts had Rs common to<br />
both foci, suggesting a shared genetic background. Strikingly, in 4 pts,<br />
we observed a branched evolutionary pattern since private Rs were<br />
present in each focus. In contrast, we observed a linear evolutionary<br />
pattern in the remaining pt, since private Rs were only found in 1<br />
of the 2 foci.<br />
Two pts were genetically very similar with ≥75% common Rs.<br />
Although the transcriptomic profiles looked very similar between<br />
the 2 foci, significant epigenomic differences were observed in 1 of<br />
the 2 pts investigated. Two other pts had 50% common Rs. In one pt<br />
there were only minor differences in transcriptomic and methylation<br />
patterns between the 2 foci. Contrastingly, in the second pt, DNA<br />
methylation patterns were dramatically discordant between the foci,<br />
suggesting that genomic, transcriptomic and epigenomic patterns are<br />
not necessarily correlated. Only in 1 pt of the 5 investigated, the 2<br />
foci were extremely different, with only 14% of common Rs. These<br />
genetic differences were associated with dramatic differences in<br />
methylation and transcriptomic profiles. Interestingly, for 4 pts some<br />
of the identified rearrangements were found in parts of tumor-adjacent<br />
histologically normal breast tissue.<br />
Conclusions: Today, the College of American Pathologists<br />
recommends analysing more than 1 focus from MBC if they differ<br />
in histology and grading (Lester 2009). Here, we demonstrated<br />
for the first time that different lesions from MBC, which concerns<br />
¼ of the ductal BC population, can differ at the (epi)genetic and<br />
transcriptomic level even when the foci present similar histology,<br />
grading, hormonal and HER2 status. Since the number of genetic<br />
alterations with potential clinical utility is rapidly growing due to<br />
increasing numbers of targeted therapies, these findings suggest<br />
that interrogating only the largest lesion might not be sufficient for<br />
adequate management of MBCs.<br />
S6-3<br />
Neurocognitive impact in adjuvant chemotherapy for breast<br />
cancer linked to fatigue: A Prospective functional MRI study<br />
Cimprich B, Hayes DF, Askren MK, Jung MS, Berman MG, Ossher<br />
L, Therrien B, Reuter-Lorenz PA, Zhang M, Peltier S, Noll DC.<br />
University of Michigan, Ann Arbor, MI; University of Washington,<br />
Seattle, WA; Rotman Research Institute at Baycrest, University of<br />
Toronto, Canada<br />
Background: Our previous research showed evidence of compromised<br />
cognitive function prior to adjuvant chemotherapy for breast cancer,<br />
with fatigue as a contributory factor. Fatigue is a common symptom<br />
reported by women treated for breast cancer, yet its association with<br />
neurocognitive function has not been systematically examined. In this<br />
prospective study, we examined possible alterations in neurocognitive<br />
responses, namely, working memory, from pre- to post- adjuvant<br />
treatment during functional magnetic resonance imaging (fMRI) and<br />
further investigated whether early fatigue might be linked to cognitive<br />
alterations over time.<br />
Methods: Women treated with either adjuvant chemotherapy<br />
(anthracyline-based combination regimen, n=29) or radiotherapy<br />
(n=37) for localized breast cancer (Stages 0-IIIa) and age-matched<br />
healthy controls (n=32) were enrolled. Participants performed a verbal<br />
working memory task (VWMT) with varying levels of demand for<br />
cognitive control during fMRI scanning and provided self-reports of<br />
fatigue (FACT-F) at two time points coincident with pre- and onemonth<br />
post chemotherapy assessments. Imaging data were analyzed<br />
with general linear models using SPM5; comparative statistics were<br />
used to determine group differences, and correlational analyses<br />
addressed relationships of fatigue and neurocognitive measures.<br />
Findings: The chemotherapy group reported significantly greater<br />
severity of fatigue (p < .05) and performed less accurately on the<br />
VWMT both pre- and one-month post-treatment than the other groups.<br />
Greater fatigue was correlated with poorer performance on the VWMT<br />
at both time points across groups, with stronger correlation posttreatment<br />
(r = -.22, p = .03). A 2 time-point (pre- vs. post-treatment) x<br />
2 group (chemotherapy vs. controls) x 2 demand-level contrasts (high<br />
minus low vs. medium minus low) analytic model showed a significant<br />
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<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
group x time interaction (p < .05), mainly due to lower pre-treatment<br />
activation in an area of the prefrontal cortex supporting working<br />
memory, the anatomical left inferior frontal gyrus (LiFG), at higher<br />
task demand in the chemotherapy group. The radiotherapy group<br />
scored between the other two groups with intermediate activation<br />
of those contrasts. Of interest, lower pre-treatment activation in the<br />
LiFG in the high-low demand contrast predicted severity of fatigue<br />
across all participants at the post-treatment assessment (r = -.27, p <<br />
.01), linking early compromise in neurocognitive performance with<br />
greater fatigue over time.<br />
Discussion: Neurocognitive alterations during a working memory task<br />
and greater fatigue were evident before any adjuvant chemotherapy<br />
for breast cancer. Notably, functional alterations in working memory<br />
processes were evident with fMRI before adjuvant chemotherapy and<br />
predicted severity of post-treatment fatigue. Importantly, across all<br />
participants, greater fatigue over time was correlated with reduced<br />
cognitive performance. Taken together, these findings indicate<br />
that pre-treatment neurocognitive compromise and fatigue are<br />
key contributors to the cognitive impact often attributed solely to<br />
chemotherapy. Early therapeutic interventions targeting fatigue may<br />
improve cognitive function and reduce the distress of “chemo brain”<br />
throughout the course of adjuvant treatment.<br />
S6-4<br />
Vitamin D, but not bone turnover markers, predict relapse in<br />
women with early breast cancer: an AZURE translational study.<br />
Coleman RE, Rathbone EJ, Marshall HC, Wilson C, Brown JE,<br />
Gossiel F, Gregory WM, Cameron D, Bell R. University of Leeds,<br />
United Kingdom; University of Sheffield, United Kingdom; University<br />
of Edinburgh, United Kingdom; Andrew Love <strong>Cancer</strong> Centre,<br />
Geelong, Australia<br />
Background: The AZURE trial evaluated the addition of zoledronic<br />
acid (ZOL) to standard adjuvant therapy on relapse rates and<br />
survival in pts with stage II/III breast cancer. While the overall<br />
analysis reported no benefit, a pre-planned subgroup analysis showed<br />
significant benefits in postmenopausal (PM) women. Here we report<br />
whether baseline measurements of 25-hydroxyvitamin D (25-OHD)<br />
and the serum bone turnover markers N-terminal propeptide type I<br />
procollagen (P1NP) and beta C-terminal telopeptide type I collagen<br />
(β-CTX) can identify pts at high risk of relapse and/or modify the<br />
treatment effects of ZOL.<br />
Methods: 872 AZURE pts consented for serum to be collected and<br />
stored for translational research projects (ZOL group n=431; control<br />
group n=441). Serum P1NP, β-CTX and 25-OHD levels were<br />
measured in 867, 863 and 856 pts respectively. These markers were<br />
analysed as categorical variables with determined cut-off points to<br />
predict bone as 1st site of distant recurrence (DR) or any distant<br />
relapse (P1NP (ng/ml), >70 versus ≤70; βCTX (ng/ml), >0.299 versus<br />
≤0.299; 25-OHD (ng/ml), ≤30 versus >30). Additionally, the markers<br />
were assessed for an interaction with ZOL. Analyses were adjusted<br />
for systemic therapy, lymph node and ER status. As in previous<br />
analyses of AZURE, the PM cohort was defined as ≥5 years since<br />
last menses; all other patients are included in a “not postmenopausal”<br />
(not-PM) group.<br />
Results: The baseline disease characteristics of the translational cohort<br />
were similar to those of the total AZURE population and showed a<br />
similar benefit of ZOL among the PM patients: hazard ratio (HR) for<br />
DR = 0.61 (95% CI 0.35, 1.07; p-value for interaction with not-PM<br />
women = 0.0173). At a median follow-up of 53.3 months, 150 pts<br />
have had a 1st DR event; 47 had bone-only relapse, 19 bone plus<br />
other distant site and 84 developed non-bone DR.<br />
Mean value of 25-OHD (ng/ml) was 18.30 (range, 3.16-54.82;<br />
SD=9.19) with 61.0% of pts 30.<br />
25-OHD levels >30 ng/ml were significantly associated with lower<br />
risk for bone relapse (HR 0.11, 95% CI 0.02, 0.76; p-value 0.0257).<br />
A similar trend was seen for any site of DR (HR 0.56, 95% CI 0.31,<br />
1.01; p-value = 0.0519). Additionally, 25-OHD levels were prognostic<br />
for bone relapse when analysed as a continuous value (HR 0.97, 95%<br />
CI 0.94, 1.00; p-value = 0.0474). Finally, 25-OHD levels >30 ng/<br />
ml predicted for benefit of treatment with ZOL in PM women with<br />
regards to DR (HR 0.09, 95% CI 0.01, 0.82; interaction p-value<br />
0.0747) but the trend was not seen in not-PM women.<br />
Mean values for P1NP and βCTX (range; SD) were 59.1 ng/ml (
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
invasive disease-free survival (IDFS) [Hudis 2007] with adjuvant CT<br />
± 1 year of BEV. Secondary outcome measures are overall survival<br />
(OS), breast cancer-free interval, disease-free survival (DFS), distant<br />
DFS, and safety (NCI CTCAE v3.0). The sample size was calculated<br />
to provide 80% power for a HR=0.75 at α=0.05 assuming 5-year<br />
IDFS of 72.0% with CT vs 78.2% with CT + BEV with 388 events.<br />
BEATRICE also includes evaluation of potential predictive and<br />
prognostic biomarkers.<br />
Results: Between Dec 2007 and Mar 2010, 2591 patients were<br />
randomized. At data cut-off (Feb 29, 2012), median follow-up was<br />
32 months.<br />
Patient characteristics, % of patients CT (N=1290)<br />
CT + BEV (N=1301)<br />
Age, years<br />
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
docetaxel (T) (Gianni L, Lancet Oncol 2012) were characterized. We<br />
assessed the association of pre-selected adaptive immune functions<br />
and key immune regulatory genes with the likelihood of achieving a<br />
pathological complete response (pCR) in NeoSphere.<br />
Methods: Baseline core biopsies were collected from 387/417<br />
patients. Gene expression profiles (Affymetrix U133 Plus 2.0) were<br />
obtained for 367 samples (88% of all patients) that were evenly<br />
distributed among arms A (TH, n=90), B (THP, n=95), C (HP, n=98),<br />
and D (TP, n=84). ER status was defined by IHC. The primary endpoint<br />
was pCR in breast. We assessed metagenes (average expression of the<br />
associated genes) corresponding to: immunoglobulins (IgG), CD8A,<br />
MHC type I and type II (MHC1, MHC2), interferon inducible genes<br />
(I-IG) and STAT1-related genes. We also assessed the individual<br />
genes PD1, PD-L1, PD-L2, CTLA4, IFNG.<br />
Results: ER+ and ER- tumors had differential mRNA expression<br />
for: CD8A, IgG, PD-L2, PD1, IFNG (overexpressed in ER-), and<br />
I-IG (overexpressed in ER+). Positive correlations were observed<br />
between most of these biomarkers. Only PD1 was inversely correlated<br />
with STAT1, interferon and MHC2. In logistic univariate regression<br />
analyses some biomarkers showed moderate association with pCR or<br />
residual disease without consistent patterns between treatment arms.<br />
However, a multivariate logistic regression model constructed for<br />
all the selected biomarkers revealed that high expression of PD-L1<br />
was consistently associated with lower pCR rate in all chemotherapy<br />
containing arms (A, B and D). A similar trend was present also in Arm<br />
C, the arm with antibody treatment alone. In all arms, high expression<br />
of IFNG and/or STAT1 were associated with higher pCR rate. In<br />
multivariate analysis PD-L1, PD1 and STAT1 were associated with<br />
pCR irrespective of the ER status in combined arms A, C and D. In<br />
arm B, both CTLA4 and PD-L1 were independently associated with<br />
lower pCR in ER- tumors.<br />
Conclusions: The association between pCR and selected immune<br />
biomarkers in patients treated with pertuzumab, trastuzumab, or both,<br />
with or without chemotherapy, supports our understanding of the key<br />
role of the immune system in contributing to HER2-targeted antibody<br />
therapy on top of signaling inhibition. High PD-L1 expression<br />
emerged for its consistent association with lower pCR. These results<br />
provide a rationale for combining HER2-targeted treatments with<br />
immune-modulating agents and may allow the prediction of treatment<br />
benefit. Validation of these results with different assays is ongoing.<br />
PD01-01<br />
Overcoming endocrine therapy resistance related to PTEN loss<br />
by strategic combinations with mTOR, AKT, or MEK inhibitors<br />
Fu X, Kumar V, Shea M, Biswal NC, Nanda S, Chayanam S, Mitchell<br />
T, Hergenroeder G, Meerbrey KL, Joshi A, Westbrook TF, Mills GB,<br />
Creighton CJ, Hilsenbeck SG, Osborne CK, Schiff R. Lester & Sue<br />
Smith <strong>Breast</strong> Center, Baylor College of Medicine, Houston, TX; Dan<br />
L Duncan <strong>Cancer</strong> Center, Baylor College of Medicine, Houston, TX;<br />
Baylor College of Medicine, Houston, TX; M.D. Anderson <strong>Cancer</strong><br />
Center, Houston, TX<br />
Background: Hyperactive PI3K signaling is associated with a more<br />
aggressive subtype of estrogen receptor (ER) positive breast cancer<br />
(BC) and with endocrine resistance. Loss or downregulation of PI3K’s<br />
inhibitor PTEN is more common in basal and luminal B vs. luminal<br />
A BC. However, the role of PTEN in modulating response to various<br />
endocrine therapies is unclear. Here we investigated the effects of<br />
PTEN knockdown (KD) on endocrine sensitivity and the potential of<br />
multiple kinase inhibitors to restore and improve responses. Methods:<br />
Nude mice bearing ER+ BC xenograft tumors of MCF7 cells stably<br />
expressing a doxycycline (Dox)-inducible PTEN-shRNA were<br />
randomized to four endocrine treatment groups [continued estrogen<br />
(E2) supplementation, or E2-deprivation (ED) alone or in combination<br />
with tamoxifen (Tam) or fulvestrant (Ful)]; all -/+ Dox. The effects of<br />
single or combined kinase inhibitors on these endocrine treatments -/+<br />
Dox were studied in vitro using inhibitors (i) to mTOR (AZD2014,<br />
0.2 µM), AKT (AZD5363, 1 µM), or MEK (Selumetinib/ARRY-<br />
142886, 1 µM). Cell growth, apoptosis, and ER and progesterone<br />
receptor (PR) signaling were analyzed using cell cytometry, qRT/<br />
PCR, and Western blotting. Synergism tests were used to examine<br />
the growth effects of the most promising combinatorial therapy with<br />
multiple kinase inhibitors in different endocrine settings. Results: In<br />
wild-type (WT) PTEN xenograft tumors, endocrine therapies were<br />
very effective, inducing frequent tumor regression. In PTEN KD<br />
tumors endocrine therapies were less effective — PTEN KD delayed<br />
tumor regression in all endocrine regimens and accelerated tumor<br />
progression in the Tam treated group. Furthermore, at day 250, only<br />
1/8 and 0/7 tumors had developed resistance in the ED and the Ful<br />
(-Dox) groups, respectively, while with PTEN KD (+Dox), 7/15 and<br />
5/15 tumors developed resistance to ED and to Ful. In vitro PTEN<br />
KD also induced resistance to all endocrine therapies. mRNA and/<br />
or protein levels of ER and PR were suppressed by PTEN KD and<br />
restored by mTORi and AKTi. In cells with WT PTEN, mTORi was<br />
highly effective with or without endocrine therapy. However, AKTi<br />
and MEKi were more effective in combination with endocrine therapy.<br />
All three inhibitors were less effective upon PTEN KD. The mTORi<br />
plus AKTi combination resulted in a potent synergistic inhibition in<br />
PTEN KD cells in the presence of E2 or with ED. In contrast, in the<br />
presence of Tam, AKTi plus MEKi, independent of PTEN status, was<br />
the most effective combination at the doses chosen. Finally, these<br />
inhibitors and combinations were more effective in the presence of<br />
Ful than ED or Tam in WT PTEN cells. AKTi combined with Ful<br />
was still highly effective even in PTEN KD cells, but mTORi and<br />
MEKi were less effective. Conclusions: Our results suggest that PTEN<br />
loss renders endocrine therapy less effective in in vitro and in vivo<br />
experimental models. Single AKT/MEK kinase inhibitors are more<br />
potent in the presence of endocrine therapy. In PTEN KD cells, the<br />
activity of all three kinase inhibitors is largely diminished, except for<br />
AKTi in the presence of fulvestrant. Kinase inhibitor combinations<br />
are generally more effective, but the optimal combinations vary by<br />
PTEN status and type of endocrine therapy.<br />
PD01-02<br />
Increased expression of phosporylated mTOR in metastatic breast<br />
tumors compared to primary tumors in patients who received<br />
adjuvant endocrine therapy<br />
Hoefnagel LDC, Beelen KJ, Opdam M, Vincent A, Linn SC, vanDiest<br />
PJ. University Medical Center, Utrecht, Netherlands; The Netherlands<br />
<strong>Cancer</strong> Institute, Amsterdam, Netherlands<br />
BACKGROUND: Activation of the PI3K pathway as an adaptive<br />
change in response to estrogen depletion results in acquired endocrine<br />
therapy resistance in vitro. Metastatic breast cancer patients with<br />
previous exposure to endocrine therapy do derive substantial benefit<br />
from the addition of an mTOR inhibitor to endocrine therapy compared<br />
to endocrine therapy alone. This suggests that compensatory PI3K<br />
pathway activation might play a role in the development of clinical<br />
resistance to endocrine therapy. We evaluated the activation of the<br />
downstream PI3K pathway protein mTOR in primary breast tumors<br />
and matched metastatic lesions.<br />
METHODS: From a previously described series of breast cancer<br />
patients from whom both primary tumor tissue as well as metastatic<br />
tumor tissue was collected, we selected estrogen receptor α (ERα)<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 1<br />
positive patients who had received endocrine therapy (N=34) and<br />
who did not receive endocrine therapy (N=37). The difference in<br />
expression of phosphorylated mTOR (p-mTOR) between primary and<br />
metastatic tumor was assessed by immunohistochemistry, which was<br />
scored by using the proportion of tumor cells with sub-membranous<br />
p-mTOR expression. We assessed whether this p-mTOR difference<br />
between primary and metastatic tumor was associated with clinicopathological<br />
factors (location of metastasis, lymph node status,<br />
T-stage, grade, progesterone receptor status) or varied between<br />
patients who did and did not receive endocrine therapy, using Mann-<br />
Whitney tests. In addition we performed a linear regression model<br />
including the same clinico-pathological factors.<br />
RESULTS: In patients who had received endocrine therapy we<br />
observed an increase in p-mTOR expression in metastatic tumor<br />
lesions compared to the primary tumor (median difference 45%).<br />
This was significantly different from the mTOR changes observed<br />
in patients who did not receive endocrine therapy (median difference<br />
between metastatic and primary lesion 0 %) (p=0.003). The difference<br />
remained significant in the multivariate regression model (p=0.001).<br />
None of the other factors was significantly associated with a<br />
differential p-mTOR change.<br />
CONCLUSION: In patients who received previous adjuvant<br />
endocrine therapy, the increase in p-mTOR expression in metastatic<br />
tumor lesions compared to the primary tumor is significantly higher<br />
than in patients who did not receive endocrine therapy. Compensatory<br />
activation of the PI3K pathway might therefore be a clinically<br />
relevant resistance mechanism resulting in secondary endocrine<br />
therapy resistance.<br />
PD01-03<br />
Phosphorylated p-70S6K predicts tamoxifen resistance in<br />
postmenopausal breast cancer patients randomized between<br />
adjuvant tamoxifen versus no systemic treatment<br />
Beelen KJ, Opdam M, Severson TM, Koornstra RHT, Vincent A,<br />
Wesseling J, Muris JJ, Berns EMJJ, Vermorken JB, vanDiest PJ,<br />
Linn SC. The Netherlands <strong>Cancer</strong> Institute, Amsterdam, Netherlands;<br />
Erasmus University Medical Center-Daniel den Hoed <strong>Cancer</strong> Center,<br />
Rotterdam, Netherlands; Antwerp University hospital, Edegem,<br />
Belgium; University Medical Center, Utrecht, Netherlands<br />
BACKGROUND: Activation of the PI3K/MAPK pathways results<br />
in anti-estrogen resistance in vitro, however a biomarker that can<br />
predict clinical resistance has not yet been identified. Common<br />
drivers of these pathways are PIK3CA mutations, loss of PTEN<br />
and over-expression of HER2 and IGF-1R. We aimed to test the<br />
prognostic and predictive value of PI3K/MAPK pathway drivers<br />
as well as downstream activated proteins in postmenopausal breast<br />
cancer patients.<br />
METHODS: We collected primary tumor tissue from 563 ERα<br />
positive breast cancer patients who were randomized between<br />
tamoxifen (1-3 years) versus no adjuvant systemic therapy. PIK3CA<br />
hotspot mutations were assessed by Sequenom Mass Spectrometry.<br />
Immunohistochemistry was performed for expression of PTEN, IGF-<br />
1R and the downstream markers p-AKT(Thr308), p-AKT(Ser473),<br />
p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models<br />
for recurrence free interval were used to assess hazard ratios and<br />
interaction between these markers and treatment.<br />
RESULTS: No significant interaction between any of the tested PI3K/<br />
MAPK pathways drivers and tamoxifen was found. [/bold]However,<br />
interactions were identified between tamoxifen and the downstream<br />
activated proteins (p-AKT(Thr308), p- mTOR, p-p70S6K and<br />
p-ERK1/2). After correcting for multiple testing, p-p70S6K remained<br />
significantly associated with tamoxifen resistance. Patients whose<br />
tumor did not express p-p70S6K did derive significant benefit from<br />
tamoxifen (HR 0.24, 95 % CI= 0.12-0.47, p< 0.0001), while patients<br />
whose tumor did express p-p70S6K did not (multivariate HR=1.02,<br />
95% CI=0.48-2.21, p=0.95), p for interaction 0.003.<br />
CONCLUSION: We conclude that the downstream marker of PI3K/<br />
MAPK activation p-p70S6K predicts tamoxifen resistance in ERα<br />
positive postmenopausal breast cancer patients.<br />
PD01-04<br />
Deep kinome sequencing identifies a novel D189Y mutation in<br />
the Src family kinase LYN as a possible mediator of antiestrogen<br />
resistance in ER+ breast cancer<br />
Fox EM, Balko JM, Arteaga CL. Vanderbilt-Ingram <strong>Cancer</strong> Center,<br />
Vanderbilt University, Nashville, TN<br />
Estrogen receptor-positive (ER+) breast tumors adapt to hormone<br />
deprivation and acquire resistance to aromatase inhibitors (AIs). The<br />
proliferative rate of tumor cells measured by Ki67 after short-term<br />
treatment with an AI has been proposed as a surrogate endpoint<br />
of long term outcome. The purpose of this study was to identify<br />
kinase mutations associated with resistance to endocrine therapy<br />
as identified by a high Ki67 score after two weeks of pre-surgical<br />
therapy with letrozole. We performed deep-kinome sequencing on<br />
4 ER+/HER2– breast tumors that retained high Ki67 scores (14.8 to<br />
24.5%) following short-term letrozole treatment. Genomic DNA from<br />
the surgically excised tumors was deep sequenced using a capture<br />
approach with 120-bp biotinylated oligonucleotides hybridizing to<br />
612 genes, including 517 kinases with ≥300x coverage.<br />
All 4 tumors contained a ‘hot spot’ mutation in PIK3CA, the gene<br />
encoding the p110α catalytic subunit of PI3K. One tumor also<br />
contained a novel D189Y somatic mutation in LYN, a member of<br />
the Src family kinases (SFKs; variant frequency of 8%). D189Y<br />
(565G>T) is located in the LYN SH2 domain. Reverse-phase protein<br />
array (RPPA) analysis available in 10 tumors in this study revealed a<br />
significant correlation (p=0.006) between Y416 P-Src (which detects<br />
all SFKs) and a high post-letrozole Ki67 score. A siRNA screen<br />
targeting 779 kinases identified LYN as one of the top hits whose<br />
knockdown significantly reduced growth of MCF-7 breast cancer cells<br />
with acquired resistance to estrogen deprivation. We next analyzed<br />
the <strong>Cancer</strong> Genome Atlas (TCGA) SNP data to detect copy number<br />
changes for 444 tumors where corresponding gene expression data<br />
were available. Copy number increases (>0.8 log2 ratio over normal<br />
matched DNA) in LYN were present in approximately 10% of breast<br />
cancers, with the highest copy number gains observed in luminal B<br />
tumors. In contrast, other SFKs showed less frequent copy number<br />
increases (YES1
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
deprivation in a subset of ER+ breast cancers. Second, ER+ breast<br />
cancers harbor multiple molecular alterations capable of mediating<br />
hormone-independent growth.<br />
PD01-05<br />
Analysis of patients with ER-positive breast tumors treated with<br />
neoadjuvant aromatase inhibition identifies chemokine receptors<br />
as potential modulators of endocrine resistance<br />
Ribas R, Ghazoui Z, Dowsett M, Martin L-A. The Institute of <strong>Cancer</strong><br />
Research, London, United Kingdom; Royal Marsden Hospital,<br />
London, United Kingdom<br />
Background: Most breast cancers (BC) at primary diagnosis are<br />
estrogen receptor positive (ER+). Estrogen (E) mediates its effects<br />
by binding to the ER. Therapies targeting the estrogenic stimulation<br />
of tumor growth reduce mortality from ER+ BC. However, resistance<br />
remains a clinical problem. To identify molecular mechanisms<br />
associated with early resistance to E-deprivation, we overlaid global<br />
gene transcription data from patients treated with neoadjuvant<br />
anastrazole with those from MCF7 cells adapted to long-term<br />
E-deprivation (LTED).<br />
Methods: Global gene expression and Ki67 data were available<br />
from 81 postmenopausal women with ER+ early BC, at baseline and<br />
2-weeks post anastrazole treatment. Genes, that changed expression<br />
in response to anastrozole, were identified using multiple testing<br />
corrected multi-group analyses. In vitro global gene expression was<br />
available from MCF7 cells adapted to LTED. Functional consequence<br />
of target genes on proliferation, ER-mediated transcription and<br />
downstream cell signaling was assessed using siRNA.<br />
Results: Overlay of genes that predicted for a poor change in Ki67<br />
in patients treated with anastrazole (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 2<br />
PD01-07<br />
High throughput sequencing following cross-linked immuneprecipitation<br />
(HITS-CLIP) of Argonaute protein reveals novel<br />
miRNA regulatory pathways of Estrogen Receptor in breast<br />
cancer.<br />
Kabos P, Kline E, Brown J, Flory K, Sartorius C, Hesselberth J, Pillai<br />
MM. University of Colorado Denver, Aurora, CO<br />
Micro RNAs (miRNAs) are a class of small non-coding RNAs with<br />
well-known regulatory roles in normal physiological processes and<br />
cancer. Conventionally their study has been based on defining single<br />
miRNA-mRNA target interactions using a combination of miRNA<br />
expression arrays and bioinformatic predictions of binding to the 3’<br />
untranslated regions of genes, followed by miRNA over-expression<br />
in the relevant cell type. These approaches present circumstantial<br />
evidence for binding of a particular miRNA to its target but do not<br />
allow the study of global interactions nor provide direct evidence<br />
of binding. In order to study the genome wide impact of miRNA<br />
regulation in breast cancer we chose to use a recently described<br />
biochemical technique called Cross-Linked Immune-Precipitation of<br />
Argonaute (AGO) protein followed by high throughput sequencing<br />
(HITS-CLIP). Cross-linking of RNA to adjacent protein moieties by<br />
ultraviolet (UV) light allows for stringent isolation of the miRNAmRNA-AGO<br />
complexes by immune precipitation (IP); miRNAmRNA<br />
interaction within the RNA-induced silencing complex (RISC)<br />
is known to occur within the folds of AGO. The isolated miRNAmRNA-AGO<br />
complexes are then analyzed with next generation<br />
sequencing (NGS) to determine the miRNA-mRNA interactome.<br />
We performed HITS-CLIP on three well characterized breast cancer<br />
cell lines that represent ER+, Her2+ and triple negative (TN) disease<br />
(MCF7, BT474 and MDA231). To determine the role of miRNAs<br />
in coordinating the response to the estrogen receptor axis, MCF7<br />
and BT474 cells were analyzed with or without short term (24 hour)<br />
estrogen treatment.<br />
Analysis of sequencing data revealed several novel miRNA-mRNA<br />
interactions that target the ER pathway. For example, miR-9 directly<br />
regulates ER expression and miR-193a is involved in regulating<br />
expression of the ER co-activator NCOA3. We confirmed the<br />
biological relevance of these results using functional in vitro studies<br />
where manipulation of both miR-193a and miR-9 altered the<br />
responsiveness of breast cancer cells to tamoxifen. These results were<br />
further validated by quantitation of both transcript (RT-PCR) and<br />
protein (Western Blot) levels after transfection of miRNA precursors.<br />
Functional binding between these miRNAs and putative binding<br />
targets in the 3’ Untranslated Regions (3’UTRs) were also validated<br />
by luciferase-based reporter assays. Finally, we performed global<br />
analysis of miRNAs and their targets (as predicted by the HITS-CLIP<br />
datasets across all cell lines); this predicted regulation of core cellular<br />
processes such as cell proliferation, DNA repair and metabolism as<br />
being targeted by highly abundant miRNAs such as miR-27a and<br />
miR-21. In addition, our datasets confirmed previous reports of<br />
miRNA regulation of ER pathway such as miR-221 regulation of<br />
ER itself and miR-34a regulation of Myc. In summary, genome-wide<br />
biochemical approaches like HITS-CLIP allow for defining novel and<br />
clinically relevant miRNA-based regulatory pathways of endocrine<br />
responsiveness and resistance in breast cancer. In addition, breast<br />
cancer subtype specific biological pathways targeted by individual<br />
miRNAs can be predicted by this approach.<br />
PD01-08<br />
Differences in estrogen receptor signaling in non-malignant<br />
primary ER-positive breast epithelial cells and breast cancer.<br />
Lim E, He HH, Chi D, Yeung TY, Schnitt S, Liu SX, Garber J,<br />
Richardson A, Brown M. Dana-Farber <strong>Cancer</strong> Institute, Boston, MA;<br />
Harvard School of Public Health, Boston, MA; Harvard Medical<br />
School, Boston, MA; Beth Israel Deaconess Medical Center, Boston,<br />
MA; Brigham and Women’s Hospital, Boston, MA<br />
Background: The estrogen receptor (ER) is expressed in ∼70% of<br />
sporadic breast cancer and activates genes driving cell proliferation<br />
and tumorigenesis. We have previously performed genome-wide<br />
analysis of ER binding sites in MCF-7 breast cancer cells, and<br />
identified distinct mechanisms of ER signaling. We have also<br />
previously used EpCAM and CD49f as markers to enrich for viable<br />
ER-positive (ER+) cells obtained from non malignant breast tissue.<br />
Here, we seek to elucidate differences in ER signaling between nonmalignant<br />
and ER+ breast cancer cells.<br />
Methods: Primary breast epithelial cells were obtained from patients<br />
undergoing reduction mammoplasties and surgical excision of ER+<br />
breast cancer. After dissociation of breast reductions into a single-cell<br />
suspension, ER+ mature luminal (ML; EpCAM+CD49f-) and luminal<br />
progenitor (LP; EpCAM+CD49f+) subpopulations were obtained by<br />
flow cytometry. Following estrogen stimulation, RNA was extracted<br />
for gene microarray analysis. ER chromatin immunoprecipitation<br />
and DNA sequencing (ChIP-seq) was performed. These results were<br />
compared to MCF-7 breast cancer cells.<br />
Results: Reduction mammoplasty and ER+ breast cancer tissues were<br />
analyzed, and compared to MCF-7 cells. Gene expression profiles<br />
were different between non-malignant tissue and ER+ breast cancer<br />
cells following estrogen stimulation, with a 2-3 fold higher number<br />
of ER regulated genes in ER+ breast cancer compared to ER+ non<br />
malignant cells, and few overlapping estrogen regulated genes. Genes<br />
that promotes cell cycling and cell proliferation were downregulated<br />
in non-malignant tissue, but were upregulated in breast cancer cells<br />
(P < 10-5). CYP1A1, a major estradiol metabolizing enzyme, was<br />
upregulated in normal cells but downregulated in ER+ breast cancer<br />
cells. Motif analysis of ER ChIP-seq data in normal and ER+ breast<br />
cancer tissues demonstrated an enrichment of ER motifs in the<br />
overlapping sites and an enrichment of FOXA1 motifs in ER+ breast<br />
cancer cells and TCF12 motifs in non-malignant ER+ epithelial cells.<br />
Conclusions: There are contrasting differences in ER signaling<br />
between normal mammary and breast cancer cells, with estrogen<br />
having anti-proliferative effects in normal luminal cells compared to<br />
pro-proliferative effects in breast cancer. ER ChIP-Seq has identified<br />
TCF12 as a major co-factor in non-malignant breast tissue whilst<br />
FOXA1 is a major co-factor in ER+ breast cancer. Our data provides<br />
evidence for key alterations in ER-signaling during tumorigenesis, and<br />
identifies potential mechanisms to target cancer specific ER signaling.<br />
PD02-01<br />
Her2 expression measured by AQUA analysis on BCIRG-005 and<br />
BCIRG-006 predicts the benefit of Herceptin therapy<br />
Christiansen J, Barakat N, Murphy D, Rimm DL, Dabbas B,<br />
Nerenberg M, Beruti S, Quinaux E, Hall J, Press M, Slamon D.<br />
Genoptix Medical Laboratory; Yale University; IDDI; University of<br />
Southern California; University of California, Los Angeles<br />
Introduction: There have been disparate results reported in breast<br />
cancer testing for HER2 assessment as measured by protein<br />
expression or DNA amplification, yet both tests are routinely used<br />
to prescribe the drug Herceptin (trastuzumab, Genentech, So <strong>San</strong><br />
Francisco, CA). Typically, immunohistochemistry (IHC) staining<br />
www.aacrjournals.org 113s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
intensity of 3+ or FISH copy ratio of ≥2.0 are used to establish the<br />
cutoff between a negative and a positive result. However, it is unclear<br />
whether positivity is correlated with differential response to therapy.<br />
We used Automated Quantitative Analysis (AQUA) and a fluorescent<br />
immunohistochemical assay to measure HER2 expression in cases<br />
scored by central laboratory FISH and also receiving Herceptin<br />
therapy. The intentions of the study were two-fold: first, to provide<br />
further validation of the AQUA technology as applied to the clinical<br />
measurement of HER2 expression in breast cancer and second, to<br />
examine the potential of drug response stratification within those<br />
patients that are considered positive.<br />
Methods: AQUA fluorescence IHC staining was performed on a<br />
multi-cohort tissue microarray (TMA) set. The assay was constructed<br />
in the Genoptix CLIA laboratory per ASCO/CAP guidelines and<br />
with a cutpoint that was validated against IHC (with FISH reflex).<br />
The trial specimens tested were from the BCIRG-005/006 studies.<br />
BCIRG-005 had n=1544 cases all assessed as FISH- while the 006<br />
cohort had n=1477 cases all assessed as FISH+. Disease free survival<br />
(DFS) was used as the variable in subsequent modeling and analysis.<br />
Results: The BCIRG 005 and 006 cohorts, examined in aggregate,<br />
allowed for an initial examination of agreement relationships between<br />
HER2 levels as assessed by AQUA scoring and HER2 levels as<br />
assessed by central lab FISH. Results indicated a 77% negative<br />
agreement, a 97% positive agreement and an 87% overall concordance<br />
agreement for a total of n=3021 cases. Additional Cox modeling of<br />
the patients that were enrolled as FISH+ and stratified for those who<br />
did or did not receive Herceptin treatment demonstrated a significant<br />
overall hazard ratio (HR=0.75, CI=0.60,0.93) and when stratified for<br />
response to Herceptin, cases determined to be positive by AQUA<br />
showed significant benefit from treatment (HR=0.66, CI =0.52,0.85)<br />
in contrast to those who were scored as negative by AQUA that did<br />
demonstrate benefit from therapy (HR=1.19, CI=0.71,1.97).<br />
Conclusions: Analysis of the cases in this study originally determined<br />
to be HER2+ by FISH indicates that AQUA may improve predictions<br />
of which patients will benefit from Herceptin therapy.<br />
PD02-02<br />
The effect of HER2 expression on luminal A breast tumors<br />
Ellsworth RE, Valente AL, Shriver CD. Henry M. Jackson Foundation,<br />
Windber, PA; Windber Research Institute, Windber, PA; Walter Reed<br />
National Military Medical Center, Bethesda, MD<br />
Background: Luminal A (LumA) tumors are the most common<br />
subtype of breast cancer and have been associated with favorable<br />
prognosis. Although tumors can be considered LumA if they have<br />
>1% expression of ER, negative HER2 status ranges from 0+ (no<br />
expression) to 2+ (weak to moderate expression in >10% of cells)<br />
without concurrent genomic amplification. It is not clear how<br />
moderate levels of HER2 expression influence tumor biology in<br />
LumA tumors.<br />
Methods: The Clinical <strong>Breast</strong> Care Project database was queried<br />
to identify all hormone receptor positive cases with HER2 status<br />
defined as 0+ (n=89) or 2+/not amplified (n=154). Clinicopathological<br />
characteristics were compared between groups using chi-square<br />
analysis. Twenty-five 0+ and 25 2+ tumors were subjected to laser<br />
microdissection and hybridized to U133 2.0 microarrays (Affymetrix).<br />
Gene expression data was analyzed using Partek Genomics Suite.<br />
Results: Age at diagnosis did not differ between patients with no (58.5<br />
years) or moderate (59.3 years) HER2 expression. Patient groups did<br />
not differ by ethnicity, tumor stage, grade or size, or lymph node status.<br />
Although breast cancer mortality was low, all patients who died of<br />
disease (n=7) had moderate levels of HER2 expression (P=0.016). At<br />
the molecular level, four genes were differentially expressed (P2x-fold change): ESRRG expressed at significantly higher levels and<br />
DHRS2, SCUBE2 and SERPINA6 expressed at significantly lower<br />
levels in tumors with moderate HER2 expression.<br />
Discussion: LumA (2+) tumors are dissimilar from LumA (0+)<br />
tumors. Increased expression of ESRRG has been associated with<br />
increased cellular proliferation and tamoxifen resistance, while<br />
decreased expression of SCUBE2 and SERPINA6 have been<br />
associated with inhibition of growth and proliferation. Together,<br />
these molecular differences suggest that LumA tumors with moderate<br />
HER2 expression, although classified as HER2 negative, have more<br />
aggressive characteristics than those without HER2 expression<br />
which may contribute to the significantly higher mortality rate seen<br />
in patients with LumA tumors expressing HER2.<br />
PD02-03<br />
Added value of HER-2 amplification testing by multiplex ligationdependent<br />
probe amplification (MLPA)<br />
van Slooten H-J, Kuijpers CC, Moelans CB, Horstman A, Al-Janabi<br />
S, Hinrichs JW, van Diest PJ, Jiwa M. Symbiant Pathology Expert<br />
Centre, Alkmaar, Netherlands; University Medical Centre Utrecht,<br />
Netherlands<br />
Introduction<br />
Accurate determination of HER-2 status is critical for selection of<br />
breast cancer (BC) patients for trastuzumab treatment. According<br />
to the most commonly used testing protocol, patients with 3+<br />
immunohistochemistry (IHC) are considered for trastuzumab. In<br />
addition, 2+ IHC cases are tested for gene amplification and, when<br />
amplified, these patients are considered for trastuzumab treatment<br />
as well. Because in our experience IHC results have been proven to<br />
be sensitive to pre-analytical variation and inter- and intra-observer<br />
variation, we apply amplification testing not solely to 2+, but also to<br />
1+ and 3+ cases. At Symbiant Pathology Expert Centre, a validation<br />
study (n=99) comparing MLPA with chromogenic in situ hybridization<br />
(CISH) showed 100% concordance. Starting from April 2011, MLPA<br />
has been used as the method for HER-2 amplification testing, because<br />
in our hands this technique is more time- and cost-effective than<br />
CISH for analyzing large sample numbers. CISH was performed<br />
when MLPA was inconclusive, IHC score was heterogeneous or<br />
when invasive carcinoma could not be physically separated from<br />
DCIS. Here we report the results of a comparison between HER-2<br />
amplification tests and IHC in a cohort of 928 BC patients.<br />
Methods<br />
Pathology reports of 928 BC patients from 4 pathology laboratories<br />
were retrospectively reviewed. 728 patients were diagnosed between<br />
April 2011 and February 2012 in one of three laboratories of Symbiant<br />
Pathology Expert Centre. The other 200 patients were diagnosed<br />
in University Medical Centre Utrecht between January 2010 and<br />
December 2011. 18 patients had multiple tumors that were included<br />
as separate cases. In total, 949 tumors were reviewed.<br />
Results<br />
With IHC, major differences are observed between the 4 pathology<br />
laboratories concerning the percentage of cases scored as 0-1+ and 2+<br />
(Table 1). A considerable number of 3+ cases (6.4%) failed to show<br />
gene amplification by MLPA and/or CISH. A smaller percentage of<br />
0-1+ cases (1.8%) did show gene amplification (Table 2). 90 equivocal<br />
cases were double tested by CISH and MLPA. In 52/90 of these cases<br />
(58%) at least one test was inconclusive. The other 38 (42%) cases<br />
showed 100% concordance between MLPA and CISH.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 2<br />
Table 1. Comparison of HER-2 IHC scoring percentages between 4 pathology laboratories.<br />
Laboratory A (n=347) B (n=261) C (n=123) D (n=218) Total (n=949)<br />
0-1+ 58.2% 72.0% 70.7% 78.0% 68.2%<br />
2+ 30.5% 15.7% 16.3% 9.2% 19.7%<br />
3+ 11.2% 12.3% 13.0% 12.8% 12.1%<br />
Table 2. HER-2/neu gene amplification according to IHC score.<br />
No amplification Amplification Total<br />
0-1+ 484 (98.2%) 9 (1.8%) 493<br />
2+ 171 (91.9%) 15 (8.1%) 186<br />
3+ 7 (6.4%) 102 (93.6%) 109<br />
Total 662 (84.0%) 128 (16.0%) 788<br />
Conclusion<br />
MLPA is an accurate and cost-effective method for the determination<br />
of HER-2 status. We recommend the use of a gene amplification test<br />
to confirm HER-2 status in all IHC scores, not just the 2+ cases.<br />
However, it is still unclear whether the small subgroups of patients<br />
showing only HER-2 protein overexpression or only HER-2 gene<br />
amplification would benefit from trastuzumab. Follow-up data are<br />
therefore needed to determine the clinical value of HER-2 status<br />
assessed by each technique in order to improve the current standard<br />
of care for HER-2 testing.<br />
PD02-04<br />
Automated Quantitative RNA In Situ Hybridization for<br />
Resolution of Equivocal and Heterogeneous ERBB2 (HER2)<br />
Status in Invasive <strong>Breast</strong> Carcinoma<br />
Wang Z, Portier BP, Gruver AM, Bui S, Wang H, Su N, Vo H-T, Ma<br />
X-J, Luo Y, Budd GT, Tubbs RR. Cleveland Clinic, Cleveland, OH;<br />
Advanced Cell Diagnostics, Hayward, CA<br />
Background: <strong>Breast</strong> carcinomas that demonstrate a<br />
heterogeneous ERBB2 (HER2) status or equivocal results by both<br />
immunohistochemistry (IHC) and fluorescence in situ hybridization<br />
(FISH) present diagnostic challenges for which there is neither a<br />
standard methodology to achieve resolution in the clinical laboratory<br />
nor a uniform approach to management. We assessed the feasibility<br />
of using a novel automated and quantitative HER2 mRNA bright<br />
field in situ hybridization (ISH) assay capable of single molecule<br />
detection to determine HER2 status in invasive breast carcinomas that<br />
demonstrated significant tumor heterogeneity or failed to be resolved<br />
by standard IHC and FISH algorithmic testing.<br />
Design: Formalin-fixed, paraffin-embedded (FFPE) breast carcinomas<br />
from a non-consecutive series of 163 patients were analyzed for<br />
HER2 mRNA using a fully automated bright field RNA ISH assay<br />
(RNAscope, Advanced Cell Diagnostics, Hayward, CA). Cases were<br />
assigned into either a training set (n=34) or a validation set (n=129)<br />
and analyzed by both Q-RT-PCR and RNAscope. automated image<br />
analysis was used to numerate the punctate signal dots per cell in<br />
RNAscope-stained slides. A HER2 mRNA score based on single-cell<br />
quantification by RNAscope was developed and correlated to HER2<br />
FISH and HER2 mRNA Q-RT-PCR results. A simple cutoff value<br />
was derived using the training set and applied to the validation set.<br />
Results: Evaluable HER2 results were obtained for 154 cases (94.5%)<br />
by RNAscope and 163 cases (100%) by Q-RT-PCR. In the training<br />
set, both FISH/IHC positive and negative cases were definitively<br />
separated by both Q-RT-PCR and RNAscope. HER2 mRNA dots per<br />
cell correlated strongly to FISH (Spearman r=0.77) and Q-RT-PCR<br />
(r=0.81). Application of both methods to the validation set resulted<br />
in correct identification of 31/31 positive cases and 41/43 negative<br />
(overall concordance=97.3%) for both RNAscope and Q-RT-PCR.<br />
RNAscope showed a significant advantage over Q-RT-PCR in<br />
correctly identifying cases equivocal by FISH that were resolved<br />
by reflex IHC testing. RNAscope classified 7 of 26 (26.9%) FISH/<br />
IHC double equivocal cases as positives. In cases with HER2 protein<br />
heterogeneity, RNAscope showed a 100% concordance with FISH<br />
results, whereas Q-RT-PCR showed a 42.9% concordance.<br />
Conclusion: RNAscope analysis of HER2 mRNA is an effective<br />
means to resolve HER2 status in double equivocal cases and cases<br />
that demonstrate heterogeneity. Automation and image analysis-based<br />
quantification minimize analytical and post-analytical variability.<br />
Quantification of single RNA transcripts in situ at single-cell<br />
level demonstrates superiority over qRTPCR and great potential<br />
in predictive biomarker analysis. Further studies of larger cohorts<br />
correlating clinical response with HER2 mRNA expression in situ<br />
are warranted.<br />
PD02-05<br />
Comparison of fluorescence in situ hybridization (FISH) and<br />
dual-ISH (D-ISH) in the determination of HER2 status<br />
Mansfield AS, Sakai Y, Walsh FJ, Wiktor AE, Sukov WR, Dogan A,<br />
Jenkins RB. Mayo Clinic, Rochester, MN<br />
Introduction: The appropriate assessment of HER2 amplification<br />
status is critical to determining which patients should receive HER2-<br />
directed therapy. An alternative to FISH is D-ISH (Ventana Medical<br />
Systems Tucson, Arizona) which utilizes chromogenic HER2 and<br />
chromosome 17 probes. Both FISH and D-ISH utilize formalin-fixed,<br />
paraffin-embedded (FFPE) human breast cancer tissue specimens.<br />
D-ISH has two principle advantages over FISH: it can be visualized<br />
using light microscopy and after analysis the specimens can be<br />
archived.<br />
Methods: We tested 250 samples with FISH and with D-ISH. Fifty<br />
specimens were controls: 25 cases with no HER2 or CEP17anomaly<br />
and 25 cases with HER2 amplification. There were also 200 test<br />
subjects of 50 cases each of chromosome 17 aneusomy, HER2 deletion<br />
(HER2/CEP17 ratio
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
PD02-06<br />
Concordance between immunohistochemistry and<br />
FISH(fluorescence in sity hybridization) & SISH(silver in situ<br />
hybridization) for assessment of the HER2<br />
Lee M-R, Cho S-H, Kim D-C, Lee K-C, Lee J-H, Kwon H-C, Lee H-W,<br />
Lee S-e. Dong-A University Medical Center, Busan, Korea<br />
Goals: Accurate assessment of the human epidermal growth<br />
factor receptor 2 (HER2) of invasive breast cancer with<br />
Immunohistochemistry (IHC) and fluorescence in situ hybridization<br />
(FISH) & Silver in situ hybridization(SISH) is very important to<br />
decide treatment of targeted therapy with the humanized monoclonal<br />
antibody trastuzumab and the dual tyrosine kinase inhibitor lapatinib.<br />
The accuracy of these three testing methods can be adversely affected<br />
by various factors. We performed a retrospective analysis of the<br />
concordance of IHC and FISH & SISH analysis for HER2/neu at<br />
Donga-A Medical Center and reviewed possible causes of disparity<br />
between these two methods.<br />
Methods: We performed retrospective review of a total of 416<br />
invasive ductal carcinomas evaluated for HER2/neu at the Department<br />
of Surgery in Dong-A Medical Center between 2005 and 2011. We<br />
reviewed this data retrospectively and evaluated the concordance<br />
between IHC and FISH & SISH.<br />
Results: Comparison of the routinely assessed immunohistochemical<br />
HER2 status and FISH & SISH revealed that ten invasive carcinomas<br />
diagnosed immunohistochemically as highly overexpressed (score<br />
3+) did not show amplification of the HER2 gene by FISH n that<br />
these are false positives (SISH : false positive : 7 cases). Eight<br />
invasive carcinomas diagnosed immunohistochemically as Negatively<br />
expressed (score 0) showed amplification of the HER2 gene by SISH<br />
on that these are false negative. Fourteen tumor, which scored as 2+<br />
by IHC, was proven to be amplified on initial testing with FISH (SISH<br />
: 6 cases). Concordance between IHC and FISH analysis was good<br />
(171/181= 94.5%) (false positive : 5.5%) (SISH : 228/235=97.0%,<br />
false positive 3.4%, false negative 2.9%) and within the published<br />
range.<br />
Conclusion: IHC as first-line testing for HER2 may result in false<br />
positive and false negative results. The novel ASCO/CAP criteria<br />
for the immunohistochemical evaluation of the HER2 status may<br />
prevent some false positive results. The discordant cases between<br />
IHC and FISH & SISH represent a well-recognized subset of genetic<br />
heterogeneity in HER2/neu, which is known to contribute to positive<br />
IHC and negative FISH & SISH tests. The most powerful method for<br />
studying HER2 status is ISH. However, in heterogeneous carcinomas<br />
even FISH may not succeed in a correct evaluation of HER2.<br />
PD02-07<br />
Next-generation sequencing of FFPE breast cancers demonstrates<br />
high concordance with FISH in calling HER2 amplifications and<br />
commonly detects other clinically relevant genomic alterations<br />
Lipson D, He J, Yelensky R, Miller V, Sheehan C, Brennan K, Jarosz M,<br />
Stephens P, Cronin M, Ross J. Foundation Medicine, Inc, Cambridge,<br />
MA; Albany Medical College, Albany, NY<br />
Background: As more therapies targeting genomic alterations<br />
become available, next-generation sequencing (NGS) is increasingly<br />
performed in tumor types where mutational status may drive treatment<br />
choice. In addition to its ability to identify base substitutions,<br />
insertions and deletions across entire exons, NGS can detect relevant<br />
copy number changes such as amplification of HER2 in breast tumors.<br />
However, for NGS to be clinically applicable, it must reliably analyze<br />
FFPE tumor samples and show concordance with the best current<br />
diagnostic methods.<br />
Methods: To confirm a clinical role for NGS in detecting copy<br />
number alterations, we identified 35 FFPE invasive breast carcinomas<br />
previously tested for HER2 status by FISH, including 15 HER2<br />
positives (≥7 copies) and 20 HER2 negatives (900X uniquely-mapping reads was obtained. Sequence data were<br />
analyzed for HER2 copy number (blinded to FISH results) based on a<br />
statistical model using allele frequencies and coverage depth of HER2<br />
exons versus a process-matched normal control, classifying cases<br />
as HER2 positive (≥6 average copies), HER2 negative (27<br />
(Bonanni et al. JCO epub May 7, 2012). The objective of the current<br />
analysis was to determine whether metformin induced a modulation<br />
of apoptosis (TUNEL) overall and by HOMA index.<br />
TRIAL DESIGN: After tumor biopsy we randomly allocated 200<br />
non-diabetic women with operable breast cancer to either metformin<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
116s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 3<br />
(850 mg/bid) or placebo for 4 weeks prior to surgery. The primary<br />
outcome measure was the difference between arms in Ki-67 after 4<br />
weeks of treatment. Here we analyzed the apoptotic cell nuclei in 88<br />
consecutive core biopsies and their paired surgical samples from the<br />
initial 100 randomized subjects.<br />
RESULTS: Median TUNEL levels at surgery (Metformin = 10%, IQR,<br />
4-20, Placebo = 8%, IQR, 3-15) were significantly higher as compared<br />
with baseline (Metformin = 4%, IQR, 2-7, Placebo = 3%, IQR, 2-6,<br />
p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Serum Biomarker (unit) Pre-Metformin Mean (Range) Post-Metformin Mean (Range) P value<br />
Insulin (uIU/mL) 18.4 (4.5-72.0) 14.3 (4.1-34.4) 0.06<br />
Glucose (mg/dL) 93 (69 -121) 93 (72-127) 0.90<br />
HOMA 4.3 (0.7-18.8) 3.3 (0.9-8.8) 0.06<br />
Cholesterol (mg/dL) 203 (146-336) 186.6 (124-272)
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 3<br />
underway and will be reported. Integrated analysis of these factors<br />
combined with the physiological and molecular data described<br />
above will further enhance understanding of metformin action in<br />
the clinical setting.<br />
PD03-06<br />
Simvastatin radiosensitizes differentiated and stem-like breast<br />
cancer cell lines and is associated with improved local control<br />
in inflammatory breast cancer patients treated with postmastectomy<br />
radiation<br />
Lacerda L, Reddy J, Liu D, Larson R, Masuda H, Brewer T, Debeb<br />
B, Xu W, Hortobagyi GN, Buchholz TA, Ueno NT, Woodward WA.<br />
Morgan Welch Inflammatory <strong>Breast</strong> <strong>Cancer</strong> Research Program<br />
and Clinic, The University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX<br />
Among women with non-inflammatory triple-negative and triplenegative<br />
inflammatory breast cancer (IBC), the 5-yr actuarial rates<br />
of local failure after radiation are 11%-35% and 45%, respectively,<br />
in part influenced by the contribution of radioresistant cancer stem<br />
cells to these cancers. Herein we explored the radiosensitization of<br />
breast cancer stem-like cells in vitro and examined the influence on<br />
local control after post-mastectomy radiation (PMRT) among IBC<br />
patients taking statins.<br />
SUM149, SUM159 and MCF-7 cells were cultured in standard<br />
monolayer cultures and stem cell enriching anchorage independent<br />
clonogenic cultures with simvastatin and treated with increasing<br />
concentrations of radiation. Survival curves were generated and<br />
t-test was used to compare surviving fraction (SF) of groups. p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Conclusions:<br />
HMGCR, the target of statin treatment, was up-regulated in breast<br />
cancer samples after atorvastatin treatment. This indicates HMGCR<br />
targeting within the tumor, which resulted in increased enzymatic<br />
activity. This study supports previous reports of statin-induced antiproliferative<br />
effects in breast cancer, and suggests that HMGCR could<br />
be used as a predictive marker for selection of breast cancer patients<br />
with beneficial anti-tumoral effects from statin treatment.<br />
PD03-08<br />
Statin use and improved survival outcome in primary<br />
inflammatory breast cancer: retrospective cohort study<br />
Brewer TM, Masuda H, Iwamoto T, Liu P, Kai K, Barnett CM,<br />
Woodward WA, Reuben JM, Yang P, Hortobagyi GN, Ueno NT. The<br />
University of Texas M.D. Anderson <strong>Cancer</strong> Center, Houston, TX;<br />
Eastern Virginia Medical School, Norfolk, VA; Okayama University<br />
Hospital, Okayama, Japan<br />
Background Inflammatory breast cancer (IBC) is the most aggressive<br />
type of breast cancer. HMG-CoA reductase inhibitors (statins)<br />
are cholesterol reducing agents with pleiotropic effects, including<br />
antitumorigenic and anti-inflammatory properties. We hypothesized<br />
that statins reduce the metastatic potential in primary IBC.<br />
Methods We retrospectively reviewed 993 patients diagnosed with<br />
and treated for IBC at The University of Texas MD Anderson <strong>Cancer</strong><br />
Center between Jan. 12, 1995 and Jan. 27, 2011. Patients with any<br />
records indicating statin use on the electronic medical record were<br />
compared with those without. We further compared clinical outcomes<br />
stratified by statin type (hydrophilic versus lipophilic). We used the<br />
Kaplan-Meier method to estimate the median disease-free survival<br />
(DFS) after surgery, overall survival (OS), and breast cancer-specific<br />
overall survival (BCOS), followed by Cox proportional hazards<br />
regression model to test the statistical significance of several potential<br />
prognostic factors.<br />
Results Primary IBC patients who used statins (n=109) were<br />
compared to those who did not (n=651). The median DFS was<br />
23.0 and 13.3 months (P
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 4<br />
Conclusion: Simvastatin was associated with a reduced risk of<br />
invasive breast cancer, and as a class, lipophilic statins were associated<br />
with a marginal benefit. This provides further evidence for possible<br />
class differences in statins with regard to chemo-preventive effects<br />
in breast cancer.<br />
PD04-01<br />
Intra-operative ultrasound in breast-conserving surgery for<br />
palpable breast cancer significantly improves both surgical<br />
accuracy and cosmetic outcome while saving costs.<br />
Haloua M, Krekel N, Coupe V, van den Tol P, Meijer S. VU Medical<br />
Center, Amsterdam, Nederland, Netherlands; Alkmaar Medical<br />
Center, Alkmaar, Noord-Holland, Netherlands<br />
Background: <strong>Breast</strong>-conserving surgery for palpable breast cancer is<br />
worldwide associated with a high rate of tumour-involved margins<br />
and excessive healthy tissue resection. This results in additional<br />
treatment and poor cosmetic outcome. Ultrasound-guided surgery<br />
(USS) may resolve both problems by improving surgical accuracy.<br />
A randomised controlled trial was initiated to compare USS with the<br />
standard palpation-guided surgery (PGS) for palpable breast cancer.<br />
Methods: A total of 134 eligible patients with palpable T1-T2 invasive<br />
breast cancer were randomised to either USS (n = 65) or PGS (n=69).<br />
Outcome measures included resection margin status, re-excision<br />
rates, mastectomy rates and additional radiotherapy. A calculated<br />
resection ratio (CRR) was derived from specimen volumes and tumour<br />
diameters, indicating healthy tissue resection. Secondary outcome<br />
measures were operative time, complications cosmetic outcome<br />
and cost-effectiveness. The costs of purchasing the US-system were<br />
included in the USS-group. The mean total costs per patient were<br />
calculated and compared between both study groups.<br />
Results: In the USS-group, 3.1% of margins were involved, compared<br />
with 17.4% in the PGS-group (P=0.009). The use of intra-operative<br />
US resulted in a significant reduction in additional therapies<br />
(P=0.015); in the PGS-group re-excisions were necessary in 3 patients<br />
(4.3%) and in 1 patient (1.5%) in the USS-group, mastectomies were<br />
performed in 5 patients (7.2%) of the PGS-group and in none of the<br />
patients of the USS-group, and additional radiotherapy boosts in 11<br />
patients (15.9%) of the PGS-group and 6 patients in the USS-group<br />
(9.2%). Excision volumes and CRR were both reduced with USS<br />
(38cc vs. 58cc and 1.0 vs. 1.7, respectively; both P23cm,<br />
so a propensity-score model was developed to balance cardiac and<br />
breast cancer risk factors between women who received AWBRT<br />
(42.5-44 Gy/16 fractions) versus CWBRT (45-50 Gy/25 fractions).<br />
The first event of a hospital admission for cardiac causes after RT<br />
was determined from hospitalization records. Cumulative incidence<br />
of cardiac morbidity was estimated at 10 years after RT for AWBRT<br />
versus CWBRT groups. Gray’s test was used to test for differences in<br />
the cumulative incidence curves between the AWBRT and CWBRT<br />
groups.<br />
RESULTS<br />
The median follow-up [range] was 13.2 [10-28] years. 485 women<br />
were treated with CWBRT and 2221 women were treated with<br />
AWBRT. The CWBRT group had a higher prevalence of diabetes,<br />
with a trend towards higher prevalence of HTN and other cardiac<br />
risk factors. Age, year of diagnosis, stage, grade, ER status, hormone<br />
and chemotherapy use were not statistically different between the RT<br />
groups. There was no statistically significant difference at 10 years<br />
in the incidence rate (as measured by first hospitalisation for cardiac<br />
morbidity) between the RT groups. The 10-year cumulative incidence<br />
of these hospitalization events for cardiac morbidity (95% CI) was<br />
20.8% (19.1-22.5) with AWBRT and 22.1% (18.5-25.9) with CWBRT.<br />
This difference was not significant between raw unadjusted values<br />
(p=0.07) or after propensity score adjustment with Gray’s test (p=0.2).<br />
Differences were also not statistically different at 15 years followup.<br />
These values are comparable with published long-term cardiac<br />
morbidity rates with CWBRT. Mortality due to cardiac cause was not<br />
statistically different between the two groups at 15 years follow-up.<br />
CONCLUSION<br />
Hospitalization for a primary or contributing cardiac cause at 15 years<br />
follow-up was not significantly different between women with leftsided<br />
early-stage breast cancer treated with AWBRT versus CWBRT<br />
even after correcting for pretreatment cardiac risk factors and events.<br />
www.aacrjournals.org 121s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
PD04-03<br />
Is breast conservation therapy an option for young women with<br />
operable breast cancer? Local recurrence rates in young women<br />
following surgery: a single centre experience.<br />
Lewis CR, Smith R, Matthews A, Choo E, Lee C. Prince of Wales<br />
<strong>Cancer</strong> Centre (POWCC), Randwick, NSW, Australia; Prince of<br />
Wales Hospital, Randwick, NSW, Australia; NHMRC Clinical Trials<br />
Unit, University of Sydney, NSW, Australia<br />
Background: <strong>Breast</strong> cancer (BC) is less common in young women<br />
(defined here as ≤ 40 years age), but is associated with more aggressive<br />
biological features, higher risk of local recurrence (LR) and poorer<br />
overall survival. This study examines and compares the incidence of<br />
LR following breast conservation therapy (BCT) versus mastectomy<br />
in women with operable BC treated at our centre.<br />
Methods: The POWCC breast cancer database was retrospectively<br />
reviewed for the period January 1995 to December 2008. 2250 eligible<br />
women with BC undergoing primary breast surgery were identified.<br />
LR rate was compared between young women and older women (age<br />
> 40 years), and according to type of surgery. Data were analysed<br />
using a competing risk Cox model to account for distant recurrence<br />
and death as competing events for local recurrence.<br />
Results: Median follow-up was 70 months. Of 2250 women, 246<br />
(11%) were young women, and the mastectomy rate was 49.2%. In<br />
older women (89%), mastectomy rate was 41.7%. LR occurred in<br />
17 (6.9%) and 57 (2.8%) in young and older women respectively<br />
(p=0.001). Amongst the young women, 12 (9.6%) and 5 (4.1%)<br />
patients recurred locally in BCT and mastectomy respectively<br />
(p=0.09). Amongst the older women, 43 (3.7%) and 14 (1.7%)<br />
patients recurred locally in BCT and mastectomy respectively<br />
(p=0.008). In univariate Cox analysis, significant risk factors for LR<br />
were BCT (p=0.003), positive surgical margins (p=0.03), age ≤ 40<br />
years (p=0.001), premenopausal status (p=0.003) and no adjuvant<br />
systemic therapy (0.02). Age remains a significant predictor of LR in<br />
multivariate Cox analysis (Table). There was no significant interaction<br />
between age and type of surgery on LR (p=0.72).<br />
Discussion: Our results demonstrate that young women who undergo<br />
BCT have the highest risk of early LR. Adjuvant systemic therapy<br />
is protective of early LR. This study is hypothesis-generating and a<br />
definitive prospective clinical trial is required to better determine the<br />
optimal type of breast surgery in young women.<br />
Multivariate Cox analysis: risk of local recurrence<br />
Characteristics HR 95% CI p-value<br />
Age > 40 years 0.48 0.25-0.92 0.03<br />
Mastectomy vs BCT 0.43 0.25-0.76 0.004<br />
Postmenopausal 0.55 0.32-0.94 0.03<br />
Systemic therapy (hormone<br />
+/- chemo) vs none<br />
0.53 0.33-0.84 0.007<br />
PD04-04<br />
What is influencing breast conservation rates in the United States?<br />
Data from the National Accreditation Program of <strong>Breast</strong> Centers<br />
Chagpar AB, Kaufman CS, Connolly J, Burgin C, Granville T,<br />
Winchester D. Yale University School of Medicine, New Haven, CT;<br />
Bellingham <strong>Breast</strong> Center; Beth Israel Deaconess, Boston, MA;<br />
National Accreditation Center for <strong>Breast</strong> Centers; Pat Nolan Center<br />
for <strong>Breast</strong> Health, Glenview, IL<br />
INTRODUCTION: <strong>Breast</strong> conservation (BC) rates have been utilized<br />
as a quality metric, yet mastectomy rates have been noted to be<br />
increasing nationwide. The purpose of this study was to evaluate the<br />
factors associated with BC in 437 US breast centers surveyed by the<br />
National Accreditation Program of <strong>Breast</strong> Centers (NAPBC).<br />
METHODS: From 2006 to 2010, 437 breast centers across the US<br />
were surveyed by the NAPBC. At each center, annual data regarding<br />
BC rates were reported in the Survey Application Record (SAR) for<br />
patients with Stage 0-II breast cancer. We evaluated characteristics<br />
of breast centers including geographic location, volume of patients<br />
treated, therapeutic modalities provided, and center organizational<br />
relationships. Non-parametric statistical analyses were performed to<br />
determine factors associated with BC rates in this cohort.<br />
RESULTS: Among the 437 breast centers surveyed from 2006-2011,<br />
data on 77,248 patients with Stage 0-II were reported. The median<br />
number of Stage 0-II breast cancer patients per center was 149 (range;<br />
10-891). The median proportion of these patients who underwent BC<br />
was 64.8% (range; 33-100%). No significant differences in median BC<br />
rate was noted over the six years of the study (range; 64.2% in 2006<br />
– 67.1% in 2011, p=0.788). However, significant regional variations<br />
were noted in median BC rates: 62.2% in the West (N=59 centers),<br />
63.8% in the South (N=145 centers), 64.1% in the Midwest (N=118<br />
centers), and 70.8% in the Northeast (N=104 centers), p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 4<br />
was performed with the Nanostring nCounter® system. Data<br />
were normalized using the nCounter® digital analyzer software for<br />
analysis.<br />
Results: Among the 108 studied cases, 66 (61%) recurred as DCIS and<br />
42 (39%) recurred as invasive cancer. Median time to recurrence was<br />
40 months (range 7-156 mo) and did not differ by type of recurrence.<br />
Similarly, patient age, grade of DCIS, ER status, use of radiation or<br />
tamoxifen therapy did not differ. Unsupervised hierarchical clustering<br />
using all 32 genes demonstrated two predominant groups, one<br />
enriched for recurrent-as-invasive (RI) tumors, and the other enriched<br />
for recurrent-as-DCIS (RD) tumors. Refined analysis by selection<br />
of 14 genes with significant differential expression between the RI<br />
and the RD tumors identified four main groups. The first cluster was<br />
dominated by ERBB2 over-expression and is equally composed of RI<br />
and RD tumors. The second cluster was composed almost exclusively<br />
of RI tumors and showed high level of COX2 and CCND1 and low<br />
level of CDKN2A (p16). The clusters 3 and 4 were enriched for RD<br />
tumors, with the fourth cluster completely devoid of RI cases. This<br />
RD-only group showed the lowest level of CCND1, but highest level<br />
of AKT3, EGFR, CDKN2A, and MKI67, thus displaying molecular<br />
traits typical of basal-like tumors.<br />
Conclusion: In this cohort of patients who recurred following<br />
conservative treatment for DCIS, HER2 expression was not<br />
predictive, however gene expression analysis demonstrated that high<br />
COX2 and CCND1 and low CDKN2a (p16) levels were strongly<br />
associated with invasive recurrences (RI), whereas increased AKT3<br />
and MKI67 were associated with non-invasive recurrences (RD).<br />
Although the optimal combination of predictive markers requires<br />
validation, these data suggest that molecular alterations associated<br />
with RI differ from those associated with RD and warrant further<br />
investigation.<br />
PD04-06<br />
Molecular Phenotypes of DCIS predict Invasive and DCIS<br />
recurrence<br />
Williams KE, Barnes NLP, Cheema K, Dimopoulos N, Bundred NJ,<br />
Landberg G. The University of Manchester, Manchester, Greater<br />
Manchester, United Kingdom<br />
Introduction: Molecular phenotypes of invasive breast cancer predict<br />
early recurrence and survival. DCIS exhibits similar phenotypes<br />
but their frequency and clinical significance remain uncertain. To<br />
determine whether molecular phenotypes of DCIS predict recurrence,<br />
273 women (median age 57 years) with primary DCIS who were<br />
screened for or entered DCIS trials (Iressa/Lapatinib/ERISAC) in<br />
one unit from 1990-2010 were studied.<br />
Methods: HER2, oestrogen receptor (ER) and progesterone receptor<br />
(PR) expression within primary DCIS were established using<br />
immunohistochemistry within the trial protocols. HER2 was scored 0<br />
(absent) to 3 (maximum). Scores ≥2 were taken as positive if amplified<br />
on FISH testing. ER and PR scored positive if ≥5% of cells stained.<br />
64.2% patients were ER positive, 43.3% were HER2 positive and<br />
31.8% were high-grade lesions. 94 underwent mastectomy whilst<br />
185 had BCS.<br />
Results: There was an overall recurrence rate of 20.14% after a<br />
median follow-up period of 74 months (range 12-240). Of these<br />
recurrences, 36.4% were invasive. Conservation surgery (BCS)<br />
was used in 185 women who suffered 47 recurrences. Molecular<br />
phenotype predicted local recurrence by Log Rank analysis (P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
respectively. The HR RT vs No RT for Triple Negative subtype was 0.40<br />
(95 % CI, 0.07-2.41) and was not adjusted because of the sparse<br />
number of events. Finally, we focused the analysis on DIN2 patients<br />
stratified by Ki-67 LI. Again, after adjustment for menopause, surgical<br />
margins, presence of necrosis, microcalcifications, and HT, RT was<br />
not effective in DIN2 patients with Ki-67 LI 500X) All classes of genomic alterations were detected.<br />
RESULTS: The site distribution and frequency of disease recurrence<br />
included: soft tissue (19) lung (4), bone and liver (3), and brain (2).<br />
The disease subtype classification based on the expression of ER,<br />
PR and HER-2 were as follow: ER-, PR-, HER-2-, Basal-like or TN<br />
(65%); ER+ and/or PR+, HER-2 -(grade3) or HER-2+, Luminal B<br />
(22%); ER-, PR-, HER2+ (13%). Genomic alterations were identified<br />
in all patients with various frequencies. Genetic mutations included:<br />
P53 (DNA-binding domain, splice site), PI3KCA (H1047R, R441N,<br />
E545K, K111E,); RB1; PTEN (D107Y); EGFR (L858R); ERBB2<br />
(V777L, S310F) in a patient with TN disease; ESR1 D538G. Gene<br />
amplifications included: MYC (26%); CCND1 (22%); ERBB2 (in<br />
a patient with TN disease), MLC-1, CCNE1, CK4, K-RAS. One<br />
patient had evidence of discordant genomic abnormalities in two<br />
simultaneous sites of recurrence (skin and pleura) suggesting disease<br />
heterogeneity. Three patients were effectively treated with genomic<br />
alterations-guided therapies.<br />
CONCLUSIONS: Genomic sequencing of advanced IBC is<br />
feasible, identifies potential therapeutic targets and can advance our<br />
understanding of the molecular alterations of this aggressive disease.<br />
PD05-02<br />
Novel mutations in lobular carcinoma in situ (LCIS) as uncovered<br />
by targeted parallel sequencing<br />
De Brot M, Andrade VP, Morrogh M, Berger MF, Won HH, Koslow<br />
Mautner S, Qin L-X, Giri DD, Olvera N, Sakr RA, King TA. Memorial<br />
Sloan-Kettering <strong>Cancer</strong> Center, New York, NY<br />
Background<br />
LCIS has traditionally been recognized as a marker of increased risk<br />
for the subsequent development of breast cancer, of either the lobular<br />
or ductal phenotype, yet due to the incidental nature of LCIS little is<br />
known about its underlying biology. Here we describe the first report<br />
of novel mutations in LCIS using targeted exome sequencing of fresh<br />
frozen tissue samples.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
124s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 5<br />
Methods<br />
Fresh frozen tissue samples from patients with a prior history of LCIS<br />
undergoing therapeutic or risk-reducing mastectomy from 2003-08<br />
were harvested and systematically reviewed to identify LCIS. Cells<br />
from individual LCIS lesions +/- associated cancers were collected<br />
by laser capture microdissection. For the purposes of this study,<br />
germline DNA (blood) and DNA from 12 unique LCIS lesions were<br />
subject to targeted parallel sequencing of exons corresponding to 230<br />
cancer genes using the Illumina HiSeq 2000 platform. DNA from<br />
an associated ductal carcinoma in situ (DCIS) and/or an invasive<br />
ductal (IDC) or lobular (ILC) lesion was also available for 7 of these<br />
cases resulting in 41 samples from 12 pts for mutational analysis.<br />
Normalized (RMA) Affymetrix U133A gene expression data were<br />
also available.<br />
Results<br />
DNA profiling reliably identified 7 somatic mutations in 5/12 LCIS<br />
samples (41.7%). Of these, 4/7 mutations were base substitutions<br />
(missense mutations); and the others included: 1 deletion; 1 silent<br />
and 1 splice-site mutation. Mutations in LCIS were identified in<br />
5/230 cancer genes analyzed, including: PIK3CA, CDH1, NOTCH4,<br />
PREX2 and ARAF. PIK3CA and CDH1 mutations were each<br />
identified in two samples, representing 4/7 (57.1%) mutations.<br />
Specific mutations found in LCIS and their frequencies are listed<br />
(table). Among 3 LCIS-ILC pairs, one shared the G914R mutation<br />
in PIK3CA, and 1/3 LCIS-IDC pairs exhibited an identical point<br />
mutation (R373W) in the NOTCH4 gene. No shared mutations were<br />
observed in 3 LCIS-DCIS pairs. Both CDH1 mutated cases were<br />
associated with decreased e-cadherin mRNA levels when compared<br />
to non-mutated cases (mean 9.88 vs 11.01), as was the NOTCH4<br />
mutation (mean 6.02 vs 6.47). Mutations in ARAF and PREX2 were<br />
associated with increased mRNA levels, mean 7.07 vs 6.52 and 4.82<br />
vs 4.22, respectively. The hotspot PIK3CA mutation (E545K) was<br />
also associated with increased gene expression (mean 5.15 vs 4.64)<br />
whereas the G914R mutant was associated with decreased expression<br />
(mean 4.13 vs 4.64).<br />
LCIS<br />
PIK3CA<br />
Sample<br />
CDH1 NOTCH4 PREX2 ARAF Shared Mutation<br />
1 - - - -<br />
Q167Q<br />
10.4% -<br />
2 - I178_splice 9.7% R373W 6.7% - - R373W IDC 10.7%<br />
3 - - - - - -<br />
4 E545K 7.2% - - - - -<br />
5 - - - - - -<br />
6 - - - - - -<br />
7 G914R 17.8% - - - - G914R ILC 29.6%<br />
8 - - - - - -<br />
9 - Indel 19.1% -<br />
G959D<br />
15.8%<br />
- -<br />
10 - - - - - -<br />
11 - - - - - -<br />
12 - - - - - -<br />
Conclusions<br />
This study represents the first targeted exon sequencing analysis of<br />
fresh frozen LCIS. Although LCIS has been regarded as a rather<br />
genetically stable lesion, somatic mutations were detected in 41.7%<br />
of lesions in this small cohort. While CDH1 mutations are expected<br />
in lobular neoplasia, this is the first report of mutations in ARAF,<br />
NOTCH4, PIK3CA and PREX2. Given the shared relevance of<br />
PIK3CA and PREX2 in the PI3K/AKT pathway, these findings<br />
suggest novel mechanisms for new chemoprevention strategies among<br />
women with LCIS.<br />
PD05-03<br />
What is the appropriate sample (s) on which to perform<br />
sequencing for mutational analysis to guide the selection of<br />
targeted therapy?<br />
Alpaugh RK, Bingham C, Fittipaldi P, Banzi M, Palmer G, Cristofanilli<br />
M. Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA; Silicon Biosystems,<br />
Spa, Bologna, Italy; Foundation Medicine, Cambridge, MA<br />
BACKGROUND: Success of targeted therapy requires expression<br />
of the protein. Tumor tissue source can include diagnostic biopsy,<br />
surgical samples from initial or follow-up surgeries, fluids e.g. pleural<br />
or ascites and circulating tumor cells (CTC). The goal of using CTCs<br />
was 1. To determine whether CTC can be used as a “liquid” tumor<br />
biopsy and enable gene sequence information at the single cell level<br />
and 2. To determine the heterogeneity represented in the circulation<br />
compared to that seen in solid tumor by examining single cells (or a<br />
small cluster of cells) for the presence of a specific mutation which<br />
was detected in tissue tumor source.<br />
METHODS: We performed sequencing for mutational analysis on<br />
tissue(s) from patients with inflammatory breast cancer (IBC). Tumor<br />
sources varied from mastectomy tissue, metastatic site(s) e.g. liver or<br />
skin from chest wall disease, pleural fluid and CTC isolated into pure<br />
single cell populations (or groups of cells) using Silicon Biosystems<br />
DEPArray. Ampli1 WGA kit was used for CTC amplification. Of<br />
the 22 patients sequenced, mastectomy primary tumor was examined<br />
in 3, metastatic site skin chest wall disease in 15, other metastatic<br />
site in 4, pleural fluid in 2 and CTC collected to investigate p53<br />
mutations in 8.<br />
RESULTS: To date 22 patients have had mutational data performed,<br />
14/22 had mutations in p53, 4/22 in RB1, 2/22 in each PI3K and<br />
ERBB2, 1/22 in each of BRAC1, BRAC2, ATM, KRAS, Notch 1,<br />
MEN1 and ESR1. Numerous amplifications were noted including<br />
AKT1, RPTOR, MLC1, MYC, CCND1 and ERBB2. For one patient’s<br />
chest wall biopsy compared to two single CTCs and a cluster of 10<br />
CTCs the same TP53C229fs*10 mutation was detected revealing<br />
the same 2bp deletion. No 2bp deletion was found in single white<br />
blood cells. Whereas, another patient which showed a TP53 S215G<br />
mutation in her skin biopsy of chest wall disease, only amplifications<br />
of AURKA, CCND1, IGF1R, MDM2 and SRC in pleural tumor<br />
cells were detected and no mutations in three single CTC, two single<br />
pleural tumor cells and in single white blood cells were seen. Primary<br />
tumor tissue is being sort for both of these patients. Mutational data<br />
reviewed to date suggest that IBC is not one disease but a multiplicity<br />
of diseases, revealing a variety of target(s). Aberrations are not<br />
consistent across tissue source.<br />
CONCLUSIONS: Successful treatment outcomes using standard of<br />
care chemotherapy combined with target therapies will require not<br />
one, but a panel, of tissue sources for sequencing to guide the selection<br />
of appropriate targeted therapies.<br />
PD05-04<br />
Targeted resequencing in oncogenetics : developing a new<br />
approach for molecular diagnostics<br />
Sevenet N, Lafon D, Dupiot-Chiron J, Hubert C, Jones N, Debled M,<br />
Tunon de Lara C, Longy M, Bonnet F. Institut Bergonie, Bordeaux,<br />
France; Centre de Génomique Foncionnelle de Bordeaux, Bordeaux,<br />
France; Institut Bergonie & Universite Bordeaux Segalen, Bordeaux,<br />
France<br />
Introduction<br />
Next-generation sequencing (NGS) appears to be an accurate tool<br />
adapted for molecular oncogenetics. In contrast to certain somatic<br />
mutations, a lack of germline mutation hotspots in genes involved<br />
www.aacrjournals.org 125s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
in cancer predisposition syndromes, especially hereditary breast and<br />
ovarian cancer (HBOC), force the molecular biologist to screen the<br />
entire coding sequence.<br />
Material & methods<br />
In order to screen a panel of genes predominantly involved in HBOC<br />
& Cowden disease in a molecular diagnostic setting, we captured 408<br />
exons (and their surrounding intronic sequences) of 25 genes using<br />
the SureSelect oligonucleotide library capture (Agilent technologies).<br />
The bioinformatics resources Earray (Agilent technologies), Ensembl<br />
human genome v62 and UCSC repeat masker were used to create the<br />
capture design. This gave us 2899 unique 120-mers oligonucleotide<br />
probes which were duplicated 19 to 38 times depending on the<br />
GC content or the size of the targeted regions. Germline DNA<br />
of 190 patients (40 with previously identified mutations and 150<br />
without previous molecular genetic analysis) was sequenced using<br />
a MiSeq bench top next-generation sequencer (Illumina) and in<br />
parallel was analyzed using our current screening method (EMMA,<br />
Enhanced Mismatch Mutation Analysis, similar to high resolution<br />
melting). Samples were prepared according the manufacturer’s<br />
recommendations (Agilent technologies).<br />
Results<br />
All previously identified mutations along with 33 mutations in<br />
previously unscreened patients were detected. In addition, more than<br />
five hundred variants described as polymorphisms were identified.<br />
NGS seems to be more sensitive than our current screening method<br />
due to its detection and identification of homozygous variants. In<br />
order to limit the interpretation time, we restricted sequence analysis<br />
to the exon, -50 bp (including the acceptor splice site of the upstream<br />
intron) and +50 bp (including the donor splice site of the downstream<br />
intron). We have validated NGS as a technique adapted for germline<br />
mutation screening in oncogenetics. From the beginning of 2013, all<br />
germline DNA samples will be screened by NGS for oncogenetic<br />
molecular diagnostics. Sample preparation, technical organization,<br />
bioinformatics workflow and comprehensive results will be presented.<br />
PD05-05<br />
RNA-seq identifies unique transcriptomic changes after brief<br />
exposure to preoperative nab-paclitaxel (N), bevacizumab (B) or<br />
trastuzumab (T) and reveals down-regulation of TGF-β signaling<br />
associated with response to bevacizumab<br />
Varadan V, Kamalakaran S, Janevski A, Banerjee N, Lezon-Geyda K,<br />
Miskimen K, Bossuyt V, Abu-Khalaf M, Sikov W, Dimitrova N, Harris<br />
LN. Philips Research North America, Briarcliff Manor, NY; Yale<br />
University School of Medicine, New Haven, CT; Yale Comprehensive<br />
<strong>Cancer</strong> Center, New Haven, CT; Yale University School of Medicine,<br />
Yale Comprehensive <strong>Cancer</strong> Center, New Haven, CT; Warren Alpert<br />
Medical School of Brown University, New Haven, CT; Seidman<br />
<strong>Cancer</strong> Center, Cleveland, OH<br />
Background: Identification of differentially expressed transcripts<br />
upon brief exposure to preoperative therapy can help determine likely<br />
response markers. We quantify and compare differential transcript<br />
expression using RNA-seq on patient samples before and after one<br />
dose of T or B or N. We also evaluate correlation of brief-exposure<br />
transcriptomic changes with response to B.<br />
Methods: We sequenced transcriptomes of core biopsy RNA from<br />
50 pairs of breast tumors obtained from neoadjuvant clinical trials<br />
BrUOG 211A/211B. Patients were given a run-in dose of B or N or<br />
T, followed by combination biologic/chemotherapy (HER2- with B/<br />
carboplatin/N; HER2+ with T/carboplatin/N). We sequenced biopsy<br />
pairs obtained pre/post 10 day exposure to run-in monotherapy.<br />
Paired-end sequencing was done on Illumina GAII platform using<br />
amplified total RNA with 74bp read length, yielding expression data<br />
for 22,302 genes and 35,768 transcripts. We evaluated transcriptomic<br />
changes upon brief exposure to monotherapy assuming Poissondistributed<br />
read-counts, followed by multiple testing correction<br />
and enrichment analysis of 185 KEGG pathways. We investigated<br />
association of transcriptomic changes upon brief exposure and<br />
pathologic complete response (pCR) in the B arm. Differential<br />
expression of previously published signatures of tumor vasculature,<br />
TGF-β, β-catenin, MYC, E2F3 and RAF-MEK pathway activities<br />
were evaluated to identify associations with pCR.<br />
Results: PAM50-based clustering showed individual samples<br />
cluster together, demonstrating that tumor subtypes do not change<br />
over the 10-day treatment. We identified unique transcripts that<br />
were significantly differentially expressed in each therapy arm<br />
(p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 5<br />
combined with RNA-seq data from an additional 77 TNBCs and 10<br />
adjacent normal tissues from the TCGA Data Portal. The merged<br />
gene expression values (RPKM) were quantile normalized, batch<br />
effect corrected, and submitted for differential gene expression<br />
analysis using Partek Genomics Suite. Differentially expressed<br />
genes were statistically determined with cutoffs of FDR±2. Pathway and network analyses utilized Ingenuity<br />
Pathway Analysis.<br />
Results: Principal components analysis (PCA) of all expressed<br />
protein coding genes revealed a close association of adjacent normal<br />
tissues to TNBCs whereas microdissected normal breast tissues were<br />
starkly separated. In comparing these 3 tissue types, 3841 genes were<br />
differentially expressed between TNBC vs. donated microdissected<br />
normal of which 1627 genes were also differentially expressed<br />
between adjacent normal vs. donated microdissected normal. The PCA<br />
along with the differential expression support the notion that adjacent<br />
normal gene expression is strongly influenced by the primary tumor,<br />
and in a significant set of genes, adjacent normal gene expression<br />
mimics the expression of primary tumors. The differential gene<br />
expression analysis also revealed 1240 genes that were restricted<br />
solely to the TNBC vs. donated microdissected normal that were not<br />
detected when TNBCs were compared to adjacent normal tissues.<br />
Examination of these genes reveals several potential kinase drug<br />
targets, genes involved in notch signaling, metabolism, cell cycle<br />
among other key cancer pathways. Preliminary analysis of the noncoding<br />
RNA component also reveals the same pattern of dysregulation<br />
in cancer associated microRNAs and lincRNAs.<br />
Conclusions: Gene expression within adjacent normal tissues<br />
is significantly impacted by the primary tumor and donated<br />
microdissected normal breast epithelium from healthy volunteers may<br />
be an optimal comparator for use in next-generation RNA sequencing<br />
breast cancer studies. Use of this comparator may identify therapeutic<br />
targets that would not otherwise be detected when using adjacent<br />
normal tissue as controls.<br />
PD05-07<br />
Detection of fusion transcripts among 100 breast cancer samples<br />
by next generation sequencing<br />
Kim J, Han W, Moon H-G, Ahn SK, In Y-H, Kim S, Lee H-S, Lee JW,<br />
Kim JY, Kim T, Kim MK, Noh D-Y. Seoul National University Hospital,<br />
Seoul, Korea; <strong>Cancer</strong> research institute, Seoul National University,<br />
Seoul, Korea; i-Pharm (Information Center for Bio-pharmacological<br />
Network) IBBI (Integrated Bioscience and Biotechnology Institute)<br />
Advanced Institute of Convergence Technology, Seoul National<br />
University, Seoul, Korea; Seoul National University, Seoul, Korea;<br />
Macrogen Inc., Seoul, Korea<br />
Introduction Fusions genes and it’s products are widely applied as<br />
biomarker and therapeutic target in hematopoietic cancers. It’s role<br />
as a “driver” of oncogenic pathway have also been proved in several<br />
epithelial solid cancers including prostate, lung and breast cancer.<br />
We performed high throughput next generation sequencing technique<br />
(RNA-Seq) to identify the novel fusion transcript(FT) in a large set<br />
of primary breast cancer samples.<br />
Materials and Method Total RNA was prepared using the Illumina®<br />
TrueSeq RNA sample Preparation Kit and TrueSeq mRNA library<br />
was constructed. Clustering was done with HiSeq 2000 and Solexa’s<br />
sequencing was performed. We used tissues extracted from previously<br />
collected 100 fresh-frozen primary breast cancer samples obtained<br />
after surgical resection. Among 100 samples, 1 failed to pass the<br />
process of RNA sequencing and no expression of fusion transcripts<br />
were observed in 7 samples resulting in 92 samples with mRNA-<br />
Seq data of fusion transcripts. Fourteen(15.2%) samples were cases<br />
with distant metastasis during follow up. Estrogen receptor(ER) was<br />
positive in 40(43.5%) samples and 23(25%) were triple negative<br />
breast cancer.<br />
Results and discussion We detected 958 fusion transcripts<br />
among 92 tumors and 58 were chosen for tumor-specific fusion<br />
transcript candidate (Fragments per kilo-base of exon per million<br />
fragments mapped, FPKM>500 and 3 times higher than average,<br />
probability>0.6). Most of the fusion transcripts were “private”,<br />
expressed only in one sample. Estrogen receptor(ER) positive<br />
breast cancer samples had 29 fusion transcripts and ER negative<br />
had 25 fusion transcripts among the 58 tumor-specific candidates.<br />
HER2 negative samples exhibited 29 fusion transcripts while 15<br />
were identified in HER2 negative samples. Triple negative sample<br />
showed 4 TF candidates. Among the 17 recurrence samples 190 fusion<br />
transcripts were identified. Of the 190 fusion transcripts in recurred<br />
samples, 24 candidates of recurrence-specific FTs were chosen by it’s<br />
high expression level (FPKM>300 and 2 times higher than average,<br />
probability>0.5). Eight were expressed both in recurred, non-recurred<br />
samples and 16 were exclusively expressed in recurred samples. No<br />
fusion transcript matched directly with the currently known actionable<br />
gene-list owing to the limited number while majority is unexploited.<br />
Further validation and functional pathway analysis is under progress<br />
to ascertain the role of highly suspected fusion transcripts with<br />
oncogenic property. Considering the high incidence of breast cancer<br />
world-wide, identification of TF expressed even in only a minor<br />
percentage among the whole breast cancer population, if druggable,<br />
it can be applicable to large number of patients.<br />
Conclusion We performed a whole-transcriptome sequencing with<br />
a large set of primary breast cancer samples and detected abundant<br />
fusion transcripts. The majority of breast cancer(92.9%, 92/99) had at<br />
least one fusion transcript suggesting it’s role during the tumorigenesis<br />
and progression process. With scarce evidence and confirmed data<br />
of actionable fusion gene and it’s product, data interpretation for it’s<br />
clinical utility is rather complicated. Accumulation of these large set<br />
data of fusion transcript must serve as a groundwork for future work.<br />
PD05-08<br />
Genomic characterisation of invasive breast cancers with<br />
heterogeneous HER2 gene amplification<br />
Ng CKY, Gauthier A, Mackay A, Lambros MBK, Rodrigues DN,<br />
Arnoud L, Lacroix-Triki M, Penault-Llorca F, Baranzelli MC, Sastre-<br />
Garau X, Lord CJ, Zvelebil M, Mitsopoulos C, Ashworth A, Natrajan<br />
R, Weigelt B, Delattre O, Cottu P, Reis-Filho JS, Vincent-Salomon A.<br />
The Breakthrough <strong>Breast</strong> <strong>Cancer</strong> Research Centre, The Institute of<br />
<strong>Cancer</strong> Research, London, United Kingdom; Institut Curie, Paris,<br />
France; CRB Ferdinand Cabanne, Centre Georges François Leclerc,<br />
Dijon, France; Institut Claudius Regaud, Toulouse, France; Centre<br />
Jean Perrin, Clermont-Ferrand, France; Centre Oscar Lambret,<br />
Lille, France<br />
Aims: HER2 gene amplification is observed in up to 15% of breast<br />
carcinomas. In a rare subset of breast cancers classified as HER2-<br />
positive by immunohistochemistry and in situ hybridisation, HER2<br />
overexpression and gene amplification are restricted to a subset of<br />
>30% but not all cancer cells. Here we sought to characterise the<br />
repertoire of gene copy number aberrations and somatic mutations<br />
in the HER2-positive and HER2-negative components of cases with<br />
heterogeneous HER2 overexpression and gene amplification.<br />
Material and methods: Cases diagnosed as HER2 positive but with<br />
>30% but
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
was re-assessed using immunohistochemistry and chromogenic and/<br />
or fluorescence in situ hybridisation. For cases with confirmed HER2<br />
gene amplification heterogeneity, HER2-positive and HER2-negative<br />
components were microdissected from tissue sections stained with the<br />
Herceptest antibody. DNA samples extracted from both components<br />
of each case were subjected to microarray-based comparative genomic<br />
hybridisation (aCGH), using a 32K BAC array platform with 50Kb<br />
resolution. The HER2-positive and HER2-negative components of<br />
cases with frozen material were also subjected to massively parallel<br />
targeted exome sequencing.<br />
Results: Twelve cases yielded sufficient DNA for aCGH analysis.<br />
Tumours were preferentially ER positive (83%) and of histological<br />
grade 3 (67%). The HER2-positive and HER2-negative components<br />
of all cases shared most of the copy number aberrations. A pairwise<br />
comparison of the genomic profiles of the two components from<br />
each case revealed that in ten of the twelve cases, copy number<br />
aberrations in addition to 17q12 amplification encompassing the<br />
HER2 gene locus were restricted to one of the two components.<br />
Exome sequencing of two cases suggested that the HER2-positive and<br />
HER2-negative components from each case harboured >30 somatic<br />
mutations in common, including identical TP53 somatic mutations<br />
in both components of each case. The HER2-negative component of<br />
one of the cases displayed a somatic mutation in NRG2, an ERBB<br />
receptor ligand, and the HER2-negative component of the other case<br />
harboured a mutation in PTTG1IP, a proto-oncogene with putative<br />
oestrogen receptor elements.<br />
Conclusions: Our results demonstrate that in HER2-positive breast<br />
cancers with heterogeneous HER2 gene amplification, the HER2-<br />
positive and HER2-negative components are clonally related. The<br />
distinct genomic profiles of HER2-positive and HER2-negative<br />
components, however, suggest that, at least in some of these cases,<br />
HER2 amplification may constitute a relatively late event in tumour<br />
evolution. Exome sequencing revealed mutations restricted to<br />
the HER2-negative components of HER2-positive tumours with<br />
heterogeneous HER2 overexpression/gene amplification, which may<br />
constitute potential drivers in the absence of HER2 overexpression/<br />
gene amplification.<br />
PD05-09<br />
Whole-genome progression of breast cancer from early neoplasia<br />
to invasive carcinoma<br />
West RB, Kashef-Haghighi D, Newburger D, Weng Z, Brunner A,<br />
Salari R, Guo X, Troxell M, Zhu S, Varma S, Sidow A, Batzoglou<br />
S. Stanford University, Stanford, CA; Oregon Health & Science<br />
University, Portland, OR<br />
<strong>Cancer</strong> evolution involves cycles of genomic damage, epigenetic<br />
deregulation, and increased cellular proliferation that eventually<br />
culminate in the carcinoma phenotype. Early breast neoplasias include<br />
usual ductal hyperplasia, columnar cell lesions, and flat epithelial<br />
atypia and some are thought to represent precursor stages. To elucidate<br />
their role in cancer evolution we performed comparative whole<br />
genome sequencing of early neoplasias, matched normal tissue, and<br />
carcinomas from six patients. The identified somatic mutations served<br />
as lineage markers to build trees that relate the tissue samples. On the<br />
basis of the lineage trees we inferred the order, timing, and rates of<br />
mutational events. We find that in a subset of cases, the last common<br />
ancestor of an early neoplasm and a carcinoma was hypermutated<br />
and had several aneuploidies, and that evolution further accelerated<br />
in the carcinoma lineage. In contrast to highly advanced tumors that<br />
are the focus of much of current cancer genome sequencing, the early<br />
neoplasia genomes, and the carcinomas as well, harbor a striking<br />
paucity of potentially functional somatic point mutations. The earliest<br />
significant events we could detect, those changes that occurred in<br />
common ancestors of neoplastic and tumor cells, are aneuploidies.<br />
Several aneuploidies are recurrent, suggesting that they are among<br />
the earliest genomic events that predispose breast tissue to eventual<br />
development of invasive carcinoma.<br />
PD06-01<br />
Automated computational Ki67 scoring in the GeparTrio breast<br />
cancer study cohort<br />
Klauschen F, Wienert S, Blohmer J-U, Mueller BM, Eiermann W,<br />
Gerber B, Tesch H, Hilfrich J, Huober J, Fehm T, Barinoff J, Jackisch<br />
C, Erbstoesser E, Loibl S, Denkert C, von Minckwitz G. Charite<br />
Universitaetsmedizin Berlin, Berlin, Germany; <strong>San</strong>kt Getrauden<br />
Hospital, Berlin, Germany; University of Munich, Munich, Germany;<br />
Klinikum Suedstadt Rostock, Rostock, Germany; Onkologisches<br />
Zentrum am Bethanien-Kankenhaus, Frankfurt, Germany; Ellenriede<br />
Hospital, Hannover, Germany; University Duesseldorf, Germany;<br />
University of Tuebingen, Germany; Kliniken Essen Mitte, Essen,<br />
Germany; Kliniken Offenbach, Offenbach, Germany; Salvator<br />
Hospital, Germany; German <strong>Breast</strong> Group, Neu-Isenburg, Germany<br />
Background: Scoring proliferation through Ki67-<br />
immunohistochemistry is an important component in predicting<br />
therapy response to chemotherapy in breast cancer patients. Therefore,<br />
an accurate and standardized Ki67-scoring is pivotal both in routine<br />
diagnostics and larger multi-center studies aiming at improving<br />
present or establishing new cut-off values for existing or novel<br />
therapy regimens. However, recent studies have cast some doubt on<br />
the reliability of “visual” Ki67 scoring by pathologists, especially<br />
within the lower - yet clinically important - proliferation range. Here,<br />
we present and apply a novel automated image analysis approach for<br />
Ki67-quantification in breast cancer tissue.<br />
Methods: We perform automated Ki67-scoring in 1219 breast cancer<br />
patients from the GeparTrio study cohort using a novel image analysis<br />
approach that avoids detection biases due to morphological variability<br />
by using a generic minimum-model approach. The method is capable<br />
of tumor-stroma-separation and may be used to process large data<br />
sets fully unsupervised in batch mode while allowing for efficient<br />
visual checks of the results. We compare these results with a different<br />
in-house-developed subtiling-based automated quantification method<br />
and moreover, gauge our approach with manual scoring performed<br />
by pathologists.<br />
Results: The results show deviations of 10% (automated method 1 vs.<br />
manual), 9% (automated method 2 vs. manual) and 3% (automated<br />
method 1 vs. automated method 2) on average. The Ki67 scores show<br />
Pearson correlations between automated and manual scoring of r>0.8<br />
(p0.95 (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 6<br />
PD06-02<br />
Standardized Assessment of Ki-67 Using Virtual Slides and<br />
Automated Analyzer for <strong>Breast</strong> <strong>Cancer</strong> Patients: Comparison of<br />
Automated and Central/Local Pathology Assessment<br />
Mizuno Y, Yamada J, Abe H, Natori T, Sato K. Tokyo-West Tokushukai<br />
Hospital, Tokyo, Japan; SRL, Inc., Tokyo, Japan<br />
Background: Ki-67 is useful in determining the effect of hormonal<br />
therapy and also as a prognostic factor. However, the method for its<br />
evaluation has not been standardized, and the results vary depending<br />
on the assessment by pathologists. We reported that the discordance<br />
rate of Ki-67 in preoperative core needle biopsy and the surgical<br />
specimens was higher than that of other biological markers, and<br />
this was considered to be due to the discrepancies in the evaluation<br />
methods (SABCS 2011). In this report, we reviewed the possibility<br />
of introducing an automated analyzer by comparing the diagnosis<br />
made by local pathologists and reassessment by central review to<br />
standardize the evaluation method for Ki-67.<br />
Subjects and Method: Of the 354 cases of primary breast cancer<br />
that had their first operation from October 2008 to March 2012,<br />
225 cases that had preoperative core needle biopsy at Tokyo-West<br />
Tokushukai Hospital were selected as the subjects of this study. Cases<br />
with ductal carcinoma in situ (DCIS) and cases with neoadjuvant<br />
chemotherapy were excluded. A cut-off value of 20% was used for<br />
Ki-67 positive criteria. The concordance rates of estrogen receptors<br />
(ER), progesterone receptor (PgR), human epidermal growth factor<br />
receptor 2 (HER2), and Ki-67 by local pathologists were reviewed,<br />
and in cases of non-matching Ki-67, tumor diameter (≈ heterogeneity)<br />
and operative method (≈ condition of formalin fixation) were studied.<br />
Next, non-matching cases (∼ to October 2011) were reassessed both<br />
by central review and by an automated analyzer (Ventana Digital<br />
Pathology) using virtual slides, and the results were studied and<br />
compared with the evaluation by local pathologists. The Wilcoxon-t<br />
test was used to review the p value for statistical analysis. Parameters<br />
such as tumor diameter, operative method were analyzed by χ 2<br />
analysis.<br />
Results: The concordance rate of Ki-67 in preoperative core needle<br />
biopsy and surgical specimens was 76.9% in 225 cases of local<br />
pathology assessment from October 2008 to March 2012. This rate<br />
was significantly lower (p < 0.001) than that of ER (95.6%), PgR<br />
(88.0%), and HER2 (91.5%). In non-matching cases, no difference<br />
was observed in tumor diameter and operative method. Reassessment<br />
of the 39 cases of non-matching Ki-67 to October 2011 using central<br />
review and an automated analyzer resulted in matching 27 cases<br />
(94.8%) and 32 (96.3%) out of 39 cases, respectively.<br />
Conclusion: The concordance rate of Ki-67 in preoperative core<br />
needle biopsy and surgical specimens was lower compared with<br />
other biological markers. However, they were nearly equal with<br />
reassessment using central review and an automated analyzer. Clinical<br />
application of Ki-67 and its standardization are challenging due to<br />
variable counting methods and measurement sites. Conducting central<br />
reviews in general clinical facilities is difficult, but introducing an<br />
automated analyzer with a Ki-67 labeling index is shown to achieve<br />
that goal.<br />
PD06-03<br />
Development of a highly reproducible clinical test for Ki67 using<br />
AQUA technology<br />
Murphy DA, Pacia E, Beruti S, Lamoureux J, Dabbas B, Diver J,<br />
Christiansen J. Genoptix Medical Laboratory, Carlsbad, CA<br />
Background: The measurement of Ki67 is showing promise in the<br />
management of breast cancer patients. It has shown potential for<br />
prognosis and as a chemotherapeutic response predictor, and also<br />
has a role in multivariate assessment of residual risk. However,<br />
the advancement in clinical testing has been arduous due to a lack<br />
of clinically validated scoring and/or cutpoints to guide clinicians.<br />
Standardization of Ki67 scoring is hindered by inter-laboratory<br />
variability in analysis of Ki67 in clinically relevant whole tissue<br />
sections, which are complicated not only by the subjective<br />
measurement required for IHC but also by heterogeneous expression<br />
due to biological variation and inconsistent fixation. In our diagnostic<br />
laboratory, we observed a significant amount of variability in the<br />
assessment of Ki67 using manual IHC scoring for percentage of<br />
positively stained nuclei. To attempt to reduce the variations in<br />
Ki67 assessment in clinically relevant specimens, our laboratory<br />
investigated the use of image analysis methods. Fluorescence<br />
immunohistochemistry (FIHC) coupled with the AQUA® technology<br />
has been established as a diagnostic test using image analysis and<br />
has been shown to eliminate much of the variation introduced in<br />
typical visual assessment. Materials and methods: FIHC, based on<br />
the SP6 antibody clone, was used with AQUA technology to assess<br />
Ki67 expression as measured by percentage of positively stained<br />
nuclei. Results were compared to manually scored IHC results<br />
generated using the commonly used anti-Ki67 MIB1 antibody. IHC<br />
interpretation was performed by three pathologists on the same slides.<br />
Results: The Ki67 assay using FIHC and AQUA technology was<br />
validated for use in a CLIA environment. Inter-reader variability by<br />
IHC was first demonstrated on whole tissues (Average difference<br />
in percent positive nuclei was 18% and ranged from 0-50%). This<br />
was further assessed on tissue microarrays, which mitigate the<br />
heterogeneity component of the tissue and resulted in the same<br />
high inter-reader variability (average percent difference was 18%).<br />
A significant correlation was observed for Ki67 percent positivity<br />
between AQUA and IHC in TMAs (Spearman: r=0.88, p< 0.0001).<br />
FIHC staining and scoring for Ki67 positivity by AQUA resulted<br />
in a 3-fold reduced variation compared to IHC and manual reads<br />
(6% variation). Using clinically relevant whole tissue sections, the<br />
accuracy of Ki67 measurement by AQUA was compared to IHC<br />
performed by an outside laboratory and resulted in a significant<br />
correlation between the two methods (Spearman: r=0.78, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Instead, the consensus introduced clinicopathological BC subtypes<br />
(cpBCST) defined as sets of risk and predictive biomarkers which<br />
are established worlwide (Table 1).<br />
Table 1: St Gallen Clinico-pathological Subtype Definition<br />
Clinico-pathological Subtype<br />
Luminal A<br />
Biomarker<br />
ER/PR+<br />
Her2 neg<br />
Proliferation ⇓<br />
Luminal B Her2 neg ER/PR+<br />
Her2 neg<br />
Proliferation ⇑<br />
Her2+<br />
ER/PR+<br />
Her2+<br />
Her2 non luminal<br />
ER/PR neg<br />
Her2+<br />
Triple-negative<br />
ER/PR neg<br />
Her2 neg<br />
Special histological types endocrine responsive ER/PR+<br />
Her2 neg<br />
endocrine non-respnsive ER/PR neg<br />
Her2 neg<br />
To discriminate Luminal A vs. Her2 negative Luminal B BCs the<br />
St Gallen Consensus recommends Ki67 for defining proliferation.<br />
Although, because no standardized methodology or cut-off definition<br />
for Ki67 is available so far ‘some alternative measure of proliferation’<br />
was suggested. We analyzed the influence of different proliferation<br />
assessment methods on BC subtype distribution.<br />
Methods<br />
cpBCST assessment including proliferation measurement by different<br />
variants of Ki67-Labeling-Index (KI67LI) was performed on 225<br />
BCs. For comparison we used the Mitotic Activity Index (MAI) as<br />
the only prospectively evaluated and best reproducible proliferation<br />
measurement (Baak et al 2008). The Ki67-LI was based on counting<br />
any nuclear staining of distinctly defined target areas: (1) 100 tumor<br />
cells within the hot spot (Ki67-100), (2) 1020 tumor cells in 3 HPF<br />
in the tumor periphery including the hot spot (Ki67-1020periphery),<br />
and (3) 1020 tumor cells in 3 HPF including hot spot, cold spot, and<br />
an intermediate area (Ki67-1020spectrum). Staining quality and<br />
counting accuracy was tested as excellent by the 2011 circulation of<br />
the German Quality Initiative in Pathology. According to St Gallen,<br />
a cut-off
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 6<br />
PD06-06<br />
RELATIONSHIP BETWEEN MOLECULAR SUBTYPE AND<br />
CHANGE IN KI-67 IN THE PLACEBO ARMS OF WINDOW<br />
OF OPPORTUNITY TRIALS<br />
Pruneri G, Gandini S, Guerrieri-Gonzaga A, Serrano D, Cazzaniga<br />
M, Lazzeroni M, Puntoni M, Toesca A, Caldarella P, Johansson<br />
H, Bonanni B, DeCensi A. European Institute of Oncology, Milan,<br />
Italy; Galliera Hospital, Genoa, Italy; University of Milan, School<br />
of Medicine, Milan, Italy<br />
Background: Window-of-opportunity (WOP), presurgical models<br />
often use Ki-67 labeling index (LI) as the main surrogate biomarker<br />
for screening therapeutic activity of candidate agents and characterize<br />
their mechanism of action. Ki-67 LI in the placebo arm has been<br />
frequently reported to be higher at surgery than at baseline biopsy<br />
in WOP studies, a finding that has been ascribed to the higher<br />
proliferative activity in the tumor edge of surgical specimens that<br />
cannot be detected in the baseline core biopsy. Since this observation<br />
has important implications in sample size calculation and effect<br />
interpretation, we investigated which factors affected the changes<br />
of Ki-67 LI in a series of patients allocated to the placebo arms of a<br />
number of WOP trials carried out at IEO.<br />
Methods: Data from 181 patients with pT 1-2 invasive breast cancer<br />
from the placebo arms of three WOP randomized trials were pooled<br />
with those of 98 untreated patients, who had a diagnostic core biopsy<br />
preceding surgery but declined participation to the study or were<br />
ineligible for histological characteristics. Ki-67 LI was measured by<br />
evaluating the prevalence of neoplastic cells showing any definite<br />
nuclear immunostaining with the Mib-1 monoclonal antibody, in the<br />
whole invasive component of baseline core biopsies and in at least<br />
2000 invasive neoplastic cells of surgical samples, in accordance to<br />
the recently licensed international recommendations.<br />
Results: We collected data of 273 breast cancer patients with<br />
information on the changes in Ki-67 LI: 46 (17%) were Luminal A,<br />
85 (31%) Luminal B/HER2-, 24 (9%) Luminal B/HER2+, 38 (14%)<br />
HER2+ and 81 (30%) Triple Negative (TN). Median (IQR) Ki-67LI<br />
at baseline in each molecular subtype was 10% (7-11), 20% (16-<br />
29), 28% (22-35), 30% (25-45) and 50% (32-75) in the Luminal A,<br />
Luminal B/HER2-, Luminal B/HER2+, HER2+ and TN, respectively.<br />
Median (IQR) age was 50 years (44-60), median BMI was 24 (22-27),<br />
50% were post-menopausal. The median (range) time elapsed from<br />
biopsy to surgery was 41 days (33-48). Overall, the median change<br />
in Ki-67 LI between baseline biopsies and surgical samples was 0<br />
(IQR, -2, 5). Results from multivariate analysis showed that none of<br />
the factors investigated, including patient and tumor characteristics,<br />
time elapsed from biopsy to surgery and circulating biomarkers<br />
(IGF-I, SHBG and ultrasensitive CRP) were associated with the<br />
Ki-67 LI change except for the immunohistochemically defined<br />
molecular subtype, which explained most of the variability of the<br />
changes (P=0.004). As a matter of fact, we observed a 5%, significant<br />
increase of Ki-67 LI both in HER2+ and TN tumors, after adjustment<br />
for baseline values.<br />
LS means and 95%CI Ki-67 LI changes (surgery-baseline biopsy) in the placebo/untreated arms by<br />
molecular subtype<br />
Luminal A<br />
Luminal B/ Luminal B/<br />
HER2- HER2+<br />
HER2+ Triple negative<br />
n 41 90 26 34 88<br />
Mean -0.9 -0.4 1.8 5.0 5.3<br />
95% CI -3.9, +2.0 -2.4, +1.6 -1.8, +5.4 +2.2, +7.9 +2.8, +7.7<br />
Conclusions: We reported a significant increase in Ki-67 LI between<br />
baseline biopsy and endpoint surgery in the placebo arms of HER2+<br />
and TN tumors. This association suggests a real biological increase<br />
in proliferation rather than an analytical artifact, and should be taken<br />
into account in designing future WOP studies.<br />
PD06-07<br />
Evaluation of an optimal cut-off point for the Ki-67 index as a<br />
prognostic factor in primary breast cancer.<br />
Tashima R, Nishimur R. Kumamoto Municipal Hospital, Kumamoto,<br />
Japan<br />
Background: The proliferation biomarker Ki-67 is considered to<br />
be a prognostic factor for breast cancer and has been investigated in<br />
several studies. However, there is no standard cut-off point for the<br />
Ki-67 index. Therefore, we retrospectively investigated an optimal<br />
cut-off point in terms of the prognostic factor in primary breast cancer.<br />
Patients&Methods: Immunohistochemical (IHC) analysis of the<br />
proliferation marker Ki-67 index was performed on 4338 patients<br />
with primary breast cancer until March 2012 at Kumamoto City<br />
Hospital. Out of these patients, there were 2375 consecutive cases<br />
with ER and/or PgR positive and HER2 negative tumors since 1997.<br />
Items examined were ER, PgR, HER2, tumor size, nodal status,<br />
nuclear grade, and p53 overexpression. The Kaplan-Meier test was<br />
used to calculate prognosis (cumulative disease-free survival (DFS)<br />
and overall survival (OS)) and tested with the log-rank procedure.<br />
Cox’s proportional hazard model was used to perform a univariate<br />
and multivariate analyses of the factors related to DFS. In addition,<br />
an analysis was conducted to determine various cut-off values for<br />
the Ki-67 index.<br />
Results: The median Ki-67 value was 21%, with a mean of 26.2%.<br />
Univariate and multivariate analysis revealed that the Ki-67 index<br />
was an independent prognostic factor for DFS and OS. A multivariate<br />
analysis revealed the following hazard ratio (HR) and cut-off values<br />
for the Ki-67 index; HR was 1.92 in cases with a cut-off value of<br />
20%, 1.91 in 35%, 1.87 in 40%, 1.89 in 45% and 1.79 in 50%,<br />
respectively. These findings suggested that the optimal cut-off point<br />
was 20%. In the cases with luminal type (ER and/or PgR positive<br />
and HER2 negative) breast cancer, a higher Ki-67 value (20% ≤)<br />
correlated with larger tumor size, positive nodes, higher grade, and<br />
overexpression of p53. Moreover, patients with a higher Ki-67 value<br />
showed significantly lower DFS / OS rates. A multivariate analysis<br />
also revealed that the Ki-67 index is a significant prognostic factor<br />
in luminal type breast cancer.<br />
Conclusion: The optimal cut-off value for the Ki-67 index is 20%.<br />
Moreover, this proliferation marker is a significant prognostic factor<br />
in evaluating primary breast cancer.<br />
PD06-08<br />
Strong prognostic concordance between Ki67 and binary, but not<br />
multi-level gene expression signatures<br />
Tobin NP, Lindström LS, Carlson JW, Bergh J, Wennmalm K.<br />
Karolinska Institutet and University Hospital, Stockholm, Sweden<br />
Background: Several proliferation-related gene signatures have<br />
been proposed to aid breast cancer management by providing better<br />
prognostic and therapy predictive information on a patient-by-patient<br />
basis. It is unclear however, whether a less demanding assessment of<br />
cell division rate (as determined by Ki67 expression) can function in<br />
place of gene profiling.<br />
Methods: Agreement between literature-, distribution-based, as well<br />
as signature-derived threshold values for Ki67, relative to the genomic<br />
grade index (GGI), the 70-gene signature, the p53 signature, the<br />
recurrence score (RS), and the molecular subtype models of Sorlie,<br />
Hu, and Parker was investigated in a representative set of 253 breast<br />
cancers with 25 years follow up. Relevance for breast cancer specific<br />
survival was assessed for contrast groups, and in uni- and multivariate<br />
Cox models.<br />
www.aacrjournals.org 131s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Results: Our broad approach identified Ki67 cutoffs in the range of<br />
10%-20%. With optimum signature-reproducing cutoffs, similarity in<br />
classification of individual tumors was high for GGI (81%), the 70-<br />
gene (78%), and the p53 (82%) signatures, but lower for the recurrence<br />
score (68%), Sorlie (68%), Parker (67%) and Hu (68%) signatures.<br />
Consistent with strong agreement, no prognostic superiority was noted<br />
for Ki67 vs. the binary GGI, 70-gene and p53 signatures respectively,<br />
in multivariate analyses. In contrast, Ki67-independent prognostic<br />
capacity could be demonstrated for RS and molecular subtypes<br />
according to Sorlie, Parker and Hu (Table 1).<br />
Conclusions: The added prognostic value of binary proliferationrelated<br />
gene signatures appears limited for Ki67-assessed breast<br />
cancers. More complex, multi-level descriptions seem to have a<br />
greater potential in pinpointing the outcome heterogeneity in breast<br />
cancer. We aim to validate our findings in a second cohort of 159<br />
breast cancer patients with over 15 years of clinical follow up.<br />
Table 1. Cox uni- and bivariate analysis, hazard ratio (HR) and 95% conf. interval (CI)<br />
Covariate Separate models HRs (CI) Combined model HRs (CI)<br />
Genomic grade index 2.0 (1.27-3.3) 1.6 (0.85-2.9)<br />
Ki67 ≥ 15 1.9 (1.21-3.1) 1.5 (0.79-2.7)<br />
70-gene signature 2.0 (1.21-3.2) 1.5 (0.84-2.7)<br />
Ki67 ≥ 11 2.0 (1.24-3.3) 1.6 (0.89-2.9)<br />
P53 signature 1.8 (1.10-2.9) 1.2 (0.64-2.3)<br />
Ki67 ≥ 16 1.8 (1.15-3.0) 1.7 (0.90-3.1)<br />
Recurrence score* 2.5 (1.43-4.6) 2.1 (1.12-3.8)<br />
Ki67 ≥ 12 2.1 (1.28-3.4) 1.7 (1.00-2.8)<br />
Molecular subtype (Sorlie)† 2.4 (1.39-4.1) 2.0 (1.15-3.5)<br />
Ki67 ≥ 16 1.8 (1.15-3.0) 1.5 (0.89-2.4)<br />
Molecular subtype (Hu)‡ 2.5 (1.57-4.1) 2.2 (1.31-3.6)<br />
Ki67 ≥ 13 2.1 (1.30-3.4) 1.7 (1.00-2.8)<br />
Molecular subtype (Parker)‡ 2.8 (1.72-4.4) 2.2 (1.35-3.7)<br />
Ki67 ≥ 13 2.1 (1.30-3.4) 1.6 (0.97-2.7)<br />
*Hazard ratio for high or intermediate recurrence score; low as reference. †Hazard ratio for luminal<br />
B subtype; others as reference. ‡Hazard ratio for luminal B or HER2 subtype; others as reference.<br />
PD07-01<br />
Z1031B Neoadjuvant Aromatase Inhibitor Trial: A Phase 2 study<br />
of Triage to Chemotherapy Based on 2 to 4 week Ki67 level > 10%.<br />
Ellis MJ, Suman V, McCall L, Luo R, Hoog J, Brink A, Watson M,<br />
Ma C, Unzeitig G, Pluard T, Whitworth P, Babiera G, Guenther M,<br />
Dayao Z, Leitch M, Ota D, Olson J, Hunt K, Allred C. Siteman <strong>Cancer</strong><br />
Center, Washington University, St Louis, MO; Mayo Clinic; Duke<br />
University; Doctor’s Hospital of Laredo; Nashville <strong>Breast</strong> Center;<br />
MD Anderson <strong>Cancer</strong> Center; St. Elizabeth Med Ctr Southwest;<br />
Univ of New Mexico; UT Southwestern; University of Maryland<br />
Medical Center<br />
Background: Neoadjuvant aromatase inhibitor (AI) therapy would<br />
become a more acceptable alternative to chemotherapy if there was a<br />
way to identify AI-resistant cases early for triage to alternate systemic<br />
treatment. We therefore conducted a Phase 2 trial of post-menopausal<br />
patients with clinical stage 2 or 3 ER+ (Allred Score 6 to 8) breast<br />
cancer who were re-biopsied 2 to 4 weeks after initiating neoadjuvant<br />
AI therapy. If the tumor Ki67 level was > 10% (AI resistant) the<br />
patient was triaged to either chemotherapy or immediate surgery<br />
and if < 10% (AI sensitive) the patient completed 16 to 18 weeks of<br />
neoadjuvant AI treatment. Co-primary endpoints were: 1) to confirm<br />
that the pathological complete response (pCR) rate to standard NCCN<br />
chemotherapy in the AI resistant population is in the range of 20%<br />
(similar to ER- disease). This required the observation of least 4/35<br />
pCRs; 2) whether patients were willing to accept a recommendation<br />
of no chemotherapy when the preoperative endocrine prognostic<br />
index score was zero (PEPI-0) (pStage 1 or 2A, Ki675 yr postmenopausal subset), and ABCSG-12.<br />
In addition, combining ZOL with standard neoadjuvant therapy<br />
improved pathologic complete response (pCR) and reduced the need<br />
for mastectomy in the AZURE trial. The open-label, multicenter,<br />
phase 2, FEMZONE trial examined the effect of neoadjuvant letrozole<br />
(LET) ± ZOL on tumor response in postmenopausal patients with<br />
hormone receptor-positive (HR + ) primary BC. Here, we report the<br />
efficacy and safety after 6 mo of treatment.<br />
Methods: Postmenopausal women with HR + BC and ECOG<br />
performance status of 0-2 were randomized to LET (2.5 mg/d) ± ZOL<br />
(4 mg q4w). The primary efficacy endpoint was objective response<br />
rate (ORR; complete + partial response per RECIST criteria) at 6<br />
mo by central review. Secondary endpoints included ORR in the<br />
per-protocol and safety populations, best response, breast-conserving<br />
surgery, pCR, change in tumor size, overall survival, and safety.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
132s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 7<br />
Between-group differences in ORR were evaluated using Fisher’s<br />
exact test.<br />
Results: Among enrolled patients (N = 168; mean age 70.9 yr;<br />
mean treatment duration 6.5 mo), patients receiving LET + ZOL<br />
experienced numerically better ORR at 6 mo versus LET alone<br />
(69.2% vs 54.5%, respectively), with a between-group difference<br />
of 14.7% (P = .106). Although the primary endpoint did not reach<br />
statistical significance because of insufficient patient recruitment, the<br />
prespecified between-group difference of ≥10% was met. A similar<br />
trend in ORR at 6 mo favoring ZOL was also seen by local assessment<br />
(∆11%, P = .192). At 4 mo, higher ORR was observed for LET + ZOL<br />
versus LET alone both for the local (33.3% vs 24%, respectively)<br />
and central assessments (41.5% vs 30.3%, respectively). Numerically<br />
more patients receiving LET + ZOL experienced a partial response<br />
at 6 mo versus LET alone (66.2% vs 54.5%, respectively). At 6 mo,<br />
the mean tumor size had decreased from 3.34 ± 1.98 cm to 2.1 ± 1.76<br />
cm in the overall patient population, and the decrease was slightly<br />
larger with LET + ZOL compared with LET alone (–1.37 ± 0.96 cm<br />
vs –1.12 ± 0.92 cm, respectively). Overall, there was no difference<br />
in the number of patients requiring mastectomy between LET +<br />
ZOL and LET alone (15.6% vs 15.2%, respectively). Incidence of<br />
adverse events (AEs) was slightly higher among patients receiving<br />
LET + ZOL versus LET alone (92.1% vs 81%, respectively), and the<br />
types of AEs were consistent with the known safety profiles of these<br />
agents. No deaths or osteonecrosis of the jaw was reported during<br />
the course of the study.<br />
Conclusions: This study provides additional confirmation of the<br />
efficacy of LET as neoadjuvant therapy for early HR + BC, and<br />
supports previous reports of ZOL’s anticancer activity in this setting<br />
(as evidenced by the trend toward improved ORR with ZOL +<br />
LET versus LET alone). These data, together with other published<br />
ZOL studies, suggest that adding ZOL to neoadjuvant therapy may<br />
be considered for postmenopausal patients scheduled to receive<br />
neoadjuvant endocrine therapy for BC.<br />
PD07-03<br />
INCREASED PATHOLOGIC COMPLETE RESPONSE RATE<br />
AFTER A LONG TERM NEOADJUVANT LETROZOLE<br />
TREATMENT IN POSTMENOPAUSAL ESTROGEN AND/OR<br />
PROGESTERONE RECEPTOR-POSITIVE BREAST CANCER<br />
Allevi G, Strina C, Andreis D, Zanoni V, Bazzola L, Bonardi S, Foroni<br />
C, Milani M, Cappelletti MR, Generali D, Berruti A, Bottini A. A.O.<br />
Istituti Ospitalieri di Cremona, Cremona, Italy; A.O.U. <strong>San</strong> Luigi<br />
Gonzaga di Orbassano, Orbassano, TO, Italy<br />
Background:<br />
Neoadjuvant endocrine therapy has been increasingly employed in<br />
clinical practice to improve surgical options for postmenopausal<br />
women with bulky hormone receptor-positive breast cancer. Recent<br />
studies indicate that tumor response and in particular the pathologic<br />
complete response (CR) in this setting may predict long-term<br />
outcome. The letrozole approval in neoadjuvant setting is based on a<br />
study that included 4 months of letrozole treatment only. Prospective<br />
studies have not investigated treatment duration beyond 6 months,<br />
and retrospective studies suggest that useful responses can occur after<br />
this period. The purpose of this study was to determine the clinical<br />
and pathologic response of 2.5 mg daily letrozole used with different<br />
schedule in breast cancer patients (pts) unfit for chemotherapy.<br />
Patients and Methods:<br />
This single Institution retrospective study comprised 102<br />
postmenopausal women with primary breast cancer (clinical stage<br />
≥T2, N0-1), who were divided into 3 subgroups (34 each in single<br />
subgroup) according to the different duration of neoadjuvant letrozole<br />
treatment: 4 months (subgroup A), 8 months (subgroup B) or 12<br />
months (subgroup C) of treatment. The subgroups were comparable<br />
in terms of baseline characteristics.<br />
Results:<br />
Pts and tumor characteristics included: median age 77.3 years (range<br />
53.9-95.4); 100% estrogen receptor-positive, 81.4% progesterone<br />
receptor-positive; median Ki67 13.5% (range 2-90%). All pts were<br />
evaluable for clinical and pathologic response. A total of 77 pts<br />
(75.5%) achieved an objective response at individual end: 40 (39.2%)<br />
clinical CR and 37 (36.3%) partial responses (PR). The clinical CR<br />
were significantly confined to subgroups C (20/34 pts, 58.8%) and<br />
B (16/34 pts, 47.1%) than to subgroup A (4/34 pts, 11.8%) (p for<br />
trend =0.00001). Objective response rate was 46.1% (47/102 pts)<br />
at month 4, 83.8% (57/68 pts) at month 8, and 94.1% (32/34 pts) at<br />
month 12 compared with baseline. As expected, letrozole induced a<br />
significant reduction of Ki67 expression after treatment in any single<br />
subgroup, without significant differences between them. With very<br />
interest, the pathologic CR rate was significantly higher in subgroup<br />
C (7/34 pts, 20.6%) than in subgroups A (1/34 pt, 2.9%) and B (1/34<br />
pt, 2.9%) (p for trend
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Results<br />
Between Oct 2007 and Apr 2011, 59 pts were randomized to arm A<br />
and 57 to arm B. Main baseline characteristics were well-balanced<br />
between the 2 arms: Median age was 68 yrs-old (53-91) in arm A<br />
and 74 yrs-old (51-88) in arm B. Histological grades were EE I-II<br />
in 53 pts (89 %) and 49 pts (86%) and median clinical size before<br />
treatment was 41.5 mm and 42.3 mm in arm A and B respectively.<br />
Neither SAE nor grade 3/4 toxicity was reported. The most common<br />
treatment-related AEs were grade1/2 hot flushes (27% and 12% of<br />
pts in arm A and B respectively), and musculoskeletal symptoms<br />
(20% and 21%).<br />
35 pts in arm A and 29 pts in arm B continued assigned treatment up<br />
to 6 mo depending on the clinical response evaluated at 4 mo. Also,<br />
the clinical response rate was estimated at 4 mo orat 6 mo. 1 death<br />
post-surgery was reported in arm B with no proven relationship with<br />
treatment.<br />
Overall clinical response rates (CR + PR) at 4 or 6 mo were 62% (CI<br />
95% [49-75]) in arm A and 46% (CI 95% [32-59]) in arm B. Clinical<br />
response rate amelioration at 6 mo was observed among 15% of pts<br />
in each arm.<br />
BCS was performed in 59% of pts in arm A and 49% in arm B. (1 pt<br />
from arm B refused surgery).<br />
Pathological response according to Sataloff classification: TA and<br />
TB tumor responses were observed in 17/59 pts (29%) in arm A vs<br />
12/57 (21%) in arm B respectively.<br />
Conclusions<br />
Both anastrozole and fulvestrant show excellent efficacy and<br />
tolerability as neoadjuvant therapy in post-menopausal pts with<br />
endocrine-dependent, HER2-negative BC.<br />
Objective response rates and improvement in surgical outcome seem<br />
to be more frequent with anastrozole. However disease stabilization<br />
and tolerability are in favour of fulvestrant.<br />
Our data suggest that neo-adjuvant HT improves surgical options<br />
for HR+ post-menopausal women. Correlation between clinical &<br />
pathological responses and outcome as well as the identification of<br />
markers of sensitivity to both treatments will be also studied.<br />
PD07-05<br />
A randomized controlled trial comparing zoledronic acid plus<br />
chemotherapy with chemotherapy alone as a neoadjuvant<br />
treatment in patients with HER2-negative primary breast cancer<br />
Hasegawa Y, Kohno N, Horiguchi J, Miura D, Ishikawa T, Hayashi<br />
M, Takao S, Kim SJ, Tanino H, Miyashita M, Konishi M, Shigeoka<br />
Y, Yamagami K, Akazawa K. Hirosaki Municipal Hospital, Hirosaki,<br />
Aomori, Japan; Tokyo Medical University Hospital, Tokyo, Japan;<br />
Gunma University Hospital, Maebashi, Gunma, Japan; Toranomon<br />
Hospital, Tokyo, Japan; Yokohama City University Medical<br />
Center, Yokohama, Kanagawa, Japan; Tokyo Medical University<br />
Hachioji Medical Center, Hachioji, Tokyo, Japan; Hyogo <strong>Cancer</strong><br />
Center, Akashi, Hyogo, Japan; Osaka University Hospital, Suita,<br />
Osaka, Japan; Naga Municipal Hospital, Kinokawa, Wakayama,<br />
Japan; Konan Hospital, Kobe, Hyogo, Japan; Hyogo Prefectural<br />
Nishinomiya Hospital, Nishinomiya, Hyogo, Japan; Yodogawa<br />
Christian Hospital, Osaka, Japan; Shinko Hospital, Kobe, Hyogo,<br />
Japan; Niigata University Medical and Dental Hospital, Niigata,<br />
Japan<br />
Background:<br />
Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate,<br />
and it induces osteoclast apoptosis and inhibits bone resorption by<br />
inhibiting the mevalonate pathway. ZOL has also been found to have<br />
antitumor effects that include an angiogenesis inhibiting action, an<br />
inhibitory effect on tumor cell adhesion to bone, an inhibitory effect<br />
on invasion of the extracellular matrix, and activation of a gdT cells.<br />
In addition, it has been found to have a synergistic anti-proliferative<br />
effect when used in combination with antitumor drugs.<br />
In this study we investigated the pathological complete response<br />
(pCR) rate when ZOL is added to anthracycline followed by taxane to<br />
treat T2 and T3 breast cancer patients as a neoadjuvant chemotherapy.<br />
Methods:<br />
Women with resectable invasive StageIIA-IIIB (T ≥3 cm or T ≥2 cm<br />
and lymph node positive) breast cancer who are HER-2-negative,<br />
between 20 and 70 years of age, and ECOG PS 0-1 were eligible.<br />
Patients with distant metastasis, patients who have had received<br />
chemotherapy, hormone therapy, or radiotherapy for breast cancer,<br />
patients with serious complications, such as heart disease or an<br />
infection, patients with a complicating dental or jaw infection or<br />
traumatic condition of the teeth, and patients with a history of<br />
treatment with a bisphosphonate within the previous 12 months<br />
were excluded.<br />
A total of 4 courses of FEC100 were administered every 3 weeks<br />
followed by weekly paclitaxel for 12 courses. ZOL 4mg was<br />
administered every 3-4 weeks a total of 7 times.<br />
Patients were randomized 1:1 to chemotherapy + ZOL group or<br />
chemotherapy alone group, according to the presence or absence<br />
of lymph node metastasis, estrogen receptor (ER) status, and their<br />
menopausal status.<br />
The primary endpoint was the rate of pCR defined as absence of<br />
invasive disease in the breast at surgery. Secondary endpoints were<br />
tumor response rate (RECIST ver1.0), the breast-conserving surgery<br />
ratio, and disease-free survival (DFS).<br />
We calculated the sample size on the basis of a pCR rate of 18% in<br />
the chemotherapy alone group and 35% in the chemotherapy + ZOL<br />
group, at 5% significance level based on the one-sided chi-square<br />
test with the statistical power of 80%, and as a result we targeted a<br />
patient sample size of 180 patients.<br />
Results:<br />
188 patients were recruited between March 2010 and April 2012.<br />
Results of the primary analysis of efficacy and safety will be presented.<br />
PD07-06<br />
NEO-ZOTAC: Toxicity data of a phase III randomized trial with<br />
NEOadjuvant chemotherapy (TAC) with or without ZOledronic<br />
acid (ZA) for patients with HER2-negative large resectable or<br />
locally advanced breast cancer (BC)<br />
van de Ven S, Liefers G-j, Putter H, van Warmerdam LJ, Kessels LW,<br />
Dercksen W, Pepels MJ, Maartense E, van Laarhoven HWM, Vriens<br />
B, Smit VTHBM, Wasser MNJM, Meershoek-Klein Kranenbarg EM,<br />
van Leeuwen-Stok E, van de Velde CJH, Nortier JWR, Kroep JR.<br />
Leiden University Medical Center (LUMC), Leiden, Netherlands;<br />
Catharina Hospital, Eindhoven, Netherlands; Deventer Hospital,<br />
Deventer, Netherlands<br />
Background: The role of bisphosphonates (BP) when added to the<br />
(neo)adjuvant treatment of BC in enhancing the efficacy of therapy<br />
is still unknown. NEOZOTAC investigates the efficacy of ZA added<br />
to neoadjuvant chemotherapy in patients with HER2-negative BC.<br />
Trial design: NEOZOTAC is a Dutch multicenter study. Patients are<br />
1:1 randomized to 3-weekly TAC (docetaxel 75mg/m 2 , adriamycin 50<br />
mg/m 2 and cyclophosphamide 500 mg/m 2 i.v., day 1) chemotherapy<br />
supported by pegfilgrastim (6 mg sc), day 2 with or without ZA (4<br />
mg i.v. within 24 hr after chemotherapy) q3 weeks.<br />
Eligibility criteria: Main inclusion criteria: stage II or III,<br />
measurable, HER2-negative BC, age ≥18 years, WHO 0-2, adequate<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
134s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 7<br />
bone marrow-, renal-, and liver function, absence of prior BP usage<br />
and absence of active dental problems.<br />
Study endpoint: The primary endpoint is the pathologic complete<br />
response (pCR) rate. Secondary endpoints are toxicity, clinical<br />
response, tumor heterogeneity in core biopsy vs. operation specimen,<br />
and (disease free) survival. Optional side studies include fluorescent<br />
imaging (SoftScan®), changes in bone markers, single nucleotide<br />
polymorphisms and the insulin-like growth factor pathway, circulating<br />
tumor and endothelial cells and the false-negative rate of the sentinel<br />
node biopsy after neoadjuvant chemotherapy.<br />
Statistical Methods: Using a 5% significance level based on the twosided<br />
Fishers exact test with a power of 80%, 250 patients (125/arm)<br />
are needed to show an improvement of the pCR-rate from 17% to<br />
34% in the experimental arm. Randomization was done according to<br />
the Pococks minimisation technique stratified by cT, cN, and estrogen<br />
receptor status. Toxicity is analyzed using the Exact (2-sided) Chi-<br />
Square test.<br />
Results: From July 2010 to April 2012, 250 patients from 25<br />
participating sites were randomized. Toxicity data of 173 patients<br />
are currently available and data of all 250 patients will be presented<br />
at SABCS. Patient characteristics are presented in table 1.<br />
Table 1. Patient Characteristics<br />
TAC-ZA TAC Total<br />
Patient nr 90 83 173<br />
WHO 0 98% 98% 98%<br />
WHO 1 2% 2% 2%<br />
Median Age (range) 49 (29-67) 49 (29-70) 49 (29-70)<br />
T-stage cT2 56% 54% 55%<br />
cT3/T4 44% 46% 45%<br />
N-stage cN+ 56% 55% 56%<br />
ER-status ER+ 81% 86% 83%<br />
Menopausal status pre 56% 56% 56%<br />
peri 11% 15% 13%<br />
post 33% 30% 31%<br />
Hematological and non-hematological toxicities were not significantly<br />
different between both treatment arms. Main grade 3/4 NCI-CTCv4<br />
toxicities were neutropenia (8%), followed by febrile neutropenia<br />
(7%), fatigue (6%), diarrhea, hypertension, nausea (3%) and vomiting<br />
(1.2%). Bone pain, myalgia, and hypocalcemia occurred in one<br />
patient in the TAC-ZA arm (0.6%). Osteonecrosis of the jaw was<br />
not observed.<br />
Conclusions: Neoadjuvant TAC supported by pegfilgrastim plus ZA<br />
is feasible. No significant difference in toxicity are reported compared<br />
with the control arm.<br />
PD07-07<br />
Prediction of antiproliferative response to lapatinib by HER3 in<br />
an exploratory analysis of HER2-non-amplified (HER2-) breast<br />
cancer in the MAPLE presurgical study (CRUK E/06/039)<br />
Dowsett M, Leary A, Evans A, A’Hern R, Bliss J, Sahoo R, Detre S,<br />
Hills M, Haynes B, Harper-Wynne C, Bundred N, Coombes G, Smith<br />
IE, Johnston S. Royal Marsden Hospital, London, United Kingdom;<br />
Institut Gustave Roussy, Paris, France; Poole Hospital, Poole,<br />
Dorset, United Kingdom; Institute of <strong>Cancer</strong> Research, London,<br />
United Kingdom; Kent Oncology Centre, Maidstone, Kent, United<br />
Kingdom; University Hospital of South Manchester NHS Trust,<br />
Manchester, United Kingdom<br />
Aim: To identify pretreatment biomarker predictors of Ki67 response<br />
to lapatinib in women with HER2- primary breast cancer.<br />
Background: Lapatinib is an EGFR/HER2 inhibitor. Its clinical use is<br />
restricted to HER2 overexpressing disease. The MAPLE (Molecular<br />
Antiproliferative Predictors of Lapatinib’s Effects) presurgical<br />
window of opportunity study of lapatinib vs placebo was conducted<br />
in women with HER2-amplified (HER2+) or HER2- primary disease.<br />
Ki67 (primary end-point) was reduced by a geomean 46% (95%CI<br />
23-63%, p=0.002) and 27% (95%CI 8-42%, p=0.008) in HER2+<br />
and HER2- disease, respectively (Leary et al, AACR 2012). We have<br />
now assessed whether predictive biomarkers of the antiproliferative<br />
response in HER2- disease could be identified.<br />
Methods: 121 primary breast cancer patients were randomized (3:1)<br />
to 14 days of 1500mg/d lapatinib or placebo before surgery. Biopsies<br />
were taken before treatment and at surgery. Ki67 responders were<br />
defined as having a >/=50% reduction in Ki67 compared to baseline<br />
(Ellis,P et al, <strong>Breast</strong> <strong>Cancer</strong> Res Treat 1998, 48, 107). ER, PgR,<br />
HER2, EGFR, pAKT, pERK1/2 (nuclear and cytoplasmic), stathmin<br />
and apoptosis (TUNEL) were assessed by IHC (+FISH for HER2[all<br />
cases]) and scored visually by continuous methods. HER2, HER3,<br />
epiregulin (epir), amphiregulin (amphir) and neuregulin (neur) were<br />
assessed by qrtPCR.<br />
Results: Three of the 121 patients were excluded because of inadequate<br />
biopsy material. Ninety-one of the remaining 118 patients received<br />
lapatinib: 7/19 (37%) HER2+ cases and 10/72 (14%) HER2- cases<br />
were Ki67 responders. Thus while the proportion of Ki67 responders<br />
was higher for HER2+ disease there was a similar or higher absolute<br />
number of responders with HER2- disease. All of the following relates<br />
to patients with HER2- disease. None of the pretreatment levels<br />
of ER, PgR, pAKT, pERK1/2, EGFR, epir, amphir or neur were<br />
associated with Ki67 response (p>0.20). However, HER3 (p=0.01)<br />
and HER2 (p=0.06) mRNA levels were associated with greater Ki67<br />
response. There was a tendency for Ki67 response to be greater with<br />
lower baseline Ki67 (p=0.07). Multivariate analysis showed only<br />
HER3 mRNA levels to be independently significant. HER2 and<br />
HER3 mRNA levels were highly correlated (rho=0.67, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
histomorphometry and measurement of serum bone markers. Presence<br />
of tumour cells in bone was detected by multiphoton microscopy.<br />
Results: OVX induced significant bone loss compared to sham<br />
within 2 weeks, which was completely inhibited by ZOL. Tumour<br />
growth was detected in the long bones of 29% of animals in the sham<br />
group on day 35 following tumour cell inoculation, and this was not<br />
affected by ZOL treatment. In contrast, 83% of the OVX animals<br />
had detectable tumours in the long bones, demonstrating that OVX<br />
mediated changes to the bone microenvironment that stimulated<br />
tumour growth. Crucially, this OVX-induced increase in tumour<br />
growth was completely prevented by weekly ZOL treatment, with<br />
only 17% of animals in the OVX+ZOL group having detectable bone<br />
tumours compared to 83% in the OVX+saline group. Multiphoton<br />
microscopy revealed that numerous individual tumour cells were<br />
present in long bones of animals in the OVX+ZOL group, supporting<br />
that ZOL acts by inhibiting an OVX-mediated trigger of tumour cell<br />
proliferation.<br />
Conclusions: Our data are in agreement with those reported from<br />
clinical trials of adjuvant zoledronic acid, showing an anti-cancer<br />
effect exclusively in the post-menopausal setting. This is the first<br />
demonstration that zoledronic acid prevents tumour progression in<br />
bone specifically through inhibition of OVX-induced proliferation<br />
of tumour cells resident in the bone marrow.<br />
PD07-09<br />
Zoledronate versus ibandronate comparative evaluation (ZICE)<br />
trial - first results of a UK NCRI 1,405 patient phase III trial<br />
comparing oral ibandronate versus intravenous zoledronate in<br />
the treatment of breast cancer patients with bone metastases.<br />
Barrett-Lee PJ, Casbard A, Abraham J, Grieve R, Wheatley D,<br />
Simmons P, Coleman R, Hood K, Griffiths G, Murray N. Velindre NHS<br />
Trust, Cardiff, Wales, United Kingdom; Cardiff University School<br />
of Medicine, Cardiff, Wales, United Kingdom; University Hospital,<br />
Coventry, England, United Kingdom; Royal Cornwall Hospital,<br />
Truro, England, United Kingdom; University Hospital, Southampton,<br />
England, United Kingdom; Weston Park Hospital, Sheffield, England,<br />
United Kingdom; Royal Adelaide Hospital, Adelaid, South Australia,<br />
Australia<br />
Introduction Bone metastases in patients with breast cancer have<br />
serious effects on health including pain, poor mobility, skeletal<br />
fractures, spinal cord compression and the need for radiotherapy/<br />
surgery. The introduction of intravenous (IV) bisphosphonates, such<br />
as zoledronic acid (Z) has significantly delayed the onset of skeletalrelated<br />
events (SRE). However, prolonged IV bisphosphonates place<br />
burdens upon patient and hospital, and can also cause renal and<br />
acute phase toxicities. Ibandronic acid (I), a third generation aminobisphosphonate<br />
in its oral form has previously been compared with<br />
placebo and was shown to be well tolerated and effective. Indirect<br />
comparisons with IV Z indicated similar efficacy in reducing bone<br />
events, but adverse events were overall comparable with placebo.<br />
One might therefore assume that oral ibandronate would be more<br />
acceptable to patients, and the ZICE Trial is the only large scale direct<br />
randomised comparison between IV Z and oral I to report. Methods<br />
Between January 2006 and October 2010, 1405 newly diagnosed<br />
metastatic breast cancer patients with proven bone metastases were<br />
randomised 1:1 to IV Z (4mg 15 min infusion every 3-4 weeks) or<br />
oral I (50mg per day) for up to 96 weeks. All patients were prescribed<br />
daily calcium & vitamin D supplementation, and patients with current<br />
active dental problems including infection were excluded. Patients<br />
also received chemotherapy, and or endocrine therapy as determined<br />
by their physician. The primary objective was to demonstrate noninferiority<br />
of oral I in comparison with IV Z in terms of the SRE rate,<br />
defined as the number of SREs reported per year (using multiple event<br />
analysis). Secondary endpoints included time to 1st SRE, proportion<br />
of patients with SRE, Pain Scores, side effect profiles including ONJ<br />
and renal toxicities, quality of life and Health resources and overall<br />
survival. The trial was run under the auspices of the NCRI, sponsored<br />
by Velindre NHS Trust, coordinated by the Wales <strong>Cancer</strong> Trials<br />
Unit, funded by an educational grant from Roche and peer reviewed/<br />
endorsed by <strong>Cancer</strong> Research UK (CRUKE/04/022). Results At the<br />
time of this analysis the last randomised patient had completed 96<br />
weeks of therapy, median follow up was 18.4 months and total number<br />
of SREs was 865 (468 in I and 397 in Z). For the primary objective,<br />
the SRE rate was 0.543 and 0.444 in I and Z groups respectively<br />
(Hazard ratio, 1.22; 95% CI, 1.04 to 1.45; P = .017). Ibandronate<br />
failed to meet the criteria for non-inferiority to Zoledronate, but was<br />
similar in delaying time to first SRE (hazard ratio, 1.11; 95% CI, 0.94<br />
to 1.31; P = .233). Overall survival (disease progression), was very<br />
similar between groups but renal AEs occurred more frequently with<br />
Z than I; Compliance with oral therapy was 82%. ONJ rate was very<br />
low in both arms (0.71%, I; 1.29%, Z; P = 0.28). Conclusion Oral I<br />
is inferior to Z in terms of the SRE rate in metastatic breast cancer<br />
patients with bone metastases, but is similar to Z in delaying time<br />
to first SRE. Both drugs had acceptable safety profiles, with adverse<br />
events consistent with those reported previously.<br />
PD08-01<br />
Utilization of Oncotype DX in an inner-city population: Race<br />
or Place?<br />
Guth AA, Fineberg S, Fei K, Franco R, Bickell N. NYU School of<br />
Medicine, New York, NY; Montefiore Medical Center, Bronx, NY;<br />
Mount Sinai School of Medicine, New York, NY<br />
Introduction: While women with early stage breast cancer frequently<br />
receive adjuvant chemotherapy to prevent recurrence, not all patients<br />
benefit from and require it. Oncotype DX(ODX) is a validated<br />
genomic predictor of outcome and response to chemotherapy in<br />
estrogen receptor (ER) positive, node-negative breast cancer. The<br />
assay has the potential to enable women to avoid unnecessary<br />
chemotherapy. There is little data available on use in minority/<br />
economically disadvantaged women.<br />
Methods: Women with an early-stage breast cancer surgically treated<br />
between 2006-2009 participated in a randomized controlled trial of<br />
patient assistance to reduce disparities in treatment.<br />
Results: Of 374 women, 225 had ER+ tumors stage 1B or greater<br />
eligible to undergo ODX testing. Chi-square/t tests and logistic models<br />
for multivariable comparisons. Race and municipal hospital were<br />
highly correlated, only 3 white women went to municipal hospitals.<br />
Because there was no racial difference in testing within tertiary<br />
centers, and only one woman in municipal hospitals got tested, we<br />
used hospital type rather than race in the final model. 23% (52/225)<br />
of women underwent ODX. Women tested had earlier stage cancer,<br />
higher income, were white and treated at tertiary referral centers.<br />
There was no racial difference in receipt of ODX among women<br />
treated at referral centers. Black and Hispanic women as compared<br />
to white women were more likely to be treated at municipal hospitals<br />
(29% vs 32% vs 3%; p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 8<br />
19/52 (37%) had an intermediate score, and 9/52 (17%) had a high<br />
recurrence risk score, with no racial difference. All 9 patients at high<br />
risk (100%) were treated with chemotherapy; 58% at intermediate<br />
risk; only 4% at low risk were treated with chemotherapy.<br />
Discussion: The most important factors influencing ODX testing<br />
were tumor stage and care at a municipal hospital. Women treated<br />
at municipal hospitals were unlikely to get ODX. When Medicaid<br />
coverage became available for ODX, minority women at tertiary<br />
centers began to undergo testing but not municipal hospitals.<br />
This suggests adoption of ODX was slower in municipal than tertiary<br />
referral hospitals resulting in apparent racial disparity even after<br />
insurance coverage would have ensured equal access and saved<br />
unnecessary chemotherapy costs to patients and hospitals. Thus, the<br />
racial disparity in ODX testing reflected the site of care and not race<br />
since women were treated equally at the tertiary referral centers, with<br />
no racial disparity in those sites. These results reflect that diffusion<br />
of innovation lags at hospitals treating minority and underprivileged<br />
patients compared to tertiary referral centers.<br />
As Oncotype DX influences treatment and can reduce overuse of<br />
chemotherapy, it is imperative to implement innovations that improve<br />
quality care at safety net hospitals. Such approaches have the potential<br />
to reduce racial and socioeconomic disparities in cancer care.<br />
PD08-02<br />
Disparities in the Utilization of Reconstruction after Mastectomy:<br />
The California Teachers Study<br />
Kruper L, Xu XX, Bernstein L, Henderson K. City of Hope <strong>Cancer</strong><br />
Center, Duarte, CA<br />
Background: For breast cancer patients undergoing mastectomy,<br />
factors such as insurance status, race/ethnicity, age, and type of<br />
hospital influence whether post-mastectomy reconstruction (PMR)<br />
is performed. This study was undertaken to determine if additional<br />
patient variables and clinicopathologic features also influence the<br />
utilization of PMR using the California Teachers Study (CTS).<br />
Methods: Patients were identified from the CTS, a cohort of<br />
approximately 133,000 female public school teachers and<br />
administrators, followed prospectively from 1995 forward to<br />
investigate exposures associated with incident cancer and other<br />
outcomes. All in situ and invasive breast cancers were identified<br />
through linkage with the California <strong>Cancer</strong> Registry, as well<br />
as with the California Office of Statewide Health Planning and<br />
Development (OSHPD) hospital discharge database to determine<br />
the rates of mastectomy with and without reconstruction. Patterns<br />
in PMR rates were examined by calendar year, age, race/ethnicity,<br />
type of insurance, type of hospital, tumor stage, body mass index<br />
(BMI), family history of breast cancer (FH), smoking history,<br />
physical activity, and prior breast implant status using a chi-square<br />
test. Univariable and multivariable-adjusted odds ratios (OR) with<br />
95% confidence intervals (CI) were estimated for relative odds of<br />
immediate reconstruction vs. mastectomy only.<br />
Results: During follow-up, 1,253 CTS participants with incident<br />
breast cancer underwent mastectomy with (N=368) and without<br />
(N=885) reconstruction. In multivariable stepwise logistic regression<br />
analyses, calendar year, age, type of insurance, tumor stage, and prior<br />
breast implant were statistically significantly associated with use of<br />
reconstruction. The proportion of patients undergoing immediate<br />
PMR increased from 21.8% during 1995-1999 to 26.4% during 2005-<br />
2009. A statistically significant dose-response was apparent between<br />
older age at surgery and decreased likelihood of post-mastectomy<br />
reconstruction (Ptrend
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
(n=10, 27%) or feeling unprepared to BRS (n=9, 24%). Five patients<br />
(13%) considered BRS as “useless”: 4 of them were ≥65 and age was<br />
the main factor in their choice. Vulnerability was not correlated with<br />
the decisions about BRS, neither was marital status. Of note, for all<br />
patients but one financial difficulties were not regarded as a critical<br />
issue and all pts were aware that BRS can be reimbursed by the public<br />
health insurance; none of them, however, knew that extra fees were<br />
the rule when BRS is performed outside of public hospitals.<br />
CONCLUSIONS: In an universal healthcare system, only a minority<br />
of low-income or vulnerable patients choose BRS. Although BRS<br />
funding is usually not regarded as a problem, numerous barriers to<br />
BRS still exist, mainly related to irrational grounds or wrong beliefs.<br />
Whether these barriers can be overcome by improved patient-doctor<br />
communication or better information remains an issue.<br />
PD08-04<br />
Factors which affect surgical management in an underinsured,<br />
county hospital population<br />
Komenaka IK, Olsen L, Klemens AE, Hsu C-H, Nodora J, Martinez<br />
ME, Thompson PA, Bouton M. Maricopa Medical Center, Phoenix,<br />
AZ; University of Arizona, Tucson, AZ; Moores <strong>Cancer</strong> Center,<br />
University of California, <strong>San</strong> Diego, CA<br />
Background: Significant variation exists between institutions in the<br />
use of lumpectomy, mastectomy, and reconstruction. Much less is<br />
known about minorities and populations outside the large academic<br />
institutions. The current study was performed to evaluate variables<br />
that affect patient choice in surgical management in a county hospital<br />
population.<br />
Methods: A retrospective review of all patients seen at the county,<br />
safety net institution with breast cancer from January 2010 to May<br />
2012. Sociodemographic, clinical, and treatment variables were<br />
evaluated. Univariate analysis was performed to identify variables<br />
which were associated with type of operation. All of the variables with<br />
a p-value
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 9<br />
<strong>Antonio</strong>, Texas (P30-CA054174), Susan G. Komen for the Cure (POP<br />
2000 704), and the National <strong>Cancer</strong> Institute via Redes En Acción<br />
(U01-CA86117 and U54 CA153511-01).<br />
PD08-06<br />
Significant Clinical impact of recurrent BRCA1 and BRCA2<br />
(BRCA) mutations in Mexico<br />
Villarreal-Garza C, Herrera LA, Herzog J, Port D, Mohar A,<br />
Perez-Plasencia C, Clague J, Alvarez RMa, <strong>San</strong>tibanez M, Blazer<br />
KR, Weitzel JN. Instituto Nacional de <strong>Cancer</strong>ologia, Mexico City,<br />
Mexico DF, Mexico; Instituto Nacional de <strong>Cancer</strong>ologia – Instituto<br />
de Investigaciones Biomedicas, UNAM, Mexico City, Mexico DF,<br />
Mexico; City of Hope, Duarte, CA<br />
Background: <strong>Breast</strong> cancer (BC) is the most commonly diagnosed<br />
cancer and the leading cancer cause of death in Hispanic women.<br />
Although the incidence of breast cancer in Hispanics is less than<br />
that for non-Hispanic white women, our studies on the prevalence of<br />
deleterious mutations in the BRCA genes among high-risk Hispanics<br />
in the US suggest that BRCA mutations may account for a higher<br />
proportion of BC in this population. However, a lack of research<br />
on BRCA mutations in Hispanics has limited the implementation of<br />
prevention efforts and the scope of comparative studies of genetic<br />
factors that influence BC and ovarian cancer (OC) risk within Hispanic<br />
populations – this is especially true of Mexico where there has been<br />
little access to clinical BRCA gene analyses.<br />
Objective/Methods: We used an economic panel assay (HISPANEL)<br />
on a mass spectroscopy platform (Sequenom) to analyze DNA from<br />
189 cancer cases (92 unselected OC; 97 BC) from the National <strong>Cancer</strong><br />
Institute in Mexico City for recurrent BRCA mutations, including a<br />
large rearrangement (BRCA1 ex9-12del) that we hypothesize is a<br />
Mexican founder mutation.<br />
Results: Overall, 14% (27/189) harbored a germline BRCA mutation<br />
(25 BRCA1, 2 BRCA2) detected by the HISPANEL (17% in OC; 11%<br />
in BC). BRCA1 ex9-12del was detected in 9.8% (9/92) of unselected<br />
OC cases, representing 56% of the 16 BRCA mutations. It also<br />
represented 36% (4/11) of the BRCA mutations detected in the BC<br />
cases. Mean age at onset of BC for BRCA-associated cases (n=11)<br />
was 46 years old (range 31-63); 8/11 were triple negative BC (TNBC)<br />
– a BRCA mutation was detected in 24% (8/34) of all TNBC cases.<br />
Conclusions: The remarkable frequency of the BRCA1 ex9-12del<br />
mutation, accounting for 56% of BRCA mutations in the OC cases<br />
and 36% of BC cases, supports our hypothesis of regional origin<br />
of this Mexican founder mutation approximately 1,474 years ago.<br />
Similar to our experience in the Mexican American population, the<br />
HISPANEL, which includes recurrent BRCA mutations found in<br />
women of Hispanic ancestry, appears to have high sensitivity and<br />
thus is likely to have clinical utility while reducing overall genotyping<br />
cost among underserved women in Mexico. Both in the US Hispanic<br />
populations and in Mexico, the prevalence of the Mexican founder<br />
mutation make it a significant public health issue, and presents an<br />
opportunity for cost effective in BC and OC prevention.<br />
PD09-01<br />
BRCA1 inactivation induces NF-κB in human breast cancer cells<br />
and in murine and human mammary glands<br />
Sau A, Arnaout A, Pratt C. University of Ottawa, ON, Canada; Ottawa<br />
Hospital, Ottawa, ON, Canada<br />
Understanding the biological mechanisms underlying the initiation<br />
and progression of breast cancer it is an important step for its<br />
prevention and treatment. In 2011 in the United States, approximately<br />
230,000 women were diagnosed with breast cancer and 40,000<br />
died. Individuals with mutations in breast cancer-associated gene 1<br />
(BRCA1) have a lifetime risk of developing breast cancer up to 85%.<br />
It is well known that BRCA1 participates in DNA damage repair and<br />
cell cycle checkpoint control, serving as a tumor suppressor gene to<br />
maintain the global genomic stability. However, BRCA1 has also been<br />
shown to play a key role in maturation of mammary stem/progenitor<br />
cells, which are the targets for carcinogenesis in individuals who have<br />
undergone loss of heterozygosity (LOH) for BRCA1. Recently, it has<br />
also been shown that NF-κB activity is increased in both mammary<br />
carcinoma cell lines and primary human breast cancer tissue. Indeed,<br />
in a previous study it has been demonstrated that NF-κB inducible<br />
kinase (NIK), p100/p52 and RelB (all components of the alternative<br />
NF-κB pathways) were increased in BRCA1-mutated tumors.<br />
Here we show that BRCA1-loss or -mutation is responsible for<br />
activation of the alternative NF-κB pathway evidenced by NIK and<br />
IκB kinase-α (IKKα) phosphorylation, processing of p100 to p52<br />
and p52/RelB nuclear localization. Moreover, increased p52 was<br />
also observed after BRCA1 inhibition. A BRCA1-mutated human<br />
breast cancer cell line (HCC1937) was also used to understand<br />
the role played by NIK in NF-κB alternative pathway activation.<br />
Indeed, NIK inhibition in HCC1937 cell line resulted in a decrease<br />
in p52 formation. Moreover, a decrease in NIK mRNA level was also<br />
observed when wild-type BRCA1 was reconstituted in HCC1937<br />
cells. BRCA1 inactivation in MCF-7 cells also induced NIK<br />
phosphorylation and nuclear localization of RelB and p52. Overall,<br />
these data show that inactivation of BRCA1 increases NIK mRNA<br />
level, associated with induction of the NF-κB alternative pathway.<br />
Stem/progenitors cells sorted using the CD24/CD49f<br />
immunophenotype derived from BRCA1 knockout mouse mammary<br />
glands showed alternative NF-κB pathway activation. Inhibition of<br />
IKKα/β using BMS-345541 completely blocked mammary colony<br />
formation in a Matrigel assay. Moreover, increased p52 formation<br />
was found in mammary stem/progenitor cells and mammary gland<br />
paraffin sections obtained from BRCA1 knockout mice. Remarkably,<br />
RelB and p100/p52 were highly expressed in 20-50% of the lobular<br />
structures in histologically normal breast tissue obtained from human<br />
BRCA1 mutation carriers while no staining was evident in normal<br />
tissue from non-carrier mastectomy samples.<br />
Our data show that BRCA1 inactivation induces alternative NF-κB<br />
activation which ultimately promotes the expansion of the mammary<br />
progenitor population. These novel findings provide a new basis for<br />
functional classification of BRCA1 mutations and a potential method<br />
for predicting breast cancer in BRCA1 mutation carriers. Lastly our<br />
results suggest that targeting the alternative NF-κB pathway could<br />
be of benefit in the prevention of BRCA1-associated breast cancer<br />
by limiting progenitor cell expansion.<br />
PD09-02<br />
BRCA1 insufficiency is predictive of superior survival in patients<br />
with triple negative breast cancer treated with platinum based<br />
chemotherapy<br />
Sharma P, Stecklein S, Kimler BF, Klemp JR, Khan QJ, Fabian CJ,<br />
Tawfik OW, Connor CS, McGinness MK, Mammen JMW, Jensen RA.<br />
University of Kansas Medical Center, Westwood, KS; University of<br />
Kansas Medical Center, Kansas City, KS<br />
Introduction: Triple negative breast cancer (TNBC) and BRCA1-<br />
associated breast cancers share many histopathologic and molecular<br />
features. BRCA1 plays a crucial role in HR-dependent DNA repair<br />
and BRCA1-deficient cells are particularly susceptible to the DNA<br />
damaging agents like platinums. Increasing evidence suggests that<br />
in addition to germline BRCA defects, other mechanisms (like<br />
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epigenetic BRCA1 silencing) can lead to BRCA1 insufficiency in<br />
TNBC. However, the impact of BRCA1 insufficiency on the efficacy<br />
of DNA damaging agents in TNBC is not known.<br />
Aim: To investigate the impact of BRCA1 insufficiency on relapsefree<br />
survival (RFS) and overall survival (OS) in patients with stage<br />
II-III TNBC treated with neoadjuvant platinum-based chemotherapy.<br />
BRCA1 insufficiency (BRCA1 insuf ) state was defined as presence of<br />
germline BRCA1/2 mutation or BRCA1 promoter methylation (PM)<br />
and/or low BRCA1 expression (lowest quartile).<br />
Methods: Thirty patients with stage II/III TNBC received neoadjuvant<br />
chemotherapy (6 cycles of Carboplatin AUC 6, Docetaxel 75mg/m 2<br />
and Erlotinib 150 mg PO) on a phase II trial between 8/2007- 6/2010.<br />
All but one patient underwent comprehensive BRCA analysis (Myriad<br />
Genetic Laboratories). Pre-treatment tumor specimens were used<br />
for evaluation of BRCA1 PM and expression. Genomic DNA was<br />
isolated from FFPE samples, bisulfite converted and then subjected<br />
to methylation-specific PCR (MSP). RNA was isolated, reverse<br />
transcribed to cDNA and assayed by quantitative real-time PCR<br />
(qRT-PCR) for determination of BRCA1 mRNA transcript levels.<br />
RFS and OS were estimated according to the Kaplan-Meier method<br />
and compared among groups with log-rank statistic. Cox proportional<br />
hazards models were fit to determine the association of BRCA1 insuf<br />
with the risk of death after adjustment for other characteristics.<br />
Results: Median age: 51yrs, African American: 20%, Median<br />
tumor size: 3.3 cm, LN positive: 40%. Six of 30 patients (20%)<br />
harbored germline BRCA mutation (4 BRCA1, 2 BRCA2). Baseline<br />
tumor specimen was available for 26/30 patients. BRCA1 MSP was<br />
successful in 92% and BRCA1 qRT-PCR was successful in 84%<br />
of specimens. BRCA1 PM and low BRCA1 expression was present<br />
in 30% and 15% of subjects, respectively. There was evidence<br />
of BRCA1 insuf in 53% (16/30) of subjects. At a median time from<br />
diagnosis of 42 months (range, 23-59 months) there have been<br />
9(30%) recurrences and 7(23%) deaths. On univariate analysis node<br />
negativity, lower stage and presence of BRCA1 insuf were associated<br />
with better OS. At the median follow up, RFS is 81% for patients with<br />
BRCA1 insuf versus 54% for patients without BRCA1 insuf (p =0.16) ; OS<br />
is 83% for patients with BRCA1 insuf versus 46% for patients without<br />
BRCA1 insuf (p =0.021). After adjustment for clinical variables patients<br />
with BRCA1 insuf had a significantly better OS compared to patients<br />
without BRCA1 insuf (p=0.036).<br />
Conclusions: Germline BRCA testing plus tissue BRCA1 PM /<br />
expression can be used to identify a BRCA1 insuf sub-population within<br />
TNBC demonstrating a favorable outcome with platinum treatment.<br />
This BRCA1 insuf criteria can be easily used to select TNBC patients<br />
likely to benefit from DNA damaging agents like platinums and<br />
PARP inhibitors.<br />
PD09-03<br />
Impact of BRCA1/2 Mutation Status in TBCRC009: A multicenter<br />
phase II study of cisplatin or carboplatin for metastatic triple<br />
negative breast cancer.<br />
Isakoff SJ, Goss PE, Mayer EL, Traina T, Carey LA, Krag KJ, Liu<br />
MC, Rugo H, Stearns V, Come S, Finkelstein D, Hartman A-R, Garber<br />
JE, Ryan PD, Winer EP, Ellisen LW. Massachusetts General Hospital,<br />
Boston, MA; Dana-Farber <strong>Cancer</strong> Institute, Boston, MA; Memorial<br />
Sloan-Kettering <strong>Cancer</strong> Center, New York, NY; University of North<br />
Carolina Lineberger Comprehensive <strong>Cancer</strong> Center, Chapel Hill, NC;<br />
Mass General/North Shore <strong>Cancer</strong> Ctr, Danvers, MA; Georgetown<br />
Lombardi Comprehensive <strong>Cancer</strong> Center, Washington, DC; University<br />
of California, <strong>San</strong> Francisco Helen Diller Family Comprehensive<br />
<strong>Cancer</strong> Center, <strong>San</strong> Francisco, CA; Sidney Kimmel Comprehensive<br />
<strong>Cancer</strong> Center at Johns Hopkins University, Baltimore, MD; Beth<br />
Israel Deaconess Medical Center, Boston, MA; Myriad Genetics, Salt<br />
Lake City, UT; Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA<br />
Background: Triple negative breast cancer (TNBC) has a poor<br />
prognosis compared to other BC subtypes and lacks identified specific<br />
therapeutic targets. TNBC is frequent among BRCA1-associated<br />
breast cancer. Platinum chemotherapy has activity in TNBC, and<br />
several studies have suggested particular efficacy of platinum agents<br />
in BRCA-associated breast cancer. TBCRC009 is a multicenter single<br />
arm phase II study of single agent platinum in metastatic TNBC.<br />
Here we sought to evaluate the impact of BRCA1/2 mutation status<br />
on outcomes in this study population.<br />
Methods: Eligible metastatic TNBC patients (pts) had measurable<br />
disease, available archival tumor, ≤ 1 prior metastatic therapy, and<br />
no prior platinum chemotherapy. Pts were assigned by physician<br />
choice (limited to equal enrollment in each arm) to cisplatin 75mg/<br />
m2 or carboplatin AUC=6 every 21 days with optional extension to<br />
28 days after cycle 1. Co-primary endpoints were: 1) Response Rate<br />
(RR) and 2) whether tumor p63/p73 expression predicts response.<br />
Secondary endpoints included determination of BRCA1/2 mutation<br />
status and exploratory analysis of correlation of BRCA1/2 status<br />
with outcomes. Baseline blood samples from all pts were analyzed<br />
by Myriad Genetics using BRCAnalysis and BART testing. Results<br />
of this exploratory analysis are presented here.<br />
Results: 86 TNBC pts enrolled between June 2007-Oct 2010. Results<br />
of primary endpoint 1 and patient characteristics were previously<br />
presented (ASCO 2011 Annual Meeting, J Clin Oncol 29: 2011 suppl;<br />
abstr 1025). In summary, median age=52 (30-78), 64% had ECOG<br />
PS=0, and 86% had adjuvant chemotherapy. Overall response rate<br />
(RR) was 30.2% (95% CI 20.8% - 41.1%), including 4 CR (4.7%),<br />
22 PR (25.6%). Among the 76 pts with BRCA1/2 status available,<br />
there were 11 (14.5%) BRCA1/2 carriers (9 BRCA1, 2 BRCA2)<br />
and 65 (85.5%) BRCA1/2 wild type (wt). Testing is ongoing for the<br />
remaining 10 pts. RR was 54.6% (5 PR, 1 CR) in BRCA1/2 carriers<br />
and 26.2% (14 PR, 3 CR) in BRCA1/2 wt (p=0.0506). There was no<br />
significant difference in PFS between BRCA1/2 carriers (median PFS<br />
99 days; 95% CI: 40-215) and BRCA1/2 wt (median PFS 86 days,<br />
95% CI: 46-146). Interestingly, 6 pts (7%), including 5 BRCA1/2 wt<br />
and 1 BRCA unknown, remain without progression for 53, 41, 33, 27,<br />
25, and 22 months as of June 2012. Of these 6 pts, 3 pts discontinued<br />
study drug due to toxicity and received no additional therapy and 3<br />
pts had major responses and had consolidation therapy with surgery,<br />
chemotherapy, or radiation.<br />
Conclusion: First or second line single agent platinum is effective<br />
in both BRCA1/2-associated and sporadic metastatic TNBC. In this<br />
exploratory analysis, we observed a higher RR in BRCA1/2 carriers<br />
than in BRCA wt patients, but we did not observe an improved PFS<br />
in this small cohort. We observed durable responses in 7% of pts<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
140s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 9<br />
which did not correlate with BRCA1/2 mutations. The lack of a<br />
clear relationship between the higher RR in patients with germline<br />
BRCA1/2 mutations and PFS is surprising and could be further<br />
elucidated by studies in a larger cohort, and our ongoing analyses of<br />
additional markers for platinum sensitivity.<br />
PD09-04<br />
Homologous Recombination Deficiency (HRD) score predicts<br />
pathologic response following neoadjuvant platinum-based<br />
therapy in triple-negative and BRCA1/2 mutation-associated<br />
breast cancer (BC)<br />
Telli ML, Jensen KC, Abkevich V, Hartman A-R, Vinayak S, Lanchbury<br />
J, Gutin A, Timms K, Ford JM. Stanford University School of<br />
Medicine, Stanford, CA; Myriad Genetics, Salt Lake City, UT<br />
Background: BC that arises in BRCA1/2 mutation carriers is<br />
characterized by defective homologous recombination DNA repair.<br />
Given the clinical potential for DNA repair-targeted therapeutics,<br />
Myriad Genetics has developed a tumor DNA-based assay that<br />
can identify underlying defects in the homologous recombination<br />
pathway, regardless of etiology, including identification of BRCA1/2<br />
mutation carriers with high sensitivity. This study was designed to<br />
assess ability of the HRD score to predict pathologic response to<br />
neoadjuvant platinum-based therapy in early-stage triple-negative<br />
and BRCA1/2 mutation-associated BC.<br />
Methods: The HRD score was assessed in a cohort of 55 fresh<br />
frozen tumors from pts with clinical stage I-IIIA triple-negative<br />
and BRCA1/2 mutation-associated BC enrolled onto a single-arm,<br />
phase II study of neoadjuvant gemcitabine, carboplatin and iniparib.<br />
Following neoadjuvant therapy (4 cycles=11; 6 cycles=44), pathologic<br />
response was assessed using the residual cancer burden (RCB) index<br />
by a central pathologist. Twenty-nine tumors were obtained from<br />
responders (RCB 0/1) and 26 tumors were from non-responders (RCB<br />
2/3). The HRD score was derived by count of the number of LOH<br />
regions (>15 Mb and < whole chromosome) observed in the tumor<br />
genome. Association of response to treatment and HRD score was<br />
performed by the Mann-Whitney U test.<br />
Results: Germline BRCA1/2 mutation status was known in all pts<br />
and 13/55 tumors were from carriers of deleterious BRCA1 (n=9),<br />
BRCA2 (n=3) or BRCA1&2 (n=1) mutations. Two mutation carriers<br />
had ER+/PR+(>5%) BC. The mean HRD score for responders is 16.5<br />
and no differences were noted between germline BRCA1/2 mutants<br />
vs. non-mutants. The mean HRD score for non-responders is 11.4.<br />
Among carriers of BRCA1/2 mutations, 12/13 achieved a favorable<br />
response. The one BRCA1 mutation carrier non-responder with<br />
TNBC had a low HRD score of 8. This pt was previously treated with<br />
chemotherapy twice 12 years prior for primary and locally recurrent<br />
contralateral TNBC. The p-value for association between response<br />
to treatment and HRD score by the Mann-Whitney U test is 0.004.<br />
If BRCA1/2 deficient samples are excluded, the association between<br />
response to treatment and HRD score remains significant (p=0.02).<br />
Multivariate analysis that includes HRD score, BRCA1/2 genotype,<br />
age, stage, tumor grade, PAM50 subtype, ER/PR status, and cycles<br />
of therapy will be presented together with data from an additional 35<br />
pts. Enrollment to the therapeutic trial is complete and final clinical<br />
results will be separately presented.<br />
Conclusion: The HRD score is significantly correlated with pathologic<br />
response to platinum-based chemotherapy in early-stage triplenegative<br />
and BRCA1/2 mutation-associated BC.<br />
PD09-05<br />
Single nucleotide polymorphism of XRCC1 which participates in<br />
DNA repair mechanism predicts clinical outcome in relapsed or<br />
metastatic breast cancer patients treated with S1 and oxaliplatin<br />
chemotherapy: Results from multicenter prospective study<br />
(TORCH_KCSG BR07-03)<br />
Im S-A, Oh D-Y, Keam B, Lee KS, Ahn J-H, Sohn J, Ahn JS, Kim JH,<br />
Lee MH, Lee KE, Kim HJ, Lee K-H, Han SW, Kim S-Y, Kim SB, Im Y-H,<br />
Ro J, Park H-S. Seoul National University Hospital, Seoul, Korea;<br />
National <strong>Cancer</strong> Center, Goyang, Korea; Asan Medical Center, Seoul,<br />
Korea; Yonsei University College of Medicine, Severance Hospital,<br />
Seoul, Korea; Samsung Medical Center, Seoul, Korea; Seoul National<br />
University Bundang Hospital, Seongnam, Korea; Inha University<br />
Hospital, Incheon, Korea; Ewha Womans University Medical Center,<br />
Seoul, Korea; Hallym University Sacred Heart Hospital, Anyang,<br />
Korea; Kyung-Hee University Hospital, Seoul, Korea; Soon Chun<br />
Hyang University Hospital, Seoul, Korea<br />
Background: S1 and oxaliplatin (SOX) combination chemotherapy is<br />
an effective regimen in anthracycline and taxane pretreated metastatic<br />
breast cancer (MBC) patients with manageable toxicities (KCSG<br />
BR07-03, SABCS 2011 #Abst P3-16-06). The aim of this study was<br />
to investigate the association of the single nucleotide polymorphisms<br />
(SNPs) and clinical outcome in MBC treated with SOX chemotherapy.<br />
Patients and Methods: A total of 87 MBC patients previously treated<br />
with or resistant to anthracycline and taxane chemotherapy were<br />
enrolled in this prospective multicenter trial. The patients received<br />
S-1 80mg/m 2 /day (day 1-14) and oxaliplatin 130 mg/m 2 (day 1)<br />
every 3 weeks till progression. Among the 87 patients, 77 patients<br />
were available for SNP analysis. Germline DNA from peripheral<br />
blood (PB) mononuclear cells was extracted. SNPs in 4 genes from<br />
pathways that may influence cellular sensitivity to S1 and oxaliplatin<br />
(TS, ERCC, XPD, and XRCC) were genotyped from PB sample using<br />
PCR-restriction fragment length polymorphism.<br />
Results: Overall response rate (RR) was 38.5% (95% CI: 27.7-49.3)<br />
and disease control rate was 67.9% (95% CI:57.5-78.3) to SOX.<br />
Median time-to-progression (TTP) and overall survival (OS) were<br />
6.0 mo (95% CI: 5.1-6.9 mo) and 19.4 mo (95% CI: not estimated),<br />
respectively. XRCC1 Arg194Trp SNP which participates in DNA<br />
repair mechanism showed correlation with the clinical outcome. RR<br />
was tend to higher in XRCC1 Arg194Trp CC genotype compared with<br />
CT or TT genotype (50.0 % vs 35.1% or 12.5%, P=0.121). TTP of<br />
patients with CC genotype in XRCC1 Arg194Trp was significantly<br />
longer than the TTP of patients with CT or TT genotype (median<br />
TTP: 6.4 mo in CC, 5.9 mo in CT, 3.0 mo in TT, P=0.007) as well as<br />
overall survival (OS) (median OS: not reached in CC, 13.9 mo in CT,<br />
7.1 mo in TT, P=0.006). After adjusting for hormone receptor status,<br />
performance status, and visceral involvement, prognostic value of<br />
XRCC1 Arg194Trp SNP remained significant (Hazard Ratio=1.322<br />
and 4.484, P=0.016). Other SNPs were not significantly associated<br />
with survival or toxicities.<br />
Conclusion: XRCC1 Arg194Trp SNP is associated with clinical<br />
outcome of MBC patients treated with SOX chemotherapy. Further<br />
studies of the relationship between germline polymorphisms in<br />
XRCC1 and functional mechanism researches are warranted.<br />
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PD09-06<br />
Two phase I trials exploring different dosing schedules of<br />
carboplatin (C), paclitaxel (P), and the poly-ADP-ribose<br />
polymerase (PARP) inhibitor, veliparib (ABT-888) (V) with<br />
activity in triple negative breast cancer (TNBC)<br />
Puhalla SL, Appleman LJ, Beumer JH, Tawbi H, Stoller RG,<br />
Owonikoko TK, Ramalingam SS, Belani CP, Brufsky AM, Abraham<br />
J, Shepherd SP, Giranda V, Chen AP, Chu E. University of Pittsburgh<br />
<strong>Cancer</strong> Institute, Pittsburgh, PA; Winship <strong>Cancer</strong> Institute of Emory<br />
University, Atlanta, GA; West Virginia University <strong>Cancer</strong> Center,<br />
Morgantown, WV; Penn State Hershey <strong>Cancer</strong> Institute, Hershey,<br />
PA; National <strong>Cancer</strong> Institute, Bethesda, MD; Abbott Laboratories,<br />
Abbott Park, IL<br />
Background:<br />
The histopathologic and molecular similarities between TNBC and<br />
BRCA-1 mutation related breast cancer provide rationale for the use<br />
of PARP inhibitors in treating sporadic TNBC. C and P are established<br />
drugs in the treatment of advanced breast cancer. In order to determine<br />
the recommend phase II dose (RP2D) of V in combination with C and<br />
P, two separate phase I trials evaluated the combination of V with C<br />
and P dosed weekly (q1wk) and every 3 weeks (q3wk).<br />
Methods:<br />
Both phase I trials were a standard 3+3 dose escalation design of C, P,<br />
and V open to patients (pts) with advanced solid tumors and enriched<br />
for pts with TNBC. In the q1wk trial, C was given weekly on day 3<br />
at an AUC of 2, P was given weekly on day 3 at a dose of 80 mg/m 2 ,<br />
and V was escalated from 50 mg twice daily (BID) to a maximum<br />
of 200 mg BID on days 1-5 every week over 4 dose levels. In the<br />
q3wk trial, C was given on day 3 every 21 days at an AUC of 6, P<br />
was given on day 3 every 21 days with the dose escalated from 150<br />
mg/m 2 to a dose of 200 mg/m 2 , and V was given on days 1-7 every 21<br />
days and escalated from 10 mg BID to a dose of 120 mg BID over 9<br />
dose levels. Toxicity was assessed by CTCAE v. 4 and response was<br />
determined using RECIST criteria.<br />
Results:<br />
The q1wk trial enrolled a total of 18 pts, 12 of whom had BC, and<br />
10 had TNBC. One TNBC pt was BRCA-1+ and the remainder were<br />
sporadic. The trial will be completed with the enrollment of one<br />
additional patient on dose level 4. Ten breast cancer pts are evaluable<br />
for response. DLT’s included thrombocytopenia on dose levels 3 (V at<br />
150 mg BID) and 4 (V at 200mg BID), and both occurred in TNBC<br />
pts. The range of cycles administered to TNBC pts was 1-11. The<br />
q3wk trial enrolled a total of 75 pts, 14 had BC (12 evaluable for<br />
response), and 9 had TNBC. One of these pts had a BRCA mutation;<br />
2 pts had a variant of undetermined significance. Three DLT’s were<br />
observed on this schedule: febrile neutropenia (C at AUC 6, P at 200<br />
mg/m 2 , V at 40 mg BID, 100 mg BID, and 120 mg BID) and grade<br />
3 hyponatremia. No DLT’s occurred in TNBC pts. The established<br />
RP2D for the q3wk schedule is C (AUC6), P (200mg/m2) and V<br />
(100mg bid) and additional pts are being accrued to an expansion<br />
cohort. The range of cycles administered to TNBC pts was 1-14.<br />
The clinical activity in TNBC is summarized in Table 1. Responses<br />
occurred in pts who had been previously treated both in the adjuvant<br />
and metastatic settings, as well as in those who received prior taxanes.<br />
Clinical Activity in TNBC pts<br />
Regimen Complete responses Partial responses Stable disease No Response<br />
Q1WK C/P/V (n=10) 2 3 3 2<br />
Q3WK C/P/V (n=9) 3 4 1 1<br />
Conclusion:<br />
There is evidence of promising clinical activity and acceptable<br />
tolerability with carboplatin, paclitaxel, and veliparib on both dosing<br />
schedules. An additional 12 pts with TNBC will be accrued to the<br />
q1wk trial with pre- and post-treatment biopsies to further evaluate<br />
underlying mechanisms of sensitivity and response with regards<br />
to DNA repair pathways. Based on our phase I experience, further<br />
randomized trials are warranted in breast cancer, particularly TNBC.<br />
PD09-07<br />
Therapeutic potential of targeting ATM-PELP1-p53 axis in triple<br />
negative breast cancer<br />
Krishnan SR, Nair BC, Sareddy GR, Mann M, Roy SS, Vadlamudi<br />
RK. UTHSCSA, <strong>San</strong> <strong>Antonio</strong>, TX<br />
Triple negative breast cancer (TNBC) comprises approximately 15%<br />
of all breast cancers, lacks expression of ER, PR, and HER2 and is<br />
clinically aggressive with shorter disease free survival. TNBC patients<br />
do not benefit from antiestrogen and herceptin-based therapies.<br />
Evolving evidence suggests that overexpression of mutant p53 is<br />
significantly associated with TNBC progression. DNA damage<br />
response (DDR) is critical for the maintenance of genome stability<br />
and serves as an anti-cancer barrier during tumorigenesis. However,<br />
the role of DDR in tumor progression and metastasis is less known.<br />
Recent studies suggest that the ATM kinase is hyperactive in late stage<br />
breast tumor tissues with lymph node metastasis. Our ongoing studies<br />
have identified proline, glutamic acid, leucine rich protein 1 (PELP1),<br />
a proto-oncogene overexpressed in breast cancer, as a novel substrate<br />
of ATM. The objective of this study is to determine the mechanism<br />
and significance of ATM mediated phosphorylation of PELP1 and<br />
its crosstalk with the p53 pathway in TNBC cells. To test this we<br />
have used three ER-negative mutant p53 breast cancer cell lines<br />
(MDA-MB-231, MDA-MB-468, BT20), with ER-positive (ZR-75<br />
and MCF7) cell lines as controls. Using PELP1 specific shRNAs, we<br />
generated model cells that have stable expression of either control or<br />
PELP1 shRNA. Our results with PELP1 knockdown models indicate<br />
that PELP1 promotes stability of p53 and functions as a co-regulator<br />
of p53. PELP1 has the potential to modulate CBP/p300 mediated<br />
acetylation of the Lysine 382 residue of p53. Immunoprecipitation<br />
and chromatin immunoprecipitation (ChIP) assays were performed to<br />
examine PELP1 interaction with p53 and its recruitment to p53 target<br />
genes respectively. ChIP assays revealed that PELP1 knockdown<br />
significantly reduces the recruitment of p53 to the target genes. The<br />
p53 regulatory role of PELP1 is mediated by the phosphorylation of<br />
PELP1 at the conserved SQ motif by ATM. We generated model cells<br />
that overexpress WT or mutant (S1033A) PELP1 and demonstrated<br />
the significance of ATM mediated phosphorylation in PELP1<br />
mediated p53 co-activation functions. Based on the sequence of the<br />
site of phosphorylation, we have developed a novel cell permeable<br />
peptide (TAT-1033PELP1 inhibitor) as well as a phospho-PELP1<br />
antibody that uniquely recognizes S1033 phosphorylated PELP1. We<br />
confirmed ATM mediated phosphorylation of PELP1 in vivo using<br />
phospho PELP1 antibody (1033p-PELP1). The TAT 1033 inhibitor<br />
peptide significantly reduced ATM mediated phosphorylation of<br />
endogenous PELP1. Treatment of ER- positive breast cancer cells<br />
with this peptide resulted in resistance to genotoxic stress compared<br />
to cells that are treated with control TAT peptide. However, in TNBC<br />
cells that has a mutant p53, PELP1 knockdown or treatment with<br />
TAT-PELP1 inhibitor resulted in significant loss of cell viability and<br />
increase in apoptosis in response to genotoxic stress. IHC analysis of<br />
tumor tissue array (n=100) revealed increased PELP1 phosphorylation<br />
in advanced ER-negative tumors and its status correlated with ATM.<br />
Collectively, our results suggest that hyperactive ATM-PELP1-p53<br />
pathway contributes to TNBC progression and that the TAT-<br />
1033PELP1 inhibitor represents a novel therapeutic to block PELP1<br />
oncogenic functions in TNBC.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
142s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 9<br />
PD09-08<br />
The potential role of TLK2 as a therapeutic target in breast<br />
cancer.<br />
Kim J-A, Cao X, Tan Y, Schiff R, Wang X. Lester & Sue Smith <strong>Breast</strong><br />
Center, Baylor College of Medicine, Houston, TX<br />
Invasive breast cancer (IBC) is a heterogeneous disease with distinct<br />
molecular and histological features as well as diverse biological<br />
behaviors. It is thus critical to find specific gene aberrations that can<br />
drive breast cancer initiation and progression as potential therapeutic<br />
targets. Our lab has established bioinformatics workflows to identify<br />
therapeutic oncogene targets. We have nominated Tousled-Like<br />
Kinase 2 (TLK2) as a candidate therapeutic target from 44,932<br />
human genes based on integrative copy number data from The<br />
<strong>Cancer</strong> Genome Atlas (TCGA). TLK2 is a nuclear serine/threonine<br />
kinase that serves as a cell cycle checkpoint regulating chromosome<br />
assembly, and is inactivated by phosphorylation through the ATM<br />
dependent manner in the response to the double strand breaks during<br />
the S-phase. Interestingly, we observed 12-14% of focal TLK2 gene<br />
amplifications and translocations in invasive breast cancers, which<br />
are more frequent in luminal B tumors. Chromosomal aberrations<br />
may leads the deregulation of TLK2 kinase activity and results in<br />
overcoming the cell cycle checkpoint upon DNA damage such as IR or<br />
chemotherapeutic drugs treatments in breast cancer, thus destabilizing<br />
the cancer genome. Indeed, our preliminary data show that TLK2<br />
knockdown substantially inhibits cell proliferation in breast cancer<br />
cells overexpressing TLK2. Further, this response is sustained in<br />
their derivative strains resistant to hormone or anti-Her2 therapies,<br />
suggesting the potential of TLK2 inhibition to sensitize these therapies<br />
as well. Overall, I expect that this study will provide compelling<br />
evidence regarding the role of TLK2 in breast cancer tumorigenesis<br />
and genomic instability, and establish its potential as a therapeutic<br />
target. The possibility of developing specific TLK2 inhibitors can<br />
be well demonstrated by the previous success of drugs against other<br />
cell cycle checkpoint kinases that are currently under clinical trials.<br />
In addition, molecular assays detecting TLK2 derangements may<br />
be applied in the clinics to identify patients who might benefit from<br />
future TLK2 inhibitor. If TLK2 endows resistance or sensitivity to<br />
other therapies, assays detecting TLK2 aberrations may also have<br />
important predictive value for personalization of these treatments.<br />
PD09-09<br />
The Akt inhibitor MK-2206 is an effective radio-sensitizer of p53<br />
deficient triple negative breast cancer (TNBC) cells.<br />
Connolly EP, Sun Y, Chao KC, Hei TK. Columbia University, New<br />
York, NY<br />
Purpose: Triple negative breast cancer (TNBC) is an aggressive<br />
tumor with a higher locoregional recurrence compared to estrogen<br />
receptor (ER) positive breast cancer. Mutations in the PI3K/Akt/<br />
mTOR pathway leading to up-regulation of Akt occur with high<br />
frequency in TNBC. Hyperactive Akt is associated with increase<br />
radiation resistance, mediated through inhibition of apoptosis and<br />
up-regulation of DNA damage-induced G2 arrest. p53 plays a key<br />
role in mediating G1 cell cycle arrest following genotoxic stress<br />
such as radiation; p53-deficient cells however must rely on alternate<br />
mechanisms for cell cycle arrest in S- and G2-phases. Inhibition of<br />
Akt therefore would be expected to act in a synthetic lethal fashion<br />
to radiosensitize p53 deficient TNBC cells by decreasing their ability<br />
to arrest in G2. Given that p53 mutations occur in 44% of TNBC this<br />
may be an effective strategy for radiosensitizing TNBC.<br />
Methods: Experiments were conducted using MDA-MB-468,<br />
MDA-MB-231 and SUM 149 cells, all well established models for<br />
p53-deficient TNBC. Cells were treated with MK-2206, a potent<br />
allosteric Akt inhibitor, alone or in combination with increasing doses<br />
of radiation from 0-8 Gy. In vitro studies preformed included; cell<br />
survival assays, MTT assay, immunoblot analysis of key proteins,<br />
FACS analysis for cell cycle, apoptosis, and gH2AX staining.<br />
Results: We found that the combination of IR and Akt inhibition by<br />
MK-2206 is synergistic. MK-2206 inhibited both endogenous and<br />
radiation-induced Akt activation and phosphorylation of its downstream<br />
targets. Decreased clonogenic survival was seen after 2 or 24<br />
hours pretreatment with MK-2206 as well as decreased viability by<br />
MTT assay. Cell cycle analysis demonstrates MK-2206 decreases<br />
the proportion of cells in G2/M arrest following irradiation, as well<br />
as induced a greater proportion of apoptosis. Evaluation of the DNA<br />
damage response pathway demonstrated decreased levels of total<br />
DNA-PK, as well as a delayed DNA damage response.<br />
Conclusions: These studies demonstrate that targeted inhibition<br />
of Akt effectively radiosensitizes p53 deficient TNBC cells lines,<br />
possibly through a synthetic lethal effect on the DNA damage<br />
response.<br />
PD09-10<br />
DNA Damage and Repair in Mammary Gland Development<br />
Kass EM, Helgadottir H, Moynahan ME, Jasin M. Memorial Sloan-<br />
Kettering <strong>Cancer</strong> Center, New York, NY<br />
Numerous factors are linked to breast cancer risk including<br />
reproductive history, early exposure to radiation, age and genetic<br />
background. Events that occur during specific stages of mammary<br />
development are believed to alter the lifetime risk of breast cancer.<br />
Epidemiological studies over the past 3 decades have suggested an<br />
association between parity and decreased lifetime breast cancer risk.<br />
Studies have also shown that breast cancer risk is significantly higher<br />
in women who received radiotherapy to the chest as adolescents<br />
compared to those who received chest radiation as adults. These<br />
associations implicate development specific changes in mammary<br />
epithelium that affect the molecular mechanisms whereby cells<br />
respond to DNA damage and, importantly, are at subsequent cancer<br />
risk.<br />
Because many of the genes linked to hereditary breast cancer<br />
are associated with DNA double-strand break (DSB) repair, we<br />
hypothesize that there are differences in overall DSB repair,<br />
homologous recombination (HR), and cell fate following damage<br />
in mammary epithelium at different stages of mammary gland<br />
development—puberty, pregnancy, lactation and post-involution. To<br />
assess these differences we are using mice containing the DR-GFP<br />
reporter targeted to chromosome 17 to study HR at chromosome<br />
breaks induced by the transient expression of I-SceI in mammary<br />
epithelial cells. DR-GFP is a widely used repair reporter in which<br />
direct repeats of two defective GFP genes are induced to recombine<br />
by I-SceI endonuclease cleavage of one of the repeats. We have<br />
observed that the efficiency of HR in primary mammary epithelial<br />
cells derived from 8-week old virgin mice is similar to that observed<br />
in other primary cells of somatic origin (approximately 0.65% of cells<br />
heterozygous for the DR-GFP reporter). Interestingly, the amount<br />
of HR is increased in mammary epithelium derived from pregnant<br />
mice compared to age-matched virgin controls (0.98 versus 0.65%).<br />
This 1.5 fold increase in HR suggests that in pregnancy, mammary<br />
epithelium is more proficient in the accurate repair of DNA DSBs.<br />
We are also assessing DNA damage signaling in different periods<br />
of mammary gland development. Preliminary analysis of histone<br />
H2AX phosphorylation following whole-body irradiation suggests<br />
more rapid kinetics of DNA damage signaling response in mammary<br />
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<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
tissue derived from pregnant as compared to age-matched virgin mice.<br />
We have recently generated DR-GFP containing mice that express<br />
I-SceI from a randomly integrated I-SceI transgene under the control<br />
of a tetracycline-inducible promoter. We are currently using these mice<br />
to assess HR in an entirely in vivo system and are in the process of<br />
breeding this reporter line with mice carrying mutations in Brca1 or<br />
Brca2. This mouse model will be used to assess HR in vivo in the<br />
mammary tissue of these mice during different stages of mammary<br />
gland development.<br />
This project will provide valuable insight into how developmental<br />
changes unique to mammary gland epithelium affect cellular<br />
responses to DNA damage. We hope to consider therapeutic<br />
manipulation of identified stage-specific differences to decrease<br />
breast cancer susceptibility.<br />
PD10-01<br />
Withdrawn by Author<br />
PD10-02<br />
Metabolic syndrome and recurrence within the 21-gene<br />
recurrence score assay risk categories in lymph node negative<br />
breast cancer<br />
Lakhani A, Guo R, Duan X, Ersahin C, Gaynor ER, Godellas C, Kay<br />
C, Lo SS, Mai H, Perez C, Albain K, Robinson P. Loyola University<br />
Medical Center, Maywood, IL<br />
Background: The incidence of the metabolic syndrome (MS) has<br />
been increasing in the United States and elsewhere. The interaction of<br />
MS with breast cancer (BC) incidence, tumor biology and outcomes<br />
are under study. We hypothesized that the presence of MS would<br />
predict BC recurrence to a variable degree across the diverse BC<br />
biology as defined by the risk categories of the 21-gene recurrence<br />
score (RS) assay.<br />
Patients and Methods: We studied consecutive patients (pts) with<br />
newly diagnosed, estrogen receptor (ER) positive, lymph node (LN)<br />
negative BC treated in our institution between 2006-2011 who had<br />
a 21-gene RS assay done on their tumors. All pts were treated with<br />
standard systemic and local therapy. The electronic medical record<br />
was queried for key diagnoses including MS and its constituent parts.<br />
The WHO definition was used to categorize pts as having MS defined<br />
as diabetes mellitus (DM) or glucose intolerance, plus at least 2 of the<br />
following: hypertension (HTN), dyslipidemia (HL), central obesity<br />
and microalbuminemia. Tumor characteristics including Ki67 index,<br />
grade, tumor size, HER2/neu status; and pt characteristics including<br />
age, race, menopausal status, body mass index were recorded. The<br />
association of MS and the tumor and patient characteristics with the<br />
RS tertiles of low, intermediate and high risk was analyzed.<br />
Results: We identified 332 pts, median age 62 years, of whom 88<br />
(27%) had MS. There was no significant association between the<br />
MS and any of the patient or tumor variables including the 21-gene<br />
RS assay, except for race (p=0.004). Eleven of 21 (52%) African-<br />
American women had MS, 68 of 284 (24%) Caucasian women had<br />
MS, and 9 of 21 (43%) others including Hispanic and Asian women<br />
had MS. However, there was a significant association between<br />
recurrence and MS (p=0.0002) independent of other factors. Of the<br />
21 pts who recurred, 13 (61.9%) had MS. There was an association<br />
of recurrence and MS within RS tertiles. For pts with low risk scores,<br />
7/44 (15.9%) with MS vs. 1/126 (0.79%) without MS had recurrence<br />
(p=0.0003). For pts with intermediate risk scores, 5/30 (16.67%)<br />
with MS vs. 4/83 (4.82%) without MS had recurrence (p=0.05). For<br />
patients with high risk scores, 1/9 (11.11%) with MS vs. 2/15 (13.33%)<br />
without MS had recurrence (p=1).<br />
Conclusion: MS is an independent risk factor for BC recurrence<br />
among women with LN negative, ER positive BC treated with<br />
standard adjuvant therapy. There is a striking impact of MS on<br />
recurrence in pts with tumor biologies defined by low (and to a lesser<br />
degree) intermediate risk 21-gene RS assay scores. However, there<br />
is no difference in recurrence risk by MS among those pts with high<br />
RS. This implies that interventions directed at modifying MS in newly<br />
diagnosed pts with early BC may potentially favorably impact survival<br />
in those with specific tumor biologies as defined by multigene assays.<br />
Thus, long-term prospective studies should be conducted to further<br />
evaluate both the short and long term effects of MS on BC outcomes.<br />
PD10-03<br />
Predictive value of a proliferation score (MS) in postmenopausal<br />
women with endocrine-responsive breast cancer: results from<br />
International <strong>Breast</strong> <strong>Cancer</strong> Study Group (IBCSG) Trial IX<br />
Sninsky J, Wang A, Gray K, Lagier R, Christopherson C, Rowland C,<br />
Chang M, Kammler R, Viale G, Kwok S, Regan M, Leyland-Jones B.<br />
Celera, Alameda, CA; Dana-Farber <strong>Cancer</strong> Institute, Boston, MA;<br />
IBCSG Coordinating Center, Berne, Switzerland; European Institute<br />
of Oncology, Milan, Italy; <strong>San</strong>ford Research, Sioux Falls, SD<br />
Background<br />
While representing the largest fraction of women diagnosed with<br />
primary breast cancer, older postmenopausal women with ER+,<br />
HER2- tumors are less responsive to chemoendocrine therapy than<br />
younger women and have been underrepresented in molecular<br />
profiling of randomized trials. IBCSG Trial IX, a randomized<br />
controlled trial in postmenopausal women, median age 61y, with<br />
node negative disease, failed to demonstrate the benefit of preceding<br />
tamoxifen (T) by 3 cycles of CMF for ER+ tumors. We sought to<br />
determine if MS, a proliferation score, could identify a subset of<br />
women who differentially benefit from addition of chemotherapy<br />
to T in this trial.<br />
Methods<br />
From 1988-1999, 1669 eligible patients (1040 with ER+, HER2-<br />
tumors) were randomized to CMF→T vs T. Disease-free survival<br />
(DFS) was the primary trial endpoint; breast cancer-free interval<br />
(BCFI) which excludes second (non-breast) malignancies and censors<br />
deaths without prior cancer event was also evaluated. Analysis was<br />
limited to the first 7 years of follow-up. From 671 (ER+, HER2-)<br />
available subjects, 568 were successfully profiled by RT-PCR. The<br />
mRNA expression levels of 14 equally-weighted proliferation genes<br />
and 3 normalization genes were used to generate MS; predetermined<br />
binary categorization of MS was used. Analysis of this post hoc,<br />
pre-specified study used results from centralized laboratory IHC and<br />
Cox models to assess the predictive value of MS on DFS and BCFI,<br />
adjusting for traditional risk factors of local treatment, age, ER, PR,<br />
Ki67, tumor size and grade.<br />
Results<br />
Subgroups of MS (low, 169 samples (30%) and high, 399 samples<br />
(70%)) were identified. MS by treatment interaction was significant<br />
for DFS and BCFI (each p≤0.004). Among patients with low MS,<br />
CMF→T improved DFS (HR 0.19, 95% CI 0.06-0.59) and BCFI<br />
(HR 0.19, 95% CI 0.05-0.72) vs T; 7y DFS was 95% vs 83% with<br />
CMF→T vs T. Among patients with high MS, CMF→T did not<br />
improve DFS (HR 1.27, 95% CI 0.79-2.05) or BCFI (HR 1.37, 95%<br />
CI 0.80-2.33) and 7y DFS of 81% for CMF→T and T. Continuous MS<br />
was moderately correlated with log Ki67 (r=0.47) but not correlated<br />
with ER or PR. The MS by treatment interaction remained significant<br />
with Ki67 in the model.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Discussion 10<br />
Conclusions<br />
Low MS was associated with differential benefit favoring those women<br />
receiving CMF→T vs T alone for both DFS and BCFI in the first 7<br />
years. The effect was independent of traditional risk factors including<br />
Ki67. Hence this study, which is unconfounded by chemotherapyinduced<br />
ovarian ablation in younger women, identifies a subset of<br />
postmenopausal women with ER+, HER2- tumors that benefit from<br />
CMF chemotherapy. This seemingly incongruous observation is<br />
consistent with a) the prior observation that only the low-proliferation<br />
subgroup by PAM50 11-gene signature benefits from the addition of<br />
weekly paclitaxel to adjuvant FEC (GEICAM/9906), b) the ability<br />
of MS to identify a subset of women with tumors with disseminated<br />
luminal progenitor cells activated through the agonistic activity of<br />
tamoxifen, and c) the repetitive dosing of cyclophosphamide and taxol<br />
being hypothesized to act via tumor stroma/anti-angiogenesis. The<br />
relative contribution of these factors is under investigation.<br />
PD10-04<br />
Predictive genomic markers to chemotherapy and adjuvant<br />
trastuzumab via whole genome expression DASL profiling in the<br />
N9831 adjuvant study<br />
Perez EA, Eckel-Passow JE, Ballman KV, Anderson SK, Thompson<br />
EA, Asmann YW, Jen J, Dueck AC, Lingle WL, Sledge GW, Winer EP,<br />
Gralow J, Jenkins RB, Reinholz MM. Mayo Clinic, Jacksonville, FL;<br />
Mayo Clinic, Rochester, MN; Mayo Clinic, Scottsdale, AZ; Indiana<br />
University Simon <strong>Cancer</strong> Center, Indianapolis, IN; Dana Farber<br />
<strong>Cancer</strong> Institute, Boston, MA; Seattle <strong>Cancer</strong> Care Alliance, Seattle,<br />
WA; Ventana Medical Systems, Inc., Tuscon, AZ<br />
Background: Adding adjuvant trastuzumab to chemotherapy for<br />
patients (pts) with resected HER2+ breast cancer (BC) improves<br />
disease free and overall survival (Perez EA, et al. J Clin Oncol<br />
2011). Understanding which pts are most likely to benefit from these<br />
therapies is a goal of our team.<br />
Methods: Baseline 1639 annotated tumor specimens from pts enrolled<br />
in the phase III N9831 adjuvant trastuzumab trial (NCT00005970)<br />
were processed via the >29,000 gene probe DASL technology<br />
(Illumina) to identify genomic predictors of pt outcome to Arm A<br />
chemotherapy or Arm C chemotherapy plus concurrent trastuzumab.<br />
Samples were spotted in 96 well plates, with appropriate replicates.<br />
Extensive quality control and internal validation were performed.<br />
The association of each gene with recurrence-free survival (RFS) was<br />
determined for each treatment arm separately using CoxPH models<br />
adjusted for clinical and tumor risk factors. A p3x ULN) and bilirubin (>2x ULN) elevation, which represent<br />
possible Hy’s Law cases and a high risk of acute liver failure,<br />
among 1194 patients randomized to lapatinib treatment from whom<br />
pharmacogenetic data was available.<br />
This study prospectively validated prior reports of the association of<br />
the specified MHC variants with elevated ALT among women treated<br />
with lapatinib. The strongest effects were observed for carriers of<br />
the HLA alleles DQA1*02:01 and DRB1*07:01, with odds ratios of<br />
20 (95% CI: 8-40) between cases (n=34) and controls (n=807-808).<br />
These two HLA alleles are highly correlated, inherited together in<br />
most individuals and are consistent with a single genetic association.<br />
The overall risk of patients having an ALT (>3xULN) elevation<br />
was 3.0% and 0.7% during treatment with lapatinib and placebo<br />
respectively. Carriers of either HLA allele had a 12% chance (positive<br />
predictive value) of having an elevated ALT (>3xULN), in contrast<br />
to a 0.9% risk (negative predictive value, 99.1%) for non-carriers of<br />
the specified HLA alleles. These associations were maintained for<br />
higher ALT elevation thresholds and for cases of concurrent ALT<br />
and TBL elevation, consistent with possible Hy’s Law cases. These<br />
results strongly support the role of Class II HLA-modulated immune<br />
mechanisms in lapatinib-induced hepatotoxicity.<br />
Our results validate the large strength of association of the HLA alleles<br />
DRB1*07:01 and DQA1*02:01 with hepatotoxicity and provide the<br />
possibility of managing the risk of hepatotoxicity in women receiving<br />
lapatinib for early or late stage HER2 positive breast cancer. This<br />
association with immune mechanisms may have implications for<br />
toxicities with other TKIs in current use in cancer patients.<br />
www.aacrjournals.org 145s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
PD10-06<br />
CXCL13 mRNA predicts Docetaxel benefit in Triple Negative<br />
tumors<br />
Wirtz RM, Leinonen M, Bono P, Isola J, Kellokumpu-Lehtinen P-L,<br />
Kataja V, Turpeenniemi-Hujanen T, Jyrkkiö S, Eidt S, Schmidt M,<br />
Joensuu H. STRATIFYER Molecular Pathology GmbH, Cologne,<br />
Germany; Pharma, Turku, Finland; Helsinki University Central<br />
Hospital and University of Helsinki, Helsinki, Finland; University<br />
of Tampere and Tampere University Hospital, Finland; Tampere<br />
University Hospital, Tampere, Finland; Kuopio University Hospital,<br />
Kuopio, Finland; Oulu University Hospital, Oulu, Finland; Turku<br />
University Hospital, Turku, Finland; Institute of Pathology at the<br />
St-Elisabeth-Hospital, Cologne, Germany; University Hospital<br />
Mainz, Germany<br />
Background: Presence of immune cell infiltrates in tumor may<br />
influence outcome of patients with node negative breast cancer (BC)<br />
(Schmidt et al 2008). High expression of CXCL13 (B lymphocyte<br />
chemoattractant chemokine) was strongly associated with favorable<br />
survival in one recent series consisting of BC patients treated with<br />
adjuvant chemotherapy (Razis et al. 2012). Here we examined the<br />
clinical significance of breast tumor CXCL13 mRNA levels within<br />
the context of the FinHer trial, where patients were randomly assigned<br />
to receive 3 cycles of either docetaxel or vinorelbine followed by<br />
3 cycles of FEC. Patients with HER2-positive BC had a second<br />
randomization for trastuzumab vs. control. Since intratumoral B cells<br />
are of particular importance for obtaining response to chemotherapy<br />
in triple negative BC (TNBC) and of limited value in luminal BC<br />
(Schmidt et al. 2012), and trastuzumab treatment is a confounding<br />
factor in HER2+ BC, we focused on TNBC.<br />
Methods: RNA was extracted from FFPE tumor tissue of 917 (90.8%)<br />
out of the 1010 patients who participated in the FinHer trial. CXCL13<br />
mRNA expression was measured using RT-qPCR. The molecular<br />
subtypes (luminal, HER2-enriched and triple-negative) were<br />
determined using IHC and central chromogenic in situ hybridization<br />
(CISH) testing. Prognostic significance of factors was assessed using<br />
univariate and multivariate analyses. Distant disease-free survival<br />
(DDFS) between groups was compared using the log-rank test.<br />
Results: Tumor CXCL13 mRNA expression showed a bimodal<br />
distribution and correlated negatively with tumor ESR1 mRNA<br />
levels (r=-0,31; p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
PD10-08<br />
Venlafaxine inhibits the CYP2D6 mediated metabolic activation<br />
of tamoxifen: Results of a prospective multicenter study:<br />
(NCT00667121)<br />
Goetz MP, Suman V, Henry NL, Reid J, Safgren S, Kosel M, Kuffel<br />
M, Sideras K, Flockhart D, Stearns V, Denduluri N, Irvin WJ, Ames<br />
M. Mayo Clinic, Rochester, MN; University of Michigan, Ann Arbor,<br />
MI; Indiana University, Indianapolis, IN; Johns Hopkins, Baltimore,<br />
MD; Fairfax-Northern Virginia Hematology-Oncology, Arlington,<br />
VA; University of North Caroloina, Chapel Hill, NC<br />
Background: CYP2D6 is the rate limiting enzyme responsible for the<br />
metabolic activation of tamoxifen (tam) to endoxifen. Compared to<br />
CYP2D6 poor metabolizers (PM), tam-treated CYP2D6 extensive<br />
metabolizers (EM) have higher endoxifen concentrations, more<br />
vasomotor symptoms (Goetz, MP J Clin Oncol 2005), and are more<br />
likely to discontinue tam (Rae, JM 2009. Pharmacogenomics J).<br />
Additionally, higher endoxifen concentrations are associated with a<br />
stepwise increase in tam side-effects (Lorizio, W <strong>Breast</strong> <strong>Cancer</strong> Res<br />
Treat 2012). The data regarding CYP2D6 genotype and recurrence is<br />
mixed. Venlafaxine is a weak CYP2D6 inhibitor not known to alter<br />
tam pharmacokinetics (PK) and commonly recommended for tam<br />
induced hot flashes. We conducted a multicenter pharmacological<br />
study to determine whether venlafaxine altered the PK of tam and to<br />
determine the distribution of CYP2D6 genotypes in this population<br />
Methods: Women taking tam for at least 4 weeks and for whom<br />
venlafaxine was recommended for the treatment of hot flashes<br />
were eligible. Blood samples were collected prior to and 8-16<br />
weeks following initiation of venlafaxine for steady state tam and<br />
metabolites. Genotyping was performed for alleles associated with<br />
no (PM; *3, *4, *5,*6); reduced (intermediate, IM; *10, 17 and<br />
*41); and ultra-rapid (UM; *1X2) metabolism. Power calculations<br />
demonstrated that 17 patients with paired samples were required<br />
(two-sided alpha=0.05 t-test, 90% power) to detect a 25% change<br />
in endoxifen levels after at least 8 weeks of concurrent treatment.<br />
Results: 30 women (median age 48.5) initiated venlafaxine. CYP2D6<br />
genotypes were within Hardy Weinberg Equilibrium (HWE). CYP2D6<br />
UM allele frequency (6.7%) was higher while CYP2D6 *4 (13.3%)<br />
was lower than expected compared to an unselected population (0.5<br />
and 21% respectively; Sachse Am. J. Hum. Genet. 1997), resulting in<br />
the absence of CYP2D6 PM/PM. Mean (min/max) baseline endoxifen<br />
concentrations (8.73; 1.5-20.5 ng/ml) were correlated with CYP2D6<br />
phenotype as follows: intermediate (EM/PM, PM/IM): 6.8 (1.5-11.2);<br />
extensive (EM/EM, EM/IM): 9.4 (1.5-20.5) and ultra-rapid (UM/<br />
EM: 11.0; 7.8-14) (r 2 = 0.35 p=0.05). In patients with paired samples<br />
(n=20), venlafaxine resulted in a 23% decrease in endoxifen (-2.06<br />
ng/ml; 95% CI -0.69 to -3.04; p=0.004), but not tam, NDMT, or<br />
4HT concentrations. Following initiation of venlafaxine, CYP2D6<br />
genotype was no longer associated with endoxifen concentrations<br />
(r 2 = 0.28 p=0.23). For women with reduced CYP2D6 metabolism<br />
[EM/PM (n=9) or PM/IM (n=1)], venlafaxine lowered endoxifen<br />
concentrations (-2.98 ng/ml) to a level (5.41 ng/ml) reported to be<br />
associated with a higher risk of recurrence in adjuvant tam treated<br />
patients (Madlensky, L Clin Pharmacol Ther 2011).<br />
Conclusions: In this study, women with tam-induced vasomotor<br />
symptoms requiring venlafaxine were comprised predominantly<br />
of CYP2D6 EM and UM metabolizers. Venlafaxine significantly<br />
decreased endoxifen concentrations. Although the optimal<br />
concentration of endoxifen is unknown, given prior data linking low<br />
endoxifen concentrations with recurrence, venlafaxine should be used<br />
with caution in tam treated patients. (Supported by R01CA133049)<br />
PD10-09<br />
CYP2D6 and adjuvant tamoxifen: Impact on outcome in pre- but<br />
not postmenopausal breast cancer patients<br />
Margolin S, Lindh J, Thorén L, Xie H, Koukel L, Dahl M-L, Eliasson<br />
E. Karolinska Institutet, Stockholm, Sweden; Karolinska University<br />
Hospital, Stockholm, Sweden; Karolinska Institutet, Karolinska<br />
University Hospital Huddinge, Stockholm, Sweden<br />
Background<br />
The therapeutic effect of tamoxifen in adjuvant treatment of hormone<br />
receptor positive breast cancer might be impaired in patients with<br />
cytochrome P450 2D6 (CYP2D6) genotypes that predispose to<br />
decreased formation of potent anti-estrogenic tamoxifen metabolites.<br />
However, previous studies have shown inconsistent findings in this<br />
regard. In light of two recent studies failing to show an impact of<br />
CYP2D6 genotype on outcome in postmenopausal patients, we<br />
hypothesized that deficient CYP2D6 might be of greater importance<br />
in premenopausal patients with high levels of circulating estrogen.<br />
We therefore aimed to study the effect of CYP2D6 activity in both<br />
pre- and postmenopausal patients who were adherent to tamoxifen<br />
treatment for at least one year.<br />
Methods<br />
382 patients, from a population-based cohort of unselected breast<br />
cancer patients that were prescribed adjuvant tamoxifen for five<br />
years, constituted the base of the study. Information on menopausal<br />
status, tumor characteristics, treatment data including compliance<br />
and outcome was retrieved from medical records. Comprehensive<br />
CYP2D6 genotyping was performed and functionally translated into<br />
constitutive, metabolic activity.<br />
Results<br />
In patients adherent to tamoxifen for at least one year (n=313) there<br />
was an association of reduced CYP2D6 activity (≤50% of normal)<br />
to both recurrence (p=0.02) and breast cancer-specific mortality<br />
(p=0.03). In a multivariable analysis including CYP2D6 activity,<br />
age at diagnosis, tumor size, lymph node status, grade, adjuvant<br />
chemotherapy and concomitant use of CYP2D6 inhibitors, CYP2D6<br />
remained an independent predictor of recurrence (HR=0.39, 95% CI:<br />
0.18-0.85, p=0.02) and breast cancer specific survival (HR=0.33,<br />
95% CI 0.12-0.90, p=0.03). Gradually decreasing CYP2D6 activity<br />
paralleled increasing risk of recurrence and breast cancer related<br />
mortality. The effect of CYP2D6 derived mainly from premenopausal<br />
patients with an association to both recurrence (p=0.01) and breast<br />
cancer specific survival (p=0.04). There was no such association in<br />
the postmenopausal group.<br />
Conclusion<br />
In a prospectively collected cohort of tamoxifen-treated breast cancer<br />
patients, an association between CYP2D6 genotype and outcome was<br />
evident in patients that were adherent to tamoxifen treatment for at<br />
least a year. Importantly, this effect derived from premenopausal<br />
patients only.<br />
P1-01-01<br />
Fluorescence mapping with indocyanine green for sentinel lymph<br />
node detection in early breast cancer – results of the ICG-10 study<br />
Benson JR, Loh S-W, Jones LA, Wishart GC. Addenbrooke’s Hospital,<br />
Cambridge, Cambridgeshire, United Kingdom<br />
Background: Dual localization methods with blue dye and<br />
radioisotope are commonly employed for SLN identification but<br />
potential drawbacks include allergic reactions, radiation exposure<br />
and mandatory licencing. Identification rates exceeding 95% have<br />
been reported using the fluorescent tracer indocyanine green (ICG)<br />
as a navigation system. A feasibility study was undertaken to confirm<br />
www.aacrjournals.org 147s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
the sensitivity and safety of ICG as a tracer agent for sentinel lymph<br />
node (SLN) identification in early breast cancer.<br />
Methods: In an open, non-randomised study, 100 clinically node<br />
negative patients (95 unilateral; 5 bilateral) scheduled to undergo<br />
routine SLN biopsy for core-biopsy proven invasive breast cancer<br />
were identified at the multidisciplinary team meeting [53 screendetected;<br />
51 symptomatic]. All patients received triple localization<br />
with blue dye (2.5% Patent Blue), radiocolloid and ICG (0.5%). The<br />
number of sentinel nodes for each patient were recorded numerically<br />
and whether blue, radioactive or fluorescent. Subcutaneous lymphatics<br />
were visualized with a Photodynamic Eye camera and sensitivity of<br />
individual tracers alone and in combination calculated. Approval was<br />
granted by the Local Research Ethics Committee and the Medicines<br />
and Healthcare Products Regulatory Agency for use of ICG as a<br />
third tracer agent.<br />
Results: Final analysis was performed on 104 procedures in 99<br />
patients (1 exclusion - benign adenomyoepithelioma on definitive<br />
pathology). A total of 242 nodes were removed of which 201<br />
were defined as sentinel (blue and/or radioactive) with an average<br />
nodal retrieval of 2.33 per procedure. Amongst these, 25 contained<br />
either macrometastases (n=16) or micrometastases (n=9), yielding<br />
procedural and node specific positivity rates of 17.3% (18/104)<br />
and 12.4% (25/201) respectively. 100% of these ‘true’ SLNs were<br />
fluorescent (201/201), 95.0% (191/201) were both fluorescent and<br />
blue, 77.6% (156/201) were fluorescent and radioactive whilst 73.1%<br />
(147/201) were blue, radioactive and fluorescent. The procedural<br />
detection rates were 99% (103/104) for blue dye, 91.3% (95/104)<br />
for radioisotope and 100% for fluorescence. All 25 positive nodes<br />
were identified with all three tracers and all 18 node positive patients<br />
had tumour deposits in the first SLN excised. The majority of ‘nonsentinel’<br />
nodes were fluorescent (36/41) and no serious adverse<br />
reactions occurred.<br />
Conclusion: ICG fluorescence imaging permits real-time visualization<br />
of lymphatics and provides an additional dimension to SLN biopsy<br />
which is safe and effective. These results confirm high sensitivity for<br />
fluorescence in SLN identification and the combined nodal sensitivity<br />
for ICG and blue dye (95.0%) was higher than for blue dye and<br />
radioisotope (73.1%). With further refinements in the technique may<br />
it may be possible to eventually rely on ICG as a sole tracer agent.<br />
Moreover, a marginally higher nodal yield with fluorescent mapping<br />
may allow more confident omission of completion axillary dissection<br />
in selected SLN positive patients.<br />
P1-01-02<br />
Withdrawn by Author<br />
P1-01-03<br />
Comparison of sentinel lymph node biopsy guided by the multimodal<br />
method of indocyanine green fluorescence, radioisotope<br />
and blue dye versus the radioisotope in breast cancer; A<br />
randomized phase II trial<br />
Jung S-Y, Kim S-K, Kim SW, Lee S, Lee J, Shin I-s, Kwon Y, Lee E.<br />
National <strong>Cancer</strong> Center, Goyang, Korea<br />
Background: Sentinel lymph node (SLN) biopsy is a standard<br />
surgery for axillary staging of early breast cancer. This study aimed<br />
to evaluate the identification rate and surgery time of SLN biopsy<br />
with the multi-modal method using the mixture of indocyanine green<br />
(ICG) fluorescence, RI and blue dye as a new method, in comparison<br />
with the RI, in clinically node negative breast cancer patients.<br />
Materials and methods: In this phase-II randomized study, 86<br />
patients with clinically node negative breast cancer were randomized<br />
to receive periareolar injection of the mixture including ICG<br />
fluorescence, RI and blue dye or the only RI for SLN biopsy. We<br />
compared the identification rate, the number of SLN, and detections<br />
time of SLN biopsy between these two groups.<br />
Results: The mean age of the multimodal group and the only RI<br />
group was 48.2 years and 51.0 years (p=0.12), respectively. There<br />
were no differences of histopathologic factors including tumor size,<br />
node positivity, hormone receptor positivity and HER2 positivity<br />
between two groups. Sentinel lymph nodes were identified in all<br />
patients of both groups (100% in the multimodal group vs 100% in<br />
the RI group). The average number of SLN in the mixture group was<br />
more than that of the RI group (3.4 ±1.37 vs 2.3 ± 1.04; p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
Results: After inj. of Tilmanocept, 100% (22/22 immediate; 88/88<br />
overall) of pts demonstrated localization. After inj. of SCI, 90.1%<br />
(127/141) and 91.5% (129/141) of pts exhibited localization<br />
immediately and overall, respectively.<br />
Localization rate and degree of localization with the benchmark for<br />
SCI, H 0 , are provided in Table 1 (significance is considered
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
vs negative) or grade (grade 1 vs 2 vs 3), these biologic factors were<br />
able to significantly discriminate patients with respect to RFS, DSS<br />
and OS (table 2).<br />
Table 2. Survival outcomes for stage I patients by ER status and grade<br />
ER pos ER neg p-value Grade I Grade II Grade III p-value<br />
RFS - 5y 96.7% 89.6%
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
P1-01-09<br />
Which nomograms may be the best for predicting nonsentinel<br />
lymph node metastasis in breast cancer patients: a meta-analysis.<br />
Chen K, Jin L, Zhu L, Shan Q, Su F. Sun Yat-sen Memorial Hopsital,<br />
Guangzhou, Guangdong, China<br />
Background: Axillary lymph node dissection (ALND) is the standard<br />
treatment for breast cancer patients with positive sentinel lymph<br />
nodes (SLNs). Several nomograms were developed to identify SLNpositive<br />
patients with low risk of nonsentinel lymph nodes (NSLNs)<br />
metastasis. These nomograms were validated in different populations<br />
and it is still unknown which is the best. This study is to present a<br />
systemic review and perform a meta-analysis to obtained the pooled<br />
AUC (Area Under the receiver-operator Curve) value of each models.<br />
Methods: This review focused on six models: Cambridge, MSKCC,<br />
Mayo, MDA, Tenon and Stanford models. A “Pubmed” search and<br />
“Web of science” search were conducted and 35 literatures were<br />
ultimately included. AUC and the number of patients with positive<br />
NSLNs were extracted. Publication bias and heterogeneity were<br />
analyzed. AUCs were converted to odds ratios (ORs) for combination.<br />
The combined ORs were converted back to AUCs to represent the<br />
integrated discriminative capabilities of each models.<br />
Findings: In total, the Cambridge, Mayo, MDA, MSKCC, Stanford<br />
and Tenon models were validated in 8, 6, 4, 39, 14 and 15 studies,<br />
with 2156, 2431, 843, 8143, 3700 and 3648 patients included,<br />
respectively. There were no publication bias or heterogeneity observed<br />
in the Cambridge, Mayo, MDA and Tenon models (Table 1). The<br />
combined ORs and the corresponding AUCs of each models were<br />
listed as follow: Cambridge (OR=3.86, AUC=0.71), Mayo (OR=3.71,<br />
AUC=0.71), MSKCC (OR=3.47, AUC=0.70), MDA(OR=3.44,<br />
AUC=0.70), Tenon (OR=3.46, AUC=0.70) and Stanford (OR=2.92,<br />
AUC=0.67). For each of the predictive models, both fixed and random<br />
effect models were used to calculate the combined OR. The presence<br />
of larger difference between the fixed and random effect analysis<br />
suggests small study effects, rendering the meta-analysis relatively<br />
less reliable. The combined ORs were identical when fixed and<br />
random effect models were used in the Cambridge and MDA models,<br />
suggesting that there was no small study effects in these two models.<br />
Table 1, Publication bias analysis, Heterogeneity analysis and Comined OR and converted AUC of<br />
each models.<br />
Test of<br />
publication Test of heterogeneity Fixed Effect Model† Random Effect Model†<br />
bias<br />
Begg’s Heterogeneity Combined Converted Combined Converted<br />
P<br />
method,P statistic<br />
OR AUC OR AUC<br />
Cambridge 0.051 4.85 0.563 3.86 0.71 3.86 0.71<br />
Mayo 0.624 6.39 0.172 3.71 0.71 4.28 0.73<br />
MSKCC
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P1-01-11<br />
Is OSNA mRNA copy number in sentinel lymph node biopsy<br />
predictive of further disease in the axilla?<br />
Rusby JE, Agabiti E, Waheed S, Barry P, Roche N, Allum W, Gui G,<br />
MacNeill F, Christaki G, Osin P, Nerurkar A. Royal Marsden NHS<br />
Foundation Trust, London, United Kingdom<br />
Introduction<br />
Intra-operative assessment of sentinel nodes (SLNs) allows immediate<br />
completion axillary dissection (cALND) in breast cancer patients.<br />
Molecular assessment such as one-step nucleic acid amplication<br />
(OSNA) promises greater sensitivity and provides a more accurate<br />
quantitative assessment than traditional methods.<br />
Our unit policy is to proceed to cALND in patients with macrometastases<br />
but not for micrometastases. However, evidence of upstaging has led<br />
us to seek to raise the threshold for proceeding to cALND. The CK19<br />
mRNA copy number is an expression of the metastatic burden in the<br />
SLN and may be related to the presence of additional disease in the<br />
cALND. Since the original copy number threshold between micro<br />
(250-5000 copies/microliter) and macrometastasis (>5000 copies/<br />
microliter) was based on few patients and serial pathological sections,<br />
we investigated the mRNA copy number in patients with and without<br />
additional disease in the cALND.<br />
Methods<br />
All patients in our unit undergo pre-operative axillary ultrasound<br />
with fine needle aspiration cytology of any suspicious nodes. Those<br />
with malignant cytology proceed directly to ALND. Radiologically<br />
and cytologically node negative patients undergo sentinel lymph<br />
node biopsy (SLNB) and OSNA. Electronic records of consecutive<br />
patients with invasive breast cancer undergoing SLNB with OSNA<br />
from August 2011 to March 2012 were retrospectively reviewed. Two<br />
parameters of mRNA copy number were examined: Copy number of<br />
the highest copy number SLN and the summed copy numbers of all<br />
positive SLNs. Their relationship to the presence of further disease<br />
in the axilla was examined using Student’s t test.<br />
Results<br />
Of 201 SLNBs, 45 (22%) had macrometastasis-positive OSNA and<br />
therefore underwent cALND (1 patient declined). Twenty patients<br />
(45%) had no further positive nodes (a negative cALND) with a total<br />
axillary metastatic burden of 1-2 in 11-27 nodes. Twenty four (55%)<br />
showed further disease (a positive cALND) with a burden of 2-20 in<br />
9-30 nodes, including the SLNs.<br />
There was no significant difference in tumour size or grade between<br />
patients with additional positive nodes in the cALND compared with<br />
those with no further disease.<br />
There was no significant difference in the copy number of the highest<br />
copy number positive SLN (p=0.44) or in the summed copy number<br />
of all positive SLNs (p=0.36) between the cALND positive and<br />
negative groups.<br />
Conclusion<br />
OSNA CK19 mRNA copy number does not correlate with the cALND<br />
metastatic burden. Therefore, raising the copy number threshold<br />
may be too simplistic as a method to better select patients with high<br />
probability of a positive cALND. A predictive model will be derived<br />
based on multivariate analysis of the larger patient population (>400<br />
patients) that will have undergone SLNB with OSNA by the time<br />
of SABCS.<br />
P1-01-12<br />
The Performance of the One Step Nucleic acid Amplification<br />
(OSNA) Assay in <strong>Breast</strong> <strong>Cancer</strong> Patients with Receiving<br />
Preoperative Systemic Therapy<br />
Yagata H, Yamauchi H, Horii R, Osako T, Iwase T, Akiyama<br />
F, Kinoshita T, Tsuda H, Tsugawa K, Nakamura S. St. Luke’s<br />
International Hospital, Tokyo, Japan; <strong>Cancer</strong> Institute Hospital of the<br />
Japanese Foundation for <strong>Cancer</strong> Research, Tokyo, Japan; National<br />
<strong>Cancer</strong> Center Hospital, Tokyo, Japan; St. Marianna University<br />
School of Medicine, Kanagawa, Japan; Showa University School of<br />
Medicine, Tokyo, Japan<br />
Background: The OSNA (One Step Nucleic acid Amplification) assay<br />
is a semi-automated lymph node examination method using molecular<br />
biological technique. The OSNA assay has been validated for breast<br />
cancer patients without receiving preoperative systemic therapy (PST)<br />
by several clinical studies and has currently become more popular as<br />
sentinel lymph node (SLN) examination method with the following<br />
two main advantages; 1) to allow examination of the whole portion of<br />
a node, 2) to allow intraoperative judgment of metastasis positive or<br />
negative. However, the feasibility of the OSNA assay in breast cancer<br />
patients treated by PST has never been confirmed. In this multi-central<br />
clinical study, we compared the judgments of the OSNA assay and of<br />
pathological examination on lymph nodes dissected after receiving<br />
PST to evaluate the performance of the OSNA assay.<br />
Material & Methods: Three hundred two nodes dissected from the 80<br />
breast cancer patients who received PST were examined. Each lymph<br />
node was divided at 2mm intervals and the slices were alternately<br />
applied to the OSNA assay and pathological examination with H&E<br />
staining and CK19 immunohistochemical staining of permanentsection.<br />
In pathological examination, judgments of metastasis positive<br />
or negative were determined by one central-review pathologist<br />
according to the criteria of AJCC 7 th edition (“positive” if >0.2mm<br />
metastases were detected).<br />
Result: The overall concordance rate between the OSNA assay and<br />
pathological examination was 91.1% (275/302) with sensitivity of<br />
88.3% (53/60) and specificity of 91.7% (222/242) (Table). These<br />
results are very similar to those of the Japanese clinical validation<br />
study in breast cancer patients without receiving PST which was<br />
conducted by the almost same protocol (Tamaki Y, et al. Clin <strong>Cancer</strong><br />
Res, 2009, 15: 2879-2884).<br />
Conclusion & Discussion: These results indicate the OSNA assay can<br />
be applicable for breast cancer patients after receiving PST as well<br />
as breast cancer patients without receiving PST. The OSNA assay<br />
will enable to examine the whole portion of nodes, leading to more<br />
detection of metastases (especially micrometastases) and more exact<br />
nodal staging for breast cancer patients treated by PST. Also, for the<br />
patients who receive sentinel lymph node biopsy after PST, the OSNA<br />
assay will be useful as intraoperative examination method of SLNs<br />
because it is expected to provide more correct judgments than current<br />
intraoperative methods such as frozen-section or touch-print cytology.<br />
Table<br />
N<br />
Overall concordance<br />
Sensitivity (95% C.I.) Specificity (95% C.I.)<br />
(95% C.I.)<br />
This study (after PST) 302 91.1% (87.3-94.0) 88.3% (77.4-95.2) 91.7% (87.5-94.9)<br />
The Japanese clinical<br />
validation study<br />
(without PST)<br />
450 92.2% (89.4-94.5) 86.1% (76.5-92.8) 93.5% (90.5-95.8)<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
152s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
P1-01-13<br />
Patterns of definitive axillary management in the era prior to<br />
reporting ACOSOG Z0011: comparison between NCCN Centers<br />
and hospitals in Michigan<br />
Breslin T, Hwang S, Mamet R, Hughes M, Otteson R, Edge S, Moy B,<br />
Rugo H, Wong Y-N, Wilson J, Laronga C, Weeks J, Silver S, Marcom<br />
P. University of Michigan, Ann Arbor, MI; Duke University; City of<br />
Hope; Dana-Farber/Brigham and Women’s <strong>Cancer</strong> Center; Roswell<br />
Park <strong>Cancer</strong> Institute; University of California <strong>San</strong> Fransicso; Fox<br />
Chase <strong>Cancer</strong> Center; Ohio State University; Moffitt <strong>Cancer</strong> Center;<br />
Massachusetts General Hospital <strong>Cancer</strong> Center<br />
Background: The results of the ACOSOG- Z0011 trial have had<br />
potential practice changing implications for the management of<br />
patients with positive sentinel lymph node (SLN) undergoing<br />
lumpectomy and radiation for breast cancer. However, some evidence<br />
suggests a shift in axillary management even prior to the initial report<br />
of data supporting sentinel lymph node biopsy (SLNB) alone in<br />
mid-2010. We analyzed data in the National Comprehensive <strong>Cancer</strong><br />
Network (NCCN) outcomes database from NCCN centers and the<br />
Michigan <strong>Breast</strong> Oncology Quality Initiative (MiBOQI) hospitals<br />
to examine institutional practice patterns with respect to use of<br />
completion axillary dissection (CALND) for SLN positive breast<br />
cancer in the years leading up to publication of these trial results.<br />
We hypothesized that CALND would be omitted more frequently<br />
in women treated at NCCN centers compared to those treated at<br />
MiBOQI programs.<br />
Methods: We identified 2,172 women with clinical T1/T2 N0 breast<br />
cancer who underwent breast surgery and SLNB and had a positive<br />
SLN from 2007 through 2010 at one of 12 participating NCCN centers<br />
or 12 MiBOQI sites. Patient and tumor characteristics, definitive<br />
breast procedure, year of diagnosis, and institutional affiliation were<br />
analyzed as predictors of use of SLNB alone in univariate Chi-Square<br />
and multivariable logistic regression models.<br />
Results: CALND was omitted in 314 (14.5%) of the 2,172 patients.<br />
Over time, there was a dramatic increase in the use of SLNB<br />
alone (12% in 2007 to 23% in 2010). In the univariate analyses,<br />
increased patient age, later year of diagnosis, lower T stage, and<br />
lower pathologic N stage were significant predictors of use of SLNB<br />
alone (all p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Results<br />
The PSM was based on age, race, region of diagnosis, tumor type and<br />
grade, tumor size, nodal status (micrometastasis vs macrometastasis)<br />
and hormone receptor status. It generated a balanced, matched cohort<br />
(3229 patients in each group) in which baseline characteristics were<br />
not significantly different. Five-year overall survival was 96.9%<br />
(95% CI 96.1-97.6%) in the ALND group and 94.0 (95% CI 92.6-<br />
95.4%) in the SLN biopsy alone group. The benefit of complete<br />
lymphadenectomy was significant: p=0.028.<br />
Conclusion<br />
Using PSM analysis, our results show evidence of benefit for ALND<br />
in case of metastatic sentinel lymph node. The results of randomized<br />
trials demonstrating no benefit for ALND may not been generalizable.<br />
P1-01-15<br />
Accuracy of sentinel lymph node in determining the requirement<br />
for second axillary surgeries in early breast cancer with<br />
retrospective application of the Z0011 criteria.<br />
Waters PS, Fennessy PJ, Alazawi D, Sweeney KJ, Kerin MJ. National<br />
University of Ireland, Galway, Ireland<br />
Background: Lymph node status is the most important prognostic<br />
marker in breast cancer management. The ACOSOG Z0011 trial<br />
reported no difference in survival in patients undergoing sentinel<br />
lymph node biopsy(SLNB) alone versus axillary lymph node<br />
dissection(ALND) in T1-T2 tumours with 1 -2 positive lymph nodes.<br />
Aims: Whether sentinel lymph node biopsy was a true representative<br />
of axillary burden. We also addressed whether application of criteria<br />
from Z0011 trial would have prevented patients undergoing second<br />
axillary surgery.<br />
Methods: All patients with T1-T2 tumours undergoing sentinel<br />
node biopsy were included in our study (n=1019). Analysis of our<br />
prospectively updated breast cancer database was performed. Minitab<br />
version 16.0 was used for statistical analysis.<br />
Results: 1019 SLNB procedures for T1 & T2 tumours were performed<br />
over a 7 year period. 730 patients were reported as histologically<br />
negative and 289 were positive(1 node =95). Of<br />
the lymph node positive group, 223 patients progressed to axillary<br />
clearance. Staging of 149 patients remained unchanged with 74<br />
patients being upstaged with having >2 lymph nodes reported as<br />
positive. 72 patients from the SLNB negative group also had an<br />
axillary clearance. 5 of these patients had further axillary disease<br />
with 1 patient being upstaged having >2 positive lymph nodes. With<br />
application of Z0011 criteria 220 patients would have avoided second<br />
axillary surgery.<br />
Conclusions: The accuracy of sentinel lymph node biopsy in<br />
determining tumour burden has been demonstrated. Furthermore<br />
application of Z0011 will have major cost savings for the health<br />
service with decreased patient stay and morbidity.<br />
P1-01-16<br />
Intraoperatively-palpable “non-sentinel” nodes: should they be<br />
removed?<br />
Crivello ML, Ruth K, Sigurdson ER, Egleston BL, Boraas M, Bleicher<br />
RJ. Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA<br />
Background:<br />
Sentinel lymphadenectomy is the standard of care for evaluation of the<br />
axilla in breast cancer. Not infrequently, despite a clinically negative<br />
axilla, axillary nodes are found and removed that are only palpable<br />
intraoperatively at the time of sentinel lymph node biopsy. There is<br />
limited data suggesting that their resection is beneficial, and there is<br />
some controversy over whether these non-hot, non-blue nodes should<br />
also be called “sentinel nodes” (SNs).<br />
Methods:<br />
A retrospective chart review was conducted of breast cancer patients<br />
who underwent sentinel lymph node biopsy from 2007 to 2011 at<br />
a single institution. Patients were only included if they had SNs<br />
removed (defined as blue and/or radioactive nodes), as well as<br />
additional non-sentinel nodes that were only palpable intraoperatively<br />
(pNSNs) and not part of an axillary dissection (ALND). Pathology<br />
of both SNs and pNSNs were reviewed. Histologic nodal evaluation<br />
was performed by H&E alone.<br />
Results:<br />
From 2007 to 2011, a total of 59 patients had both SNs and pNSNs<br />
removed. Fifty-five patients (93.2%) were female and the average<br />
age was 55 years old. Fifty-two patients (88.1%) had invasive ductal<br />
carcinoma while 7 had lobular carcinoma (11.9%). Average tumor<br />
size was 2.0 cm. Among the 59 patients, a total of 109 SNs (mean<br />
1.8, median 1, range 1-6) and 202 pNSNs (mean 3.4, median 2, range<br />
1-30) were removed at the same surgery. Twenty patients (33.9%)<br />
had metastases in either the SNs and/or pNSNs with 16 (80.0%) of<br />
these having metastases in the SNs alone. Sixteen patients proceeded<br />
to an ALND. There were 4 patients (6.8%, 95% CI 1.9-16.5%) who<br />
had SNs negative for tumor but pNSNs positive for tumor, and 4<br />
(6.8%, 95% CI 1.9-16.5%) separate patients who had extracapsular<br />
extension (ECE) in their pNSNs but no ECE in the SNs. The pNSNs<br />
thus provided information altering operative treatment by American<br />
College of Surgeons Oncology Group (ACOSOG) Z0011 trial criteria<br />
in 8 patients (13.6%). Two patients (3.4%, 95% CI 0.4-11.7%) had<br />
ECE present in ALND nodes, but not present in either their SNs or<br />
pNSNs.<br />
Conclusion:<br />
pNSNs provide information that changes the surgical plan by<br />
ACOSOG Z0011 criteria in 14% of cases. Whether their removal<br />
changes patient outcomes remains unclear, especially as SNs and<br />
pNSNs may, together, be falsely-negative for ECE present within<br />
the axilla. While we recommend their removal at this time based<br />
upon the added information they provide, further study is required to<br />
determine whether the changes resulting from pNSN dissection (i.e.<br />
need for ALND) provide any outcome benefit in this era of effective<br />
systemic therapy.<br />
P1-01-17<br />
The impact of triple negativity on lymph node positivity in breast<br />
cancer.<br />
Weber JJ, Bellin LS, Milbourn DE, Wong J. East Carolina University,<br />
Brody School of Medicine, Greenville, NC; University of North<br />
Carolina, Lineberger Comprehensive <strong>Cancer</strong> Center, Chapel Hill, NC<br />
Introduction<br />
Triple negative breast cancer (TNBC), defined as estrogen,<br />
progesterone, and HER2/Neu receptor-negative is biologically more<br />
aggressive than non-TNBC. Whether TNBC presents at a more<br />
advanced local/regional stage is controversial. We sought to determine<br />
whether TNBC had more frequent lymph node positivity.<br />
Methods<br />
ER and PR status was determined by routine immunohistochemical<br />
analysis. HER2/Neu status was determined by immunohistochemistry;<br />
if 2+ equivocal status was noted, fluorescence in situ hybridization<br />
was performed for confirmation. Patients with a clinically negative<br />
axilla underwent sentinel lymph node biopsy, and if the sentinel<br />
node was positive, underwent immediate completion axillary node<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
154s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
dissection. Lymph node positivity was determined by hematoxlyneosin<br />
staining. The main outcome measures were lymph node status<br />
and pathologic tumor size. Statistical differences were compared by<br />
means of paired t-test and chi-squared test where appropriate.<br />
Results<br />
Between January 1, 2004 and December 31, 2010, 501 women<br />
with invasive breast cancer were treated at our institution. These<br />
patients ranged in age from 25 to 93 years (mean 57.6 yr), with<br />
53.1% of patients self-reported as non-Hispanic white and 43.7%<br />
non-Hispanic black. TNBC patients were younger (mean 55.0 yr vs.<br />
58.3 yr, p=0.005), and were more often non-Hispanic black (52.7%<br />
vs. 41.1%, p=0.03). The mean pathological tumor size of the entire<br />
population was 1.86 cm (range 0 to 18 cm). One hundred twelve<br />
patients (22.4%) were TNBC. The mean pathological tumor size<br />
for TNBC compared to non-TNBC patients was 2.07 cm (range 0<br />
to 8.7 cm) and 1.80 cm (range 0 to 18 cm) (p=0.068). There was<br />
a statistically significant difference in the T-stage at presentation<br />
between TNBC and non-TNBC tumors (T1, 58.9% TNBC vs. 72.0%<br />
non-TNBC; T2, 34.8% TNBC vs. 22.4% non-TNBC; T3/T4, 6.3%<br />
TNBC vs. 5.6% non-TNBC, p=0.02). One hundred sixty patients<br />
(31.9%) were node positive. The number of positive lymph nodes in<br />
the TNBC patients ranged from 1-18, and the non-TNBC ranged from<br />
1-35 (TNBC mean 2.94 vs. non-TNBC mean 3.94, p=0.09). TNBC<br />
patients were more often node positive than non-TNBC (39.3% vs.<br />
29.3%, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P1-01-20<br />
Clinicopathlogic Analysis of Invasive <strong>Breast</strong> Carcinoma with<br />
Micropapillary Component<br />
Yamanaka T, Suganuma N, Yamanaka A, Kojima I, Nishiyama S,<br />
Mukaibashi T, Nakayama H, Matsuura H, Matsuzu K, Chiba A,<br />
Inaba M, Rino Y, Yoshida A, Shimizu S, Masuda M. Yokohama City<br />
University, Yokohama-City, Kanagawa, Japan; Kanagawa <strong>Cancer</strong><br />
Center, Yokohama-City, Kanagawa, Japan; Ito Hospital, Tokyo, Japan<br />
Background: Invasive micropapillary carcinoma(IMPC) is a rare<br />
variant of invasive breast cancer that is associated with a high<br />
incidence of lymph node(LN) metastasis. But, the meaning of focal<br />
micropapillary component has not been fully elucidated.<br />
Methods: We retrospectively reviewed 88 invasive breast carcinoma<br />
cases with IMPC and focal micropapillary component.<br />
Results: Sixty-four cases had micropapillary component only in<br />
operative specimens, 18 cases had only in core-needle specimens,<br />
and 6 cases had in both. Sixteen were diagnosed as IMPC, and 72<br />
cases had focal micropapillary component with other histological<br />
type of invasive breast carcinoma; 65 cases with invasive ductal<br />
carcinoma, 6 cases with mucinous carcinoma and one with metaplastic<br />
carcinoma. There was one male patient. Mean age was 56.5 years<br />
old. Median tumor size was 2.5 cm. Forty two (47.7%) cases were<br />
nuclear grade(NG)1, 16 (18.2%) were NG2 and 30 (34.1%) were<br />
NG3. Seventy eight cases (90%) were ERand/orPgR positive and<br />
18.5% were HER2 positive. Six cases had distant metastasis at<br />
initial diagnosis. LN metastases were observed in 63.6% of all<br />
cases, and this high rate of LN metastasis could be seen even in<br />
small tumor group; 45.5% in cases with tumor equal or less than 2<br />
cm. In the group of IMPC, 40.0% had LN metastasis, and 56.9% in<br />
cases with focal micropapillary component. There was no significant<br />
difference between IMPC and focal micropapillary component<br />
by univariate analysis(p=0.055). Multivariate analysis of all cases<br />
showed that tumor size(>2cm)(p=0.047), NG(1 vs 2&3, p=0.017),<br />
and lymphatic invasion(p=0.001) were significantly associated<br />
with LN metastasis. No significant difference between IMPC<br />
and focal micropapillary component was showed by multivariate<br />
analysis also (p=0.60). Hormone receptor status or HER2 status<br />
were also not correlated(p=0.92, p=0.27 respectively). Among<br />
female patients without neoadjuvant chemotherapy, sentinel lymph<br />
node biopsy(SLNB) were underwent in 38 cases, and 16 cases<br />
(42.1%) had positive sentinel lymph node(SLN). Fourteen patients<br />
underwent additional axillary dissection and 7 cases (50%) had<br />
non-SLN metastases. Among patients with SLNB, 12 patients had<br />
micropapillary component in needle biopsy specimens, and 6 (50%)<br />
cases had positive SLN.<br />
Conclusion: Our data showed very high rate of LN metastasis in<br />
patients with micropapillary component, and this tendency still exists<br />
in cases with only focal micropapillary pattern. High positivity of<br />
SLNB was observed in these groups, and our data suggests that the<br />
findings of micropapillary component in CNB specimen could be<br />
used as a predictor of SLN metastasis.<br />
P1-01-21<br />
Sentinel Lymph Node detection after previous breast tumour<br />
surgical resection: identification rate and false negative rate<br />
through a prospective multi institutional study.<br />
Classe J-M, Andrieux N, Tunon de Lara C, Charitansky H, Lecuru<br />
F, Houpeau J-L, Faure C, De Blaye P, Houvenaeghel G, Kere D,<br />
Marchal F, Raro P, Lefebvre C, Dupré P-F, Rodier J-F. Institut de<br />
<strong>Cancer</strong>ologie de l’Ouest, Nantes Saint Herblain, France; Institut<br />
Bergonié, Bordeaux, France; Institut Claudius Regaud, Toulouse,<br />
France; Centre Hospitalier Georges Pompidou, Paris, France; Centre<br />
Oscar Lambret, Lille, France; Centre léon Bérard, Lyon, France;<br />
Centre Hospitalier Les Oudairies, La Roche sur Yon, France; Institut<br />
Paoli Calmettes, Marseille, France; Institut Jean Godinot, Reims,<br />
France; Centre Alexis Vautrin, Nancy, France; Centre Hospitalier<br />
Universitaire, Angers, France; Centre Hospitalier Morvan, Brest,<br />
France; Centre Paul Strauss, Strasbourg, France<br />
Background: Large multi institutional studies have pointed that<br />
previous surgical resection of breast tumours before axillary sentinel<br />
node detection (ASLND) was the main criteria of failure of this<br />
technique. Screening campaigns provide small tumours and despite<br />
efforts to obtain a diagnosis of early breast cancer, this is not always<br />
obtained , due to small tumours or false negative results of micro<br />
biopsies. The aim of our series was to assess identification rates and<br />
false negative rates of ASLND after previous surgical resection of<br />
breast tumours.<br />
Material and Methods: In a prospective multi institutional setting<br />
(14 multidisciplinary teams), we have included patients with a<br />
previous breast tumour surgical resection for the diagnosis of<br />
infiltrative breast adenocarcinoma. Patients with only a core biopsy<br />
and no surgical removal of the tumor before axillary surgery were<br />
not included. Each patient underwent a secondary surgical procedure<br />
for ASLND and axillary lymphadenectomy, and sometimes a breast<br />
secondary surgical procedure for margins. ASLND was performed<br />
with the combined method, with blue dye and technetium. Pathology<br />
was performed with serial sectioning, eosin safron and immune histo<br />
chemistry (IHC).<br />
Results: From July 2006 to November 2011, 138 patients where<br />
included. The median tumor size was 9mm. Identification rate was<br />
86% (118/138). A macrometastasis was found in 11 cases, in a sentinel<br />
node (9), or in a non sentinel node(2). False negative rate was 9% (1<br />
false negative sentinel node with macrometastasis in non sentinel node<br />
from lymphadenectomy/11 cases with a macrometastasis in either a<br />
sentinel node or a non sentinel node). In 1 case a micrometastasis was<br />
found in a sentinel node through IHC, with a macrometastasis in a<br />
non sentinel node from lymphadenectomy. Without IHC or without<br />
the decision of performing a complementary lymphadenectomy in the<br />
case of micrometastasis, the false negative rate would have been 18%.<br />
Conclusions: After previous surgical resection of early breast cancer,<br />
ASLND remains feasible with a low identification rate of 86%, despite<br />
the use of the combined method. The False negative rate is acceptable<br />
with the use of IHC.<br />
P1-01-22<br />
The utility of axillary ultrasound and sentinel lymph node biopsy<br />
in the management of metaplastic breast carcinoma<br />
Hieken TJ, Fazzio RT, Reynolds C, Jones KN, Ghosh K, Glazebrook<br />
KN. Mayo Clinic, Rochester, MN<br />
Background: Metaplastic breast carcinoma (MBC) accounts for
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
or osseous) elements. Patients typically present with large triple<br />
negative tumors and have a poor prognosis. The likelihood of lymph<br />
node (LN) involvement has been reported to be low in MBC patients.<br />
Due to the paucity of data, we undertook this study to explore the<br />
role of axillary ultrasound (US) and sentinel LN biopsy (SLNB) in<br />
the management of MBC.<br />
Methods: With IRB approval, we retrospectively identified patients<br />
diagnosed with MBC from 2001-2011 from the surgical pathology<br />
database. Histopathology and imaging were reviewed. Demographic,<br />
treatment and outcome data were obtained by clinical chart review.<br />
Data were analyzed using JMP 9.0 software.<br />
Results: We identified 41 women with MBC. Median age was 60 years<br />
(range 33-90). Histologic subtypes were spindle cell (46%), mixed<br />
adenocarcinoma and mesenchymal elements (20%), squamous cell<br />
(17%) chondroid/osseous (10%) and adenosquamous (7%). Tumor<br />
stage was T1 (24%), T2 (44%), T3 (12%) and T4 (20%). 26 patients<br />
(63%) were treated by mastectomy and 15 (37%) by wide excision.<br />
Of the 38 patients who underwent LN surgery (6 low-grade MBC, 32<br />
intermediate/high-grade MBC), 10 (26%) were LN positive. All lowgrade<br />
MBC patients were LN negative while 10 of 32 intermediate/<br />
high-grade MBC patients (31%) had LN metastasis. 22 patients had a<br />
preoperative axillary US. 14 patients had a negative axillary US and<br />
none had LN metastasis. 4 of 8 patients with suspicious axillary US<br />
findings had a preoperative axillary LN fine needle aspiration biopsy<br />
(FNAB) and 3 were positive for cancer. These patients proceeded<br />
directly to axillary LN dissection (ALND). 24 patients had a SLNB<br />
of whom one was SLN positive and underwent completion ALND.<br />
LN metastasis was associated with larger tumor size (p=0.003), higher<br />
tumor grade (p=0.04), angioinvasion (p=0.07) and abnormal axillary<br />
US (p=0.003). Surviving patients were followed for a mean (median)<br />
of 41 (30) months during which 13 (32%) recurred at a median of<br />
6 months (IQR 3-17 months) and 11 (27%) subsequently died of<br />
disease. One SLN negative patient developed an axillary recurrence<br />
at 8 months, was successfully treated by ALND and is disease-free at<br />
38 months. There were no axillary LN relapses after ALND.<br />
Conclusions: For clinically node-negative MBC patients, our<br />
contemporary data series suggests the incidence of occult LN<br />
metastasis is sufficiently high to warrant LN staging especially<br />
for patients with intermediate and high-grade tumors. This can<br />
be accomplished in a minimally invasive fashion with reasonable<br />
accuracy (∼97%) with axillary US, FNAB of sonographically<br />
suspicious LNs, and SLNB for patients with negative axillary US or<br />
FNAB. Axillary LND should be performed for patients with clinically<br />
and/or FNAB-positive LN for enhanced disease control.<br />
P1-01-23<br />
Increased Diagnostic Performance of Sentinel Lymph Node<br />
Biopsy Combined with Radiologic-pathologic Factors After<br />
Neoadjuvant Chemotherapy in <strong>Breast</strong> <strong>Cancer</strong> Patients with<br />
Cytologically Proven Node Metastasis at Diagnosis<br />
Park S, Koo JS, Kim MJ, Park JM, Cho JH, Hwang H, Park HS,<br />
Kim E-K, Kim SI, Park B-W. Yonsei University College of Medicine,<br />
Seoul, Korea<br />
Background: It is undetermined whether sentinel lymph node biopsy<br />
(SLNB) is feasible and accurate for predicting final nodal status after<br />
neoadjuvant chemotherapy (NCT) in breast cancer patients with<br />
cytologically proven node metastasis at the time of diagnosis, although<br />
currently completion node dissection is a standard surgical procedure<br />
for the management of axilla. The aim of this study was to investigate<br />
diagnostic performance of SLNB after NCT in this subgroup.<br />
Methods: Of 374 patients with T1-T3 breast cancer who received<br />
NCT, 178 had initially biopsy proven axillary/supraclavicular<br />
metastasis and subsequently underwent SLNB using radioisotope<br />
alone followed by completion node dissection between 2008 and<br />
2011. Detection rate, sensitivity, false negative rate (FNR), negative<br />
predictive value (NPV), and accuracy of SLNB were retrospectively<br />
analyzed and it was explored using regression analysis whether<br />
combination with clinicopathologic factors improved performance.<br />
Results: At initial presentation, 60.7% of patients were cT2 stage<br />
and 88.2% treated with concurrent or sequential anthracycline plus<br />
taxane preoperatively. SLNB was successfully performed in 169<br />
(94.9%) patients. The mean number of sentinel and regional nodes<br />
retrieved was 2.1 ± 1.6 and 12.8 ± 6.3, respectively. Tumoral nonresponder<br />
and extensive residual nodal disease were significantly<br />
associated with detection failure of SLNB. Conversion to nodenegative<br />
disease was noted in 69 (40.8%) patients. Sensitivity, FNR,<br />
NPV, and accuracy of SLNB were 78.0%, 22.0%, 75.8%, and 87.0%,<br />
respectively and diagnostic performance increased when ≥ 3 sentinel<br />
nodes were evaluated. By logistic regression model, tumoral and nodal<br />
responder, absent lymphovascular invasion (LVI), estrogen receptor<br />
(ER)-negativity, and HER2-positivity were significantly associated<br />
with node-negative disease after NCT. Area under the receiver<br />
operating characteristic curve increased from 0.890 to 0.949 when<br />
considering radiologic-pathologic factors and FNR was the lowest<br />
value of 14.3% in 46 patients with tumoral responder, absent LVI,<br />
and ER-negative tumor.<br />
Conclusions: SLNB was technically feasible but solely showed<br />
higher FNR in this study. Improved diagnostic performance of SLNB<br />
combined with radiologic-pathologic characteristics suggests possible<br />
clinical value of SLNB after NCT in highly selected patients with<br />
node metastasis at diagnosis.<br />
P1-01-24<br />
Which combinations are helpful to predict axillary lymph node<br />
metastasis in T1 breast cancer with ultrasonography and contrastenhanced<br />
MRI and contrast-enhanced 18F-FDG PET-CT?<br />
Hwang SO, Park HY, Jung JH, Kim WW, Lee YH, Lee JJ, Choi HH,<br />
Hwangbo SM. Kyungpook National University School of Medicine,<br />
Daegu, Korea; Hyosung Hospital, Daegu, Korea<br />
Backgrounds: Axillary lymph node(ALN) status has been important<br />
factor of treatment and prognosis for patients with breast cancer. Even<br />
though the better ultrasonographic instruments have been developed,<br />
it is still difficult to predict axillary lymh node metastasis (ALNM)<br />
with only ultrasonography(US) in T1 breast cancers which most of<br />
newly diagnosed breast cancers are recently since T1 breast cancers<br />
have low rate and less tumor burden of ALNM. This study evaluated<br />
the accuracy of prediction of ALNM in T1 breast cancer with US,<br />
contrast-enhanced MRI (cMRI) and contrast-enhanced 18F-FDG<br />
PET/CT (cPET/CT) and found out adequate combinations of these<br />
modalities.<br />
Method: Retrospectively, we reviewed 351 breast cancer patients with<br />
tumors(T1) ≤2cm in size between January 2008 and December 2011<br />
who were preoperatively examined with US, cMRI, and cPET/CT and<br />
underwent pathologic evaluation of axillary lymph nodes acquired<br />
by sentinel lymph node biopsy or axillary dissection.<br />
www.aacrjournals.org 157s<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Clinical characteristics(n=351)<br />
Character-<br />
Character-<br />
Character-<br />
Charactern(%)<br />
n(%)<br />
n(%)<br />
n(%)<br />
istics<br />
istics<br />
istics<br />
istics<br />
Age(yrs) Surgery T stage Histology<br />
Mean(range) 51.3±10.2 <strong>Breast</strong><br />
(25∼79)<br />
1mi 10(2.8) IDC 319(90.9)<br />
≤40 52(14.8) BCS 231(65.8) 1a 17(4.8) ILC 15(4.3)<br />
>40 299(85.2) MRM 120(34.2) 1b 53(15.1) mucinous 8(2.3)<br />
Sex Axilla 1c 271(77.2) others 9(2.5)<br />
Female 349(99.4) SLNB 266(75.8) N stage Grade<br />
Male 2(0.6) SLNB+ALND 73(20.8) 0 257(73.2) 1 91(25.9)<br />
Palpability of ALN ALND 12(3.4) 1mi 8(2.3) 2 170(48.4)<br />
Yes 8(2.3) 1 68(19.4) 3 79(22.5)<br />
No 343(97.7) 2 15(4.3)<br />
3 3(0.9)<br />
ALN:axillary lymph node;BCS:breast conserving surgery;MRM:modified radical<br />
mastectomy;SLNB:sentinel lymph node biopsy;ALND:axillary lymph node dissection; IDC:invasive<br />
ductal carcinoma, NOS;ILC:invasive lobular carcinoma<br />
Prediction of Axillary lymph node metastasis by image studies<br />
Sensitivity Specificity PPV NPV Accuracy<br />
USG 0.457 0.887 0.597 0.817 0.772<br />
cMRI 0.489 0.887 0.613 0.826 0.780<br />
cPET/CT 0.447 0.942 0.737 0.823 0.809<br />
Used<br />
modalities<br />
≥1 0.563 0.809 0.520 0.835 0.744<br />
≥2 0.478 0.914 0.671 0.827 0.798<br />
≥3 0.351 0.992 0.943 0.807 0.821<br />
USG&cMRI 0.426 0.934 0.702 0.816 0.798<br />
USG&cPET/<br />
CT<br />
0.362 0.977 0.850 0.807 0.812<br />
cMRI&cPET/<br />
CT<br />
0.394 0.988 0.925 0.817 0.829<br />
PPV:positive predictive value;NPV:negative predictive value<br />
Results: 94(26.8%) patients of 351 had ALNM. The sensitivity,<br />
specificity, positive predictive value(PPV), negative predictive value<br />
(NPV), and accuracy of ALNM with US were 0.457, 0.887, 0.597,<br />
0.817, 0.772, respectively. cMRI had similar results with US. The<br />
sensitivity, specificity, positive predictive value (PPV), negative<br />
predictive value (NPV), and accuracy of ALNM with cPET/CT were<br />
0.447, 0.942, 0.737, 0.823, 0.809, respectively. The sensitivity if any<br />
one or more modalities were suspicious was 0.563. The specificity<br />
if all modalities were suspicious was 0.992. The PPV if cMRI and<br />
cPET/CT were suspicious was highest than if other combinations<br />
were suspicious.<br />
Conclusion: US, cMRI, and cPET/CT are helpful in prediction of<br />
ALNM of T1 breast cancers. However, there are no definite modality<br />
and combination of modalites to predict ALNM of T1 breast cancers.<br />
P1-01-25<br />
Sentinel lymph node biopsy in breast cancer: The approach in day<br />
surgery under local anaesthesia for quality-of-life and significant<br />
cost reduction<br />
Ricci F, Capuano LG, Saralli E, Di Legge P, Violante A, Polistena A,<br />
Scala T, Pacchiarotti A, Cannas P, Cianni R, Fanelli G, Bellardini P,<br />
De Masi C. S.M. Goretti Hospital, Latina, Italy; LILT, Latina, Italy;<br />
S.M. Goretti, Latina, Italy<br />
Background: Sentinel lymph node biospy (SLNB) is widely used in<br />
the management of breast cancer patients without axillary metastases<br />
or inflammatory breast cancer (IBC).<br />
Methods: From Jan. 1 st 2006 through Dic. 31 st 2011 we performed<br />
302 SLNB at St. M. Goretti Hospital. Mammary carcinoma was<br />
diagnosed as malignant by aspiration citology and/or biospy. In all<br />
cases with positive citology or biospy, we performed quadrantectomy<br />
and SLNB at the same time. All patients underwent pre-operative<br />
lymphoscintigraphy with intradermal pericicatritial and/or periareola<br />
injection of 12-15 MBq 99Tc colloidal albumin particles 50-80 nm<br />
size range, in 0,2 ml saline solution. We never used vital blue dye.<br />
All patients underwent surgical treatment 3-12 h. later. We performed<br />
SLNB and quadrantectomy in day surgery (DS) and local anaesthesia<br />
(LA) with 2% of Carbocaine. Axillary incision was 3-4 cm. This study<br />
was approved by an ethics committee, was discussed with all patients<br />
and informed consent was obtained.<br />
Purpose of the study is to investigate the approach in DS under LA<br />
for quality of life and significant cost reduction.<br />
Results: Six patients underwent pre-operative lymphoscintigraphy<br />
the radiotracer did not show any sentinel lymph node (SLN), in five<br />
cases we performed axillary dissection (AD). In one case of young<br />
patient who had previously been treated with chemotherapy for<br />
non-Hodgkin’s lymphoma, negative positron emission tomography<br />
(PET), we performed quadrantectomy without AD. In three cases<br />
the axilla was positive. In four cases of multifocal (MF) and two of<br />
multicentric (MC) invasive breast cancer, the SLN was identified<br />
in axilla and SLNB was perfomed. SLNB in MF and MC tumors<br />
was similar to unifocal cancers. Only one case of MC cancer the<br />
SLN was positive. Six patients classified T4b according to AJCC,<br />
were treated with neoadjuvant chemotherapy (NC). The axilla was<br />
negative to ultrasound (US), PET and citology. After completion of<br />
NC, lymphatic mapping was able to identify SLN and we performed<br />
SLNB. In these patients SLN was negative. In two cases of male<br />
cancer the axilla was negative to clinical examination, in both cases<br />
SLN was positive for macrometastases. Six cases showed axillary<br />
isolated tumor cells (ITC). Eighteen micrometastases. Thirty-two<br />
macrometastases. In two case of negative SLN there was a positive<br />
second palpable lymph node. One case showed a double SLN in<br />
the axilla and internal mammary chain, only the internal mammary<br />
lymph node was positive.<br />
The SLN identification rate was 99%. After surgery we distributed a<br />
questionnaire to the patients about the acceptability of this approach.<br />
P1-01-26<br />
Procoagulant biomarkers may direct axillary nodal surgery<br />
Shaker H, Bundred NJ, Glassey E, Kirwan CC. University Hospital<br />
of South Manchester, Manchester, United Kingdom; University of<br />
Manchester, United Kingdom<br />
Background<br />
Preoperative accurate staging of the axilla (through identifying<br />
invasive breast cancers with subclinical nodal metastases) will reduce<br />
the need for repeat axillary surgery.<br />
Tissue factor (TF) is overexpressed in cancer and is shed into the<br />
circulation leading to activation of the thrombin (extrinsic clotting)<br />
pathway. D-dimer is a fibrin degradation product and reliable systemic<br />
marker of thrombin pathway activation. TF and d-dimer are raised in<br />
breast cancer and may act as biomarkers to identify invasive cancer<br />
patients with undiagnosed lymph node (LN) metastases requiring<br />
axillary nodal clearance.<br />
Methods<br />
Plasma d-dimer and TF were measured pre-operatively using ELISA<br />
in patients undergoing curative surgery and sentinel node biopsy<br />
(SNB) for invasive breast cancer (n=125). D-dimer was considered<br />
to be raised if it was above the clinically used upper limit of normal<br />
of 500ng/ml and if TF was above 200pg/ml. D-dimer and TF were<br />
correlated with the presence or absence of axillary metastases at<br />
sentinel node biopsy.<br />
Results<br />
Median age was 61 years (range 24-84). Mean invasive tumour size<br />
was 16.7 mm (range 1.6-70). One hundred and eleven (79%) invasive<br />
cancers were oestrogen receptor positive, 93 (67%) were progesterone<br />
receptor positive and 17(12%) were HER2 receptor positive.<br />
Pre-operative d-dimer was higher in LN positive (mean 599 ng/<br />
ml,95% CI 415-864, n=32) versus LN negative (454ng/ml, 95% CI<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
158s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
400-514, n=93, p=0.068) invasive cancer. TF was not significantly<br />
higher in LN positive cancer (vs LN negative), although TF did show<br />
weak correlation with d-dimer (r=0.2, p=0.03).<br />
Sixty eight patients (54%) had raised TF and 59 (47%) had raised<br />
d-dimer. On multivariate analysis (age, tumour size, invasive grade,<br />
ER status and presence of lymphovascular invasion as covariates) a<br />
raised pre-operative d-dimer combined with a raised pre-operative<br />
TF was a significant independent predictor of node positivity (odds<br />
ratio 6.43, CI 1.70 – 24.27, p=0.006). Markers of systemic thrombin<br />
pathway activity (i.e. a combination of plasma d-dimer and TF) had<br />
a sensitivity of 91%, specificity of 32%, positive predictive value of<br />
32% and negative predictive value of 92%.<br />
D-dimer >500ng/ml AND TF >200pg/ml<br />
No Yes<br />
Lymph node metastasis No 30 63 93<br />
Yes 3 29 32<br />
33 92 TOTAL<br />
Conclusion<br />
High levels of clotting activation are seen in breast cancer patients.<br />
Over 90% of patients with no axillary lymph node metastases had<br />
normal pre-operative levels of plasma TF and d-dimer. Combination<br />
of systemic markers of thrombin pathway activation may help predict<br />
axillary nodal involvement.<br />
The role of thrombin pathway activation in breast cancer metastasis<br />
is under ongoing investigation.<br />
P1-01-27<br />
Novel diagnostic procedure of metastasis to the sentinel lymph<br />
node of breast cancer using a semi-dry dot-blot method<br />
Otsubo R, Oikawa M, Shibata K, Hirakawa H, Yano H, Matsumoto<br />
M, Hatachi T, Nakao K, Hayashi T, Abe K, Kinoshita N, Nakashima<br />
M, Taniguchi H, Omagari T, Itoyanagi N, Nagayasu T. Nagasaki<br />
University Hospital, Nagasaki, Japan; The Japanese Red Cross<br />
Nagasaki Genbaku Hospital, Nagasaki, Japan; Aiyuukai Memorial<br />
Hospital, Chiba, Japan; Nagasaki University Atomic Bomb Disease<br />
Institute, Nagasaki, Japan; St. Francis Hospital, Nagasaki, Japan<br />
Background: Sentinel lymph node (SLN) biopsy is a common<br />
surgical procedure. However, novel diagnostic modalities are<br />
required because of a shortage of pathology specialists in Japan<br />
and discordance between the intraoperative and final pathological<br />
diagnosis of SLN metastasis. Efficient methods that use molecular<br />
markers for detecting SLN metastasis, such as one-step nucleic acid<br />
amplification, are commercially available, but special equipment<br />
(e.g., thermal cycler) is costly and the problem of false-negatives<br />
for CK19 non-expressing cells remains unresolved. Recently, we<br />
developed an easy, quick and cost-effective method for detection of<br />
cancer cells in lymph nodes by applying dot-blot analysis technology,<br />
called the “semi-dry dot-blot method (SDB method)”. The SDB<br />
method visualizes the presence of cancer cells with washing of<br />
sectioned lymph nodes by anti-pancytokeratin antibody (AE1/AE3)<br />
and chromogen on a dot-blot membrane. This method can detect 0.01<br />
mg/mL protein extracted from cancer tissue and 20 suspension cells<br />
(MCF-7) in approximately 20 minutes. The current study evaluated<br />
the efficacy of our SDB method in the diagnosis of SLN metastasis<br />
in breast cancer.<br />
Methods: (I) One hundred eighty dissected lymph nodes from 29<br />
cases, including breast, lung, gastric and colorectal cancer, were<br />
analyzed. Each lymph node was sliced at the maximum diameter<br />
and washed by phosphate-buffered saline (PBS), and this lavage<br />
fluid (PBS) was used for diagnosis of LN metastasis by the SDB<br />
method, and washed lymph node was sent to pathological section<br />
for pathological diagnosis. The sensitivity, specificity and accuracy<br />
of the SDB method were determined to compare with the final<br />
pathology report.<br />
(II) A multicenter prospective clinical trial was conducted, where 132<br />
SLN samples from 78 cases of clinically node-negative breast cancer<br />
were analyzed. Each SLN was sliced at 2-mm intervals and washed by<br />
PBS. Lavage fluid of sliced SLNs was used for the diagnosis of SLN<br />
metastasis by the SDB method in a blinded manner. The sensitivity,<br />
specificity, accuracy and the time required for the SDB method were<br />
determined and compared with the intra-operative pathology report.<br />
Results: (I) Lymph node metastasis was detected in 35 lymph nodes<br />
(19.4%). Comparison of the results between the final pathology and<br />
the SDB method showed complete concordance (accuracy: 100%).<br />
(II) Of the 132 lymph nodes eligible for analysis, 13 (10.0%) were<br />
assessed as positive and 114 as negative by the SDB method and intraoperative<br />
pathological examination, with an accuracy of 96.2%. All<br />
pathologically positive nodes, which included one micro metastasis,<br />
were also detected by the SDB method; (sensitivity: 100%). One<br />
hundred fourteen of the 119 pathologically negative nodes were<br />
assessed as negative with the SDB method (specificity: 95.8%). The<br />
mean required times of 16 cases for intra-operative pathological<br />
diagnosis and simultaneous SDB method were 43.5 and 42.2 minutes,<br />
respectively.<br />
Conclusions: The SDB method is simple, fast, accurate and costeffective<br />
for the intra-operative diagnosis of SLN metastasis.<br />
Because there is no loss of lymph node tissue, the SDB method and<br />
pathological investigation can be performed simultaneously.<br />
P1-01-28<br />
What is the actual impact of micrometastases in sentinel lymph<br />
nodes in regards to global survival and disease free survival<br />
Barbosa EM, Araujo Neto JT, Filho EC, Infante KP, Felzener MM,<br />
Matielle CR, Modesto MG, Basso R, Goes JCS. Instituto Brasileiro<br />
de Controle do <strong>Cancer</strong> - IBCC, Sao Paulo, Brazil<br />
OBJECTIVE: Assess the clinical relevance of micro metastasis<br />
in sentinel lymph nodes in the overall survival and disease free<br />
survival of 1,211 patients undergoing sentinel lymph node biopsy.<br />
METHODS: Retrospective cohort study including 1,211 patients<br />
undergoing consecutive SLB from 1998 to 2010. SLB were performed<br />
in patients with invasive carcinoma of the breast with clinically<br />
negative axilla. Age, tumor size, and histologic grades, estrogen and<br />
progesterone receptors expression, HER-2, lymphovascular invasion<br />
and size of metastases in lymph nodes were assessed. Tumor sizes<br />
were divided according to pathologic staging into pT1(< 2,0mm)<br />
and pT2(>2,0mm). Lymph nodes were classified as negative (pN0),<br />
positive with micro metastases with diameter ranging from 0,21mm<br />
to 2,0mm(pN1mi) and positive with macro metastases with diameter<br />
greater than 2,0mm(pN1). Statistical analyses were performed by<br />
the Likelihood ratio test or Chi-square test for insufficient samples<br />
between macro metastases and micro metastases in SLB. Time was<br />
considered in months and the overall follow-up time was 125 months<br />
and mean time was 65 months. Local regional and distant recurrences<br />
were considered as events for disease free survival and Kaplan-<br />
Meier survival functions were constructed, testing time between<br />
metastases sizes in SLB using the Log-rank test, with a significance<br />
level of 5%. RESULTS: Of the studied variables, lymphovascular<br />
invasion(p=0,068) and local regional and distant metastases(p=0,002)<br />
had a statistically significant association with overall survival. Tumor<br />
size(p=0,016); lymph vascular invasion(p=0,002) and metastases<br />
types in sentinel lymph node(p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
lymph node, the following were statistically significant: age(p=0,004),<br />
tumor size(p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
identified. While there may be a trend towards not excising some of<br />
these high-risk lesions, we believe that a core biopsy demonstrating<br />
FEA still warrants surgical excision.<br />
P1-02-02<br />
Receptor discordance in breast cancer recurrence: Is re-biopsy<br />
a necessity?<br />
Fujita T, Sawaki M, Hattori M, Kondo N, Horio A, Ushio A, Gondo<br />
N, Hiroji I. Aichi <strong>Cancer</strong> Center Hospital, Nagoya, Japan<br />
Background: Decision making on systematic treatment of patients<br />
with metastatic breast cancer is based on features like estrogen<br />
receptor (ER), progesterone receptor (PgR), and HER2 status assessed<br />
on the primary tumor. Recent prospective studies have investigated<br />
discordance in receptor status between the primary and metastatic<br />
tumor. We evaluated the discordance of receptor status between the<br />
primary and metastatic tumor and assessed the impact of re-biopsy<br />
on patient management.<br />
Methods: In breast cancer patients who underwent surgical resection<br />
of primary tumor and re-biopsy of metastatic tumor at Aichi <strong>Cancer</strong><br />
Center hospital, we examined the discordance of ER status, PgR<br />
status, and HER2 status between the primary and metastatic tumor. For<br />
sampling of metastases, core needle biopsy (CNB), trans-bronchial<br />
lung biopsy (TBLB), or surgical resection was performed. And fineneedle<br />
aspiration biopsy was not used.<br />
The ER and PgR status were assessed using Allreds scoring system<br />
by IHC. These statuses were categorized as positive when the total<br />
score was more than two. HER2 expression status was tested by IHC<br />
and FISH. HER2 3+ by IHC, or 2+ and FISH positive were judged<br />
as HER2 positive.<br />
Results: 48 patients underwent re-biopsy from 2003 to 2012. Twentyeight<br />
were loco-regional (local: 25, Supraclavicular: 2, Axilla: 1) and<br />
21 were distant (Lung: 14, Liver: 6, Bone: 1). Discordance in ER,<br />
PgR, or HER2 between the primary and metastatic tumor were 6.2%<br />
(3/48), 16.7% (8/48), and 4.2% (2/48), respectively. One patient had<br />
discordance on re-biopsy with initial triple negative primary tumor<br />
(1/5, 20%). 11/48 patients (22.9%) changed the molecular subtype<br />
(Group A), and 37/48 patients (77.1%) did not change (Group B).<br />
Time to recurrence (TTR) was significantly longer in Group A than<br />
Group B (82.3 months vs 51.2 months, p=0.04). No significant<br />
difference in re-biopsy techniques (CNB and TBLB vs surgical<br />
resection), metastatic lesions (loco-regional vs distant), and adjuvant<br />
therapy were observed between Group A and Group B.<br />
Conclusions: Our results show the low level of discordance for ER<br />
and HER2 between the primary and metastatic tumor. But re-biopsy<br />
should be considered in the patients with long TTR, since it is likely<br />
to impact treatment choice. Further study is needed to determine the<br />
value of re-biopsy.<br />
P1-03-01<br />
Evidence for the Warburg effect in mammary atypia from highrisk<br />
African American women.<br />
Seewaldt V, Hoffman A, Ibarra-Drendall C. Duke University, Durham,<br />
NC<br />
Background: Aggressive cancers are known to consume glucose<br />
avidly and produce lactic acid (rather than fully metabolize glucose<br />
via the Tricarboxylic Acid (TCA) cycle). This shift toward lactate<br />
production, even in the presence of adequate oxygen, is termed the<br />
Warburg effect. The Warburg effect is thought to be a late event in<br />
breast cancer, however, our studies in high-risk women provide<br />
evidence that the Warburg effect occurs during cancer initiation.<br />
This is an important observation as glucose-signaling can be readily<br />
targeted for breast cancer prevention with minimal toxicity. Here we<br />
investigated the role of the Warburg effect in breast cancer initiation<br />
in young high-risk women.<br />
Methods and Results: Similar to fluorodeoxyglucose, 2-(N-(7-<br />
nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG)<br />
is a fluorescent glucose analog that can be used to track glucose uptake<br />
and glycolysis. 2-NBDG spectroscopy provides a means to track<br />
glucose metabolism in live mammary epithelial cells from high-risk<br />
women. We used 2-NBDG spectroscopy to measure glucose uptake<br />
in ER- breast cancer and live atypical mammary epithelial cells<br />
from high-risk premenopausal women. We observe that both triplenegative<br />
breast cancer and a subset of atypia exhibits accumulation<br />
of 2-NBDG.<br />
There is growing recognition that phosphoprotein signaling networks<br />
(rather than single genes) play a key role in breast cancer initiation<br />
and progression. Our team used Reverse Phase Proteomic Microarray<br />
(RPPM) profiling to test for activation of phosphoprotein signaling<br />
networks in atypical RPFNA cytology from high-risk premenopausal<br />
women in our cohort. RPFNA were obtained from two independent<br />
sets of 39 and 38 high-risk premenopausal women; 45% of these<br />
women were African American. The signaling network most highly<br />
expressed in precancerous cells contained activated signaling proteins<br />
associated with the Warburg effect (AKT/mTOR/PI3K), insulin<br />
signaling (pACC, IRS1) and epithelial to mesenchymal transition<br />
(EMT) IL6/Stat3/vimentin.<br />
Conclusions: This is the first evidence that abnormal glucose uptake<br />
and the Warburg effect occurs during breast cancer initiation in<br />
high-risk premenopausal women. These studies demonstrate our<br />
ability to identify abnormal glucose and activated signaling networks<br />
associated with the Warbug effect in atypical mammary cells from<br />
high-risk women.<br />
P1-03-02<br />
“Normal” tissue adjacent to breast cancer is not normal<br />
Clare SE, Pardo I, Mathieson T, Lillemoe HA, Blosser RJ, Choi M,<br />
Sauder CAM, Doxey DK, Badve S, Storniolo AMV, Atale R, Radovich<br />
M. Indiana University School of Medicine, Indianapolis, IN; Susan<br />
G. Komen for the Cure Tissue Bank at the IU Simon <strong>Cancer</strong> Center,<br />
Indiana University School of Medicine, Indianapolis, IN<br />
Background: Gene expression data from pancreatic cancer,<br />
histologically normal tissue adjacent to the cancer and normal<br />
pancreas reveals that adjacent normal has already acquired a number<br />
of transcriptional alterations and is not, therefore, an appropriate<br />
baseline for comparison with cancers. (Gadaleta et al., 2011) The<br />
purpose of this study was to determine if this is also the case for<br />
breast cancer and, if so, to identify the differences in gene expression<br />
between adjacent normal and normal breast.<br />
Methods: RNA-Seq data from breast cancer and adjacent normal was<br />
downloaded from the TCGA (The <strong>Cancer</strong> Genome Atlas) data portal.<br />
The epithelia from 20 frozen tissue cores from healthy premenopausal<br />
donors to the Susan G. Komen for the the Cure® Tissue Bank at the<br />
IU Simon <strong>Cancer</strong> Center were microdissected and the RNA isolated.<br />
RNA-seqeuncing was carried out using the Life Technologies SOLiD<br />
Platform. RPKM gene expression values from TCGA and sequencing<br />
of the Komen normal tissues were merged, quantile normalized, and<br />
batch effect corrected. Normalization and differential gene expression<br />
was performed using Partek Genomics Suite.<br />
Results: Principal component analysis (PCA) reveals complete<br />
separation between adjacent normal and healthy normal breast tissue.<br />
Setting a maximum FDR (false discover rate) of 5%, 2239 genes are<br />
www.aacrjournals.org 161s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
differentially expressed between adjacent normal and healthy normal.<br />
Ingenuity pathway analysis reveals that the Fos, Jun and TGFbeta<br />
pathways are active in the adjacent normal.<br />
Conclusions: Tissue adjacent to a primary breast cancer is not normal<br />
when using healthy breast tissue as a comparator. As RNA-Seq data<br />
is digital, it is possible to quantify the changes in gene expression<br />
starting from healthy normal to normal adjacent to tumor to tumor.<br />
Increasing and decreasing gene expression values provide clues to the<br />
fundamental molecular changes occurring in histologically normal<br />
appearing adjacent tissue. The differences in gene expression we have<br />
identified are some of the earliest changes in breast carcinogenesis<br />
and provide insight into the etiology of this disease and, potentially,<br />
its prevention.<br />
P1-03-03<br />
milk deposition in women’s mammary duct has been a potential<br />
risk factor of breast tumor<br />
Xu Z, Gu Y, Gong G, Zhang Y. <strong>Breast</strong> Disease Institution of Jilin<br />
Province, Changchun, Jilin, China; Spinal Disease Institution of<br />
Jilin Province, Changchun, Jilin, China<br />
Background: According to the pathology and general resection<br />
specimens, so many patients have breast tumors together with<br />
deposited milk. Therefore, we performed this retrospective study to<br />
determine the distribution and characteristics of breast diseases in<br />
women undergoing mammary ductoscopy and explore the clinical<br />
values and implications of mammary ductoscopy in the management<br />
of the breast diseases.<br />
Materials & Methods: Total of 10,082 women(20,082 breasts) with<br />
a mean age of 39.2 years old (ranging from 12 to 84 years old)<br />
underwent mammary ductoscopy from 2002 to 2011.We studied<br />
NSND in contrast with SND duct, specially focused on the situation<br />
of duct with intraductal mass. Comparing with the pathology, we<br />
studied the relationship between duct milk deposition and epithelial<br />
hyperplasia.<br />
Results:<br />
Table 1. disease distribution under mammary ductoscopy of 20,018 ductoscopic investigations<br />
(cases)<br />
FDS Reports NSND SND cases n(%)<br />
Intraductal mass 17 1414 1,431(7.15)<br />
Ductal milk deposition 3981 4604 8,585(42.89)<br />
Duct occlusion inflammation 6613 0 6,613(33.04)<br />
Duct inflammation with dilation 970 53 1,023(5.11)<br />
Duct dilation 454 1836 2,290(11.44)<br />
Negative results 76 0 76(0.4)<br />
From this study we concluded that duct milk deposition was a<br />
common disease in 25-59 years old women, it occupied 42.89%<br />
cases of the mammary ductal disease and almost 46% are NSND.<br />
The character of deposited milk became solid from liquid with the<br />
age growing up. Duct milk deposition 476/1431(33.26%)was mostly<br />
associated with intraductal masses(total 1431 cases), followed by<br />
duct dilatation 517/1431(36.13%). Pathology of patients diagnosed<br />
by FDS for duct milk deposition are epithelial hyperplasia(100%),<br />
adenosis(86.5%), chronic inflammation(8.8%), metaplasia(16.9),<br />
florid hyperplasia(10.8%), tumor-like hyperplasia (57.2%), intraductal<br />
tumor or fibroadenoma (27.8%), dysplasia (3.0%), breast cancer<br />
(11.7%).<br />
Discussion: Diagnosis of duct milk deposition, which may not<br />
necessarily presented by nipple discharge, is the most common finding<br />
and associated with proliferation and thus intraductal mass, etc. we<br />
should noticed 30-50 years old women groups,cause they have have<br />
stopped breast-feeding for years but still had yellow or brown, liquid<br />
or solid milk-like things in their lactiferous ducts. We predict duct<br />
milk deposition may be related with breast carcinogenesis. It is a kind<br />
of long time mechanical stimulation in the duct, both the physicochemical<br />
properties and the acid-alkaline environment had changes by<br />
years. Still, the deposited milk would be a best medium for microbial<br />
and virus , which would cause the genesis of hyperplasia even breast<br />
cancer. Therefore, we should go on the research of deposited milk<br />
and the changes of the microenvironment of the duct to find the<br />
pathogenesis of breast disease.<br />
P1-04-01<br />
Loss of Notch4 reduces mammary tumorigenesis by MYC and<br />
activated KRAS<br />
Rodriguez EM, Bishop JM. G. W. Hooper Research Foundation,<br />
University of California, <strong>San</strong> Francisco, CA<br />
Over-expression of Notch receptors and aberrant Notch signaling<br />
have been reported in both preinvasive ductal carcinoma in situ<br />
and invasive breast cancer. The Notch 4 receptor, in particular, is<br />
preferentially activated in human breast cancer stem cell-enriched<br />
populations, and inhibition of Notch 4 reduces tumor formation of<br />
human breast cancer cells in xenograft models (Harrison, 2010).<br />
Myc gene amplification has also been found in about 15% of breast<br />
tumors, and 22%-35% of tumors exhibit overexpression of Myc at the<br />
transcriptional level. Transgenic mice over-expressing MYC develop<br />
invasive adenocarcinomas and preferentially harbor secondary<br />
activating mutations in KRas. We examined whether Notch receptors<br />
were activated in mouse mammary tumors over-expressing MYC and<br />
activated KRAS (KRASV12) and found Notch 4 to be significantly<br />
activated in these tumors compared to normal mammary tissue.<br />
Furthermore, Notch 4 was localized to the nucleus in the tumors<br />
over-expressing MYC and KRASV12, but not in mammary glands<br />
over-expressing MYC or activated KRASV12 alone. To examine<br />
the requirement of Notch4 in mammary tumorigenesis by MYC and<br />
KRASV12, we transplanted mammary epithelial cells isolated from<br />
Notch4 knockout mice and wild-type mice that have been transduced<br />
with MYC and KRASV12 into the mammary glands of syngeneic<br />
mice. There was a significant reduction in the onset of tumorigenesis<br />
in mammary glands that had been transplanted with mammary<br />
epithelial cells lacking Notch4. These findings suggest that Notch4<br />
is important in mammary tumorigenesis induced by cooperation of<br />
MYC and activated RAS. We are currently examining the relevance<br />
of Nocth4 activation in human breast cancers that over-express MYC<br />
and the mechanism by which Notch4 promotes tumorigenesis by<br />
Myc and activated RAS.<br />
P1-04-02<br />
The role of the mTORC1/S6K1 signaling pathway in ER-positive<br />
breast cancer.<br />
Holz MK, Unger HA, Sedletcaia A. Stern College for Women of<br />
Yeshiva University; Albert Einstein College of Medicine<br />
The mammalian target of rapamycin complex 1 (mTORC1) is a central<br />
signaling node in mediating cellular responses to mitogens, hormones<br />
and nutrients. The 40S ribosomal S6 kinase 1 (S6K1) is a conserved<br />
serine/threonine protein kinase that belongs to the AGC family of<br />
protein kinases, which also includes Akt, RSK and many others.<br />
S6K1 is the principal kinase effector downstream mTORC1. S6K1 is<br />
sensitive to a wide range of signaling inputs, including growth factors,<br />
amino acids, energy levels, and hypoxia. S6K1 relays these signals to<br />
regulate a growing list of substrates and interacting proteins in control<br />
of oncogenic processes, such as cell growth and proliferation, cell<br />
survival and apoptosis, and cell migration and invasion.<br />
Growing evidence indicates that there exists a close interaction<br />
between the mTORC1/S6K1 pathway and estrogen receptor (ER)<br />
signaling. Notably, endocrine resistance is often associated with<br />
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ligand-independent activation of ERα signaling due to hyperactivation<br />
of the mTORC1 signaling pathway, and can be reversed by the<br />
mTORC1 inhibitor everolimus in vitro.<br />
Several lines of evidence suggest an important role for S6K1 in<br />
ER-positive breast cancer. We demonstrated that S6K1 directly<br />
phosphorylates ERα on Ser167, leading to activation of its<br />
transcriptional activity. While the MAPK-regulated p90 RSK also<br />
contributes to phosphorylation of this site, its contribution is early and<br />
transient, while the phosphorylation of Ser167 by S6K1 is prolonged<br />
and sustained. Intriguingly, we also found that S6K1 expression is<br />
estrogenically regulated. This regulation involves the transcription<br />
factor GATA-3 and others. Thus it appears that S6K1 expression<br />
is maintained in two modes: a basal level of expression, typical of<br />
normal cells, and an estrogen/ERα-dependent specific upregulation.<br />
Therefore, there exists a feed-forward regulatory loop whereby S6K1<br />
activates ERα transcriptional activity, leading to increased expression<br />
of S6K1. This finding is of great interest since it not only sheds light<br />
on the mode of transcriptional regulation of S6K1 expression, but<br />
may help understand the role of S6K1 overexpression and activation<br />
in the development and progression of breast cancer.<br />
Therefore, hyperactivation of mTORC1/S6K1 signaling may be<br />
closely related to ER-positive status in breast cancer, and may be<br />
utilized as a marker for prognosis and a therapeutic target.<br />
P1-04-03<br />
Knocking down Suppressor of Cytokine Signaling 7 in breast<br />
cancer: The role in Insulin-like Growth Factor - I / Phospholipase<br />
Cγ-1 signaling<br />
Sasi W, Ye L, Jiang WG, Mokbel K, Sharma A. St George’s Hospital<br />
Medical School, University of London, United Kingdom; Cardiff<br />
University School of Medicine, Cardiff, Wales, United Kingdom;<br />
The London <strong>Breast</strong> Institute, The Princess Grace Hospital, London,<br />
United Kingdom<br />
BACKGROUND:<br />
Suppressor of Cytokine Signaling 7 (SOCS7) is a member of the<br />
SOCS family and is known to interact with Phospholipase Cγ-1<br />
(PLCγ-1), one of the Insulin like Growth Factor - I (IGF-I) receptor<br />
downstream molecules. In the present study, we sought to examine the<br />
effect of knocking down SOCS7 gene on breast cancer cells growth<br />
and migration and to elucidate whether this has involved IGF-I —<br />
PLCγ-1 signaling using the PLCγ-1 blocker U73122.<br />
METHODS:<br />
Suitable breast cancer cells (MCF7 and MDA-MB-231) were<br />
transfected with anti-SOCS7 ribozymal transgene, to create sublines<br />
with SOCS7 knockdown that was verified by RT-PCR. The growth<br />
and migration of the cells were evaluated in the presence or absence of<br />
IGF-I and PLCγ-1 inhibitor using in vitro growth assay and Electrical<br />
Cell Impedance Sensing (ECIS) migration assay.<br />
RESULTS:<br />
MCF7 ∆SOCS7 and MDA-MB-231 ∆SOCS7 (SOCS7 knockdown) were<br />
constructed. Both sublines showed a higher rate of growth compared<br />
to control cells with and without IGF-I stimulation. U73122 treatment<br />
did not appear to change this growth outcome. Using ECIS migration<br />
assay, it was shown that knocking down SOCS7 had a significant<br />
positive effect on the migration of MCF7 and MDA-MB-231<br />
cells, and that both IGF-I treatment and SOCS7 knockdown had a<br />
synergistic positive influence on their migration (p < 0.05). We further<br />
demonstrated that the impact of U73122 on the IGF-I migratory<br />
effect was dependent upon SOCS7 knockdown as it has significantly<br />
blocked the stimulatory effect of IGF-I on MCF7 ∆SOCS7 and MDA-MB-<br />
231 ∆SOCS7 migration but not that of the control cells. While SOCS7 has<br />
acted to control the IGF-I effect, it appeared to cancel the inhibitory<br />
function of U73122, indicating a specific anti - PLCγ-1 role for SOCS7<br />
in IGF-I induced breast cancer cellular migration.<br />
CONCLUSION<br />
SOCS7 loss resulted in increased growth and migration of breast<br />
cancer cells and this had a synergistic effect on their response to IGF-I.<br />
This role could be related to its interaction with PLCγ-1 during the<br />
cellular migration but not the growth. It may be possible that SOCS7<br />
acts through different mechanism to control the cellular growth.<br />
P1-04-04<br />
KSR1 is involved in functional interaction between p53 and<br />
BRCA1 and is an independent predictor of overall survival in<br />
breast cancer<br />
Zhang H, Lombardo Y, Filipovic A, Periyasamy M, Coombes RC,<br />
Stebbing J, Giamas G. Imperial College London, United Kingdom<br />
Background: Our recent human kinome screening to identify new<br />
regulators of estrogen receptor α (ERα) suggested an important role<br />
of kinase suppressor of ras 1 (KSR1) in breast cancer. KSR1 was<br />
originally identified as a positive regulator interacting with both RAS<br />
and RAF in the mitogen-activated protein kinase (MAPK) pathway.<br />
Recent studies have suggested that KSR1 may have dual functions as<br />
a scaffolding protein and also a protein kinase. Although KSR1 has<br />
been implicated in Ras-dependent cancers, its clinical significance<br />
and function in breast cancer have not been elucidated.<br />
Methods: The clinical significance of KSR1 was assessed by<br />
analyzing its expression in breast cancer tissue microarrays (TMAs,<br />
n=1000) by immunohistochemistry. Pearson chi 2 and Fisher’s Exact<br />
Test were used to correlate the expression levels with various tumor<br />
biomarkers; Kaplan Meier analyses were used to investigate impact<br />
on disease-free (DFS) and overall survival (OS). Multivariate Coxproportional<br />
hazards analysis was also performed to evaluate the<br />
significant of KSR1 as an independent factor in breast cancer-specific<br />
survival (BCSS) and disease-free interval (DFI). The expression levels<br />
of KSR1 in breast cancer cell lines were measured by RT-qPCR and<br />
western blotting. A KSR1 stable over-expression breast cancer cell<br />
line (MCF7-KSR1) was generated to study its effect on growth and<br />
colony formation by 3D matrigel assay and soft agar assay in vitro.<br />
Furthermore, MCF7-KSR1 stable cells were also used in nude mice<br />
xenograft model in vivo. Luciferase reporter assay was employed to<br />
examine the effect of KSR1 on p53 transcriptional activity. Further<br />
immunofluorescence staining, western blotting and reporter assays<br />
were performed to elucidate the interaction between KSR1, BRCA1<br />
and p53.<br />
Results: KSR1 was expressed with low (60%) and high levels (40%)<br />
in breast cancer patients. High expression correlated significantly<br />
with longer DFS (p=0.014) and longer OS (p=0.012) in more than<br />
20 yrs follow-up. Interestingly, KSR1 was positively associated with<br />
BRCA1 (p=0.002) and reversely with p53 (p=0.038). High KSR1<br />
levels were a significant predictor of longer breast cancer-specific<br />
survival BCSS (p = 0.001) and longer disease free interval DFI (p =<br />
0.002) independent of tumour stage, grade and size. RT-qPCR and<br />
western blotting demonstrated that KSR1 is ubiquitously expressed<br />
in breast cancer cell lines. In vitro 3D matrigel and soft agar assay<br />
showed that MCF7-KSR1 cells had a significant decreased number<br />
of colonies and formed smaller size colonies compared to MCF7-<br />
vector cells. Furthermore, over-expression of KSR1 (MCF7-KSR1)<br />
significantly suppressed the growth of breast cancer xenografts in<br />
nude mice. Finally, KSR1 was involved in the functional interaction<br />
between BRCA1 and p53 and elevated KSR1 potentially resulted<br />
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in up-regulated BRCA1. KSR1 also inhibited p53-dependent<br />
transcriptional activity through suppression of p53 acetylation and<br />
promotion of p53 neddylation.<br />
Conclusion: KSR1 is an independent prognostic factor in breast<br />
cancer and high KSR1 expression correlates with longer DFS and<br />
OS. Furthermore, it is potential that KSR1 is important in tumour<br />
suppression by its involvement in functional feedback regulation of<br />
BRCA1 and p53.<br />
P1-04-05<br />
Role of the Rb and p53 Tumor Suppressor Pathways in Mammary<br />
Tumorigenesis<br />
Jones RA, Liu JC, Zhe J, Schimmer AA, Eldad Z. University Health<br />
Network, Toronto, ON, Canada<br />
The retinoblastoma (Rb) and p53 tumor suppressor pathways are<br />
frequently altered in human malignancies including breast cancer. To<br />
investigate the role of these pathways in mammary tumorigenesis, we<br />
crossed mice expressing Cre recombinase in the mammary epithelium<br />
(MMTV-Cre) with mice harboring Rb and p53 floxed alleles to<br />
generate MMTV-Cre:Rb f/f :p53 f/f mutant mice. Combined somatic loss<br />
of Rb and p53 led to the formation of aggressive triple-negative tumors<br />
(ER - , PR - , HER2 - ) that often displayed features of an epithelial to<br />
mesenchymal transition (EMT) including sarcomatoid differentiation<br />
and high expression of the mesenchymal marker N-Cadherin.<br />
Molecular profiling revealed Rb/p53 deficient tumors shared similar<br />
gene expression profiles with mouse and human claudin-low breast<br />
cancers. Interstingly, limiting dilution transplantation analysis also<br />
suggests that Rb/p53 deficient claudin-low tumors are enriched for<br />
tumor-initiating cells (TICs).<br />
To investigate the cellular origin of claudin-low tumors, the Rb f/f and<br />
p53 f/f alleles were deleted within the luminal and basal compartments<br />
of the mammary gland using a Cre-expressing adenovirus (Ad-Cre)<br />
and CD24-CD49f-based FACS analysis. The different cellular<br />
fractions were then transplanted into the cleared mammary fat pad<br />
of recipient mice which are currently being monitored for tumor<br />
development.<br />
Finally, primary cell lines isolated from Rb/p53 deficient mammary<br />
tumors were used in conjunction with high-throughput chemical and<br />
genetic screens to identify new therapeutic targets. A primary screen<br />
of 260 kinase inhibitors and 312 FDA-approved off-patent drugs has<br />
identified novel candidates and a genome wide negative selection<br />
(‘drop-out’) screen is currently in progress.<br />
Ultimately, the results of this research will provide important insight<br />
into the biology of triple-negative breast cancer and will lead to the<br />
identification of novel therapeutic targets for the treatment of patients<br />
living with this disease.<br />
P1-04-06<br />
Insertional mutagenesis identifies HACE1 as a HER2/Neu<br />
Cooperating <strong>Breast</strong> <strong>Cancer</strong> Tumor Suppressor Gene<br />
Goka E, Miller P, Baker K, Stark G, Lippman ME. University of Miami<br />
Miller School of Medicine, Miami, FL; Cleveland Clinic, Cleveland,<br />
OH; University of Miami, FL<br />
The development of human breast cancer is a multi-step process<br />
leading from normal epithelium to fully transformed breast cancer.<br />
Early genetic changes result in hyperplasias which evolves into<br />
ductal carcinoma in situ (DCIS) and culminates as invasive ductal<br />
carcinoma. The transition from DCIS to invasive disease has been<br />
implicated as the key transition in breast cancer progression. Specific<br />
genomic, transcriptomic, and proteomic alterations responsible for<br />
this transition process have yet to been elucidated.<br />
HER2/Neu, a member of the EGFR family of receptor tyrosine<br />
kinases, is associated with poor clinical outcome. HER2/Neu<br />
overexpression/amplification is commonly seen (50-60%) in noninvasive<br />
lesions but is significantly less common (20-30%) in invasive<br />
and metastatic breast carcinoma. This indicates that HER2/Neu gives<br />
normal epithelium a proliferative advantage but additional genetic<br />
alterations are required for full malignant transformation. This idea<br />
is supported by the fact that transgenic mice that overexpress HER2/<br />
Neu develop spontaneous mammary tumors but only after a prolonged<br />
latency period.<br />
Recent forward genetic approaches use insertional mutagenesis to<br />
randomly integrate a strong promoter into the genome, activating<br />
downstream gene transcription that can lead to either gain or lossof-function<br />
mutations based on the integration site. We used this<br />
insertional mutagenesis approach to induce anchorage-independent<br />
growth of isolated murine HER2/Neu over-expressing mammary<br />
epithelial cells. We identified HECT domain and ankyrin repeat<br />
containing E3 ubiquitin protein ligase 1 (HACE1) as a putative<br />
breast tumor suppressor protein whose loss leads to the formation of<br />
anchorage-independent colonies.<br />
Loss of HACE1 expression is commonly seen in breast cancer patients<br />
[as well as other tumor types] supporting the role of HACE1 as a<br />
breast tumor suppressor gene. Knockdown of HACE1 in human<br />
mammary epithelial cells (HMECs) results in the acquisition of<br />
anchorage-independent growth. Moreover, knockdown of HACE1<br />
in established breast cancer cell lines that express moderate levels<br />
of HACE1 results in enhanced cloniginicity.<br />
Therefore, we propose that the loss of HACE1 can potentially be<br />
used as a predictive marker for breast cancer progression. Additional<br />
studies investigating the mechanism of HACE1 action may also<br />
identify therapeutic targets that counteract HACE1 loss.<br />
P1-04-07<br />
The mRNA Expression of DAP1 in Human <strong>Breast</strong> <strong>Cancer</strong>:<br />
Correlation with Clinicopathological Parameters<br />
Wazir U, Jiang WG, Sharma AK, Mokbel K. St Georges’ Healthcare<br />
NHS Trust, London, United Kingdom; Cardiff University-Peking<br />
University Oncology Joint Institute, Cardiff, United Kingdom; The<br />
London <strong>Breast</strong> Institute, The Princess Grace Hospital, London,<br />
United Kingdom<br />
BACKGROUND: This pilot study is the first to focus on the potential<br />
role for death-associated protein 1 (DAP1) in human breast cancer.<br />
MATERIAL AND METHODS: mRNA expression of DAP1 in breast<br />
cancer tissues (n= 127) and normal background tissues (n=33) were<br />
determined using quantitative polymerase chain reaction (qPCR) and<br />
correlated with clinicopathological data accumulated over a 10-year<br />
follow-up period. Furthermore the effects of DAP1 knockout in breast<br />
cancer cell lines were investigated.<br />
RESULTS: The expression of DAP1 mRNA was demonstrated to<br />
decrease with increasing Nottingham Prognostic Index (NPI2 vs.<br />
NPI3, p = 0.0026), and TNM stage (TNM1 vs. 4, p=0.0039). Lower<br />
DAP1 expression levels were significantly associated with local<br />
recurrence (p=0.02) and distant metastasis (p=0.001).<br />
The knockout of the DAP1 gene in MCF-7 cell lines resulted in a<br />
significant decrease in the mRNA expression of P-21 and DELE<br />
compared with controls, p=0.04). However, the knockout of DAP1<br />
had no effect on the expression of caspase 8 and 9.<br />
CONCLUSIONS: This study demonstrates an inverse association<br />
between DAP1 mRNA levels and tumour stage and clinical<br />
outcome in breast cancer. This may be suggestive of a relationship<br />
between oncogenesis and the autophagy pathway meriting further<br />
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investigation. These results also indicate that the pro-apoptotic<br />
function seems to be estrogen-dependent but independent of caspase<br />
8 and 9. The DAP1 pro-apoptotic pathway may involve P-21 and<br />
DELE proteins.<br />
P1-04-08<br />
Evidence for anti-apoptosis function of GNB1 in human breast<br />
cancer<br />
Wazir U, Kasem A, Sharma AK, Jiang W, Mokbel K. The London<br />
<strong>Breast</strong> Institute, The Princess Grace Hospital, London, United<br />
Kingdom; Cardiff University-Peking University Oncology Joint<br />
Institute, Cardiff, United Kingdom; St Georges’ Healthcare NHS<br />
Trust, London, United Kingdom<br />
INTRODUCTION: Guanine nucleotide binding protein beta<br />
polypeptide 1 (GNB1) integrates signals between receptors and<br />
effector proteins and regulates certain signal transduction receptors<br />
and effectors. We have hypothesised that GNB1 is involved in the<br />
anti-apoptosis pathway mediated by mTor. Therefore, this protein<br />
may play role in human carcinogenesis, however, there has been no<br />
investigations of this potential role published in the literature. The<br />
aim of the study was to investigate the mRNA expression of GNB1<br />
in human breast cancer and examine the relationship between its<br />
expression and the tumour characteristics and disease outcome.<br />
Furthermore, the correlation between GNB1 and mTORC1 was also<br />
investigated.<br />
METHODS: Specimens of breast cancer (BC) tissues (N=136)<br />
and normal tissues (N=30) underwent RNA extraction and reverse<br />
transcription. GNB1 transcript levels were determined using realtime<br />
quantitative PCR. Expression levels were analysed against<br />
clinicopathological data accrued over a 10 year follow-up period.<br />
RESULTS: Significantly higher mRNA transcript levels were found<br />
in the breast cancer specimens compared to normal glandular tissue<br />
in paired samples (p=0.0029). The expression of GNB1 mRNA was<br />
demonstrated to increase with increasing TNM stage (from 0.01 to<br />
15.9) and this reached statistical significance when comparing TNM1<br />
vs. TNM2/3/4 (p=0.036). Furthermore, the expression levels increased<br />
with increasing tumour grade and this reached statistical significance<br />
when comparing grade 2 vs. grade 3 (p=0.006). GNB1 expression<br />
was found to be higher in ductal tumours compared with non-ductal<br />
tumours (p=0.0081). The patients who developed recurrent disease<br />
or died from breast cancer had higher expression levels than those<br />
who had been disease-free after a median follow-up period of 10<br />
years (p=0.017). Those who died from breast cancer had significantly<br />
higher levels than those who have remained disease-free (33.9 vs.<br />
0.01, p=0.0009). GNB1 showed a significantly positive correlation<br />
with mTORC1 mRNA levels (r= 0.57, p < 0.000001).<br />
CONCLUSION: GNB1 expression was found to be significantly<br />
higher in BC specimens compared to normal breast tissue. Higher<br />
transcript levels were significantly associated with unfavourable<br />
pathological parameters and adverse clinical outcomes. These<br />
observations in addition to the positive correlation with mTORC1<br />
levels support the hypothesis that GNB1 is an important upstream<br />
component of the anti-apoptosis pathway and, therefore, can be a<br />
potential target for therapeutic intervention in human breast cancer.<br />
P1-04-09<br />
mTORC1 and Rictor expression in human breast cancer:<br />
correlations with clinicopathological parameters and disease<br />
outcome<br />
Wazir U, Kasem A, Sharma AK, Jiang WG, Mokbel K. The London<br />
<strong>Breast</strong> Institute, The Princess Grace Hospital, London, United<br />
Kingdom; Cardiff University-Peking University Oncology Joint<br />
Institute, Cardiff, United Kingdom; St Georges’ Healthcare NHS<br />
Trust, London, United Kingdom<br />
BACKGROUND:mTOR (the mammalian target of rapamycin)<br />
plays a key role in regulation of cellular metabolism, growth, and<br />
proliferation. It forms two multi-protein complexes known as<br />
complex 1 (mTORC1) and 2 (mTORC2). Raptor and Rictor are the<br />
core proteins for mTORC1 and mTORC2 respectively. There is a<br />
growing body of evidence that mTORC1 is up-regulated in many<br />
cancers and plays a role in carcinogenesis. The aim of the study was<br />
to investigate the mRNA expression of mTOR and Rictor in human<br />
breast cancer and examine the relationship between their expression<br />
and clinicopathological parameters.<br />
METHODS: Specimens of breast cancer (BC) tissues (N=150)<br />
and normal tissues (N=31) underwent RNA extraction and reverse<br />
transcription. mTOR and Rictor transcript levels were determined<br />
using real-time quantitative PCR. Expression levels were analyzed<br />
against tumor size, grade, nodal involvement, TNM stage, and clinical<br />
outcome over a 10 year follow-up period.<br />
RESULTS: Significantly higher mRNA transcript levels of mTOR<br />
were found in the breast cancer specimens compared to normal<br />
glandular tissue (p=0.0018). The expression of mTOR mRNA was<br />
demonstrated to increase with increasing NPI (53 for NPI1 to 219 for<br />
NPI3) and tumor grade (37 for grade 2 vs. 159 for grade 3, p=0.047).<br />
mTOR expression was found to be higher in ductal tumors compared<br />
with non-ductal tumors (p=0.0014). The patients who developed<br />
recurrent disease or died from breast cancer had higher expression<br />
levels than those who had been disease-free after a median followup<br />
period of 10 years (p=0.17). Higher expression levels were<br />
significantly associated with worse overall survival (p=0.01).<br />
In contrast, higher levels of Rictor mRNA expression were found<br />
in normal breast tissue, lower NPI stage (NPI1 vs. 2: p= 0.03) and<br />
lower tumor grade (grade 1 vs. grade 3: p=0.01). Patients with higher<br />
Rictor expression had a significantly better overall (p=0.037) and<br />
disease-free (p=0.048) survival.<br />
CONCLUSIONS: mTOR expression was found to be significantly<br />
higher in BC specimens compared to normal breast tissue. Higher<br />
transcript levels were significantly associated with unfavorable<br />
pathological parameters and adverse clinical outcomes. The core<br />
protein of the less predominant mTORC2 was associated with<br />
favorable pathological parameters and clinical outcome. Taken<br />
together these observations are consistent with mTORC1 role in<br />
the anti-apoptosis pathway and suggest that selective inhibitors of<br />
mTORC1 are likely to be a more effective therapeutic strategy than<br />
dual inhibitors in human breast cancer.<br />
P1-04-10<br />
PDGFRA signaling in Inflammatory breast cancer.<br />
Joglekar M, van Golen K. University of Delaware, Newark, DE<br />
Inflammatory breast cancer is the most lethal form of locally advanced<br />
breast cancer. It is clear from the recent research advancements in IBC<br />
that it is entirely a different entity, not only in its clinical presentation<br />
but also in its molecular expression profile. Therefore, it is essential<br />
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to carry out molecular expression studies in IBC compared to non-<br />
IBC as well as to pursue these differences to study their effects on<br />
IBC phenotype.<br />
In collaboration with the Translational <strong>Cancer</strong> Research group in<br />
Antwerp Belgium, our lab has recently found that PDGFRA is<br />
significantly over expressed in IBC patient samples (between 15-<br />
36%) compared to non-IBC patient samples. This project focuses on<br />
identifying the PDGFRA activation signature in SUM149 IBC cells.<br />
Upon ligand stimulation, PDGFR can either homo or heterodimerize<br />
(AA, AB, BB) and produce an array of signaling events responsible<br />
for cell growth, cell proliferation, cell differentiation in normal cells as<br />
well as in several cancer cells. SUM149 and SUM190 cells lack ER,<br />
PR and HER-2 expression and hence are named triple negative IBC<br />
cells. Triple negative breast cancers are highly aggressive in nature<br />
and therefore suffer from poor prognosis. We seek to determine if<br />
signaling via over expressed PDGFRA could be a potential surviving<br />
factor in producing such fast growing and highly invasive IBC tumors.<br />
Preliminary data on immunostaining of PDGFRA with and without<br />
permeabilization suggests intracellular localization of PDGFRA.<br />
We also know that SUM149s and SUM190s express all four PDGF<br />
ligands (A, B, C, D). This unusual expression of all the PDGF lignads<br />
suggests the self-sufficiency of these cells for PDGFRA signaling. In<br />
other words, these cells maintain constitutively active PDGFRA via<br />
intracrine/autocrine loop. Protein expression of active PDGFRA was<br />
studied by using two different phospho specific PDGFRA antibodies<br />
(Tyr 1018 and Tyr 849) without any prior stimulation by PDGF<br />
ligands. Moreover our data shows that PDGFR- activation in IBC,<br />
unlike in n-IBC, is PDGF-C driven.<br />
Possibility of such intracrine/autocrine loop could significantly<br />
increase the overall PDGFRA signaling in IBC cells and hence<br />
can produce fast growing aggressive IBC tumors. Thus targeting<br />
PDGFRA, an important biomarker in IBC could stand as a novel and<br />
systematic therapeutic approach.<br />
P1-04-11<br />
EZH2 Expands <strong>Breast</strong> Stem Cells via NOTCH Signaling, Acting<br />
to Accelerate <strong>Breast</strong> <strong>Cancer</strong> Initiation<br />
Kleer CG, Li X, Moore HM, Toy KA, Gonzalez ME. University of<br />
Michigan, Ann Arbor, MI<br />
Introduction: EZH2 is a critical epigenetic regulator of cellular<br />
memory and has oncogenic functions in breast cancer. EZH2<br />
upregulation signals increased risk for breast cancer when detected<br />
in benign breast biopsies. We hypothesized that EZH2 may promote<br />
breast cancer initiation through regulation of mammary stem cells.<br />
Methods: EZH2 was overexpressed in nontumorigenic breast<br />
cells using a Dox-regulated or an adenoviral system. EZH2 was<br />
downregulated in breast cancer cell lines and cells derived from<br />
fresh patients’ tumors. The effect of EZH2 levels on mammary<br />
stem cells was investigated using the mammosphere assay and flow<br />
cytometry (ALDH1+ and CD44+/CD24- assays). PCR-based stem<br />
cell microarray was used to discover EZH2 regulated genes. To<br />
investigate the effect of EZH2 on NOTCH1 transcriptional activity<br />
and promoter binding we employed reporter and ChIP assays. The<br />
effect of EZH2 in tumor initiation was investigated using xenografts<br />
and genetic mammary-specific EZH2 overexpression in MMTV-neu<br />
mice.<br />
Results: EZH2 overexpression (EZH2-OV) increased, while EZH2<br />
knockdown (KD) decreased the number of mammospheres and the<br />
percentage of ALDH1+ and CD44+/CD24- cells in nontumorigenic<br />
and in breast cancer cells, respectively. NOTCH1 was one of the<br />
most significantly downregulated genes and pathways upon EZH2<br />
KD in breast cancer cells. In nontumorigenic breast cells, EZH2-OV<br />
led to NOTCH1 mRNA and protein upregulation, and an increase in<br />
NOTCH1 transcriptional activity. We found that EZH2 binds to the<br />
NOTCH1 promoter (at -1.2kb). This function requires the HII domain<br />
of EZH2, is independent of the SET domain, and occurs in association<br />
with an increased H3K4me3 activating mark and RNA polymerase<br />
binding. Genetic mammary-specific EZH2 overexpression in MMTVneu<br />
mice led to accelerated tumor initiation (log rank p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
microscopy and cytokine antibody microarray respectively along<br />
with additional biochemical methods and gene expression analysis<br />
by oligo microarray.<br />
Conclusions/Significance<br />
We demonstrate here for the first time that LASP-1 translocates to<br />
the nucleus through activation of i) GPCRs -chemokine receptors<br />
CXCR2, CXCR4 and ii) Receptor tyrosine kinases - EGF receptor<br />
and HER2. Shuttling of LASP1 to the nucleus through the activation<br />
of a variety of receptors present in the tumor cells, macrophages,<br />
neutrophils and endothelial cells of the tumor microenvironment is of<br />
high significance. Silencing of LASP-1 in breast cancer cells revealed<br />
an altered profile of the 3D-clusters and the secreted cytokines.<br />
P1-05-02<br />
Epithelial-to-epithelial transition precedes collective breast<br />
cancer invasion<br />
Cheung KJ, Ewald AJ. Johns Hopkins School of Medicine, Baltimore,<br />
MD<br />
BACKGROUND: Invasion represents a fundamental step in tumor<br />
progression and is a driving force for metastasis and cancer-related<br />
mortality. Invasion has been studied largely in the context of single<br />
cells, but in vivo, most tumor cells are not found in isolation, but<br />
rather are found as ensembles of cells with substantial molecular<br />
heterogeneity. It remains poorly understood in this context which<br />
cells are invasive, how these cells arise or how these cells interact<br />
collectively to accomplish invasion.<br />
RESULTS: We developed an ex-vivo 3D culture assay enabling us<br />
to distinguish invasive from non-invasive cells and to interrogate<br />
their molecular phenotype. In two mouse models of luminal breast<br />
cancer, we find that invasive cells express markers of basal epithelium<br />
including cytokeratin K14, p63 and P-cadherin. Invasive K14+<br />
cells were also molecularly and functionally distinct from normal<br />
myoepithelial cells and co-expressed luminal K8 and E-cadherin.<br />
In vivo, K14+ cells were localized to tumor-stromal interfaces in<br />
the primary tumor and in lung micro and macro-metastases. Using<br />
a molecular biosensor and time-lapse microscopy, we observed that<br />
K14+ invasive cells were derived from K14-negative luminal tumor<br />
cells by direct phenotypic conversion. Interestingly, the capacity of<br />
luminal tumor cells to acquire basal markers varied by model, with<br />
few K14+ cells in MMTV-Her2 and many K14+ cells in MMTV-<br />
PyMT mice, correlating with the known in vivo kinetics of tumor<br />
progression in these models. To block this epithelial to epithelial<br />
transition, we tested the activity of an inhibitor of ribosome S6 kinase<br />
(RSK), which has been shown previously to inhibit myoepithelial<br />
differentiation in normal mammary epithelium. RSK inhibition caused<br />
relative depletion of K14+ tumor cells in 3D culture and abrogation<br />
of invasion. Finally, our assay revealed that in fresh primary tissue<br />
from human ER+ luminal breast cancers, invasive cells also expressed<br />
basal epithelial markers.<br />
CONCLUSIONS: Taken together, these data suggest that an epithelialto-epithelial<br />
transition precedes collective invasion in luminal breast<br />
cancers. Because we observe K14+ leader cells independent of tumor<br />
estrogen receptor status, these data may be generally applicable to<br />
breast cancer invasion across subtypes. Because many epithelial<br />
tissues have basal populations, K14+ tumor cells may also lead<br />
invasion in other cancers.<br />
P1-05-03<br />
A requirement for neural precursor cell-expressed developmentally<br />
downregulated gene 9 during the initiation of mammary<br />
tumorigenesis in MMTV-neu mice<br />
Serzhanova VA, Little JL, Izumchenko E, Seo S, Kurokawa M,<br />
Egleston B, Klein-Szanto AA, Golemis EA. Fox Chase <strong>Cancer</strong> Center,<br />
Philadelphia, PA; Ben Gurion University of the Negev, Beer Sheva,<br />
Israel; University of Tokyo, Japan<br />
The Neural precursor cell-Expressed Developmentally Downregulated<br />
gene 9 (NEDD9; also HEF1, CAS-L) scaffolding protein regulates<br />
many signaling pathways associated with mitosis, survival, migration,<br />
and ciliary integrity. Within the last few years, elevated NEDD9<br />
expression has been implicated in progression and metastasis of<br />
several types of cancer, including those of the lung, skin, and brain. We<br />
have investigated the consequences of introducing a Nedd9 genotype<br />
into the MMTV-neu mouse mammary tumor model, which in many<br />
respects recapitulates features of human HER2+ breast cancer. 80% of<br />
wild-type MMTV-Neu; Nedd9+/+ animals developed tumors with an<br />
average latency of 339 days, but only 18% of MMTV-Neu;Nedd9-/-<br />
animals developed tumors with an average latency of 416 days. This<br />
highly significant difference indicates that the Nedd9-/- genotype<br />
significantly prevents neu-dependent mammary tumor formation.<br />
HER2-positive human breast tumors and MMTV-neu-induced tumors<br />
originate from mammary luminal epithelial progenitor cells. We<br />
evaluated mammary progenitor cell populations from non-tumor<br />
bearing MMTV-neu;Nedd9-/- versus MMTV-neu;Nedd9+/+ 4-month<br />
old mice (2 months prior to appearance of tumors). Flow cytometry<br />
analysis indicated a significantly reduced CD24high;CD49flow<br />
luminal progenitor subpopulation in MMTV-neu;Nedd9-/- and<br />
Nedd9-/- mammary glands, that could be contributed to the<br />
tumorigenesis resistance in the MMTV-neu;Nedd9-/- model. The<br />
MMTV-neu;Nedd9-/-genotype negatively affected the Matrigel<br />
mammosphere colony-forming potential of luminal progenitor cells<br />
compared to MMTV-neu; Nedd9+/+cells, causing formation of<br />
fewer colonies with aberrant size and morphology. Quantification<br />
of mitotic division planes of MMTV-neu;Nedd9-/- mammospheres<br />
revealed no contribution to the observed defects. However, MMTVneu;Nedd9-/-<br />
mammospheres had defective expression of signaling<br />
proteins governing cell attachment, with reduced levels of FAK and<br />
more cytoplasmic localization of SRC.<br />
The results reported above, together with other data, support three<br />
main conclusions. First, they revealed a very substantial requirement<br />
for Nedd9 during early stages of HER2/neu-dependent tumor<br />
formation. Second, these results are the first to demonstrate a role<br />
for Nedd9 in supporting the abundance and colony-forming potential<br />
of mammary luminal progenitor cells. Third, they indicate that the<br />
defects in mammosphere growth likely involve perturbation of crucial<br />
cellular attachment signaling pathways involving FAK and SRC. In<br />
sum, these data provide a strong justification for future analysis of<br />
NEDD9 in the defective signaling of transformed mammary epithelial<br />
progenitor cell populations that initiate human breast cancer.<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P1-05-04<br />
Expression of Quiescin Sulfhydryl Oxidase 1 is associated with a<br />
highly invasive phenotype and correlates with a poor prognosis<br />
in Luminal B breast cancer.<br />
Katchman BA, Ocal T, Hostetter G, Cunliffe HE, Wantanabe A, Lake<br />
DF. Arizona State University, Tempe, AZ; Mayo Clinic Arizona,<br />
Scottsdale, AZ; Translational Genomic Research Institute, Phoenix,<br />
AZ<br />
Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups<br />
to form disulfide bonds in proteins. Informatic analysis using the<br />
newly available “Gene Expression Based Outcome for <strong>Breast</strong> <strong>Cancer</strong><br />
Online” (GOBO) tool indicated high levels of QSOX1 expression<br />
in Estrogen Receptor positive (ER+) subtypes of breast cancer. We<br />
confirmed this finding by evaluation of QSOX1 protein expression in<br />
breast tumors and in a panel of breast cancer cell lines. In addition,<br />
Kaplan Meyer analyses revealed QSOX1 as a significant predictive<br />
marker for both relapse and poor overall survival in Luminal B tumors,<br />
but not in other intrinsic subtypes. To investigate malignant cell<br />
mechanisms in which QSOX1 might play a key role, we suppressed<br />
QSOX1 protein expression using short hairpin (sh) RNA in ER+<br />
MCF7 and ER- BT549 breast cancer cell lines. Suppression of<br />
QSOX1 protein dramatically slowed cell proliferation but did not<br />
significantly effect apoptosis or cell cycle regulation. Inhibition of<br />
QSOX1 did however dramatically inhibit MCF7 and BT549 breast<br />
tumor cells from invading through Matrigel in a modified Boyden<br />
chamber assay. Inhibition of invasion could be rescued by the<br />
exogenous addition of recombinant QSOX1. Gelatin zymography<br />
indicated that QSOX1 plays an important role in activation of MMP-9<br />
a key mediator of breast cancer invasive behavior. Taken together, our<br />
results suggest that QSOX1 is a novel biomarker for risk of relapse<br />
and poor survival in Luminal B breast cancer, and has a pro-invasive<br />
role in malignant progression through post-translational activation<br />
of MMP-9.<br />
P1-05-05<br />
Podocalyxin is a key regulator of breast cancer progression and<br />
metastasis.<br />
Snyder KA, Hughes MR, Graves M, Roskelly C, McNagny KM.<br />
University of British Columbia, Vancouver, BC, Canada<br />
Podocalyxin (gene name Podxl) is a CD34-related sialomucin<br />
that has been shown to be important in regulating cell adhesion,<br />
migration, and polarity of hematopoietic progenitors and vascular<br />
endothelia. In breast cancer, we have shown that podocalyxin is<br />
overexpressed on a subset of node-negative tumors and its expression<br />
is strongly associated with poor overall survival. To determine<br />
whether podocalyxin directly regulates breast cancer cell behavior,<br />
we ectopically expressed podocalyxin in the human breast cancer cell<br />
line, MCF7, which expresses low levels of endogenous podocalyxin,<br />
is minimally invasive, and non-metastatic. Upon ectopic expression<br />
of podocalyxin, MCF7 “bulge apically”, produce apical and lateral<br />
microvilli, are less adhesive in vitro, and are delayed in targeting<br />
integrins to the basolateral surface. In contrast to MCF7, MDA.MB-<br />
231 is a basal-like breast cancer cell-line, which expresses high levels<br />
of endogenous podocalyxin, exhibits poorly polarized monolayer<br />
and mammosphere architecture in vitro and forms “metastatic” lung<br />
tumors in vivo. Using Podxl-targeted shRNA vectors we show that<br />
expression of podocalyxin is required for MDA.MB-231 cells to form<br />
distant metastases in a competitive in vivo assay utilizing humanized<br />
NOD/SCIDIL-2rγ-/- (NSG) mice. Previously, we observed that<br />
Podxl-deficient hematopoietic cells have impaired CXCR4-mediated<br />
chemotaxis to CXCL12, a known axis for tumor metastasis. Our<br />
current hypothesis is that podocalyxin regulates chemotaxis of tumorinitiating<br />
cells (TICs) to the CXCL12-rich tissues of the lungs, liver,<br />
and bone marrow. Up-regulation of podocalyxin on breast cancer<br />
cells may be a key event in tumor progression and likely enables<br />
these cells to sense chemokines and metastasize to peripheral sites.<br />
P1-05-06<br />
A novel mutation in the tyrosine kinase domain of ErbB2:<br />
molecular and proteomic investigation of its role in breast cancer<br />
invasion<br />
O’Hara J, Kast J. University of British Columbia, Vancouver, BC,<br />
Canada<br />
•Introduction<br />
A landmark genomic study revealed 17 somatic coding mutations<br />
in a lobular metastatic breast tumor, none of which were present<br />
in the patient’s primary tumor. Among these was a novel mutation<br />
in the tyrosine kinase domain of ErbB2, a gene often amplified in<br />
breast cancer. Other mutations in this domain have been shown<br />
to stimulate transformation, growth and invasion in breast cancer<br />
cells. We hypothesize that an accumulation of mutations in the<br />
primary tumor over time preceded the development of an invasive<br />
clone, which allowed it to metastasise. Therefore, we investigated<br />
the specific effects of ErbB2 on cellular signalling and invasion, in<br />
conjunction with proteomic analyses to show its effects on global<br />
protein expression.<br />
• Methods<br />
Wild-type and mutant ErbB2 cDNAs were cloned into V180 pLP<br />
3X FLAG-tagged expression vectors. T47D breast cancer cells were<br />
transfected with one of these constructs. Protein was detected by<br />
immunoblotting with an anti-ErbB2 antibody. Membranes were then<br />
immunoblotted with an anti-phospho-ERK1/2 antibody. Transfected<br />
cells were seeded onto Matrigel; cells that migrated through the matrix<br />
were stained and counted after 48h.<br />
To identify global proteomic changes caused by mutant ErbB2, T47D<br />
cells transfected with mutant/wild-type ErbB2 or vector control,<br />
were differentially labeled by growing them in medium containing<br />
various lysine/arginine isotopes (known as stable isotope labeling of<br />
amino acids in cell culture; SILAC). Protein lysates were mixed and<br />
subjected to LC-MS/MS mass spectrometry. Proteomic changes were<br />
analysed using MaxQuant and DAVID software.<br />
• Results<br />
Overexpression of the wild-type or mutant ErbB2 genes produced<br />
protein expression in T47D, a non-invasive breast cancer cell line,<br />
confirmed by western blotting. To measure signalling downstream<br />
of ErbB2, we measured levels of the MAP kinase phospho-ERK1/2.<br />
Increased phosphorylation of ERK1/2 was demonstrated in cells<br />
expressing mutated ErbB2, compared with cells transfected with<br />
wild-type. This indicates increased activation of mutant ErbB2,<br />
demonstrating distinct phenotypic effects between wild-type and<br />
mutant ErbB2 in breast cancer cells. To analyze whether increased<br />
activation was accompanied by enhanced invasive properties, invasion<br />
assays were performed using Matrigel. A greater number of cells (1.5-<br />
fold increase) expressing mutant ErbB2 migrated across this matrix<br />
compared with wild-type-expressing cells.<br />
Global proteomic analysis of T47D cells overexpressing wild-type<br />
or mutant ErbB2 yielded 1,357 total proteins, of which 543 could<br />
be quantified. Two subsets of proteins were identified, whose levels<br />
were either increased or decreased, in the mutant versus wild-typetransfected<br />
lysates (compared to control ratios). Proteins elevated<br />
in the mutant-expressing cells included candidates involved in cell<br />
migration, inhibition of apoptosis and promotion of cellular survival.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
168s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
Proteins showing reduced expression were involved in pathways<br />
including adhesion and DNA damage response.<br />
• Conclusion<br />
This previously undescribed mutation in the tyrosine kinase domain<br />
of ErbB2 differentially effects downstream signalling pathways and<br />
may play a role in invasion of breast cancer cells.<br />
P1-05-07<br />
Prognostic relevance of Claudin-2 expression in metastatic breast<br />
cancer<br />
Hedenfalk I, Kimbung S, Kovacs A, Skoog L, Einbeigi Z, Walz T,<br />
Malmberg M, Loman N, Fernö M, Hatschek T, TEX Study Group.<br />
Lund University, Lund, Sweden; CREATE Health Strategic Center<br />
for Translational <strong>Cancer</strong> Research, Lund University, Lund, Sweden;<br />
Sahlgrenska University Hospital, Gothenburg, Sweden; Karolinska<br />
University Hospital, Solna, Sweden; Linköping University Hospital,<br />
Linköping, Sweden; Helsingborg General Hospital, Helsingborg,<br />
Sweden<br />
The site of relapse is known to be a strong prognostic factor of<br />
survival from metastatic breast cancer. The liver is the third most<br />
frequent site affected and patients with hepatic metastases have an<br />
inferior prognosis relative to patients with bone and lung metastases.<br />
Predicting the likelihood of liver metastasis after adjuvant therapy<br />
of primary breast cancer is challenging. The aim of this study was to<br />
identify and characterize genes associated with breast cancer liver<br />
metastases. We thus performed global transcriptional profiling of<br />
120 metastatic lesions from different anatomical sites from breast<br />
cancer patients enrolled in a randomized clinical trial 1 and found<br />
that while the expression of other matrix remodelling and tightjunction<br />
molecules was down-regulated in liver metastases, Claudin-2<br />
(CLDN2) was significantly up-regulated (P=0.001). Furthermore, high<br />
expression of CLDN2 was also observed amongst patients diagnosed<br />
with a liver metastasis, irrespective of the specific site of the metastasis<br />
that was profiled, compared to patients without hepatic metastases<br />
(P=0.001). We further investigated the prognostic significance of<br />
CLDN2 protein expression by immunohistochemical staining of<br />
primary tumours and matched lymph node metastases from a larger<br />
cohort of patients (n∼200) with metastatic breast cancer. We found<br />
CLDN2 to be significantly more frequently expressed in lymph<br />
node metastases compared to primary tumours (P=0.013). Also,<br />
consistent with mRNA expression levels, more frequent expression<br />
of CLDN2 protein was observed in the primary tumours of patients<br />
who eventually developed a liver metastasis (p=0.027). Interestingly,<br />
high expression of CLDN2 in the primary tumour was associated with<br />
a shorter time to recurrence (P=0.032). Specifically, high expression<br />
of CLDN2 in the primary tumour was associated with a shorter<br />
progression to liver metastasis (P=0.002). These data highlight a<br />
potential role of CLDN2 in the development and prognosis of breast<br />
cancer liver metastases.<br />
1. Hatschek, T., et al. Individually tailored treatment with epirubicin<br />
and paclitaxel with or without capecitabine as first-line chemotherapy<br />
in metastatic breast cancer: a randomized multicenter trial. <strong>Breast</strong><br />
<strong>Cancer</strong> Res Treat. 2012, 131(3):939-47.<br />
P1-05-08<br />
Targeting integrin signaling suppresses invasive recurrence in a<br />
three-dimensional model of radiation treated ductal carcinoma<br />
in situ<br />
Nam J-M, Ahmed KM, Costes S, Zhang H, Sabe H, Shirato H, Park<br />
CC. Hokkaido University Graduate School of Medicine, Sapporo,<br />
Hokkaido, Japan; Ernest Orlando Lawrence Berkeley National<br />
Laboratory, Berkeley, CA; UCSF, <strong>San</strong> Francisco, CA<br />
Background: DCIS (ductal carcinoma in situ) is comprised<br />
of cancerous cells that are contained within the milk duct and<br />
separated from the stroma by a basement membrane. Akt activation<br />
is implicated in breast cancer progression and also upregulated in<br />
∼30% of DCIS lesions. We have previously shown that β1-integrin<br />
inhibition enhanced the efficacy of ionizing radiation (IR) in invasive<br />
breast cancer, via an Akt-mediated effect. Radiation therapy (RT) is<br />
commonly used to treat DCIS, resulting in a decrease in recurrence<br />
risk by ∼50%. However, DCIS still recurs in a substantial number<br />
of patients, and as invasive disease half of the time. This study<br />
aimed to identify the effects of IR on Akt-driven DCIS, and possible<br />
mechanisms underlying invasive progression in surviving cells.<br />
Materials and Methods: To model DCIS, we took advantage of the<br />
ability of non-invasive mammary epithelial cells, MCF10A that form<br />
duct-like structures in 3-dimensional laminin-rich extracellular matrix<br />
(3D lrECM), and overexpressed an activated myristoylated form of the<br />
serine/threonine kinase, Akt. The 3D lrECM cultured MCF10A-Akt<br />
cells show filled lumen and retained basal polarity, characteristic of<br />
DCIS lesions in vivo. After DCIS structures formed in 3D lrECM,<br />
cultures were exposed to 8 Gy IR. Confocal microscopy analysis,<br />
western blot analysis, matrigel chemoinvasion assay and matix<br />
degradation assay were performed to characterize the IR effect on<br />
luminal or basal cells of the DCIS like structures.<br />
Results: MCF10A-Akt structures post-8 Gy IR shows a significant<br />
increase in apoptosis measured by cleaved caspase-3 (n=3, P <<br />
0.05). When we propagated cells post-IR in 3D lrECM, an invasive<br />
phenotype emerged in a sub-population of survivors (n=3, P <<br />
0.01). We also confirmed that inhibitory antibodies to β1-integrin<br />
suppressed the invasive phenotype that was induced by 8 Gy IR. In<br />
addition to this, invasion activity emerged by 8 Gy IR was inhibited<br />
by nuclear factor-kappaB (NF-κB) inhibitor JSH-23 (n=3, P < 0.01).<br />
Finally, inhibition of β1-integrins or NF-κB translocation completely<br />
suppresses the formation of invasive colonies.<br />
Discussion: In present study, we found that inhibition of β1-integrins<br />
abrogates the emergence of an invasive phenotype among surviving<br />
clones. Our current data suggest that regulation of β1-integrin<br />
signaling via NF-κB plays an important role in the emergence of<br />
invasive disease after radiation, and may be an important clinical<br />
target.<br />
P1-05-09<br />
FH535 inhibited migration and growth of breast cancer cells<br />
Dorchak JA, Iida J, Clancy R, Luo C, Chen Y, Hu H, Mural RJ, Shriver<br />
CD. Windber Research Institute, Windber, PA; Walter Reed National<br />
Military Medical Center, Bethesda, MD<br />
Background: Given the lack of effective targeted therapies for<br />
triple-negative (TN) breast cancer patients, a better understanding<br />
of the mechanisms of growth and invasion of these tumors will<br />
provide valuable insight into developing novel approaches to lower<br />
the mortality associated with TN breast cancer. There is substantial<br />
evidence indicating that the canonical Wnt signaling pathway is<br />
activated in TN breast cancer tissues. Previous studies report that<br />
FH535, a small molecule inhibitor of the Wnt signaling pathway,<br />
www.aacrjournals.org 169s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
decreases growth of cancer cells but not normal fibroblast cells,<br />
suggesting this pathway plays a role in tumor progression and<br />
metastasis. In this study, we test FH535 as a potential inhibitor of<br />
migration, invasion, and growth against malignant phenotypes of<br />
breast cancer.<br />
Methods and Results: We show that FH535 significantly inhibits<br />
growth, migration, and invasion of TN breast cancer cells (MDA-<br />
MB-231 and HCC38) using established protocols, implicating<br />
the Wnt signaling pathway plays a role in tumor progression and<br />
metastasis. FH535 is a potent growth inhibitor for TN breast cancer<br />
cells (MDA-MB-231 and HCC38), but not in other breast cancer cells<br />
(MCF-7, T-47D, or SK-BR-3) when cultured in three dimensional<br />
type I collagen gel. Additionally, western blotting analysis shows<br />
that treatment of MDA-MB-231 cells with FH535 markedly<br />
inhibits the expression of NEDD9, but not FAK, Src, or p130Cas,<br />
suggesting specificity of the Wnt signaling pathway in regulating gene<br />
expressions. Co-immunoprecipitation studies suggest that NEDD9 is<br />
specifically immunoprecipitated with CSPG4, but not with β1 integrin<br />
or CD44, implying CSPG4 and NEDD9 form a molecular complex<br />
for facilitating tumor migration, invasion, and growth. Statistical<br />
analysis (ANOVA) of The <strong>Cancer</strong> Genome Atlas (TCGA) project<br />
gene expression data (https://tcga-data.nci.nih.gov/) suggests that<br />
tumors from patients with basal-type breast cancer had significantly<br />
higher CSPG4 expression than tumors from patients with other<br />
subtypes, with all the p values
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
Material and Methods:<br />
We enrolled 40 patients diagnosed with breast cancer from Ain<br />
Shams University Hospitals. Patients were sub-grouped into negative<br />
(zero) and positive (4) LN metastasis patients. All enrolled patients<br />
had not received neo-adjuvant chemotherapy. During modified<br />
radical mastectomy or conservative breast surgery, 15-20 ml of<br />
blood were collected from axillary vein tributaries for the isolation<br />
of tumor-associated leukocytes by Ficoll-Hypaque density gradient<br />
centrifugation. The immunophenotype of the isolated mononuclear<br />
cells was assessed using flow cytometry to identify the percentage of<br />
T lymphocytes (CD3+) and their subpopulations (CD4+ and CD8+),<br />
NK cells (CD56+) and B-lymphocytes (CD19+). Tumor-associated<br />
leukocytes isolated from positive and negative LN patients were<br />
seeded overnight in appropriate culture media at 37°C in a humidified<br />
CO2 incubator. Conditioned media containing secreted cytokines/<br />
chemokines were profiled using RayBio human cytokine antibody<br />
arrayIIIand then analyzed and quantified using ImageJ software. In<br />
addition, using immunoblottingwe assessed the level of expression<br />
of total and phospho NF-kβ in leukocyte lysates from positive and<br />
negative LN patients.<br />
Result:<br />
Flow cytometric analysis revealed a significant increase in the<br />
percentage of T lymphocytes and T helper(CD3+/CD4+) cells<br />
collected from axillary tributaries of positive LN patients as<br />
compared to negative LN patients. Leukocytesisolated from positive<br />
LN patients were characterized by more than five-foldincreases in<br />
IL-12,Thrombopoietin, IL-13, INF-ϒ, TARC, IGF-1, IL-3, TNF-α,<br />
IL-4, GCSF, IL-5 and IL-1α. Moreover, we detected an increase in<br />
cellular expression of total and phospho NF-kβ in leukocytes isolated<br />
from positive LN as compared to negative LN breast cancer patients.<br />
Conclusion: Our results demonstrate for the first time that tumorassociated<br />
leukocytes of positive LN patients possess different<br />
cytokine patterns than those ofnegative LN patients. Moreover, we<br />
identified major cytokines that may contribute to LN metastasis and<br />
could be therapeutically targeted.<br />
P1-05-12<br />
Metastatic xenograft models of human estrogen receptor negative<br />
breast cancer primary cultures are driven by the recruitment of<br />
myeloid-derived suppressor cells<br />
Drews-Elger K, Iorns E, Brinkman JA, Berry DL, Lippman ME,<br />
El-Ashry D. Sylvester Comprehensive <strong>Cancer</strong> Center, Braman<br />
Family <strong>Breast</strong> <strong>Cancer</strong> Institute, University of Miami, FL; Science<br />
Exchange, Palo Alto, CA; Georgetown University Medical Center,<br />
Washington, DC<br />
The study of early stage and metastatic breast cancer relies heavily<br />
on the use of established cell lines often derived from metastatic<br />
lesions rather than from primary tumors, limiting our understanding<br />
of primary tumor development. Study of the mechanisms governing<br />
the metastatic process in its entirety is not always feasible with<br />
these types of cellular and xenograft models, as often the primary<br />
tumor needs to be excised, or breast cancer cells are introduced into<br />
circulation of host mice. While this approach has allowed a better<br />
understanding of metastasis, it may unintentionally enhance the<br />
colonization efficiency and pass over important events occurring in<br />
the tumor microenvironment. In order to provide a cellular model that<br />
more closely recapitulates breast cancer development and progression,<br />
we generated breast cancer cellular cultures by dissociating specimens<br />
of human estrogen receptor-negative primary breast tumors and<br />
placing them in culture. Within our group of dissociated tumor (DT)<br />
cell cultures, we had shown that five cultures are formed by breast<br />
cancer cells and these were classified by PAM50 predictor analysis as<br />
belonging to the ER-/PR-/Her2+ and triple negative subtypes. DT cells<br />
are tumorigenic in NOD/Scid and NOD/Scid gamma (NSG) mice.<br />
Our first aim was to assess the metastatic potential of the DT cells in<br />
two mouse models. We show that 3 of the 5 cultures are metastatic to<br />
lymph nodes, liver and or lungs; common sites of metastasis in breast<br />
cancer patients. Spontaneous metastases were observed without the<br />
requirement of primary tumor excision. The metastatic frequency<br />
ranged from 25-90% in NOD/Scid mice, and from 80-100% in NSG<br />
mice. Moreover, expression of key proteins such as epidermal growth<br />
factor receptor (EGFR) detected in primary tumors was also found<br />
in the metastatic lesions. Because the DT cells have been isolated<br />
from primary breast tumors they represent a clinically relevant and<br />
valuable model to study breast cancer and metastasis.<br />
A critical factor influencing tumor progression and metastasis is the<br />
infiltration of immune cells including myeloid-derived suppressor<br />
cells (MDSCs), which have been shown to be increased in a tumordependent<br />
manner in xenograft models of breast cancer. Previous<br />
work from our lab has shown that stroma of tumor-bearing mice<br />
exhibited gene expression changes, including increased expression<br />
of calcium binding proteins S100A8 and S100A9, that are consistent<br />
with myeloid immune cell infiltration. Our second aim was thus to<br />
analyze the recruitment of S100A8+ MDSCs by xenografted DT<br />
tumors. We show that the recruitment of S100A8+ MDSCs is detected<br />
in DT tumors and sites of metastasis, and more importantly, their<br />
presence was significantly greater in the tumors that metastasized<br />
compared to those that did not. These data strongly suggest that the<br />
metastatic potential of breast cancer cells may be driven at least in<br />
part by the recruitment of S100A8+ MDSCs. Taken together, our<br />
observations and our closer-to-primary xenograft models may lead<br />
to a better understanding of metastatic disease, as well as to the<br />
development and pre-clinical screening of targeted breast cancer<br />
therapeutics, particularly in the metastatic setting.<br />
P1-05-13<br />
CLIC3 is associated with invasive behaviour and poorer prognosis<br />
in estrogen receptor-negative breast cancer.<br />
Macpherson IR, Dozynkiewicz M, Kalna G, Speirs C, Chaudhary<br />
S, Edwards J, Timpson P, Norman J. University of Glasgow, United<br />
Kingdom; Beatson Institute for <strong>Cancer</strong> Research, Glasgow, United<br />
Kingdom<br />
Background: We previously described a Chloride Intracellular<br />
Channel-3 (CLIC3)-dependent recycling pathway which trafficked<br />
active integrins from late endosomes to the cell surface and which was<br />
required for the migratory and invasive behaviour of A2780 ovarian<br />
cancer cells in vitro. We also demonstrated that elevated expression<br />
of CLIC3 was associated with poor prognosis in pancreatic cancer.<br />
We therefore set out to investigate the role of CLIC3 in breast cancer.<br />
Materials and Methods: CLIC3 expression was assessed by<br />
immunohistochemistry and the weighted histoscore method in a tissue<br />
microarray (TMA) consisting of triplicate cores from 141 patients<br />
diagnosed with invasive estrogen receptor (ER)-negative early<br />
breast carcinoma between 1995 and 1998. Full clinicopathological<br />
and follow-up data were available. Further data were obtained from<br />
publicly available gene expression datasets (Desmedt, GSE7390)<br />
and Oncomine TM . Knockdown of CLIC3 in the ER-ve MDA-MB231<br />
breast cancer cell line was achieved by nucleofection of 2 different<br />
siRNA sequences (Dharmacon). Inverse invasion assays measured<br />
invasion into a plug of matrigel supplemented with fibronectin over<br />
72 hours whilst organotypic invasion assays measured invasion into<br />
a fibroblast-containing collagen matrix over 6 days.<br />
www.aacrjournals.org 171s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Results: CLIC3 mRNA expression was significantly elevated in breast<br />
cancer in comparison to normal breast tissue in two independent data<br />
sets. High CLIC3 protein levels were associated with significantly<br />
shorter breast cancer specific survival (p=0.026) in a TMA of 141 ERve<br />
patients. This finding was corroborated by the observation that high<br />
CLIC3 mRNA levels were associated with shorter overall survival in<br />
198 patients in the Desmedt dataset (p=0.038). Transient silencing of<br />
CLIC3 expression using two independent siRNA sequences had no<br />
effect on proliferation of MDA-MB231 cells but significantly reduced<br />
their invasiveness by 46% and 93% respectively in an inverse invasion<br />
assay and by 36% and 42% respectively in an organotypic invasion<br />
assay. CLIC3 was found to co-localise with Rab7 and LAMP1 in late<br />
endosomes/lysosomes in MDA-MB231 cells.<br />
Conclusions: Our clinical and in vitro data indicate an important<br />
role for CLIC3 in the invasive and metastatic behaviour of some<br />
breast cancers. Further work to elucidate molecular mechanisms is<br />
underway and will be presented.<br />
P1-05-14<br />
Multiscale computational modeling of breast cancer invasion:<br />
Towards a predictive patient-based tool<br />
Trucu D, Thompson A, Chaplain MAJ. University of Dundee, United<br />
Kingdom; Ninewells Hospital, University of Dundee, United Kingdom<br />
Background<br />
Understanding the mechanisms of the growth and spread of cancer<br />
cells in the human breast and providing effective treatment continues<br />
to remain a significant challenge. <strong>Cancer</strong> cell invasion of breast<br />
tissue plays a pivotal role in the metastatic cascade through complex,<br />
coupled dynamics of the constituent processes occurring over a range<br />
of spatial and temporal scales, ranging from genetic events through<br />
intracellular signaling pathways through cell-matrix interactions to<br />
tissue scale changes.<br />
Method<br />
While most previous computational modeling has been carried out<br />
at the level of a single spatial or temporal scale, the work presented<br />
here has developed a novel multiscale modeling and computational<br />
simulation framework. Formulated in both two and three spatial<br />
dimensions, this approach is based on a new type of multiscale<br />
moving boundary computational model that explores the crucial role<br />
that matrix degrading enzymes, secreted by individual cancer cells<br />
(micro-scale) along the invasive edge of the tumour, play in the overall<br />
dynamics of the tissue-scale invasion (macro-scale).<br />
Results<br />
The computational simulation results we have obtained reveal a rich<br />
variety of cancer invasion patterns that emerge in the vicinity of a<br />
primary breast cancer. In the presence of heterogeneous tissue, our<br />
computational simulation results show well-defined “lobular” and<br />
“fingering” invasion patterns, consistent with the spread of a breast<br />
carcinoma, and which remain robust with respect to any changes made<br />
in the model parameters. These patterns are found to be compatible<br />
with respect to both the dynamic heterogeneity of cancer cell macroscale<br />
distributions and to the evolution of the heterogeneity of the<br />
surrounding breast tissue.<br />
Conclusions<br />
By exploring the dynamics of the molecular processes of matrix<br />
degrading enzymes and of tissue-scale spatio-temporal cancer tissue<br />
evolution, this novel multiscale computational modeling framework<br />
faithfully replicates the cancer invasion process. Development of this<br />
computational tool should allow pre-operative breast cancer patient<br />
data to be used to predict the extent of breast cancer invasion and<br />
hence the extent of surgical resection.<br />
P1-05-15<br />
Identification of a novel Hypoxia Inducible Factor-1 regulated<br />
gene involved in breast cancer growth and metastasis<br />
Peacock DL, Schwab LP, Seagroves TN. University of Tennessee<br />
Health Science Center, Memphis, TN<br />
Introduction: Hypoxia is a hallmark of most solid tumors. In response<br />
to hypoxic stress tumor cells adapt by regulating survival, metabolism<br />
and angiogenesis. The heterodimeric Hypoxia-Inducible Factor<br />
(HIF)-1 transcription factor is a master regulator of this response. HIF-<br />
1alpha protein is over-expressed in ∼30% of primary breast tumors<br />
and ∼70% of metastases, which independently correlates with poor<br />
prognosis and decreased survival in patients. Moreover, conditional<br />
deletion of Hif1a in the mammary epithelium of the MMTV-polyoma<br />
middle T (MMTV-PyMT) transgenic model of breast cancer<br />
significantly delays mammary tumor initiation and lung metastasis<br />
burden. Methods: Our lab has established primary mammary tumor<br />
epithelial cells (MTECs) from late stage carcinomas originating in<br />
PyMT+; Hif1α floxed mice (FVB/Nj strain, F11). These MTECs<br />
were exposed to either Adenovirus-eta-βgal or -Cre to create wildtype<br />
(WT) and knock-out (KO) cells, respectively. PyMT MTECs<br />
are transplantable into syngeneic FVB/Nj female recipients. Deletion<br />
of HIF-1 activity reduced primary tumor growth by ∼60% and the<br />
formation of lung macrometastases originating from mammary fat<br />
pad tumors by >90%. Microarray profiling was conducted to identify<br />
genes differentially expressed between WT and KO cells cultured<br />
at normoxia (21% O2) or hypoxia (0.5% O2) as well as between<br />
end-stage WT and KO tumors derived from the parental cell lines.<br />
Several genes were down-regulated in both gene sets in response to<br />
deletion of Hif1a. One mRNA of particular interest, creatine kinase<br />
brain isoform (Ckb) was down-regulated in KO cells >100 fold and >2<br />
fold in end-stage tumors. Pools of stable Ckb knockdown (KD) PyMT<br />
cells were generated via lentiviral transduction of two independent<br />
shRNA constructs (pLKO.1 shc59 or shc61, each producing >75%<br />
knockdown) to determine the effects of Ckb knockdown on cell<br />
proliferation, migration and metastasis. Results: No differences in<br />
cell proliferation were observed between WT and Ckb KD cells when<br />
cultured in standard culture conditions. In contrast, when cells were<br />
introduced to the mammary fat pad, initiation of palpable tumors<br />
was delayed by >30 days for each shRNA KD line, suggesting that<br />
CKB function may be modulated by the tumor microenvironment. A<br />
significant decrease in invasion through Matrigel was also observed<br />
for each shRNA Ckb cell line. Likewise, when cells were introduced<br />
into circulation via tail vein injection, 20% of mice injected with either<br />
shc59 or shc61 cells developed lung metastases whereas 100% of mice<br />
injected with WT cells developed metastases. Bioinformatic analyses<br />
indicate that multiple putative HIF-1 binding sites (HREs) are present<br />
in both the mouse and human CKB gene promoters; chromatin<br />
immunoprecipiation (ChIP) experiments are in progress to validate<br />
that CKB is a direct HIF-1 target gene. Conclusions: HIF-1alpha<br />
strongly promotes metastasis, the major cause of mortality in breast<br />
cancer patients. Further characterization of genes downstream of<br />
HIF-1alpha, such as CKB, that play a key role in driving invasion and<br />
tumor initiation may identify new pathways amenable to therapeutic<br />
intervention for patients with metastatic breast cancer.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
172s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
P1-05-16<br />
Sushi Domain Containing 2 (SUSD2): a plasma membrane protein<br />
that increases immune evasion in breast tumorigenesis<br />
Watson AP, Davis EM, Egland KA. <strong>San</strong>ford Research/USD, Sioux<br />
Falls, SD<br />
Routinely used therapies are not adequate to treat the heterogeneity<br />
of breast cancer, and consequently, more therapeutic targets are<br />
desperately needed. To identify novel targets, we generated a breast<br />
cancer cDNA library enriched for breast cancer genes that encode<br />
membrane and secreted proteins. From this library we identified<br />
SUSD2 (Sushi Domain Containing 2), which encodes an 822 amino<br />
acid protein containing a transmembrane domain and functional<br />
domains inherent to adhesion molecules. Previous studies describe<br />
the mouse homolog, mSVS-1, but there are no studies on the human<br />
gene associated with breast cancer.<br />
Reverse-Transcriptase PCR analysis using total RNA from frozen<br />
breast cancer samples showed that SUSD2 is expressed in 19 of 24<br />
breast tumors. Immunohistochemistry (IHC) analysis was performed<br />
on human breast tissues using an anti-SUSD2 antibody. IHC showed<br />
weak or no expression of SUSD2 in normal epithelial cells, with the<br />
endothelial lining of vessels staining positive for SUSD2. However,<br />
staining was observed in pathological breast lesions and in lobular<br />
and ductal carcinomas.<br />
To explore the role of SUSD2 in breast tumorigenesis, we performed<br />
in vitro analyses of stable cell lines generated to over-express SUSD2.<br />
Our studies indicate that over-expression of SUSD2 increases the<br />
invasion of breast cancer cells through Matrigel and adhesion to<br />
fibronectin, an extracellular matrix protein. Additionally, contact<br />
between peripheral blood mononuclear cells (PBMCs) and breast<br />
cancer cells that express SUSD2 leads to diminished secretion<br />
of chemotactic cytokines and increased secretion of angiogenic<br />
cytokines compared to the empty-vector control. A similar co-culture<br />
experiment with Jurkat T cells showed increased induction of T cell<br />
apoptosis when cultured with cancer cells expressing SUSD2.<br />
Using an in vivo model with immunocompetent mice, we observed<br />
increased tumor growth and decreased survival in mice with<br />
mammary tumors expressing mSVS-1. Interestingly, increased tumor<br />
growth rate was not due to higher proliferative rates of the cells, as<br />
the Ki67 index was similar for all tumors. IHC staining with an anti-<br />
CD31 antibody revealed disordered and tortuous microvasculature<br />
in tumors expressing mSVS-1. We also characterized the population<br />
of lymphocytes in the blood, spleen and tumors of the mice as a<br />
measure of the immune response. While proportions of CD4 and<br />
CD8 cells were unchanged in the spleen and blood samples, we found<br />
significantly fewer CD4 tumor infiltrating lymphocytes in mice with<br />
tumors expressing mSVS-1.<br />
SUSD2 interacts with Galectin-1 (Gal-1), a 14-kDa secreted protein<br />
that is synthesized by carcinoma cells and promotes tumor immune<br />
evasion, angiogenesis and metastasis. Several previous studies suggest<br />
that cellular localization of Gal-1 is essential for its multiple roles in<br />
tumorigenesis. Interestingly, cell surface localization of Gal-1 was<br />
observed only in cell lines expressing SUSD2 but not the empty-vector<br />
control. Because the localization of Gal-1 on the surface of cells is<br />
dependent on the presence of SUSD2, using SUSD2 as a therapeutic<br />
target may disrupt this interaction and inhibit events required for<br />
tumorigenesis.<br />
P1-05-17<br />
S100A7/RAGE axis enhances breast cancer growth by activating<br />
Stat3 signaling<br />
Nasser MW, Wani NA, Qamri Z, Ahirwar D, Powell CA, Ganju RK.<br />
The Ohio State University, Columbus, OH<br />
S100A7 has been shown to be highly expressed in high grade ductal<br />
carcinoma in situ and invasive breast cancers. Its expression is also<br />
related to poor prognosis and associated with increased inflammatory<br />
infiltrates and various inflammatory disorders. However, the exact<br />
mechanism by which S100A7 enhances breast cancer growth and<br />
metastasis is not known. In the present study, we determined the<br />
molecular mechanisms by which S100A7 enhances growth and<br />
metastasis of breast cancer. Recently, we have shown that S100A7<br />
may mediate signaling by binding to receptor for advanced glycation<br />
end-products (RAGE). In this study, we first observed high expression<br />
of RAGE in ER-negative MDA-MB-453, MDA-MB-231 and highly<br />
metastatic SCP2 breast cancer cell lines by FACS analysis. We have<br />
also shown that S100A7 is secreted in the conditioned media of<br />
S100A7 overexpressing MDA-MB-231 cells. Recombinant soluble<br />
S100A7 was shown to induce cell migration and wound healing<br />
in MDA-MB-453, MDA-MB-231 and SCP2 cells. These effects<br />
were mediated through RAGE, as RAGE neutralizing antibody<br />
blocked S100A7-mediated functional effects. To further analyze<br />
the molecular mechanisms of S100A7-mediated signaling, we<br />
observed that recombinant S100A7 enhanced the activation of Stat3<br />
in MDA-MB-231 and SCP2 cell lines. Further analysis of molecular<br />
mechanisms revealed that S100A7 enhances ERK phosphorylation<br />
and Stat3 downstream target cyclinD1. These effects were attenuated<br />
by the treatment of soluble RAGE. We further analyzed the role of<br />
murine S100A7 (mS100a7a15) on Stat3 activation in in vivo inducible<br />
bi-transgenic MMTV-mS100a7a15 mice. These mice treated with<br />
Stat3 inhibitor showed reduced mS100a7a15-induced mammary<br />
hyperplasia and Stat3 activation in the mammary gland. We also<br />
observed that mS100a7a15 induction enhanced proliferation of<br />
mammary epithelial cells (MEC) isolated from bi-transgenic mice<br />
and this effect was attenuated by Stat3 inhibitor. Taken together,<br />
these studies reveal that S100A7 may enhance breast tumor growth<br />
and metastasis by binding to RAGE and activating Stat3 signaling.<br />
These studies may help in the development of S100A7/RAGE/Stat3<br />
as novel therapeutic targets for ER negative, especially triple-negative<br />
and basal-like cancers, which are highly aggressive and have currently<br />
been shown to enhance the Stat3 signaling pathway.<br />
P1-05-18<br />
Determining the molecular mechanism of the breast cancerinduced<br />
brain metastasis and a role of a novel pan-TGF-β<br />
inhibitor as a potential therapy for brain metastasis in a mouse<br />
xenograft model<br />
De Mukhopadhyay K, Elkahloun AG, Hinck AP, Yoon K, Cornell JE,<br />
Shu L, Yang J, Sun L. ; University of Texas Health Science Center,<br />
<strong>San</strong> <strong>Antonio</strong>, TX; National Human Genome Research Institute-NIH,<br />
Bethesda, MD<br />
<strong>Breast</strong> cancer (BCa) is the most common malignant disease in women<br />
in the U.S. Nearly 20% of patients with advanced BCa are eventually<br />
diagnosed with brain lesions, which is a devastating complication in<br />
patients with BCa over-expressing EGF receptor family members<br />
including Her2 positive and triple negative breast cancer. It is the<br />
most feared complication of BCa in part because are not capable of<br />
significantly treating the BCa-induced brain metastases due to the<br />
inability of the available treatment regimens to effectively penetrate<br />
the blood brain barrier (BBB) and also due to our limited knowledge<br />
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<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
on cellular and molecular mechanisms that drive the homing to<br />
and growth in the brain of BCa cells. Therefore, there is a need of<br />
efficient model system that can significantly contribute towards<br />
our understanding of different factors from both host and tumor<br />
leading to brain metastasis. We have recently isolated a novel BCa<br />
cell line B6TC that was generated through fusion between human<br />
BCa, MDA-MB-231 and ZR-75-1 cells in mouse bone marrow.<br />
This B6TC cell line showed higher propensity to metastasize to<br />
brain than its parental cells when inoculated through intracardiac<br />
injection in female athymic nude mice. In order to generate a highly<br />
brain metastatic breast cancer model for mechanistic research, we<br />
subjected the B6TC cells through four rounds of selection for cells<br />
that were capable of trans-endothelial cell invasion to obtain cells<br />
that could invade through BBB. This in vitro selected cell line was<br />
further subjected through three rounds of in vivo selection for cells<br />
that were capable of metastasizing to the brain and the cells after third<br />
round selection was named N3LR, which has the highest potential<br />
to cause brain metastasis. In searching for genes and pathways that<br />
may contribute to the increased brain metastasis of N3-LR cell with<br />
microarray analysis, we found that the transforming growth factorbeta<br />
(TGFβ) signaling pathway is upregulated in N3-LR cell in<br />
comparison with B6TC cell, in addition to the EGF and prostaglandin<br />
signaling pathways that have been reported to be associated with brain<br />
metastatic breast cancer cells. Functional comparison also showed that<br />
N3-LR cell was more migratory than B6TC cell and more responsive<br />
to TGFβ-induced phosphorylation of Smad3 as well as migration,<br />
suggesting that TGFβ signaling may contribute to the increased<br />
brain metastatic potential. We next investigated whether metastatic<br />
tumor growth in the brain microenvironment can be inhibited by<br />
systemic administration of a potent pan-TGFβ inhibitor, BG E RIIa<br />
recombinant fusion protein containing the endoglin domain of<br />
betaglycan (BGE) and the extracellular domain of RII. The animals<br />
were inoculated intracardically with N3LR, the most potent subline<br />
of highly metastatic B6TC cells, and were then treated with vehicle<br />
or BG E RII systemically via i.p. injection right after the inoculation.<br />
After three weeks, the BG E RII treated group showed lower brain<br />
metastasis incidence and tumor burden as detected by whole mouse<br />
bioluminescence and GFP imaging. Further analyses to understand the<br />
underlying molecular and regulatory mechanism of brain metastasis<br />
and its intervention in our mouse model is underway for the discovery<br />
of novel molecularly targeted drugs to prevent and eradicate BCa<br />
metastasis initiation, progression and recurrence.<br />
P1-05-19<br />
Modeling <strong>Cancer</strong> Recurrence and the Therapeutic Effect of<br />
Adjuvant Systemic Therapy<br />
Ganesan S, Bhanot G, Boemo M, Lee JH. <strong>Cancer</strong> Institute of New<br />
Jersey- UMDNJ, New Brunswick, NJ; Rutgers University, Piscataway,<br />
NJ<br />
Despite complete surgical removal of early stage cancers, recurrence<br />
can occur at distant locations in time spans ranging from months to<br />
decades. This is due to the presence of disseminated cancer cells that<br />
can ultimately transition into active growth leading to recurrence.<br />
Systemic adjuvant therapy can decrease the incidence of distant<br />
relapse and lead to improved survival in some cancers. In this study,<br />
data on natural recurrence patterns of different breast cancer subtypes<br />
is used to build a probabilistic model of distant recurrence. The central<br />
hypothesis of this model is that after initial local therapy, a fraction of<br />
patients will have the presence of one or more disseminated dormant<br />
metastatic foci (DMF). The transition of DMF into actively growing<br />
metastatic foci (AMF) is described using a stochastic model. DMF<br />
of individual breast cancer subclasses each have a distinct probability<br />
per unit time of entering active growth. Fitting of this model to<br />
clinical trial data of early stage breast cancers treated with surgery<br />
alone demonstrates that DMF present in estrogen receptor negative<br />
(ER-) cancers and Luminal B cancer have greater probabilities<br />
of transition to active growth per unit time than Luminal A breast<br />
cancers. Clinical trial data were then used to determine the effect<br />
of adjuvant therapy on the dynamics of tumor recurrence. The data<br />
strongly support a model in which adjuvant chemotherapy works by<br />
eliminating only a fraction of DMF that have transitioned into AMF<br />
during the time of chemotherapy treatment. Thus short duration<br />
adjuvant chemotherapy would have greater efficacy in ER-, HER+ and<br />
Luminal B breast cancers, which have fast dynamics of recurrence,<br />
and little effect in Luminal A breast cancers with far slower dynamics<br />
of recurrence. Similarly, analysis of adjuvant hormonal therapy trial<br />
data, demonstrate that hormonal therapy also affects only DMF that<br />
transition into active growth during the period of hormonal therapy.<br />
This model can explain why extended duration therapy of up to 5<br />
years is more effective than shorter duration of adjuvant hormonal<br />
therapy. Interestingly some adjuvant treatments, such as trastuzumab<br />
for HER2+ breast cancers, affect recurrence rates in a way that<br />
suggest that these interventions directly kill DMF. This model of<br />
tumor recurrence has several clinical implications that could inform<br />
future clinical trial design.<br />
P1-05-20<br />
Fluorescent Hyaluronan Probes Distinguish Heterogeneous<br />
<strong>Breast</strong> <strong>Cancer</strong> Cell Subsets and Predict their Invasive Behavior<br />
Veiseh M, Kwon DH, Borowsky AD, Toelg C, Leong H, Lewis J, Turley<br />
EA, Bissell MJ. Lawrence Berkeley National Laboratories, Berkeley,<br />
CA; University of California Davis, Davis, CA; London Health<br />
Sciences Centre-London Regional <strong>Cancer</strong> Program; University of<br />
Western Ontario, London, ON, Canada<br />
Background: Tumor heterogeneity is a determining factor in diagnosis<br />
and therapy of breast cancer (Bca). We investigated Bca cellular<br />
heterogeneity by a functional fluorescent hyaluronan (HA) probe, and<br />
monitored its binding characteristics in relation to the degree of Bca<br />
aggression. HA is a polysaccharide ligand for CD44 and RHAMM<br />
receptors, which are linked to cell plasticity and predict poor clinical<br />
outcome in Bca. Methods: Fluorescent HA probes, multiplexed<br />
profiling, and cell sorting strategies were developed and used to detect/<br />
capture tumor cell subpopulations with differences in HA binding<br />
(HA -/low vs. HA high ) and HA receptors surface display. Whereas we<br />
concentrated on the most metastatic cell line, MDA-MB-231, we<br />
also monitored the presence of subpopulations in other Bca lines<br />
and showed heterogeneity in all. Results: The HA probe binding was<br />
highly heterogeneous, and the highest binding level was detected in<br />
highly invasive triple-negative basal subtypes such as MDA-MB-231.<br />
HA probes bound to the cell surface but also accumulated in cytoplasm<br />
and nucleus. Binding levels were dramatically reduced upon<br />
‘reversion’ of highly malignant cells to a non-malignant phenotype<br />
in three-dimensional cultures, suggesting that the level of cellular<br />
binding to fluorescent HA probe provides a measure of malignant<br />
behavior. Comparison between HA high and HA -/low subpopulations<br />
revealed surprising differences in morphology, proliferation and<br />
invasion in culture, which were retained in two in vivo models. HA high<br />
subpopulations exhibited higher levels of invasion but surprisingly<br />
lower levels of proliferation compared to either unsorted parental cells<br />
or the HA -/low subpopulation. Conclusions: Querying HA binding in<br />
Bca lines reveals an unexpected heterogeneity with respect to tumor<br />
phenotype in vivo, morphology in 3D, invasion and proliferation.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
174s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
These results may aid in diagnosis and therapy of invasive Bca<br />
subpopulations and early sorting of cancer patients needing intensive<br />
chemotherapy.<br />
Keywords: Heterogeneity, 3D cultures, Hyaluronan, CD44,<br />
RHAMM/HMMR, Tumor phenotype, <strong>Breast</strong> cancer, Invasion.<br />
P1-05-21<br />
The role of epsin in promoting Epithelial-Mesenchymal Transition<br />
and metastasis by activating NF-kB signaling in breast cancer<br />
Cai X, Brophy ML, Hahn S, McManus J, Chang B, Pasula S, Chen<br />
H. Oklahoma Medical Research Foundation, Oklahoma City, OK;<br />
University of Oklahoma Health Science Center, Oklahoma City, OK<br />
Background: <strong>Breast</strong> <strong>Cancer</strong> progression and metastasis are multistep<br />
processes that involve local tumor growth and invasion followed<br />
by tumor dissemination to and re-establishment at distant sites.<br />
The ability of a tumor to metastasize is the major determinant of<br />
the mortality of cancer patients. Thus, elucidating the molecular<br />
pathways essential for tumor metastasis is of high priority in cancer<br />
biology. We have previously demonstrated that deficiency of epsins,<br />
a family of endocytic clathrin adaptor proteins, decreases tumor<br />
growth by enhancing VEGF signaling in vascular endothelial cells and<br />
subsequently promoting dysfunctional tumor angiogenesis. Research<br />
Objective: Our immediate aim in the current research is to determine<br />
the role of epsin in regulating breast cancer growth and metastasis<br />
by activating NF-κB signaling. Our ultimate goal is to seek better<br />
treatment for breast cancer patients. Rationale: Our preliminary data<br />
demonstrate that epsins are overexpressed in human cancers, including<br />
breast cancer. Knockdown of epsins in human breast cancer cell line<br />
MDA-MB-231 inhibits in vitro cell proliferation and migration.<br />
Xenograft or tail-vein injection of epsin-deficient breast cancer cells<br />
reveals marked reduction in in vivo tumorigenesis and lung metastasis.<br />
Moreover, E-cadherin is increased and vimentin decreased in epsindeficient<br />
MDA-MB-231 and in tumors derived from epsin-deficient<br />
MDA-MB-231 tumor models. Conversely, overexpression of epsin<br />
in breast epithelial cell line MCF10A and MDA-MB-231 results in<br />
decreased E-cadherin and increased vimentin expression. Hypothesis:<br />
We hypothesize that epsin regulates EMT through modulating NFκB<br />
signaling. Methods: we use combined techniques of western<br />
blot, confocal immunofluorescence and RT-PCR to examine NF-κB<br />
activation. Results: NF-κB phosphorylation, nuclear translocation<br />
and NF-κB target gene snail/slug expression is downregulated in<br />
epsin-deficient MDA-MB-231. Epsin overexpression in MDA-<br />
MB-231 increases NF-κB phosphorylation. Mechanistically, we show<br />
that epsin co-immunoprecipitates with components of TNF Receptor<br />
Signaling Complex (TNFR-SC) including TNFR1, TRADD, RIP,<br />
TRAF2 and NEMO in MDA-MB-231, which can be enhanced by<br />
TNFα stimulation. Conversely, recruitment of NEMO and TRAF2<br />
to TNFR1 is impaired in epsin-deficient MDA-MB-231 compared to<br />
control upon TNFα treatment. Given that ubiquitin-interacting motifs<br />
(UIM) of epsin is important for its interaction with ubiquitinated<br />
proteins, we show that wild type (WT) but not a UIM-deficient<br />
mutant epsin (epsin ∆UIM) coprecipitates with TNFR1 in 293T<br />
cells. Overexpression of epsin ∆UIM inhibits NF-κB activation in<br />
MDA-MB-231 and 293T cells compared to WT. In addition, UIM of<br />
epsin and polyubquitination of RIP are required for the interaction of<br />
epsin with RIP in 293T cells response to TNFα. Conclusion: epsin<br />
promotes breast cancer growth and metastasis by upregulating NFkB<br />
signaling and EMT. Epsin serves as scaffolding protein through<br />
UIM-polyubiquitin chain interaction to stabilize TNFR1 signaling<br />
complex (TNFR-SC) and subsequently enhance NF-kB signaling in<br />
breast cancer cells. Our study provides a basis for novel therapeutic<br />
targets for the development of anti-metastatic cancer treatments.<br />
P1-05-22<br />
<strong>Breast</strong> cancer cells that undergo an Epithelial-to-Mesenchymal<br />
transition co-opt LPP, a regulator of mesenchymal cell migration<br />
and invasion.<br />
Ngan E, Northey JJ, Ursini-Siegel J, Siegel PM. McGill University,<br />
Montreal, QC, Canada; Lady Davis Institute for Medical Research,<br />
Montreal, QC, Canada<br />
Transforming Growth Factor β (TGFβ) promotes breast cancer cell<br />
metastasis to multiple sites, including the bone and lungs. TGFβ is a<br />
strong inducer of Epithelial-to-Mesenchymal transitions (EMT) and<br />
breast cancers that exhibit features of an EMT acquire stem cell-like<br />
characteristics, are highly aggressive, are resistant to therapy and<br />
are refractory to tumor suppressive processes. While TGFβ itself is<br />
non-oncogenic, it is a potent modifier of the malignant phenotype in<br />
breast cancer and is capable of enhancing the migration, invasion and<br />
metastasis of ErbB2 expressing breast cancer cells.<br />
We have identified Lipoma Preferred Partner (LPP) as an<br />
indispensable regulator of TGFβ-induced migration and invasion of<br />
ErbB2 expressing breast cancer cells. LPP is ubiquitously expressed<br />
in smooth muscle cells where it mediates cell adhesion, migration<br />
and the formation of lamellipodial extensions. We hypothesize that<br />
breast cancer cells capable of undergoing an EMT can utilize novel<br />
mediators that are engaged in promoting the migration and invasion<br />
of mesenchymal cells. We propose that LPP is one such example,<br />
which promotes the migration and invasion of ErbB2 expressing<br />
breast cancer cells that have undergone a TGFβ-induced EMT.<br />
We demonstrate that ErbB2 expressing breast cancer cells display<br />
significant increases in cell migration and invasion upon TGFβ<br />
stimulation, and such responses are dependent on LPP expression.<br />
We show that LPP re-localizes to focal adhesion complexes following<br />
TGFβ-induced EMT and it is a critical determinant in focal adhesion<br />
turnover. Furthermore, we determined that LPP targeting to focal<br />
adhesions through its LIM1 domain requires the cooperation of<br />
ErbB2 and TGFβ signaling pathways. Finally, we demonstrate that<br />
LPP promotes TGFβ-induced migration and invasion of ErbB2<br />
expressing breast cancer cells through recruitment of α-Actinin, an<br />
actin cross-linking protein.<br />
Overall, we have identified LPP as a novel mediator that integrates<br />
TGFβ and ErbB2 signaling to promote the migration and invasion of<br />
breast cancer cells that undergo an EMT. Our data reveal that breast<br />
cancer cells, which can transition from an epithelial to mesenchymal<br />
phenotype, can engage a regulator of mesenchymal cell migration<br />
and invasion.<br />
P1-05-23<br />
Blockade of mTORC1 decreases CXCR4-mediated migration<br />
and metastasis<br />
Dillenburg Pilla P, Patel V, T. Dorsam R, Masedunskas A,<br />
Amornphimoltham P, Weigert R, A. Molinolo A, Gutkind JS. NIH,<br />
Bethesda, MD<br />
Tumor cells can co-opt the promigratory activity of chemokines and<br />
their cognate G protein–coupled receptors (GPCRs) to metastasize<br />
to regional lymph nodes or distant organs. Indeed, the migration<br />
toward SDF-1 (stromal cell–derived factor 1) of tumor cells bearing<br />
CXCR4 [chemokine (C-X-C motif) receptor 4] has been implicated<br />
in the lymphatic and organ-specific metastasis of various human<br />
malignancies, including breast cancer. The downstream mechanisms<br />
of CXCR4-mediated migration are not fully elucidated. The study<br />
of the precise signaling pathways involved in cell migration and<br />
metastasis in each tumor type may help identify novel therapeutic<br />
targets for improving cancer therapy. Here we show that blockade<br />
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of mTOR complex 1 (mTORC1) by Rapamycin or knocking down<br />
Raptor decreases CXCR4-Gαi mediated cell migration. Moreover,<br />
using a spontaneous lymph node metastasis model, we were able<br />
to show that pharmacological blockade of mTORC1 decreases<br />
lymph node metastasis in vivo. Taken together our data suggest that<br />
Rapamycin, a FDA-approved drug, could be beneficial to prevent<br />
tumor cells spreading from the primary tumor and metastasize.<br />
Molecular events underlying the effects of Rapamycin on CXCR4-<br />
induced migration will be presented.<br />
This research was supported [in part] by the Intramural Research<br />
Program of the NIH, NIDCR.<br />
P1-05-24<br />
Pharmacologic reversion of epigenetic silencing of the PRKD1<br />
promoter blocks breast tumor cell invasion and metastasis.<br />
Borges S, Doppler H, Andorfer CA, Perez EA, Sun Z, Anastasiadis<br />
PZ, Thompson AE, Geiger XJ, Storz P. Mayo Clinic, Jacksonville,<br />
FL; Mayo Clinic, Rochester, MN<br />
Epigenetic silencing of tumor suppressing genes by promoterspecific<br />
DNA methylation is common in many types of cancer.<br />
As an early event, this process has been well shown to promote<br />
tumor initiation and progression; however little is known how<br />
such epigenetic silencing can contribute to tumor metastasis. The<br />
PRKD1 gene encodes Protein Kinase D1 (PKD1), a serine/threonine<br />
kinase expressed in epithelial cells of the normal mammary gland<br />
that maintains the epithelial phenotype of normal breast cells and<br />
prevents epithelial-to-mesenchymal transition (EMT). PKD1 is<br />
also a critical suppressor of tumor cell invasion and is silenced in<br />
expression and activity during breast tumor progression. Here, we<br />
show that aberrant methylation of PRKD1 promoter region is not only<br />
correlated with the silencing of its expression but is also associated<br />
with invasiveness of breast cancer cell lines and with aggressiveness<br />
of breast tumors. Using the highly invasive MDA-MB-231 cells,<br />
we show that the inhibition of PRKD1 promoter methylation with<br />
the DNA methyltransferase inhibitor decitabine restores PKD1<br />
expression and significantly decreases their invasive abilities in<br />
vitro. More importantly, in a tumor xenograft model it dramatically<br />
blocks tumor spread and metastasis to the lung in a PKD1-dependent<br />
fashion. Our data suggest that the status of epigenetic regulation of the<br />
PRKD1 promoter can provide valid information on the invasiveness<br />
of breast tumors, and therefore could serve as an early diagnostic<br />
marker. Moreover, targeted upregulation of PKD1 expression may<br />
be used as a therapeutic approach to reverse the invasive phenotype<br />
of breast cancer cells.<br />
P1-06-01<br />
Upregulation of metabolism as a potential resistance mechanism<br />
to bevacizumab in primary breast cancer<br />
Mehta S, Hughes NP, Adams RF, Li SP, Han C, Kaur K, Taylor NJ,<br />
Padhani AR, Makris A, Buffa FM, Harris AL. Weatherall Institute of<br />
Molecular Medicine, Oxford, United Kingdom; Stanford University,<br />
Stanford, CA; Oxford University Hospitals NHS Trust, Oxford, United<br />
Kingdom; Mount Vernon <strong>Cancer</strong> Centre, Northwood, Middlesex,<br />
United Kingdom; <strong>Cancer</strong> and Haematology Centre, Churchill<br />
Hospital, Oxford, United Kingdom; Paul Strickland Scanner Centre,<br />
Mount Vernon Hospital, Northwood, Middlesex, United Kingdom<br />
Background: Recently the FDA has withdrawn the indication for<br />
bevacizumab in metastatic breast cancer after several clinical studies<br />
failed to demonstrate an overall survival benefit. These studies<br />
however did report an increase in response rates to chemotherapy<br />
and improvement in progression free survival, suggesting a pattern<br />
of response to the drug followed by the development of resistance.<br />
We have little knowledge of the molecular mechanisms driving the<br />
development of resistance to bevacizumab. To better understand these<br />
mechanisms, we have conducted a window of opportunity study<br />
using a single cycle of bevacizumab with detailed pharmacodynamic<br />
assessments using gene expression arrays and dynamic contrastenhanced<br />
magnetic resonance imaging (DCE-MRI).<br />
Methods: After ethical approval, 47 newly diagnosed locally<br />
advanced breast cancer patients were prospectively enrolled in this<br />
trial. Patients received single dose bevacizumab (15mg/ kg) 2 weeks<br />
prior to neoadjuvant chemotherapy and underwent core biopsies for<br />
gene expression and immunohistochemistry analysis and DCE-MRI<br />
scans before and 2 weeks after bevacizumab. 35 patients who had<br />
invasive ductal carcinoma together with good quality MRI scans and<br />
core biopsies before and after bevacizumab were included in this<br />
analysis. Pharmacokinetic (PK) modelling techniques were used to<br />
quantify PK parameters (K trans , k ep , v e ) from the DCE-MRI data. Gene<br />
expression profiling was performed using the Affymetrix Human<br />
Exon 1.0 ST arrays.<br />
Results: The majority of patients (28 / 35) showed a significant<br />
reduction in vessel permeability and blood flow of at least 30%<br />
following bevacizumab, with a mean decrease in the forward transfer<br />
constant (P < 0.0001) and the reverse rate constant k ep (P < 0.0001).<br />
From gene expression and immunohistochemistry analyses, we<br />
identified several key metabolism-related genes that are significantly<br />
up-regulated after bevacizumab treatment, including pyruvate<br />
dehydrogenase kinase isozyme 1 (PDK1) (fig.1) and carbonic<br />
anhydrase 9 (CA9). In addition, we found a number of interesting<br />
genes that are down-regulated after bevacizumab treatment, including<br />
sulfatase-1 (SULF1), and cyclin E1 (CCNE1).<br />
Discussion: This study highlights that the combination of DCE-MRI<br />
and gene expression arrays can lead to an improved understanding<br />
of the molecular mechanisms governing response and resistance to<br />
anti-angiogenic therapy. Heterogeneity of response to bevacizumab<br />
was demonstrated, with some tumours showing increases or no<br />
change in K trans and others marked reductions, which may be of value<br />
in early stratification for therapy maintenance. Furthermore, the gene<br />
expression analysis showed activation of pathways, which could<br />
contribute to the development of resistance. For example, we observed<br />
significant up regulation of genes involved in regulating the switch<br />
from mitochondrial metabolism to glycolysis, such as PDK1. This<br />
suggests that using bevacizumab with the other targeted agents such<br />
as Dichloroacetate, a PDK1 inhibitor might be helpful in overcoming<br />
the development of resistance and ultimately lead to improved patient<br />
survival. Our preclinical studies strongly support this possibility.<br />
P1-06-02<br />
A newly angiogenic biomarker Vasohibin-1 expression in ductal<br />
carcinoma in situ of the breast.<br />
Tamaki K, Tamaki N, Kamada Y, Uehara K, Miyashita M, Ishida T,<br />
Ohuchi N, Sasano H. Nahanishi Clinic Okinawa, Naha, Okinawa,<br />
Japan; Tohoku University Graduate School of Medicine, Sendai,<br />
Miyagi, Japan; Tohoku University Hospital, Sendai, Miyagi, Japan<br />
Vasohibin-1 is a recently identified negative feedback regulator of<br />
angiogenesis induced by VEGF-A and bFGF. Our previous study<br />
was the first study demonstrating the status of vasohibin-1 in human<br />
breast lesions, which indicates that vasohibin-1 is associated with<br />
neovascularization and may especially play important roles in the<br />
regulation of intratumoral angiogenesis in human breast cancer.In<br />
this study, we first evaluated mRNA expression of vasohibin-1 and<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
176s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
CD31 in 39 Japanese emale breast carcinoma specimens including<br />
22 invasive ductal arcinoma (IDC) and 17 ductal carcinoma in situ<br />
(DCIS) using a real-time quantitative RT-PCR (QRT-PCR) with<br />
LightCycler system. Table shows the primer sequences used in realtime<br />
PCR in this study.<br />
Primer sequences used in real-time PCR in this study<br />
Gene (accession no.) Primer for PCR Size (bp)<br />
CD31 (NM000442) Forward: GATGTCAGAAACCATGCAA 199<br />
Reverse: AGCCTTCCGTTCTAGAGTATC<br />
Vasohibin-1 (KIAA1036) Foreward: AGATCCCCATACCGAGTGTG 167<br />
Reverse: GGGCCTCTTTGGTCATTTCC<br />
RPL13A (NM012523) Forward: CCTGGAGGAGAAGAGGAAAAG 125<br />
Reverse: TTGAGGACCTCTGTGGTATTT<br />
In addition, we also immunolocalized vasohibin-1 and CD31 and<br />
compared their immunoreactivity to nuclear grades and histological<br />
grades of 100 carcinoma cases (50 IDC and 50 DCIS). There were<br />
no statistically significant differences of CD31 mRNA expression<br />
and the number of CD31 positive vessels between DCIS and<br />
IDC (P = 0.250 and P = 0.191, respectively), whereas there was a<br />
statistically significant difference in vasohibin-1 mRNA expression<br />
and the number of vasohibin-1 positive vessels in DCIS and IDC (P<br />
= 0.022 and P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
as 0, 1+, 2+ or 3+; however, scoring was tabulated in two ways. The<br />
first was an absolute HER2 score based solely on analysis of the<br />
carcinoma, and the second was a normalized HER2 score, obtained<br />
by subtracting the score of the non-neoplastic breast epithelium from<br />
that of the infiltrating cancer. FISH was performed using the Vysis<br />
PathVysion combined HER2 and CEP17 probe kit with morphometric<br />
analysis performed using a MetaSystems image analysis system that<br />
incorporated the Metafer software. A score of > 2.2 was required for<br />
classification as amplified, and 2.0), borderline (1.5 to 2.0)<br />
and negative. (2.0, 1.8 to 2.0 and
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
P1-07-05<br />
Evaluation of tissue processing factors affecting HER2 IHC<br />
staining intensity in breast cancer cell lines<br />
Jensen K, Erickson J, Webster S, Pedersen HC. Dako Denmark,<br />
Glostrup, Denmark; Dako North America, Carpinteria, CA<br />
Background<br />
In breast cancer the HER2 status as established by IHC (e.g.<br />
HercepTest) determines eligibility for HER2 targeted therapy.<br />
Pre-analytical procedures including tissue processing create variation<br />
in HER2 intensity seen in breast cancer tissues. Therefore, there is a<br />
need for a greater understanding of the effects of the individual tissue<br />
processing steps on HER2 staining intensity.<br />
Control cell lines (CCL) are commonly used as staining run controls<br />
in immunohistochemistry (IHC) in both pharmacodiagnostic,<br />
routine and in clinical research. As a surrogate for cancer tissue,<br />
these immortalized cancer cells can serve as a model system for<br />
investigating the effect of process variables on staining intensity.<br />
This study was designed to investigate if variations in cell/tissue<br />
processing (fixation, embedding and sectioning) affect the IHC<br />
staining intensity in a HER2 formalin- fixed, paraffin-embedded<br />
(FFPE) control cell lines.<br />
To introduce a more objective scoring we have evaluated the<br />
application of digital image analysis combined with design of<br />
experiment (DOE) statistics.<br />
Methods<br />
The following tissue processing parameters were investigated:<br />
embedding medium (HistoGel or agarose), fixation time (18 or 48<br />
hours in neutral buffered formalin), density of cells (25% or 50%)<br />
and thickness of cut sections (2 µm, 4 µm or 6 µm). Factors were<br />
set up in a 2 k factorial experimental design; all slides were stained<br />
with Dako HercepTest. All slides were scanned, analyzed and<br />
compared on two different image analysis systems: ACIS®III (Dako)<br />
and Scanscope CS (Aperio).<br />
The DOE statistical analysis revealed the contribution of individual<br />
factors as well as any additive effect of a combination of factors.<br />
Analysis was based on the level of intensity as well as histoscores.<br />
Results<br />
In a 2 4 DOE experiment, several of the parameters described above<br />
were associated with decreased staining intensity: increased fixation<br />
time (p < 0.001), decreased section thickness (p < 0.001) and<br />
decreased cell density (p < 0.001). In a separate 2 3 experiment, it<br />
was shown that fixation media in combination with cell density was<br />
associated with changes in staining intensity (p values from 0.001 to<br />
0.022). Three different algorithms and two different slide scanners<br />
were tested and results were consistent regardless of the image<br />
analysis system or the algorithm used.<br />
Conclusions<br />
This study identified several tissue processing factors which impact<br />
IHC staining intensity in a HER2 expressing CCL. The discovery<br />
of these effects has advanced the understanding of processing<br />
methodology and the influence of pre-analytical factors on HER2<br />
IHC staining intensity.<br />
The application of a DOE setup with quantification by image<br />
analysis can be a useful tool for the systematic evaluation of several<br />
variables compared with the standard “one factor at a time” design.<br />
A multifactor effect between fixation media and cell density was<br />
detected which would not have been possible in a “one factor at a<br />
time” design. Implementing the knowledge achieved from this study<br />
provides a methodology for standardizing tissue processing and<br />
thereby improving HER2 testing in breast cancer.<br />
P1-07-06<br />
Effect of biospecimen variables on proteomic biomarker<br />
assessment in breast cancer<br />
Meric-Bernstam F, Akcakanat A, Chen H, Sahin A, Tarco E, Carkaci<br />
S, Adrada B, Singh G, Anh-Do K, Garces Z, Mittendorf EA, Babiera<br />
G, Wagner J, Bedrosian I, Krishnamurthy S, Symmans WF, Gonzalez-<br />
Angulo AM, Mills G. UT MD Anderson <strong>Cancer</strong> Center, Houston, TX;<br />
Ohio State University, Columbus, OH<br />
Background: PI3K/Akt/mTOR signaling is being actively pursued as<br />
a therapeutic target. We sought to determine how tumor heterogeneity<br />
and biospecimen variables affect assessment of PI3K/Akt/mTOR<br />
pathway activation.<br />
Methods: Intraoperative image-guided core-needle biopsies (CNB)<br />
of primary breast tumors were prospectively collected in 53 patients<br />
with invasive breast cancer. After surgery, specimens were collected<br />
from the center and periphery of the excised tumor. CNB, central<br />
and peripheral surgical specimens were assessed with reverse phase<br />
proteomic arrays (RPPA), H&E and immunohistochemistry (IHC).<br />
Results: The expression of standard of care markers ER, PR, and<br />
HER2 by RPPA correlated well between biospecimen types. Overall,<br />
there was a significant correlation between the expression of 132<br />
(86%) of 154 different markers in the center and periphery; the<br />
correlation was significantly higher for smaller tumors, and with<br />
shorter cold ischemia time. Expression of many investigational<br />
prognostic markers and druggable targets on CNB correlated with<br />
expression in the surgical specimen (average of center and periphery),<br />
while others, such as EGFR and c-MET, had a weak correlation. Of<br />
154 RPPA markers, 132 (86%) were not statistically different between<br />
the center and periphery, and 97 (67%) were not different between<br />
the CNB and the surgical specimen. On analysis of the PI3K/AKT/<br />
mTOR pathway, pAkt S473 and PTEN had a significant correlation<br />
between central and peripheral specimens, and between CNB and<br />
surgical specimens. However, pAkt S473, pS6 S235/236 and pS6<br />
240/244 levels were higher in CNB than the central specimens both<br />
by RPPA and by IHC. When patients were classified by RPPA PI3K<br />
pathway activation score, there was a moderate agreement between<br />
classification on the CNB and central specimens (Cohen’s Kappa<br />
0.539). However 9 of 20 tumors classified as having PI3K activation<br />
on CNB were classified as not having pathway activation on central<br />
specimens.<br />
Conclusions: There is remarkable homogeneity in expression<br />
of biomarkers within a tumor. However, proteomic markers are<br />
differentially expressed by biospecimen type and other preanalytic<br />
variables. PI3K pathway activation is greater in CNB compared to<br />
surgical samples.<br />
P1-07-07<br />
Inflammatory gene expression variations in the interval between<br />
core needle biopsy and excisional biopsy in early breast cancer<br />
Jeselsohn RM, Regan MM, Werner L, Fatima A, He HH, Brown M,<br />
Iglehart JD, Richardson AL, Come S. Beth Israel Deaconess Medical<br />
Center, Boston, MA; Dana Farber <strong>Cancer</strong> Institute, Boston, MA;<br />
Brigham and Women’s Hospital, Boston, MA<br />
Introduction: Advancements in molecular biology have unveiled<br />
multiple breast cancer promoting pathways and potential therapeutic<br />
targets. Large randomized clinical trials remain the ultimate means<br />
of validating therapeutic efficacy, but they require large cohorts of<br />
patients and are lengthy and costly. An alternative approach is to<br />
conduct a window of opportunity study in which patients are exposed<br />
to a drug pre-surgically during the interval between the core needle<br />
biopsy (CNB) and the definitive surgery (excisional biopsy (EB)).<br />
www.aacrjournals.org 179s<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
These are non-therapeutic studies and the end point is not clinical or<br />
pathological response but rather evaluation of molecular changes in<br />
the tumor specimens that can predict response. However, since the end<br />
points of the non-therapeutic studies are biologic, it is critical to first<br />
define any biologic changes that occur in the absence of treatment. In<br />
this study, we compared the molecular profiles of breast cancer tumors<br />
at the time of the diagnostic biopsy versus the definitive surgery in<br />
the absence of any intervention.<br />
Methods: The study was conducted with DFCI/HCC IRB approval<br />
and patient consent. Post-menopausal women with a breast lesion<br />
suspected to be cancerous were eligible for this study. We obtained<br />
a tissue specimen at the time of a CNB and if determined to be<br />
consistent with invasive carcinoma a second specimen was obtained at<br />
the time of the EB. We used the Nanostring Ncounter system to study<br />
the expression level of 148 transcripts. Since we expected that most<br />
of the tumors will be hormone receptor positive (HR+), the library<br />
included; genes that have been shown to be prognostic in HR+ tumors<br />
(Oncotype DX®, PAM50), estrogen receptor (ER) modulators, ER<br />
responsive genes and inflammatory genes. The Wilcoxon’s signed<br />
rank test was used to evaluate for changes in gene expression levels<br />
between the paired samples.<br />
Results: 25 patients were enrolled in this study and paired tumor tissue<br />
samples were obtained from all patients. 21 of the paired samples<br />
were successfully analyzed by the nanostring system. 86% of the<br />
patients are HR+/Her2-.We found that the gene expression levels<br />
of 14 out of the 148 genes (9%) did change between the CNB and<br />
EB without any intervention (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
Method. Patients with primary breast carcinoma treated at our center<br />
who had complete ER status from January 1990 to December 2011<br />
were included in this study. Patients were excluded if they presented<br />
with recurrent or metastatic disease. For statistical analyses, patients<br />
who underwent surgery for breast cancer were separated into three<br />
groups: ER-positive ≥10%, ER-positive 1-10% and ER negative.<br />
Analyses comparing various clinical and pathologic characteristics<br />
among patients with different ER status were performed. Survival<br />
rates were calculated by the Kaplan-Meier method.<br />
Result. Patients whose tumors were ER-positive 1-10% (2.7%)<br />
were younger (median age 53 Vs. 56 years, P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
structures were analyzed at 100X. IHC was performed using Abs<br />
directed to the following PR phosphorylated sites (pAb) pSer 162,<br />
190, 294, 400 and 554. Six samples were selected for IHF using a<br />
secondary fluorescent Ab. RESULTS: All cases were PR [+]. At<br />
high magnification (100X), 2 PR nuclear distribution patterns were<br />
observed: a diffuse finely granular staining (D) or an aggregated<br />
pattern (A). This resulted in 3 tumor phenotypes (PR B Ab): A cells<br />
only in 2 cases, D cells only in 6, and a mixture of both A and D cells<br />
(AD) in 4. PR [-] malignant cells were present in various proportions.<br />
The IHF results were consistent with IHC studies. Only pAb to<br />
pSER190 was specific and sensitive, with a smaller number of [+]<br />
malignant cells relative to the standard PRB. CONCLUSION: We<br />
have developed an IHC method that utilizes formalin-fixed paraffinembedded<br />
tissue allowing the technique to be applied on a routine<br />
basis. Three classes of PR nuclear distribution have been defined: D,<br />
A and AD. D is consistent with the expression of PR that is weakly<br />
transcriptionally active or inactive and thus potentially predictive of<br />
poor patient response to antiPg. The A or AD pattern of PR nuclear<br />
distribution indicates active PR; patients with this pattern may exhibit<br />
a increased probability of benefiting from an antiPg. Preclinical<br />
studies have demonstrated that activated PR [+] cells can in turn<br />
stimulate PR [-] (stem or progenitor) mammary epithelial cells via<br />
secreted factors. In light of these findings, we are expanding the<br />
cohort to refine and confirm this biomarker technique. Additional<br />
preclinical work is ongoing to expand the biological rationale and to<br />
evaluate this technique alongside other technologies such as PR gene<br />
expression analysis. We anticipate that approximately 50% of PR+<br />
BC cases contain the A/AD phenotye and therefore may benefit from<br />
antiPg. The method of IHC described herein is a clinically applicable<br />
tool that may allow for selection of patients most likely to respond<br />
to antiPg treatment.<br />
and negation identification. The output from the NLP system was<br />
further processed in three steps: Identification of the HER2 concept,<br />
followed by extraction of the most likely HER2 value, and lastly, a<br />
decision module to select the most likely HER2 value if there were<br />
conflicting values.<br />
Results:<br />
Use the cancer registry data as the gold standard, for positive and<br />
negative HER2 values, the sensitivity and specificity of the NLP<br />
algorithm were 94.7% and 93.3%, respectively, including the cases<br />
where NLP did not select either positive or negative values. A manual<br />
chart review was performed on the discrepant cases. We found that the<br />
NLP were correct for many of these cases. For example, out of the 39<br />
NLP positive but registry negative cases, 4 were false positives and<br />
35 were true positives. Compared to the cancer registry data, NLP<br />
increased capture of positive and negative HER2 cases from 49% to<br />
73% of the cohort population.<br />
Discussion:<br />
NLP provides the opportunity to process clinical notes which are added<br />
to the EMR after the cancer registry has completed documenting the<br />
patients’ initial course of cancer treatment. On the other hand, NLP<br />
was not able to access some of the HER2 related clinical notes. For<br />
example, according to our chart review, some notes were stored as<br />
scanned images and not retrievable. In addition, clinical notes with<br />
incorrect filing dates so patients without any diagnosis date were not<br />
processed. We also identified key challenges in determining HER2<br />
results using NLP in this study. First, non-standard terminology for the<br />
HER2 receptor in the clinical notes hampered the NLP effectiveness.<br />
Second, clinicians described HER2 results in many different ways.<br />
NLP compared to the <strong>Cancer</strong> Registry<br />
HER2 Values # of Patients NLP Positive NLP Negative NLP neither Pos/Neg<br />
Registry Positive 266 252 9 5<br />
Registry Negative 1140 39 1064 30<br />
P1-07-12<br />
Using Natural Language Processing to Identify and Extract HER2<br />
Value from a large EMR system<br />
Zheng C, Avila C, Haque R. Kaiser Permanente Southern California,<br />
Pasadena, CA<br />
Background:<br />
HER2 status is important in breast cancer prognosis but has not been<br />
well collected in NCI-SEER affiliated cancer registries until recent<br />
years. For example, in a cohort of 2,846 women who were diagnosed<br />
with breast cancer from 1997 to 2011 in a large health plan, only<br />
49% of these patients had known HER2 status. However, many of<br />
these with missing HER2 status were documented in clinical notes.<br />
This study used Natural Language Processing (NLP) technology<br />
to identify and extract HER2 status. NLP results were validated by<br />
comparison with cancer registry data and any discrepancies were<br />
manually reviewed.<br />
Method:<br />
We assembled a cohort of 2,846 breast cancer patients from the<br />
membership of a health plan based in southern California, Kaiser<br />
Permanente. All free text notes including pathology reports, progress<br />
notes, and discharge summaries were extracted from our electronic<br />
medical record (EMR) system. A window of 9 months before and after<br />
the diagnosis date was applied to restrict the number of notes needed<br />
to be processed. Overall, 513,903 clinical notes were processed and<br />
indexed, which averages to 180 notes per patient. Separate ontologies<br />
were created for the HER2 terminology and HER2 status. HER2<br />
status values included positive, negative, borderline, test performed<br />
and test not performed. The NLP system employed additional<br />
components such as spelling correction, acronym recognition<br />
P1-07-13<br />
Prognostic relevance of statistically standardized estrogen<br />
receptor (ER), progesterone receptor (PR), and human epidermal<br />
growth factor receptor 2 (HER2) in tamoxifen(TAM)-treated<br />
NCIC CTG MA.14 patients<br />
Chapman J-AW, Sgroi D, Goss PE, Richardson E, Binns SN, Zhang Y,<br />
Schnabel CA, Erlander MG, Pritchard KI, Han L, Shepherd LE, Pollak<br />
MN. NCIC Clinical Trials Group, Queen’s University, Kingston, ON,<br />
Canada; Harvard University, Boston, MA; bioTheranostics, Inc.,<br />
<strong>San</strong> Diego, CA; Sunnybrook Odette <strong>Cancer</strong> Centre, University of<br />
Toronto, ON, Canada; Jewish General Hospital, McGill University,<br />
Montreal, QC, Canada<br />
Background: Poor inter-laboratory comparability of common<br />
clinically used breast cancer biomarkers led to a proposal of statistical<br />
standardization (SS) of laboratory results, similar to bone mineral<br />
density (BMD) z-scores. This analysis is the first utilization of SS in a<br />
trial where all women received TAM. Methods: MA.14 allocated 667<br />
postmenopausal women to TAM +/- Octreotide LAR (OCT) based on<br />
locally determined ER/PR, without HER2 status. At 9.8 yrs median<br />
follow-up, the secondary endpoint of relapse-free survival (RFS) had<br />
a non-significant hazard ratio (HR) for TAM-OCT to TAM of 0.87<br />
(95% CI 0.63-1.21; p=0.40). 299 patients who were representative of<br />
MA.14 patients by treatment and stratification factors (exact Fisher<br />
p-values=0.19-0.90) had their tumors centrally assessed for ER, PR,<br />
and HER2 by RT-PCR. Continuous values were used for SS of each<br />
biomarker. Univariate (uni) assessment used similar categorizations<br />
as those for BMD, assigning ER/PR/HER2 values by number of<br />
standard deviations (SD) about the mean (Group 1, z-score ≥1.0 SD<br />
below mean; Group 2, z-score
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
≤1.0 SD above mean; Group 4, z-score >1.0 SD above mean). A logrank<br />
statistic was used to test for differences between SS biomarker<br />
groups with K-M plots for graphical description. Multivariate (multi)<br />
effects of SS biomarkers and baseline patient characteristics on RFS<br />
were examined with exploratory (un)stratified Cox step-wise forward<br />
regression, adding a factor if likelihood ratio criterion was p≤0.05.<br />
Sensitivity analyses used a prior external HER2+ cut-point of ≥1.32<br />
SD. Results: 292 patient samples passing internal analytical quality<br />
control were included in this analysis. Uni analyses indicated SS<br />
ER was not associated with RFS (p=0.31). SS PR had a significant<br />
uni effect on RFS [p=0.03; Group 4 compared to Group 1, HR of<br />
0.33 (95% CI 0.12-0.90); Group 3 compared to Group 1, HR of 0.42<br />
(95% CI 0.21-0.83); and Group 2 compared to Group 1 HR of 0.70<br />
(95%CI 0.36-1.37)]. SS HER2 also had a significant uni effect on<br />
RFS [p=0.004; Group 4 compared to Group 1, HR of 0.90 (95% CI<br />
0.37-2.16)]; Group 3 compared to Group 1, HR of 0.39 (95% CI<br />
0.18-0.84); and, Group 2 compared to Group 1, HR of 0.34 (95%<br />
CI 0.16-0.70)]. Multi stratified/unstratified Cox models indicated T1<br />
tumours (p=0.02/p=0.0002) and higher SS PR (p=0.02/0.01) were<br />
associated with significantly longer RFS; other unstratified results<br />
showed that N-ve patients had better RFS (p0.05). The HER2+ cut-point<br />
of ≥1.32 SD indicated directionally worse RFS (uni p-value=0.05;<br />
multi p-value=0.06). Discussion: In MA.14, all women received<br />
TAM. Local ER/PR status using categorical or semi-quantitative<br />
values did not impact RFS. A statistically standardized approach using<br />
continuous centralized ER, PR, HER2 by RT-PCR demonstrated that<br />
increasing PR values were associated with better RFS. Evaluation in<br />
other trials may provide support for this methodology.<br />
P1-07-14<br />
Enabling biomarker validation in breast cancer molecular<br />
subtypes: sensitivity and specificity of array-based subtype<br />
classification in 983 patients<br />
Györffy B, Lanczky A. Semmelweis University<br />
Background: The diverse breast cancer molecular subtypes have<br />
different clinicopathological characteristics and outcomes. Here,<br />
we assessed the correlation between microarray-defined and authorreported<br />
molecular subtypes using publicly available breast cancer<br />
datasets.<br />
Methods: GEO was searched for datasets where the authors<br />
determined molecular subtypes. The molecular subtype was recalculated<br />
for each patient using the StGallen guidelines by assessing<br />
the microarray-based expression of ER, HER2 and MKI67 (Basal:<br />
ER negative + HER2 negative, Luminal A: ER positive + HER2<br />
negative + low MKI67, HER2 enriched: HER2 positive + ER negative,<br />
Luminal B: ER positive + HER2 positive and ER positive + HER2<br />
negative + high MKI67). The thresholds used were 500 for ER (probe<br />
set 205225_at), 4800 for HER2 (216836_s_at) and 470 for MKI67<br />
(212021_s_at). Sensitivity and specificity were calculated for each<br />
subtype separately.<br />
Results: Molecular subtype was published in all together six datasets<br />
(GSE1456, GSE21653, GSE25066, GSE20711, GSE31519 and<br />
GSE17907) for 983 patients. In these, 380, 306, 169 and 128 were<br />
Basal, Luminal A, Luminal B and HER2 enriched, respectively. The<br />
microarray-based molecular subtype determination resulted in a<br />
sensitivity of 0.70, 0.55, 0.63 and 0.38 and a specificity of 0.96, 0.87,<br />
0.67 and 0.99 for Basal, Luminal A, Luminal B and HER2 enriched<br />
subtypes, respectively. Finally, the option to filter for molecular<br />
subtypes was implemented into our online biomarker validation<br />
platform at www.kmplot.com.<br />
Discussion. Microarray data provided highest sensitivity and<br />
specificity to independent subtype classification for Basal tumors,<br />
while the luminal B subtype displayed the highest discordance.<br />
Our registration-free online service enables the validation of gene<br />
expression based biomarkers in each subtype separately.<br />
P1-07-15<br />
Revisiting chromosome 17q copy number aberrations in early<br />
high-risk breast cancer<br />
Kotoula V, Bobos M, Eleftheraki AG, Timotheadou E, Razis E, Goussia<br />
A, Levva S, Kalogeras KT, Pectasides D, Fountzilas G. Hellenic<br />
Cooperative Oncology Group (HeCOG), Athens, Greece<br />
Background — Aim: HER2 and TOP2A gene status are of prognostic/<br />
predictive relevance and are broadly determined with fluorescent in<br />
situ hybridization (FISH). For this purpose, probes against (A)<br />
17p11.1-q11.1 (>5Mb, CENtromere), (B) 17q12 (600Kb, including<br />
HER2 among other genes), and (C) 17q21-22 (500Kb, similarly<br />
including TOP2A) are used, and gene pathology is determined by<br />
B/A and C/A signal ratios according to consensus cut-offs. However,<br />
chromosome 17 (chr17) and 17q pathology is complex and may be<br />
misinterpreted by this approach, especially in cases with low copy<br />
gains. Herein, we profiled A, B and C signals in 1027 adjuvantly<br />
treated, early breast cancer patients.<br />
Methods: Maximal A, B, C copy numbers (raw FISH data) were<br />
submitted to hierarchical clustering as continuous variables. Clusters<br />
were compared with clinicopathological parameters, conventional<br />
FISH ratios, and were evaluated for their prognostic significance<br />
(overall survival, OS) with respect to tumor Ki67 status (13% cut-off),<br />
TopoIIa protein (5% cut-off) and ER/PgR positivity (1% cut-off).<br />
Results: Clustered values resulted into 832 (81%) putatively chr17<br />
stable tumors (ABC low ) and 195 17q unstable tumors. Out of these,<br />
43 (4%) had possible chr17 gain (ABC high ), 30 (3%) HER2/TOP2A<br />
gain (BC high ), and 122 (12%) HER2 gain (B high ). Unstable 17q was<br />
more frequent in Ki67 high, ER/PgR negative, high-grade tumors, and<br />
were almost exclusively present in luminal-HER2 and HER2-enriched<br />
tumors (all Pearson’s p’s
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P1-07-16<br />
Liver derived epithelial cells as source of false positive circulating<br />
tumor cells in early breast cancer<br />
Habets L, Körber W, Frenken B, Danaei M, Kusche M, Peisker<br />
U, Kroll T, Pachmann K. Metares.e.V, Aachen, NRW, Germany;<br />
Brustzentrum Aachen Kreis Heinsberg, Aachen, NRW, Germany;<br />
Medizinische Universitätsklinik Jena, Thueringen, Germany<br />
The MAINTRAC technique as introduced by our coworkers from<br />
Jena (RBC lysis,fluorometric detection and analysis on Olympius<br />
ScanR) detects more circulating epithelial cells than techniques<br />
using enrichment. Also cells with a low EPCAM expression are<br />
detected and not only the typical cells with bright expression found<br />
after immunomagnetic enrichment. The relative cheapness and<br />
reproducibility allows frequent monitoring during and after therapy<br />
Using 3 colour detection (EPCAMfitc, DAPI, Vimentin PE) living and<br />
dead circulating epithelial cells in EMT, or cells in EMT with stemcell<br />
markers (EPCAMfitc, Vimentin-PE, CD44PacBlue) can be detected.<br />
In early breast cancer (n=135) cells can be found in 60% of patients<br />
and in 40% higher cell counts (>100 ml are detectable. A control<br />
population(n=100) showed low numbers in 98% (e.g (
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
P1-07-18<br />
Association between Bone Turnover Markers in patients<br />
with breast cancer and bone metastases on treatment with<br />
bisphosphonates (ZOMAR study)<br />
Tusquets I, De la Piedra C, Manso L, Crespo C, Gómez P, Calvo L,<br />
Ruiz M, Martínez P, Perelló A, Antón A, Codes M, Margelí M, Murias<br />
A, Salvador J, Seguí MA, De Juán A, Gavilá J, Luque M, Pérez D,<br />
Zamora P, Arizcum A, Chacón JI, Heras L, Barnadas A. Hospital<br />
del Mar, Barcelona, Spain; Instituto de Investigación <strong>San</strong>itaria<br />
Fundación Jiménez Díaz, Madrid, Spain; Hospital 12 de Octubre,<br />
Madrid, Spain; Hospital Universitario Ramón y Cajal, Madrid, Spain;<br />
Hospital Universitario Vall d’Hebrón, Barcelona, Spain; Hospital<br />
Universitario A Coruña Juan Canalejo, A Coruña, Spain; Hospital<br />
Universitario Virgen del Rocío, Sevilla, Spain; Hospital de Basurto,<br />
Vizcaya, Spain; Hospital Son Dureta, Palma de Mallorca, Spain;<br />
Hospital Miguel Servet, Zaragoza, Spain; Hospital Virgen Macarena,<br />
Sevilla, Spain; H. Universitario Trias y Pujol, Barcelona, Spain;<br />
Hospital Universitario Insular de Gran Canaria, Gran Canaria,<br />
Spain; Hospital Nuestra Señora de Valme, Sevilla, Spain; Hospital<br />
Parc Taulí Sabadell, Barcelona, Spain; Hospital Marqués Valdecilla,<br />
<strong>San</strong>tander, Spain; Instituto Valenciano de Oncología, Valencia, Spain;<br />
Hospital General de Asturias, Oviedo, Spain; Hospital Costa del Sol,<br />
Málaga, Spain; Hospital La Paz, Madrid, Spain; Hospital Palencia<br />
Río Carrión, Palencia, Spain; Hospital Virgen de la Salud, Toledo,<br />
Spain; Hospital Cruz Roja Hospitalet del Llobregat, Barcelona,<br />
Spain; Hospital <strong>San</strong>ta Creu i <strong>San</strong>t Pau, Barcelona, Spain<br />
Background:<br />
The presence of bone metastases (BMe) alters the balance of bone<br />
remodeling and consequently, levels of bone turnover markers (BTM).<br />
Increased levels of these biomarkers are related to the risk of skeletalrelated<br />
events (SREs), disease progression and death. Treatment with<br />
bisphosphonates reduces the probability of SREs through osteoclastic<br />
activity inhibition. The aim of this study was to determine the relation<br />
between BTM, bone metastasis development and SREs, disease<br />
progression and death in patients with breast cancer (BC) and BMe.<br />
Patients and methods:<br />
Observational, prospective and multicenter study. Patients with BC<br />
and BMe; no previous bone treatment in the last 6 months prior to<br />
study entry. Urinary aminoterminal telopeptide of collagen I (NTX,<br />
Osteomark NTx Urine, Wampole Laboratories, USA); urinary<br />
alpha-alpha-isomer of carboxyterminal telopeptide of collagen I<br />
(αα-CTX, ALPHA Crosslaps EIA, ids, UK) and serum bone alkaline<br />
phosphatase (BALP, OSTASE BAP, ids, UK) were determined at<br />
baseline (V0) and every 3 mo along 18 months (V6). Patients were<br />
treated with zoledronic acid (ZA) at inclusion and every 3-4 weeks.<br />
Results:<br />
234 patients with BC and BMe were analyzed. BTM results were<br />
available for 219 patients at basal visit (V0) and every 3 mo of<br />
treatment along 18 months (V6). Population basal characteristics<br />
(234 patients): mean age: 59.8 years; ER+: 80.3%; PR+: 64.9%;<br />
HER 2+: 18.3%. Patients with pathologic baseline levels were: 49.8%<br />
NTX, 39.6% αα-CTX and 83.4% BALP. A significant decrease was<br />
observed in BTM at V2 vs V0 after 6 months: 13.7%, 8.4% and 58.4%<br />
presented pathologic values of NTX, αα-CTX and BALP respectively.<br />
Normalized levels remained steady throughout 18 mo follow-up,<br />
finding significant decrease for each BMT for each time point except<br />
at V6 for αα-CTX. Regarding association between BTM and SREs,<br />
progression and exitus, a significant association was observed between<br />
pathologic levels of BTM throughout follow-up: with SRE at V3,V4<br />
for NTX; with disease progression at V3,V4,V5,V6 for NTX, at V2<br />
for αα–CTX and at each follow up visit for BALP; and with death<br />
at V1,4,5 for NTX, at V5 for αα–CTX and at V1,2,3,4,5 for BALP.<br />
Conclusions:<br />
Addition of ZA to standard systemic therapy reduced BTM levels<br />
during the first 3 months of treatment and normalized levels remained<br />
steady throughout 18 months follow up except at Month 18 for αα-<br />
CTX. Pathological levels of BTM were significantly associated with<br />
SRE, disease progression and death.<br />
P1-07-19<br />
Mass Spectrometry Based Quantitative Analysis of the HER<br />
Family receptors in FFPE <strong>Breast</strong> <strong>Cancer</strong> Tissue<br />
Hembrough TA, Scaltriti M, Serra V, Jimenez J, Perez J, Liao<br />
W-L, Thyparambil S, Cortes J, Baselga J, Burrows J. OncoPlex<br />
Diagnostics, Inc., Rockville, MD; Vall d’Hebron Istitute of Oncology,<br />
Barcelona, Spain; Massachusetts General Hospital, Boston, MA<br />
The human EGF receptor family (HER’s) consists of two clinically<br />
validated drug targets (EGFR and HER2), a third (HER3) currently<br />
under investigation for its possible role in the acquisition of multidrug<br />
resistance and a fourth (HER4), the role of which is still matter of<br />
debate. Drugs inhibiting EGFR or HER2 show significant antitumor<br />
activity in the clinic, however, acquisition of resistance is a hallmark<br />
of these and most targeted therapies. In the case of EGFR and HER2,<br />
one of the emerging resistance mechanisms is the co-expression<br />
of HER3. Indeed, recent reports show that inhibition of the PI3K<br />
pathway leads to upregulation of HER3, and subsequent resistance.<br />
Clinical analysis of protein levels in formalin fixed paraffin embedded<br />
(FFPE) tissues is limited to immunohistochemistry (IHC), which<br />
is semi-quantitative and requires significant amounts of tissue.<br />
Moreover, the vast majority of research groups consider specific<br />
HER3 staining by IHC particularly challenging. However, accurate<br />
measurement of these targets is critical both for properly defining<br />
treatment groups and predicting patterns of resistance.<br />
In order to address these issues, we used trypsin digestion mapping<br />
and stable isotope labeled peptides to develop a panel of quantitative<br />
mass spectrometric (MS) assays to measure the levels of EGFR,<br />
HER2, HER3 and other clinically relevant targets in FFPE breast<br />
cancer tissue. These quantitative MS assays were then multiplexed<br />
to analyze 1µg of tumor protein.<br />
In this study, we multiplexed HER family analysis on 31 HER2<br />
positive breast cancers. Tumor tissue was microdissected from<br />
FFPE sections, and subjected to quantitative MS analysis of EGFR,<br />
HER2, HER3 as well as IGF1R and cMET. Quantitation of HER2<br />
showed a broad range of HER2 expression in these tissues. The<br />
highest expresser measured 26 fmol/ug tumor tissue, representing<br />
amplification and massive protein over expression. In contrast, five<br />
tissues showed low levels of HER2 expression, below 1 fmol/ug,<br />
similar to HER2 non-amplified cell lines. This suggests that MS<br />
quantitation can identify patients with low expression of HER2 who<br />
are unlikely to respond to trastuzumab therapy. As a matter of fact, 3<br />
of these 5 low expressing patients had outcome data and showed no<br />
response to trastuzumab treatment.<br />
In 28 of 31 patient tissue samples, HER3 showed low levels of<br />
expression (100-300 amol/ug tumor tissue) similar to HER3<br />
expression in cell lines, and comparable to low expressing EGFR<br />
and HER2 cell lines. The remaining 3 patients had no detectable<br />
HER3. This study demonstrates the feasibility of measuring HER3<br />
in multiplex in FFPE breast cancer tissue. Based on the low but<br />
widespread expression of HER3 in this cohort, it may be most useful<br />
to assess HER3 expression after initial treatment as a marker of<br />
potential resistance to targeted therapies.<br />
Taken together, these data demonstrate that a sensitive and quantitative<br />
assay to measure oncoproteins in FFPE clinical samples may help<br />
www.aacrjournals.org 185s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
stratify patients with variable expression of these targets. Our<br />
quantitation of oncogene expression from clinical samples uses a<br />
small amount of tissue, is clinically applicable and alleviates the<br />
problem of scoring either positive or negative for the expression of<br />
a given protein.<br />
P1-08-01<br />
Effects Of An Allosteric AKT Inhibitor (MK2206) Administered<br />
With Or Without The Aromatase Inhibitor Vorozole In An ER +<br />
Rat Mammary <strong>Cancer</strong> Model: Preventive And Therapeutic<br />
Effects<br />
Lubet RA, Ellis MJ, Grubbs CJ. National <strong>Cancer</strong> Institutes, Bethesda,<br />
MD; University of Washington at Saint Louis, MO; University of<br />
Alabama at Birmingham, AL<br />
The AKT inhibitors appear to hold some promise with regards to<br />
inhibition of ER + breast cancers which have relapsed. It has been<br />
hypothesized that the combination of an aromatase inhibitor plus an<br />
AKT inhibitor may be particularly effective. We, therefore, tested<br />
whether an allosteric AKT inhibitor (MK2206) alone or together<br />
with the aromatase inhibitor vorozole would be effective in a<br />
preventive and/or therapeutic setting. Female Sprague-Dawley rats<br />
were administered a single IV dose of methylnitrosourea (MNU)<br />
at 50 days of age. Beginning 5 days later, rats were administered<br />
the AKT inhibitor. In a preliminary study, two treatment regimens<br />
were employed: (1) dosing with inhibitor (100 mg/Kg BW/day, 7X/<br />
week) or (2) dosing with inhibitor (700 mg/Kg BW, 1X/week). These<br />
treatments minimally affected tumor multiplicity, but did significantly<br />
decrease tumor weights. We then examined the effects of combining<br />
the AKT inhibitor once weekly with a suboptimal dose of vorozole<br />
(0.12 mg/Kg BW/day) in a therapeutic setting. In a separate study,<br />
rats were treated with MNU and were allowed to develop their first<br />
palpable cancer. They were then treated with the combination of<br />
vorozole plus the AKT inhibitor or vehicle for 6 weeks. While tumors<br />
in vehicle treated rats grew an average of 600%, tumors treated with<br />
the inhibitor grew an average of only 95%; and, in fact, 5/12 showed<br />
a decrease in tumor size. Finally, we performed a similar combined<br />
study in a prevention setting. Dosing was: (a) AKT inhibitor (700 mg/<br />
Kg BW, 1X/week), (b) Vorozole (0.12 mg/Kg BW/day, 7X/week),<br />
(c) a plus b combined, and (d) vehicle. A, b, and c reduced tumor<br />
multiplicity by 26, 48 and 77%, respectively. Thus, combining an AKT<br />
inhibitor with an aromatase inhibitor showed synergy in prevention<br />
and treatment of ER + tumors.<br />
P1-08-02<br />
Gene expression changes in methylnitrosourea (MNU)-induced<br />
ER + mammary cancers following short-term treatment of rats<br />
with SERMs (Tamoxifen and Arzoxifene)<br />
Lubet R, Vedell P, Grubbs C, Bernard P, You M. National <strong>Cancer</strong><br />
Institute, Bethesda, MD; Medical School of Wisconsin, Milwaukee,<br />
WI; Hunstman <strong>Cancer</strong> Center, Salt Lake City, UT; University of<br />
Alabama at Birmingham, AL<br />
SERMs have proven to be highly effective in both therapy and<br />
prevention of ER + breast cancers. Tamoxifen has been the most<br />
commonly used SERM, but arzoxifene (another high- affinity<br />
competitive SERM agonist) showed strong activity in early clinical<br />
trials against ER + breast cancer; although further development was<br />
discontinued. Both SERMs have shown a dose dependent effect on<br />
prevention and therapy of rat mammary tumors in the ER + MNU<br />
model of cancer. Of interest, the doses required for prevention was<br />
significantly lower than the doses required for therapy. In the present<br />
study, rats bearing mammary cancers induced by MNU were treated<br />
with tamoxifen (0.66, 3.3, 20 and 100 ppm in diet) or arzoxifene (3.0<br />
ppm in diet) for 5 days. Global gene expression analysis showed<br />
that more than 100 genes were down-regulated and more than 100<br />
genes were up-regulated (p< 0.05 and fold change >1.5) in cancers<br />
treated with tamoxifen doses > 3 ppm; and that many of these gene<br />
changes were dose dependent. The genes modulated by tamoxifen<br />
and arzoxifene were enriched in the cell cycle pathway that were<br />
related to chromosome condensation in prometaphase [including<br />
Aurora-A, Aurora-B, Bub1B, non-SMC condensing I complex,<br />
subunit H (BRRN1), Condensin, CAP-G, CAP-G/G2, CAP-H/H2,<br />
CAP-D2/D3, CAP-E, TOP2, Cyclin A, Cyclin B, CDK1, Histone<br />
H1 and inter-centromere protein (INCENP]. Employing a different<br />
set of tamoxifen treated samples, we were able to confirm that many<br />
of the same genes were modulated employing a quantitative RT-<br />
PCR assay. Finally, we will compare certain of the gene changes<br />
obtained in the animal model with gene changes observed in human<br />
neoadjuvant trials.<br />
P1-09-01<br />
Long-term effect of tamoxifen use on the risk of contralateral<br />
breast cancer<br />
Mellemkjær L, Steding-Jessen M, Frederiksen K, Andersson M, Olsen<br />
JH. Danish <strong>Cancer</strong> Society Research Center, Copenhagen, Denmark;<br />
Copenhagen University Hospital, Rigshospitalet, Copenhagen,<br />
Denmark<br />
Background: Tamoxifen has been used widely in the treatment of<br />
breast cancer due to its beneficial effects on recurrences and mortality.<br />
Both randomized trials and observational studies give evidence that<br />
tamoxifen also reduces the incidence of contralateral breast cancer.<br />
The effect of tamoxifen seems to be present not only during treatment<br />
but also after termination of treatment, but the question is how long<br />
this effect lasts. Few studies have presented long-term follow-up<br />
data on risk of contralateral breast cancer after tamoxifen treatment.<br />
Material and Methods: In the Danish <strong>Breast</strong> <strong>Cancer</strong> Cooperative<br />
Group (DBCG) Database, we identified 50,323 women who had<br />
undergone surgery for invasive breast cancer and who had received<br />
treatment according to DBCG guidelines during 1978-2007. Among<br />
these women, 16,319 were users of tamoxifen while 34,004 were<br />
non-users. Contralateral breast cancer cases were identified in the<br />
Danish <strong>Cancer</strong> Registry and in the DBCG Database through 2009.<br />
The incidence of contralateral breast cancer among users of tamoxifen<br />
was compared to that of non-users by estimating incidence rate<br />
ratios (IRRs) in Cox regression analyses with adjustment for age at<br />
first breast cancer diagnosis, calendar period at first breast cancer<br />
diagnosis, histology of first breast cancer, radiotherapy, chemotherapy<br />
and other endocrine treatments besides tamoxifen.<br />
Results: During follow-up, 295 cases of contralateral breast cancer<br />
were observed among users of tamoxifen while 1,485 cases were<br />
observed among non-users resulting in an IRR of 0.82 (95% CI =<br />
0.71-0.94) after adjustments. Further analyses will include calculation<br />
of IRRs for contralateral breast cancer by time since breast cancer<br />
diagnosis, duration of tamoxifen and time since cessation of tamoxifen<br />
as well as calculation of IRRs after restriction to estrogen receptor<br />
positive breast cancer patients. Results of these analyses will be<br />
presented.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
186s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
P1-09-02<br />
Pilot study of a 1-year intervention of high-dose vitamin D in<br />
women at high risk for breast cancer.<br />
Sivasubramanian PS, Hershman DL, Maurer M, Kalinsky K, Feldman<br />
S, Brafman L, Refice S, Kranwinkle G, Crew KD. Columbia University,<br />
New York, NY<br />
Background: Selective estrogen receptor modulators (SERMs)<br />
have been shown to decrease breast cancer incidence among highrisk<br />
women, but uptake for prevention has been poor. Observational<br />
studies have demonstrated that serum 25-hydroxyvitamin D (25-<br />
OHD) is inversely related to breast cancer risk, such that levels >40<br />
ng/ml are associated with about a 40% reduction in breast cancer risk<br />
compared to women who are vitamin D deficient (25-OHD 5 years) were assigned to a 1-year intervention of<br />
vitamin D3 20,000 or 30,000 IU weekly. Other eligibility criteria<br />
included baseline mammographic density (MD) ≥25%, serum 25-<br />
OHD ≤32 ng/ml, no current SERM use and no history of kidney<br />
stones. Women underwent a digital mammogram at baseline and<br />
12 months, and serial blood draws every 3 months. In addition,<br />
random core breast biopsies were conducted in premenopausal<br />
women, whereas postmenopausal women underwent a breast MRI<br />
at baseline and 12 months. Participants were monitored for toxicity,<br />
particularly hypercalcemia and hypercalciuria, every 3 months. The<br />
primary objective is to determine the safety and feasibility of highdose<br />
vitamin D in this study population. Secondary objectives are<br />
to determine changes in breast density and blood-based biomarkers<br />
(25-OHD, 1,25(OH)D, PTH, IGF-I, IGFBP-3). Serum 25-OHD was<br />
measured by Diasorin radioimmunoassay.<br />
Results: From November 2007 to January 2011, 292 women were<br />
screened and 142 were ineligible. Main reasons for ineligibility (%)<br />
included 25-OHD >32 ng/ml (27), opted for SERM (23), prior kidney<br />
stones (11), and MD 0.37) and 1 withdrew due to dyspepsia. Mean serum 25-OHD<br />
rose to 47 ng/ml at 3 months, 49.1 ng/ml at 6 months, and 53.7 ng/ml<br />
(range, 26-77) at 12 months. No significant hypercalcemia (serum Ca<br />
>10.5 mg/dl) occurred at either dose level. Imaging and biomarker<br />
analyses are ongoing.<br />
Discussion: We have demonstrated that a 1-year intervention of<br />
high-dose vitamin D3 is well tolerated and can increase serum 25-<br />
OHD above a target level of 40 ng/ml. This preliminary data has<br />
informed an ongoing phase IIb randomized placebo-controlled trial<br />
(SWOG 0812) of high-dose vitamin D in 200 high-risk premenopausal<br />
women and highlights the importance of early phase breast cancer<br />
chemoprevention trials with intermediate biomarker endpoints to<br />
test novel agents.<br />
P1-09-03<br />
Chemoprevention in patients with newly diagnosed breast cancers<br />
Refinetti AP, Chun J, Schnabel F, Guth A, Axelrod D. NYU Langone<br />
Medical Center, New York, NY<br />
Background<br />
Chemoprevention (including tamoxifen, raloxifene, and exemestane)<br />
is a strategy to reduce breast cancer incidence in high risk women.<br />
Studies have shown at least a 50% decrease in the incidence of breast<br />
cancer in users of these drugs. Despite this benefit, the majority<br />
of high risk, unaffected women who are offered chemoprevention<br />
decline the therapy. However, there is a growing population of women<br />
who have used these agents for primary prevention, and a larger<br />
population of survivors who have used these drugs as part of their<br />
systemic treatment. The purpose of this study was to identify a cohort<br />
of women with newly diagnosed breast cancers who had utilized<br />
chemoprevention and describe their patterns of disease.<br />
Methods<br />
The <strong>Breast</strong> <strong>Cancer</strong> Database of NYU Langone Medical Center was<br />
queried for patients who used chemopreventive drugs and developed<br />
breast cancer between 1/2010-1/2012. Patients were divided into<br />
primary and secondary chemoprevention groups (no previous history<br />
of breast cancer and previous history of breast cancer, respectively).<br />
Descriptive statistics were utilized.<br />
Results<br />
In the study period, 24 (2%) of 996 patients had used a chemopreventive<br />
agent. For 16 of the 24 (67%), the drug was part of systemic therapy<br />
for prior breast cancer, with a median of 12 years from the initial<br />
diagnosis to the diagnosis of a second breast cancer. The primary<br />
chemoprevention group included women with risk based on family<br />
history and atypical hyperplasias. The majority of patients were<br />
diagnosed with early stage disease (88% DCIS and stage I). This<br />
likely reflects their screening behaviors. In both groups, the majority<br />
of cancers were ductal in origin. Five of the 8 patients in the primary<br />
chemoprevention group were on treatment at the time of their cancer<br />
diagnosis, while 63% of patients in the secondary group were prior<br />
users. In the secondary group, the majority of cases were contralateral<br />
second primary breast cancers, with 31% ipsilateral recurrences.<br />
Interestingly, the majority of cancers in both groups were ER/PR<br />
positive.<br />
Clinical Characteristics<br />
VARIABLES TOTAL N=24 (%) PRIMARY N=8 (%)<br />
SECONDARY N=16<br />
(%)<br />
FHBC<br />
Positive 14 (58) 5 (63) 9 (56)<br />
Negative 10 (42) 3 (37) 7 (44)<br />
AH, LCIS<br />
AH 6 (25) 5 (63) 1 (6)<br />
LCIS 2 (8) 2 (25) 0 (0)<br />
HISTOLOGY<br />
DCIS 9 (38) 5 (63) 4 (25)<br />
IDC 13 (54) 2 (25) 11 (69)<br />
ILC 0 (0) 0 (0) 0 (0)<br />
Mixed 2 (8) 1 (12) 1 (6)<br />
ER<br />
Positive 19 (79) 7 (88) 12 (75)<br />
Negative 5 (21) 1 (12) 4 (25)<br />
PR<br />
Positive 15 (63) 6 (75) 9 (56)<br />
Negative 9 (37) 2 (25) 7 (44)<br />
CHEMOPREVENTION TYPE<br />
Tamoxifen 17 (71) 4 (50) 13 (81)<br />
Raloxifene 5 (21) 4 (50) 1 (6)<br />
AI 2 (8) 0 (0) 2 (13)<br />
CHEMOPREVENTION DURATION<br />
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
will need to be modified in light of prior hormonal treatment. Many<br />
of the patients in the secondary group were past users of prevention<br />
agents and further work is needed to clarify the duration of benefit<br />
of these drugs. In a similar vein, we look forward to research efforts<br />
to define the optimal age to initiate primary chemoprevention in<br />
high risk women.<br />
P1-09-04<br />
Down-regulation of trefoil protein 1(TFF1) in normal breast<br />
tissue of postmenopausal women at increased risk for breast<br />
cancer on exemestane<br />
Gatti-Mays M, Kallakury BVS, Makariou E, Venzon D, Permaul<br />
E, Isaacs C, Cohen P, Warren R, Gallagher A, Eng-Wong J.<br />
Georgetown University Hospital, Washington, DC; National <strong>Cancer</strong><br />
Institute, National Institutes of Health, Bethesda, MD; Lombardi<br />
Comprehensive <strong>Cancer</strong> Center, Georgetown University Medical<br />
Center, Washington, DC; Lombardi Comprehensive <strong>Cancer</strong> Center,<br />
Georgetown University Hospital, Washington, DC<br />
Background: Aromatase inhibitors (AI) are effective for breast cancer<br />
risk reduction in postmenopausal women. TFF1, also known as pS2,<br />
is an estrogen response gene present in normal mammary tissue with<br />
increased expression in estrogen receptor positive breast cancer.<br />
Previous studies have demonstrated down-regulation of TFF1 and Ki-<br />
67, a marker of proliferation, in postmenopausal women with locally<br />
advanced breast cancer who receive neoadjuvant AIs. TFF1 and<br />
proliferating cell nuclear antigen (PCNA) may serve as biomarkers<br />
of effect of AIs in women at increased risk for breast cancer.<br />
Methods: We conducted a single-arm phase II trial of exemestane<br />
in women at increased risk for breast cancer and examined the<br />
impact on TFF1 and PCNA. Postmenopausal women at increased<br />
risk for invasive breast cancer by clinical or histological criteria<br />
received 25mg of exemestane daily for 2 years. Subjects were<br />
required to have stopped any hormonal medication ≥ 3 months prior<br />
to enrollment. Image guided breast biopsies targeting dense breast<br />
tissue were performed at baseline and at 12 months. Core specimens<br />
were obtained under local anesthesia at each time point from the<br />
same area of the breast. One core biopsy sample was formalin-fixed,<br />
paraffin-embedded and examined for pathologic abnormalities, as<br />
well as TFF1 and PCNA. TFF1 was assessed by intensity of stain (0<br />
to 3+) and percent of cells with any staining; PCNA was assessed<br />
by percent of cells staining within the tissue section. The pathologist<br />
(B.K.) was blinded to the time of biopsy. Change in intensity and %<br />
positive cells were evaluated by paired t-test.<br />
Results: Thirty four subjects underwent both baseline & 12 month<br />
breast biopsies. Eight biopsies at baseline and 5 biopsies at 12 months<br />
did not contain any ductal or lobular tissue and were not analyzed.<br />
Twenty-two subjects had evaluable breast tissue at both time points<br />
for TFF1 analysis and 23 subjects for PCNA analysis. No high risk<br />
lesions or invasive cancers were identified. Of the baseline specimens,<br />
95.5% were positive for TFF1: 59.1% (13 of 22) were scored as<br />
3+(intense), 31.8% (7 of 22) were 2+(moderate) and 4.5% (1 of 22)<br />
were 1+(low). Percent of cells staining for TFF1 ranged from 0 to 20%<br />
(median=1%). After 1 year on exemestane TFF1 intensity decreased<br />
in 17 subjects (77.3%), 4 had no change and 1 increased. Mean TFF1<br />
change was -1.32 (95% CI -1.87 to -0.76; p < 0.001). The change in<br />
% positive cells for PCNA ranged from -15 to +30% (median = 0%).<br />
Discussion: Assessing tissue biomarkers with repeat core needle<br />
biopsies in a phase II prevention trial in high risk women is feasible.<br />
Since prevention agents are not universally protective, determining<br />
biomarkers of effect may allow tailored therapy. TFF1 is a biologically<br />
plausible biomarker of AI activity that was down-regulated in 77% of<br />
breast tissue following exemestane therapy. This is the first study to<br />
evaluate this tissue marker in the prevention setting. Further study is<br />
needed to correlate with other biomarkers of interest, e.g. change in<br />
mammographic density, serum hormone levels and clinical outcomes.<br />
P1-09-05<br />
The RAZOR trial: a phase II prevention trial of screening plus<br />
goserilin and raloxifene versus screening alone in pre-menopausal<br />
women at increased risk of breast cancer.<br />
Motion J, Ashcroft L, Dowsett M, Cuzick J, Hickman J, Evans G,<br />
Eccles D, Eeles R, Greenhalgh R, Affen J, Bundred S, Boggis C,<br />
Sergeant J, Fallowfield L, Adams J, Howell A. University Hospital<br />
South Manchester, Manchester, United Kingdom; The Christie NHS<br />
Foundation Trust, Manchester, United Kingdom; Royal Marsden<br />
Hospital, London, United Kingdom; Queen Mary, University of<br />
London, United Kingdom; Princess Anne Hospital, Southampton,<br />
United Kingdom; The Institute of <strong>Cancer</strong> Research, Royal Marsden<br />
Hospital, London, United Kingdom; University of Sussex -<br />
(SHORE-C), Brighton, United Kingdom; University of Manchester,<br />
United Kingdom; Manchester Royal Infirmary, Manchester, United<br />
Kingdom<br />
Background: Observational studies indicate that oophorectomy at<br />
about age 40 reduces breast cancer risk by approximately a half in<br />
high risk women. Widespread use of risk reducing oophorectomy is<br />
unlikely to be acceptable to these women. We explored the feasibility<br />
of giving goserelin to produce reversible ovarian suppression together<br />
with raloxifene to maintain bone mineral density (BMD). Objectives:<br />
The primary study objective was adherence to treatment. Secondary<br />
objectives were uptake of randomisation, side effects/quality of life<br />
and measures of effect on bone and in serum. Methods: Recruitment<br />
was from 3 UK Family History Clinics. Consenting women at ≥ 1 in 3<br />
lifetime risk of breast cancer were randomised to control or monthly<br />
subcutaneous goserelin 3.6 mg and raloxifene 60 mg/d orally for two<br />
years. Questionnaires (Endocrine Symptom Checklist, Trait & State<br />
Anxiety, Sexual Activity & <strong>Cancer</strong> Worry) measuring toxicity/quality<br />
of life were administered by nurses. Dual energy X-ray absorptiometry<br />
(DXA) BMD measurements were performed in the treatment arm<br />
annually. Lipids and collagen breakdown products were measured by<br />
standard methods. Results: 75 of 511 (14.7%) women approached<br />
agreed to randomisation (38 to treatment and 37 to control). The<br />
major reason for non-entry was fear of side effects (85%). Median<br />
age was 37 and 35 years, for the experimental (A) and control arm<br />
(B), respectively. Median follow up is 8.8 years. 20/38 in arm A and<br />
27/37 of controls completed the 24 m study. 18/38 women in arm A<br />
withdrew (13 [34%] because of side effects) and 10/37 in arm B for<br />
various reasons including the desire for risk reducing surgery (n=4).<br />
No significant differences were seen in the Endocrine Symptom Subscale,<br />
State or Trait anxiety or <strong>Cancer</strong> Worry. However, Hot flushes,<br />
night and cold sweats (together p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
significant symptoms and bone loss, thus methods to ameliorate these<br />
need to be developed if ovarian suppression is to play a role in breast<br />
cancer prevention.<br />
P1-09-06<br />
Biological Effects of Green Tea Capsule Supplementation in Presurgery<br />
<strong>Breast</strong> <strong>Cancer</strong> Patients<br />
Yu S, Spicer D, Hawes D, Wu A. University of Southern California,<br />
Los Angeles, CA<br />
Green tea is rich in antioxidant polyphenols consisting primarily<br />
of epicatechins, epigallocatechin, epicatechin gallate, and<br />
epigallocatechin gallate ( EGCG). There are suggestive evidence<br />
from observational epidemiologic studies that regular green tea<br />
consumers may have lower risk of breast cancer development and<br />
mortality. Inhibition of cell proliferation and angiogenesis and<br />
enhancement of apoptosis are some of the mechanisms that have been<br />
proposed to explain the anti-cancer actions of the bioactive extracts<br />
of green tea. We conducted a randomized pre-surgical pilot study<br />
of green tea capsules in women diagnosed with breast cancer at the<br />
Los Angeles County-University Southern California Medical Center.<br />
Women in both the green tea and control arms were non-green tea<br />
drinkers at baseline ( i.e. less than 1 cup of green tea per week at the<br />
time of breast cancer diagnosis). Women (n=17) who participated<br />
in the green tea arm took 3 green tea capsules daily (Pro Health<br />
Green Tea Mega EGCG, 3 capsules contained ∼ 870 mg EGCG;<br />
equivalent to ∼ 8 cups of green tea) between their breast cancer<br />
diagnosis until their scheduled surgery date. The average duration<br />
of green tea intake was 35 days. Women in the control arm did not<br />
drink green tea between diagnosis and surgery date. Participants in<br />
the green tea and control groups donated blood and urine specimens<br />
at enrollment and before surgery which were tested for urinary tea<br />
catechin levels as a measure of compliance. Baseline urinary tea<br />
catechin concentrations were low in both green tea and control arms.<br />
Tea catechin concentrations remained low for women in the control<br />
arm but increased significantly ( 2-10 folds for different catechins) for<br />
women in the green tea arm. The differences in pre-surgery urinary<br />
green tea levels were significantly different between these groups of<br />
participants We conducted standard immunohistochemical analysis<br />
of the formalin-fixed paraffin-embedded respective markers of cell<br />
proliferation (Ki67), apoptosis (BAX), and angiogenesis (CD34).<br />
Separate analysis was performed on benign and malignant breast<br />
cancer tissue. The changes in these three biomarkers pre- and posttreatment<br />
in the two groups will be presented.<br />
Supported by the WHH Foundation.<br />
P1-09-07<br />
Topical 4-OHT trial in women with DCIS of the breast: report of<br />
plasma and breast tissue concentration of tamoxifen metabolites<br />
Lee O, Chatterton RT, Muzzio M, Page K, Jovanovic B, Helenowski I,<br />
Dunn B, Heckman-Stoddard B, Foster K, Shklovskaya J, Skripkauskas<br />
S, Bergan R, Khan SA. Northwestern University, Chicago, IL; IIT<br />
Research Institute, Chicago, IL; National <strong>Cancer</strong> Institute, Bethesda,<br />
MD<br />
Background: Earlier studies have shown that 1-2mg of<br />
4-hydroxytamoxifen (4–OHT) gel applied to the breast skin reduced<br />
cell proliferation in estrogen receptor (ER) positive invasive cancers<br />
to a similar degree as oral tamoxifen (TAM), with significantly lower<br />
plasma levels. We now report results of a Phase IIB pre-surgical<br />
window trial of women with DCIS, designed to obtain pilot data in<br />
early lesions. Our ultimate goal is to develop transdermal 4-OHT as an<br />
alternative to oral TAM for women at high risk for breast cancer and<br />
those with DCIS. The study was closed early because the manufacturer<br />
discontinued the drug supply, but remains blinded until all biomarker<br />
analysis is complete. Here we report the plasma and breast adipose<br />
tissue concentration of TAM metabolites from the topical 4-OHT<br />
gel group (4 mg) in comparison with the oral TAM group (20mg).<br />
Methods: Women with DCIS were enrolled, and randomized to<br />
4-OHT gel (4mg/day, 2mg per breast, E: Z isomers =1:1,) or to oral<br />
(Z) TAM (20mg/day) for 4-10 weeks before surgery. Blood was<br />
collected on the day of surgery, and breast adipose tissue was collected<br />
at surgery. There were a total of 22 patients with matched blood and<br />
breast adipose tissue. The concentration of TAM metabolites in plasma<br />
and breast tissue was determined with liquid chromatography/tandem<br />
mass spectrometry. We assumed that the subjects with detectable<br />
N-desmethyl TAM (NDT) in plasma belong to the oral TAM group<br />
because NDT is not a product of 4-OHT metabolism. Under this<br />
assumption, 13 subjects were categorized into oral TAM group, and<br />
9 subjects into the topical 4-OHT group. Wilcoxon rank-sum test was<br />
used for statistical analysis.<br />
Results: The results are shown in the table. The concentration is<br />
presented as mean ± SD; the lowest quantitation limit (LQL) was 1<br />
ng/mL for plasma, and 3 ng/g for tissue. TAM and its metabolites<br />
were found in the plasma of the presumed oral TAM group, with high<br />
levels of TAM and NDT. In the presumed 4-OHT gel group, only (Z)<br />
4-OHT was found in the plasma although both (E) and (Z) forms were<br />
applied. The mean plasma level of 4-OHT in the gel group was 70%<br />
lower than the mean of 4-OHT in the oral TAM group (p=0.004).<br />
In breast tissue, similar amounts of (E) and (Z) forms of 4-OHT<br />
were found in the 4-OHT gel group, with the (Z) 4-OHT level being<br />
equivalent to that in the oral TAM group (p=0.48). Endoxifen was<br />
only found in the oral TAM group. We saw no evidence of further<br />
metabolic transformation of 4-OHT in the breast following topical<br />
administration.<br />
Compounds measured Plasma, ng/mL<br />
<strong>Breast</strong> tissue, ng/g<br />
Oral TAM(n=13) 4-OHT gel(n=9) Oral TAM(n=13) 4-OHT gel(n=9)<br />
(Z) TAM 92.8 ± 46.3
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
expression of MMP-9. MMP-9 mRNA levels were analyzed by realtime<br />
PCR. NF-κB and AP-1 DNA binding was analyzed by EMSA.<br />
Results: Our results showed that curcumin inhibits TPA-induced<br />
MMP-9 expression and cell invasion through suppressing NF-κB<br />
and AP-1 activation. Curcumin strongly repressed the TPA-induced<br />
phosphorylation of p38 and JNK and also inhibited TPA-induced<br />
translocation of PKCa from the cytosol to the membrane, but did not<br />
affect the translocation of PKCδ.<br />
Conclusion: It is concluded that curcumin inhibits the TPA-induced<br />
MMP-9 expression and cell invasion through the suppression of<br />
the PKCα/MAPK/NF-kB/AP-1 pathway in MCF-7 breast cancer<br />
cells. Accordingly, curcumin may have the therapeutic potential in<br />
restricting breast cancer metastasis.<br />
P1-10-02<br />
Comparative Preventive Efficacy of Select Chinese Herbs in<br />
<strong>Breast</strong> Carcinoma Derived Isogenic Cells with Modulated<br />
Estrogen Receptor Functions<br />
Telang NT, Li G, Katdare M, Sepkovic DW, Bradlow HL, Wong<br />
GYC. Palindrome Liaisons, Montvale, NJ; American Foundation<br />
for Chinese Medicine, New York, NY; Skin of Color Research<br />
Institute, Leroy T. Canoles Jr. <strong>Cancer</strong> Research Center, Hampton<br />
University, Eastern Virginia Medical School, Hampton, VA; David<br />
& Alice Jurist Institute for Research, Hackensack University Medical<br />
Center, Hackensack, NJ; David & Alice Jurist Institute for Research,<br />
Hackensack, NJ; American Foundation for Chinese Medicine, Beth<br />
Israel Medical Center, New York, NY<br />
Background: Human mammary carcinoma derived estrogen receptor<br />
positive (ER + ) MCF-7 cells depend on 17β-estradiol (E 2 ) for cellular<br />
proliferation in vitro and for tumor development in vivo. Traditionally,<br />
ER functions as a ligand activated nuclear transcription factor with E 2<br />
as its physiological ligand, and limited availability of E 2 modulates<br />
ER functions. We have recently demonstrated preventive efficacy of<br />
selected Chinese nutritional herbs in this MCF-7 cell culture model.<br />
The present study screened additional Chinese nutritional herbs for<br />
their preferential preventive efficacy on MCF-7 cells with modulated<br />
ER functions.<br />
Methods: MCF-7 cells were maintained in medium supplemented<br />
with either 0.7% serum,
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
Conclusion:<br />
<strong>Breast</strong> cancer incidence is significantly reduced by both physical<br />
exercise and weight loss, especially in the postmenopausal population.<br />
Intensity, timing and nature of the exercise did not significantly alter<br />
the protective effect.<br />
P1-12-01<br />
Evaluation on efficacy and safety of capecitabine plus docetaxel<br />
versus docetaxel monotherapy in metastatic breast cancer patients<br />
pretreated with anthracycline: Results from a randomized phase<br />
III study (JO21095)<br />
Sato N, Yamamoto D, Rai Y, Iwase H, Saito M, Iwata H, Masuda<br />
N, Oura S, Watanabe J, Kuroi K. Niigata <strong>Cancer</strong> Center Hospital,<br />
Niigata, Japan; Kansai Medical University Hirakata Hospital,<br />
Hirakata, Osaka, Japan; Sagara Hospital, Kagoshima, Japan;<br />
Kumamoto University Hospital, Kumamoto, Japan; Juntendo<br />
University Hospital, Bunkyo, Tokyo, Japan; Aichi <strong>Cancer</strong> Center<br />
Hospital, Nagoya, Aichi, Japan; National Hospital Organization<br />
Osaka National Hospital, Osaka, Japan; Wakayama Medical<br />
University, Wakayama, Wakayama, Japan; Shizuoka <strong>Cancer</strong> Center,<br />
Nagaizumi-cho, Suntou-gun, Shizuoka, Japan; Tokyo Metropolitan<br />
<strong>Cancer</strong> and Infectious Diseases Center Komagome Hospital, Bunkyo,<br />
Tokyo, Japan<br />
Introduction: A previous large-scale phase III study demonstrated<br />
that, compared with docetaxel (T) alone, capecitabine (X) and T in<br />
combination (XT) offered significantly superior progression free<br />
survival (PFS) and overall survival (OS) in metastatic breast cancer<br />
(MBC). However, XT increased Grade 3/4 adverse events (AEs)<br />
which led to more frequent dose reductions than with T alone. Optimal<br />
dose of XT in Japanese was examined in a phase Ib study. Based<br />
on the background, we conducted a phase III randomized study in<br />
Japanese HER2 negative MBC patients pre-treated with anthracycline<br />
to compare efficacy and safety of XT therapy and T therapy.<br />
Methods: Eligible pts were HER2-negative MBC pts with<br />
anthracycline-pretreatment, a measurable tumor, and ECOG<br />
performance status of 0 or 1. Pts were randomly assigned to the XT<br />
group or the T→X group. The XT group received concurrent therapy<br />
of X (1650 mg/m 2 /day from day 1 to 14) and T (60 mg/m 2 ) in 3-week<br />
cycle. The T→X group received sequential therapy of T (70 mg/m 2 )<br />
in 3-week cycle followed at disease progression by X (2500 mg/m 2 /<br />
day from day 1 to 14 followed by 1-week rest). Primary endpoint<br />
was PFS. Secondary endpoints were OS, overall response rate (ORR),<br />
time to treatment failure (TTF), safety, and quality of life. The XT<br />
group and the T phase of the T→X group (T group) were compared<br />
in our evaluation.<br />
Results: Of 163 pts enrolled, 156 were eligible. Baseline<br />
characteristics of all pts in each group were well balanced. The<br />
median delivered dose was 79.0% and 95.1% of the planned dose<br />
respectively for X and T in the XT group, and it was 97.2% in the T<br />
group. Median PFS in the XT group was 10.5 months compared to<br />
9.8 months in the T group (hazard ratio [HR], 0.62; 95% confidence<br />
interval [CI], 0.40–0.97). The ORR was 70% and 61%; the median<br />
TTF was 9.6 months and 7.0 months in the XT group and the T<br />
group, respectively. Median OS has not been reached yet. Subgroup<br />
analysis showed PFS was longer in pts with liver metastasis (HR,<br />
0.39; 95% CI, 0.19–0.84) and in pts with lung metastasis (HR, 0.43;<br />
95% CI, 0.21–0.90) in the XT group. Incidence of treatment related<br />
AEs (TR-AEs) ≥Grade 3 was 74.4% (61 pts) in the XT group and<br />
76.3% (61 pts) in the T group. Frequently reported TR-AEs ≥Grade 3<br />
were; decrease in neutrophil count (XT, 57.3%; T, 60.0%), neutropenia<br />
(XT, 8.5%; T, 12.5%) and febrile neutropenia (XT, 6.1%; T, 10.0%).<br />
TR-AE ≥Grade 3 in the XT group with incidence at least 5% higher<br />
than the T group was hand-foot syndrome (XT, 7.3%; T, 0%). On the<br />
other hand, TR-AEs ≥Grade 3 in the T group with incidence at least<br />
5% higher than the XT group were fatigue (XT, 2.4%; T, 8.8%) and<br />
peripheral edema (XT, 1.2%; T, 6.3%).<br />
Conclusion: The concurrent therapy of XT demonstrated significant<br />
improvement of PFS compared with T alone. Superior efficacy of XT<br />
therapy was reported as same as the previously reported study on<br />
XT versus T although the dose was lower in our study. Considering<br />
the efficacy and tolerability, we consider concurrent Japanease dose<br />
XT therapy is a preferable treatment for MBC pts with liver or lung<br />
metastasis.<br />
P1-12-02<br />
Results of a phase 2, multicenter, single-arm study of eribulin<br />
mesylate as first-line therapy for locally recurrent or metastatic<br />
HER2-negative breast cancer<br />
Vahdat L, Schwartzberg L, Glück S, Rege J, Liao J, Cox D,<br />
O’Shaughnessy J. Weill Cornell Medical College, New York, NY; The<br />
West Clinic, Memphis, TN; Sylvester Comprehensive <strong>Cancer</strong> Center,<br />
Miami, FL; Eisai Inc, Woodcliff Lake, NJ; Texas Oncology-Baylor<br />
Charles A. Sammons <strong>Cancer</strong> Center, Dallas, TX<br />
Background: Eribulin mesylate is a novel nontaxane microtubule<br />
dynamics inhibitor that is approved in patients (pts) with metastatic<br />
breast cancer (MBC) who have previously received at least two<br />
chemotherapeutic regimens for MBC. We are reporting a preliminary<br />
planned analysis (first 6 cycles of treatment) of a phase 2 study that<br />
evaluates efficacy and safety of eribulin as first-line therapy for<br />
HER2-negative MBC.<br />
Methods: Pts with measureable HER2-negative locally recurrent or<br />
MBC with at least 12 months since prior neoadjuvant or adjuvant<br />
chemotherapy received eribulin mesylate at 1.4 mg/m 2 IV on days<br />
1 and 8 of each 3-week cycle. Endpoints include objective response<br />
rate (ORR) (primary), safety, progression free survival (PFS), time to<br />
response (TTR), and duration of response (DOR). Tumor assessments<br />
were evaluated every 6 weeks for the first 6 cycles and every 6-12<br />
weeks thereafter per RECIST 1.1.<br />
Results: 54 of 56 enrolled pts had at least 1 post-baseline assessment.<br />
The median number of cycles delivered was 7 (range 1,21). Pt<br />
characteristics: median age, 56 yrs (range 31-85); ECOG of 0, 32<br />
(57%); 29% had de novo stage IV; 38/56 (68%) had prior neo/adjuvant<br />
(45% had anthracycline and 45% taxane, the majority of which were<br />
given together). Seventy percent have visceral disease (45% liver,<br />
38% lung); 41 (73%) have estrogen receptor-positive (ER) disease<br />
and 12 (21%) have triple negative (TN) (ER-/PR-/HER2-) disease.<br />
Objective response data are found in Table 1.<br />
Table 1. Summary of Efficacy<br />
Efficacy<br />
ALL, n (%) (N=54) ER+, n (%) (N=40) ER-/PR-/HER2-, n (%) (N=11)<br />
ORR 17 (31) 13 (32) 4 (36)<br />
CR 0 0 0<br />
PR 17 (31) 13 (32) 4 (36)<br />
SD 26 (48) 21 (53) 4 (36)<br />
CBR (ORR+ ≥6<br />
mo SD)<br />
26 (48) 22 (55) 4 (36)<br />
Median months<br />
TTR 1.4 (1.2,2.7) 1.4 (1.3,2.7) 2.0 (1.1,5.6)<br />
DOR 5.8 (4.6,NE) 7.4 (3.3,NE) 5.8 (4.7,NE)<br />
PFS 6.1 (4.1,7.4) 6.8 (4.6,8.5) 3.5 (1.2,NE)<br />
3 pts were ER-/PR+ with no objective response (1 SD, 2 PD).<br />
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The most common treatment-related AEs are reported in Table 2.<br />
Table 2. Percentage of treatment-related adverse events<br />
Adverse Event (N=56) All events (%) Grade 3/4 (%)<br />
Leading to study drug discontinuation 9 9<br />
Leading to dose reduction 32 25<br />
Common AEs (≥25%)<br />
Alopecia 79 NA<br />
Neutropenia 66 48<br />
Fatigue 52 2<br />
Peripheral neuropathy 52 16<br />
Nausea 45 0<br />
Anemia 38 0<br />
Treatment-related serious AEs occurred in 5 (9%) pts, neutropenia<br />
(4%), and febrile neutropenia (5%). Five pts stopped study therapy<br />
due to adverse events. Fourteen pts remain on study treatment.<br />
Conclusions: The preliminary results of this first-line study suggest<br />
that eribulin has antitumor activity in ER+/HER2- and TN MBC with<br />
an acceptable safety profile. Further exploration of this treatment as<br />
part of neo/adjuvant therapy is warranted.<br />
P1-12-03<br />
Low-dose capecitabine monotherapy in HER-2 negative<br />
metastatic breast cancer: a retrospective study.<br />
Ambros T, Zeichner SB, Zaravinos J, Montero AJ, Ahn E, Mani A,<br />
Kronish L, Mahtani RL, Vogel CL. University of Miami, FL; Mount<br />
Sinai Medical Center, Miami Beach, FL; Memorial Hospital West,<br />
Pembroke Pines, FL; SUNY Downstate, Brooklyn, NY<br />
Background: Capecitabine (CAPE) has clinical activity in metastatic<br />
breast cancer (MBC) at an FDA approved dose of 1,250mg/m 2 twice<br />
daily for 14 days every 21 days (BID Q14). This schedule has been<br />
adopted by many United States oncologists, although the starting<br />
dose is often reduced. To determine if lower doses of CAPE have<br />
comparable clinical activity as the FDA approved dose, we performed<br />
a retrospective analysis. Methods: A retrospective review of records<br />
from a large breast cancer oncology practice and from Sylvester<br />
<strong>Cancer</strong> Center Deerfield Beach from 2000-2008 was performed after<br />
approval of the University of Miami IRB. Standard practice was<br />
CAPE low dose (CAPE-L) 1,000mg BID Q14. Primary outcome was<br />
clinical benefit rate (CBR) defined as complete response (CR), partial<br />
response (PR) or stable disease (SD) lasting for ≥ 6 months. Response<br />
rates (RR) in patients with measurable disease, progression free<br />
survival (PFS), overall survival (OS) defined as time period between<br />
beginning of CAPE and death, and adverse events (AE) defined<br />
according to the NCI CTCAE version 3.0 were secondary endpoints.<br />
A literature review was performed for comparison. Results: Data<br />
from 296 patients (pts) with HER-2 negative MBC were reviewed.<br />
Of those, 73 received CAPE-L at a starting dose between 303 mg/<br />
m 2 and 965 mg/m 2 (median 614 mg/m 2 ) BID Q14. Median number<br />
of prior lines of therapy was 1 (range 0 - 10); 34/73 (46.6%) of pts<br />
received CAPE-L as first line therapy. 23.3% of pts required dose<br />
reductions because of palmar-plantar erythrodysesthesia (PPE) (44%),<br />
diarrhea (17%), mucositis (11%) or other (28%). RR in 61 patients<br />
with measurable disease was 25%. PR occurred in 16/73 (22%),<br />
CR (0%), SD ≥ 6 months 21/73 (29%), and PD 31/73 (43%), with a<br />
CBR of 37/73 (51%). Median PFS and OS were 6.2 months (95% CI,<br />
4.4 to 8) and 21.4 months (95% CI, 14.4 to 28.6), respectively. AEs<br />
are reported in table 2. We recognized 12 trials that used the FDA<br />
approved dose in 1,949 patients. Bidimensionally measurable disease<br />
was present in 1,630 patients. CBR was reported as 62% in 1,006<br />
patients and RR as 24% in 398. Weighted averages of median PFS<br />
and OS were 5.1 months (95% CI, 4.5 to 5.7) and 12 months (95%<br />
CI, 9.6 to 14.4), respectively. Detailed toxicity data were available<br />
in 11 trials with 1,883 patients. A comparison of current series with<br />
literature review at standard dose follows (table 1). Conclusion:<br />
Compared with previously published data, CAPE-L appeared more<br />
tolerable with comparable clinical efficacy as package insert doses.<br />
Efficacy<br />
Current Series<br />
Literature<br />
CBR (%) 37/73 51 1006/1630 62<br />
RR (%) 15/61 25 398/1630 24<br />
Median prior line<br />
of Rx (range)<br />
1 (1 -10) 2 a (0 - 6)<br />
Median PFS (mo)<br />
6.2 (4.4 - 8)<br />
(95% CI)<br />
5.1 (4.5 - 5.7) b<br />
Median OS (mo)<br />
(95% CI)<br />
21.4 (14.4 - 28.6) 12 (9.6 - 14.4) c<br />
a<br />
n=759, 6 trials (n=1190) did not report individual data. b n=1949. c n=1411, 2 trials (n=538) did not<br />
reach 50% mortality.<br />
Adverse Events<br />
Current Series<br />
Literature (n=1883)<br />
n % n %<br />
PPE<br />
GI-II 20 27.4 709 37.7<br />
GIII-IV 4 5.5 215 11.4<br />
Diarrhea<br />
GI-II 12 16.4 509 27<br />
GIII-IV 4 5.5 193 10.2<br />
Mucositis<br />
GI-II 7 9.6 212 11.2<br />
GIII-IV 0 0 36 1.9<br />
Fatigue<br />
GI-II 12 16.4 343 18.2<br />
GIII-IV 0 0 57 3<br />
P1-12-04<br />
Carboplatin, nab-paclitaxel and bevacizumab as first-line<br />
treatment for metastatic breast cancer.<br />
Lo SS, Guo R, Czaplicki KL, Robinson PA, Gaynor E, Barhamand<br />
FB, Schulz WC, Kash JJ, Horvath LE, Bayer RA, Petrowsky C, De<br />
la Torre R, Park JH, Albain KS. Loyola University Medical Center,<br />
Maywood, IL; Hematology Oncology Consultants Ltd., Naperville,<br />
IL; Swedish Americal Regional <strong>Cancer</strong> Center, Rockford, IL; Edward<br />
<strong>Cancer</strong> Center, Naperville, IL; Central Dupage <strong>Cancer</strong> Center,<br />
Winfield, IL; CDPG Oncology at Delnor, Delnor, IL<br />
Background: Bevacizumab added to weekly paclitaxel resulted in<br />
improved progression free survival (PFS) and objective response rates<br />
(ORR) compared to weekly paclitaxel alone. Nab-paclitaxel and the<br />
platins are active in MBC. We conducted an efficacy and safety study<br />
of carboplatin, nab-paclitaxel and bevacizumab.<br />
Methods: A phase II open label prospective multi-site study enrolled<br />
patients (pts) who had measurable MBC according to RECIST 1.1<br />
criteria and no prior chemotherapy for advanced disease. The primary<br />
endpoint was PFS with secondary endpoints of overall survival<br />
(OS), ORR, and safety. Pts initially received carboplatin AUC 6 day<br />
1, 22,43, plus weekly nab-paclitaxel 100mg/m 2 and bevacizumab<br />
15mg/m 2 day 1,22,43 of a 56 day cycle. This was later changed to<br />
carboplatin AUC 6 day 1, nab-paclitaxel 100mg/m 2 day 1,8,15, and<br />
bevacizumab 10mg/m 2 day 1,15 of a 28 day cycle. Thirty-two pts<br />
were required to detect an increase in median PFS from 6.7 to 10.5<br />
mo with 80% power based on a one-sided p = 0.05. Kaplan–Meier<br />
analyses estimated PFS and OS. The log rank test was used for the<br />
comparison of survival curves between pts with triple negative MBC<br />
(TNBC) and pts with non-TNBC.<br />
Results: Thirty-two pts were enrolled between 2/2008 and 11/2011<br />
by 1 academic and 5 community oncology practices. Two pts were<br />
ineligible due to non-measurable disease and not included in the<br />
response analyses. The median age was 58 years (range 35-81), 22<br />
pts (69%) had an ECOG PS 0, 9 (28%) had a PS 1, 1 (3%) PS 2.<br />
Twenty-four (75%) pts had ER+ disease, 7 (22%) had TNBC, 1 (3%)<br />
had ER-HER2+ disease not eligible for trastuzumab-based therapy.<br />
Metastatic sites were bone (26%), liver (18%), loco-regional (16%),<br />
and lung (12%). One pt (3%) had bone and loco-regional disease only,<br />
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<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
19 (59%) had visceral dominant disease. The median number of weeks<br />
on treatment was 28.9 (range 5-131). The median PFS in all pts was<br />
13.6 months (mo) (95% CI 11.2-21.9), with a median OS of 26.8 mo<br />
(95% CI 13.3-41.2). The ORR (2 CR and 18 PR) was 66.7% (CI 47.2-<br />
82.7). There also were 6 (20%) unconfirmed PR and 3 (10%) stable<br />
disease, resulting in a clinical benefit rate of 96.7% (CI 82.78-99.92).<br />
There was no significant difference in PFS (median 13.6 vs 16.1mo,<br />
p=0.37) or OS (median 13.6 vs 26.8mo, p=0.32) in pts with TNBC<br />
versus non-TNBC disease. The most common toxicities of any grade<br />
(gr) include neutropenia and thrombocytopenia in 24 pts (75%) each,<br />
leukopenia and fatigue in 17 pts (53%) each, anemia in 15 (47%), and<br />
neuropathy in 10 (31%). Gr 4 neutropenia was seen in 7 pts (22%)<br />
without febrile neutropenia, and gr 4 thrombocytopenia occurred in<br />
6 (19%). There were no pts with gr 4 sensory neuropathy. All pts<br />
required chemotherapy dose delays, 15 (47%) had chemotherapy<br />
dose reductions.<br />
Conclusions: The carboplatin, nab-paclitaxel and bevacizumab<br />
combination is highly effective with good tolerance in first line<br />
MBC. As the role of anti-angiogenic therapy in first line metastatic<br />
breast cancer is being clarified, this would be an attractive regimen<br />
to test in the (neo)adjuvant setting and together with novel molecular<br />
targeted agents.<br />
P1-12-05<br />
First-line chemotherapy with pegylated liposomal doxorubicin<br />
versus capecitabine in elderly patients with metastatic breast<br />
cancer: results of the phase III OMEGA study of the Dutch <strong>Breast</strong><br />
<strong>Cancer</strong> Trialists’ Group (BOOG)<br />
Smorenburg CH, Seynaeve C, Wymenga MANM, Maartense E, de<br />
Graaf H, de Jongh FE, Braun HJ, Los M, Schrama JG, Portielje<br />
JEA, Hamaker M, van Tinteren H, de Groot SM, van Leeuwen-Stok<br />
EAE, Nortier HWR. Medical Center Alkmaar, Alkmaar, Netherlands;<br />
Erasmus Medical Center-Daniel den Hoed <strong>Cancer</strong> Center, Rotterdam,<br />
Netherlands; Medisch Spectrum Twente, Enschede, Netherlands;<br />
Reinier de Graaf Hospital, Delft, Netherlands; Medical Center<br />
Leeuwarden, Leeuwarden, Netherlands; Ikazia Hospital, Rotterdam,<br />
Netherlands; Vlietland Hospital, Schiedam, Netherlands; St.<br />
Antonius Hospital, Nieuwegein, Netherlands; Spaarne Hospital,<br />
Hoofddorp, Netherlands; Haga Hospital, The Hague, Netherlands;<br />
Diaconessehuis, Utrecht, Netherlands; Antoni van Leeuwenhoek<br />
Hospital/Netherlands <strong>Cancer</strong> Institute, Amsterdam, Netherlands;<br />
Comprehensive <strong>Cancer</strong> Centre the Netherlands, Amsterdam,<br />
Netherlands; Dutch <strong>Breast</strong> <strong>Cancer</strong> Trialists’ Group BOOG,<br />
Amsterdam, Netherlands; Leiden University Medical Center, Leiden,<br />
Netherlands<br />
Background The efficacy and feasibility of chemotherapy in elderly<br />
metastatic breast cancer (MBC) patients (pts) have been studied in<br />
various phase II studies. However, results of prospective randomized<br />
studies in elderly MBC pts are scarce.<br />
Methods In this phase III multicenter study, MBC pts ≥ 65 years<br />
eligible for first-line chemotherapy were randomized between<br />
pegylated liposomal doxorubicin (PEGdoxo) (45mg/m 2 , IV, q 4 wks)<br />
or capecitabine (Cape) (1000 mg/m 2 PO bid, days 1-14, q 3 wks).<br />
Other eligibility criteria were ECOG performance status (PS) ≤ 2 (3<br />
allowed if due to pain or pre existing comorbidity), adequate bone<br />
marrow and organ functions. Stratification factors were PS (0-1 vs<br />
2-3), HER2 status, visceral/non-visceral disease, adjuvant hormonal<br />
therapy (HTx), and HTx for MBC. Baseline geriatric assessment<br />
(GA) included functional status, instrumental activities of daily<br />
living, cognition, mood, comorbidity, polypharmacy and nutritional<br />
status. Chemotherapy was continued for 24 wks in the absence of<br />
progressive disease (PD) or unacceptable toxicity. Primary endpoint<br />
was progression-free survival (PFS), secondary endpoints were<br />
response rate, overall survival (OS), toxicity (CTC criteria) and<br />
compliance.<br />
Results Between April 2007 and August 2011, 78 pts were<br />
randomized to PEGdoxo (n=40) or Cape (n=38). The study was<br />
prematurely closed due to slow accrual and supply problems with<br />
PEGdoxo. Mean age was 74 years (range 65-86; 75+ 54%; 80+<br />
13%). Pt characteristics were balanced between the two arms: PS<br />
0-1 77%, ER+ 68%, HER2+ 5%, visceral/non-visceral disease<br />
76%/24%, adjuvant HTx 46%, HTx for MBC 56%, ≥ 3 metastatic<br />
sites 50%. Only 22 out of 75 pts with a baseline GA had no geriatric<br />
condition (29%), while 32 pts (43%) and 21 pts (28%) had one or<br />
≥ 2 geriatric conditions, respectively. Chemotherapy was given for<br />
6 months in 38%, with a mean dose intensity of 84% in both arms.<br />
Reasons for early treatment discontinuation were: PD (31%), toxicity<br />
(28%), pt withdrawal (3%). After a median follow up of 32 months,<br />
74 pts had PD and 56 pts had died. The median PFS was 5.7 and<br />
7.7 months with PEGdoxo and Cape (HR 0.68, 95% CI: 0.42-1.11,<br />
p=0.12) and the median OS was 13.8 and 16.8 months, respectively<br />
(HR 0.84, 95% CI: 0.49-1.42, p=0.51). Response was evaluable in<br />
64 pts, with a partial response (PR) in 7 (21%) and 6 pts (19%), and<br />
stable disease in 21 (64%) and 17 pts (55%) for PEGdoxo and Cape,<br />
respectively. Toxicity was acceptable, mainly being grade 1-2, with<br />
for PEGdoxo/Cape grade 1 alopecia in 14/4 pts (grade 2 in 1 PEGdoxo<br />
pt), grade 3 fatigue in 5/5 pts, grade 3 HFS in 4/6 pts and grade 3<br />
mucositis in 4/1 pts, respectively. Pts with ≥ 1 geriatric condition<br />
more frequently experienced grade 3-4 toxicity, after correcting for<br />
type of chemotherapy, age and PS (HR 2.24, 95% CI: 1.21-4.16). Pts<br />
aged 75+ had a twofold higher risk of dying, irrespective of treatment<br />
arm (HR 2.31, 95% CI: 1.31-4.07).<br />
Conclusions First-line chemotherapy with either PEGdoxo or Cape<br />
was feasible in elderly MBC pts, with adequate dose intensity and<br />
acceptable toxicity, even in non-fit pts or pts aged 75+. Baseline GA<br />
correlated with toxicity.<br />
P1-12-06<br />
N0937 (Alliance): Preliminary results of a phase II clinical trial<br />
of cisplatin and the novel agent brostallicin in patients with<br />
metastatic triple negative breast cancer (mTNBC)<br />
Moreno-Aspitia A, Rowland, Jr. KM, Allred JB, Liu H, Stella PJ, Gross<br />
HM, Soori GS, Karlin NJ, Perez EA. Mayo Clinic, Jacksonville, FL;<br />
Carle Foundation - Carle <strong>Cancer</strong> Center, Urbana, IL; Mayo Clinic,<br />
Rochester, MN; St. Joseph Mercy Health System, Ann Arbor, MI;<br />
Hematology & Oncology of Dayton, Inc., Dayton, OH; Missouri<br />
Valley <strong>Cancer</strong> Consortium CCOP, Omaha, NE; Mayo Clinic,<br />
Scottsdale, AZ<br />
Background: TNBC is characterized by unique molecular profiles,<br />
aggressive behavior, poor prognosis and lack of targeted therapies.<br />
Brostallicin is a novel synthetic compound from the class of DNA<br />
minor groove binding (MGB) anti-cancer agents, making it a logical<br />
agent to evaluate in the setting of TNBC. It retains activity in cancer<br />
cells resistant to alkylating agents, topoisomerase I inhibitors and<br />
is fully active against DNA-mismatch repair deficient tumor cells.<br />
Preclinical models using cell lines demonstrate that cells expressing<br />
relatively high glutathione/glutathione S-transferase (GSH/GST)<br />
levels are more susceptible to brostallicin’s antitumor efficacy.<br />
Cisplatin administration increases expression of GSH/GST in tumor<br />
cells, thus leading to an increased anti-tumor efficacy of brostallicin.<br />
Methods: Phase II cooperative group study in pts with mTNBC (³18<br />
years of age with measurable metastatic disease, ER/PR ≤1%; HER2<br />
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negative, who had received 0-4 prior chemotherapy regimens in the<br />
metastatic setting; with adequate hematologic, renal and hepatic<br />
functions; and no active CNS metastases; prior exposure to cisplatin<br />
allowed). Cisplatin on Day 1 followed by brostallicin on Day 2,<br />
repeated every 21 days. Aim: efficacy of brostallicin and proof of<br />
concept of its mechanism of action in mTNBC. Primary endpoint<br />
progression-free survival (PFS) at 3 months with 89% power (0.10<br />
significance level) to detect an absolute difference of 20% (35% vs<br />
55%), based on the median PFS of 60 days in pts with mTNBC from<br />
the N0234 trial of erlotinib and gemcitabine as 1 st /2 nd line. Secondary<br />
endpoints include ORR, duration of response (DOR), 6-month PFS,<br />
OS and AE profile. Tertiary endpoints include assessment of 1) GSH<br />
levels prior to the administration of cisplatin and of brostallicin;<br />
and 2) the prevalence of BCRA-1 mutation by IHC in primary or<br />
metastatic tumor.<br />
Results: Study closed on 3/28/12 and it accrued 48 pts (median<br />
f/u 2.3 mo; 0-15.3); 33 pts are off treatment and 15 pts remain on<br />
study; 38 pts evaluable for response, and 43 evaluable for AEs. 50%<br />
received therapy as 3rd to 5th line. Median number of cycles 2.5<br />
(off-treatment: 2; on-treatment: 3, range 0-15). There are currently 5<br />
confirmed responses (4 PR and 1 CR); DOR: 2.8-13.3 months. The<br />
6-mo PFS is currently 19.2% (95% CI: 8.9%, 41.3%); the median<br />
TTP is 3.0 months (95% CI: 1.7 months, 4.2 months). Current data<br />
are premature to determine the primary endpoint (3-mo PFS) but<br />
we expect to report such data by November 2012.Current toxicity<br />
data: 69.7% G3/4 heme toxicity. Non-heme toxicity G3 (30.2%) and<br />
G4 (9.3)% (febrile neutropenia 21%; fatigue G3 14%); and no G5<br />
non-heme AE.<br />
Conclusions: The current preliminary data of this trial show very<br />
encouraging activity of this regimen (brostallicin plus cisplatin) in<br />
mTNBC. Near 1/3 of pts are still currently receiving therapy, and we<br />
expect to provide primary and additional secondary endpoint data at<br />
SABCS 2012.<br />
P1-12-07<br />
A Retrospective Analysis of nab-Paclitaxel as First-Line Therapy<br />
for Metastatic <strong>Breast</strong> <strong>Cancer</strong> Patients With Poor Prognostic<br />
Factors<br />
O’Shaughnessy J, Gradishar W, Bhar P, Iglesias J. Baylor Sammons<br />
<strong>Cancer</strong> Center, Texas Oncology and US Oncology, Dallas, TX;<br />
Maggie Daley Center for Women’s <strong>Cancer</strong> Care, Robert H. Lurie<br />
Comprehensive <strong>Cancer</strong> Center, Northwestern University Feinberg<br />
School of Medicine, Northwestern Memorial Hospital, Chicago,<br />
IL; Celgene Corporation, Durham, NC; Celgene Corporation,<br />
Mississauga, ON, Canada<br />
Background: Solvent-based taxanes have demonstrated activity in<br />
metastatic breast cancer (MBC) patients with poor prognostic factors,<br />
an important subset of patients with aggressive disease who require<br />
special consideration in treatment optimization. nab-Paclitaxel has<br />
been compared with solvent-based (sb-) paclitaxel in a randomized<br />
phase III trial (CA012; N = 454) and docetaxel in a randomized<br />
phase II trial (CA024; N = 300) for the treatment of MBC, revealing<br />
a favorable clinical benefit for nab-paclitaxel in both intent-to-treat<br />
(ITT) populations. This retrospective analysis examines whether<br />
the safety and efficacy of nab-paclitaxel observed in these trials are<br />
maintained in patients with poor prognostic factors.<br />
Methods: This retrospective analysis evaluated safety and efficacy of<br />
the first-line treatment of patients with MBC with the poor prognostic<br />
factors of visceral dominant metastases (dominant metastatic lesion<br />
localized to visceral tissue [ie, not in bone or soft tissues]) and early<br />
disease recurrence (≤ 2 years after completing neoadjuvant or adjuvant<br />
treatment) in the CA012 and CA024 trials.<br />
Results: In CA012 (n = 186 first-line patients), nab-paclitaxel 260<br />
mg/m 2 every 3 weeks (q3w) demonstrated a higher overall response<br />
rate (ORR) vs sb-paclitaxel 175 mg/m 2 q3w in patients with visceral<br />
dominant metastases (42% vs 23%, P = .022) and in patients with<br />
early disease recurrence (43% vs 33%, P = not significant [NS]). In<br />
CA024 (n = 300 first-line patients), significantly higher ORRs for<br />
nab-paclitaxel at 100 mg/m 2 (63%, P = .002) and 150 mg/m 2 (76%,<br />
P < .001) the first 3 of 4 weeks (qw 3/4) vs docetaxel 100 mg/m 2 q3w<br />
(37%) were observed in patients with visceral dominant metastases.<br />
The difference in ORR in this subgroup between nab-paclitaxel 300<br />
mg/m 2 q3w (44%, P = NS) and docetaxel 100 mg/m 2 q3w was not<br />
statistically different. As in CA012, the differences in ORR among<br />
patients with early disease recurrence in CA024 were not statistically<br />
significant (35% to 64% for the nab-paclitaxel arms vs 21% for<br />
the docetaxel 100 mg/m 2 q3w arm, all P = NS). Progression-free<br />
survival (PFS) and overall survival (OS) showed trends similar to<br />
that of ORR in both trials. Statistical significance was only achieved<br />
for median PFS in CA024 among patients with visceral dominant<br />
metastases (13.1 months for nab-paclitaxel 150 mg/m 2 qw 3/4 vs<br />
7.5 months for nab-paclitaxel 100 mg/m 2 qw 3/4 [P = .010] and vs<br />
7.8 months for docetaxel 100 mg/m 2 q3w [P = .019]). Safety results<br />
were similar to those of previous reports for the ITT populations;<br />
in CA024, the lowest rates of neutropenia, sensory neuropathy, and<br />
fatigue were observed with nab-paclitaxel 100 mg/m 2 qw 3/4 in both<br />
patient subgroups.<br />
Conclusions: nab-Paclitaxel showed similar efficacy in patients with<br />
poor prognostic factors to that in the ITT populations of these 2 trials.<br />
In each trial, consistent trends in favor of nab-paclitaxel were observed<br />
for ORR, PFS, and OS vs a solvent-based taxane in the specified poor<br />
prognostic factor subgroups. No new safety signals were observed.<br />
P1-12-08<br />
Withdrawn by Author.<br />
P1-13-01<br />
A randomized trial of CEF versus dose dense EC followed by<br />
paclitaxel versus AC followed by paclitaxel in women with node<br />
positive or high risk node negative breast cancer, NCIC CTG<br />
MA.21: Results of the final relapse free survival analysis.<br />
Burnell MJ, Shepherd L, Gelmon K, Bramwell V, Walley B,<br />
Vandenberg E, Chalchal H, Pritchard K, Whelan T, Albain K, Perez<br />
E, Rugo H, O’Brien P, Chapman J, Levine M. NCIC Clinical Trials<br />
Group, Queen’s University, Kingston, ON, Canada; British Columbia<br />
<strong>Cancer</strong> Agency (BCCA), Vancouver, BC, Canada; University of<br />
Calgary, AB, Canada; Saint John Regional Hospital, Saint John, NB,<br />
Canada; London Regional <strong>Cancer</strong> Centre, London, ON, Canada;<br />
Sunnybrook <strong>Cancer</strong> Centre, Toronto, ON, Canada; Juravinski<br />
<strong>Cancer</strong> Centre, Hamilton Health Sciences Centre, Hamilton, ON,<br />
Canada; Loyola University Medical Center, Maywood, IL; Mayo<br />
Clinic Jacksonville, FL; University of California, <strong>San</strong> Francisco, CA;<br />
McMaster University, Hamilton, ON, Canada; Allan Blair <strong>Cancer</strong><br />
Centre, Regina, SK, Canada<br />
Background: In 2000, cyclophosphamide(C), epirubicin(E) and<br />
fluorouracil (F) (CEF) and doxorubicin (A) and C followed by<br />
paclitaxel (T) (AC/T) given every three weeks were commonly used<br />
regimens in Canada and the USA to treat women with node positive<br />
or high risk node negative operable breast cancer. In a previous trial in<br />
women with locally advanced breast cancer, 3 months of dose-dense<br />
EC was equivalent to six months of CEF. We hypothesized that the<br />
addition of 3 months of a taxane following dose-dense EC would<br />
be superior to CEF alone or AC/T. In a randomized trial in women<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
with early breast cancer we compared CEF, dose dense EC/T and<br />
AC/T. An interim analysis (JCO, 2010) conducted when 50% of the<br />
events for the relapse-free-survival (RFS) analysis were observed,<br />
demonstrated that AC/T administered every 3 weeks was significantly<br />
inferior to CEF or EC/T. The results of the final RFS including CEF<br />
versus EC/T will be presented. Methods: Women, 60 years or younger,<br />
with operable axillary node positive or high risk node negative breast<br />
cancer were randomized to adjuvant CEF, EC/T or AC/T. CEF was<br />
given for 6 cycles and consisted of: C 75 mg/m2 orally on Days<br />
1-14, and E 60 mg/m2 and F 500 mg/m2, IV on Days 1 and 8. CEF<br />
patients received concurrent antibiotic prophylaxis. EC/T consisted<br />
of 6 cycles of EC every 14 days; E 120 mg/m2 and C 830 mg/m2,<br />
both IV on Day 1 with filgrastim 5 [ug]/kg/day subcutaneous from<br />
Days 2-13 and epoetin alpha 40,000 units subcutaneous once weekly.<br />
After completion of EC, 4 cycles of T 175 mg/m2 every 21 days with<br />
filgrastim and epoetin alpha were given. The AC/T regimen consisted<br />
of A 60 mg/m2 and C 600 mg/m2 IV every 21 days for 4 cycles.<br />
This was followed by T 175 mg/m2 every 21 days for 4 cycles. The<br />
final analysis for RFS was planned when 453 events were observed<br />
permitting the detection of a hazard ratio (HR) of 1.43 between CEF<br />
and AC/T and a HR of 1.43 between EC/T and the best of the other<br />
two arms. Quality of Life data using the EORTC C-30 and the <strong>Breast</strong><br />
<strong>Cancer</strong> Chemotherapy questionnaires were collected throughout the<br />
study. The results will be available at the time of the presentation.<br />
Results: A total of 2104 women were enrolled between December<br />
2000 and April 2005. The required 453 events for the RFS analysis<br />
were observed by the clinical cut-off date of March 30, 2012. At this<br />
point 369 deaths had been observed. The median follow-up is 87.5<br />
months. Outstanding data and queries are currently being collected<br />
and reviewed with an expected database lock and final analysis mid<br />
August, 2012. Febrile neutropenia remains higher on the CEF and<br />
EC/T arms while more neuropathy was seen in the taxane containing<br />
regimens. Conclusions: Although the two regimens considered a<br />
standard of care at the time the study was initiated are no longer widely<br />
used, the trial results will enhance our understanding of the magnitude<br />
of benefit of taxane following an anthracycline, the significance of<br />
cumulative anthracycline dose, and the role of dose density/ intensity<br />
as backbone of conventional chemo regimens.<br />
P1-13-02<br />
Withdrawn by Author<br />
P1-13-03<br />
Mature analysis of UK Taxotere as Adjuvant Chemotherapy<br />
(TACT) trial (CRUK 01/001); effects of treatment and<br />
characterisation of patterns of breast cancer relapse.<br />
Bliss JM, Ellis P, Kilburn L, Bartlett J, Bloomfield D, Cameron D,<br />
Canney P, Coleman RE, Dowsett M, Earl H, Verril M, Wardley A,<br />
Yarnold J, Ahern R, Atkins N, Fletcher M, McLinden M, Barrett-Lee P.<br />
Institute of <strong>Cancer</strong> Research, Sutton, Surrey, United Kingdom; Guy’s<br />
Hospital, Kings Health Partners AHSC, London, United Kingdom;<br />
Velindre NHS Trust <strong>Cancer</strong> Centre, Cardiff, United Kingdom;<br />
Edinburgh <strong>Cancer</strong> Research Centre, University of Edinburgh, United<br />
Kingdom; The Christie Hospital, Manchester, United Kingdom;<br />
Northern Centre for <strong>Cancer</strong> Care, Newcastle upon Tyne, United<br />
Kingdom; Brighton & Sussex University Hospitals, Brighton, United<br />
Kingdom; Ontario Institute for <strong>Cancer</strong> Research, Toronto, Canada;<br />
Beatson West of Scotland <strong>Cancer</strong> Centre, Glasgow, United Kingdom;<br />
Leeds Institute of Molecular Medicine, University of Leeds, Leeds,<br />
United Kingdom; ICR and Royal Marsden NHS Trust, London, United<br />
Kingdom; University of Cambridge, University of Cambridge and<br />
NIHR Cambridge Biomedical Research Centre, Cambridge, United<br />
Kingdom; Weston Park Hospital, Sheffield, United Kingdom; NHS<br />
National Services Scotland, Edinburgh, United Kingdom<br />
Introduction: TACT, an investigator-led study in 4162 women with<br />
node positive (N+ve) or high risk node negative (N-ve) early breast<br />
cancer (EBC), is the largest taxane trial unconfounded by treatment<br />
(trt) duration. At principal analysis, with 5 years follow-up (fup), no<br />
evidence of improved disease-free survival (DFS) was observed by<br />
switching to 4 cycles of docetaxel (D) after 4 cycles of FEC (Ellis,<br />
Lancet 2009). Results were provocative in suggesting differential<br />
effects according to ER & HER2 status. Longer fup provides<br />
opportunity to detect emergence of late trt effects overall & within<br />
phenotypic subgroups & explore patterns of recurrence, by tumor<br />
characteristics.<br />
Patients & methods: TACT recruited women with histologically<br />
confirmed completely resected invasive EBC from 104 centers (UK<br />
(103), Belgium (1)) between 02/2001 & 07/2003. Centers chose FEC<br />
(600/60/600 mg/m 2 q3wk x 8) or E-CMF (E 100mg/m 2 q3wk x 4 →<br />
CMF 100mg/m 2 PO d1-14 or 600mg/m 2 IV d1&8 /40/600 mg/m 2<br />
q4wk x 4) as their control, reflecting standard UK practice. Patients<br />
(pts) were randomized to FEC-D (FEC q3wk x 4 → D 100 mg/m 2<br />
q3wk x 4) or control. 2523 pts were from FEC centers (FEC=1265:<br />
FEC-D=1258) & 1639 from E-CMF centers (E-CMF=824;<br />
FEC-D=815). Endocrine therapy was given for 5 years. Few pts<br />
received HER2 directed therapy; 589 pts had unknown HER2 status.<br />
Median fup is now 97.5 months; this analysis updates DFS & overall<br />
survival in the ITT population. It also explores patterns of relapse<br />
by phenotypic & clinical characteristics. Analyses of trt effect are<br />
stratified by ER status due to issues of non-proportionality of hazard<br />
associated with length of fup.<br />
Results: DFS events have been reported for 1329 pts (FEC-D=640,<br />
Control=689) giving an unadjusted hazard ratio (HR) & 95%CI<br />
(stratified by control regimen & ER status) of 0.93 (0.83, 1.03) overall;<br />
p=0.16 in favor of FEC-D & for ER+ve/HER2-ve of 0.99 (0.84,<br />
1.17), for ER+ve/HER2+ve) 0.97 (0.73, 1.30), for ER-ve/HER2+ve<br />
0.74 (0.53, 1.03), & ER-ve/HER2-ve 0.93 (0.73, 1.17). 1017 patients<br />
have died (FEC-D=500, Control=517); unadjusted HR=0.98 (95%CI:<br />
0.86, 1.10); p=0.69 with intercurrent deaths (prior to distant relapse)<br />
reported for 80 pts (FEC-D=40, Control=40).<br />
Annual event rates show different pattern of disease relapse by<br />
phenotypic subgroup<br />
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<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
DFS annual<br />
event rate N+ N-<br />
(years)<br />
2 5 8 2 5 8<br />
ER+ve &/<br />
or PgR+ve<br />
and HER2- 4.6 (3.7, 5.8) 4.5 (3.5,5.7) 5.1 (3.8,6.8) 1.6 (0.6,4.2) 2.2 (0.9,5.3) 1.3 (0.3,5.1)<br />
ve(N+=1745,<br />
N-=256)<br />
HER2+ve<br />
(N+=691, 15.0 (12.2, 18.5) 5.1 (3.4, 7.8) 2.8 (1.3,6.0) 5.3 (2.6,10.5) 1.5 (0.4,5.8) 0.0 (-,-)<br />
N-=158)<br />
ER-ve/<br />
HER2-ve<br />
(N+=397,<br />
N-=326)<br />
19.3 (15.1, 24.7) 4.3 (2.3,8.0) 3.5 (1.6,7.8) 4.9 (3.0,8.2) 4.1 (2.3,7.5) 2.0 (0.7,5.3)<br />
Graphical representation will further explore these patterns &<br />
associated sites of relapse.<br />
Discussion: With a median fup of >8 years no clear benefit has<br />
emerged for D over standard anthracyclines within the TACT pt<br />
group. Differential effects associated with different patterns of relapse<br />
remain of interest. TACT precedes use of antiHER2 therapy which<br />
is known to have impacted on early relapse risk in HER2+ve pts.<br />
The high relapse risk observed for pts with ER-ve/HER2-ve disease<br />
remains a current clinical challenge.<br />
P1-13-04<br />
Optimal duration of adjuvant chemotherapy for high risk node<br />
negative breast cancer patients: 6-year results of the prospective<br />
randomized phase III trial PACS 05.<br />
Kerbrat P, Coudert B, Asselain B, Levy C, Lortholary A, Marre A,<br />
Delva R, Rios M, Viens P, Brain E, Serin D, Edel M, Mauriac L,<br />
Campone M, Mouret-Reynier M-A, Bachelot T, Foucher-Goudier<br />
M-J, Roca L, Martin A-L, Roche H. Centre Eugene Marquis, Rennes,<br />
France; Centre Georges François Leclerc, Dijon, France; Institut<br />
Curie, Paris, France; Centre Francois Baclesse, Caen, France;<br />
Centre Catherine de Sienne, Nantes, France; Centre Hospitalier,<br />
Rodez, France; ICO Centre Paul Papin, Angers, France; Centre<br />
Alexis Vautrin, Vandoeuvre-les-Nancy, France; Institut Paoli<br />
Calmettes, Marseille, France; Institut Curie, Saint Cloud, France;<br />
Institut Sainte-Catherine, Avignon, France; Centre Hospitalier Emile<br />
Muller, Mulhouse, France; Institut Bergonié, Bordeaux, France;<br />
ICO Centre René Gauducheau, Saint Herblain, France; Centre<br />
Jean Perrin, Clermont-Ferrand, France; Centre Léon Berard, Lyon,<br />
France; Centre Hospitalier Bretagne-Sud, Lorient, France; Centre<br />
Val d’Aurelle, Montpellier, France; R&D Unicancer, Paris, France;<br />
Institut Claudius Regaud, Toulouse, France<br />
BACKGROUND In 2000, the NIH Consensus meeting concluded<br />
that 4 to 6 cycles of adjuvant chemotherapy appeared to provide an<br />
optimal benefit; So, we underwent a prospective randomized trial<br />
comparing 4 and 6 cycles of FEC 100 (JCO 2005; 23: 2686-2693)<br />
for high risk node negative breast cancer patients.<br />
METHODS This study enrolled 18-65 y women with operable breast<br />
cancer, without axillary lymph node involvement, or presence of<br />
isolated tumor cells, with size superior to 1 cm and another poor<br />
prognostic factor : T > 2 cm, HR –, SBR grade II or III, age < 35 y.<br />
After adequate breast surgery and axillary lymph node dissection or<br />
sentinel node technique, they were randomized between arm A, 6<br />
cycles of FEC 100, and arm B, 4 cycles, every three weeks. The local<br />
regional treatment was completed following usual recommendations.<br />
All HR+ patients received hormonal therapy for 5 years. After August<br />
2005, patients with HER2+ tumors were excluded from this study.<br />
The primary end point was PFS at 5 years. This study was powered<br />
to detect a 6% difference in favour of 6 cycles.<br />
Between August 2002 and September 2006, 1516 patients were<br />
randomized; 1515 are analysed in ITT. Three patients in the B group<br />
did not receive any chemotherapy. There is no significant difference<br />
between the two arms for tumor and patient characteristics.<br />
RESULTS At a median follow-up of 73 months we observed regarding<br />
PFS a low event rate, 197 for the entire population (13%) 91 in arm<br />
A median PFS, vs. 106 in arm B median PFS, without any difference<br />
between the two groups for DFS, DDFS, local relapse, overall<br />
survival. There was no unexpected toxicity. In the arm A we observed<br />
more grade III and IV neutropenia, without congestive heart failure.<br />
CONCLUSION At a follow-up of 73 months, we observed a low<br />
relapse rate, with no significant difference between the two arms.<br />
Duration of FEC100 does not induce different outcomes in this<br />
population. Question of length of adjuvant treatment is still open<br />
with and without taxanes.<br />
P1-13-05<br />
The association between timing in adjuvant chemotherapy<br />
administration and overall survival for women with breast cancer<br />
within the National Comprehensive <strong>Cancer</strong> Network (NCCN)<br />
Vandergrift JL, Breslin TM, Niland JC, Edge SB, Wolff AC, Marcom<br />
PK, Rugo HS, Moy B, Wilson JL, Ottesen RA, Weeks JC, Wong Y-N.<br />
National Comprehensive <strong>Cancer</strong> Network, Fort Washington, PA;<br />
University of Michigan Comprehensive <strong>Cancer</strong> Center, Ann Arbor,<br />
MI; City of Hope Comprehensive <strong>Cancer</strong> Center, Duarte, CA; Dana-<br />
Farber/Brigham Women’s <strong>Cancer</strong> Center, Boston, MA; Roswell Park<br />
<strong>Cancer</strong> Institute, Buffalo, NY; The Sidney Kimmel Comprehensive<br />
<strong>Cancer</strong> Center at Johns Hopkins, Baltimore, MD; Duke <strong>Cancer</strong><br />
Institute, Durham, NC; UCSF Helen Diller Family Comprehensive<br />
<strong>Cancer</strong> Center, <strong>San</strong> Francisco, CA; The Ohio State University<br />
Comprehensive <strong>Cancer</strong> Center and James <strong>Cancer</strong> Hospital and<br />
Solove Research Institute, Columbus, OH; Massachusetts General<br />
Hospital <strong>Cancer</strong> Center, Boston, MA; Fox Chase <strong>Cancer</strong> Center,<br />
Philadelphia, PA<br />
Introduction: Population based studies (eg, Hershman et al. BCRT<br />
2006 and Lohrisch et al. JCO 2006) showed poorer survival associated<br />
with long delays in adjuvant chemotherapy (CTX) initiation following<br />
definitive surgery (DS) for women with breast cancer (BC). Delays in<br />
CTX following diagnosis (DX) have not been evaluated. The ASCO/<br />
NCCN quality measures (QMs) recommend CTX 90-day (d) DS-to-<br />
CTX threshold, based on poor outcomes observed in prior studies,<br />
and a >120d DX-to-CTX threshold, based on the ASCO/NCCN QMs.<br />
Results: Median follow-up was 7.2 years and OS at 7 years was<br />
89%. Overall, 401 (8.7%) patients received CTX >120d after DX and<br />
113 (2.4%) patients received CTX >90d after DS. The DX-to-CTX<br />
interval was more strongly correlated with the DX-to-DS (r=0.74)<br />
interval than DS-to-CTX (r=0.54) interval. A >90d DS-to-CTX<br />
interval was significantly associated with poorer survival (HR: 1.65,<br />
95% CI 1.04-2.60, p=0.03) in adjusted analyses. Shorter DS-to-CTX<br />
thresholds of >60d (n=636, HR: 1.13, 95% CI: 0.89-1.43, p=0.319)<br />
or >75d (n=273, HR: 1.05, 95% CI 0.74-1.49, p=0.76) were not<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
associated with OS. The association between a >120d DX-to-CTX<br />
interval and OS was not statistically significant (HR: 1.32, 95% CI<br />
0.99-1.76, p=0.06). Patients who received CTX >135d (n=231, HR<br />
1.25, 95% CI: 0.87-1.81, p=0.22) or >150d (n=128, HR 1.15, 95% CI:<br />
0.59-2.24, p=0.69) after DX did not display an increased risk of death.<br />
Excluding pathological staging factors from the model had no effect<br />
on the results. In subgroup analyses stratified by ER/PR, LVI, grade,<br />
T stage or N stage, a >120d delay in CTX did not display significant<br />
associations with OS. Among ER/PR negative patients, the association<br />
between a >120d delay and OS was borderline non-significant after<br />
adjusting the p-value for multiple hypothesis testing using the false<br />
discovery rate method (HR: 1.80, 95% CI: 1.16-2.79, p=0.09).<br />
Conclusion: Consistent with previous studies, CTX delays of >90<br />
days following surgery were associated with poorer survival. OS<br />
was not significantly compromised in patients with DX-to-CTX<br />
intervals >120 days although this analysis may have limited power<br />
to detect small effects. More variation in the DX-to-CTX interval<br />
was attributed to pre-surgery time which may explain the differences<br />
observed between the DX-to-CTX and DS-to-CTX intervals. Among<br />
patients with ER/PR negative disease, a non-significant association<br />
between OS and a >120 day DX-to-CTX interval was observed that<br />
warrants further examination.<br />
P1-13-06<br />
Withdrawn by Author<br />
P1-13-07<br />
Association Between Delayed Initiation of Adjuvant Chemotherapy<br />
and Survival in <strong>Breast</strong> <strong>Cancer</strong>: A Single-institution Study and A<br />
Systematic Review and Meta-analysis<br />
Yu K-D, Fan L, Yang C, Shao Z-M. <strong>Cancer</strong> Center and <strong>Cancer</strong><br />
Institute, Shanghai Medical College, Fudan University, Shanghai,<br />
China<br />
Objective<br />
Adjuvant chemotherapy (AC) improves survival among patients with<br />
operable breast cancer. However, the effect of delay in AC initiation on<br />
survival is unclear. We performed a single-institution data analysis and<br />
a systematic review and meta-analysis to determine the relationship<br />
between time to AC and survival outcomes.<br />
Methods<br />
PubMed, EMBASE, Cochrane Database of Systematic Reviews, and<br />
Web-of-Science databases (before March-20, 2012) were searched to<br />
identify relevant eligible studies. An additional retrospective analysis<br />
including 1,408 patients from the prospectively maintained database<br />
of Shanghai <strong>Cancer</strong> Center was performed and results were also<br />
included. Hazard ratios (HRs) for overall survival (OS) and diseasefree<br />
survival (DFS) from each study were converted to a regression<br />
coefficient (β) and its standard error corresponding to a continuous<br />
representation per 4-week delay of AC. Individual adjusted β were<br />
combined using a fixed-effects or random-effects model depending<br />
on heterogeneity.<br />
Results<br />
We included 8 eligible studies with 10 independent analytical groups<br />
involving 21,221 patients, 1 prospective observational study, 2<br />
secondary analyses in randomized trials (4 analytical groups), and<br />
5 hospital-/population-based retrospective studies. In our singleinstitution<br />
study, every 4-week delay in initiation of AC significantly<br />
decreased OS (HR=1.38; 95% confidence interval [CI], 1.03-1.87)<br />
and DFS (HR=1.35; 95% CI, 1.08-1.69) after adjustment for other<br />
prognostic variables. The overall meta-analysis demonstrated that<br />
a 4-week increase in time to AC was associated with a significant<br />
decrease in both OS (HR=1.20; 95% CI, 1.03-1.39; random-effects<br />
model) and DFS (HR=1.21; 95% CI, 1.08-1.36; fixed-effects model).<br />
One study caused a significant between-study heterogeneity for OS<br />
(P=0.001; I 2 =74.1%); after excluding that single study, there was no<br />
heterogeneity (P=0.345; I 2 =11.1%) and the HR was more significant<br />
(HR=1.24; 95% CI, 1.14-1.35; P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
chemotherapy and those who had chemotherapy alone. There was also<br />
no statistically significant difference in B cell depletion or recovery<br />
between different age groups, initial tumour size or grade of tumour.<br />
Conclusions<br />
These results confirm that B cells are especially vulnerable to<br />
chemotherapy toxicity. Detailed phenotyping of B cells revealed<br />
that chemotherapy has a profound effect on B cell subpopulations.<br />
The significance of this on host immunity is under investigation. We<br />
have additionally identified two factors responsible for delayed B cell<br />
repopulation, which highlight the need for lymphocyte assessments<br />
to be performed during and after chemotherapy.<br />
P1-13-09<br />
A multicenter randomized study comparing the dose dense<br />
G-CSF-supported sequential administration of FEC followed by<br />
docetaxel versus paclitaxel as adjuvant chemotherapy in women<br />
with axillary lymph node positive breast cancer.<br />
Mavroudis D, Malamos N, Boukovinas I, Kakolyris S, Kourousis C,<br />
Athanasiadis A, Ziras N, Makrantonakis P, Polyzos A, Christophylakis<br />
C, Georgoulias V. Hellenic Oncology Research Group (HORG),<br />
Athens, Greece<br />
Purpose: To compare the efficacy of dose dense docetaxel versus<br />
paclitaxel following FEC as adjuvant chemotherapy in node positive<br />
early breast cancer.<br />
Patients and treatment: Women 18-75 years old with histologically<br />
confirmed HER2-negative invasive breast carcinoma surgically<br />
resected with at least one infiltrated axillary lymph node and<br />
absence of metastatic disease were randomized to receive 4 cycles of<br />
fluorouracil (700mg/m2), epirubicin (75mg/m2), cyclophosphamide<br />
(700mg/m2) followed by 4 cycles of either docetaxel (75mg/m2) or<br />
paclitaxel (175mg/m2). All chemotherapy cycles were administered<br />
every 14 days with G-CSF support. Stratification was based on<br />
menopausal status, number of involved nodes and hormone receptor<br />
expression. The primary endpoint of the study was to compare the<br />
disease-free survival (DFS) at 3 years and 239 patients were scheduled<br />
to enroll on each arm.<br />
Results: Between 2004-2007, 481 women were randomized and<br />
received FEC followed by docetaxel (arm A; n=240) or paclitaxel (arm<br />
B; n=241). The median age was 55 years in both arms, premenopausal<br />
status 31.3% versus 32.8%, more than 10 involved axillary nodes<br />
in 12.9% versus 12.4%, histological grade 3 tumor in 36.3% versus<br />
35.3% and hormone receptor negative disease in 14.6% versus 12%<br />
of patients in arms A and B, respectively. After a median follow up<br />
of 56.3 and 55.6 months (p=0.3) for arms A and B, respectively, there<br />
were 42 (17.5%) versus 47 (19.5%) disease relapses (p=0.5) and 20<br />
(8.3%) versus 22 (9.1%) disease-related deaths (p=0.7), respectively.<br />
The 3-year DFS rates were 88.1% versus 87.3% for arms A and B,<br />
respectively. Toxicity included grade 2-4 neutropenia in 31% versus<br />
21% (p=0.01), thrombocytopenia 3.5% versus 0.8% (p=0.06), febrile<br />
neutropenia 2.1% versus 1.2% (p=0.5), diarrhea 3.7% versus 2.5%<br />
(p=0.4), neurotoxicity 2.9% versus 4.6% (p=0.3) of patients in arms<br />
A and B, respectively. There were no toxic deaths.<br />
Conclusion: The dose dense administration with G-CSF support<br />
of FEC followed by either docetaxel or paclitaxel as adjuvant<br />
chemotherapy in women with node positive early breast cancer is<br />
well tolerated and results in a similar 3-year DFS rate.<br />
P1-13-10<br />
Efficacy, toxicity and quality of life in older patients with earlystage<br />
breast cancer treated with oral Tegafur-uracil or classical<br />
CMF (cyclophosphamide, methotrexate, and fluorouracil): an<br />
exploratory analysis of National Surgical Adjuvant Study for<br />
<strong>Breast</strong> <strong>Cancer</strong> (N-SAS BC) 01 Trial<br />
Hara F, Watanabe T, Shimozuma K, Ohashi Y. NHO Shikoku <strong>Cancer</strong><br />
Center, Matsuyama, Ehime, Japan; Hamamatsu Oncology Center,<br />
Hamamatsu, Shizuoka, Japan; College of Life Sciences, Ritsumeikan<br />
University, Kusatsu, Shiga, Japan; School of Public Health,<br />
University of Tokyo, Bunkyo-ku, Tokyo, Japan<br />
Background: It is critically important to consider the issue of<br />
treatment for older breast cancer patients in developed countries<br />
where aging has been rapidly advanced such as in Japan. According<br />
to Oxford Overview analysis of 15-year results, benefit of adjuvant<br />
chemotherapy in older than 70 years remains uncertain. Recently<br />
CALGB 49907 trial clearly showed standard chemotherapy of<br />
either cyclophosphamide, methotrexate, and fluorouracil (CMF) or<br />
doxorubicin plus cyclophosphamide (AC) is superior to capecitabine<br />
in patients with early-stage breast cancer who are 65 years or older.<br />
In contrast, we demonstrated equivalent efficacy between six cycles<br />
of classical CMF and 2 years of oral Tegafur-uracil (UFT) in phaseIII<br />
randomized controlled trial: N-SAS BC01 (Watanabe T et al, JCO<br />
2009). Of interest, UFT showed a trend toward better suppression<br />
of recurrence in patients over 50 years of age in this trial. In current<br />
exploratory analysis, we sought to examine whether UFT is not<br />
inferior to CMF in terms of efficacy, toxicity and quality of life (QOL)<br />
in older patients with early-stage breast cancer.<br />
Patients and Methods: N-SAS BC 01 trial was a randomly assigned<br />
trial comparing adjuvant oral UFT with classical CMF in patients with<br />
node negative, high risk breast cancer. In this exploratory analysis,<br />
patients of 65 years or older enrolled in N-SAS BC 01 trial were<br />
analyzed in terms of efficacy, toxicity and quality of life.<br />
Results: Of the 707 patients enrolled in N-SAS BC 01 trial, 97 patients<br />
(13.7%) were 65 years or older. Median age was 68 years (range, 65<br />
to 75 years). The 5-year relapse-free survival (RFS) rate was 92.5%<br />
in the CMF arm and 93.0% in the UFT arm. Overall survival (OS)<br />
rate at 5 years were 98.1% and 97.7%, respectively. The hazard ratios<br />
of the UFT arm relative to the CMF arm were 1.07 for RFS (95%<br />
CI, 0.31 to 3.55) and for OS (95% CI, 0.15 to 10.25). However 95<br />
% CIs were very wide due to the small sample size. Among patients<br />
who received CMF, frequency of grade 3/4 leukopenia (3.8%) and<br />
neutropenia (13.5%) were higher than 0% and 4.8% with UFT,<br />
respectively. Similarly, grade 3/4 increased liver enzyme and nausea/<br />
vomiting were more frequent with CMF than with UFT. In contrast,<br />
elevation of total bilirubin and diarrhea were more observed in UFT<br />
arm. Compared with patients received CMF, patients with UFT had<br />
better QOL scores assessed by EORTC QLQ-C30/BR23 and the<br />
FACT-B questionnaire. The rate of adherence was 79.2% (42/53) at 6<br />
months in the CMF arm and 74.4% (32/43) at 2 years in the UFT arm.<br />
Conclusion: The result of this study indicated that UFT might not<br />
be inferior to CMF in patient with early stage breast cancer who are<br />
65 years of age or older in terms of efficacy, toxicity and QOL. UFT<br />
would be a promising option for adjuvant chemotherapy in older<br />
women with node-negative, high-risk breast cancer. Further larger<br />
randomized clinical trial in this patient population would be warranted<br />
to validate these results.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
198s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
P1-13-11<br />
Adjuvant treatment of early-stage breast cancer with eribulin<br />
mesylate following dose-dense doxorubicin and cyclophosphamide:<br />
preliminary results from a phase 2, single-arm feasibility study<br />
Traina TA, Hudis C, Fornier M, Lake D, Lehman R, Berkowitz AP,<br />
Rege J, Liao J, Cox D, Seidman AD. Memorial Sloan-Kettering<br />
<strong>Cancer</strong> Center, New York, NY; Eisai Inc, Woodcliff Lake, NJ<br />
Background: Despite recent improvements in breast cancer<br />
outcomes, patients (pts) with high-risk, early-stage breast cancer<br />
continue to experience recurrences and death due to disease.<br />
Chemotherapy regimens with the ability to extend survival remain an<br />
important drug development goal. Eribulin mesylate has demonstrated<br />
antitumor activity and improved overall survival (OS) in pts with<br />
heavily pretreated, locally recurrent or metastatic breast cancer when<br />
compared to treatment of physician’s choice. This study examines<br />
the feasibility of eribulin as adjuvant therapy following dose-dense<br />
(dd) doxorubicin (A) and cyclophosphamide (C) in patients with<br />
early-stage breast cancer.<br />
Methods: Eligible pts have histologically confirmed, HER2-normal,<br />
stage I-III invasive breast cancer and adequate bone marrow, liver, and<br />
renal function. Treatment consists of dd AC (A 60mg/m 2 IV; C 600mg/<br />
m 2 IV) on Day 1 of each 14-day cycle x4 cycles, followed by eribulin<br />
mesylate 1.4mg/m 2 IV over 2-5min on Days 1 and 8 every 21 days<br />
x4 cycles. Radiation/hormonal therapy were allowed per standard of<br />
care. The primary objective of feasibility is defined as the ability to<br />
complete 4 cycles of eribulin without a treatment-related dose delay<br />
(defined as >2 days) or reduction. Feasibility rates will be reported<br />
for pts with and without growth factor use. Secondary/exploratory<br />
endpoints include evaluation of the safety via NCI-CTCAEv4 of 4<br />
cycles of AC followed by 4 cycles of eribulin, and 3-year diseasefree<br />
survival and OS.<br />
Results: As of 5/22/12, 46 of 80 planned pts have been treated; 38<br />
pts have had ≥1 dose of eribulin and are evaluable for eribulin-related<br />
toxicity. Pt characteristics are as follows: median age 50 yrs (27-65<br />
yrs); 100% female; ECOG of 0=81.6%; breast cancer stage at study<br />
entry: stg 1: 7.5%; stg 2: 72.5%, stg 3: 20%. Select treatment-related<br />
AEs are reported as total (all cycles) and eribulin-related events; many<br />
AEs overlapped during treatment (Table).<br />
ALL CYCLES<br />
ERIBULIN CYCLES<br />
Adverse event (N=38) All events (%) Grade 3/4 (%) All events (%) Grade 3/4 (%)<br />
Peripheral neuropathy 50 3 42 3<br />
Fatigue 78 3 42 0<br />
Neutropenia 32 18 29 16<br />
Febrile neutropenia 8 8 3 3<br />
Leukopenia 16 13 18 10<br />
Alopecia 58 NA 21 NA<br />
Nausea 66 0 24 0<br />
Serious treatment-related AEs were reported in 2 pts, the most<br />
common (5.3%) being febrile neutropenia attributed to AC. Currently,<br />
13 pts have had eribulin dose modification or delays; 10 of the<br />
events were related to eribulin (7 reductions, 5 delays, 1 withdraw).<br />
Eribulin-related AEs associated with dose delay or reduction are:<br />
6 gr-3 neutropenia, 1 gr-3 febrile neutropenia, 1 gr-3 peripheral<br />
neuropathy, 1 gr-3 respiratory infection, 1 gr-3 fatigue. Six pts have<br />
discontinued (DC) treatment (2 AEs, 1 disease recurrence, 3 withdrew<br />
consent). Five of the 6 pts requiring eribulin delay/modification due<br />
to neutropenia were able to complete therapy with growth factor<br />
support. One pt DC eribulin therapy due to neuropathy.<br />
Conclusions: Preliminary results from this study suggest that adjuvant<br />
treatment with eribulin following dose-dense AC therapy has an<br />
acceptable safety profile. Accrual is ongoing and study completion<br />
is anticipated prior to SABCS 2012.<br />
P1-13-12<br />
Withdrawn by Author<br />
P1-13-13<br />
First planned efficacy analysis of the NNBC 3-Europe trial:<br />
Addition of docetaxel to anthracycline containing adjuvant<br />
chemotherapy in high risk node-negative breast cancer patients.<br />
Thomssen C, Kantelhardt EJ, Meisner C, Vetter M, Schmidt M, Martin<br />
P-M, Veyret C, Augustin D, Hanf V, Paepke D, Meinerz W, Hoffmann<br />
G, Wiest W, Sweep FCGJ, Schmitt M, Jaenicke F, von Minckwitz G,<br />
Harbeck N, On Behalf of the NNBC 3-Europe Study Group. Martin-<br />
Luther University Halle-Wittenberg, Halle an der Saale, Germany;<br />
Eberhard-Karls-University Tuebingen, Tuebingen, Germany;<br />
Johannes Gutenberg-Universität Mainz, Mainz, Germany; Medical<br />
Faculty Marseille, Marseille, France; Henri Becquerel Center, Rouen,<br />
France; Klinikum Deggendorf, Deggendorf, Germany; Klinikum<br />
Fürth, Fürth, Germany; Technical University Munich, München,<br />
Germany; St. Vincenz-Hospital, Paderborn, Germany; St. Josefs-<br />
Hospital, Wiesbaden, Germany; Katholisches Klinikum, Mainz,<br />
Germany; Radbourd University Nijmegen, Nijmegen, Netherlands;<br />
University Hamburg, Hamburg, Germany; German <strong>Breast</strong> Group,<br />
Neu-Isenburg, Germany; Ludwig-Maximilian-University, Munich,<br />
Germany<br />
Background: Risk assessment in node-negative (N0) breast<br />
cancer patients (pts) is routinely performed by established clinicopathological<br />
algorithms (CP) (Schmidt et al. Ann Oncol 2009). ASCO<br />
guidelines also recommend invasion markers uPA/PAI-1 (UP; Harris<br />
et al. JCO 2007). The prospective randomized multicenter NNBC<br />
3-Europe trial had two questions: 1) Does UP compared to the CP<br />
algorithm improve identification of low-risk node-negative breast<br />
cancer patients? 2) Does addition of taxanes to adjuvant chemotherapy<br />
improve DFS probability in high-risk node-negative breast cancer?<br />
Data are mature to report on the second question only.<br />
Methods: Between 2002 and 2009, 4,147 node-negative breast cancer<br />
pts were recruited. Risk assessment was performed by CP (43 %) or<br />
by UP (57 %). High-risk pts were randomized to receive FE 100 C*3-<br />
Doc*3 (FEC-D) versus FE 100 C*6 (FEC) as adjuvant chemotherapy.<br />
Primary endpoint was disease-free survival probability (DFS). It was<br />
planned to accrue 2,572 pts allowing detection of 4% reduction in<br />
recurrence probability at 5 years with a power of 80 % at a level of<br />
α=0.05 (LogRank) after a minimum observation time of 2.5 years<br />
for every recruited patient.<br />
Results: In the intent-to-treat population (ITT, n=2,541), 1,286 highrisk<br />
pts received FEC-D, and 1,255 received FEC. In July 2012, 90.8<br />
% of patients had reached the minimum observation time – median<br />
follow-up was 43.8, and 44.4 months. Main patients’ characteristics<br />
were distributed similarly between the two chemotherapy arms:<br />
median age was 53 yrs, 37.4 % of pts were premenopausal, median<br />
tumor size was 1.90 cm, grade 3 was seen in 53.8 %, hormone<br />
receptor status was negative in 30.1 % and HER2 was overexpressed<br />
in 20.0 %. Mastectomy was performed in 11 %. All planned courses<br />
of FEC-D were given in 84.4 %, of FEC in 91.4 % (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P1-14-01<br />
Adding capecitabine and trastuzumab to neoadjuvant breast<br />
cancer chemotherapy - first survival analysis of the GBG/AGO<br />
intergroup-study GeparQuattro.<br />
von Minckwitz G, Rezai M, Loibl S, Fasching PA, Huober J, Tesch<br />
H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C,<br />
Blohmer J-U, Costa S-D, Jackisch C, Paepke S, Schneeweiss A,<br />
Kuemmel S, Denkert C, Mehta K, Untch M. German <strong>Breast</strong> Group,<br />
Neu-Isenburg; Louisenkrankenhaus Düsseldorf; University Erlangen;<br />
University Duesseldorf; Bethanien-Kankenhaus Frankfurt; Klinikum<br />
Landshut; Eilenriedeklinik Duesseldorf; University Kiel; University<br />
Rostock; Roteskreuzklinikum Muenchen; <strong>San</strong>kt Gertrauden Berlin;<br />
University Magdeburg; Klinikum Offenbach; Frauenklinik München;<br />
University Heidelberg; Kliniken Essen Mitte; Charite Berlin; Helios<br />
Kliniken Berlin<br />
Background: Previous results of the GeparQuattro study<br />
demonstrated that adding capecitabine either simultaneously or<br />
sequentially to EC-Docetaxel (D) neoadjuvant chemotherapy could<br />
not increase pathological complete response rates (pCR) (von<br />
Minckwitz G, JCO 2010). However, patients with HER2-positive<br />
disease treated simultaneously with trastuzumab showed a significant<br />
higher pCR rate than patients with HER2-negative disease treated with<br />
chemotherapy alone (Untch M, JCO 2010). We here report survival<br />
after a median follow up of 58 months including 279 relapses and<br />
191 deaths.<br />
Patients and methods: Patients with either large operable (cT3) and<br />
locally advanced (cT4) tumors, or hormone-receptor (HR)-negative<br />
receptor status, or HR-positive tumors but clinically node-positive<br />
disease were recruited to receive 4 cycles of EC (90mg/m 2 / 600mg/<br />
m 2 ) and randomized to either 4 cycles of D (100mg/m 2 ) or 4 cycles<br />
of DX (75mg/m 2 / 1800mg/m 2 ) or 4 cycles of D (75mg/m 2 ) followed<br />
by 4 cycles of X (1800mg/m 2 ) (D→X). Patients with HER-2 positive<br />
tumors received 1 year of trastuzumab, the first part concurrent to<br />
all chemotherapy cycles. All patients with HR+ tumors received<br />
endocrine therapy according to current standard. The intent-totreat<br />
survival analysis included 1421 patients for the chemotherapy<br />
question and 1495 patients for the trastuzumab question. Analyses<br />
were adjusted by age, stage, size, nodal status, histologic type, grade,<br />
hormone-receptor (HR) and HER2-status at baseline (if applicable).<br />
Results: No difference in DFS and OS was seen for patients receiving<br />
D, DX or D-X overall (hazard ratio 0.978, P=0.984 and hazard<br />
ratio 0.986, P=0.684, respectively) as well as by phenotype defined<br />
according to St. Gallen (all P>0.354).<br />
Patients with HER2-positive disease treated additionally with<br />
trastuzumab showed significantly better OS (P=0.015) compared<br />
to patients with HER2-negative disease treated with chemotherapy<br />
alone. DFS was significantly better for trastuzumab-treated patients<br />
with HR-negative tumors (P=0.046), but not with HR-positive<br />
tumors (P=0.790). OS after first relapse was significantly better in<br />
trastuzumab-re-treated patients with HER2-positive tumors (P=0.032)<br />
compared to relapsed patients with HER2-negative tumors.<br />
Patients with an early response after 4 cycles, with a clinical response<br />
at surgery and with a pCR showed a significantly better DFS and OS<br />
compared to patients without pCR (P=0.022, P
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
breast cancer. Treatment discontinuation rate was significantly higher<br />
in TX than T group, however the pCR rate in patients in TX group<br />
who required treatment discontinuation or dose-reduction was similar<br />
to that in patients who completed as scheduled, which was different<br />
from T group. Determination of pre-/ post-treatment Ki67LI looks<br />
useful for predicting pCR and DFS.<br />
P1-14-03<br />
Overall survival results of a multicenter randomized phase II<br />
study in locally advanced breast cancer patients treated with<br />
or without neoadjuvant Trastuzumab for HER2 positive tumor<br />
(Remagus 02 trial)<br />
Giacchetti S, Pierga J-Y, Asselain B, Delaloge S, Brain E, Espié M,<br />
Mathieu M-C, Bertheau p, de Cremoux P, Tembo O, Marty M. Hôpital<br />
Saint Louis, Assitance Publique-Hôpitaux, Paris, France; Institut<br />
Curie, Paris, France; Institut Gustave Roussy, Villejuif, France;<br />
Institut Curie-Saint Cloud, Saint Cloud, France<br />
Background: Trastuzumab is indicated in neoadjuvant setting in<br />
locally advanced HER2 positive breast cancer patients (Gianni L.<br />
Lancet 2010). There is no data on the impact of the use of neoadjuvant<br />
Trastuzumab (T) compared to adjuvant T on survival.<br />
Patients and methods: From May 2004 to October 2007, 341<br />
stage II-III breast cancer patients were included in a phase II<br />
randomized trial and received 4 cycles (c) of epirubicin (75 mg/m2<br />
d1)–cyclophosphamide (750 mg/m2 d1) q 3 w followed by 4 (c) of<br />
docetaxel (100 mg/m2 d1) q 3 w. Pts with HER2+++ tumor (120<br />
pts) were randomized to receive or not neoadjuvant T combined<br />
with docetaxel. From September 2005, all pts with HER2+cancer<br />
received adjuvant T for a total of 18 c (106 pts). All pts with hormone<br />
receptors positive tumor received hormonal treatment according to<br />
menopausal status (Pierga et al BCRT 2010). We report here overall<br />
survival (OS) and disease free survival (DFS) data at 5 year and<br />
associated prognostic factors.<br />
Results: At a median follow up of 49 months, the median DFS was<br />
not reached for the whole population and was statistically superior<br />
for the HER2 positive cancer patients treated with chemotherapy plus<br />
neoadjuvant T compared to the other groups, p=0.018 . The median<br />
OS is not reached for the whole population and is statistically higher<br />
in HER2 positive tumor group compared to HER2 negative group<br />
(p=0.00077). For 106 HER2 positive breast cancer patients who had<br />
received one year of complete trastuzumab treatment, there was no<br />
significant difference in OS and DFS between pts who started T in<br />
neoadjuvant setting versus in adjuvant setting. DFS and OS were<br />
not significantly influenced by pathological Complete Response<br />
rate (pCR) (respectively, p = 0.22 and p = 0.56). At multivariate<br />
analysis including 6 factors (age, tumor size, clinical lymph node,<br />
ER, PgR), factors which influenced OS were tumor size (p =0.03)<br />
and ER expression (p = 0.06) and for DFS,clinical lymph node status<br />
(p=0.049) and PgR expression (p = 0.046).<br />
Conclusion: pCR is not a surrogate of survival in the HER2+subgroup.<br />
HER2 positive breast cancer pts receiving trastuzumab have a<br />
significant higher OS than those with HER2 negative tumors. OS<br />
and DFS do not seem to differ between the neoadjuvant T group and<br />
the T adjuvant group.<br />
P1-14-04<br />
Long- term outcome after neoadjuvant radiochemotherapy in<br />
locally advanced non-inflammatory breast cancer and predictive<br />
factors for a pathologic complete remission;<br />
results of a multi-variate analysis<br />
Matuschek C, Boelke E, Roth S, Bojar H, Audretsch W, Janni JW,<br />
Nestle-Kraemling C, Sauer R, Speer V, Budach W. Heinrich Heine<br />
University, Düsseldorf, Germany; European Institute for Molecular<br />
Oncology, Düsseldorf, Germany; Marien Hospital, Düsseldorf,<br />
Germany; Krankenhaus Gerresheim, Düsseldorf; University of<br />
Erlangen, Germany<br />
Background: An earlier published series of neoadjuvant radiochemotherapy<br />
(NRT-CHX) in locally advanced non-inflammatory<br />
breast cancer (LABC) has now been updated with a follow up of<br />
more than 15 years. Long- term outcome data and predictive factors<br />
for pathologic complete response (PCR) were analyzed.<br />
Patients and Methods: 315 LABC patients (cT1-cT4 /cN0-N1) were<br />
treated during 1991-1998 with NRT-CHX. Preoperative radiotherapy<br />
(RT) consisted of external beam radiation therapy (EBRT) of 50 Gy<br />
(5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph<br />
nodes combined with an electron boost in 214 cases afterwards or – in<br />
case of breast conservation – an 10-Gy interstitial boost with 192Ir<br />
afterloading before EBRT. Chemotherapy was administered prior to<br />
RT in 192 patients, and concomitantly in 113; 10 patients received no<br />
chemotherapy. The update of all follow up ended in November 2011.<br />
Age, tumor grade, nodal status, hormone receptor status, simultaneous<br />
vs. sequential CHX and the time interval between end of RT and<br />
surgery were examined in multivariate terms with as endpoint pCR<br />
and overall survival.<br />
Results: The total PCR rate after neoadjuvant RT-CHX reached 29.2<br />
% with LABC breast conservation becoming possible in 50.8%. In<br />
initially node-positive cases (cN+), a complete nodal response (pN0)<br />
after NRT-CHX was observed in 56% (89/159). The multivariate<br />
analysis revealed that a longer time interval to surgery increased<br />
the probability for a pCR (HR 1,17 [95% CI 1,05-1,31], p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
associated with a high incidence of cardiotoxicity. The risk of cardiac<br />
damage can be significantly reduced through liposomal encapsulation<br />
of anthracyclines. This phase I/II study was initiated to evaluate<br />
the combination of non-pegylated liposomal doxorubicin (NPLD),<br />
paclitaxel and lapatinib as primary treatment for patients with early<br />
stage, HER2-positive primary breast cancer.<br />
Patients and Methods: Patients with newly diagnosed HER2-positive<br />
(IHC 3+ or FISH+) early stage (T1c N1-2 or T2 N0-2) breast cancer<br />
were treated with NPLD (60mg/m 2 ; day 1), paclitaxel (175mg/m 2 , day<br />
1) and lapatinib (750-1500 mg orally daily) in 3-week intervals for up<br />
to 6 cycles. The primary endpoints were dose-limiting toxicities (DLT)<br />
and pathological complete response (pCR). Secondary endpoints<br />
include safety, incidence of cardiac events, and clinical response.<br />
Exploratory endpoints include molecular markers for sensitivity or<br />
resistance to chemotherapy and/or lapatinib evaluated.<br />
Results: A total of 84 patients have been included. No dose-limiting<br />
toxicity were observed and the maximum tolerated doses were NPLD<br />
60mg/m 2 , paclitaxel 175mg/m 2 and lapatinib 1500mg. Recommended<br />
phase 2 doses (P2D) were NPLD 60mg/m 2 , paclitaxel 175mg/m 2 and<br />
lapatinib 1250mg. The treatment was generally well tolerated and<br />
associated with toxicities that were consistent with the known sideeffects<br />
of the individual agents. No cardiac event has been observed<br />
to date. Preliminary efficacy data confirm a pCR breast rate of 41.7%<br />
and pCR rate in breast and lymph nodes of 37.5%, in 32 evaluable<br />
patients treated at ≥P2D.<br />
Conclusions: The combination of NPLD, paclitaxel and lapatinib is<br />
well tolerated and has high antitumor activity in patients with HER2-<br />
positive primary breast cancer. Updated results of all 84 patients will<br />
be presented.<br />
P1-14-06<br />
Significance of examining biomarkers of residual tumors after<br />
neoadjuvant chemotherapy using trastuzumab in combination<br />
with anthracycline and taxane in patients with primary HER2-<br />
positive breast cancer<br />
Kurozumi S, Takei H, Inoue K, Matsumoto H, Hayashi Y, Ninomiya<br />
J, Kubo K, Tsuboi M, Nagai S, Ookubo F, Oba H, Kurosumi M,<br />
Horiguchi J, Takeyoshi I. Saitama <strong>Cancer</strong> Center, Saitama, Japan;<br />
Gunma University Graduate School of Medicine, Gunma, Japan<br />
Background: Neoadjuvant chemotherapy (NAC) with taxane and<br />
FEC concurrently with trastuzumab is a potent regimen in women<br />
with HER2-positive breast cancer (BC), and several studies revealed<br />
high pCR rates in BC patients treated with this regimen. In the present<br />
study, we compared the status of biomarkers before and after NAC,<br />
and evaluated rates and patterns of discordant biomarker expression.<br />
We also evaluated differences of prognosis between patients<br />
with discordant biomarker expression and those with concordant<br />
expression.<br />
Patients and Methods: We investigated 118 Japanese women with<br />
invasive HER2 positive BC. Patients received 12 cycles of paclitaxel<br />
or 4 cycles of docetaxel followed by 4 cycles of FEC-75 with<br />
concomitant trastuzumab for 24 weeks and were followed for ≥1<br />
year after surgery. Of these, 27 patients with residual tumors 5 mm<br />
or larger were analyzed. HER2, ER, PgR, and Ki67 were examined<br />
in primary and residual tumors. Furthermore, recurrence-free survival<br />
(RFS) and overall survival (OS) were analyzed between patients<br />
classified based on these biomarkers.<br />
Results: Patients with pCR after NAC (75/118; 63.5%) had<br />
significantly better RFS than non-pCR patients (median follow-up:<br />
41 months). Residual tumors were obtained from 27 of 43 nonpCR<br />
patients and examined for immunohistochemical biomarker<br />
expression. In 14/27 non-pCR patients (51.9%), residual tumors were<br />
HER2 negative, despite being HER2 positive before NAC: HER2<br />
score changed from 3+ to 0 or 1+ in 8/18 patients (44.4%) and from<br />
2+ to 0 or 1+ in 6/9 (66.7%). ER expression changed in 2 patients (1<br />
positive to negative and 1 negative to positive). Patterns of biomarker<br />
expression in residual tumors were HER2 (+)/ER (–), 6 patients<br />
(22.2%); HER2 (+)/ER (+), 7 (25.9%); HER2 (–)/ER (+), 11 (40.7%);<br />
and triple negative (TN), 3 (11.1%). Recurrence was observed in 8/27<br />
(29.6%) non-pCR patients, and patterns of biomarker expression in<br />
residual tumors were HER2 (+)/ER (–), 3 patients; HER2 (+)/ER (+),<br />
2; and HER2 (–)/ER (+), 3. In addition, 1 patient with a HER2 (+)/<br />
ER (+) tumor and 1 patient with a HER2 (-)/ER (+) tumor died. RFS<br />
and OS were not statistically different between patients classified<br />
based on ER and Ki67 expressions. However, in the 18 non-pCR<br />
patients with primary tumor HER2 score of 3+ (overexpression of<br />
HER2 protein), the 10 with HER2-positive residual tumors showed<br />
significantly lower RFS than the 8 with HER2-negative (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
Results In total, 201 patients (n=100 AC-T, n=101 TAC) were enrolled<br />
between February 2006 and April 2009. Baseline characteristics (AC-<br />
T/TAC) were well balanced. The clinical overall response rate (cCR<br />
and cPR) to 4 AC was comparable to that seen with 3 cycles TAC<br />
(48% versus 54%). Also, the clinical overall response rate to 8 AC-T<br />
was comparable to that seen with 6 TAC (81% versus 72%). In the<br />
AC-T arm, a third of the patients with cSD halfway reached a cCR<br />
or cPR after 8 cycles, whereas in the TAC arm only 18% of patients<br />
with cSD halfway reached a cCR or cPR after chemotherapy. In the<br />
sequential AC-T arm, 16% of the patients with cSD halfway reached<br />
a pCR after switching to docetaxel monotherapy. In contrast, in the<br />
TAC arm cSD halfway rarely resulted in pCR after 6 cycles. Patients<br />
with a cCR after chemotherapy had a pCR in 58% and 49% of cases,<br />
respectively. For patients with cPR these rates were 29% and 18%,<br />
respectively, and for patients with cSD 6% and 0%, respectively.<br />
Conclusion<br />
Clinical response rates are related to pCR rates. The meaning of<br />
cSD halfway should be differently interpreted for sequential versus<br />
concurrent chemotherapy. In concurrent chemotherapy schedules,<br />
a switch to a non-cross resistant drug may be worthwhile. Early<br />
clinical response may be used as a decision aid during neoadjuvant<br />
chemotherapy to recognize non-responders.<br />
Support: Unrestricted grants from sanofi-aventis NL BV and Amgen<br />
BV. Dutch breast cancer trialists’ group (BOOG).<br />
P1-14-08<br />
A prospective multicenter randomized phase II neo-adjuvant<br />
study of 5-fluorouracil, epirubicin and cyclophosphamide (FEC)<br />
followed by docetaxel, cyclophosphamide and trastuzumab (TCH)<br />
versus TCH followed by FEC versus TCH alone, in patients (pts)<br />
with operable HER2 positive breast cancer: JBCRG-10 study<br />
Masuda N, Sato N, Higaki K, Kashiwaba M, Matsunami N, Takano T,<br />
Yamamura J, Kaneko K, Takahashi M, Ohno S, Fujisawa T, Tsuyuki<br />
S, Miyoshi Y, Ohtani S, Yamamoto Y, Bando H, Onoda T, Kawabata<br />
H, Morita S, Ueno T, Toi M. NHO Osaka National Hospital, Osaka,<br />
Japan; Niigata <strong>Cancer</strong> Center Hospital, Niigata, Japan; Hiroshima<br />
City Hospital, Hiroshima, Japan; Iwate Medical University, Morioka,<br />
Japan; Osaka Rosai Hospital, Sakai, Japan; Toranomon Hospital,<br />
Tokyo, Japan; Hokkaido <strong>Cancer</strong> Center, Sapporo, Japan; National<br />
Kyushu <strong>Cancer</strong> Center, Fukuoka, Japan; Gunma Prefectural <strong>Cancer</strong><br />
Center, Ohta, Japan; Osaka Red Cross Hospital, Osaka, Japan;<br />
Hyogo College of Medicine, Nishinomiya, Japan; Kumamoto<br />
University Hospital, Kumamoto, Japan; University of Tsukuba,<br />
Faculty of Medicine, Tsukuba, Japan; Yokohama Asahi Central<br />
General Hospital, Yokohama, Japan; Yokohama City University<br />
Graduate School of Medicine and Medical Center, Yokohama, Japan;<br />
Kyoto University, Kyoto, Japan<br />
Background: The current standard treatment of primary systemic<br />
therapy (PST) in HER2 positive breast cancer is anthracyclines (A)<br />
and/or taxanes combined with trastuzumab (H) which demonstrates<br />
high pathological complete response (pCR). The pCR is considered<br />
as a predictive marker of prognosis although results are slightly<br />
different depending on the hormone receptor status. We conducted<br />
a randomized phase II study to examine sequence of treatments and<br />
necessity of A in the treatments using TCH to improve outcome and<br />
reduce cardiac toxicity in Japanese HER2 positive pts.<br />
Methods: Pts were treated with FEC (5FU 500 mg/m 2 , epirubicin 100<br />
mg/m 2 , cyclophosphamide 500 mg/m 2 ) and/or TCH (docetaxel 75 mg/<br />
m 2 , cyclophosphamide 600 mg/m 2 , H 6 mg/kg, loading by 8 mg) in<br />
3 groups: 4 cycles of FEC followed by 4 cycles of TCH (A-TCH); 4<br />
cycles of TCH followed by 4 cycles of FEC (TCH-A) or 6 cycles of<br />
TCH. An unplanned interim analysis was conducted due to one death<br />
by interstitial lung disease (ILD) in the A-TCH after completion of<br />
8 cycles. The pCR results suggested A containing regimens did not<br />
exceed benefit from the current standard regimen. The study was<br />
continued by limiting allocation only to the TCH group considering<br />
efficacy and safety. The primary endpoint was pCR and secondary<br />
endpoints were overall response rate (ORR) and safety.<br />
Results: A total of 103 pts were enrolled between Sep. 2009 and Sep.<br />
2011; 21 pts in the A-TCH, 22 pts in the TCH-A and 60 pts in the<br />
TCH including pts enrolled after termination of random allocation.<br />
Characteristics of the 103 pts were; median age of 54 (range, 33-70),<br />
median tumor size of 35 mm (range, 12-80), 42 pts with N(+) (40.8%)<br />
and 62 ER positive pts (60.2%). Characteristics of pts in the TCH<br />
were; median age of 54.5 (range, 33-67), median tumor size of 35.5<br />
mm (range, 12-80), 25 pts with N(+) (41.7%) and 34 ER positive pts<br />
(56.7%). No major difference was reported between groups treated<br />
with or without A. Per protocol population was 59 pts in the TCH and<br />
its pCR rate was 45.8% (95% CI, 32.2-59.3: ER negative, 61.5%; ER<br />
positive, 33.3%). ORR was 86.4% assessed by MRI or CT. Although<br />
it is an exploratory analysis, the pCR rate of A containing regimens<br />
was 39.0% (ER negative, 57.1%; ER positive, 29.6%). Adverse events<br />
≥grade 3 were reported in 50 pts (48.5%). Reported ILD was in 5 pts<br />
(A-TCH,1; TCH-A, 1; TCH, 3). The mean left ventricular ejection<br />
fraction (LVEF) decreased from 70.0% to 69.0% after treatment<br />
(A-TCH, 65.9%; TCH-A, 70.4%; TCH, 69.0%). Decrease of LVEF<br />
in the A-TCH was significant (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
docetaxel (60 mg/m 2 on day 8 every 3 weeks) with capecitabine (1650<br />
mg/m 2 on days 1-14 every 3 weeks) followed by four cycles of FEC.<br />
Subtypes were classified into luminal A (lumA) (ER+ and/or PgR+,<br />
HER2-, Ki6714%), triple-positive (TP) (ER+ and/or PgR+, HER2+), HER2<br />
(ER-, PgR-, HER2+), and triple-negative (TN) (ER-, PgR-, HER2-)<br />
by using immunohistochemically stained specimen obtained by core<br />
needle biopsy. Absence of invasive tumor cells in the breast at the<br />
time of surgery was defined as pCR.<br />
Results<br />
We found 34 women in lumA, 54 in lumB, 15 in TP, 8 in HER2,<br />
33 in TN. The median age in each group was 53, 51, 50, 57 and<br />
53 respectively (p=.397). The mean tumor size was 3.2cm, 3.5cm,<br />
4.4cm, 3.9cm and 3.6cm respectively (p=.158). The clinical response<br />
rate measured by physical examination (calliper) was 80.6%, 93.9%,<br />
86.7%, 100% and 82.4% (p=.378). pCR rate was 5.9%, 14.8%.<br />
13.3%, 50%, 21.2% respectively (p=.031). The multivariate analysis<br />
showed ER negative, PgR negative and intrinsic subtype (TN) were<br />
the significant predictive factors of pCR (p=.027, p=.003, p=.004).<br />
Conclusion<br />
This study indicated that immunohistochemical classification of<br />
intrinsic subtype might be a useful predictive biomarker of pCR in<br />
breast cancer patients treated with preoperative chemotherapy.<br />
P1-14-10<br />
Final results of neoadjuvant trial of bevacizumab (B) and<br />
trastuzumab (T) in combination with weekly paclitaxel (P) as<br />
neoadjuvant treatment in HER2-positive breast cancer: A phase<br />
II trial (AVANTHER)<br />
Fernandez M, Calvo I, Martinez N, Herrero M, Quijano Y, Duran H,<br />
Garcia-Aranda M, Suarez A, Lopez-Rios F, Perez D, Perea S, Hidalgo<br />
M, Garcia-Estevez L. Centro Integral Oncológico Clara Campal,<br />
Madrid, Spain; Hospital Ramón y Cajal, Madrid, Spain; Hospital<br />
Costa del Sol, Marbella, Spain<br />
Background: B in combination with T has shown meaningful activity<br />
in patients (pts) with metastatic HER2-positive breast cancer.<br />
Pathological complete response (pCR) was defined as the absence<br />
of invasive disease at the time of histological study and there is a<br />
relationship between pCR and disease-free survival (DFS) and overall<br />
survival (OS). The complete pathological response rate is between 9<br />
to 34% of patients receiving primary treatment prior to surgery with<br />
chemotherapy and when the Herceptin was administrated, a pCR of<br />
39% was reached.<br />
AVANTHER is a Phase II trial of preoperative systemic therapy<br />
combining B with T and P in a weekly regimen in HER2 positive<br />
breast cancer to assess safety and efficacy of the combination.<br />
Methods: Pts with centrally-confirmed HER2- positive (IHC 3+<br />
or FISH positive) breast cancer (stage II or III including locally<br />
advanced) received neoadjuvant chemotherapy (NC) with weekly P<br />
(80mg/m2/week) for 12 weeks in combination with weekly T (4mg/<br />
kg loading dose and 2 mg/kg maintenance) and B (15mg/kg every<br />
3 weeks) for 4 cycles. After surgery all pts received T (1 year) and<br />
liposomal doxorubicin plus cyclophosphamide every 3 weeks (4<br />
cycles); primary endpoint was rate of pathological complete response<br />
(pCR) in breast and axilla. For all patients, a tissue sample at baseline<br />
as well as at surgery was collected for biomarker analyses.<br />
Results: A total of 44 pts have been enrolled. Median tumor size: 3.9<br />
cm. Nine (21%) pts had stage IIA; 19 (45%) stage IIB; 10 (24%) stage<br />
IIIA and 4 (10%) stage IIIB. Twenty-nine (69%) pts had estrogen<br />
positive receptors.<br />
Data from surgery of 42 patients from a total of 44 patients enrolled<br />
were presented in this abstract, but the final results will be present<br />
in the symposium. pCR was achieved in 18 (42.9%) pts. Safety and<br />
tolerability were good, with rare adverse events of grade 3 [1 (2.4%)<br />
episode of severe hypertension, 1 (2,4%) mucosal inflammation].<br />
We presented the results of relationship between magnetic resonance<br />
imaging (MRI) and pCR that is one of the secondary objectives of<br />
the study.<br />
100% of the patients without pathologic response had stable disease<br />
at resonance imaging. Of all patients who had pCR only 55.6% had<br />
complete radiological response.<br />
Conclusions: These data show that the combination of P with T and<br />
B without an anthracycline for 12 weeks is very effective as NC in<br />
HER2 positive breast cancer pts with a high rate of pCR and minimal<br />
side effects.<br />
And the MRI is useful for identifying the persistence of residual<br />
disease however it only predicts half of the complete pathological<br />
responses<br />
P1-14-11<br />
Assessing Prognosis and Therapy Response in Primary Systemic<br />
Therapy of <strong>Breast</strong> <strong>Cancer</strong> with Magnetic Resonance Spectroscopy<br />
Bolan PJ, Wey A, Eberly LE, Nelson MT, Haddad TC, Yee D, Garwood<br />
M. University of Minnesota, Minneapolis, MN; Masonic <strong>Cancer</strong><br />
Center, University of Minnesota, Minneapolis, MN<br />
PURPOSE: We have previously reported results of a pilot study<br />
in patients with locally advanced breast cancer receiving primary<br />
systemic chemotherapy (PST) showing that a decrease in tumor<br />
choline concentration ([tCho]) measured one day after starting<br />
treatment was associated with clinical response based on MRI. In<br />
this follow-up study with a larger cohort, we assessed whether early<br />
changes in [tCho] were associated with clinical response, based on<br />
both MRI and pathology, and survival.<br />
METHODS AND MATERIALS: Women with locally advanced<br />
breast cancer scheduled for PST were scanned using a high-field MRI/<br />
MRS protocol prior to treatment, day 1 after treatment, and at the end<br />
of the first course of chemotherapy. MRI/MRS was performed on a<br />
4 T Varian system with unilateral transmit/receive breast coils. MRI<br />
consisted of contrast-enhanced T1-weighted 3D gradient echo scans<br />
with one-minute temporal resolution. A single-voxel MR spectrum<br />
was acquired from the index lesion after MRI, and the concentration<br />
of total choline compounds ([tCho]) was quantified using water as<br />
an internal reference. Clinical response was assessed using RECIST<br />
criteria for measuring the longest diameter (LD) of the index lesion,<br />
and by pathologic complete response (pCR) at definitive surgery.<br />
Overall survival (OS) and invasive disease free survival (IDFS) were<br />
assessed by retrospective review of clinical records and the social<br />
security death index. The associations of change in [tCho] with pCR/<br />
LD response and with IDFS/OS were assessed using logistic/Cox<br />
regression, respectively, adjusted for node positivity and pCR status.<br />
RESULTS: Of the 74 women enrolled in the trial, 51 women (ages<br />
28-71, median 47 years) were scanned at all time points and included<br />
in the final analysis. Of these, 17 subjects had a partial or complete<br />
imaging RECIST response based on a ≥30% decrease of the LD of the<br />
index lesion. Pathologic complete response, defined as no detectable<br />
invasive disease in the breast, was observed in 13/51 overall subjects<br />
and in 6/35 hormone receptor positive (ER+ or PR+) subjects. Median<br />
follow-up time for survival analysis was 64 months (range 11-102<br />
months). Linear models showed no significant association between<br />
change in [tCho] and either pCR or RECIST response. An increase<br />
in [tCho] between the pretreatment scan and day 1 after treatment<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
204s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
was found to be associated with reduced likelihood of both OS and<br />
IDFS. We found no association between pCR status and either OS or<br />
IDFS when considering all subjects and in the HR+ cohort (see Table<br />
1). No results could be reported for the HR- group (14 subjects) due<br />
to an insufficient number of events.<br />
Table 1 - Survival Hazard Ratios<br />
All<br />
HR+<br />
OS [tCho] ↑ 25% 1.94 (p=0.003) * 2.24 (p=0.020) *<br />
pCR 0.78 (p=0.746) 2.14 (p=0.334)<br />
IDFS [tCho] ↑ 25% 1.98 (p=0.001) * 2.02 (p=0.019) *<br />
pCR 1.15 (p=0.835) 1.87 (p=0.429)<br />
* statistically signficant at p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P1-14-14<br />
Neoadjuvant Sunitinib (S) Administered with Weekly Paclitaxel<br />
(P) /Carboplatin(C) in Patients (Pts) with Locally Advanced<br />
Triple-Negative <strong>Breast</strong> <strong>Cancer</strong> (TNBC): Preliminary Results<br />
from a Phase I/II Trial of the Sarah Cannon Research Institute.<br />
Yardley DA, Barton J, Hendricks C, Webb C, Priego V, Nimeh<br />
N, Gravenor D, Shastry M, Chirwa T, Burris HA. Sarah Cannon<br />
Research Institute, Nashville, TN; Tennessee Oncology, PLLC,<br />
Nashville, TN; National Capital Clinical Research Consortium,<br />
Bethesda, MD; Baptist Hospital East, Louisville, KY; Center for<br />
<strong>Cancer</strong> and Blood Disorders, Bethesda, MD; <strong>Cancer</strong> Center of<br />
Southwest Oklahoma Research, Lawton, OK; Family <strong>Cancer</strong> Center<br />
Foundation, Inc., Memphis, TN<br />
Background: S is an oral, small molecule, multi-targeted tyrosine<br />
kinase inhibitor of vascular endothelial growth factor receptor,<br />
platelet-derived growth factor receptor, stem cell factor receptor,<br />
and colony-stimulating factor-1 receptor with demonstrated single<br />
agent activity in multiple tumor types including breast cancer. S’s<br />
anti-proliferative and anti-angiogenic activity stimulated interest<br />
in combining it with a variety of chemotherapy regimens. In the<br />
previously reported Phase I portion of this trial, S 25mg PO daily was<br />
determined feasible in combination with weekly P and C, an active<br />
regimen for TNBC. We now report the feasibility and efficacy of the<br />
phase II evaluation of this combination as neoadjuvant therapy with<br />
pathologic complete response (pCR) as the primary endpoint.<br />
Methods: Eligibility criteria included: invasive adenocarcinoma,<br />
triple negative histology defined as ER/ PR negative ( 5% of pts.<br />
Conclusions: The addition of sunitinib to paclitaxel and carboplatin<br />
was accompanied by significant hematologic toxicity resulting<br />
in the inability to deliver the planned study therapy. Treatment<br />
discontinuations were frequent as was the need for dose adjustments<br />
and modifications. The sunitinib-paclitaxel/carboplatin combination<br />
evaluated in this study is not recommended for further use in locally<br />
advanced breast cancer.<br />
P1-14-15<br />
Recent experience of neoadjuvant chemotherapy according to<br />
breast cancer subtype: experience from a large United Kindgom<br />
teaching hospital<br />
Rattay T, Kaushik M, Ahmed S, Shokuhi S. University Hospitals of<br />
Leicester, United Kingdom<br />
INTRODUCTION:<br />
The most recent United Kingdom (NICE, 2009) guidelines<br />
recommend neoadjuvant chemotherapy as the most appropriate initial<br />
treatment for locally advanced breast cancer followed by mastectomy.<br />
Neoadjuvant chemotherapy should also be offered to patients with<br />
early breast cancer who are considering breast conserving surgery that<br />
is not advisable at presentation. However, the evidence base is still<br />
gathering. This study reviews the recent experience of neoadjuvant<br />
chemotherapy in a large United Kingdom breast unit according to<br />
breast cancer subtype.<br />
METHODS:<br />
Retrospective chart review of patients who received neoadjuvant<br />
chemotherapy for breast cancer at University Hospitals of Leicester<br />
between January 2008 and March 2011. Patients were identified<br />
from the unit database. <strong>Breast</strong> cancers were typed according to<br />
immunehistochemical marker profile: luminal A (ER or PR positive,<br />
HER2 negative), luminal B (ER or PR positive, HER2 positive), triple<br />
negative (ER and PR negative, HER2 negative), and HER2 positive<br />
(ER and PR negative, HER2 positive).<br />
RESULTS:<br />
Of 2,489 new patients with breast cancer seen during the study period,<br />
153 patients received neoadjuvant chemotherapy. 20 patients had<br />
lobular-type cancers, and the remaining 133 patients had ductal- or<br />
mixed-type histology. 101 patients had locally advanced disease<br />
and 52 patients presented as early breast cancer. 24 of all patients<br />
(15 %) achieved complete pathological response. 18 patients (12 %)<br />
never proceeded to surgery, eight of whom died during the study<br />
period. In total to date, 23 patients (15 %) have died including one<br />
death due to complications from chemotherapy. Of 120 patients<br />
initially scheduled for mastectomy, the tumor was downsized in 26<br />
patients (22 %) so that they were able to undergo breast conserving<br />
surgery (BCS), with margins involved in six patients. The outcome<br />
of neoadjuvant chemotherapy according to breast cancer subtype is<br />
presented (Tables 1 and 2).<br />
Table 2<br />
Subtype No of patients pCR No pathological response Deaths<br />
Luminal A 73 3 4 % 22 30 % 8 11 %<br />
Luminal B 28 7 25 % 4 14 % 1 4 %<br />
Triple negative 35 10 29 % 4 11 % 10 29 %<br />
HER2+ 17 4 24 % 2 12 % 4 24 %<br />
Table 2<br />
Subtype no surgery<br />
initially for<br />
converted to BCS<br />
mastectomy<br />
positive margins<br />
Luminal A 6 8 % 57 12 21 % 4 33 %<br />
Luminal B 2 7 % 24 5 21 % 1 20 %<br />
Triple<br />
negative<br />
5 14 % 27 6 22 % 1 17 %<br />
HER2+ 5 29 % 12 3 25 % 0 0 %<br />
CONCLUSIONS:<br />
In our experience, patients receive neoadjuvant chemotherapy for<br />
breast cancer for a variety of indications. Compared to our standard<br />
population of breast cancer patients, early mortality remains relatively<br />
high, particlularly in the hormone receptor negative subtypes. BCS<br />
conversion rates were similar across breast cancer subtypes, but BCS<br />
was less likely to be successful in the Luminal A group. Luminal<br />
A cancers were also significantly less likely to achieve pCR after<br />
neoadjuvant chemotherapy. <strong>Breast</strong> cancer subtype should be taken<br />
into account when scheduling patients for neoadjuvant chemotherapy.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
206s<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
P1-14-16<br />
Young age: predicts poor response rate after neoadjuvant<br />
chemotherapy in endocrine-responsive breast cancer<br />
Kim MK, Noh D-Y, Han W, Moon H-G, Ahn S-K, Kim JS, Kim T,<br />
Kim JY, Lee JW. Seoul National University Hospital, Seoul, Korea<br />
Background; <strong>Breast</strong> cancer rarely occurs in very young<br />
women(age0.05); and concentric shrinkage mode was<br />
observed only in 1 case (3.9%). More diffusive residual DCIS was<br />
observed in pts with diffusive microcalcifications on mammography<br />
before NAC than those without (76.5% vs. 7.7%, κ=0.670, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Patients and methods/: From May 2004 to October 2007, 340<br />
stage II-III breast cancer patients were included in a phase II<br />
randomized trial and received 4 cycles (c) of epirubicin (75 mg/<br />
m2)–cyclophosphamide (750 mg/m2) q 3 w followed by 4 (c) of<br />
docetaxel (100 mg/m2) q 3 w. Pts with HER2 negative tumors (220<br />
pts) were randomized to receive or not neoadjuvant celecoxib (200<br />
mg bid) combined with docetaxel. All pts with hormone receptors<br />
positive tumor received hormonal treatment according to menopausal<br />
status (Pierga et al BCRT 2010). We report here overall survival<br />
(OS) and disease free survival (DFS) data and prognostic factors<br />
analyses at 5 years.<br />
Results/: At a median follow up of 49 months, the median DFS and<br />
OS are not reached for the whole population and none of them is<br />
significantly different between pts who received celecoxib or who did<br />
not (p = respectively 0.62 and 0.36). Celecoxib had no impact either<br />
on clinical and pathological complete response rate (pCR). DFS is<br />
significantly higher in patients who achieved pCR as compared to<br />
those who did not (p = 0.017; RR = 0.21 [0.051-0.88], whereas OS<br />
is borderline significant [p = 0.07; RR = 0.19 (0.026-1.4)]. Patients<br />
with triple negative (TN) tumors (78 pts) achieved worst DFS (p=<br />
0.02) and OS (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
Conclusion :. This NCT provided high pCR, specially in the HRsubgroup<br />
with a very favourable toxicity profile and merits further<br />
exploration.<br />
P1-15-01<br />
Patterns of granulocyte colony stimulating factor (G-CSF) use in<br />
elderly breast cancer (BC) patients receiving myelosuppressive<br />
chemotherapy<br />
Blaes AH, Chia V, Solid C, Page J, Barron RL, Choi MR, Arneson TJ.<br />
University of Minnesota, Minneapolis, MN; Amgen, Inc., Thousand<br />
Oaks, CA; Minneapolis Medical Research Foundation, Minneapolis,<br />
MN<br />
Background: Febrile neutropenia (FN) is a common and potentially<br />
serious complication of myelosuppressive chemotherapy treatment<br />
in cancer patients. Oncology guidelines recommend primary G-CSF<br />
prophylaxis (PPG) in patients with a high risk of developing FN,<br />
which is risk >20% based on myelotoxicity of the regimen itself<br />
or from a combination of the therapy, older age, comorbidities and<br />
disease characteristics (Lyman <strong>Cancer</strong> 2011). Current patterns of<br />
G-CSF use and FN occurrence among elderly patients receiving<br />
myelosuppressive chemotherapy for BC have not been previously<br />
reported. To determine this, we performed a retrospective analysis<br />
using a subset of the Medicare 5% database.<br />
Methods: The Medicare 5% claims data set (includes a representative<br />
5% systematic sample of Medicare beneficiaries) was used to identify<br />
BC patients age 65+ initiating chemotherapy between 7/1/2003<br />
and 6/30/2009. Chemotherapy courses were identified for each<br />
patient; only the first course was used for this analysis. Using the<br />
National Comprehensive <strong>Cancer</strong> Network guidelines on Myeloid<br />
Growth Factors (NCCN V1.2012), chemotherapy course regimens<br />
were classified as high risk (HR) or intermediate risk (IR) for FN.<br />
Duration of first cycle was from date of first chemotherapy claim<br />
to the chemotherapy claim at day 21 or later, which defined the<br />
first day of the second cycle, etc., to a maximum of 9 cycles. First<br />
administration of G-CSF [filgrastim (NEUPOGEN®) or pegfilgrastim<br />
(Neulasta®)] was classified as either PPG (within first 5 days of<br />
first cycle), secondary prophylaxis (within first 5 days of second or<br />
subsequent cycles), or reactive (day 6 or later of first or subsequent<br />
cycles). FN assessed during the chemotherapy course was defined as<br />
hospitalization with a code for neutropenia in any position.<br />
Results: 885 courses with high FN risk and 1046 with IR FN risk were<br />
identified. The HR cohort was younger (71.4 vs 74.5 yrs) and had<br />
fewer comorbidities than the IR cohort. Selected aspects of G-CSF<br />
use patterns are summarized in the table. Among HR courses, 11.8%<br />
had ≥1 FN hospitalization and 2.1% had 2+; among IR courses 5.6%<br />
had ≥1 and 0.4% had 2+.<br />
Conclusion: NCCN recommends PPG be used with HR regimens and<br />
older age (notably >65 yr), an important risk factor for developing<br />
severe neutropenic complications. Despite this, PPG was used for<br />
elderly breast cancer patients in only 52% of chemotherapy courses<br />
with high risk of FN and in 10% of IR courses. More than 10%<br />
of patients with a HR regimen had an FN hospitalization. Careful<br />
attention to FN risk factors, including regimen and patient age, is<br />
needed when planning treatment strategy.<br />
Any G-CSF Use During Course<br />
Regimen’s FN Risk Any G-CSF Any filgrastim Any pegfilgrastim Both G-CSFs No G-CSF<br />
High (n=885) 73.8% 20.1% 64.0% 10.3% 26.2%<br />
IR (n=1046) 30.9% 13.8% 21.5% 4.4% 69.1%<br />
First G-CSF Use<br />
Regimen’s FN Risk Primary Prophylaxis Secondary Prophylaxis Reactive<br />
High (n=885) 70.6% 11.9% 17.5%<br />
IR (n=1046) 31.6% 30.0% 38.5%<br />
HR regimens: TAC (389); dose dense AC→T (345);<br />
docetaxel+trastuzumab (61); doxorubicin+docetaxel (50);<br />
doxorubicin+paciltaxel (21); docetaxel q14(19). IR regimens: CMF<br />
classic (481); paclitaxel q21 (337); docetaxel q21 (94); paclitaxel+<br />
trastuzumab (87); FEC (47).<br />
P1-15-02<br />
Febrile neutropenia (FN) risk assessment and granulocyte colonystimulating<br />
factor (G-CSF) guideline adherence in patients with<br />
breast cancer – results from a German prospective multicentre<br />
observational study (PROTECT)<br />
Steffens C-C, Eschenburg H, Kurbacher C, Goehler T, Schmidt M,<br />
Eustermann H, Schaffrik M, Otremba B. MVZ für Hämatologie/<br />
Onkologie, Klinik Dr. Hancken; Praxis für Hämatologie und<br />
internistische Onkologie, Güstrow; Praxis für Gynäkologie und<br />
gynäkologische Onkologie, Medizinisches Zentrum Bonn; Praxis für<br />
Hämatologie und internistische Onkologie, Dresden; Gynäkologische<br />
Onkologie, Universitätsfrauenklinik Mainz; WiSP Wissenschaftlicher<br />
Service Pharma GmbH, Langenfeld; Amgen GmbH, München;<br />
Onkologische Praxis Oldenburg/Delmenhorst<br />
Background: FN is a dose-limiting toxicity of chemotherapy which<br />
can affect patient (pt) outcomes. EORTC guidelines recommend<br />
G-CSF primary prophylaxis when the overall FN risk assessment<br />
is ≥20%. We evaluated risk assessment and guideline adherence<br />
(prophylaxis in high-risk pts) in clinical practice among breast cancer<br />
patients.<br />
Methods: Eligible pts were enrolled consecutively at centres selected<br />
based on experience and geographical spread. Key inclusion criteria<br />
were diagnosis of solid tumour or lymphoma, physician-assessed<br />
overall FN risk ≥10% (chemotherapy risk plus individual risk factors<br />
per EORTC guidelines), and planned primary (PPP) or secondary<br />
(PSP) prophylaxis with pegfilgrastim. Pegfilgrastim administered >3<br />
days after chemotherapy completion was classified as therapeutic use.<br />
The primary objective was to describe the proportion of pts with an<br />
investigator-assessed overall FN risk of >20% or 10-20% receiving<br />
PPP or PSP. Secondary objectives included evaluating FN incidence<br />
and chemotherapy dose reductions/delays. Data from breast cancer<br />
patients only are reported, and prophylaxis in high-risk patients was<br />
determined to evaluate guideline adherence.<br />
Results: 1003 pts were enrolled from Nov 2007 to Sept 2010. Mean<br />
(±SD) age was 54.4 (±11.2) years, almost all pts (99%) were female.<br />
Treatment intent was deemed curative by the investigator in 91% of<br />
pts. The investigator-assessed FN risk was >20% in 505 (50%) pts<br />
and 10-20% in 414 (41%) pts. Despite eligibility criteria, 84 (8%) pts<br />
were assessed by investigators as 20% (N=505)<br />
Planned prophylaxis PPP 470 (93%)<br />
PSP 35 (7%)<br />
Given prophylaxis PPP 404 (80%)<br />
PSP 80 (16%)<br />
Therapeutic use or use not according to label 21 (4%)<br />
www.aacrjournals.org 209s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Conclusion: Adherence to G-CSF guidelines, and reasons for<br />
differences between planned and administered prophylaxis warrants<br />
further investigation. Comparison of outcomes between prophylaxis<br />
groups should be interpreted with caution; however, FN incidence<br />
remained low with pegfilgrastim PP among breast cancer pts in<br />
German clinical practice.<br />
P1-15-03<br />
Comparison of efficacy of primary prophylaxis with pegfilgrastim,<br />
filgrastrim and a biosimilar filgrastim in TAC regimen (docetaxel,<br />
doxorubicin and cyclophosphamide)<br />
Brito M, Esteves S, Andre R, Isidoro M, Moreira A. Portuguese <strong>Cancer</strong><br />
Institute Francisco Gentil, Lisbon, Portugal<br />
Background<br />
Febrile neutropenia (FN) is a major toxicity of myelosupressive<br />
chemotherapy. Primary prophylactic use of granulocyte colony<br />
stimulating factors (G-CSF) is recommended in high risk FN<br />
regimens.<br />
The comparison of pegfilgrastim (Peg) and filgrastim (Fil) FN<br />
prophylactic effectiveness is still an issue of debate. Very recently<br />
Nivestim (Niv), a new biosimilar filgrastim, has also become<br />
commercially available.<br />
We aimed to compare the efficacy of the 3 mentioned types of G-CSF<br />
in the primary prophylaxis of FN.<br />
Methods:<br />
Single-center, retrospective study to evaluate the incidence of FN in<br />
women with breast cancer treated with adjuvant or neo-adjuvant TAC<br />
(FN risk ≥20%). Patients (Pt) were divided in 3 consecutive cohorts<br />
according to G-CSF primary prophylaxis (Fil, Peg and Niv) FN was<br />
defined as axillary temperature ≥38,3 °C and absolute neutrophil<br />
count < 500/ul.<br />
Results:<br />
We included a total of 421 women (median age 51 y, 25-76) with<br />
Stage II (56%) and Stage III (44%) breast cancer. Age and stage<br />
distribution were similar in the 3 cohorts.<br />
A single dose of Peg was administered in all 767 cycles (cy). The<br />
standard dose of Fil and Niv was 7 daily injections, only in in 13%<br />
Fil pt and 10% Niv pt < 7 administrations were done.<br />
The incidence of FN per patient and per cycle is presented in Table 1.<br />
In all cohorts, approximately half of NF episodes occurred in the 1st<br />
cycle (48% Fil, 59% Peg, 42% Niv).<br />
Table 1<br />
Fil Peg Niv P-value<br />
(147 pts; 840 cy) (140 pts; 767 cy) (134 pts; 710 cy) Fisher test<br />
% Pt FN 15,6% (23/147) 8,6% (12/140) 13,4% (18/134) Niv vs Peg<br />
IC95%:10,4-2,8% IC95%:4,5-14,5% IC95%:8,2-20,4% p= 0.25<br />
Niv vs Fil<br />
p = 0.62<br />
Fil vs Peg<br />
p = 0.07<br />
% Cy FN 3,2% (27/840) 2,2% (17/767) 3,7% (26/710) Niv vs Peg<br />
IC95%: 2,2-4,7% IC95%: 1,3-3,5% IC95%: 2,4-5,3% p = 0.12<br />
Niv vs Fil<br />
p = 0.68<br />
Fil vs Peg<br />
p = 0.28<br />
Conclusions:<br />
No differences in terms of efficacy existed between Biosimilar Niv<br />
and original biological reference Fil.<br />
Seven daily injections of Fil and Niv seem equivalent to single dose<br />
Peg.<br />
Besides efficacy, questions like cost-effectiveness and convenience<br />
of administration should be taken into account when approaching<br />
this topic.<br />
Our data showed a predominance of events in the 1st cycle (regardless<br />
of the type of G-CSF). This has been consistently described in the<br />
literature and may support the necessity to recommend other NF<br />
preventive measures in this cycle.<br />
P1-15-04<br />
The relationship of relative dose intensity and supportive care<br />
to febrile neutropenia rates in patients with early stage breast<br />
cancer receiving chemotherapy: a prospective cohort study of<br />
chemotherapy-associated toxicity<br />
Culakova E, Poniewierski MS, Wogu AF, Kuderer NM, Crawford J,<br />
Dale DC, Lyman GH. Duke University, Durham, NC; University of<br />
Washington, Seattle, WA<br />
Background: Febrile neutropenia (FN) represents a major doselimiting<br />
toxicity of cancer chemotherapy resulting in considerable<br />
morbidity, mortality, and cost. Patients have the highest risk of the<br />
initial neutropenic event in cycle 1 when most patients receive full<br />
dose chemotherapy. This study evaluates time course of neutropenic<br />
events in patients receiving chemotherapy for early-stage breast<br />
cancer (ESBC) and supportive care interventions that modify FN risk<br />
in ESBC patients treated in actual oncology practice.<br />
Methods: A prospective cohort study of adult cancer patients with<br />
solid tumors or lymphoma starting a chemotherapy regimen was<br />
conducted at 115 U.S. sites. Toxicities associated with chemotherapy<br />
were recorded in up to 4 cycles including severe neutropenia (SN),<br />
FN, and infection. Documented clinical interventions included<br />
reductions in chemotherapy relative dose intensity (RDI), the use of<br />
colony-stimulating factors (CSFs), and antibiotics.<br />
Results: A total of 1202 ESBC patients starting chemotherapy were<br />
analyzed, of which 1154, 1099, and 896 reached the midcycle of<br />
cycles 2, 3, and 4, respectively. While the majority of neutropenic<br />
and infection events occurred in cycle 1, decreasing rates of FN and<br />
infection in later cycles correlated with increasing reductions in dose<br />
intensity and increased use of CSFs and antibiotics.<br />
Table 1: Cycle specific and cumulative events (all patients)<br />
Cycle 1 Cycle 2 Cycle 3 Cycles 1-4<br />
% % % %<br />
FN 9.7 5.7 3.8 16.3<br />
SN or FN 32.1 22.7 18.5 44.0<br />
Infection 14.9 10.9 8.0 27.0<br />
RDI < 85% 13.4 19.4 19.8 32.5<br />
Cumulative CSFs 26.7 51.2 60.8 62.1<br />
Cumulative antibiotics 3.8 20.9 29.1 33.0<br />
The overall risk of FN in all patients combined was 16.3 %. It reached<br />
21.1% for patients who started with planned RDI≥85% and without<br />
primary CSF prophylaxis. There was no significant difference in FN<br />
rates by menopausal status or hormone receptors.<br />
Table 2: Patients with planned RDI≥85% and no primary CSFs prophylaxis<br />
Cumulative<br />
events<br />
Pre-menop Post-menop HR+ HR-<br />
% % % %<br />
FN 21.1 21.1 19.9 22.4<br />
SN or FN 56.8 58.1 55.1 62.5<br />
Infection 28.0 29.5 27.4 31.5<br />
RDI < 85% 16.6 31.4 25.9 24.6<br />
Cumulative CSFs 51.9 52.6 51.9 52.2<br />
Cumulative<br />
antibiotics<br />
34.3 36.2 33.6 40.5<br />
HR=hormone receptors<br />
Conclusions: While the risk of neutropenic complications is highest<br />
during the first cycle of chemotherapy, reductions in neutropenic<br />
events during subsequent cycles are associated with reduced<br />
chemotherapy dose intensity or increased use of supportive care<br />
measures. Nevertheless, the cumulative risk of neutropenic events<br />
remains high in ESBC patients receiving full dose chemotherapy<br />
without prophylactic measures overall and across menopausal and<br />
hormone receptor subgroups.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
210s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
P1-15-05<br />
GSTP1 polymorphism is associated with chemotherapy induced<br />
neuropathy<br />
Miltenburg NC, Opdam M, Winter M, van Geer M, Oosterkamp HM,<br />
Boogerd W, Linn SC. The Netherlands <strong>Cancer</strong> Institute, Amsterdam,<br />
Netherlands; The Netherlands <strong>Cancer</strong> Institute<br />
Background:<br />
Peripheral neuropathy is a common and potentially debilitating<br />
side-effect of microtubule-stabilizing agents like docetaxel and is<br />
characterized by sensory symptoms like numbness, tingling and<br />
burning pain. Docetaxel induced neuropathy may occur in up to<br />
37% of patients and can be dose limiting, thus potentially reducing<br />
its chemotherapeutic efficacy. Doxorubicine has occasionally been<br />
described to be associated with neuropathy.<br />
With this background we investigated the role of various single<br />
nucleotide polymorphisms (SNPs) to predict chemotherapy-induced<br />
neuropathy. The exploration of SNPs and an association with<br />
incidence or severity of neuropathy is important, because it can<br />
result in identifying individuals being at higher risk of neurotoxicity.<br />
Methods:<br />
The MATADOR study is a prospective, non-blinded randomized<br />
phase II/III trial for patients with invasive breast cancer, comparing<br />
TAC (docetaxel 75 mg/m² as 1 hour i.v. infusion q 3 weeks, in<br />
combination with doxorubicin and cyclophosphamide for 6 cycles)<br />
with AC dose dense (doxorubicin and cyclophosphamide q 2 weeks)<br />
( ISRCTN61893718).<br />
In total 180 interesting SNPs were selected that are involved in<br />
metabolism, distribution and excretion of drugs and tested on DNA<br />
that was isolated from tumor or from tumor surrounding tissue. We<br />
selected 20 SNPs for further analyses because of reported associations<br />
with chemotherapy-induced neuropathy (see table).<br />
In the first analysis DNA of 45 patients was analyzed as a pilot,<br />
comparing DNA of 23 neuropathy patients with that of 22 controls.<br />
The primary hypothesis was to identify SNPs associated with NCI-<br />
CTC grade ≥2 neuropathy.<br />
Results:<br />
Interim toxicity data from the MATADOR study demonstrated that<br />
30 of 580 patients had grade ≥2 neuropathy. GSTP1 114Ala/114Val<br />
genotype was associated with grade ≥2 neuropathy. Twelve out of<br />
14 (86%) patients with this genotype had chemotherapy-induced<br />
neuropathy compared to 11 out of 31 (35%) without this genotype<br />
(chi-square test p=0.002).<br />
Conclusion:<br />
We found a correlation between GSTP1 114Ala/114Val genotype,<br />
involved in detoxification, and development of grade ≥2 neuropathy<br />
during treatment with chemotherapy. Updated results will be<br />
presented at the meeting.<br />
SNPs analyzed<br />
1. ABCB1 rs1045642<br />
2. ABCB1 rs1128503<br />
3. ABCB1 rs2032582<br />
4. ABCB1 rs3213619<br />
5. CYP2C8 rs1058930<br />
6. CYP2C8 rs10509681<br />
7. CYP2C8 rs11572080<br />
8. CYP2C8 rs11572103<br />
9. CYP2C8 rs72558195<br />
10. CYP2C8 rs72558196<br />
11. CYP3A4 rs2740574<br />
12. CYP3A5 rs776746<br />
13. CYP3A5 rs10264272<br />
14. CYP3A5 rs41303343<br />
15. CYP3A5 rs55965422<br />
16. GSTM1 rs1065411<br />
17. GSTP1 rs1695<br />
18. GSTP1 rs1138272<br />
19. RWDD3 rs2296308<br />
20. TECTA rs1829<br />
P1-15-06<br />
The impact of musculoskeletal toxicity on adherence to endocrine<br />
therapy in women with early stage breast cancer– observations<br />
in a non-trial setting<br />
Dent SF, Campbell MM, Crawley FL, Clemons MJ. The Ottawa<br />
Hospital Regional <strong>Cancer</strong> Center, Ottawa, ON, Canada<br />
Background: Aromatase inhibitor (AI) use is standard of care in the<br />
treatment of postmenopausal (PM) women with early stage breast<br />
cancer (EBC). Approximately 35% of patients (pts) discontinue their<br />
initially prescribed AI due to toxicity, the most commonly reported<br />
reason being musculoskeletal toxicity (MSKT). We report on the<br />
discontinuation rates of AI therapy based on MSKT in PM women<br />
with EBC treated at a tertiary care cancer centre.<br />
Methods: PM women with hormone receptor positive EBC treated<br />
with endocrine therapy (ET) that included an AI (upfront or after<br />
tamoxifen) at The Ottawa Hospital <strong>Cancer</strong> Center between 01/99<br />
and 02/06. Data included: demographics, type of ET, duration of<br />
treatment, incidence of patient-reported MSKT and treatment of<br />
MSKT. Comparisons between ETs were analyzed using Chi-square<br />
and Fischer’s t-tests.<br />
Results: A total of 626 pts, median 59 years (r: 30-92), median followup<br />
98 months, with stage: I (196 pts; 31%), II (341 pts; 54%) or III (89<br />
pts; 14%s) EBC. Treatment strategies included: AI(s) only (251 pts;<br />
40%); tamoxifen (TAM) followed by AI(s) (323 pts; 51.6%); AI(s)<br />
followed by TAM (16 pts; 2.6%); TAM-AI(s)-TAM (24 pts; 3.8%)<br />
and unknown (12 pts). Patient-reported MSKT was experienced by<br />
significantly more women treated with AIs than TAM (64% vs 36%,<br />
p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P1-15-07<br />
Ixabepilone-associated peripheral neuropathy in metastatic<br />
breast cancer patients and its effects on the ultrastructure of<br />
neurons<br />
Jain S, Carlson K, Chuang E, Cigler T, Moore A, Donovan D, Lam C,<br />
Cobham MV, Schneider S, Ramnarain A, Carey B, Ward M, Lane M,<br />
Strickland S, Vahdat L. Weill Cornell Medical College; Rockefeller<br />
University<br />
Background: Peripheral neuropathy is a dose-limiting toxicity of<br />
most microtubule-stabilizing chemotherapeutic agents. Ixabepilone,<br />
a semisynthetic analog of the natural epothilone B, has activity in<br />
a wide range of tumors including taxane-resistant disease. In this<br />
study, we sought to understand the effect of ixabepilone on the<br />
development of peripheral neuropathy both clinically and its effect<br />
at the ultrastructural level of the peripheral nerves and circulating<br />
factors over time. Parallel studies in animal models of neuropathy<br />
were performed at the same time (Proc AACR 2010 <strong>Abstract</strong> 4184).<br />
Methods: This open-label, non-randomized phase II study enrolled 14<br />
patients with metastatic breast cancer. Ixabepilone was administered<br />
by 2 schedules: the FDA approved dose of 40 mg/m² every 3 weeks<br />
(q3w) and 16 mg/m² on day 1, 8, and 15 of a 28-day cycle (weekly).<br />
Five controls, 2 with residual taxane-associated peripheral neuropathy<br />
and 3 with no prior chemotherapy or peripheral neuropathy, were<br />
also accrued. The primary objectives were to characterize the<br />
natural history of ixabepilone-associated peripheral neuropathy<br />
using the Total Neuropathy Score Clinical (TNSc) assessment tool<br />
prior to each cycle and to correlate changes in the ultrastructure<br />
of dermal myelinated nerve fibers via a 3 mm punch biopsy of an<br />
area 10 cm above the lateral malleolus every 2 cycles with electron<br />
microscopy (EM), as well as circulating factors (both inflammatory<br />
and neurotrophic) considered to be important in the pathogenesis of<br />
chemotherapy-induced peripheral neuropathy. Secondary objectives<br />
included progression-free survival (PFS) and non-neurologic toxicity.<br />
Results: 14 patients were enrolled and were equally divided<br />
between the 2 schedules of ixabepilone chemotherapy. There were<br />
no differences in baseline characteristics between the two groups.<br />
Mean age was 54 years (range 32-71). Mean number of previous<br />
chemotherapy regimens was 3.5 (range 0-8). 57% of patients had<br />
received a taxane in the adjuvant setting and 64% in the metastatic<br />
setting. The mean neuropathy score (TNSc) at baseline was 4.6<br />
(range 1-11). At a mean cumulative dose of 185 mg/m², the TNSc<br />
with ixabepilone q3w schedule was 3.7 points higher/worse (95%<br />
CI: 2.2-5.3, p=0.03) than the mean score observed in patients on the<br />
weekly schedule. The sensory component was most significantly<br />
affected, predominantly numbness. In 3 patients, the chemotherapy<br />
schedule was changed from every 3 weeks to weekly due to > grade<br />
2 toxicity at a mean cumulative dose of 107 mg/m², and TNSc<br />
decreased/improved by 2.7 points. PFS in patients on q3w ixabepilone<br />
was 133 days (range 28-280) and in patients on weekly ixabepilone<br />
was 179 days (range 66-336), nonsignificant. Evaluation of EM and<br />
circulating factors is ongoing.<br />
Conclusions: Weekly ixabepilone appears to have a more favorable<br />
neurotoxicity profile compared to the standard q3w schedule.<br />
Integration of the EM data and the circulating factor data are underway<br />
and will be presented. Ixabepilone-associated peripheral neuropathy<br />
may improve in patients switched to weekly ixabepilone without<br />
compromising efficacy.<br />
P1-15-08<br />
Higher toxicity of docetaxel for obese women with early breast<br />
cancer: lean body mass is a significant predictor of chemotherapy<br />
dose intensity reduction<br />
Gouerant S, Clatot F, Modzlewski R, Chaker M, Rigal O, Veyret<br />
C, Leheurteur M. Henri Becquerel Center, Rouen, France; Rouen<br />
University Hospital, Rouen, France<br />
Background: Prevalence of obesity has been increasing in the last<br />
years and obesity is known as a risk factor of post menopausal<br />
breast cancer. Despite the high number of obese women treated by<br />
docetaxel for breast cancer, few data are published about toxicity and<br />
its predictive factors in this population. A low lean body mass (LBM)<br />
was shown as a predictive factor of toxicity for other chemotherapy<br />
and can be measured by software on an abdominal computerized<br />
tomography (CT), we aimed to assess the predictive value of LBM<br />
in docetaxel toxicity.<br />
Methods: This is a monocentric retrospective analysis of patients<br />
treated for early breast cancer from January 2008 to December<br />
2010, who received a sequential chemotherapy with FEC 100 and<br />
docetaxel. All obese patients (BMI≥30 mg/m2) treated over these<br />
3 years were included (n=100), and the same number of non-obese<br />
patients were randomly selected among all those treated during this<br />
same period. We collected data from objective toxicity (hematologic<br />
and cardiologic toxicity, hospitalizations), and data related to dose<br />
intensity (dose diminution, delayed cure, modification drug, cessation<br />
of chemotherapy) to calculate the ratio [Total Received Dose (mg)/<br />
Total Planned Dose (mg)] (TRD/TPD ratio) for each drug. We<br />
measured the LBM for patients who had abdominal CT at diagnosis<br />
(n=89) to calculate the ratio [Planned Dose per cycle (mg) / LBM<br />
(kg)] (PD/LBM ratio).<br />
Results: Among 469 patients who received a sequential chemotherapy<br />
FEC 100/Docetaxel for an early breast cancer in these three years,<br />
100 were obese (21%). Obese and non-obese patients have similar<br />
clinical and histological characteristics except for T4d stage (10 in<br />
obese group and 1 in non-obese group, p=0,02).<br />
The TRD/TPD ratio of docetaxel is significantly lower in obese<br />
patients: 18 obese and 6 non-obese patients had a ratio less than<br />
1 (p=0,02), the main cause was cutaneous toxicities. On the other<br />
hand, there is no significant difference for the TRD/TPD ratio of<br />
epirubicine: 3 obese and 1 non-obese patients had a ratio less than 1<br />
(p=0,62). In univariate analysis, 4 factors are predictive of a TRD/<br />
TPD ratio of docetaxel less than 1: high age (p=0,01), high weight<br />
(p=0,02), high body surface area (p=0,05) and high BMI (p=0,006).<br />
In multivariate analysis, only BMI is predictive of a TRD/TPD ratio<br />
of docetaxel less than 1<br />
Patients with a TRD/TPD ratio of docetaxel less than 1 had a<br />
significantly higher PD/LBM compared to patients with a TRD/TPD<br />
ratio greater than 1, respectively 4,75 [3,02-6,04] and 3,75 [2,23-<br />
5,79] (p=0,01). In univariate analysis, the other predictive factors of<br />
TRD/TPD ratio of docetaxel less than 1 are high BMI (p=0,02), high<br />
weight (p=0,02) and high BSA (p=0,03). In multivariate analysis, only<br />
PD/LBM is predictive of a TRD/TPD ratio of docetaxel less than 1.<br />
Conclusion: Docetaxel is less well tolerated and the dose intensity<br />
received is lower for obese patients. The lean body mass measured<br />
by computed tomography is a new significative predictor of docetaxel<br />
dose intensity reduction in the early breast cancer.<br />
Key words: Early breast cancer-Chemotherapy-Docetaxel-<br />
Epirubicine-Body Mass Index-Lean Body Mass-Dose Intensity-<br />
Toxicity<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
212s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 1<br />
P1-15-09<br />
Multi-Institutional Evaluation of Bioimpedance Spectroscopy<br />
(BIS) in the Early Detection of <strong>Breast</strong> <strong>Cancer</strong> Related<br />
Lymphedema<br />
Vicini F, Arthur D, Shah C, Anglin BV, Curcio L, Laidley AL, Beitsch<br />
P, Whitworth P, Lyden M. Michigan Healthcare Professionals/21st<br />
Century Oncology; Virginia Commonwealth University; Beaumont<br />
Health System; The Medical Center of Plano; Advanced <strong>Breast</strong><br />
Care Specialists of Orange County; Texas <strong>Breast</strong> Specialists; Dallas<br />
Surgical Group; Nashville <strong>Breast</strong> Center; Biostat Inc.<br />
Background: Limited data is available examining the impact of early<br />
detection in the management of breast cancer related lymphedema<br />
(BCRL) with bioelectrical impedance spectroscopy (BIS) offering the<br />
potential for subclinical diagnosis of BCRL. The purpose of the study<br />
was to evaluate BIS’s ability to detect and monitor extracellular fluid<br />
accumulation of the upper limb in patients treated for breast cancer<br />
as it relates to the extent of loco-regional therapy.<br />
Methods: A total of 125 patients with breast cancer from 4 clinical<br />
practices were evaluated with BIS at baseline and following locoregional<br />
procedures. In order to assess the ability of BIS to detect<br />
sub-clinical changes by treatment modality, the change in L-Dex<br />
score from baseline to measurements taken within 180 days following<br />
surgery were calculated.<br />
Results: Mean age was 55 years with 68 patients (54.4%) undergoing<br />
sentinel lymph node (SLN) sampling while 57 (45.6%) underwent<br />
an axillary dissection (ALND). The mean number of nodes sampled<br />
was 7.9 (range:1.0-37.0) with 40.8%, 18.4%, 13.6%, and 27.2%<br />
of patients having 0-3, 4-6, 7-9, or greater than 10 lymph nodes<br />
sampled. Fifty-one patients (40.8%) underwent lumpectomy and 74<br />
(59.2%) mastectomy with 37 patients (29.6%) requiring more than<br />
one surgical procedure. Sixty-five patients (52%) underwent radiation<br />
therapy (RT). While controlling for baseline L-Dex score and the<br />
number of nodes removed, patients receiving RT had a significantly<br />
increased change (pre v. post radiation treatment) in mean L-Dex<br />
score (-2.5 v. 0.8, p=0.03) compared with those patients not receiving<br />
RT. When evaluating changes in mean L-Dex score from baseline<br />
BIS assessment to the first assessment within 180 days of surgery,<br />
no difference in the change in score was noted by surgical procedure<br />
(lumpectomy 1.8 v. mastectomy 2.2, p = 0.97); however, ALND was<br />
associated with a significantly increased change in mean L-Dex score<br />
(0.3 v. 5.0, p=0.003) compared with SLN biopsy. When stratifying<br />
by the number of nodes removed, a statistically significant increase<br />
in the change in mean L-Dex score was noted (0.4 v. 0.4 v. 4.3 v.<br />
6.4, p=0.04) for 0-3, 4-6, 7-10, and greater than 10 lymph nodes<br />
removed. Similar findings were noted when evaluating the impact<br />
of ALND (0.3 v. 4.0, p=0.0002) and nodes removed (0.5 v. 0.3 v. 2.9<br />
v. 4.9, p=0.006) when comparing the baseline BIS assessment to the<br />
first post-surgical assessment regardless of when the assessment was<br />
performed post-operatively.<br />
Conclusions: In this multi-institutional analysis, L-Dex scores<br />
generated from multi-frequency bioimpedance spectroscopy (BIS)<br />
mirrored the aggressiveness of loco-regional therapy with respect<br />
to nodal sampling and radiation therapy. These findings suggest<br />
that BIS can be used in the early detection of BCRL and should be<br />
implemented before and following loco-regional therapies. Further<br />
studies are needed to help validate the extent, degree, and chronologic<br />
time frame of these changes to help define recommendations for closer<br />
monitoring and possible early intervention and to compare them to<br />
concurrent clinical assessments.<br />
P1-15-10<br />
Chemotherapy-Induced Neutropenia in <strong>Breast</strong> <strong>Cancer</strong> Patients<br />
Receiving Sequential Anthracycline and Taxane Chemotherapy:<br />
An institutional experience<br />
Staudigl C, Seifert M, Tea M-K, Pfeiler G, Fink-Retter A, Fritzer<br />
N, Singer CF. Medical University of Vienna, Austria; Alps-Adria<br />
University Klagenfurt, Klagenfurt, Austria<br />
Background: Sequential regimen of anthracyclines and taxanes<br />
are commonly used in patients with early stage breast cancer (BC)<br />
and curative treatment intent. Due to the associated myelotoxicity,<br />
internationally accepted guidelines recommend granulocyte-colony<br />
stimulating factors (G-CSF) as primary or secondary prophylaxis,<br />
dependent on chemotherapy (CT) and patient-associated risk of febrile<br />
neutropenia. As part of a quality control initiative at our center, we<br />
have analyzed rates of grade 1 or 2 (1.0 x 109/L) and 3 or 4<br />
(
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P1-15-11<br />
The Kampo medicine Goshajinkigan prevents docetaxel-related<br />
peripheral neuropathy in breast cancer patients<br />
Abe H, Mori T, Kawai Y, Itoi N, Tomida K, Cho H, Kubota Y, Umeda<br />
T, Tani T. Shiga University of Medical Science Hospital, Otsu, Shiga,<br />
Japan; Shiga University of Medical Science, Otsu, Shiga, Japan<br />
Background: Although taxanes have become a key chemotherapeutic<br />
drug in breast cancer treatment. Taxanes inhibit the growth of cancer<br />
cells by disrupting the functioning of their microtubules; however,<br />
the microtubules of nerve cells are also affected by this process,<br />
which can cause neurological disorders. The Kampo medicine<br />
Goshajinkigan (GJG) is a traditional Japanese medicine that is used<br />
for the treatment of several neurological symptoms including pain<br />
and numbness, GJG is comprised of 10 herbs, each of which contains<br />
numerous active ingredients. Recently, GJG has been reported to<br />
prevent anticancer drug-induced peripheral neuropathy in colorectal<br />
cancer. We performed the present prospective randomized study to<br />
confirm the effects of GJG and mecobalamin (B12) against docetaxel<br />
(DOC)-associated peripheral neurotoxicity in breast cancer patients.<br />
Patients and method: Between May 2007 and April 2011, 60<br />
breast cancer patients were treated with DOC. Thirty-three patients<br />
(GJG group) received oral administration of 7.5 g/day GJG and 27<br />
patients (B12 group) received oral administration of 1500 µg/day<br />
B12. The patients were treated with TC (75mg/m 2 docetaxel and<br />
600 mg/m 2 cyclophosphamide) every 3 weeks for 4 cycles, docetaxel<br />
alone (100mg/m 2 ) every 3 weeks for 4 cycles, and XT (900mg/m 2<br />
capecitabine administered orally twice a day on days 1-14 plus 60 mg/<br />
m 2 docetaxel) every 3 weeks for 6 cycles. Peripheral neuropathy was<br />
evaluated during every course according to DEB-NTC (Neurotoxicity<br />
Criteria of Debiopharm), Common Terminology Criteria for Adverse<br />
Events (NCI-CTC) ver.3.0, and a visual analogue scale (VAS).<br />
Results: The median age of the GJG group was 58 years old (35 to<br />
70 years old), the B12 group was 55 years old (33 to 69 years old),<br />
and they were all females. For the regimens, in the GJG group, TC,<br />
DOC only, and XT were administered in 19 cases, 13 cases and 1<br />
case, respectively. In the B12 group, they were 15 cases, 11 cases and<br />
12 cases, respectively. The cumulative dose of DOC was 338.5 mg/<br />
m2 in the GJG group, and 340 mg/m2 in the B12 group. Peripheral<br />
neuropathy occurred significantly less frequently in the GJG group<br />
(39.3%) than the B12 group (88.9%) (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
cells (CTCs) isolated by CellSearch® from peripheral blood of MBC<br />
patients was shown to be an additional strong independent prognostic<br />
factor for survival and progression of disease. The aim of this study<br />
was to combine CTC and other predictors in a nomogram that would<br />
allow clinicians to assess, on an individual basis, the prognosis of<br />
patients starting first-line chemotherapy for MBC.<br />
Patients and Methods: CTCs were counted before the start of treatment<br />
using the US Food and Drug Administration–cleared CellSearch®<br />
technology. We used a training set of 237 MBC patients starting<br />
a first line chemotherapy from the MD Anderson <strong>Cancer</strong> Center<br />
(MDACC, Houston, TX, USA), and nomograms were established<br />
to calculate the predicted probability of overall survivals (OS) at 1,<br />
2 and 3 years. These nomograms were externally validated using an<br />
independent data set of 260 patients starting a first line chemotherapy<br />
from the prospective Institut Curie 2006-04 study (Paris, France).<br />
Discriminatory ability of the models was assessed using Harrell’s<br />
c-statistic examining the model in the training sample (U.S. data) and<br />
the validation sample (French data). Accuracy of the nomograms was<br />
assessed both within the training sample and the validation sample<br />
via calibration plots at 1, 2 and 3 years. Covariates computed in the<br />
model were: age, subtype of disease, presence of visceral metastasis,<br />
bone metastasis, performance status, and CTCs.<br />
Results: Table1 describes patient characteristics. Median follow-up<br />
was of 24.5 and 29 months, respectively in the MDACC and Institut<br />
Curie. The C-statistics for OS was 0.7338 in the training set and<br />
0.7229 in the validation set. For the calibration plots, we averaged Cox<br />
predictions at two years within the quintiles of the ordered predictions.<br />
Within each quintile, we also estimated the unadjusted probability<br />
of death using Kaplan-Meier survival estimators. We then plotted<br />
unadjusted versus model average predictions at 1, 2 and 3 years. The<br />
nomograms discriminated OS prediction at 1, 2 and 3 years very well.<br />
Conclusions: Patients with first-line MBC present a wide range of<br />
survival duration, and our ability to assess prognosis and predict risks<br />
of progression and death on the basis of clinic-pathologic findings<br />
is limited. The validated nomograms represent an important tool for<br />
estimating prognosis, support treatment-decisions and clinical trial<br />
stratification in MBC.<br />
Patient characteristics<br />
MDACC cohort ICurie cohort<br />
Characteristics No. % No. % P value<br />
Total patients 236 100 210 100<br />
Age at diagnosis, years<br />
median 49.6 54.5 0.0004<br />
mean 50.3 58.4<br />
Receptor status<br />
ER+ or PR+, and HER2- 130 55.1 125 59.5 0.629<br />
HER2+ 43 18.2 36 17.1<br />
ER-, PR-, and HER2- 63 26.7 49 23.3<br />
Presence of visceral metastasis 144 61 169 80.5 40 35 14.8 28 13.3<br />
Missing data not included.<br />
P2-01-02<br />
Circulating Tumor Cells (CTC) may Express HER2/neu in<br />
Patients With Early HER2/neu Negative <strong>Breast</strong> <strong>Cancer</strong> – Results<br />
of the German SUCCESS C Trial<br />
Jaeger BAS, Rack BK, Andergassen U, Neugebauer JK, Melcher<br />
CA, Scholz C, Hagenbeck C, Schueller K, Lorenz R, Decker T,<br />
Heinrich G, Fehm T, Schneeweiss A, Lichtenegger W, Beckmann<br />
MW, Pantel K, Sommer HL, Friese K, Janni W. Klinikum der Ludwig-<br />
Maximilians-Universitaet, Munich, Germany; Heinrich Heine<br />
University, Duesseldorf, Germany; Stat-up Statistische Beratung<br />
und Dienstleistung, Munich, Germany; Gemeinschaftspraxis Dr.<br />
Lorenz/Hecker/Wesche, Braunschweig, Germany; Studienzentrum<br />
Onkologie Ravensburg, Ravensburg, Germany; Praxis Dr. Heinrich,<br />
Fuerstenwalde, Germany; Eberhard Karls Universitaet Tuebingen,<br />
Tuebingen, Germany; National Center for Tumor Disease and<br />
Department of Gynecology and Obstetrics, University Hospital<br />
Heidelberg, Germany; Charité Medical University, Berlin, Germany;<br />
Universitaet Erlangen, Germany; University Medical Center<br />
Hamburg-Eppendorf, Hamburg, Germany<br />
Background:<br />
There is growing evidence that the HER2/neu-status of distant<br />
metastases or minimal residual disease in blood and bone marrow<br />
may differ from the primary tumor in patients with breast cancer. The<br />
HER2/neu-status of CTCs was prospectively evaluated in patients<br />
with HER2/neu negative primary breast cancer randomized into the<br />
German multicenter SUCCESS C study.<br />
Methods:<br />
The SUCCESS C trial is a randomized Phase III study comparing<br />
FEC-Docetaxel (FEC-Doc) vs. Docetaxel-Cyclophosphamid (DC)<br />
as well as 2 years of a lifestyle-intervention in patients with early,<br />
HER2/neu negative, node positive or high-risk node negative primary<br />
breast cancer.<br />
As part of the translational research program, 23ml peripheral<br />
blood were drawn after adjuvant chemotherapy. In 505 samples, the<br />
prevalence of CTCs and their HER2/neu-status were assessed using<br />
the CellSearch System (Veridex, USA). After immunomagnetic<br />
enrichment with an anti-Epcam-antibody, cells were labelled with<br />
anti-CK8/18/19 and anti-CD45 antibodies. A fluorescein conjugate<br />
antibody with anti-CK-Fluorescein Isothiocyanate (FITC) was used<br />
for HER2/neu phenotyping. The cut-off for CTC-positivity was ≥ 1<br />
CTC and for HER2/neu ≥ 1 CTC with strong HER2/neu-staining<br />
(+++).<br />
Results:<br />
26,9% of pts (n=136) were positive for CTCs (mean 1.78; range 1-7;<br />
median = 1). The number of detected CTC was distributed as follows:<br />
1 CTC (n=76; 55.9%), 2 CTCs (n=35; 25.7%), 3 CTCs (n=13; 9.6%),<br />
4 CTCs (n=7; 5.2%) and ≥ 5 CTCs (n=5; 3.7%). HER2/neu staning<br />
of CTCs was not detectable or weak in 26.5% (n=36) and 4.4% (n=6)<br />
of CTC positive patients respectively and therefore categorized as<br />
HER2/neu negative. In 32.4% of the CTC-positive patients (n=44),<br />
we detected moderate and in 36.8% (n=50) strong HER2/neu-staining<br />
of ≥ 1 CTC per sample. No association was found between CTCs<br />
or the HER2/neu-status of CTCs with tumor size, histopathological<br />
grading, hormone receptor status or axillary lymph node involvement.<br />
Conclusions:<br />
The data of this trial confirm previous findings that patients with<br />
HER2/neu negative primary breast cancer can show HER2/neu<br />
positive minimal residual disease. These results underline the<br />
importance of frequent HER2/neu determination during follow up and<br />
disease progression. Survival data within the Success C trial will give<br />
further insight into the tumor biology of HER2/neu negative disease.<br />
www.aacrjournals.org 215s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P2-01-03<br />
Truncated HER2 receptor in circulating tumor cells (CTCs) of<br />
early and metastatic breast cancer patients<br />
Kallergi G, Nasias D, Papadaki M, Mavroudis D, Georgoulias V,<br />
Agelaki S. University of Crete, Heraklion, Crete, Greece; University<br />
General Hospital of Heraklion, Crete, Greece<br />
Introduction: Trastuzumab confers significant clinical benefit in<br />
patients with early and metastatic HER2-positive breast cancer.<br />
However, trastuzumab treated patients will eventually develop<br />
resistance to therapy. The presence of a truncated receptor with loss<br />
of the extracellular portion of HER2 (p95HER2) has been proposed<br />
as a potential mechanism of resistance. Preclinical and clinical<br />
data suggest that the expression of p95HER2 is associated with<br />
poor overall prognosis, resistance to trastuzumab and sensitivity to<br />
lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor. We have<br />
previously shown that approximately 50% of breast cancer patients<br />
express HER2 in their CTCs (Kallergi et al., 2007; Kallergi et al.,<br />
2008). The aim of the present study was to characterize, for the first<br />
time, the expression of p95HER2 in CTCs of breast cancer patients<br />
in comparison with the p95HER2 expression of the corresponding<br />
primary tumors. Methods: Two different cells lines (SKBR3 and<br />
SCOV3) were used as positive controls expressing the normal<br />
and truncated HER2 receptor, respectively. Western blot analysis<br />
revealed that SCOV3 was positive for p95 fragment of HER2<br />
receptor while SKBR3 had the full length protein. Consequently<br />
we developed a novel triple immunofluorescent (IF) assay for the<br />
simultaneous evaluation of the extracellular and intracellular domain<br />
of HER2 receptor using the corresponding anti-rabbit and anti-mouse<br />
antibodies respectively. Cells were also stained with pancytokeratin<br />
A45-B/B3 antibody (as a marker of CK-positive cells). Triple staining<br />
experiments were performed in peripheral blood mononuclear cells<br />
(PBMC) cytospins’ from patients with early (n=24) and metastatic<br />
(n=33) breast cancer. Slides were analysed with either confocal laser<br />
scanning microscopy or with the Ariol system. Results: Cytokeratin<br />
positive cells were identified in 17 (71%) out of 24 early and in<br />
20 (61%) out of 33 metastatic patients. HER2 positive CTCs were<br />
identified in 53% of early and 50% of metastatic, CTC-positive, breast<br />
cancer patients. HER2-positive CTCs lacking the extracellular domain<br />
of the receptor (p95HER positive CTCs) were identified in 7 out of<br />
20 (35%) of metastatic and 2 out of 17 (12%) of early, breast cancer<br />
patients. Exclusively p95HER2 positive CTCs were detected in 2 out<br />
of 20 (10%) patients with metastatic but not in patients with early<br />
disease. The corresponding primary tumors from 8 HER2-positive<br />
breast cancer patients were also triple stained. These experiments<br />
revealed that in two out of eight patients, p95HER2-positive cells<br />
were detected in a subgroup (5-10%) of cancer cells. Conclusions: Our<br />
results suggest that the truncated p95HER2 receptor is expressed in<br />
CTCs of both early and metastatic breast cancer patients. This finding<br />
has important therapeutic implications and may explain the observed<br />
increased efficacy of the trastuzumab plus lapatinib combination in<br />
HER2 positive breast cancer.<br />
P2-01-04<br />
Long term independent prognostic impact of circulating tumor<br />
cells detected before neoadjuvant chemotherapy in non-metastatic<br />
breast cancer: 70 months analysis of the REMAGUS02 study<br />
Bidard F-C, Delaloge S, Giacchetti S, Brain E, de Cremoux P, Vincent-<br />
Salomon A, Marty M, Pierga J-Y. Institut Curie, France; Institut<br />
Gustave Roussy, France; Hopital Saint Louis, France<br />
Background: Circulating tumor cells (CTCs) isolated by CellSearch ®<br />
from peripheral blood of metastatic breast patients have been shown<br />
as strong independent prognostic factor for progression-free and<br />
overall survival. With this technique, the REMAGUS02 prospective<br />
multicentric study was the first to report that CTC detection<br />
(≥1CTC/7.5ml) before and/or after neoadjuvant chemotherapy<br />
was independently associated with distant metastasis-free survival<br />
(DMFS, 18 months follow-up, Pierga CCR 2008) and with overall<br />
survival (OS, 36 months follow-up, Bidard Ann Oncol 2010).<br />
Patients and Methods: In 115 non-metastatic patients diagnosed with<br />
large operable or locally advanced breast cancer, we prospectively<br />
detected CTC using the CellSearch system before and after<br />
neoadjuvant chemotherapy in the REMAGUS02 trial (Pierga, BCRT<br />
2010). For this report, survival analyses were performed at a median<br />
follow-up of 70 months.<br />
Results: After a median follow-up of 70 months, 20 distant metastatic<br />
relapses and 14 deaths have been observed among the 115 patients<br />
included. CTC detection before chemotherapy (in 23% of patients) is<br />
an independent prognostic factor for both DMFS [P=0.03, relative risk<br />
(RR)=3.2] and OS [p=0.05, RR=3.7] in multivariate analyses, together<br />
with triple negative tumor status. At long-term, CTC detection after<br />
chemotherapy (17%) had no clear prognostic significance (p=0.15<br />
and 0.22, respectively). Complete pathological response as well as<br />
tumour size and all other variables tested did not appear as predictive<br />
in this model.<br />
Conclusions: Baseline CTC detection is a new independent<br />
prognostic factor in the neoadjuvant setting, and is, in this trial,<br />
superior to pathological tumor response to predict the survival of nonmetastatic<br />
breast cancer patients. We confirm therefore our previous<br />
results reported with shorter follow-up.<br />
Supported by PHRC AOM/2OO2/02117, Pfizer inc., Roche, sanofiaventis.ISRCTN10059974<br />
P2-01-05<br />
Parallel DNA and RNA profiling of EpCAM-positive cells in<br />
blood of metastatic breast cancer (MBC) patients confirm their<br />
malignant nature<br />
Magbanua MJM, Hauranieh L, Sosa EV, Pendyala P, Scott JH, Rugo<br />
HS, Park JW. University of California, <strong>San</strong> Francisco, CA<br />
Background: Molecular studies of EpCAM-positive cells found in<br />
the blood of cancer patients have been limited to immuno-enriched<br />
samples containing a high background of leukocytes. We developed<br />
a process to isolate rare EpCAM-positive cells and subjected them<br />
to DNA and RNA profiling.<br />
Methods: Blood was subjected to immunomagnetic enrichment<br />
using EpCAM beads followed by fluorescence activated cell sorting<br />
(IE/FACS) to isolate EpCAM-positive cells away from leukocytes<br />
(CD45+). Duplicate samples of 20 cells were isolated from the same<br />
enriched blood from 53 MBC patients and then subjected to DNA<br />
and RNA profiling in parallel. For DNA profiling, sorted cells were<br />
subjected to BAC array comparative genomic hybridization analysis<br />
following whole genome amplification. For RNA profiling, QPCR<br />
analysis was performed on sixty four (64) cancer-related genes using<br />
Taqman® low density arrays. For non-tumor controls, RNA profiling<br />
was performed on matched leukocytes (CD45+) isolated from the<br />
same enriched blood samples from 44 of the 53 patients.<br />
Results: Differential gene expression analysis between EpCAMpositive<br />
cells and matched leukocytes confirmed the up-regulation<br />
of EPCAM and other genes including MUC1 and KRT19 (adjusted p<br />
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
hierarchical clustering analysis of RNA profiles showed that EpCAMpositive<br />
cells clustered away from the leukocytes. Genome-wide copy<br />
number analysis of EpCAM-expressing cells revealed gains (e.g. 1q<br />
and 8q), losses (e.g. 8p and 16q), and focal amplifications (e.g. on 8q<br />
and 11q including CCND1) frequently seen in primary breast cancers.<br />
Discussion: We demonstrate the feasibility of isolation and molecular<br />
analysis of highly pure EpCAM-positive cells in the blood. Our results<br />
strongly suggest that epithelial cells captured from blood of MBC<br />
patients are malignant in nature and are therefore circulating tumor<br />
cells. This approach can serve as a non-invasive source of highly pure<br />
metastatic tumor tissue for further molecular characterization. This<br />
study was supported by CALGB and BCRF.<br />
P2-01-06<br />
Association between Circulating Tumor Cells and Bone Turnover<br />
Markers in patients with breast cancer and bone metastases on<br />
treatment with bisphosphonates (ZOMAR study)<br />
Manso L, Barnadas A, Tusquets I, Crespo C, Gómez P, Calvo L, Ruiz<br />
M, Martínez P, Perelló A, Antón A, Codes M, Margelí M, Murias<br />
A, Salvador J, Seguí MA, De Juán A, Gavilá J, Luque M, Pérez D,<br />
Zamora P, Arizcum A, Chacón JI, Heras L, De la Piedra C. Hospital<br />
12 de Octubre, Madrid, Spain; Hospital <strong>San</strong>ta Creu i <strong>San</strong>t Pau,<br />
Barcelona, Spain; Hospital del Mar, Barcelona, Spain; Hospital<br />
Universitario Ramón y Cajal, Madrid, Spain; Hospital Universitario<br />
Vall d’Hebrón, Barcelona, Spain; Hospital Universitario A Coruña<br />
Juan Canalejo, A Coruña, Spain; Hospital Universitario Virgen del<br />
Rocío, Sevilla, Spain; Hospital Basurto, Vizcaya, Spain; Hospital<br />
Son Dureta, Palma de Mallorca, Spain; Hospital Miguel Servet,<br />
Zaragoza, Spain; Hospital Virgen Macarena, Sevilla, Spain; Hospital<br />
Universitario Trias y Pujol, Barcelona, Spain; Hospital Universitario<br />
Insular de Gran Canaria, Gran Canaria, Spain; Hospital Nuestra<br />
Señora de Valme, Sevilla, Spain; Hospital Parc Taulí Sabadell,<br />
Barcelona, Spain; Hospital Marqués Valdecilla, <strong>San</strong>tander, Spain;<br />
Instituto Valenciano de Oncología, Valencia, Spain; Hospital General<br />
de Asturias, Oviedo, Spain; Hospital Costa del Sol, Málaga, Spain;<br />
Hospital La Paz, Madrid, Spain; Hospital Palencia Río Carrión,<br />
Palencia, Spain; Hospital Virgen de la Salud, Toledo, Spain; Hospital<br />
Cruz Roja Hospitalet del Llobregat, Barcelona, Spain; Instituto de<br />
Investigación <strong>San</strong>itaria Fundación Jiménez Díaz, Madrid, Spain<br />
Background:<br />
Quantification of Circulating Tumor Cells (CTC) has demonstrated<br />
an important role in assessing disease progression and outcomes,<br />
and pathological CTC levels are an independent prognostic factor of<br />
disease progression. High CTC levels may be associated with bone<br />
turnover markers (BTM) levels and have also been associated with<br />
the risk of skeletal-related events (SREs), disease progression and<br />
death. The aim of this study was to determine the relation between<br />
CTC, BTM, and SREs, disease progression and death in patients in<br />
patients with breast cancer (BC) and bone metastasis (BMe) treated<br />
with zoledronic Acid.<br />
Patients and methods:<br />
Observational, prospective and multicenter study. Patients with<br />
BC and BMe; no previous bone treatment in the last 6 months<br />
prior to study entry. CTC (fluorescently labelled with nucleic acid<br />
dye 4,6-diamidino-2-phenylindole DAPI, monoclonal antibodies<br />
specific for leukocytes CD45-allophycocyanin and epithelial cells<br />
cytokeratin 8,18,19–phycoerythrin; Cell Search System Veridex);<br />
urinary aminoterminal telopeptide of collagen I (NTX, Osteomark<br />
NTx Urine, Wampole Laboratories, USA); urinary alpha-alpha-isomer<br />
of carboxyterminal telopeptide of collagen I (αα-CTX, ALPHA<br />
Crosslaps EIA, ids, UK) and serum bone alkaline phosphatase (BALP,<br />
OSTASE BAP, ids, UK) were determined at baseline (V0) and every<br />
3 mo along 18 months (V6). Patients were treated with zoledronic<br />
acid (ZA) at inclusion and every 3-4 weeks.<br />
Results:<br />
234 patients with BC and BMe were analyzed, being available CTC<br />
results for 114 patients and BTM results for 219 patients at basal visit<br />
(V0) and every 3 mo of treatment along 18 months (V6). Population<br />
basal characteristics (234 patients): mean age: 59.8 years; ER+:<br />
80.3%; PR+: 64.9%; HER 2+: 18.3%. 55.3% of patients (n=114)<br />
had detectable CTC (CTC≥1) at V0, and 32.5% of them presented<br />
pathological (CTC≥5) at V0. A significant decrease was observed at<br />
V1, with 39.8% of patients with detectable CTC levels and 14.0%<br />
of patients with pathologic CTC levels (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
expressed ALDH1 both before and after chemotherapy, however<br />
high ALDH1 expression levels in CTCs were more frequently<br />
observed after treatment (91% vs 54%). The median percentage of<br />
ALDH1high expressing CTCs per patient was also increased after<br />
chemotherapy (86% vs 64%). TWIST expression was observed in<br />
the great majority of CTCs both before and after chemotherapy,<br />
however nuclear localization of TWIST in CTCs was more often<br />
encountered after treatment (92% vs 54%). The median percentage<br />
of TWISTnuclear expressing CTCs per patient also increased after<br />
chemotherapy (89% vs 48%). High ALDH1 expression in CTCs<br />
was positively correlated with nuclear localization of TWIST, both<br />
pre- and post-chemotherapy (p=0.0000001 and p=0.001, respectively,<br />
Spearman analysis). Concerning the co-expression of these molecules,<br />
the phenotype ALDH1high TWISTnuclear was the most abundant<br />
at both time points, however it was more frequently observed after<br />
treatment (90% vs 41% of CTCs). In addition, the median percentage<br />
of ALDH1high TWISTnuclear expressing CTCs per patient was also<br />
increased after chemotherapy (71% vs 0%).<br />
Conclusions: Stemness and EMT markers are co-expressed in CTCs<br />
from patients with metastatic breast cancer, both before and after the<br />
first-line chemotherapy. However chemotherapy seems to enrich these<br />
characteristics on CTCs, suggesting that CTCs possessing or acquiring<br />
these features are resistant to chemotherapy. Evaluation of the postchemotherapy<br />
samples is ongoing and final results will be presented.<br />
P2-01-08<br />
Different numbers and prognostic significance of circulating<br />
tumour cells in patients with metastatic breast cancer according<br />
to immunohistochemical subtypes.<br />
Peeters DJ, van Dam P-J, Wuyts H, Van den Eynden GG, Jeuris K,<br />
Prové A, Rutten A, Peeters M, Pauwels P, Van Laere SJ, Hauspy J,<br />
van Dam PA, Vermeulen PB, Dirix LY. GZA Hospitals Sint-Augustinus,<br />
Antwerp, Belgium; University of Antwerp, Belgium; Catholic<br />
University of Leuven, Leuven, Vlaams-Brabant, Belgium<br />
Introduction: The enumeration of circulating tumour cells (CTCs) with<br />
the EPCAM-based CellSearch system has prognostic significance in<br />
patients with metastatic breast cancer (MBC). However, breast<br />
cancer has been shown to be a molecularly heterogeneous disease.<br />
The aim of this study was to assess potential differences in the<br />
detection and prognostic significance of CTCs according to the<br />
immunohistochemically defined molecular subtypes of breast cancer.<br />
Methods: CellSearch CTC counts were obtained from 110 patients<br />
with MBC prior to first line systemic treatment, treated at GZA<br />
Hospitals Sint-Augustinus between november 2007 and december<br />
2011. Clinicopathological variables were prospectively entered in<br />
a database. Based on the St-Gallen surrogate definitions of intrinsic<br />
breast cancer subtypes (Goldhirsch et al. Ann Oncol 2011), patients<br />
were divided in 5 groups: luminal A (ER/PR+, HER2-, Bloom-<br />
Richardson histological grade I-II), luminal B – HER2 negative (ER/<br />
PR+, Her2-, grade III), luminal B – HER2 positive (ER/PR+, HER2+,<br />
any grade), HER2 positive – non luminal (ER/PR-, HER2+), and<br />
triple negative (TN) (ER/PR-, HER2-). Differences in progression<br />
free survival (PFS) and overall survival (OS) according to the FDA<br />
approved prognostic cut-off of ≥5 CTC/7.5 ml blood were estimated<br />
using Kaplan Meier and Cox proportional hazard statistics.<br />
Results: CTC were detected in 78 of 110 (71%) patients. Higher<br />
detection rates and numbers of CTC were observed in patients with<br />
luminal A and TN breast cancer as compared to patients with luminal<br />
B and HER2 positive disease. However, no differences in positivity<br />
rates were observed between molecular subtypes according to the<br />
5 CTC prognostic cut-off point (table 1). After a median FU time<br />
of 3.1 years, 39 patients had died. In the total study population, the<br />
presence of ≥5 CTC was an independent predictor of PFS and OS in<br />
multivariate analysis (PFS: HRCTC≥5=2.236 (1.366-3.658), p=0.001;<br />
OS: HRCTC≥5=3.180 (1.553-6.509), p=0.002). When analyzing<br />
subgroups separately, a lower prognostic power was observed in the<br />
HER2 positive and luminal B subgroups.<br />
N<br />
Median #CTC/<br />
7.5 ml (range)<br />
N (%) with<br />
≥1 CTC/<br />
7.5 ml<br />
N (%) with ≥5<br />
CTC/7.5 ml<br />
Log Rank P-value<br />
PFS (< vs ≥5<br />
CTC/7.5 ml)<br />
Log Rank<br />
P-value OS<br />
(< vs ≥5 CTC/<br />
7.5 ml)<br />
All 110 3.5 (0-2262) 78 (71%) 54 (49%) 0.003 0.0002<br />
LumA 37 10.0 (0-2262) 28 (76%) 21 (57%) 0.039 0.020<br />
LumB -<br />
HER2-<br />
22 0.5 (0-253) 11 (50%) 7 (32%) 0.362 0.098<br />
LumB -<br />
HER2+<br />
24 3.5 (0-115) 15 (63%) 12 (50%) 0.616 0.678<br />
HER2+ -<br />
12 5.0 (0-86)<br />
nonluminal<br />
10 (83%) 6 (50%) 0.197 0.157<br />
TN 15 7.0 (0-1101) 14 (93%) 8 (53%) 0.033 0.026<br />
Kruskal-Wallis: Chi square: Chi square:<br />
p=0.042 p=0.034 p=0.46<br />
Table 1<br />
Conclusion: Significant differences were observed in the detection<br />
and prognostic significance of EPCAM positive CTC according to the<br />
immunohistochemically defined breast cancer subtypes. Interestingly,<br />
CTC were detected more frequently in patients with luminal A and TN<br />
tumors. Furthermore, our data suggest a lower prognostic significance<br />
of CTC evaluation in HER2 positive patients with MBC. Our data<br />
independently confirm those reported by Giordano et al. (Ann Oncol<br />
2010) in a large clinically uniform population of patients with MBC<br />
before the start of first-line treatment.<br />
P2-01-09<br />
Tumor cell emboli in the lung and transcriptional profiles<br />
of circulating tumor cells derived from different vascular<br />
compartments in patients with metastatic breast cancer.<br />
Peeters DJ, Van den Eynden GG, Rutten A, Onstenk W, Sieuwerts<br />
AM, De Laere B, van Dam PA, Peeters M, Pauwels P, Van Laere SJ,<br />
Vermeulen PB, Dirix LY. GZA Hospitals Sint-Augustinus, Antwerp,<br />
Belgium; University of Antwerp, Belgium; Erasmus University<br />
Medical Center and <strong>Cancer</strong> Genomics Center, Rotterdam, South<br />
Holland, Netherlands; Catholic University of Leuven, Leuven,<br />
Vlaams-Brabant, Belgium<br />
Background: We have shown that in up to 50% of patients with<br />
metastatic breast cancer (MBC) significantly higher numbers of<br />
circulating tumor cells (CTCs) can be detected in central venous blood<br />
(CVB) as compared to peripheral venous blood (PVB), suggesting that<br />
the lungs might retain a substantial number of CTCs from the blood<br />
stream (Peeters et al. Br J <strong>Cancer</strong> 2011). The aim of this study was<br />
1) to investigate the relation between elevated numbers of CTCs and<br />
the presence of (intravascular) tumor cell emboli (TCE) in the lung<br />
in patients with advanced carcinomas, and 2) to investigate whether<br />
CTCs derived from CVB and PVB exhibit differential transcriptional<br />
characteristics.<br />
Methods: Seven patients with MBC and 1 patient with metastatic<br />
cervical carcinoma, all suffering from end-stage disease, were<br />
included in the first part of this study. CTCs were isolated and<br />
enumerated with the CellSearch system (Veridex, Raritan, NJ, USA)<br />
in 7.5 ml blood obtained from the central venous access catheter<br />
(CVB) and/or a peripheral vein (PVB). All blood samples were<br />
obtained within 5 days prior to death. The presence of TCE was<br />
studied in lung tissue samples obtained at autopsy. For the second<br />
study aim, paired CVB and PVB CTC samples were collected from<br />
an additional 10 MBC and 2 LABC patients. Transcriptional profiles<br />
were obtained for 91 breast cancer related genes as described by<br />
Sieuwerts et al. (Clin <strong>Cancer</strong> Res 2011).<br />
Results: Multiple TCE were observed in 4 out of 6 patients with highly<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
218s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
elevated numbers of CTCs (>100 CTC/7.5 ml blood). These TCE were<br />
located exclusively intravascularly in 2 patients, while the other 2<br />
patients had a more diffuse infiltration pattern with perivascular and<br />
lymphovascular TCE. All 4 patients had a history of rapidly evolving<br />
respiratory distress in the last week of life although radiological<br />
examination of the lungs did not show significant interval changes.<br />
In another 2 MBC patients with >100 CTCs and 2 MBC patients<br />
with
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
significant correlations for the expressions of CK8 (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
breast cancer cells within the bloodstream. Whereas only rare (0.1-<br />
10%) cells in the primary tumor expressed both mesenchymal and<br />
epithelial markers, such biphenotypic as well as purely mesenchymal<br />
cells were enriched among CTCs, across all histological subtypes of<br />
breast cancer. Analysis of the therapy response in 8 patients suggest<br />
an association of mesenchymal CTCs with disease progression. In<br />
an index patient followed longitudinally, fluctuation in epithelial and<br />
mesenchymal states was observed as a function of initial response<br />
and subsequent resistance to therapy. Mesenchymal markers were<br />
predominant in clusters of tumor cells, many of which had adherent<br />
platelets. Finally, RNA sequencing of mesenchymal CTC clusters<br />
identified TGF-B and other EMT-related signatures, which were<br />
absent from more epithelial CTCs. FOXC1, a known regulator of<br />
EMT, was abundantly expressed in mesenchymal CTCs and was<br />
detectable within localized regions of the primary breast tumor.<br />
Together, these data support a role for EMT in the blood-borne<br />
dissemination of breast cancer and point to the dynamic nature of<br />
this cell fate change.<br />
P2-02-01<br />
Accurate identification of metastatic breast cancer using<br />
methylated gene markers in circulating free DNA in peripheral<br />
blood<br />
Sukumar S, Fackler MJ, Lopez-Bujanda Z, Teo WW, Jeter S, Umbricht<br />
C, Visvanathan K, Wolff AC. Johns Hopkins University School of<br />
Medicine, Baltimore, MD<br />
Background: Preliminary studies from our lab have shown that<br />
a panel of methylation markers in tissue identifies 100% of tested<br />
breast cancer and 95% of tested DCIS, and has high accuracy in cells<br />
from ductal fluid and spontaneous nipple discharge 1,2 . Other groups<br />
have reported on the use of a single marker or a panel of markers to<br />
detect breast cancer in serum or plasma. Cell-free DNA studies in<br />
the peripheral blood of breast cancer patients with advanced disease<br />
or with early-stage disease after completion of local therapy support<br />
the hypothesis that methylated DNA markers in serum or plasma<br />
could be used to monitor response to therapy and for long-term<br />
surveillance. Validation studies to test these hypotheses have been<br />
hampered by assay methodological issues such as the very small<br />
amount of DNA shed in the serum by tumor compared to the total<br />
DNA shed by normal cells.<br />
Methods: To overcome this problem, we developed a modified<br />
quantitative methylation-specific PCR that directly measures the<br />
number of copies of methylated DNA markers in a small aliquot of<br />
serum (Serum-QM-MSP) and robustly detects less than 25 copies<br />
of DNA in 300 µL of serum. We then conducted a genome-wide<br />
methylome analysis to identify key markers that are preferentially<br />
methylated in serum from women with breast cancer and compared the<br />
profiles to those from women with no breast cancer. We then analyzed<br />
300 µL each of sera from 55 normal women (single time point) and<br />
43 women with metastatic breast cancer using this newly developed<br />
panel of markers and the Serum-QM-MSP assay. We also examined<br />
changes after therapy in a subset of patients with metastatic disease.<br />
Results: Methylation markers were quantitatively detected in sera<br />
of 39 out of 43 (91% sensitive) metastatic breast cancer patients<br />
with varying tumor burdens, and not in sera of any of 55 women<br />
(100% specific) for an AUC=0.95, using a laboratory threshold of<br />
7.2 cumulative methylation units. 28 of the 43 patients had sampling<br />
repeated 3-5 weeks after therapy started. Sera from patients whose<br />
tumors regressed and from those that had stable disease showed a<br />
quantitative reduction, while those with progressive disease showed<br />
an increase in methylation levels of several genes.<br />
Conclusion: Our results suggest that methylated DNA in serum<br />
accurately discriminates between blood samples from normal women<br />
and from metastatic breast cancer patients. Also, early changes after<br />
therapy initiation for metastatic disease may correlate with subsequent<br />
clinical outcome. Assay analytical validation studies are ongoing.<br />
Studies examining a potential role in surveillance in the adjuvant<br />
setting and therapeutic benefit in the metastatic setting are warranted.<br />
1. Fackler MJ et al. Genome-wide methylation analysis identifies<br />
genes specific to breast cancer hormone receptor status and risk<br />
of recurrence. <strong>Cancer</strong> Res. 2011 Oct 1;71(19):6195-207. PMCID:<br />
PMC3308629.<br />
2. Fackler MJ, et al. Hypermethylated genes as biomarkers of cancer<br />
in women with pathologic nipple discharge. Clin <strong>Cancer</strong> Res. 2009<br />
Jun 1;15(11):3802-11. PMID: 19470737<br />
P2-02-02<br />
Prognostic significance of the ratio of absolute neutrophil to<br />
lymphocyte counts for breast cancer patients in neoadjuvant<br />
setting<br />
Koh YW, Lee HJ, Ahn J-H, Lee JW, Gong G. University of Ulsan<br />
College of Medicine, Asan Medical Center, Seoul, Korea; Seoul<br />
National University Bundang Hospital, Seongnam, Bundang-Gu,<br />
Kyeonggi-Do, Korea<br />
Background: The baseline absolute neutrophil count/absolute<br />
lymphocyte count ratio (NLR) has potential prognostic importance in<br />
solid tumors, including breast cancer. However, NLR as a predictive<br />
factor of the pathologic complete response (pCR) or as a prognostic<br />
factor has not been fully studied in breast cancer patients who have<br />
received neoadjuvant chemotherapy.<br />
Materials and Methods: Using receiver operating characteristic curve<br />
analyses, we retrospectively examined the predictive and prognostic<br />
impact of the NLR at the diagnosis in 401 patients with primary breast<br />
cancer who were treated with neoadjuvant chemotherapy, followed by<br />
definitive surgical resection. Of the 401 included patients, 72 (18%)<br />
received anthracycline-based, 285 (71%) received anthracycline- and<br />
taxane-based, 37 (9.2%) received herceptin-based, and 7 (1.7%)<br />
received fluorouracil-based regimens. The significance of NLR<br />
was analyzed according to clinicopathologic variables and clinical<br />
outcomes.<br />
Results: Forty-three (10.7%) patients achieved pCR. On univariate<br />
analysis, high NLR (> 2.2) correlated with poor recurrence-free<br />
survival (RFS; P = 0.001) and overall survival (OS; P = 0.003).<br />
Subgroup analysis of the non-pCR group showed that NLR was<br />
significant for RFS and OS (P = 0.002 and P = 0.007, respectively).<br />
Multivariate analysis showed NLR to be an independent prognostic<br />
factor for RFS and OS (P = 0.002 and P = 0.007, respectively).<br />
Multivariate analyses of recurrence-free survival and overall survival according to clinicopathologic<br />
variables<br />
Multivariate<br />
Variables<br />
analysis<br />
Recurrencefree<br />
survival<br />
95%<br />
Harzard<br />
confidence<br />
ratio<br />
interval<br />
P<br />
Harzard<br />
ratio<br />
Overall<br />
survival<br />
95%<br />
confidence<br />
interval<br />
Lymphovascular<br />
(-) vs. (+) 1.48 0.912–2.402 0. 112 1.413 0.740–2.700 0. 295<br />
invasion<br />
ER and PR status (-) vs. (+) 0.32 0.198–0.517
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Conclusion: Our results suggest that the NLR is an independent<br />
prognostic factor for RFS and OS in breast cancer patients receiving<br />
neoadjuvant chemotherapy and may provide additional prognostic<br />
information for patients not achieving a pCR to determine who might<br />
profit from further therapy.<br />
P2-02-03<br />
The Collagen Receptor Endo180: A Metastatic Plasma Marker In<br />
<strong>Breast</strong> <strong>Cancer</strong> Modulated By Bisphosphonate Treatment<br />
Sturge J, Caley MP, Purshouse K, Fonseca A-V, Rodriguez-Teja M,<br />
Kogianni G, Waxman J, Palmieri C. Imperial College London, United<br />
Kingdom; The University of Hull, Hull, United Kingdom<br />
Purpose: To establish whether the collagen remodelling receptor,<br />
Endo180, should be given consideration as a useful plasma marker<br />
in metastatic breast cancer.<br />
Patients and Methods: Analysis of MCF-7 and MDA-MB-231 cell<br />
conditioned medium validated the anti-human (39.10) monoclonal<br />
antibody as suitable for the detection of soluble Endo180 in<br />
plasma. Eighty-seven breast cancer patients with early primary,<br />
locally advanced and metastatic disease were included in the study.<br />
Correlations between Endo180, CA 15-3 antigen (MUC1; mucin 1)<br />
and bisphosphonate treatment were investigated.<br />
Results: Endo180 was elevated in metastatic compared to early breast<br />
cancer (P
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
disease-free survival (DFS) were calculated from the date of diagnosis<br />
and analyzed with Kaplan-Meier survival plots. Cox multivariate<br />
proportional hazards model was also performed.<br />
Results: Of the 103 evaluable patients, 45 patients received<br />
neoadjuvant chemotherapy, 35 adjuvant chemotherapy and 23 no<br />
chemotherapy. The median follow-up was 40 months (range 7-66<br />
months). Patients with CSCs in BM had a hazard ratio (HR) of<br />
8.8 for DFS (p = 0.002); patients with Aldefluor+ CSCs had a HR<br />
of 5.9 (p = 0.052) for DFS. Seven patients have expired and all of<br />
them had CSCs in BM. Moreover, we evaluated the presence of<br />
DTCs by FACS (CD326+CD45-) in 104 patients. Sixty-one (75%)<br />
of patients had positive BM samples for DTC (CD326+CD45- BM<br />
cells ≥ 0.53%). No association was shown between DTC in BM as<br />
determined by FACS and CTCs in PB. In a multivariate model, after<br />
adjusting for age (< 45 years old), clinical T stage, N stage, ER, PR,<br />
HER2 status, and nuclear grading, the presence of CSCs was found<br />
to be an independent predictor of DFS (HR = 15.8, P = 0.017) as<br />
was the presence of CTCs (HR = 13.9, P = 0.007). In this subset of<br />
patients, the presence of Aldefluor+ CSCs and DTCs was not found<br />
to be predictive of DFS in the multivariate model including the same<br />
factors as listed above.<br />
Conclusions: Our data indicate that the presence of BM metastasis<br />
is correlated to CSCs, and CSCs irrespective of ALDH activity are<br />
independent adverse prognostic factors in EBC patients. Moreover,<br />
the presence of CTCs was a strong independent predictor of DFS.<br />
P2-04-01<br />
Development of mouse breast cancer models based on induced<br />
cancer stem cells (iCSC).<br />
Takamoto Y, Onishi N, Kai K, Saya H. Institute for Advanced Medical<br />
Research (IAMR), School of Medicine, Keio university, Shinjyuku-ku,<br />
Tokyo, Japan; The University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX<br />
<strong>Breast</strong> cancer is one of the leading causes of death in women<br />
worldwide. To develop novel therapeutic approaches for the<br />
refractory cases, the mouse models which recapitulate the tumor<br />
tissues biologically and pathologically similar to human breast<br />
cancer are required. Although xenograft models of established cell<br />
lines in immune-deficient mice are frequently used for preclinical<br />
experiments, such xenograft models are not sufficient because the<br />
heterogenous structure based on the microenvironment and the<br />
intrinsic characteristics of cancer cells is not correctly formed.<br />
In this study, we have established induced cancer stem cells (iCSC)<br />
from normal mouse mammary stem/progenitor cells through minimal<br />
required genetic manipulations and generated mouse breast cancer<br />
models by inoculating the iCSCs in the mammary fat pads. Initially,<br />
we established iCSC by introducing the H-RasV12 into Ink4a/Arfknockout<br />
mammary stem/progenitor cells and this iCSC formed tumor<br />
similar to human triple negative breast cancer in mouse. This finding<br />
suggested that two genetic events, an activation of oncogenic signal<br />
and a tumor suppressor inactivation, are required for generating the<br />
breast cancer iCSC.<br />
Anaplastic Lymphoma Kinase (ALK) gene, which encodes a receptor<br />
tyrosine kinase, was reported to be amplified and/or overexpressed<br />
up to 86% of patients in inflammatory breast cancer, and pleiotrophin<br />
(PTN), which is a physiological ligand for ALK, was also shown to be<br />
highly expressed in about 60% of human breast cancers. Therefore, we<br />
hypothesized that ALK pathway is involved in tumorigenesis of breast<br />
cancers and, then, attempted to generate iCSC by using ALK gene.<br />
Interestingly, we found that one of the naturally occurring mutations<br />
of ALK is sufficient for generating iCSC and tumor formation in<br />
vivo without any prior tumor suppressor inactivation. The ALKinduced<br />
iCSCs developed highly aggressive breast cancers in mice.<br />
Furthermore, the tumor formation was significantly suppressed when<br />
the ALK-induced iCSCs were generated by using mammary stem/<br />
progenitor cells derived from mouse deficient in CD44 which is a<br />
CSC marker. We have recently revealed a role of CD44, in particular<br />
that of a variant isoform (CD44v), in the protection of CSCs from<br />
high levels of oxidative stress derived from both tumor cells and their<br />
microenvironment (<strong>Cancer</strong> Cell 19: 387-400, 2011; <strong>Cancer</strong> Res 72:<br />
1438-1448, 2012; Nat Commun 3: 883, 2012). We will discuss the<br />
underlying mechanism of ALK-induced tumorigenesis and a role of<br />
CD44 in the CSC functions.<br />
P2-04-02<br />
Identification of genes associated with breast cancer<br />
micrometastatic disease in bone marrow using a human-inmouse<br />
xenograft system<br />
Aft R, Li S, Mudalagiriyappa C, Dasgupta N, Watson M, Fleming T,<br />
Ellis M, Pillai S. Washington University, St. Louis, MO<br />
Disseminated tumor cells (DTCs) found in the bone marrow (BM)<br />
of breast cancer patients portend a poor prognosis and are thought<br />
to be the intermediaries in the metastatic process. Study of these<br />
cells has been limited due to their scarcity. To develop a clinically<br />
relevant model to characterize hese cells, we have employed a human<br />
in mouse (HIM) xenograft model for propagating, isolating, and<br />
molecularly characterizing DTCs. Human breast adenocarcinomas<br />
were prospectively collected from 5 patients and implanted into<br />
humanized NOD/SCID mouse mammary fat pads. BM was collected<br />
from the long bones at varying passages of the tumors and analyzed<br />
for human-specific gene expression by qRT-PCR and gene expression<br />
microarray. Human-specific gene expression of SNAI1, GSC, FOXC2,<br />
KRT19, and STAM2, presumably originating from disseminated<br />
tumor cells, was detectable in the BM of all mice that had developed<br />
metastatic disease to other solid organs, but was not detectable<br />
in xenotransplanted mice that did not develop metastatic disease.<br />
Comparative gene expression microarray analysis of the HIM primary<br />
tumor, the corresponding BM from mice with metastatic disease,<br />
and BM from control mice identified additional patterns of gene<br />
expression enriched in BM-associated DTCs which included several<br />
genes associated with epithelial-mesenchymal transition, aggressive<br />
clinical phenotype, and metastatic disease development in primary<br />
human tumors. We have found that BM DTCs can be detected using<br />
the HIM xenograft model and have identified unique patterns of gene<br />
expression associated with BM DTCs, which may provide further<br />
insight into the biology and therapeutic vulnerability of metastatic<br />
tumor cell populations in breast cancer patients.<br />
P2-04-03<br />
A robust transgenic mouse model to study male breast cancer.<br />
Krause S, Lurvey HL, Tobin H, Ingber DE. Boston’s Children’s<br />
Hospital, Boston, MA; Wyss Institute of Biologically Inspired<br />
Engineering, Boston, MA<br />
Male breast cancer accounts for about 1% of all breast cancers and<br />
even though it is a rare disease, the incidence rate has increased<br />
steadily during the past 20 years. Study of the male form of the<br />
disease has been hampered by a lack of relevant animal models as<br />
it is commonly believed that male mammary glands do not contain<br />
ducts. Female FVB C3(1)-SV40Tag transgenic mice spontaneously<br />
develop hyperplastic mammary lesions that progress to invasive<br />
mammary tumors, whereas most of the transgenic males develop<br />
prostatic hyperplasia that progresses to adenocarcinoma. However,<br />
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upon closer examination, we discovered that approximately 45% of<br />
transgenic males develop mammary tumors by 40 weeks of age, often<br />
prior to developing prostate tumors. The course of male mammary<br />
development is similar to that observed in the females but with a<br />
later onset. Hyperplastic ducts form as early as 15 weeks of age<br />
and progress into DCIS-resembling tumors before developing into<br />
invasive tumors that invade locally into adipose tissue and muscle<br />
and occasionally form metastases to lung and other organs. We then<br />
examined male mammary development in the FVB background<br />
strain (wild type) and showed that all males develop mammary<br />
ducts that continue to grow and branch throughout adulthood. The<br />
morphology of these ducts was similar to that of females with a<br />
central lumen surrounded by concentric layers of luminal epithelium,<br />
myoepithelium, a basement membrane and surrounding stroma. A<br />
study of CD1 male mice confirmed that male mammary development<br />
was not specific to the FVB strain but rather, CD1 males showed<br />
similar mammary ductal development. Male mammary development<br />
in FVB wild type animals and tumor progression in the transgenic<br />
males was characterized in terms of cell proliferation, apoptosis and<br />
expression of various markers of differentiation including hormone<br />
receptor status. In summary, our results demonstrate that FVB C3(1)-<br />
SV40Tag transgenic males represent a highly robust and reproducible<br />
model for the study male breast cancer. Our long-term goal is to<br />
leverage the information we uncovered through this effort to design<br />
novel therapies for breast cancer treatment in men.<br />
P2-04-04<br />
Prolactin cooperates with loss of p53 to promote mammary<br />
tumorigenesis.<br />
O’Leary KA, Sullivan R, Rugowski DE, Schuler LA. University of<br />
Wisconsin, Madison, WI<br />
Prolactin (PRL) is critical for mammary development and lactation.<br />
Epidemiological studies also support a role for PRL in breast cancer.<br />
In order to study the contributions of PRL to tumor development and<br />
progression, we developed a transgenic mouse model that expresses<br />
PRL in the mammary epithelial cells (NRL-PRL), mimicking the<br />
mammary PRL production in women. Loss of function of the tumor<br />
suppressor p53 is a common occurrence in many human cancers<br />
including breast tumors. Interactions between PRL and p53 were<br />
examined by crossing the NRL-PRL mouse to p53 knockout mice<br />
which were made congenic on the FVB/N background. To circumvent<br />
the problem that p53 -/- mice are prone to multiple nonmammary<br />
tumors, mammary cells from 10-12 week old wild-type, NRL-<br />
PRL, p53 -/- , and NRL-PRL/ p53 -/- were transplanted to wild type<br />
mammary glands. Histological analysis of the donor glands showed<br />
that NRL-PRL glands displayed marked epithelial proliferation<br />
and focally dilated ducts, whereas p53 -/- glands exhibited irregular<br />
ductal epithelium with increased stromal density compared to<br />
wild type mice. In contrast, glands of donor PRL/ p53-/- females<br />
showed widespread epithelial hyperplasias and highly irregular<br />
ductal epithelium often surrounded by dense stroma. By one year of<br />
age, no tumors had developed from either wild-type or NRL-PRL<br />
transplanted epithelium. However, recipients of either p53 -/- or NRL-<br />
PRL/ p53 -/- mammary epithelium developed histologically similar<br />
anaplastic carcinomas. The presence of transgenic PRL decreased<br />
tumor latency (205 vs 244 days) and significantly increased tumor<br />
cell proliferation. In addition, these carcinomas appeared to be more<br />
aggressive: 5/16 (32%) of the NRL-PRL/ p53 -/- tumors invaded into<br />
the peritoneal cavity, compared to 0/10 p53 -/- tumors. Expression of<br />
matrix metalloproteinase 9 (MMP-9), but not MMP-2, was found to be<br />
significantly higher in the NRL-PRL/ p53 -/- , compared to p53 -/- tumors.<br />
MMP-9 is regulated by the transcription factor, AP-1, and PRL can<br />
signal through AP-1. NRL-PRL/ p53 -/- tumors displayed significantly<br />
increased expression of the AP-1 family members, c-Jun and FosL, but<br />
not JunD or c-Fos compared to tumors from p53 -/- mice. In addition,<br />
levels of c-Jun and FosL proteins increased in a similar pattern. In<br />
summary, interactions between PRL and loss of p53 promote breast<br />
cancer by increasing proliferation and invasiveness, potentially via<br />
AP-1 target genes. Supported by CDMRP BC053412.<br />
P2-04-05<br />
Prolonged targeted overexpression of Aurora-A in mammary<br />
epithelium promotes mammary adenocarcinoma with genomic<br />
instability<br />
Treekitkarnmongkol W, Katayama H, Sen S. University of Texas M.D.<br />
Anderson <strong>Cancer</strong> Center, Houston, TX<br />
Aurora kinase-A (referred to as Aurora-A) identified as a sereine/<br />
threonine kinase induces mitotic progression process including<br />
centrosome amplification, bipolar spindle formation and chromosome<br />
segregation through modulation of activity and localization of its<br />
interacting proteins during cell division. Beside its essential roles in<br />
mitosis, cancer profiling studies have revealed that Aurora-A function<br />
is implicated in tumor relevant signaling pathways and overexpressed<br />
in many human tumors. The findings showed highly frequent<br />
overexpression of Aurora-A in human breast ductal carcinoma in<br />
situ and primary invasive ductal breast carcinoma. Moreover, the<br />
Aurora-A overexpression correlates with poor prognosis in breast<br />
carcinoma, deregulated overexpression of Aurora-A associates with<br />
centrosome anomalies and chromosome instability in rodent models<br />
of mammary caricinogenesis.<br />
However, published studies in several transgenic mouse models<br />
attempting to address the role of Aurora-A in tumorigenesis and<br />
genomic instability have raised conflicting results. In this report we<br />
targeted expression of Aurora-A transgene in an inducible mouse<br />
model in which expression of Aurora-A was restricted to mammary<br />
epithelium during multiple pregnancy and lactation cycles under the<br />
activity of β-lactoglobulin promotor. The results demonstrate that<br />
overexpression of Aurora-A could induce tumorigenesis in mouse<br />
mammary epithelium. The tumor incidence was 70% of Aurora-A<br />
transgenic mice at 16 months of age. Of note, overexpression<br />
of Aurora-A led to genomic instability. Comparative genomic<br />
hybridization (CGH) array analyses revealed loss of Trim12a,<br />
Trim12c, Trim30b, Trim30d, Trim30e, Cdkn2d, Pten, Cep55 and<br />
gain of Adam6. Notably, Aurora-A overexpression caused nuclear<br />
accumulation of cyclin D1, activation of AKT, overexpression of<br />
TPX2 and PLK1and loss of ERα expression in tumors. Our findings<br />
indicated that prolonged Aurora-A expression in mammary epithelium<br />
leads to mammary adenocarcinomas with genomic instability.<br />
Aurora-A driven adenocarcinoma reveals deregulation of critical<br />
tumor relevant genetic pathways involving both oncogenes and tumor<br />
suppressor genes. These transgenic mouse model findings indicate that<br />
Aurora-A may be an important therapeutic target for mammary cancer.<br />
Keywords: Aurora-A, carcinogenesis.<br />
P2-04-06<br />
Transgenic expression of a breast-cancer specific GATA3 mutant<br />
leads to mammary hyperplasia<br />
Kenny PA, Chandiramani N. Albert Einstein College of Medicine,<br />
Bronx, NY<br />
GATA3 is expressed in normal luminal breast epithelial cells and is<br />
a key transcription factor in mammary gland development. In human<br />
breast tumors, high GATA3 protein levels are associated with estrogen<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
224s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
receptor (ER) positivity and low grade. Recent published reports<br />
indicate that somatic mutations of GATA3 occur in up to 21% of ER+<br />
tumors. These authors suggest, but do not demonstrate, that these<br />
GATA3 mutations are loss-of-function null alleles and that GATA3<br />
is a haploinsufficient tumor suppressor gene.<br />
The published mutational data indicate a striking enrichment of<br />
GATA3 mutations in exons 5 and 6 (amino acids 309-443) which<br />
encode the second of two DNA binding zinc fingers. This suggests<br />
that mutant proteins lacking this zinc finger may confer a survival<br />
advantage on breast cancer cells. Given this apparently strong<br />
selective pressure for mutations in this hotspot, it seems unlikely that<br />
these mutations are loss-of-function alleles.<br />
We explored this directly by generating a MMTV-GATA3mutant<br />
mouse which specifically expresses a mutant GATA3 protein in<br />
the mammary gland. Non-parous pubertal transgenic mice exhibit<br />
a pronounced mammary hyperplasia and have increased ductal<br />
branching compared to wildtype littermates. These data confirm<br />
that the mutant GATA3 mutations commonly found in breast cancer<br />
are not null alleles, but that they instead have a gain-of-function<br />
phenotype. We are currently evaluating the effect of mutant GATA3<br />
on the kinetics of mammary tumorigenesis by crossing these mice<br />
to the MMTV-PyMT model.<br />
P2-04-07<br />
Modeling orthotopic and metastatic progression of mammary<br />
tumors to evaluate the efficacy of TGF-β inhibitors in a preclinical<br />
setting<br />
Biswas T, Yang J, Zhao L, Sun L. UTHSCSA, <strong>San</strong> <strong>Antonio</strong>, TX;<br />
UCSD, CA<br />
Preclinical models are elemental in understanding drug efficacy and<br />
safety in vivo. Many existing models of breast cancer metastasis use<br />
immune compromised animals and do not effectively characterize<br />
the differential stages of metastasis. Transforming growth factor-β<br />
(TGF-β) has been shown to be a major contributor in epithelialmesenchymal<br />
transition and enhances various steps during metastasis.<br />
The aim of this study is to develop mouse models of tumor metastasis<br />
using murine mammary cells in a syngeneic background. This will<br />
help illustrate the effect of TGF-β inhibitors on metastasis in an<br />
immune competent environment, and also allow determining the<br />
optimal time of drug administration. We demonstrate that TGF-β<br />
signaling has differential effects on a pair of murine mammary<br />
cell lines derived from PyMT tumors in C57Bl/6 mice. These cell<br />
lines represent luminal (Py 230) and basal (Py 8119) epithelial cell<br />
populations in the tumor. In vitro characterization revealed differences<br />
in viability, motility, and transcriptional and translational activation of<br />
Smad. Py 230 (clonal luminal) cells are growth inhibited and exhibit<br />
epithelial-mesenchymal transition on treatment with TGF-β, whereas<br />
Py 8119 (basal cells) are non-responsive to both effects. Furthermore,<br />
intra cardiac injections were performed using luciferase-GFP labeled<br />
PyMT cells in syngeneic background and animals were treated with<br />
either placebo or TβRI-KI (kinase inhibitor for TGF-β receptor I).<br />
Results from Py 8119 cell injections showed that TβRI-KI treatment<br />
enhanced bone and brain metastases. Further results will shed light on<br />
the effect of TβRI-KI during specific stages of metastasis progression.<br />
P2-04-08<br />
Targeted Expression of the Human Chaperone BAG3 to the<br />
Murine Mammary Gland Dysregulates Mammary Gland<br />
Development and Differentiation By Unrestricted Expansion of<br />
Luminal Cells<br />
Virador VM, Casagrange G, Raafat A, Callahan R, Kohn E. National<br />
<strong>Cancer</strong> Institute, Bethesda, MD<br />
BAG3 is a pro-survival pro-invasion chaperone. We hypothesized that<br />
human BAG3 overexpression in murine breast would contribute to<br />
mammary tumorigenesis. We generated transgenic mice ectopically<br />
expressing hBAG3 in the mammary gland under the control of the<br />
Mouse Mammary Tumor Viral promoter (MMTV-hBAG3). hBAG3<br />
was expressed in luminal cells throughout the ductal tree in multiple<br />
transgenic lines. Targeted expression of hBAG3 dysregulated<br />
mammary gland development by both increasing proliferation and<br />
differentiation. hBAG3 mammary glands had increased epithelial<br />
elongation at 5 weeks of age, premature glandular differentiation at 10<br />
weeks, and features of ductal hyperplasia at week 13 with increased<br />
Ki67 and p-Histone H3 in the luminal compartment. At week 13<br />
hBAG3 induced acinar differentiation. BAG3 pro-survival gain of<br />
function was recapitulated post-partum with delayed involution.<br />
Mammary glands of MMTV-hBAG3 had alveolar persistence<br />
three days after forced involution where non-transgenic controls<br />
demonstrated typical involution-driven apoptosis and remodeling.<br />
We crossed heterozygous MMTV-hBAG3 to WAP-Int3 mice with<br />
absent alveolar development in pregnancy. hBAG3 caused alveolar<br />
budding in the WAP-Int3 background. We hypothesized hBAG3 gain<br />
of function in the mammary gland would promote tumorigenesis.<br />
On aging, mammary glands of heterozygous MMTV-hBAG3<br />
displayed densely crowded acinar structures with atypia, consistent<br />
with hyperplastic alveolar nodule (HAN). We subjected MMTVhBAG3<br />
mice to either multiparity or chemical carcinogenesis. After<br />
two pregnancies, most MMTV-hBAG3 animals had hyperplastic<br />
mammary ductal lesions (MMTV-hBAG3 6/7, 86%; FVB/N 1/7,<br />
14%). Eighteen weeks post 7,12-dimethylbenz(a)antracene (DMBA)<br />
treatment, virgin females from five different transgenic lines had<br />
more hyperplastic lesions (MMTV-hBAG3 mean 6.3 lesions/gland,<br />
N=13, FVB/N mean 3.6 lesions/gland, N=9; p=0.04), some with<br />
atypical hyperplasia. Transgenic MMTV-hBAG3 females developed<br />
ER and PR (+) malignant tumors (5/19), 26% while non-transgenic<br />
controls had none (0/12). WAP-Int3 mice developed tumors as early<br />
as two pregnancies. Heterozygous WAP-Int3xMMTV-BAG3 had<br />
the same tumor frequency but preliminary data suggest increased<br />
aggressiveness and metastasis. Collectively, our results indicate that<br />
MMTV-hBAG3 promotes proliferation, dysregulates mammary gland<br />
development and promotes hyperplasia and tumorigenesis and may<br />
provide a novel mouse model to represent the human ER+ luminal<br />
breast cancer subtype.<br />
P2-05-01<br />
Gene expression changes associated with response to neoadjuvant<br />
chemotherapy are observed early in treatment: results from the<br />
I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657)<br />
Wolf DM, Yau C, Magbanua M, Boudreau A, Davis S, Haqq C, Park<br />
J, I-SPY TRIAL-1 Investigators, Esserman L, van’t Veer L. University<br />
of California, <strong>San</strong> Francisco, CA; I-SPY 1 TRIAL Institutions<br />
Background: Prior gene expression profiling studies have identified<br />
markers that are predictive of chemotherapy response using pretreatment<br />
biopsies. However, this approach does not account for<br />
chemotherapy-induced perturbation in signaling within tumors<br />
early in treatment that may predict response to therapy with<br />
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superior sensitivity to baseline signatures. We hypothesized that<br />
measuring early changes in gene expression induced by neoadjuvant<br />
chemotherapy might yield improved markers of treatment efficacy<br />
and patient outcome.<br />
Methods: Transcriptome data from 34K probe cDNA microarrays<br />
were assembled using serial biopsies obtained from 36 I-SPY<br />
1 TRIAL patients before treatment (T1), and 24-72 hours after<br />
beginning neoadjuvant anthracycline-based chemotherapy (T2).<br />
Outcome parameters included residual cancer burden (RCB) after<br />
therapy and recurrence free survival (RFS). Gene expression changes<br />
occurring between T1 and T2 (T2-T1) were compared between<br />
known responders (RCB 0/1) and non-responders (RCB 2/3) using<br />
a permutation test based on the t-statistic; Cox proportional hazards<br />
modeling was used to identify early response genes associated with<br />
RFS. Due to the small sample sizes, we adopted a relaxed significance<br />
threshold for outcome associations (p-value
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
P2-05-04<br />
Differential potency of TORC1/C2 (INK/MLN-128) and<br />
pan-PI3K (GDC0941) inhibitors on breast cancer polysome<br />
composition and phosphoprotein response biomarkers<br />
Wilson-Edell KA, Yevtushenko M, Hanson I, Rogers AN, Scott GK,<br />
Benz CC. Buck Institute for Research on Aging, Novato, CA<br />
The PI3K (phosphoinositide-3 kinase)/AKT (protein kinase B)<br />
pathway is dysregulated in over 70% of breast cancers, including<br />
more than 40% of non-basal breast cancers that possess activating<br />
PIK3CA mutations and 15% of basal breast cancers with functional<br />
loss of PTEN (n=357 TCGA samples), suggesting that inhibitors of<br />
this signaling pathway may be clinically beneficial. Moreover, the<br />
recently reported BOLERO-2 trial (N Engl J Med, 2012) demonstrated<br />
the potential clinical benefit of using a TORC1 (target of rapamycin<br />
complex I) inhibitor, Everolimus, to treat patients with advanced<br />
non-basal, ER-positive breast cancers presumeably enriched with<br />
PIK3CA mutations. Among the new PI3K/AKT/TOR pathwaytargeted<br />
therapeutics now under clinical development are the dual<br />
TORC1/C2 inhibitor, INK/MLN-128, and the pan-PI3K inhibitor,<br />
GDC0941. Despite having comparable nanomolar target affinities,<br />
it is unclear whether similar subsets of breast cancers will respond<br />
similarly to these agents, or if targeting this PI3K/AKT/TOR pathway<br />
either upstream (e.g. by GDC0941) or downstream (e.g. by INK/<br />
MLN-128) will yield comparable antitumor effects. Many of the<br />
downstream cellular responses regulated by this pathway, including<br />
tumor cell survival, growth, metabolism, invasiveness and angiogenic<br />
potential, are mediated by phosphorylation of polysome effector<br />
proteins, including the known TORC1 regulated eukaryotic translation<br />
initiation factor 4 binding protein (4eBP1) and 40S ribosomal protein<br />
S6. Therefore, we compared the effects of INK/MLN-128 and<br />
GDC0941 on cell growth and polysome protein phosphorylation<br />
profiles using a model breast cancer cell line (SKBr3) with amplified<br />
upstream receptor (HER2) activation of the PI3K/AKT/TOR pathway.<br />
Continuous dosing of these two agents against SKBr3 cultures (0-625<br />
nM x5 days) revealed a 50-fold greater anti-proliferative efficacy for<br />
INK/MLN-128, with IC 50 = 9nM compared to the GDC0941 IC 50 =<br />
479nM. This difference in antiproliferative activity correlated with<br />
their 50-fold different doses required to inhibit polysome formation<br />
(relative to free 40S, 60S, and 80S ribosomes) and polysomal 40S<br />
Rack1 and 60S RPL24 content. Likewise, INK/MLN-128 more<br />
potently inhibited the phosphorylation of two polysome-associated<br />
proteins of 32 KD and 60 KD size, recognized by an antibody toward<br />
a motif phosphorylated by AKT and related kinases (RXXS*/T*); the<br />
32 KD substrate has been identified as S6. With equipotent dosing<br />
(0.1 mM INK/MLN-128 and 5 mM GDC0941), these two agents<br />
showed comparable inhibitory effects on polysome formation and<br />
protein phosphorylation. In summary, in a breast cancer model bearing<br />
upstream receptor activation of the PI3K/AKT/TOR pathway, distal<br />
pathway inhibition of TORC1/C2 by INK/MLN-128 appeared more<br />
potent and effective than more proximal inhibition of pan-PI3K by<br />
GDC0941. Furthermore, polysome inhibitory effects following INK/<br />
MLN-128 exposure were apparent within 8 h of treatment, and the<br />
most sensitive polysome response biomarker for this agent appeared<br />
to be phospho(T389)-S6 kinase, providing rationale for the use of<br />
this response biomarker in future clinical trials.<br />
P2-05-05<br />
Circulating HER2 extracellular domain (ECD) predicts a poor<br />
prognosis for metastatic breast cancer patients<br />
Wang X-j, Shao X-Y, Xu X-H, Chen Z-H, Wang S, Cai J-F, Huang J,<br />
Huang P, Lou C-J, Ling Z-Q, Han MX. Zhejiang <strong>Cancer</strong> Hospital,<br />
Hangzhou, Zhejiang, China; Hangzhou Polar Gene Company,<br />
Hangzhou, Zhejiang, China<br />
Background: Amplification or overexpression of HER2 has been<br />
shown to play an important role in approximately 30% of breast<br />
cancers and is strongly associated with increased recurrence and a<br />
worse prognosis. The HER2 extracellular domain (ECD) may be<br />
cleaved and shed from the surface of breast cancer cells and serum<br />
HER2 ECD levels can be detected by enzyme-linked immunosorbent<br />
assay (ELISA). In this study, we explored the relationship between<br />
circulating HER2 ECD and tissue HER2 status, then we also examined<br />
its predictive value in a cohort of metastatic breast cancer patients.<br />
Methods: Two hundred and seven metastatic breast cancer patients<br />
from March 2009 to July 2011 were involved in this prospective<br />
study at Zhejiang <strong>Cancer</strong> Hospital. The patients were identified<br />
histopathologically as having breast cancer by pathologists and<br />
staged mainly based on the pathology, the clinical manifestation, and<br />
the imaging findings of CT and MRI according to the classification<br />
system of the International Union Against <strong>Cancer</strong>. Serum HER2 ECD<br />
levels were measured by ELISA. Tissue HER2 was determined by<br />
IHC and FISH in tumor samples, respectively.<br />
Results: The level of serum HER2 ECD was at least more than 15 ng/<br />
ml in 31.4% (65/207) metastatic breast cancer patients, 39.1%(43/110)<br />
in HER2-positive patients and 23.4%(22/94) in HER2-negative cases,<br />
respectively, P=0.017. We also found that high serum HER2 ECD<br />
levels (≥15 ng/ml) were significantly associated with elevated serum<br />
CEA (52.1% v 21.5%, OR 3.978, 95%CI 2.138-7.401, P=0.000),<br />
CA125 (48.5% v 23.5%, OR 3.064, 95%CI 1.650-5.691, P=0.000),<br />
CA153 (53.2% v 17.1%, OR 5.48, 95%CI 2.897-10.366, P=0.000),<br />
LDH (53.3% v 23.1%, OR 3.798, 95%CI 2.011-7.173, P=0.000) and<br />
AKP (51.2% v 26.5%, OR 2.911, 95%CI 1.442-5.879, P=0.002),<br />
respectively. For the effect of HER2 ECD on the site of relapse, still<br />
there were statistically significant correlation between increased<br />
serum HER2 ECD levels and liver involvement (42.7% v 24.0%,<br />
OR 2.358, 95%CI 1.294-4.297, P=0.005), brain metastasis (50.0%<br />
v 26.7%, OR 2.744, 95%CI 1.397-5.391, P=0.003) and visceral<br />
involved (37.9% v 14.8%, OR 3.511, 95%CI 1.548-7.961, P=0.002),<br />
respectively. While serum HER2 ECD levels were not related to age,<br />
BMI, tumor size, lymph node involvement and hormone receptors<br />
status, respectively (P>0.05).<br />
Conclusions: Monitoring the circulating levels of the HER2 ECD in<br />
patients with metastatic breast cancer provides a real-time assessment<br />
of tumor burden and indicates poor prognosis, and may provide<br />
important information for reassessment of HER2 in HER2-negative<br />
metastatic breast cancer.<br />
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P2-05-06<br />
Quantitative measurement of HER2 expression in breast cancers:<br />
comparison with “real world” HER2 testing in a multi-center<br />
Collaborative Biomarker Study (CBS) and correlation with<br />
clinicopathological features<br />
Yardley DA, Kaufman PA, Adams JW, Krekow L, Savin M, Lawler WE,<br />
Zrada S, Starr A, Einhorn H, Schwartzberg LS, Huang W, Weidler<br />
J, Lie Y, Paquet A, Haddad M, Anderson S, Brigino M, Bosserman<br />
L. Sarah Cannon Research Institute, Nashville, TN; Tennessee<br />
Oncology PLLC, Nashville, TN; Dartmouth Hitchcock Medical<br />
Center, Lebanon, NH; Arlington <strong>Cancer</strong> Center, Arlington, TX; Texas<br />
Oncology Bedford, Bedford, TX; Texas Oncology at Medical City<br />
Dallas 2, Dallas, TX; St. Jude Heritage Medical Group, Fullerton,<br />
CA; The Center for <strong>Cancer</strong> and Hematologic Disease, Cherry Hill,<br />
NJ; Monroe Medical Associates, Harvey, IL; Swedish American<br />
Regional <strong>Cancer</strong> Center, Rockford, IL; The West Clinic, Memphis,<br />
TN; Monogram Biosciences, Inc., So. <strong>San</strong> Francisco, CA; Center<br />
for Molecular Biology and Pathology, Laboratory Corporation<br />
of America, Inc., Research Triangle Park, NC; Wilshire Oncology<br />
Medical Group, Rancho Cucamonga, CA<br />
Background: Accurate determination of HER2 status is critical<br />
in determining appropriate therapy for breast cancer patients. The<br />
HERmark ® assay is a novel method to quantitatively measure HER2<br />
total protein expression (H2T) in breast cancer. In this study, we<br />
compared HERmark H2T with central laboratory HER2 retesting<br />
and local (site reported) HER2 testing of formalin-fixed, paraffinembedded<br />
(FFPE) breast cancer tissues. The quantitative total HER2<br />
measurements (H2T) by HERmark and results of local HER2 tests<br />
were correlated with tumor pathohistological characteristics and<br />
overall survival of breast cancer patients.<br />
Methods: 232 FFPE breast cancer tissues were provided by 11 CBS<br />
study sites for HER2 testing by the HERmark assay and central<br />
laboratory IHC re-testing performed in blinded fashion. Local HER2<br />
immunohistochemistry and/or fluorescence in situ hybridization<br />
(FISH) results and valid HERmark H2T and central HER2 IHC results<br />
were obtained in 192 cases for analysis.<br />
Results: H2T showed a significant correlation with central HER2 IHC<br />
staining intensity (P
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
trastuzumab may convert HER2-positive (HER+) primary breast<br />
tumors to HER2 negative (HER-) after neoadjuvant chemotherapy.<br />
We compared the HER2 status in breast cancer patients before and<br />
after neoadjuvant treatment by using dual-color in situ hybridization<br />
(DISH).<br />
Methods<br />
We retrospectively identified 46 patients from the <strong>Breast</strong> <strong>Cancer</strong><br />
database at Tokai University Hospital, in whom HER2-positive<br />
primary breast cancer was diagnosed between 2000 and 2010, and<br />
who were treated with neoadjuvant chemotherapy or endocrine<br />
therapy with or without trastuzumab. Surgical specimens from<br />
patients achieving less than pCR were assessed to determine if<br />
there was enough residual tissue to evaluate the post-treatment<br />
HER2 status by DISH. HER2 status was defined as positive if DISH<br />
demonstrated a gene copy ratio of HER2:CEP17 >2.0. Paraffin<br />
tissue sections (4-µm thick) were mounted on glass slides (New<br />
Sliane III, Catalog No. 5126-25; MUTO PURE CHEMICALS, CO.<br />
LTD., Tokyo, Japan) and stained using the newly developed, fully<br />
automated HER2 Dual ISH assay on a BenchMark@ XT slide stainer<br />
according to the recommended procedure (Ventana Medical Systems<br />
Inc., Tucson, AZ). Thereafter, the stained slides were rinsed with<br />
tap water containing neutral detergent and then rinsed again with<br />
distilled water. The slides were dried at room temperature for at least<br />
60 min and cover-slipped with cover grass for SGC (MUTO PURE<br />
CHEMICALS). HER2 Dual ISH and H&E images were obtained<br />
using an Olympus BX51 microscope.<br />
Results<br />
A pCR was achieved in 9 of the 46 patients (19.6%). Specimens from<br />
core needle biopsy were not sufficient to assess the pretreatment<br />
HER2 status in 3 patients. In 9 patients, the post-treatment HER2<br />
status could not be assessed because residual tumors were DCIS only<br />
in 4 patients and there were less than 20 invasive cells in 5 patients.<br />
Residual tumor was sufficient to assess the post-treatment HER2<br />
status in 25 patients. In pretreatment specimens, of the 25 patients<br />
identified as HER2 + by immunohistochemical analysis, 3 patients<br />
were identified as HER2- by DISH. No post-treatment specimens<br />
were found to be HER2- by DISH among the tumors identified as<br />
HER2+ by DISH at pretreatment. Among the 3 pretreatment tumors<br />
identified as HER2- by DISH, 1 tumor was found to be HER2+ by<br />
DISH at post-treatment, and 2 showed a stable HER2 status.<br />
Conclusion<br />
DISH revealed a stable HER2 status in pretreatment breast tumors<br />
and in residual tumors. However, we found a discrepancy in the<br />
HER2 status between the immunohistochemical analysis and DISH.<br />
P2-05-09<br />
Identification and validation of a miRNA signature associated<br />
with breast cancer progression<br />
Waters PS, Dwyer RM, Kerin MJ. National University of Ireland,<br />
Galway, Ireland<br />
Introduction: MiRNAs are aberrantly expressed in both the<br />
circulation and tissue of patients with breast tumours, however little<br />
is currently known about the relationship between circulating and<br />
tissue miRNAs. The aim of this study was to quantify circulating<br />
and tumour tissue miRNA expression in a murine model of breast<br />
cancer and identify novel circulating markers of disease progression.<br />
Materials and Methods: Athymic nude mice (n=20) received<br />
either a mammary fat pad (n=8, MFP), or subcutaneous (n=7, SC)<br />
injection of MDA-MB-231 cells. Controls received no tumour cells<br />
(n=5). Tumour volume was monitored weekly and blood sampling<br />
performed at weeks 1, 3 and 6 following tumour induction (total<br />
n=60). Animals were sacrificed at week 6 and tumour tissue (n=15),<br />
lungs (n=20) and enlarged lymph nodes (n=3) harvested. RNA were<br />
extracted from all samples (n=98) and relative expression of miRNAs<br />
previously associated with tumour progression were quantified using<br />
RQ-RCR. A microRNA array was also preformed comparing animals<br />
with early (weeks 1, n=5) versus late (week 6, n=5) disease and results<br />
were analysed using RQ-PCR in all blood samples (n=60). Reverse<br />
transcription for the relevant targets and endogenous controls was<br />
carried out and expression was quantified using RQ-PCR.<br />
Results: MiR-10b expression was significantly higher in MFP<br />
compared to SC tumours (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
lesions in bone, liver, lung and, to a lesser degree, lymph nodes. The<br />
50 mg dose resulted in approximately 75% decrease in liver uptake<br />
of 64 Cu and improved the visualization of hepatic metastasis. We have<br />
initiated the second phase of the study utilizing the pre-administration<br />
of 50 mg trastuzumab in women with HER2 1+ and 2 + disease. To<br />
date we have imaged one patient.<br />
Conclusion: 64 Cu-DOTA-trastuzumab PET imaging is feasible and<br />
image quality is improved with the pre-administration of 50 mg<br />
trastuzumab. Enrollment of women with IHC 1+ and 2+ disease<br />
continues. This work was supported by the Department of Defense<br />
grant # 1024511.<br />
P2-05-11<br />
Proteomic identification and in-silico verification of subtypespecific<br />
signatures in breast cancer.<br />
Pavlou MP, Dimitromanolakis A, Diamandis EP. University of<br />
Toronto, ON, Canada; Mount Sinai Hospital, Toronto, ON, Canada;<br />
University Health Network, Toronto, ON, Canada<br />
<strong>Breast</strong> cancer is a highly heterogeneous disease with different<br />
subtypes presenting distinct clinical characteristics. During the last<br />
decade has been shown that molecular classification of breast cancer<br />
holds the promise for the development of novel prognostic tools and<br />
the identification of novel treatment targets. However, proteins are the<br />
main mediators of biological processes and the molecular targets of<br />
the majority of drugs. Moreover, the proteome integrates the cellular<br />
genetic information and environmental influences. Hence coupling<br />
proteomic and transcriptomic studies may augment the development<br />
of targeted therapies and the identification of disease-relevant proteins<br />
networks.<br />
Here, we report an extensive mass spectrometry-based (MS)<br />
secretome analysis of eight breast cancer cell lines representing,<br />
the three main breast cancer subtypes (luminal, basal and HER2-<br />
neu amplified) in search of subtype-specific proteomic signatures.<br />
Following a bottom-up proteomic approach coupled to tandem mass<br />
spectrometry the conditioned media of 8 breast cancer cell lines were<br />
analyzed. More than 5,200 non-redundant proteins were identified in<br />
the conditioned media of the 8 cell lines with a false positive rate less<br />
than 1%. The mass spectrometry-based identification of 5 proteins<br />
was successfully verified by ELISA.<br />
For the generation of subtype-specific proteomic signatures, proteins<br />
common to all cell lines of the same subtype but not present in the<br />
other two subtypes were identified. Twenty-three, four and four<br />
proteins were found uniquely in basal, HER2-neu amplified and<br />
luminal breast cancer cells. Notably, ERBB2 was one of the proteins<br />
uniquely identified in the HER2-neu amplified subtype verifying the<br />
validity of our approach.<br />
Given that most of these proteins have no quantitative methods<br />
available at present, we opted to preliminarily examine the<br />
relationship of these candidates with breast cancer subtypes by using<br />
an in silico approach, based on transcriptomic data. We performed an<br />
in silico mRNA expression analysis using publicly available data from<br />
four independent experiments containing a total of 1039 patients with<br />
primary breast cancer. The expression profiles of 15 of 31 proteins<br />
investigated showed significant correlation with estrogen receptor<br />
expression and power to distinguish subtypes. The development<br />
of multiplex quantitative mass spectrometry-based assays for the<br />
quantification of the proteomic signatures in relevant biological<br />
specimens along with immunohistochemical studies for two of the<br />
31 candidates are currently ongoing.<br />
The significance of these subtype-specific proteins in breast cancer<br />
prognosis and disease progression warrants further investigation.<br />
P2-05-12<br />
Effects of de-escalated bisphosphonate therapy on bone turnover<br />
or metastasis markers and their correlation with risk of skeletal<br />
related events – A biomarker analysis in conjunction with the<br />
REFORM study.<br />
Addison CL, Zhao H, Mazzarello S, Mallick R, Amir E, Tannock<br />
I, Clemons M. Ottawa Hospital Research Institute, Ottawa, ON,<br />
Canada; Princess Margaret Hospital, Toronto, ON, Canada; The<br />
Ottawa Hospital <strong>Cancer</strong> Centre, Ottawa, ON, Canada<br />
Background: Despite variability in an individual’s risk of skeletal<br />
related events (SREs) from bone metastases (BM), all patients<br />
are treated using a similar dose and schedule (q3-4 wk) of IV<br />
bisphosphonate (BP). The REFORM trial (Amir et al., Am J Clin<br />
Oncol, in press) was a pilot randomised study evaluating the efficacy<br />
of de-escalated (q12 wk) versus standard (q3-4 wk) pamidronate<br />
in maintaining C-telopeptide (CTx) levels in the low risk range<br />
(
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
P2-05-13<br />
Correlation of conventional versus experimental biomarkers of<br />
bone turnover and metastasis behaviour with skeletal related<br />
events – A biomarker analysis in conjunction with the TRIUMPH<br />
study.<br />
Addison CL, Kuchuk I, Bouganim N, Zhao H, Mazzarello S,<br />
Vandermeer L, Mallick R, Goss GD, Clemons M. Ottawa Hospital<br />
Research Institute, Ottawa, ON, Canada; The Ottawa Hospital<br />
<strong>Cancer</strong> Centre, Ottawa, ON, Canada; McGill University Health<br />
Centre, Montreal, QC, Canada<br />
BACKGROUND: Despite considerable variability in patient (pt) risk<br />
of skeletal related events (SREs) from bone metastases (BM), all pts<br />
are treated using a one size fits all approach, namely the same dose and<br />
dosing schedule (q3-4 wk) of IV bisphosphonate (BP). Identification<br />
of novel markers of individual SRE risk are thus required to better<br />
tailor treatment. TRIUMPH is an ongoing clinical trial evaluating<br />
q12 wk IV BP therapy for 1 year, following >3 months of standard<br />
q3-4 wk BP, in women with low risk bone metastases [defined by<br />
the bone resorption marker C-telopeptide (CTx) levels 600 ng/ml or SRE) or of SRE alone using<br />
logistic regression analysis.<br />
RESULTS: Although baseline CTx and NTx were elevated in pts who<br />
went on to develop SREs, this did not reach statistical significance.<br />
Baseline activinA trended towards total number of prior SREs<br />
(p=0.07). Baseline TGF-β correlated with duration of BM (p=0.004).<br />
Change in activinA (baseline to week 6) was the only biomarker that<br />
trended to predict coming off study early (p=0.043). Results of other<br />
baseline biomarkers and changes in biomarkers from baseline to wk<br />
12 will also be presented.<br />
CONCLUSIONS: This study further questions the role of CTx and<br />
NTx for driving treatment decisions around de-intensification of BP<br />
therapy (Coleman et al. J Clin Oncol 2012, suppl; abstr 511), and<br />
highlights the need for novel markers of SRE risk. Baseline levels of<br />
activinA was associated with the incidence of SREs in patients with<br />
BM and changes in levels from baseline to 6 weeks correlated with<br />
coming off study early. These findings warrant future studies in breast<br />
cancer pts assessing activinA as a predictor of SRE risk associated<br />
with breast cancer bone metastases.<br />
This study was supported by grants from the Ontario Institute for<br />
<strong>Cancer</strong> Research with funding from the Government of Ontario, and<br />
from the Ontario Chapter of the Canadian <strong>Breast</strong> <strong>Cancer</strong> Foundation.<br />
P2-05-14<br />
Clinical significance of Lysil oxidase-like 2 (LOXL 2) in breast<br />
cancer<br />
Ahn SG, Lee HM, Hwang SH, Lee SA, Jeong J, Lee H-E. Gangnam<br />
Severance Hospital, Yonsei University Medical College, Seoul,<br />
Republic of Korea<br />
Introduction<br />
Several preclinical studies provided relevant evidences that lysine<br />
oxidase-like 2 (LOXL2) is associated with invasiveness and<br />
metastasis in breast cancer. To investigate the clinical significance<br />
of LOXL2, we performed survival analysis with LOXL-2 in breast<br />
cancer patients.<br />
Method<br />
A cohort treated at Gangnam Severance hospital, Seoul, Korea<br />
between January 1996 and December 2004 was studied. The<br />
immunohistochemical analyses with LOXL-2 antibody were<br />
performed in the 309 patients. The patients was stratified into two<br />
groups based on the expression level of LOXL-2. Kaplan-Meier and<br />
Cox’s methods were used to define prognostic factors associated with<br />
breast cancer survival.<br />
Results<br />
LOXL-2 positive group was 50 patients (16.2%) and 259 patients<br />
(83.8%) are LOXL-2 negative group. The proportion of estrogen<br />
receptor-negative patients was significantly higher in LOXL-2<br />
positive group (54.0 vs. 37.0 %, P =0.040). The Kaplan-Meier overall<br />
survival estimate at 5 year for the breast cancer patients with negative<br />
LOXL-2 was higher than that for the patients with positive LOXL-2<br />
(88.0 vs. 71.8 %, P = 0.008). In the multivariate analysis for overall<br />
survival, lymph node metastasis (Hazard Ratio (HR) 0.32, 95%<br />
confidence interval (CI) 0.17-0.61) and positive LOXL-2 (HR 0.53,<br />
95% CI 0.29-0.97) were significantly associated. In the multivariate<br />
analysis for distant metastasis-free survival, age younger than 35 years<br />
(HR 0.52, 95% CI 0.30-0.91), lymph node metastasis (HR 0.29, 95%<br />
CI 0.16-0.54), high histologic grade (HR 0.54, 95% CI 0.32-0.89) and<br />
positive LOXL-2 (HR 0.55, 95% CI 0.31-0.97) were demonstrated<br />
as significant prognostic factors.<br />
Conclusion<br />
In breast cancer patients, overexpression of LOXL-2 is a poor<br />
prognostic factor for overall survival and distant metastasis-free<br />
survival.<br />
P2-05-15<br />
Assessment of Notch Signaling Pathway Components as<br />
Biomarkers for Triple Negative <strong>Breast</strong> <strong>Cancer</strong>: Comparison of<br />
Triple Negative <strong>Breast</strong> <strong>Cancer</strong> Cell Lines and Human <strong>Breast</strong><br />
<strong>Cancer</strong> Samples.<br />
Zlobin A, Olsauskas-Kuprys R, Hodge S, O’Toole M, Ersahin C,<br />
Osipo C. Loyola University Chicago, Cardinal Bernardin <strong>Cancer</strong><br />
Center, Maywood, IL<br />
Background: Treatment options for patients presenting with TNBC<br />
are limited, primarily because there is no approved targeted therapy<br />
available. Canonical breast cancer targets such as estrogen receptor<br />
and HER2/neu proteins are absent in TNBC. Furthermore, there is an<br />
urgent need to uncover biomarkers in this disease in light of its costly<br />
treatment as compared to non-TNBC treatment and, more importantly,<br />
its poor prognosis as evidenced by aggressive tumor metastasis and<br />
high patient mortality. While Notch-1 target gene expression has been<br />
reported to be linked to various types of malignancies, we propose that<br />
since Notch signaling pathway is involved in cancer cell proliferation<br />
and survival it could be a likely oncogenic driver and possible target<br />
in certain TNBC patients.<br />
www.aacrjournals.org 231s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Methods: Human TNBC cell lines BT-549, MDA-MB-231, and<br />
MDA-MB-468 were used to measure endogenous relative mRNA<br />
transcript levels of Notch genes and gene targets by means of real time<br />
PCR. In addition, the RNA from formalin-fixed, paraffin-embedded<br />
specimen from women-diagnosed with TNBC who had undergone<br />
breast surgery was also analyzed for comparable gene expression for<br />
similar targets following Laser capture micro-dissection.<br />
Results: The in vitro results show that mRNA transcripts of Notch-4,<br />
Deltex-1, Hes-1 and -Hes5, as well as upstream Notch regulator<br />
PEA3 targets IL-8 and MMP-9 were increased in MDA-MB-468<br />
and BT-549 cells as compared to MDA-MB-231 cells (n=3-5). In the<br />
clinical sample specimens, Notch-1, Jagged-1, and Hes-5 genes were<br />
up-regulated, while the Notch-4 gene was down-regulated in TNBC<br />
patients as compared to normal control specimens from reduction<br />
mammoplasty (n=4).<br />
Conclusions: Our data present the heterogeneity of TNBC disease.<br />
They also indicate that the Notch signaling pathway is up-regulated<br />
in certain TNBC cell lines and human TNBC breast cancer tissue.<br />
Lastly, these results suggest that some components of Notch signaling<br />
may be viable biomarkers to better predict Notch activity for future<br />
therapeutic interventions using Notch inhibitors.<br />
P2-05-16<br />
Expression of β-III tubulin, foxo 3 protein and deoxythymidine<br />
kinase in breast cancer patients receiving neoadjuvant<br />
chemotherapy<br />
Chow LWC, Loo WTY, Yip AYS, Ong EYY, Ng W-K. UNIMED Medical<br />
Institute, Hong Kong; Organisation for Oncology and Translational<br />
Research, Hong Kong; Central Hospital, Hong Kong<br />
Background:<br />
β-III tubulin is a major protein involved in cell division during<br />
metaphase by forming microtubules. Chemotherapeutic drugs target<br />
the dynamics of cytoskeleton, blocks mitosis and cell proliferation to<br />
induce apoptosis. FoxO1, FoxO3, FoxO4, and FoxO6 transcriptional<br />
factors suppress different types of human tumors. The transcriptional<br />
up-regulation of FoxO3a might be induced by chemo-drugs treatment<br />
and enhance apoptosis. Deoxythymidine kinase (DTYMK) is a<br />
key enzyme involved in DNA replication. Its expression level was<br />
identified as an independent prognostic marker and indicator of<br />
tumor burden. This study was to investigate the expression of β-III<br />
Tubulin, FOXO3 and DTYMK in breast cancer patients receiving<br />
neoadjuvant chemotherapy.<br />
Method:<br />
The expression of β-III tubulin, FOXO3 and DTYMK was evaluated<br />
by immunohistochemical assay (IHC) on 103 pre-treatment and 81<br />
post-treatment tumor samples from patients with locally advanced<br />
breast cancer. Samples were taken before and after 4 cycles of<br />
anthracycline-based neoadjuvant chemotherapy (5-fluorouracil,<br />
epirubicin, and cyclophosphamide). The expression of β-III tubulin,<br />
FOXO3 and DTYMK in tumor samples was measured in terms of<br />
percentage of cancer cells. T-test was applied to analyze the statistical<br />
significance of protein expression.<br />
Results:<br />
Median age of patients was 46 (range: 22-66) and the mean tumor<br />
size was 4.47±1.51 cm. Among 103 patients, 95 (92.2%), 5 (4.9%)<br />
and 2 (1.9%) patients had infiltrating ductal, lobular and mucinous<br />
carcinoma respectively, whereas 1 (1%) patient had unknown type<br />
of invasive tumor. At diagnosis, breast tumors were found to express<br />
β-III tubulin and DTYMK with a prevalence of 28.9% and 50%<br />
while the expression decreased to 11.1% and 25% after neoadjuvant<br />
treatment respectively. The expression of FOXO3 was 25% before<br />
treatment and increased to 75% post-treatment (p < 0.05). The change<br />
in expression before and after treatment was statistically significant.<br />
Conclusions:<br />
Comparison of the expression of β-III Tubulin, FOXO3 and DTYMK<br />
in breast cancer patients receiving neoadjuvant chemotherapy may<br />
serve as clinical assessing markers to predict the treatment outcome<br />
and prognosis.<br />
P2-05-17<br />
Correlation between cyclin D1, estrogen and progesterone<br />
receptors in invasive breast cancer after short-term treatment<br />
with tamoxifen or anastrozole<br />
Millen EC, Mattar A, Logullo AF, Nonogaki S, Soares FA, Gebrim<br />
LH. Federal University of Sao Paulo, Sao Paulo, SP, Brazil; Perola<br />
Byington Hospital, Sao Paulo, SP, Brazil; Federal University of Sao<br />
Paulo, Sao Paulo, SP; Arnaldo Vieira de Carvalho, Sao Paulo, SP,<br />
Brazil<br />
INTRODUCTION: Hormone therapy is associated with reduced<br />
breast cancer mortality. The use of biomarkers that are predictive of<br />
early cellular responses has been explored as a predictor of hormone<br />
resistance. Estrogen and progesterone receptor positivity and cyclin<br />
D1 have been associated with resistance to treatment with tamoxifen.<br />
OBJECTIVES: The aim of this study was to investigate the variations<br />
in the levels of cyclin D1 and the estrogen and progesterone receptors<br />
(ER and PR, respectively) in postmenopausal patients with ER- or<br />
PR-positive breast cancer after short-term treatment (26 days) with<br />
tamoxifen, anastrozole or a placebo.<br />
METHODS: This was a prospective, randomized double-blind study<br />
conducted in 71 patients with infiltrating ductal carcinoma (stages<br />
II and III) receiving care at either Pérola Byington Hospital or São<br />
Paulo Hospital (São Paulo, Brazil). The patients were divided into<br />
three groups based on their treatment during the preoperative period<br />
(26 days): P (placebo, N = 26), T (tamoxifen, 20 mg/day, N = 22)<br />
and A (anastrozole, 1 mg/day, N = 23). The biopsies were performed<br />
at diagnosis and after mastectomy (26th day), and the tumors were<br />
isolated by tissue microarray. Immunohistochemistry was performed<br />
using anti-cyclin D1 (Novocastra DCS-6), anti-ER (Dako-M7047)<br />
and anti-PR (Dako-M3569) antibodies. The semiquantitative analyses<br />
were performed using Allred criteria, and the statistical analyses were<br />
performed with the ANOVA parametric test (p ≤ 0.05).<br />
RESULTS: A reduction in the mean PR level from 4.22 (pre-treatment)<br />
to 1.94 (post-treatment) was observed only in patients treated with<br />
anastrozole (p = 0.01). A positive linear correlation between cyclin<br />
D1 and PR levels was observed in group A (p = 0.0001), whereas<br />
group T exhibited a negative correlation (p = 0.0001). No correlation<br />
was observed in group P (p = 0.35)*.<br />
CONCLUSION: PR and cyclin D1 are likely predictive of an early<br />
response to aromatase inhibitors in breast cancer.<br />
P2-05-18<br />
Withdrawn by Author<br />
P2-05-19<br />
Pathway-based analysis of breast cancer<br />
Song D, Cui M, Fan Z, Yang Y, Xue L, Zhang DY, Ye F. The First<br />
Hospital of Jilin University, Changchun, Jilin, China; The Mount<br />
Sinai Medical Center, New York, NY; Nanfang Hospital Southern<br />
Medical University, Guangzhou, China<br />
Objective: Although HER2 and ER pathways are predominant<br />
pathways altered in breast cancer, it is now well accepted that many<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
232s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
other signaling pathways are also involved in the pathogenesis<br />
of breast cancer, especially in triple negative breast cancer. The<br />
understanding of these additional pathways may assist in identifying<br />
new therapeutic approaches for breast cancer.<br />
Methods: 13 invasive ductal carcinoma tissues and 5 benign breast<br />
tissues were analyzed for the mRNA expression level of 1243<br />
cancer pathway-related genes using SmartChip (WaferGen, CA),<br />
a real-time PCR-base method. In addition, the levels of 154 cancer<br />
pathway-related proteins and phosphoproteins were measured using<br />
our innovative Protein Pathway Array.<br />
Results: Out of 1,243 mRNAs, 68.7% were detected in breast cancer<br />
and 73 mRNAs were statistically significant between benign and<br />
cancer tissues. Of these mRNAs, 105 only expressed in breast cancer<br />
tissues and 33 mRNAs only expressed in normal breast tissues. Out<br />
of 154 proteins and phosphoproteins, 39% were detected in cancer<br />
tissues and 50 proteins were significantly differentiated between tumor<br />
and normal tissues. Interestingly, only 3 genes (CDK6, Vimentin and<br />
SLUG) showed decrease of both protein and mRNA. Six proteins<br />
(BCL6, CCNE1, PCNA, PDK1, SRC and XIAP) showed differentially<br />
expressed between tumor and normal tissues but no differences were<br />
observed at mRNA levels. Analyses of mRNA and protein data using<br />
Ingenuity Pathway Analysis showed more 15 pathways were altered<br />
in breast cancers and 6 of them shared between mRNAs and proteins,<br />
including p53, IL17, HGF, NGF, PTEN and PI3K/AKT.<br />
Conclusion: There is a broad dysregulation of various pathways in<br />
breast cancer both at protein levels and mRNA levels. It is important<br />
to note that mRNA expression does not correlate with protein level,<br />
suggesting that different regulation mechanisms between proteins<br />
and mRNAs.<br />
P2-05-20<br />
Validation and comparison of CS-IHC4 score with a nomogram<br />
based on Ki67 index, Adjuvant! Online, and St. Gallen risk<br />
stratification to predict recurrence in early Hormone Receptor<br />
(HR)-positive breast cancers<br />
Park YH, Im S-A, Cho EY, Ahn JH, Woo SY, Kim S, Keam B, Lee JE,<br />
Han W, Nam SJ, Park IA, Noh D-Y, Yang JH, Ahn JS, Im Y-H. Samsung<br />
Medical Center; Seoul National University College of Medicine<br />
Background: Recently, the information in the IHC score was reported<br />
to be similar to that in the 21-gene Genomic Health recurrence score<br />
(GHI-RS). The aim of this study is to develop a nomogram based<br />
on Ki67 index to predict recurrence and to validate the nomogram<br />
by comparison with CS-IHC4 as well as Adjuvant! Online and St.<br />
Galen risk stratification. In addition, we validated our nomogram<br />
with external cohort.<br />
Methods: We retrospectively analyzed the clinicopathologic<br />
characteristics and outcomes of 1,070 postoperative HR-positive<br />
breast cancer patients between 2004 and 2007 at the Samsung<br />
Medical Center to determine recurrence-free survival (RFS). We<br />
constructed nomogram using Cox proportional hazard model and<br />
validated externally in a cohort of 1,028 at Seoul National University<br />
Hospital. A prognostic model that used classical variables, Adjuvant!<br />
Online, St. Gallen risk stratification, and the four IHC markers (IHC4<br />
score) were created and assessed in our cohort by LR-χ 2 test using<br />
the bootstrapping method.<br />
Results: Nomogram showed an area under the receiver operating<br />
characteristic curve (AUC) of 0.70 (95% CI, 0.62-0.75) in the training<br />
set. The validation set showed a good discrimination with an AUC<br />
of 0.65 (95% CI, 0.58-0.72). In LR-χ 2 test, the nomogram score was<br />
found to be more informative than the IHC4 with CS (LR-χ 2 4.0539<br />
[df1], 95% CI; 0.1038-8.004 for CS-IHC4 + nomogram score vs.<br />
CS-IHC4).<br />
Average change in LR-χ² value and 95% Bootstrap CIs based on 1000 re-samplings for assessing<br />
the amount the amount of information added by the nomogram score or Adjuvant! Online or St.<br />
Galen risk stratification to the CS-IHC4 to a model containing the nomogram<br />
Model df LR-χ² 95% CI<br />
CS-IHC4 + nomogram score vs CS-IHC4 1 4.0539 0.1038 8.004<br />
CS-IHC4 + Adjuvant! Online vs CS-IHC4 1 0.2732 -4.1697 4.7162<br />
CS-IHC4 + St.Gallen vs Cs-IHC4 2 1.7558 -1.7859 5.2975<br />
RFS: Recurrence free survival, 95% CI: 95% confidence interval<br />
Prognostic significance was more prominent in N1 diseases than in the<br />
others (LR-χ 2 4.199, 95% CI; 1.496-6.902 for CS-IHC4 + nomogram<br />
score vs. CS-IHC4).<br />
Average change in LR-χ² value and 95% Bootstrap CIs based on 1000 re-samplings for assessing<br />
the amount the amount of information added by the nomogram score or Adjuvant! Online to the<br />
CS-IHC4 to a model containing the nomogram according to the nodal status (N0-3)<br />
CS-IHC4 + CS-IHC4 +<br />
Model<br />
Nomogram vs CS- Adjuvant! Online<br />
IHC4<br />
vs CS-IHC4<br />
CS-IHC4 + St.<br />
Gallen vs CS-IHC4<br />
N0 LR-χ² 0.442 0.272 0.566<br />
95% CI 0.109-0.776 -0.858-1.402 0.104-1.028<br />
N1 LR-χ² 4.199 1.212<br />
95% CI 1.496-6.902 -0.538-2.962<br />
N2 LR-χ² 0.659 1.573<br />
95% CI -0.131-1.448 1.435-1.710<br />
N3 LR-χ² 0.003 0.197<br />
95% CI -0.975-0.982 -0.439-0.832<br />
RFS: Recurrence free survival, 95% CI: 95% confidence interval<br />
However, Adjuvant! Online and St. Galen risk stratification did not<br />
show any definitive additional prognostic value.<br />
Conclusions: We developed and validated a nomogram based on Ki67<br />
index in external patients’ cohort. It was compared with CS-IHC4 in<br />
our patients’ cohort in early HR-positive breast cancers. This study<br />
implicates the amount of prognostic information contained in the<br />
nomogram is superior to that in the CS-IHC4 score.<br />
P2-05-21<br />
Molecular subtypes of invasive breast cancers show differential<br />
expression of the proliferation marker Aurora Kinase A (AURKA)<br />
Kovatich AJ, Luo C, Chen Y, Hooke JA, Kvecher L, Rui H, Shriver<br />
CD, Mural RJ, Hu H. Windber Research Institute, Windber, PA;<br />
Walter Reed National Military Medical Center, Bethesda, MD; MDR,<br />
Global Systems LLC, Windber, PA; Thomas Jefferson University,<br />
Philadelphia, PA<br />
Background: Invasive breast cancer (IBC) has been classified into<br />
four major subtypes based on gene expression profiling. The luminal<br />
A subtype (LA) has the best prognosis, when compared to luminal<br />
B (LB), HER2+, and basal-like (Basal). Ki67 by gene expression or<br />
immunohistochemistry (IHC) is commonly used as a proliferation<br />
index. The function of Ki67 in proliferation remains unknown.<br />
AURKA (STK15) is known to play an important role in mitosis, and<br />
is a component of the 21-gene recurrence score of the Oncotype Dx.<br />
With multiple platforms of molecular data available from hundreds of<br />
IBC tissues in The <strong>Cancer</strong> Genome Atlas project (TCGA), we sought<br />
to study the association of AURKA with different IBC subtypes and<br />
explore its use as a proliferation marker in IBCs.<br />
Methods: Gene expression (Agilent, log2 transformed), relative<br />
DNA copy number (CN, Affymetrix SNP 6.0), and exome sequence<br />
mutation (Illumina) data for 459 IBC cases were downloaded from the<br />
TCGA data portal. PAM50 classification results of all samples were<br />
obtained from the TCGA breast cancer AWG group and included 203<br />
LA, 113 LB, 51 HER2+, 84 Basal-like, and 8 Normal-like which were<br />
not used in this study due to the low numbers. Kruskal-Wallis tests<br />
were used to evaluate the differences among four subtypes on AURKA<br />
expression and CN, followed by Wilcoxon Mann-Whitney test with<br />
Bonferroni adjustment for pairwise analyses. Pearson’s Correlation<br />
Coefficient was used for correlation analyses. All statistical analyses<br />
were performed using SAS and R, and two-sided, p values
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
mRNA levels were significantly lower in LA (mean±SD, -2.61±0.63)<br />
compared to LB (-1.45±0.78), HER2+ (-1.38±0.61), and Basal<br />
(-1.26±0.62) subtypes (p values all < 0.0001). No significant<br />
difference was detected between other subtype pairs. In CN analysis,<br />
Basal (0.09±0.22) was lower than HER2+ (0.32±0.308, p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
To assess significance of the CLS, we found three primary/metastatic<br />
clonal pairs in the TCGA to serve as positive controls. To serve as<br />
negative controls, from 357 ER+ and 46 TN primary TCGA tumors,<br />
we formed a total of 16,422 independent ER+/TN pairs. For the 3<br />
clonal TCGA pairs, the CLS values were 39.3%, 58.5% and 60.0%.<br />
Most of the independent TCGA pairs had a CLS of zero (98.5%),<br />
with a maximum CLS of 2.8%. As the CLS for Case 1 lies above<br />
maximum observed CLS among 16,422 independent tumor pairs, we<br />
reject the hypothesis that this tumor pair is independent, at p80% of SNVs, consistent with clonal evolution of metastasis. The<br />
two tumors from Case 2 have few shared SNVs, consistent with<br />
independent origin. CNA results were consistent. This is the first<br />
clonality analysis reported from deep sequencing of phenotypically<br />
discordant synchronous bilateral breast cancers, and demonstrates that<br />
next-generation sequencing can distinguish clonal from independent<br />
tumor pairs with high confidence.<br />
Funding: The <strong>Breast</strong> <strong>Cancer</strong> Research Foundation<br />
P2-06-02<br />
Genomic evolution from primary breast cancers to distant<br />
metastases<br />
Hoefnagel LDC, Moelans CB, van der Groep P, van der Wall E, van<br />
Diest PJ. University Medical Center Utrecht, Netherlands<br />
Purpose: Genomic evolution is an accepted concept during cancer<br />
development and progression. However, little is known about the<br />
changes that occur during the metastatic process despite the fact<br />
that breast cancer metastases are the leading cause of death in breast<br />
cancer patients. The purpose of this study was therefore to investigate<br />
whether distant breast cancer metastases show progression in copy<br />
number changes of onco- and tumor suppressor genes compared to<br />
their primary tumor.<br />
Material and methods: Multiplex ligation-dependent probe<br />
amplification (MLPA) was used to compare copy number of 21<br />
established oncogenes and tumor suppressor genes between primary<br />
breast cancer samples and corresponding distant metastases in 55<br />
patients. Genes studied were ESR1, EGFR, FGFR1, ADAM 9, IKBKB,<br />
PRDM14, MTDH, MYC, CCND1, EMSY, CDH1, TRAF4, CPD,<br />
MED1, HER2, CDC6, TOP2A, MAPT, BIRC5, CCNE1 and AURKA.<br />
Results: Overall, there was no significant difference in mean copy<br />
number between primary tumors (1.26 +/- 0.6) and metastases (1.27<br />
+/- 0.64) (p=0.826), but on the individual gene level, mean copy<br />
number for PRDM14 (p=0,023), MED1 (p=0.001) and CCNE1<br />
(p=0.039) were significantly higher while TRAF4 (p=0.038) copy<br />
number was significantly lower in the metastases. Using dichotomized<br />
MLPA data, MTDH amplifications were significantly more frequent<br />
in the primary cancers compared to the metastases (27.3% vs.14.6%,<br />
p=0.039), while significantly more CDH1 losses were found in the<br />
metastases compared to the primary tumor (23.6% vs. 9.1%, p=0.039).<br />
Conclusion<br />
Distant breast cancer metastases show genomic evolution from<br />
the primary cancer as reflected by copy number changes in several<br />
established onco- and tumor suppressor genes.<br />
P2-06-03<br />
Specific Transcriptional Response of Four Blockers of Estrogen<br />
Receptors on Estrogen-Modulated Genes in ZR-75-1 <strong>Breast</strong><br />
<strong>Cancer</strong> Xenografts<br />
Calvo E, Luu-The V, Martel C, Labrie F. Laval University Hospital<br />
Research Center (CRCHUL), Quebec City, QC, Canada; Laval<br />
University, Quebec City, QC, Canada; EndoCeutics Inc., Quebec<br />
City, QC, Canada<br />
Introduction: Acolbifene (ACOL) is a novel compound completely<br />
free of estrogen-like activity in both the human and rat mammary<br />
gland and uterus. In previous studies, it was observed that ACOL<br />
could have a cytotoxic or tumoricidal rather only tumorostatic activity,<br />
with a lack of development of tumor resistance. The objective of the<br />
present study was to obtain information on the molecular basis of<br />
the tumoricidal properties of acolbifene, as well as on the identity<br />
of the genes potentially implicated in the resistance to tamoxifen<br />
(TAM). The specificity of action of ACOL was compared to the<br />
pure antiestrogen fulvestrant (FUL) as well as to tamoxifen (TAM)<br />
and raloxifene (RAL). Methods: The gene expression profile of the<br />
ZR-75-1 breast cancer xenografts was studied following treatment<br />
with ACOL, RAL, TAM and FUL. Ovariectomized female nude<br />
mice (10/group) bearing human ZR-75-1 breast cancer xenografts<br />
were supplemented with estrone (E 1 ) (subcutaneous silastic implants)<br />
and were injected daily with the vehicle alone or 50 µg of ACOL,<br />
RAL, TAM or FUL for 6 months. Mice were killed 24h after the last<br />
injection and ZR-75-1 tumors were collected and processed for RNA<br />
extraction and microarray analyses (Affymetrix GeneChip U133 Plus<br />
2.0). Results: Long-term exposure of ZR-75-1 xenografts to E 1 causes<br />
a massive modulation of E 1 -responsive genes. When the antiestrogens<br />
were administered simultaneously with E 1 , some compound-specific<br />
prevention of the effect of E 1 was observed. Globally, the efficacy of<br />
the compounds was ACOL>FUL or RAL>TAM. ACOL significantly<br />
prevented the effect of E 1 on 195 responsive genes. Among these,<br />
the most enriched gene ontological group in Molecular Function was<br />
Receptor Activity, including ER, insulin, retinoid and thrombospondin<br />
receptor activity. One of the transcriptional repressors of the<br />
estrogen signaling pathway, the NKX31, was down-regulated by<br />
E 1 and completely blocked by ACOL (fold-change -1.64 and 2.54,<br />
respectively). The most enriched biological processes were associated<br />
with mammary gland development, positive regulation of glucose<br />
metabolic processes and blood vessel morphogenesis. Between the<br />
genes implicated in cell death/apoptosis of breast cancer cells, the<br />
changes of expression of 57, 51, 48 and 31 genes were significantly<br />
neutralized by ACOL, RAL, FUL and TAM, respectively. Sixteen<br />
genes implicated in tumor resistance to TAM were significantly<br />
blocked by ACOL, including DEGS1, a gene implicated in the<br />
inhibition of EGF receptor biosynthesis. The other 15 genes in the<br />
group were up-regulated by E 1 , changes which were significantly<br />
blocked by ACOL. Conclusion: The present data offer a possible<br />
explanation for the potent tumoricidal action of acolbifene in<br />
human breast cancer xenografts, thus offering a new paradigm in the<br />
hormonal therapy of breast cancer.<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P2-06-04<br />
Impact of genomic testing on chemotherapy utilization<br />
Riley L, Nakijima H, Balinger K, Anderson D. St. Luke’s University<br />
Health Network, Bethlehem, PA<br />
Genomic testing for breast cancer has become a common practice. The<br />
two main tests at our institution are Oncotype DX ® and MammaPrint<br />
®<br />
. Each test has unique features and criteria. We sought to compare<br />
the practice pattern between these tests and compare them to patients<br />
who did not undergo any genomic testing.<br />
Methods: This is a retrospective review of all breast cancer patients<br />
between May 2008 and August 2011. Data was primarily thorough<br />
our tumor registry database. In some cases individual charts were<br />
also reviewed. Results: We analyzed 1093 breast cancers in 1064<br />
patients. The average age was 62. The stage at diagnosis was 19%<br />
DCIS, 41% stage I, 24% stage II, 11% stage III and 5% stage IV.<br />
Of the 1093 cancers, 70 (6%) had an Oncotype test performed, 180<br />
(16%) had a MammaPrint test done, 4 (0.4%) had both test, and 839<br />
(77%) had no genomic test performed. Patients with an Oncotype test<br />
were more likely to be stage I than those with a MammaPrint (66% vs<br />
48%). Additionally, patients who had a MammaPrint test more often<br />
received chemotherapy when compared to either the Oncotype test<br />
or no genomic testing.<br />
Percent of Patients that Received Chemotherapy<br />
Stage Oncotype Mammaprint Neither<br />
I 4% (2/46) 31% (27/86) 17% (51/306)<br />
II 30% (6/20) 66% (44/66) 55% (93/169)<br />
III 100% (4/4) 79% (15/19) 79% (78/99)<br />
Total 17% (12/70) 49% (89/180) 30% 248/839)<br />
Chemotherapy Utilization<br />
Low Intermediate High<br />
Oncotype 8% (3/38) 29% (6/21) 100% (2/2)<br />
Mammaprint 22% (18/82) NA 74% (64/86)<br />
With a mean follow-up of 1.5 years, there have been 28 recurrences (0<br />
in the Oncotype group, 5 in the MammaPrint group, and 23 in the no<br />
genomic testing group). All five of the MammaPrint recurrences were<br />
high risk and received adjuvant chemotherapy. Of the 23 recurrences<br />
in the no genomic testing group, eight patients were node negative<br />
and could have been considered appropriate for genomic testing, 6<br />
of these eight did not have adjuvant chemotherapy.<br />
Conclusions: There are distinct practice pattern differences between<br />
Oncotype DX ® and MammaPrint ® utilization. MammaPrint<br />
testing was ordered more often in higher staged patients and was<br />
associated with an increased use of chemotherapy. This may relate<br />
to MammaPrint’s previous requirement for fresh tissue that typically<br />
occurs before the final nodal status is known. This difference should<br />
diminish with the recent availability of MammaPrint on FFPE<br />
tissue. All patients who underwent genomic testing and developed a<br />
recurrence had been treated with adjuvant chemotherapy. In contrast,<br />
patients who did not have a genomic test and experienced a recurrence<br />
may have benefited from genomic testing.<br />
P2-06-05<br />
Single-cell RNA sequencing of paclitaxol-treated breast cancer<br />
cell lines to find individual cell response<br />
Vaske CJ, Lee W, Benz SC, <strong>San</strong>born JZ, Emerson BM, Pourmand N,<br />
Lopez Diaz F. Five3 Genomics, LLC, <strong>San</strong>ta Cruz, CA; University of<br />
California, <strong>San</strong>ta Cruz, CA; Salk Institute, La Jolla, CA<br />
<strong>Cancer</strong> treatments act on a population of cells, each of which<br />
may experience different individual responses to treatment. Such<br />
differential response will result in resistance to treatment even if a<br />
majority of cancerous cells are eliminated. To examine differential<br />
cell response, we simultaneously profiled the gene expression and<br />
mutation spectrum of individual cells from the MDAMB231 cell<br />
line using next generation sequencing of isolated RNA. A total of<br />
23 transcriptomes were characterized from paclitaxel-treated and<br />
paclitaxel-surviving cells. We found significant different changes in<br />
mutation rates between paclitaxel treated cells, with a dose-dependent<br />
increase in single nucleotide changes in RNA in paclitaxel-treated<br />
cells. Cells undergoing exposure to paclitaxel also showed higher<br />
pathway activity in SRC, as well as an integrin switch from ITGB1<br />
to ITGB3. In contrast, cells that survived a high dose of paclitaxel<br />
showed an insignificant number of single nucleotide changes,<br />
suggesting that these cells either evaded initial paclitaxel exposure or<br />
were better able to repair the effects of paclitaxel exposure. Despite the<br />
RNA sequence similarity between surviving and untreated cells, there<br />
were changes in gene expression and pathway activities including<br />
higher PI3K activity. Paclitaxel-surviving cells also showed activation<br />
of pathways associated with higher proliferation.<br />
P2-06-06<br />
Integrating multiple molecular profiles with pathways to learn<br />
sub-type specific interactions with PARADIGM<br />
Sedgewick AJ, Vaske CJ, Benz SC. Five3 Genomics, <strong>San</strong>ta Cruz, CA;<br />
University of Pittsburgh, PA<br />
High-dimensional omics profiling provides a detailed molecular view<br />
of individual breast cancers. We extended the Paradigm algorithm,<br />
a pathway analysis method for combining multiple omics data types<br />
with curated interactions on 7132 genes, to learn the strength and<br />
direction of curated interactions. Using only a single dataset, the<br />
568 samples from the TCGA breast cancer cohort, we found strong<br />
high-throughput support for the majority of curated interactions. Gene<br />
set enrichment found that targets of the strongest interactions were<br />
significantly enriched for apoptosis and cell morphogenesis, and that<br />
strong regulators were significantly associated with phosphorylation.<br />
Within the TCGA breast cancer cohort the interactions some of the<br />
strongest support centered around ER alpha, IL23, GREB1, AKT1,<br />
and p53. We also assessed different strength between breast cancer<br />
subtypes, and found interactions associated with the MYC pathway<br />
and the ER alpha network to be among the most differential between<br />
basal and luminal A subtypes. Finally, we extended the method to<br />
assess the contextual dependence of interactions and found significant<br />
correlation between FOXM1 and JUN in regulation of CDK1.<br />
P2-06-07<br />
Exome sequencing identifies somatic mutations in basal-like<br />
breast cancer before and after neoadjuvant chemotherapy<br />
Jiang Y-Z, Yu K-D, Shao Z-M. Shanghai <strong>Cancer</strong> Center, Shanghai,<br />
Shanghai, China<br />
Purpose<br />
Among the five breast cancer subtypes, basal-like breast cancers<br />
(BLBCs) have drawn much attention, because they are associated<br />
with poor clinicopathological features, lack of effective treatment<br />
targets, and have poor prognosis. We designed the experiment to test<br />
the hypothesis that significant mutational evolution of BLBCs might<br />
occur during chemotherapy.<br />
Methods<br />
We performed exome sequencing (100-fold coverage) to examine the<br />
exomes of 11 paired BLBC samples (pretreatment tumor biopsies and<br />
posttreatment tumors). The molecular subtype of BLBC was proven<br />
by gene-expression profile as well as by immunohistochemistry assay.<br />
Firstly, we sequenced the tumor genomic DNA obtained before and<br />
after neoadjuvant chemotherapy and their matched normal breast<br />
tissues. After analyzing and comparing potential somatic single<br />
nucleotide variations (SNVs) and insertions & deletions (indels),<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
236s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
we focused on the functional mutations in certain genes or pathways.<br />
Furthermore, after validation of the mutations by <strong>San</strong>ger sequencing,<br />
we investigated their biological functions (e.g. drug-resistance, cell<br />
proliferation, etc.).<br />
Results<br />
Compared with pretreatment biopsies, analysis of whole-exome<br />
sequence data identified and validated TEKT4 (tektin 4) — a<br />
constitutive protein of microtubules in cilia, flagella, basal bodies<br />
and centrioles — as a significantly mutated gene in posttreatment<br />
tumors with a mutation frequency of approximately 17.6% in an<br />
independent extension cohort of 84 paired BLBC samples. TEKT4<br />
mutations are biologically relevant, as ectopic expression of mutant<br />
TEKT4 increased paclitaxel resistance of BLBC cell lines both in vitro<br />
and in vivo. Additionally, compared with the normal breast tissues, 16<br />
significantly mutated genes were identified and validated in the paired<br />
cancer samples, including TP53, ARID1A, BEND5, LCT, COL4A4,<br />
GAP43, COL6A6, LOC728369, STAP1, KCNK17, LZTS2, TST,<br />
IL9R, HDLBP, RASL11A and FAM22D. These genes have functions<br />
that could be broadly grouped into five biological classes: (i) MAPK<br />
signaling, (ii) PI3K/AKT signaling, (iii) cell cycle, (iv) metabolism<br />
and (v) loss of genome stability.<br />
Conclusion<br />
Our data reveal the novel concept that significant evolution might<br />
occur during chemotherapy and mutational heterogeneity could<br />
be a property of BLBCs. In addition, the identification of somatic<br />
mutations as biomarkers for pCR (pathologic complete remission)<br />
prediction and prognosis might help us optimize choice for sequential<br />
therapy and improve patients’ survival. Prospective clinical trials<br />
based on these findings might illustrate the drug-resistant mechanism<br />
and identify resistance pathways that can be exploited for therapeutic<br />
selection.<br />
P2-07-01<br />
BRCA1 regulates RHAMM function in breast cancer<br />
Fleisch MC, Yang Y, Mei Q, Sadat F, Brandi L, Iwaniuk KM,<br />
Honisch E, Maxwell CA, Niederacher D. Heinrich Heine University,<br />
Duesseldorf, Germany; University of British Columbia, Vancouver,<br />
BC, Canada<br />
Objectives: The receptor for hyaluronan-mediated motility (RHAMM,<br />
intracellular hyaluronan binding protein [IHABP], CD168), whose<br />
over-expression in tumors is associated with poor prognosis and<br />
early age at diagnosis, localizes to the centrosome, interacts with<br />
microtubules, functions in the maintenance of spindle pole stability<br />
and is required for centrosomal targeting. A previous study has shown<br />
that genetic variation at the HMMR locus (encoding for RHAMM)<br />
modifies breast cancer risk among BRCA1 mutation carriers and<br />
interplay between BRCA1, AURKA (aurora kinase A), RHAMM<br />
and phosphorylated RHAMM (pRHAMM) plays an important role<br />
in epithelial apicobasal polarization and breast carcinogenesis. Aim of<br />
this study was to investigate mechanisms by which BRCA1 regulates<br />
the function of RHAMM.<br />
Methods: Four pairs of shBRCA1 oligonucleotides containing target<br />
sequences against BRCA1 transcript were designed and synthesized.<br />
After annealing, these four double-strand shBRCA1 fragments were<br />
inserted into pLVTH vector and stably transfected into MCF-12A<br />
cells for knock-down of BRCA1 expression. The BRCA1 knockout<br />
breast cancer cell line HCC1937 with homozygous BRCA1<br />
c.5382insC mutation was transfected with the full length wt-BRCA1<br />
to restore BRCA1 function. HCC1937 cells were also transfected<br />
with the BRCA1-delExon11 isoform that lacks BRCA1 exon 11<br />
in its entirety. Western blotting analysis and immunohistochemical<br />
staining with anti-BRCA1, anti-RHAMM, anti-pRHAMM and anti-<br />
AURKA antibodies were performed. Real-time PCR was used to<br />
quantify RHAMM and AURKA expression in these different cell<br />
lines and transfectants .<br />
Results: Stable transfection of MCF-12A cells with the different<br />
shRNAs resulted in a significant decrease of BRCA1 transcript and<br />
protein levels. Real-time PCR showed increased RHAMM expression<br />
in MCF-12A cells transfected with shRNA BRCA1 knock-down<br />
constructs. Increased RHAMM gene expression was also determined<br />
in HCC1937 cells lacking BRCA1 function due to homozygous<br />
deleterious BRCA1 mutation c.5382insC. Restored wt-BRCA1<br />
expression in HCC1937 cells transfected with the full length BRCA1<br />
cDNA results in was significantly reduced RHAMM expression.<br />
Inhibition of RHAMM gene expression was even more pronounced<br />
in HCC1937 cells transfected with the BRCA1-delExon11variant<br />
lacking 1,143 amino acids of the BRCA1 protein. On the protein<br />
level loss of BRCA1 function affects nuclear localization of pT703-<br />
RHAMM the product of AURKA activity: pT703-RHAMM staining<br />
was revealed to be strong at the nuclear envelope in MCF12A BRCA1<br />
knock-down transfectants compared to the homogenous and less<br />
intense but clearly nuclear pT703-RHAMM staining in MCF12A<br />
wt-BRCA1 cells.<br />
Conclusions: BRCA1 negatively regulates RHAMM gene expression<br />
and might be involved in the nuclear localization of pRHAMM.<br />
Interestingly on the transcription level the BRCA1delexon11 isoform<br />
of BRCA1 displayed a stronger RHAMM repressor function than<br />
BRCA1 wild type. Taken together, our data provide insight into new<br />
functions of BRCA1 regulating RHAMM expression and mediating<br />
pRHAMM function.<br />
P2-08-01<br />
PIK3CA mutations associate with decreased Ki67 in early stage<br />
breast cancer (BC) and better outcomes in patients even among<br />
those with low Ki67 tumors.<br />
Datko FM, Patil S, Kalinsky K, Asher M, Wen YH, Hedvat C,<br />
Moynahan ME. Memorial Sloan-Kettering <strong>Cancer</strong> Center; Columbia<br />
University Medical Center<br />
Background: In studies of over 450 BC patients (pts) with > 10 years<br />
follow-up, pts with PIK3CA-mutated primary tumors had improved<br />
clinical outcome (Kalinsky et al 2009, Cizkova et al 2012). PIK3CA<br />
mutations associated with favorable clinicopathologic features: lower<br />
grade, smaller size, lymph node negativity (-), ER positivity (+),<br />
HER2-. In BC, several studies have suggested that PIK3CA mutations<br />
do not associate with PI3K/mTOR pathway activation (Loi et al 2010,<br />
Stemke-Hale et al 2008). To gain additional insight into the favorable<br />
biology imparted by a PIK3CA mutation in early stage BC and to<br />
identify predictive biomarkers, we performed immunohistochemistry<br />
(IHC) on tissue microarrays (TMA) constructed from 590 primary<br />
BCs.<br />
Methods: TMAs derived from FFPE tumors previously genotyped<br />
for PIK3CA mutations (rate of 32.5%, 192/590) were stained for ER,<br />
HER2 and AR (Kalinsky et al 2009). Here, we performed additional<br />
stains for MIB1 (Ki67 proliferation index, Ki67), p53 and markers<br />
of PI3K pathway activation (pS6, PTEN). Slides were scanned with<br />
Aperio ScanScope XT and segmented using TMALab (Aperio).<br />
Images were analyzed with the Aperio algorithm based on staining<br />
pattern (nuclear, cytoplasmic, membrane) and scored for % + and<br />
intensity. Manual review was performed for tumors with less than 3<br />
cores or discordant results. PTEN was scored manually: 0 (no tumor<br />
staining, PTEN loss), 1 (tumor < stroma), or 2 (tumor ≥ stroma). P<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
values were based on the log-rank test for comparison of Kaplan-<br />
Meier curves for disease free survival (DFS), Chi-square test for<br />
categorical variables and t-test for continuous variables.<br />
Results: On average, 66 cases (11%) were non-informative for each<br />
IHC stain, due to missing cores or insufficient tumor cells. In a binary<br />
analysis of Ki67 using a cutoff of ≥10% + cells, PIK3CA mutated<br />
tumors demonstrated significantly lower proliferation index with only<br />
9.4% of tumors (16/170) having high Ki67 as compared to 23.6% of<br />
wild-type PIK3CA tumors (82/347) (P=.001). Ki67 was also highly<br />
associated with PIK3CA genotype when analyzed with a cutoff of<br />
≥13.25% + cells or as a continuous variable. Importantly, DFS was<br />
significantly different when analyzed by PIK3CA genotype and<br />
Ki67 (P=.01). Among pts with low Ki67 tumors (n=419), PIK3CA<br />
mutation associated with longer DFS (10yr 79%, CI 69-85) as<br />
compared to wild-type PIK3CA (10yr 71%, CI 64-77). When PI3K<br />
pathway interactions were analyzed, PTEN loss associated with<br />
wild-type PIK3CA (P
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
challenge because of ploidy changes induced by drugs. We made<br />
a HER2 genetic examination by Fluorescent in situ Hybridization<br />
(FISH) of invasive breast cancers before and after taxane treatment.<br />
After treatment we found supernumerary HER2 gene copies up to 15<br />
copies in the cases non-amplified at diagnosis.<br />
Material and methods: All 410 invasive breast carcinoma samples<br />
were collected in a single laboratory (Service de Pathologie, Centre<br />
Jean Perrin). Tumor samples were collected by biopsy at diagnosis or<br />
by surgical excision after taxanes chemotherapy. For all cases we had<br />
matched samples, one before and one after therapy. Tumor samples<br />
were formalin-fixed paraffin-embedded. IHC staining was done to<br />
detect the expression of HER2 protein. Only cases which were IHC<br />
2+ or IHC 1+ (with scattered HER2 heterogeneous staining) were<br />
checked by FISH.<br />
Results: After taxane-based neoadjuvant chemotherapy (4-8<br />
cycles) thirty patients (HER2 negative at Dg) out of 344 showed<br />
supernumerary HER2 gene copies detected in giant cells with large<br />
polyploid nuclei. The proportion of polyploid post-therapy cells<br />
among regular-size cancer cells (diploid) was from 15 to 30%. The<br />
FISH examination of polyploid cells revealed an increase of HER2<br />
copy number (and chromosome 17centromere) up to 15. The same<br />
copy number raise was observed with EGFR and ALK FISH probes.<br />
The ratio of all 30 cases with two distinct tumor cell populations<br />
(near diploid cells and giant cells) was up to 1.65 (not amplified).<br />
In one third of cases the average number of HER2 gene copies was<br />
higher than 6.<br />
Conclusions and recommendations: As a result of taxane<br />
administration, polyploid cells are formed and that most (if not<br />
all) chromosomes have been replicated simultaneously because<br />
of absent chromosomal segregation secondary to microtubule<br />
inhibition by taxanes. This HER2 copy increase is distinct from the<br />
mechanisms accounting for a more restricted gene amplification<br />
during carcinogenesis. The viability of giant polyploid cells is<br />
particularly low and most if not all of these cells succumb to mitotic<br />
catastrophe, an onco-suppressive mechanism causing cell cycle<br />
arrest and cell death. Irrespective of this consideration, it would be<br />
a critical error to classify cases as HER2 amplified solely only the<br />
bases of HER2 copy number >6. We recommend that the detection<br />
of more than 6 HER2 copies after taxane-based chemotherapy should<br />
be prompt a validation step involving the exclusion of polyploid cells<br />
from the analysis, as well as hybridization with a second and third<br />
probe specific for a chromosome other than 17. This validation step<br />
appears crucial to avoid unnecessary, costly treatments with HER2-<br />
targeted therapies after the failure of taxane-based chemotherapies.<br />
The clinico-pathological parameters of tumors with giant cells will<br />
be discussed.<br />
P2-09-01<br />
Reactivation of epigenetically silenced retinoic acid receptorbeta<br />
for therapy of breast cancer- from molecular mechanism to<br />
potential clinical applications<br />
Ordentlich P, Nguyen N, Jin K, Sadik H, Han L, Sukumar S. Syndax<br />
Pharmaceuticals; Sidney Kimmel <strong>Cancer</strong> Center, Johns Hopkins<br />
University School of Medicine<br />
Background: Triple negative breast cancer (TNBC) is a subgroup of<br />
breast cancer that is characterized by a lack of expression of targets<br />
for validated targeted therapies. Although responses to chemotherapy<br />
are observed, resistance develops rapidly. Genomic and molecular<br />
profiling of TNBC has identified multiple contributors to their<br />
uncontrolled growth including epigenetic dysregulation of genes<br />
important for normal cell growth and differentiation. Recent studies<br />
have shown that histone deacetylase (HDAC) inhibitors reverse the<br />
epigenetic profile of tumors, resulting in the re-expression of silenced<br />
genes encoding proteins such as ERα, EGFR, and RARβ. Entinostat is<br />
an oral, class 1 isoform selective HDACi recently shown in a phase 2<br />
study to be active in ER+ breast cancer. Clinical trials with entinostat<br />
in HER2+ and TNBC are also in progress. We hypothesized that<br />
combining epigenetic therapy using entinostat, with differentiation<br />
therapy using a retinoic acid receptor agonist- All Trans Retinoic<br />
Acid (ATRA) will provide an effective strategy for impeding the<br />
growth of TNBC and potentially sensitize tumors to commonly used<br />
chemotherapies (doxorubicin, carboplatin, paclitaxel).<br />
Methods: Combination studies of entinostat combined with ATRA<br />
with and without non-toxic doses (half clinical) of chemotherapy were<br />
carried out in vitro and in xenograft models of TNBC. Expression<br />
of RARb and downstream effectors were measured in cell lines and<br />
tumors from xenograft studies.<br />
Results: Nontoxic (half clinical) doses of doxorubicin when combined<br />
with entinostat and ATRA in vitro and in vivo exerted the best response<br />
when compared with combinations using paclitaxel and carboplatin.<br />
Re-expression of the silenced RARβ and downstream effectors was<br />
observed in the cell lines treated in vitro and in tumor xenografts<br />
of MDA-MB-231 and SUM159 cells in vivo. To gain insight into<br />
mechanism of action for the entinostat – doxorubicin combinations<br />
we examined the expression of enzyme targets of doxorubicin and<br />
determined that entinostat treatment reduced the expression of<br />
topoisomerase (Topo) II enzymes. Besides its conventional role in<br />
cell replication and division, Topo II has an important function in<br />
regulating transcription, especially in the nuclear receptor pathways<br />
such as ER and RAR. Our results demonstrated that Topo IIβ has a<br />
dual role in regulating the expression of RARβ. Inhibition of Topo IIβ<br />
in a time- and dose dependent manner up-regulated the expression of<br />
RARβ and its downstream genes. However, completely eliminating<br />
Topo IIβ decreased expression of RARβ.<br />
Conclusions: Our detailed study provides a new approach to treating<br />
TNBC using combinations of nontoxic doses of chemotherapeutic<br />
drugs with epigenetic therapy, and a deeper understanding of the<br />
molecular pathways involved in this response. These results suggest<br />
that combination of entinostat and a retinoic acid receptor agonist<br />
with low dose doxorubicin will provide an effective strategy for<br />
treatment of TNBC.<br />
P2-09-02<br />
Epigenetic Regulation of histone variants - a role in hormone<br />
therapy resistant breast cancer?<br />
Nayak SR, Oesterreich S, Pathiraja T. Magee Women’s Research<br />
Institute, University of Pittsburgh Medical Center, Pittsburgh, PA;<br />
Lester & Sue Smith <strong>Breast</strong> Center, Baylor College of Medicine,<br />
Houston, TX<br />
OBJECTIVE To utilize a genome wide approach to characterize<br />
epigenetic changes associated with resistance to estrogen deprivation,<br />
thus mimicking resistant to AIs.<br />
BACKGROUND Mechanisms of endocrine resistance include the<br />
activation of growth factor receptor pathways, overexpression of<br />
ER co-activators, and metabolic resistance due to polymorphisms<br />
in metabolizing enzymes. Recently, epigenetic mechanisms have<br />
been investigated to explain endocrine resistance. The majority of<br />
mechanisms for acquired resistance have been described following<br />
tamoxifen therapy, but the mechanisms for resistance to aromatase<br />
inhibitors (AI) remain less well known.<br />
HYPOTHESIS Estrogen deprivation results in altered methylation<br />
and altered expression of critical target genes in breast cancer cells,<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
which helps the cell to survive in the absence of estrogen, contributing<br />
to acquired AI resistance in breast cancer patients.<br />
MATERIALS AND METHODS We utilized derivatives of the<br />
ER_ MCF-7 cell line which were isolated after being cultured in<br />
estrogen-free media for 9 months (C4-12 cell line) and 18-24 months<br />
(LTED, Long term estrogen deprivation cell line). A genome-wide<br />
methylation screen was performed using Methyl CpG binding Domain<br />
(MBD) pull down assay followed by hybridization into Affymetrix<br />
Human Promoter 1.0R Array. Altered DNA methylation was validated<br />
by bisulfite genomic sequencing assays while gene expression of<br />
candidate genes was studied by qRT-PCR and Western blotting.<br />
RESULTS There were a significant amount of differentially<br />
methylated genes in C4-12 and LTED when compared to<br />
MCF7. Intriguingly, among the genes which were significantly<br />
hypomethylated in both endocrine resistant cell lines were a number<br />
of histone genes, with the homomorphic variant HIST1H2BE<br />
showing the strongest hypomethylation. Canonical histones have<br />
both homomorphic and heteromorphic variants, which differ in their<br />
timing of expression and similarity to the canonical histone protein’s<br />
amino acid sequence. Overexpression of various heteromorphic<br />
histone variants have been implicated in carcinogenesis, but to date,<br />
there have been no studies on homomorphic variants, and specifically<br />
H2B variants, in regards to their role in tumorigenesis. We show that<br />
hypomethylation of HIST1H2BE was associated with its upregulation<br />
in C4-12 and LTED cells. Furthermore, knockdown of of HIST2BE<br />
resulted in decreased growth in the endocrine resistant cells, but not<br />
in the parental MCF-7 cell lines.<br />
CONCLUSION & FUTURE DIRECTIONS The study is novel<br />
in two ways; first, this is the first study to show a potential role for<br />
histone variants in endocrine resistance. Second, this is one of very<br />
few examples where hypomethylation (instead of hypermethylation)<br />
results in altered expression of genes critical in tumorigenesis.<br />
Current studies include the detailed characterization of the phenotype<br />
following over-expression and knockdown of HIST1H2BE, the<br />
examination of the timing of expression of this variant in the S phase,<br />
and finally we are measuring methylation and expression of HIST2BE<br />
in a large collection of tumors from AI-treated breast cancer patients.<br />
P2-09-03<br />
Identifying a landscape of DNA methylation-driven genes in<br />
breast cancer using MethylMix<br />
Gevaert O, Plevritis S. Stanford University<br />
Background<br />
DNA methylation is being recognized as an important mechanism that<br />
contributes to oncogenesis. Hyper- and hypo-methylation of genes<br />
have been identified as critical events in multiple human cancers. A<br />
vast amount of data is now available that allows a comprehensive<br />
genome wide study of DNA methylation levels of cancer compared<br />
to normal tissue. Yet few statistical algorithms exist that exploit these<br />
vast datasets to quantify methylation levels and identify hypo- and<br />
hyper-methylated genes in cancer.<br />
Methods<br />
We developed a new computational method called MethylMix based<br />
on a Gaussian mixture modeling to identify DNA methylation states<br />
relative to normal tissue. We applied MethylMix on breast cancer<br />
data from The <strong>Cancer</strong> Genome Atlas (TCGA). Using paired gene<br />
expression data; we associate DNA methylation with gene expression<br />
data to identify functional DNA methylation events. Moreover, we<br />
searched for patient subgroups with similar methylation patterns and<br />
compare these with normal methylation data.<br />
Results<br />
MethylMix identified 344 and 172 significantly hyper- and<br />
hypo-methylated genes respectively. For example MTAP is<br />
hypermethylated in 30% of the samples and is known to be codeleted<br />
with the tumor suppressor gene CDKN2A. MTAP is also<br />
more frequently hypermethylated with increasing stage (Fisher<br />
exact test p-value 0.0007). Another interesting example is MUC1,<br />
hypermethylated in 17% of the samples but also significantly<br />
hypomethylated in the remaining 83% of the samples. MUC1’s<br />
methylation status differentiates between basal and luminal A tumors<br />
through hypermethylation in basal and hypomethylation in luminal A<br />
tumors (Fisher exact test p-value < 0.0001) consistent with MUC1’s<br />
role associated with ER positive breast cancer. Next, we observed<br />
hypomethylation of PTPN22 in the basal breast cancers (Fisher<br />
exact test, p-value < 0.0001) a tyrosine phosphatase involved in<br />
T cell receptor signaling. Similarly MMP7 is hypomethylated in<br />
basal breast cancers and hypermethylated in luminal (Fisher exact<br />
test, p-value < 0.0001). In contrast, a number of breast cancer genes<br />
previously reported to be methylated could not be confirmed due to<br />
various reasons. We found no functional or differential methylation<br />
for APC, CCND2, CDH1, CDH13, RARB, CDKN2A, HOXA5 and<br />
TWIST1 due to lack of correlation with gene expression or lack<br />
of significant difference with normal DNA methylation. We also<br />
confirmed a significant methylation pattern associated with basal<br />
breast cancer characterized by hypomethylation of genes related to the<br />
extracellular space. In addition, we observed a significant difference<br />
in the number of hypermethylated genes per molecular subtype. More<br />
specifically the luminal A and B subtypes together have significantly<br />
more hypermethylated genes compared to the basal subtype (164<br />
hypermethylated genes in luminal vs. 88 in basal, Wilcoxon rank<br />
sum test = -0.2, and ratio of<br />
tumor to normal mean beta >= 2.0).<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
240s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
Estrogen receptor-negative BC is a more aggressive form than ER<br />
positive BC with approximately double the incidence in African<br />
Americans than in Caucasian Americans. The emerging differential<br />
methylation pattern within hormone receptor negative breast cancers<br />
would further help stratify them into distinct subgroups. Promotor<br />
methylation being potentially reversible, methylated genes may serve<br />
as future molecular targets for demethylating therapies.<br />
Support: Komen Foundation: KG110218<br />
P2-09-05<br />
Screening of significantly hypermethylated genes in breast cancer<br />
using MIRA-based microarray and identifying their expression<br />
levels<br />
Lian Z-q, Wang Q, Li W-p, Zhang A-q, Wu L. <strong>Breast</strong> Disease Center,<br />
Guangdong Women and Children Hospital of Guangzhou Medical<br />
College<br />
Background. Despite extensive studies in recent years, molecular<br />
biomarkers for early detection of breast cancer are urgently needed.<br />
This study aims to screen candidate methylation markers for early<br />
detection of breast cancer and explore the relationship between<br />
methylation and gene expression.<br />
Methods. We performed methylated-CpG island recovery<br />
assay(MIRA) combined with CpG island array on 61982 CpG sites<br />
across 4162 genes in 10 breast cancer tissues and 10 non-cancer<br />
breast tissues. Direct bisulfite sequencing and combined bisulfite<br />
restriction analysis (COBRA) were carried out in independent cancer<br />
and non-cancer samples. Gene expressions were analyzed by using<br />
microarray and validated by using RT-PCR.<br />
Results. We detected 70 significantly hypermethylated genes in breast<br />
cancer tissues, including many novel hypermethylated genes such<br />
as ITGA4, NFIX, OTX2 and FGF12. Direct bisulfite sequencing<br />
showed widespread methylations occurred in intragenic regions of<br />
WT1, PAX6 and ITGA4 genes and promoter region of OTX2 gene in<br />
breast cancer tissue. COBRA assay confirmed that WT1, OTX2 and<br />
PAX6 genes were hypermethylated in breast cancer tissues. Clustering<br />
analysis of gene expressions of 70 significantly hypermethylated<br />
genes revealed that most hypermethylated genes in breast cancer were<br />
not expressed in breast tissues. RT-PCR assay validated that WT1 and<br />
PITX2 were only weakly expressed in the breast cancer tissues and<br />
weren’t expressed in most non-cancer breast tissues. OTX2 and PAX6<br />
weren’t expressed in both breast cancer tissues and non-cancer tissues.<br />
Conclusions. Our results will expand our knowledge of<br />
hypermethylated genes and methylation sites for early detection<br />
of breast cancer and deepen our understanding of relationship<br />
between methylation and gene expression. MIRA approach can more<br />
effectively screen candidate methylated genes for further clinical<br />
validation than gene expression microarray-based strategy.<br />
P2-09-06<br />
The structure design and biological activities of inhibitory<br />
peptides, which block the interactions among polycomb repressive<br />
complex 2<br />
LI KK, Luo L, Kong X, Li L, Luo C. Rui Jin Hospital Affiliated with<br />
the Shanghai JiaoTong University School of Medicine, 197 Rui Jin<br />
Road II, Shanghai, China; Shanghai Institute of Materia Medica,<br />
Chinese Academy of Sciences, Shanghai, Shanghai, China<br />
Polycomb repressive complex (PRC2) contains several proteins,<br />
including embryonic ectoderm development (EED), suppressor<br />
of zeste 12 (SUZ12) and enhancer of zeste homolog 2 (EZH2).<br />
Excessive EZH2 concentrations have been reported as a marker of<br />
aggressive breast cancer and associated with invasion and cancer<br />
progression. EZH2 levels were elevated in patients with invasive<br />
breast carcinoma relative to normal or atypical hyperplasia. Except<br />
for the C-terminal SET domain, which functions as a histone-lysine<br />
N-methyltransferases, EZH2 has an N-terminal alpha helix region,<br />
which forms tight complex with EED protein. The in vivo enzymatic<br />
activity of EZH2 relies on and be tightly regulated by the interaction<br />
with EED. We designed series of artificial peptides trying to block<br />
the interaction between EZH2 and EED. By using label-free surface<br />
plasmon resonance (SPR) technology, the dynamic binding capacities<br />
of these peptides were tested. There were 3 leading structures standing<br />
out from the screening of more 80 peptides. After several round of<br />
co-crystal structure based optimization, the binding capacity of one<br />
inhibitor was reached to several nM levels, which indicated the<br />
availability for being a drug candidate. Finally, the biological activities<br />
of the inhibitory peptides were tested in several breast cancer cell<br />
lines. The PRC2 inhibitory peptides in this study are the first time<br />
reported PRC2 targeting epigenetic molecules with biological activity<br />
in breast cancer.<br />
P2-10-01<br />
PAM50 gene signature is prognostic for breast cancer patients<br />
treated with adjuvant anthracycline and taxane based<br />
chemotherapy<br />
Liu MC, Pitcher BN, Mardis ER, Davies SR, Snider JE, Vickery T,<br />
Reed JP, DeSchryver K, Singh B, Friedman PN, Gradishar WJ, Perez<br />
EA, Martino S, Citron ML, Norton L, Winer EP, Hudis CA, Perou CM,<br />
Ellis MJ, Barry WT. Georgetown University Lombardi Comprehensive<br />
<strong>Cancer</strong> Center, Washington, DC; Duke University Medical Center,<br />
Durham, NC; Washington University, St. Louis, MO; Washington<br />
University School of Medicine, St. Louis, MO; New York University<br />
Medical Center, New York, NY; University of Chicago, IL; Robert<br />
H. Lurie Comprehensive <strong>Cancer</strong> Center, Northwestern University<br />
Feinberg School of Medicine, Chicago, IL; Mayo Clinic, Jacksonville,<br />
FL; The Angeles Clinic and Research Institute, <strong>San</strong>ta Monica, CA;<br />
Hofstra North Shore-LIJ School of Medicine, ProHEALTH Care<br />
Associates, Lake Success, NY; Memorial Sloan-Kettering <strong>Cancer</strong><br />
Center, New York, NY; Dana Farber <strong>Cancer</strong> Institute, Harvard<br />
Medical School, Boston, MA; Lineberger Comprehensive <strong>Cancer</strong><br />
Center, University of North Carolina at Chapel Hill, NC; Siteman<br />
<strong>Cancer</strong> Center, Washington University School of Medicine, St. Louis,<br />
MO<br />
Background: Intrinsic breast cancer subtypes determined by the<br />
PAM50 assay are reported to be prognostic independent of standard<br />
clinicopathological variables. The CALGB (Alliance) 9741 adjuvant<br />
trial randomized treatment in a 2x2 factorial design to (i) 2-wk<br />
(dose dense; DD) vs 3-wk therapy and (ii) sequential vs concurrent<br />
doxorubicin, cyclophosphamide, paclitaxel (A-->T-->C vs AC -->T).<br />
DD therapy improved disease-free survival and overall survival (OS)<br />
(Citron et al. JCO 2003.). A significant interaction between intrinsic<br />
breast cancer subtypes and the use of DD therapy was hypothesized.<br />
Methods: C9741 was conducted in collaboration with ECOG,<br />
NCCTG, and SWOG. Biospecimens were collected from 1652 of<br />
2005 subjects. Multiplexed gene expression profiling (NanoString<br />
Technologies, Inc) generated PAM50 subtype calls (luminal A,<br />
luminal B, HER2-enriched, basal-like), risk of relapse (ROR) score,<br />
and proliferation score for 1321 cases (80%). Excluded samples were<br />
due to insufficient tumor (n=181) or RNA (n=150). The primary<br />
endpoint was relapse-free survival (RFS). The primary analysis<br />
to determine if the clinical benefit of DD therapy is dependent on<br />
intrinsic subtype was conducted as a test of interaction in a Cox<br />
proportional hazards model (3 degrees of freedom, df; alpha=0.05).<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Similar analyses were performed for ROR score and proliferation<br />
score as continuous measures of risk (1 df). PAM50 subtype, ROR<br />
score, and proliferation score were evaluated in separate multivariate<br />
models adjusting for number of positive nodes, menopausal status,<br />
dose density, and sequence of therapy.<br />
Results: Improved outcomes for DD therapy in the evaluable subset<br />
mirrored results from the complete dataset (HR=1.20; 95%CI 0.99-<br />
1.44) with a median follow-up of 12.3 yrs. Subtype analysis identified<br />
32% luminal A (n=417), 26% luminal B (n=341), 20% HER2-enriched<br />
(n=267), and 22% basal-like (n=296). Intrinsic subtypes were<br />
prognostic of RFS (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
also observed with other breast signatures and RS, including an<br />
imputed 70-gene signature of MammaPrint (rho=0.59, p=3e-8) and<br />
the 50-gene PAM50 risk-of-relapse score (rho=0.54, p=8e-7), while<br />
poor correlation was seen for the GENIUS prognostic model (rho =<br />
0.06, p = 0.6). Discovery of gene-level associations to RS identified<br />
28 genes, including known cancer-associated genes such as BRCA2<br />
(FWER adj p=0.002), Cyclin E1 (FWER adj p=0.015), and CDCA5<br />
(FWER adj p=0.048). Pathway-level association in KEGG and GO<br />
Biologic Processes, identified 24 and 104 categories respectively,<br />
including Cell Cycle pathways KEGG:04110 (FDR adj p=0.002)<br />
and GO:0000085 (FDR adj p=0.0007). Among 22 in-vitro derived<br />
oncogenic pathway signatures, significant negative correlation is seen<br />
with p53 (rho=-0.56, adj p=4e-6) and positive correlation with betacatenin<br />
(rho=0.38, adj p=0.015). A multi-gene model of association<br />
to OncotypeDX RS classification is being developed using Prediction<br />
Analysis of Microarrays (PAM).<br />
Conclusions: Microarray-based prognostic breast cancer signatures<br />
are generally concordant. However, their application across platforms<br />
is currently sub-optimal. In the context of OncotypeDX RS, additional<br />
key cancer-associated genes and pathways are found to be associated<br />
with breast cancer prognosis, potentially providing insight into<br />
treatment opportunities for ER+ breast cancer. Validation efforts of<br />
these findings in an independent patient cohort are underway.<br />
Funding: NCI: RC2CA14041-01 and W81XWH-07-1-0394<br />
P2-10-04<br />
The Mammostrat Test is an Effective Tool to Stratify Patient<br />
Samples Previously Characterized as Intermediate by the<br />
Oncotype Dx Test<br />
Bloom KJ, Kyshtoobayeva A, Hilaire L, Gutekunst K. Clarient<br />
Diagnostic Services, Aliso Viejo, CA<br />
Mammostrat is a well validated, 5-antibody immunohistochemistry<br />
(IHC) based assay initially developed to assess the risk of recurrence<br />
in patients with early stage estrogen receptor (ER) positive breast<br />
cancer. Recent data from the TEAM trial demonstrated that<br />
Mammostrat predicted distant relapse free survival (DRFS) for both<br />
exemestane and tamoxifen-exemestane treated patients irrespective of<br />
nodal status and chemotherapy. OncoType Dx® is a recurrence assay<br />
frequently used by oncologists to aid in the selection of early stage<br />
breast cancer patients who may benefit from adjuvant chemotherapy.<br />
It is currently unclear whether patients whose tumors demonstrate an<br />
intermediate risk score should receive chemotherapy. We sought to<br />
determine if tumors with intermediate OncoType Dx® scores would<br />
be clearly classified as high or low risk with the Mammostrat assay.<br />
Formalin fixed paraffin embedded tissue blocks were retrieved from<br />
143 patients whose tumor were previously assessed as intermediate<br />
with the OncoType Dx® assay (Genomic Health, Redwood City,<br />
Ca). Six serial 5 micron sections were cut from the tissue block. One<br />
section was stained with H&E and the remaining five sections were<br />
stained with the Mammostrat antibodies, NDRG1 (AGI-3-3-12E<br />
clone, Clarient, Aliso Viejo, CA), TRMT2A (AGI-2-33-12E clone,<br />
Clarient, Aliso Viejo, Ca), P53 (D07 clone, Dako, Carpenteria, CA),<br />
CEACAM (S0235 08/28/06 clone, Clarient, Aliso Viejo, CA)and<br />
SLC7A5 (AGI-1-108-2E clone, Clarient, Aliso Viejo, CA). Slides<br />
were reviewed by a single pathologist (KJB) using previously<br />
published Mammostrat criteria and a risk score of low, moderate or<br />
high was generated.<br />
Of the 143 tumors, 62 (43%) were classified as low risk, 51 (36%)<br />
were classified as high risk and 30 (21%) were classified as moderate<br />
risk. Thus, 113 (79%) cases were defined as either low risk or high<br />
risk by the Mammostrat assay.<br />
The Mammostrat assay reclassified 79% of OncoType Dx®<br />
intermediate tumors into a clear high risk or low risk category. Based<br />
on data from the TEAM trial, node negative patients categorized<br />
as low risk by Mammostrat had a 5 year DRFS of 96%, while data<br />
from the NSABP-B20 trial showed that patients categorized as high<br />
risk by the Mammostrat assay derived a significant benefit from<br />
adjuvant chemotherapy. Mammostrat may be an effective tool to aid<br />
oncologists and patients in treatment decisions when Oncotype Dx®<br />
classifies a tumor as intermediate risk.<br />
P2-10-05<br />
Continuous association of a 200-gene prognostic risk score<br />
with probability of neoadjuvant chemotherapy response and<br />
translation from fresh frozen to FFPE tissue for clinical use.<br />
van Laar R, DiPaola J, Carbaugh H, Murphy T, DiRamio A, Flinchum<br />
R, Brown N, Albino T. Signal Genetics, New York, NY<br />
<strong>Breast</strong>PRS is a suite of complimentary gene signatures that resolves<br />
several of the significant limitations of current gene expression<br />
signatures in breast cancer. Notably, <strong>Breast</strong>PRS can accurately provide<br />
prognosis prediction, histological grade resolution and molecular<br />
subtyping of invasive breast cancer. The 200-gene prognostic<br />
component was previously validated in an independent retrospective<br />
series of 1,016 previously published fresh-frozen breast cancers and<br />
has now been applied to data from over 6,000 patients.<br />
In part one of this study, a meta-analysis of 890 previously published<br />
neoadjuvant treated breast cancer patients was performed. A<br />
highly significant association was observed between prognosis<br />
risk group (high vs low), continuous risk score (0-100), and a<br />
patient’s probability of achieving complete pathologic response with<br />
neoadjuvant chemotherapy. Data from both fine-needle-aspirate and<br />
biopsy tissue were included in the cohort. Notably, fewer than 10%<br />
of patients with the lowest (most favorable) pre-treatment <strong>Breast</strong>PRS<br />
prognosis scores achieve pCR. Probability of pCR was observed<br />
to increase steadily to over 40% for individuals with the highest<br />
prognosis scores.<br />
In part two of the analysis, 50 paired fresh-frozen and FFPE tumors<br />
were profiled on whole genome microarrays containing all three<br />
signatures, in a CLIA-certified high throughput genomics laboratory.<br />
Results will be presented that highlight the consistency of the<br />
prognosis, grade and subtype signatures in clinically relevant FFPE<br />
tissue.<br />
This suggests that <strong>Breast</strong>PRS, in addition to identifying 10-year<br />
recurrence risk, histologic grade and molecular subtype, may enable<br />
physicians to determine a patients benefit from receiving neoadjuvant<br />
chemotherapy with more granularity than current clinical or genomic<br />
methods.<br />
<strong>Breast</strong>PRS Prognostic Index vs Neoadjuvant Chemotherapy Response<br />
<strong>Breast</strong>PRS Prognostic Risk<br />
Score Percentile<br />
Percent of patients achieving pCR Percent of patients with RD<br />
0 to 10th 11% 89%<br />
10th to 20th 7% 93%<br />
20th to 30th 12% 88%<br />
30th to 40th 19% 81%<br />
40th to 50th 18% 82%<br />
50th to 60th 26% 74%<br />
60th to 70th 26% 74%<br />
70th to 80th 34% 66%<br />
80th to 90th 35% 65%<br />
90th to 100th 42% 58%<br />
www.aacrjournals.org 243s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P2-10-06<br />
Multicenter I-SPY 1 TRIAL (CALGB 150007/150012): <strong>Breast</strong><br />
cancer stem cells are associated with intrinsic chemoresistance<br />
and worse survival.<br />
Landis MD, Yau C, Neumeister V, Rimm DL, I-SPY 1 TRIAL<br />
Investigators, Esserman L, Chang JC. The Methodist Hospital,<br />
Houston, TX; University of California, <strong>San</strong> Francisco, CA; Yale<br />
University School of Medicine, New Haven, CT<br />
<strong>Breast</strong> cancer stem cells (CSCs) contribute to therapeutic resistance.<br />
I-SPY is a multi-center neoadjuvant trial for women with locally<br />
advanced breast cancers (3cm or greater) who received neoadjuvant<br />
doxorubicin and cyclophosphamide then paclitaxel. We hypothesized<br />
that CSC markers will be increased by neoadjuvant chemotherapy in<br />
patients who did not achieve a pathologic complete response, and that<br />
women with elevated CSC markers will have worse survival in this<br />
multicenter study. Methods: 215 women completed surgery, of those<br />
156 had residual tumor, of whom 56 had sufficient tumor sampled preand<br />
post-neoadjuvant chemotherapy to enable measurements of CSCs<br />
by automated quantitative analysis (AQUA) of immunofluourescent<br />
staining for aldehyde dehydrogenase (ALDH1), CD44, and ALDH1/<br />
CD44. A threshold of background staining was determined for each<br />
marker from a tissue microarray representing multiple cell lines<br />
and patient specimens and was used to define samples positive for<br />
CSCs. Effect of treatment on proportion of samples positive for CSCs<br />
was assessed using the McNemar test. Association between CSC<br />
markers and recurrence free survival (censored at 5 years) (RFS)<br />
were evaluated using Kaplan-Meier analysis of cohorts dichotomized<br />
at optimal marker thresholds as determined from ROC analysis for<br />
RFS prediction, as well as univariate Cox analysis of continuous<br />
CSC marker scores. Results: Of the 56 patients studied median<br />
tumor size was 6cm, 30% HR-neg, and 75% HER2 neg (by central<br />
and/or local IHC and/or FISH). In the HER2-neg subset, despite<br />
reducing tumor size in approximately 76% of cases, chemotherapy<br />
significantly increased the proportion of samples positive for CSCs:<br />
ALDH1 (38% to 74%), CD44 (67% to 88%), and ALDH1 in CD44<br />
compartment (43% to 76%) (McNemar test p = 0.0007, 0.03, and<br />
0.001, respectively). Within this HER2-neg subset, tumors with high<br />
pre-treatment CSC expression (i.e. CSC marker scores greater than<br />
optimal thresholds for RFS prediction – ALDH1 score ≥470.5, CD44<br />
score ≥8662, ALDH1 in CD44 compartment score ≥742.5) appeared<br />
to have worse RFS with a hazard ratio of 3.7, 2.8, and 2.1 respectively<br />
(log rank p=0.03, 0.07, 0.17). Interestingly, Cox regression analysis<br />
revealed that pretreatment ALDH1 score, as well as the ALDH1 in<br />
CD44 compartment score appeared significantly associated with<br />
RFS in the HR positive HER2 neg subset (n=33) (hazard ratio:<br />
2.2 (1.3 - 3.8), p=0. 003, and hazard ratio: 1.8 (1.1 – 2.8), p=0.01<br />
respectively). Surprisingly, post-treatment CSC markers expression<br />
did not show significant RFS associations within the HER2 neg<br />
or the HR positive HER2 neg subsets. Conclusion: These results<br />
from this multicenter study validate the hypothesis of treatmentresistant<br />
cancer stem cells, with an increase in CSC markers post<br />
chemotherapy, and suggest worse prognosis in women whose tumors<br />
have high expression of these stem cell markers, especially for HER2<br />
negative patients. Surprisingly, only pre- (and not post-) treatment<br />
CSC marker expression appears to associate with RFS. Studies to<br />
evaluate inhibitors of stem cell self-renewal and conventional therapy<br />
should be considered for HER2-neg breast cancers.<br />
P2-10-07<br />
Stem cell marker aldehyde dehydrogenase 1 in stromal cells<br />
strongly correlates with prognosis in breast cancer<br />
Sjöström M, Hartman L, Holmdahl J, Grabau D, Malmström P, Fernö<br />
M, Niméus-Malmström E. Lund University, Lund, Sweden<br />
Background: <strong>Breast</strong> cancer stem cells have the potential to provide<br />
prognostic information and be a therapeutic target. Aldehyde<br />
dehydrogenase 1 (ALDH1) is a widely used marker for cells with stem<br />
cell properties. The aim of this study was to evaluate the prognostic<br />
information of ALDH1, and its correlation with other clinical variables<br />
in early breast cancer.<br />
Material and methods: ALDH1 expression was investigated by<br />
immunohistochemistry in tissue microarrays of breast tumors from<br />
220 premenopausal node-negative breast cancer patients, mainly<br />
not subjected to any adjuvant systemic treatment. <strong>Cancer</strong> cells were<br />
evaluated for both staining intensity (negative, weak, moderate<br />
and strong) and percentage of stained cells. Stromal cells were<br />
evaluated for staining intensity. Spearman’s rank correlation was<br />
used to investigate correlation with continuous clinical variables, the<br />
Jonckheere-Terpstra Test for ordinal variables and Mann-Whitney for<br />
binary variables. For survival analysis with 5 years of follow-up the<br />
Kaplan-Meier method and Log-rank test for trend were used with<br />
distant disease-free survival (DDFS) as endpoint. Cox regression<br />
analysis was used to obtain hazard ratios, and for multivariate<br />
modeling.<br />
Results: ALDH1 staining intensity in stroma correlated positively<br />
with both ER and PR (p=0.004 and p=0.001). Stroma staining<br />
intensity was negatively correlated with Ki67 expression and high<br />
histological grade (p=0.002 and p=0.002). There was no significant<br />
correlation of stroma intensity with age, HER2 or tumor size. Stroma<br />
intensity showed a strong correlation with increased DDFS (Log-rank<br />
test for trend p=0.007).<br />
Both ALDH1 staining intensity in cancer cells as well as percentage<br />
of positively stained cancer cells correlated negatively with PR status<br />
(p=0.08 and p=0.03) while no correlation was found for ER (p=0.65<br />
and p=0.59). Staining intensity and percentage of positively stained<br />
cancer cells correlated positively with Ki67 expression (p=0.03<br />
and p=0.02). <strong>Cancer</strong> cell intensity showed a tendency of positive<br />
correlation with high histological grade (p=0.07). There was no<br />
correlation of percentage of positively stained cancer cells with<br />
histological grade (p=0.21), nor of staining intensity and percentage<br />
of positively stained cancer cells with HER2, tumor size, or age at<br />
diagnosis. <strong>Cancer</strong> cell intensity and percentage of positive cancer<br />
cells showed no correlation with DDFS (log rank test for trend<br />
p=0.79 and p=0.78).<br />
A multivariate model of ALDH1 in stroma including ER, HER2,<br />
Ki67, age (continuous), and tumor size showed that ALDH1 was an<br />
independent prognostic marker (p=0.036). Interestingly, ALDH1 in<br />
stroma (HR 0.58, mean per step in intensity) had stronger influence<br />
on the prognosis than ER status (HR 1.12), Ki67 (HR 1.62) and<br />
tumor size (HR 1.17).<br />
Conclusion: Strong ALDH1 staining intensity in stromal cells,<br />
in comparison with negative or weak staining, is a strong marker<br />
for increased DDFS in breast cancer and outperforms well-known<br />
prognostic markers such as ER, Ki67 and tumor size as an independent<br />
prognostic marker. The finding that stromal cell staining is correlated<br />
to DDFS may be an indication of the importance of the tumor<br />
microenvironment.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
244s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
P2-10-08<br />
Prospective comparison of Recurrence Score and different<br />
definitions of luminal subtypes by central pathology assessment<br />
of single markers in early breast cancer: results from the phase<br />
III WSG-planB Trial<br />
Gluz O, Kreipe HH, Kates RE, Christgen M, Liedtke C, Shak S,<br />
Clemens M, Salem M, Liedtke B, Aktas B, Markmann S, Uleer C,<br />
Augustin D, Thomssen C, Nitz U, Harbeck N. West German Study<br />
Group, Moenchengladbach, NRW, Germany; Ev. Bethesda Hospital,<br />
Moenchengladbach, NRW, Germany; Medizinische Hochschule<br />
Hannover, Niedersachsen, Germany; University of Muenster,<br />
Muenster, Germany; Genomic Health, Inc., Germany; Clinics<br />
Mutterhaus, Trier, Germany; University of Cologne, Germany;<br />
Ev. Hospital, Bergisch Gladbach, Germany; University of Essen,<br />
Germany; Clinics Südstadt, Rostock, Germany; Gemeinschaftspraxis<br />
Hildesheim, Hildesheim, Germany; Clinics Deggendorf, Deggendorf,<br />
Germany; University of Halle, Germany; University of Munich,<br />
Munich, Bavaria, Germany<br />
Background: Routine use of multigene RT-PCR based assays as<br />
Recurrence Score (RS) vs. single markers (grade, uPA/PAI-1, HR,<br />
HER2, Ki-67) is controversially discussed in early BC. Several<br />
definitions of luminal A/B subtypes have been proposed by St. Gallen<br />
guidelines and individual researchers (grade 1/2 vs. 3, Ki-67 cut-offs<br />
14 or 20%). Recently, integration of PR>20% was proposed as an<br />
immunhistochemical luminal A subtype definition (Ki-67
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
adherence to internal protocols and mandatory participation in quality<br />
assurance programs. These results provide further confirmation that<br />
the vast majority of patients eligible for trastuzumab are not deprived<br />
from an effective treatment by using this algorithm.<br />
P2-10-10<br />
Clinical implications of molecular heterogeneity in highly<br />
proliferative, ER-positive, HER2-negative breast cancer<br />
Bianchini G, Pusztai L, Kelly CM, Iwamoto T, Callari M, Symmans<br />
WF, Gianni L. Ospedale <strong>San</strong> Raffaele, Milan, Italy; MD Anderson<br />
<strong>Cancer</strong> Center, Houston, TX; Mater Misericordiae University<br />
Hospital, Dublin, Ireland; Okayama University Hospital, Okayama,<br />
Japan; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy<br />
Objectives: Different clinical behaviors are observed in tamoxifentreated<br />
and untreated ER-positive, HER2-negative highly-proliferative<br />
breast cancer (BC) that demonstrate either high (highERS) or low<br />
(lowERS) expression of estrogen-related genes (Bianchini SABCS<br />
2011). LowERS tumors are intrinsically endocrine resistant and<br />
at significant risk of relapse in the first 5 yrs after diagnosis. We<br />
studied lowERS and highERS BC in pts treated with neoadjuvant<br />
chemotherapy (NAC) and examined prognostic and predictive<br />
markers in the highest risk group of lowERS BC.<br />
Methods: We examined affymetrix gene expression data from<br />
193 ER+/HER2-, high proliferation BC from pts treated with<br />
taxane-anthracycline-based NAC followed by endrocrine therapy.<br />
Previously defined cut-offs for markers of proliferation (MKS),<br />
and estrogen-related genes were applied (Bianchini SABCS 2011).<br />
Within the lowERS group, we examined pts treated with no systemic<br />
adjuvant therapy (n=137; 50 events); adjuvant tamoxifen-only<br />
(n=141; 36 events); and NAC (n=127, 27 RCB0/I). We performed<br />
gene enrichment analysis for 2617 gene sets with known biological<br />
function (by 5000 random permutations). Primary endpoints were<br />
distant event free survival (DEFS) with follow-up censored at 5-yrs<br />
and pathological response (pathR) using the residual cancer burden<br />
(RCB) (Symmans JCO 2007).<br />
Results: The median follow-up of the NAC series was 3.1yrs. The<br />
DEFS at 4yrs was 0.94 [0.87-1.00] and 0.70 [0.60-0.81] in the high<br />
and low ERS groups, respectively (p=0.004) (despite the higher rate<br />
of pathR (RCB0/I) to NAC in the low ERS group (9.5% and 21.9%;<br />
p=0.04)). The pathR was prognostic in the lowERS group [HR 9.1<br />
(CI 1.23-67.4); p=0.009] but not in highERS (p=0.485). In contrast,<br />
a different outcome was observed in BC with RCBII-III, were the<br />
4-yrs DEFS was 0.93 [0.86-1.00] and 0.61 [0.49-0.76] in high and low<br />
ERS group, respectively (p=0.0007). In the lowERS group there was<br />
substantial overlap in biological functions associated with prognosis in<br />
both tamoxifen-treated and untreated pts. At a conservative threshold<br />
of p 1700) demonstrated a prognostic power of the EP score<br />
beyond what can be achieved by combining the commonly used<br />
clinicopathological parameters (Filipits M, 2011). The performance<br />
of the EP in chemotherapy-treated patients has not been evaluated<br />
yet. Here, we analyzed the EndoPredict score in node-positive ER+/<br />
HER2- BC patients from the GEICAM-9906 trial, treated with<br />
adjuvant chemotherapy followed by hormonal therapy.<br />
Methods: Patients included in this study participated in the<br />
GEICAM/9906 trial and were either treated with fluorouracil,<br />
epirubicin, and cyclophosphamide (FEC) or with FEC followed by<br />
weekly paclitaxel (FEC-P) (Martin M, 2008). ESR1 and ERBB2 gene<br />
expression were assessed by qRT-PCR in 800 formalin-fixed paraffin<br />
embedded (FFPE) tumor samples out of 1246 patients included in<br />
the GEICAM/9906 trial. The EndoPredict score (including eight<br />
prognostic genes) was successfully determined in 555 out of the<br />
566 ER+/HER2- patients. Patients were assigned into two categories<br />
(high/low), according to the predefined EP cut-off value (Filipits M,<br />
2011). The primary endpoint for the analysis was distant metastasis.<br />
Metastasis rates were estimated using the Kaplan–Meier method.<br />
Multivariate analysis was performed using Cox regression. Interaction<br />
between treatment effects and EP was tested as well.<br />
Results: Twenty-five percent of patients (n=141) were classified as<br />
EP-low-risk. Kaplan Meier analysis demonstrated that the metastasisfree<br />
survival (MFS) was 92% in the EP-low risk vs. 69% in the<br />
EP-high-risk group (absolute difference of 23%, HR 4.4 (2.3-8.4) p<br />
< 0.0001). Multivariate analysis showed that EP is an independent<br />
prognostic parameter after adjustment for age, grade, lymph node<br />
status and tumor size. EP was found to be prognostic in pre-<br />
(p=0.0002, HR = 5.5 (2.2-13.6)) and postmenopausal (p=0.0129, HR<br />
= 3.3 (1.3-8.2)) BC patients. There were not statistically significant<br />
differences in MFS between treatment arms (FEC vs. FEC-P) neither<br />
in the high nor in the low-risk groups. Interaction test between<br />
chemotherapy arm and EP score was not significant.<br />
Conclusions: The results of this study shows that the EndoPredict<br />
score is an independent prognostic parameter in node-positive, ER+/<br />
HER2- BC patients treated with adjuvant chemotherapy followed<br />
by hormonal therapy. EndoPredict was not found to be predictive of<br />
weekly paclitaxel efficacy. Novel predictive biomarkers are needed<br />
to identify the small subset of patients with ER+/HER2- tumors that<br />
actually benefit from weekly paclitaxel-containing regimens.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
246s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
P2-10-12<br />
How well predict the 2011 St Gallen early breast cancer surrogate<br />
phenotypes metastatic survival?<br />
Vanderstichele A, Brouckaert O, Tuyls S, Amant F, Leunen K, Smeets<br />
A, Berteloot P, Van Limbergen E, Weltens C, Peeters S, Moerman P,<br />
Floris G, Paridaens R, Wildiers H, Vergote I, Christiaens M-R, Van<br />
Calster B, Neven P. University Hospitals, Leuven, Belgium<br />
BACKGROUND<br />
The five prognostic surrogate phenotypes, defined by the 2011 St<br />
Gallen consensus, predict metastatic relapse following early breast<br />
cancer treatment (Brouckaert et al Ann Oncol 2012). It is unknown to<br />
what extent these surrogate phenotypes defined on the primary tumor<br />
predict metastatic survival (MS) in a cohort of consecutive women<br />
with metachronous metastases.<br />
PATIENTS & METHODS<br />
All 4318 patients with primary operable breast cancer, diagnosed<br />
between 01-01-2000 and 31-12-2009 and treated in our center were<br />
prospectively entered in our institutional database. We included 345<br />
patients with a (distant) metastatic relapse during their follow-up.<br />
We observed metastatic survival as the time between the diagnosis<br />
of the relapse and death. Tumor subtype was defined according to<br />
the 2011 St Gallen recommendations in 5 groups: luminal A (ER+/<br />
HER2-, grade 1-2), luminal B1 (ER+/HER2-, grade 3), luminal B2 or<br />
luminal-HER2 (ER+/HER2+), HER2-like (ER-/HER2-) and triplenegative.<br />
We focused on the value of the primary tumor subtype as<br />
a major prognostic determinant, but also assessed age at diagnosis,<br />
tumor size, lymph node involvement, tumor subtype, PR-status,<br />
primary detection (screening vs. palpation), histology, adjuvant<br />
therapy, distant-metastasis free interval (DMFI), first-line metastatic<br />
hormonal therapy, recurrence sites (isolate or multiple) and metastasis<br />
detection (clinical vs. biochemical).<br />
RESULTS<br />
In our cohort, we recorded a median metastatic survival (MS) of<br />
22.3 months (95% CI: 19.7 – 25.6) and a 5-year survival probability<br />
of 15%. Significant differences in median MS were noted when<br />
considering the primary tumor subtype (cf. table).<br />
We observed an independent prognostic effect for multiple recurrence<br />
sites (HR = 1.78, 95% CI 1.37-2.32), first-line metastatic hormonal<br />
therapy (HR = 0.30, 95% CI 0.18 - 0.49), DMFI (HR = 0.92 CI 0.85-<br />
0.98) and, finally, primary tumor subtype.<br />
Independent prognostic factors in metastatic breast cancer survival<br />
VARIABLE N (%)<br />
DESCRIPTIVE<br />
UNIVARIATE<br />
MULTIVARIATE<br />
ANALYSIS<br />
ANALYSIS<br />
ANALYSIS<br />
Median MS P-value Hazard Ratio P-value Hazard Ratio P-value<br />
(95% CI) (Logrank) (95% CI) (Logrank) (95% CI) (Wald)<br />
Luminal A 100 (29.2) 2.61 (2.14 - 3.07)
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Results:<br />
34 675 non-TNBC patients achieved a DFS of 92,4 % at 2 years and<br />
81,2 % at 3 years whereas out of 3728 TNBC-patients only 79 %<br />
were disease-free at 2 years and 57,4 % at 3 years.<br />
With regards to overall survival 97,3 % of non-TNBC patients were<br />
alive at 2 years and 92,2 % at 3 years, whereas 89,3 % TNBC-patients<br />
were alive at 2 years and 82,9 % at 3 years.<br />
Conclusion:<br />
In this large registry of certified breast units from the West German<br />
<strong>Breast</strong> Center we could underline the significant differences of<br />
prognosis as to DFS and OS between the non-TNBC and TNBCsubgroup<br />
of patients, displaying survival rates with modern 3 rd<br />
generation chemotherapy, surgical treatment and radiotherapy in a<br />
controlled setting with prospectively collected data.<br />
To is, to our best knowledge, one of the largest data sets ever exploring<br />
the differences in prognosis between TNBC and non-TNBC-patients.<br />
P2-10-15<br />
Evaluation of Prognostic and Predictive Performance of <strong>Breast</strong><br />
<strong>Cancer</strong> Index and Its Components in Hormonal Receptor-Positive<br />
<strong>Breast</strong> <strong>Cancer</strong> Patients: A TransATAC Study<br />
Sgroi DC, Sestak I, Zhang Y, Erlander MG, Schnabel CA, Goss PE,<br />
Cuzick J, Dowsett M. Massachusetts General Hospital and Harvard<br />
Medical School, Boston, MA; Queen Mary University, London, United<br />
Kingdom; bioTheranostics Inc, <strong>San</strong> Diego, CA; Royal Marsden<br />
Hospital, London, United Kingdom<br />
Background: The Arimidex, Tamoxifen, Alone or in Combination<br />
(ATAC) trial compared the efficacy and safety of 5 years of<br />
anastrozole with tamoxifen as adjuvant treatment for postmenopausal<br />
women with localized HR+ breast cancer. At a median follow-up of<br />
10 years, a statistically significant improvement with anastrozole<br />
vs. tamoxifen for disease-free survival, time to recurrence and time<br />
to distant recurrence was observed. The HOXB13:IL17BR gene<br />
expression ratio (H/I) quantifies recurrence risk in ER positive (ER+)<br />
breast cancer patients and is predictive of benefit from endocrine<br />
therapy. Molecular Grade Index (MGI) is a five-gene index that<br />
provides quantitative and objective molecular assessment of tumor<br />
grade and proliferative status. <strong>Breast</strong> <strong>Cancer</strong> Index (BCI) combines<br />
H/I and MGI into a continuous risk model that provides a likelihood<br />
of distant recurrence in patients treated with endocrine therapy, and<br />
efficacy from neoadjuvant chemotherapy. In the current analysis,<br />
evaluation of the prognostic and predictive performance of BCI, H/I<br />
and MGI in the ATAC study cohort was conducted.<br />
Methods: Under the TransATAC protocol, formalin-fixed, paraffinembedded<br />
(FFPE) blocks of primary tumor were collected from HR+<br />
patients from each monotherapy arm. The current study examined<br />
samples collected from the United Kingdom, which constituted<br />
79% of the collection. RNA extracted from 1102 samples from the<br />
TransATAC study was amplified, converted to cDNA and subjected<br />
to RT-PCR with primers and probes to HOXB13, IL17BR, BUB1A,<br />
CENPA, NEK2, RACGAP1 and RRM2. H/I, MGI and BCI were<br />
calculated and risk groups were determined using pre-specified<br />
cutpoints.<br />
Results: Of 1102 tumor specimens assayed, 29 failed QC criteria,<br />
leaving 1073 samples for analysis. Detailed results on the prognostic<br />
and predictive performance of BCI, H/I and MGI will be presented.<br />
Data on whether BCI and its components provided independent<br />
prognostic information in the presence of classical variables, their<br />
prognostic value for risk of late recurrence, interaction by treatment<br />
arms, and comparative performance vs other models will also be<br />
discussed.<br />
Discussion: The ATAC trial has established the long-term efficacy and<br />
safety of anastrozole over tamoxifen as initial adjuvant treatment for<br />
post-menopausal early stage breast cancer patients. Continued efforts<br />
are needed to improve on quantification of residual risk in patients<br />
who were treated with endocrine therapy to guide decision-making<br />
in selecting additional adjuvant chemotherapy and/or administering<br />
extended endocrine treatment. This study will help to establish the<br />
strategy to more effectively select patients for adjuvant therapies.<br />
P2-10-16<br />
Quantitative HER3 protein expression and PIK3CA mutation<br />
status in matched samples from primary and metastatic breast<br />
cancer tissues and correlation with time to recurrence<br />
Sperinde J, Lara J, Michaelson R, Sun X, Conte P, Guarneri V,<br />
Barbieri E, Ali S, Leitzel K, Weidler J, Lie Y, Cook J, Haddad M,<br />
Paquet A, Winslow J, Howitt J, Hurley L, Eisenberg M, Petropoulos<br />
C, Huang W, Lipton A. Monogram Biosciences/Integrated Oncology/<br />
LabCorp, South <strong>San</strong> Francisco, CA; Saint Barnabas Medical Center,<br />
Livingston, NJ; University of Modena, Modena, Italy; Penn State/<br />
Hershey Medical Center, Hershey, PA; Lebanon VA Medical Center,<br />
Lebanon, PA; Laboratory Corporation of America, Research Triangle<br />
Park, NC<br />
Background: HER3 is thought to play a prominent role in resistance<br />
to HER2-directed breast cancer therapies. Recent data suggest that<br />
HER3 levels also influence HER2-normal breast tumor biology. HER3<br />
and PI3K signaling are linked in that in HER3 signaling activates<br />
PI3K and inhibition of PI3K activity can upregulate HER3 expression.<br />
Here, we measured quantitative HER3 protein expression levels and<br />
PIK3CA mutation status in matched tissues from the primary tumor<br />
and site of metastasis to assess correlations with time to recurrence.<br />
Methods: 44 pairs (8 HER2+ by HERmark®) of matched tissues from<br />
the primary tumor and the site of metastasis were evaluated for HER3<br />
protein expression using a sensitive, quantitative assay for HER3<br />
protein expression in FFPE tissue sections (VeraTag®). Matched<br />
samples were also evaluated for quantitative HER2 expression<br />
(HERmark) and for PIK3CA mutations at exon 9 (E542K and E545K)<br />
and exon 20 (H1047R).<br />
Results: HER3 protein expression at the metastatic site was largely<br />
independent of HER3 levels at the primary site (Spearman p=0.50) in<br />
contrast to HER2 expression (Spearman p=0.0004). HER3 expression<br />
in the primary tumor correlated with time to recurrence (TTR)<br />
(HR=2.0 per 2-fold increase in HER3; p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
tumor but not the metastatic tumor were associated with longer TTR.<br />
These observations suggest that HER3 protein expression may be an<br />
important prognostic factor for breast cancer progression.<br />
P2-10-17<br />
SET index predicts response to endocrine therapy rather than<br />
prognosis independently of other genomic signatures in a blinded<br />
validation study.<br />
Karn T, Hatzis C, Symmans F, Pusztai L, Ruckhäberle E, Schmidt M,<br />
Müller V, Hanker L, Heinrich T, Holtrich U, Kaufmann M, Rody A.<br />
Goethe-University; Nuvera Biosciences; The University of Texas MD<br />
Anderson <strong>Cancer</strong> Center; Gutenberg-University Mainz; University<br />
Hospital Hamburg-Eppendorf; Saarland-University, Homburg<br />
Background:<br />
A genomic index for sensitivity to endocrine therapy (SET) was<br />
previously derived from genes strongly positively and negatively<br />
coexpressed with estrogen receptor (Symmans et al. 2010, JCO<br />
28:4111). This SET index has been reported to predict survival benefit<br />
from adjuvant endocrine therapy independently of prognosis.<br />
Materials and Methods:<br />
Affymetrix gene expression profiling was performed on 307 ER<br />
positive primary breast cancers from a retrospective cohort treated<br />
solely with endocrine therapy. In a blinded study the SET index’ ability<br />
to predict survival was analyzed in this previously unpublished dataset.<br />
Affymetrix profiles (CEL files) were anonymized and provided to the<br />
developers of SET index (Nuvera Biosciences) without any clinical<br />
information. The 261 profiles that passed QC were categorized into<br />
SET classes based on the published prespecified cutoffs. Samples<br />
categorized as ER negative based on gene expression were excluded.<br />
Subsequently classifications were unblinded and clinical associations<br />
analyzed according to a predefined protocol. Exploratory analyses<br />
were performed on the relationship of SET index to other genomic<br />
signatures. We also assessed a potential pure prognostic value of<br />
SET index in an additional dataset of 164 node negative ER positive<br />
patients that did not receive any adjuvant treatment.<br />
Results:<br />
A lower SET index significantly correlated with higher grade<br />
(P=0.009) and negative PgR status (P=0.016). We detected no<br />
significant differences for age, tumor size, lymph node status, and<br />
HER2 status between patients with high, intermediate, and low SET<br />
index. In the lymph node negative (LNN) cohort (n=120) we observed<br />
a significant difference in DFS (5yr DFS 77.1±10.2% vs 94.4±2.2%;<br />
HR 4.20, 95% CI 1.72-10.2; P=0.002) and DMFS (HR 3.18, 95%<br />
CI 1.20-8.47; P=0.020) for patients with low SET index. In contrast,<br />
we found no prognostic value of SET index in lymph node positive<br />
patients (n=95). In multivariate analyses of LNN patients including<br />
SET, age, tumor size, histological grade, and PgR status, only SET<br />
was significantly associated with DFS (HR 3.37, 95% CI 1.25-9.01;<br />
P=0.016) and DMFS (HR 3.03, 95% CI 1.08-8.55; P=0.036). In<br />
exploratory analyses SET index was not correlated to other genomic<br />
signatures related to proliferation (as Recurrence Score, GGI, and<br />
NKI70) or immune response (e.g. 7IGS, SDPP). When we included<br />
all these genomic signatures as continous scores in a multivariate<br />
stepwise Cox regression model in the LNN endocrine treated cohort,<br />
only SET remained as significant (P=0.025) while Recurrence Score<br />
displayed a strong trend (P=0.054). We also verified that SET had<br />
no pure prognostic value in an additional dataset of 164 ER positive<br />
patients that did not receive any adjuvant treatment.<br />
Conclusions:<br />
In a blinded analysis the predictive ability of SET index was<br />
prospectively validated in an independent cohort of node-negative<br />
patients. Our exploratory analysis demonstrates that SET index is<br />
unrelated to other genomic signatures and delivers independent<br />
information on the response of patients to endocrine therapy rather<br />
than prognosis.<br />
P2-10-18<br />
Cell Cycle Profiling – risk score (C2P-RS) based on the specific<br />
activity of CDK1 and CDK2 predicts relapse in node-negative,<br />
hormone receptor-positive breast cancer treated with endocrine<br />
therapy<br />
Kim SJ, Masuda N, Tsukamoto F, Inaji H, Akiyama F, Sonoo H,<br />
Kurebayashi J, Yoshidome K, Tsujimoto M, Takei H, Masuda S,<br />
Nakamura S, Noguchi S. Graduate School of Medicine, Osaka<br />
University, Suita, Osaka, Japan; National Hospital Organization<br />
Osaka National Hospital, Osaka, Japan; Osaka Koseinenkin<br />
Hospital, Osaka, Japan; Osaka Medical Center for <strong>Cancer</strong> &<br />
Cardiovascular Diseases, Osaka, Japan; The <strong>Cancer</strong> Institute of<br />
Japan Foundation for <strong>Cancer</strong> Research, Tokyo, Japan; Kawasaki<br />
Medical School, Kurashiki, Okayama, Japan; Osaka Police Hospital,<br />
Osaka, Japan; Saitama <strong>Cancer</strong> Center, Kita-Adachi, Saitama, Japan;<br />
Nihon University School of Medicine, Tokyo, Japan; Showa University<br />
School of Medicine, Tokyo, Japan<br />
Background: We have previously reported on the Cell Cycle Profiling<br />
(C2P) assay for determining the specific activity (SA, activity/<br />
expression) of cyclin-dependent kinases (CDKs). The C2P-risk<br />
score (C2P-RS) based on CDK1 and CDK2 SAs was significantly<br />
associated with “tumor growth speed” in xenograft models and<br />
relapse in early breast cancer. This study was conducted to confirm<br />
the prognostic performance of C2P-RS classification in node-negative<br />
and hormone receptor (HR)-positive (ER- and/or PR-positive) breast<br />
cancers.<br />
Methods: This multicenter and blinded retrospective study included<br />
patients with node-negative, HR-positive tumors treated with<br />
endocrine therapy alone. Patients treated with adjuvant chemotherapy<br />
or trastuzumab or any kind of neoadjuvant treatments were excluded.<br />
C2P-RS was determined via the C2P assay (Sysmex Corporation,<br />
Kobe, Japan) using frozen samples obtained during surgery. C2P-RS<br />
classification based on C2P-RS and CDK1 SA classified patients into<br />
three groups (low, intermediate, and high C2P-RS groups) using the<br />
same cut-off values as previously reported. ER, PR, HER2, and Ki-<br />
67 expressions were centrally evaluated with immunohistochemistry.<br />
The primary endpoint was the 5y-relapse-free survival (RFS) rate.<br />
Results: Of 317 patients enrolled in this study, 266 (24-85 y) were<br />
eligible: menopausal status: pre- 44%, post- 56%; histologic grade:<br />
I 24%, II 58%, III16%; ER: positive 93%; PR: positive 82%; HER2:<br />
negative 96%. 22 (8.3%) patients relapsed within 5 y after surgery<br />
(median follow-up period, 73 mo). The distribution of each C2P-RS<br />
group was 71.8% in the low group, 12.0% in the intermediate group,<br />
and 16.2% in the high group. The Kaplan-Meier method showed that<br />
the 5y-RFS rate in the high C2P-RS group (74.4%) was significantly<br />
lower than that in the intermediate (84.3%) or the low C2P-RS<br />
groups (97.3%) (P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
and Ki-67 expression (P=0.009) were significantly associated with<br />
relapse. However, multivariate Cox analysis showed that only C2P-<br />
RS classification was a significantly independent prognostic factor<br />
(the low C2P-RS group vs. the high C2P-RS group: P
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
ER- disease in a large scale breast cancer cohort with long term follow<br />
up. The effect seems unrelated to systemic endocrine treatment or<br />
chemotherapy.<br />
P2-10-21<br />
Prognostic value of estrogen receptor status in women with<br />
synchronous or metachronous breast cancers<br />
Huo D. University of Chicago, IL<br />
Background: Estrogen receptor (ER) is an important prognostic<br />
and predictive factor for breast cancer (BC) patients. For women<br />
with two primary breast cancers, however, estrogen receptor status<br />
measured at the two tumors is not always the same, either due to<br />
tumor heterogeneity, or because of limited reproducibility of receptor<br />
assays. For women with metachronous breast cancers, it is unclear if<br />
estrogen receptor status of previous cancer has prognostic value. For<br />
women with synchronous breast cancers, it is important to know if<br />
inconsistent receptor status predicts worse clinical outcome.<br />
Methods: Data on ER status of two primary breast cancers were<br />
obtained from the Surveillance, Epidemiology, and End Results<br />
program 1990-2009. We used piecewise proportional hazard Cox<br />
models to examine the joint effect of ER statuses of two tumors on<br />
overall survival or disease-free survival. Hazard ratio (HR) and 95%<br />
confidence interval (CI) were calculated, after adjusting for age,<br />
stage, race/ethnicity, histology, grade, and treatments in Cox models.<br />
Synchronous and metachronous cases were analyzed separately.<br />
Results: There are 12,285 patients with synchronous breast cancers;<br />
81.2% had both tumors being ER positive, 10.2% had one tumor<br />
being ER positive but the other being ER negative, and 5.6% had<br />
both tumors being ER negative. As shown in the Table, patients with<br />
inconsistent ER status (heterogeneity) had worse short-term survival<br />
rate than patients with double ER positive tumors. Among the 14,470<br />
patients with metachronous breast cancers, 60.2% had two ER+<br />
tumors, 13.8% had two ER- tumors, 11.8% had ER status changing<br />
from negative to positive, and 14.1% had ER status changing from<br />
positive to negative. In addition to ER status of the index cancer, ER<br />
status of the first cancer has independent prognostic value in predicting<br />
both short-term and long-term outcome (p=0.0002).<br />
Table. Overall survival and estrogen receptors status in two primary breast cancers<br />
HR (95% CI), < 5 years HR (95% CI), >= 5 years<br />
ER in synchronous cases<br />
Both + 1.0 (ref.) 1.0 (ref.)<br />
One +, one - 1.72 (1.49-1.98) 0.99 (0.77-1.26)<br />
Both - 2.55 (2.22-2.93) 0.75 (0.57-0.99)<br />
ER in metachronous cases<br />
Both + 1.0 (ref.) 1.0 (ref.)<br />
- to + 0.96 (0.82-1.11) 0.75 (0.59-0.96)<br />
+ to - 1.46 (1.30-1.64) 0.67 (0.53-0.85)<br />
Both - 2.08 (1.85-2.35) 0.62 (0.47-0.82)<br />
Conclusions: Our study found that estrogen status of previous cancer<br />
has independent prognostic value for women with metachronous<br />
breast cancers. We also found that inconsistency in ER status between<br />
two tumors predicts worse survival for women with synchronous<br />
breast cancer. These findings suggest that heterogeneity or change<br />
in estrogen receptor expression in patients with two breast cancers<br />
should be considered during decision making on treatment or<br />
counseling on prognosis.<br />
P2-10-22<br />
Phosphorylation of Steroid Receptor Coactivator 3 (SRC3) at<br />
Ser543 is a novel independent prognostic marker in breast cancer<br />
Palmieri C, Gojis O, Rudraraju B, Abdel-Fatah TMA, Moore D,<br />
Shaw J, Green A, Ellis IO, Coombes RC, Ali S. Imperial College<br />
London, United Kingdom; Nottingham University City Hospital,<br />
Nottingham, United Kingdom; University of Leicester, United<br />
Kingdom; Nottingham University Hospitals, City Hospital Campus,<br />
Nottingham, United Kingdom<br />
Introduction:<br />
Steroid receptor coactivator 3 (SRC3) acts as a coactivator of nuclear<br />
receptors including estrogen receptor-alpha (ER). SRC3 has been<br />
implicated in the pathogenesis of breast cancer (BC) as well as in<br />
resistance to endocrine therapy. SRC3 is phosphorylated at a number<br />
of residues following the stimulation of growth factors or hormones.<br />
Tyr24 and Ser543 are both phosphorylated upon estrogen stimulation,<br />
while Tyr24 is modulated by JNK and Ser543 by both p38 and JNK.<br />
To date, the importance and potential role of phosphorylation at these<br />
residues has not been explored in BC. In this study we assessed the<br />
protein expression of SRC3, pTyr24 and pSer543 and association<br />
with clinico-pathological features and outcome in a well defined<br />
breast cancer series.<br />
Methods:<br />
The expressions of SRC3, pTyr24 and pSer543 were assessed in the<br />
Nottingham Tenovus Primary <strong>Breast</strong> <strong>Cancer</strong> Series which consists<br />
of 1650 cases of primary invasive. SRC3, pTyr24 and pSer543 were<br />
correlated with clinico-pathological data as well as outcome.<br />
Results:<br />
SRC3 expression was significantly associated with unfavourable<br />
clinicopathological features including ER -ve (p=0.02), PR –ve<br />
(p=.038), HER2 overexpression (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Conclusion:<br />
Phosphorylation at Ser543 is associated with a luminal phenotype,<br />
positive prognostic factors and sensitivity to tamoxifen. Furthermore,<br />
it is an independent prognostic factor. pS543 is a novel prognostic<br />
marker in BC and warrants further investigation.<br />
P2-10-23<br />
Lymphovascular Invasion (LVI) and Overall Survival in Nodenegative<br />
and Node-positive <strong>Breast</strong> <strong>Cancer</strong> Patients: A Metaanalysis.<br />
Sahebjam S, Diaz-Padilla I, Ocana A, Seruga B, Amir E. Princess<br />
Margaret Hospital; Institute of Oncology Ljubljana<br />
Introduction: LVI is an important prognostic factor in patients with<br />
lymph node-negative invasive breast cancer. The prognostic value of<br />
LVI in lymph node-positive disease or in other subgroups remains<br />
unclear. Here we present a meta-analysis of studies assessing the<br />
impact of LVI on overall survival (OS) in different subgroups of<br />
breast cancer patients.<br />
Methods: A published data meta-analysis was conducted. Studies<br />
reporting hazard ratios (HR) for the association of LVI with OS in<br />
a multivariable model were included. Those not reporting HR or<br />
utilizing only univariable analyses were excluded. HR and 95%<br />
confidence intervals (CI) were extracted or computed and pooled<br />
using the DerSimonian and Laird random effects model. Subgroup<br />
analyses were conducted for the differential effect of lymph node<br />
involvement, estrogen receptor (ER) status, extent of LVI and decade<br />
in which the study was conducted (pre 1990, 1990-1999 and 2000<br />
onwards).<br />
Results: Twenty studies comprising 40,417 patients were included<br />
in the analysis. There was marked heterogeneity in the effect size<br />
between studies (Cochran Q p=5 U/ml had an 81% increased risk for<br />
recurrence (HR=1.810 [CI: 1.111-2.948]) and reduced overall<br />
survival (HR=1.020 [CI: 1.004 – 1.037]). In the multivariate analysis<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
252s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
taking into account tumor size, nodal status, grading, age, hormonal<br />
and HER2/neu receptor status increasing CA27.29 levels were an<br />
independent prognostic marker.<br />
Conclusions: An increase of the tumor marker CA27.29 2 years after<br />
CHT compared to pre-chemotherapy baseline was associated with<br />
a worse prognosis. By using this approach, more patients at risk for<br />
recurrence were detected than with the standard threshold approach.<br />
Therefore, the use of relative change could help to identify more<br />
patients at risk for relapse who might benefit from an intensified<br />
follow up.<br />
P2-10-26<br />
Association between circulating tumor cells and molecular breast<br />
cancer subtypes<br />
Gang N, Haibo W, Funian L, Chen L, Xiaoyi L, Xingang W, Zhidong L.<br />
Affiliated Hospital of Medical College, Qingdao University, Qingdao,<br />
Shandong, China<br />
Background and Objective: Circulating tumor cells (CTCs) provide<br />
crucial information for the management of breast cancer patients.<br />
CTCs analysis can be used as a liquid biopsy approach for prognostic<br />
and predictive purposes in breast and other cancers. Several<br />
contradictory results presented about the breast cancer subtypes of<br />
CTCs recently. The aim of this study was therefore to analysis the<br />
association between the CTCs and molecular breast cancer subtypes.<br />
Methods: Blood samples were obtained from 143 breast cancer<br />
patients admitted to <strong>Breast</strong> Surgery Department, Affiliated Hospital of<br />
Medical College, Qingdao University. CTCs were detected by using<br />
immunomagnetic enrichment and a commercial kit, based on RT-PCR,<br />
was used to characterize CTCs. The expression of ER, PR, HER2<br />
was detected by immunohistochemistry. The molecular subtypes were<br />
defined as: luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/<br />
or PR+, HER2+), TNBC (ER-, PR-, HER2-), and HER2+, (ER-,PR-,<br />
and HER2+). The relations between the positive rate of CTCs and<br />
clinicopathological characteristics of primary tumor and molecular<br />
subtypes of breast cancer patients were analyzed.<br />
Results: Overall positive rate of CTCs was 39.8% (57/143). The<br />
positive rate of CTCs in patients with Luminal A, Luminal B ,HER2+<br />
and TNBC subtype was 33.8% (26/77), 47.1% (8/17),50.0% (6/12)<br />
and 45.9%(17/37).There was significant difference in positive rate<br />
of CTCs by different molecular subtypes (P = 0.0415), especially<br />
at different AJCC stages (P = 0.004).The positive rate of CTCs in<br />
patients with Luminal A subtype was significantly lower than patients<br />
with the others breast cancer subtypes (P=0.0387).<br />
Conclusion: Our study suggests that presence of CTCs was more<br />
frequently found in patients with HER2+ and Luminal B subtypes.<br />
The presence of CTCs in patients with TNBC subtype was not as<br />
high as we wished. Theoretically, the positive rate of CTCs in TNBC<br />
subtype should be higher than that of others subtypes for being more<br />
aggressive histologically features and having increased potential to be<br />
invasive. One possible explanation for this might because of lacking<br />
epithelial markers expression and epithelial-mesenchyme transition<br />
(EMT) characteristics, CTCs of TNBC subtype are missed when using<br />
the standard EpCAM-based method. Shortage of patient’s number<br />
was another possible reason. Further research on the Association<br />
between CTCs and molecular breast cancer subtypes will contribute<br />
to a better understanding of the biology of metastatic development<br />
in cancer patients.<br />
P2-10-27<br />
No Discordant Receptor Status Results among 50 Paired <strong>Breast</strong><br />
and Axillary Metastasis Core Biopsies when Pre-analytic<br />
Variation is Controlled.<br />
Miller DV, Rosenthall RE, Avent JM, Carter CC, Hansen J, Hammond<br />
MEH. Intermountain Healthcare, Salt Lake City, UT<br />
Background: Discrepancy in Her2, estrogen receptor (ER), and<br />
progesterone receptor (PR) status among primary breast tumors and<br />
their axillary lymph node metastases has been reported in the range<br />
of 6-18%, leading to uncertainty as to the optimal sample for testing.<br />
It has been hypothesized this reflects heterogeneity within a given<br />
patient’s tumor, however the pre-analytic conditions (particularly<br />
time to fixation and fixation duration) for samples in these studies<br />
were either nonuniform for the sample pairs or else unspecified.<br />
Altered tissue antigenicity rather than true biologic alterations in<br />
receptor expression may account for some the discrepancy reported<br />
in the literature. This study of paired primary and metastatic tumors<br />
processed in a uniform fashion attempts to address this issue.<br />
Design: Core biopsy samples from 50 primary invasive ductal<br />
carcinomas and their corresponding ipsilateral axillary lymph node<br />
metastases obtained at the same procedure, using the same core biopsy<br />
sampling device, fixed under the same conditions, stained on the same<br />
staining runs, and analyzed using digital image analysis comprise the<br />
study cohort. Patient demographics and tumor characteristics (from<br />
subsequent excision specimens or clinical imaging) were obtained<br />
from medical records.<br />
Results: Complete agreement in Her2, ER, and PR scores was seen<br />
among all paired samples.The mean age of the 50 women was 51.72<br />
(27-86). Mean time to fixation was 2.55 minutes and the mean duration<br />
of fixation was 12.87 hours (6.4 -29.7). The Her2 scores were 0 = 2,<br />
1+ = 13, 2+ = 12, 3+ = 23. For 3+ cases, the mean tumor size was<br />
3.47 cm, 44% were ER negative and the mean tumor grade was 2.61<br />
(of 3). For 0/1+ cases, the mean tumor size was 3.86 cm, the mean<br />
tumor grade was 2.46 (38% were grade 3 and triple negative). The<br />
ER (Allred) scores were 0 = 17, 3 = 1, 4 = 1, 5 = 3, 6 = 9, 7 = 7, 8 =<br />
12. For ER negative tumors the mean tumor grade was 2.76. For ER<br />
positive tumors the mean tumor grade was 2.39 including all 3 grade<br />
1 tumors. Only minor discrepancies in Allred scores occurred between<br />
the paired samples; 5 with a difference of 1 (6-7, 7-8, 8-7, 7-6, 8-7);<br />
and one with a difference of 2 (8-6). The PR (Allred) scores were 0<br />
= 24, 2 = 3, 3 = 4, 4 = 8, 5 = 2, 6 = 6, 7 = 1. For PR negative tumors<br />
the mean tumor grade was 2.75. For PR positive tumors the mean<br />
tumor grade was 2.40, including all 3 grade 1 tumors. Only minor<br />
discrepancies in Allred scores occurred between the paired samples; 4<br />
with a difference of 1 (3-4, 4-5, 4-5, 6-7); and three with a difference<br />
of two (3-5, 4-6, 4-6). The mean age did not differ significantly by<br />
any receptor status.<br />
Conclusion: Under matched processing conditions, these 50 paired<br />
primary breast tumors and their corresponding lymph node metastases<br />
show congruent Her2 and ER staining results. This number of cases<br />
should have detected discrepancies in the range of 6-18%. Minor<br />
differences in staining intensity and %positive cells were noted, but<br />
none resulted in a positive vs negative mismatch. These data suggest<br />
the possibility that these minor differences, magnified through the<br />
influence of disparate fixation conditions, could account for the higher<br />
discrepancy rates reported in the literature.<br />
www.aacrjournals.org 253s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P2-10-28<br />
The Prognostic Index, KiGE, Combining Proliferation,<br />
Histological Grade and Estrogen Receptor Status Challenges<br />
Gene Profiling – A Study in 1,854 Chemo-Naïve Women with N0/<br />
N1 Primary <strong>Breast</strong> <strong>Cancer</strong>.<br />
Strand C, Bak M, Borgquist S, Chebil G, Falck A-K, Fjällskog M-L,<br />
Grabau D, Hedenfalk I, Jirström K, Klintman M, Malmtröm P, Olsson<br />
H, Rydén L, Stål O, Bendahl P-O, Fernö M. Lund University, Division<br />
of Oncology, Skåne University Hospital, Lund, Sweden; Odense<br />
University Hospital, Odense, Denmark; Mammography, Bergaliden,<br />
Helsingborg, Sweden; Helsingborg Hospital, Helsingborg, Sweden;<br />
Uppsala University Hospital, Uppsala, Sweden; Lund University,<br />
Skåne University Hospital, Lund, Sweden; Lund University, Division<br />
of Pathology, Lund, Sweden; Skåne University Hospital, Lund,<br />
Sweden; Linköping University, County Council of Östergötland,<br />
Linköping, Sweden; Lund University, Division of Surgery, Skåne<br />
University Hospital, Lund, Sweden<br />
Purpose<br />
The aim was to validate the prognostic value of a previously defined<br />
index (CAGE), combining proliferation (Cyclin A), histological<br />
grade, and estrogen receptor (ER) in different subsets of primary<br />
breast cancer patients. In the present study, Ki67 was included in the<br />
index (KiGE) instead of cyclin A, since it is the generally accepted<br />
proliferation marker in clinical routine.<br />
Patients and methods<br />
1,854 chemo-naive patients with primary breast cancer were included.<br />
The low KiGE group consisted of histological grade 1 cases and grade<br />
2 cases which were ER-positive and had low Ki67 expression. High<br />
KiGE consisted of all other cases.<br />
Results<br />
The KiGE index separated patients into groups with different<br />
prognosis. In multivariate analysis, KiGE was significantly associated<br />
with disease-free survival, when adjusted for age at diagnosis,<br />
tumor size and adjuvant endocrine treatment (hazard ratio: 3.5, 95%<br />
confidence interval: 2.6-4.7, P
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
P2-10-30<br />
Expression of lipid metabolism genes in contralateral unaffected<br />
breast associated with estrogen receptor status of breast cancer<br />
Wang J, Scholtens D, Holko M, Ivancic D, Lee O, Hu H, Chatterton<br />
RT, Khan SA. Northwestern university, Chicago, IL<br />
Background: Risk biomarkers that are specific to ER subtypes of<br />
breast cancer would help developing distinct prevention strategies.<br />
The contralateral unaffected breast of women with unilateral breast<br />
is a good model for defining subtype specific risk as women with<br />
ER- primary tumor are at high risk for subsequent ER- tumor in<br />
contralateral breast.<br />
Methods: We performed random fine needle aspiration of unaffected<br />
breast of cases. RNA samples from 30 subjects (15 ER+ and 15 ER-)<br />
were used for Ilumina expression array analysis. Findings were<br />
validated by qRT-PCR using independent sample set consisted of<br />
36 subjects (12 ER+, 12 ER-, and 12 standard risk healthy controls).<br />
Results: Gene array studies identified 18 genes with significant<br />
higher expression in ER- case samples , 8 of which were associated<br />
with lipid metabolism. This pattern was confirmed by qRT-PCR<br />
in the same samples and in the 24 cases of validation set. When<br />
compared to the healthy controls, significant over-expression of 4<br />
genes (DHRS2, HMGCS2, HPGD, ACSL3) was observed in ERcases,<br />
with significant lower expression of UGT2B11 and APOD in<br />
ER+ cases, and decreased expression of UGT2B7 in both subtypes.<br />
Conclusion: Differential expression of lipid metabolism genes my<br />
be involved in the risk for subtypes of breast cancer, which might be<br />
potential biomarkers of ER specific breast cancer risk.<br />
P2-10-31<br />
Correlation of quantitative p95HER2 and total HER2 levels<br />
with clinical outcomes in a combined analysis of two cohorts of<br />
trastuzumab-treated metastatic breast cancer patients<br />
Duchnowska R, Sperinde J, Leitzel K, Szostakiewicz B, Paquet A, Ali<br />
SM, Jankowski T, Haddad M, Fuchs E-M, Arlukowicz-Czartoryska<br />
B, Winslow J, Singer C, Wysocki PJ, Lie Y, Horvat R, Foszczynska-<br />
Kloda M, Petropoulos C, Radecka B, Litwiniuk M, Debska S, Weidler<br />
J, Huang W, Biernat W, Köstler WJ, Jassem J, Lipton A. Military<br />
Institute of Medicine, Warsaw, Poland; Monogram Biosciences/<br />
Integrated Oncology/LabCorp, South <strong>San</strong> Francisco, CA; Penn State/<br />
Hershey Medical Center, Hershey, PA; Medical University of Gdansk,<br />
Poland; Lublin Oncology Center, Lublin, Poland; Medical University<br />
of Vienna, Austria; Bialystok Oncology Center, Bialystok, Poland;<br />
Greater Poland <strong>Cancer</strong> Center, Poznan, Poland; West Pomeranian<br />
Oncology Center, Szczecin, Poland; Opole Oncology Center, Opole,<br />
Poland; Poznan University of Medical Sciences, Poznan, Poland;<br />
Regional <strong>Cancer</strong> Center, Lódz, Poland<br />
Background: Expression of p95HER2 (p95), a truncated form of<br />
HER2 also known as p110 or M611-CTF, is a possible trastuzumab<br />
resistance mechanism and has been associated with poor prognosis in<br />
trastuzumab-treated HER2-positive metastatic breast cancer (MBC).<br />
Previously we reported on optimal clinical cutoffs for quantitative<br />
p95 (Clin <strong>Cancer</strong> Res, 16:4226, 2010) and quantitative HER2 protein<br />
expression (H2T) by HERmark® (<strong>Cancer</strong>, 116:5168, 2010) that<br />
defined patient subsets with different progression-free survival (PFS).<br />
These cutoffs were confirmed in an independent trastuzumab-treated<br />
MBC cohort (ASCO 2011, #586). Here, using individual patient data,<br />
we performed an analysis on the combined data set of 243 cases from<br />
the discovery and validation cohorts to derive optimal cutoffs for<br />
quantitative p95 and H2T.<br />
Methods: Both quantitative H2T (HERmark, Monogram Biosciences)<br />
and p95 assays employed the VeraTag® method to quantify protein<br />
expression in formalin-fixed, paraffin-embedded tumor samples from<br />
two cohorts of 101 and 142 cases of trastuzumab-treated MBC with<br />
7.4 and 9.2 months median PFS, respectively. All analyses were<br />
stratified by hormone receptor status, tumor grade (3 vs. 1+2) and<br />
cohort. H2T measurements were compared to pre-specified cutoffs for<br />
HERmark negative (H2T17.8 RF/mm 2 ), derived from<br />
the 95 th percentile of centrally determined HER2-negatives, respectively,<br />
within a reference database of 1,090 breast cancer patient samples.<br />
Results: Patients classified as HERmark-positive had longer PFS<br />
than those classified as HERmark-negative (HR=0.52; p=0.0006;<br />
medians 10.0 and 5.9 months). The previously determined optimal<br />
H2T cutoff of 13.8 RF/mm 2 in the center of the HERmark-equivocal<br />
zone, gave a similar result (HR=0.54; p=0.0005). This was close to<br />
the optimal cutoff of 12.75 RF/mm 2 (HR=0.48; p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Whitney tests. Spearman’s correlation determined the non-parametric<br />
correlation between the serum levels of sLeX and the inflammatory<br />
mediators. The receiver operating characteristic (ROC) curves and<br />
the corresponding area under the curve (AUC) analyses were used<br />
to determine the sensitivity and specificity of a given cut-off value<br />
for a particular serum marker.<br />
Results: The median sLeX level tended to increase with the stage of<br />
disease: MBC > EBC > DCIS albeit without significant differences<br />
among the disease stages. Among MBC patients, patients with sLeX<br />
below 1.75 U/mL had significantly improved overall survival (OS,<br />
mean survival 11.1 vs. 33.7 months, P = 0.002) and progression-free<br />
survival (PFS, mean survival 9.7 vs. 20.9 months, P= 0.042). The<br />
Hazard Ratio of high sLeX for OS was 5.5 (95% CI 1.6 to 18.9, p =<br />
0.007) and 2.3 for PFS (95% CI 1.0 to 5.2, P = 0.048). EBC and MBC<br />
patients have significantly higher serum levels of IL-1, IL-1RA, IL-<br />
6, IL-8, MCP-1, MCP-3, and MIP-1βthan those of HD. In addition,<br />
there were positive correlations between the serum levels of sLeX<br />
and cytokines IL-1β, IL-1RA, IL-2, IL-8, MIP-1β, and MCP-3. The<br />
AUC for sLeX was 0.598 (P = 0.016), and a cut-off of 3.13 pg/mL<br />
distinguished hormone receptor (HR)-positive from HR-negative<br />
patients (χ2 = 4.0, P = 0.045). Likewise, the AUC for TNF-α was<br />
0.620 (P = 0.003), and a cut-off 7.18 pg/mL distinguished HR-positive<br />
from HR-negative patients (χ2 =12.6, P < 0.001). Using a cut-off<br />
value established by ROC curves, few MBC patients (9 of 66, 13.6%)<br />
had a serum IL-2 level > 7.1 pg/mL compared to 57 of 185 (30.8%)<br />
non-MBC patients (χ2 =7.4, P = 0.007), suggesting that metastatic<br />
disease may be associated with immune suppression related to low<br />
serum IL-2. Conversely, 31of 66 (47%) MBC patients had a serum<br />
MCP-1 level > 750 pg/mL vs. 37 of 185 non-MBC patients (20%)<br />
(χ2 =23.8, P < 0.0001), suggesting that a high level of MCP-1 may<br />
play an important role in metastasis.<br />
Conclusion:<br />
Serum levels of sLeX were able to distinguish HR-positive from HRnegative<br />
patients and predict overall survival in metastatic patients.<br />
Serum sLeX and some inflammatory mediators tended to increase<br />
with the severity of disease, and together may facilitate local invasion<br />
of tumor cells. Furthermore, serum levels of MCP-1 and IL-2 may<br />
have prognostic value in breast cancer patients.<br />
P2-10-33<br />
Mitotic Component of Grade Can Distinguish <strong>Breast</strong> <strong>Cancer</strong><br />
Patients at Greatest Risk of Local Relapse<br />
Done SJ, Miller NA, Wei Shi W, Pintilie M, McCready DR, Liu F-F,<br />
Fyles A. University Health Network, Toronto, ON, Canada; Princess<br />
Margaret Hospital, University Health Network, Toronto, ON, Canada;<br />
University of Toronto, ON, Canada<br />
Background<br />
With the recent recognition of many different molecular subtypes of<br />
breast cancer a desire to more specifically categorize tumors to allow<br />
tailoring of treatment to individual patients has developed. This has<br />
largely involved the development of molecular tests rather than the<br />
re-examination of current pathologic criteria. We wanted to evaluate<br />
standard pathologic features to determine their ability to predict for<br />
local recurrence.<br />
Materials and Methods<br />
Slides were retrieved for review from 280 of 769 women who had<br />
participated in a trial of tamoxifen with or without breast irradiation<br />
between December 1992 and June 2000 and for whom outcome<br />
data up to 18 years was available. All women were 50 years of age<br />
or older at the time of enrollment and had T1 or T2 node negative<br />
breast cancer. The cases for which slides were obtained were<br />
representative of the whole group. The slides were reviewed by two<br />
breast pathologists (SJD and NAM). Several features were evaluated;<br />
modified Nottingham histologic grade and its components- degree of<br />
tubule formation, nuclear pleomorphism and mitotic count. Mitotic<br />
component of grade was calibrated to the microscopic field size used.<br />
The presence of lymphatic/vascular space invasion was also scored. A<br />
statistical analysis was performed to relate these pathologic features<br />
to local recurrence at up to 18 years.<br />
Results<br />
The strongest predictor of local recurrence was the mitotic component<br />
of the Nottingham histologic grade with 5.7% for mitotic score 1/3<br />
(n=200), 19.6% for mitotic score 2/3 (n=37) and 19.8% for mitotic<br />
score 3/3 (n=43)(Gray’s p-value = 0.0021). Overall grade was also<br />
able to predict for local recurrence with 2.6% for Grade 1 (n=49),<br />
10.6% for Grade 2 (n=162) and 17.9% for Grade 3 (n=71)(Gray’s<br />
p-value=0.026). However, neither architecture (0% vs. 9.5% vs.<br />
9.8%, Gray’s p-value=0.74) nor degree of nuclear pleomorphism<br />
(0% vs. 7.9% vs. 11.5%, Gray’s p-value=0.37), the other components<br />
of histologic grade, showed a statistically significant difference<br />
for recurrence. The presence or absence of endothelial lined space<br />
invasion was also found to be not statistically different (9.3% vs.<br />
13%, Gray’s p-value=0.55).<br />
Conclusion<br />
Within this cohort of tamoxifen treated T1 and T2 breast cancer<br />
patients 50 years of age or older, mitotic index could stratify women<br />
into groups with high and low risk of recurrence. If validated this may<br />
be a useful way of allocating patients to different treatment groups.<br />
Additional validation studies are planned on similar groups of patients.<br />
P2-10-34<br />
Development and validation of ClinicoMolecular Triad<br />
Classification (CMTC), a platform for breast cancer (BC)<br />
prognostic and predictive gene signature portfolios.<br />
Leong WL, Wang D-Y, Done S, McCready D. University Health<br />
Network, Toronto, ON, Canada<br />
Background: Numerous gene signatures have claimed prognostic<br />
significance in BCs. Each of these gene signatures was designed<br />
to answer a specific clinical or biological question, often by<br />
dichotomizing the targeted populations into a good and a bad risk<br />
group. None of these gene signatures on its own has sufficient degree<br />
of complexity to fully characterize this very heterogenous group of<br />
diseases, and hence lacks the flexibility to personalize treatments.<br />
To exploit the full potential of the genomic approach, we developed<br />
an 803-gene molecular classification, termed ClinicoMolecular<br />
Triad Classification (CMTC) that categorized BCs into 3 clinical<br />
treatment groups (triad) that can serve as a basic framework to<br />
guide management. CMTC also provide a detailed "portfolio" of 14<br />
other gene signatures and 19 oncogenic pathways to allow further<br />
customization of the treatments. The ability to get CMTC portfolio<br />
results at the time of initial diagnosis offers the unique advantage<br />
of early treatment planning, including the use of pre-operative<br />
chemotherapy to improve breast conservation in selected patients.<br />
This study aimed to validate the CMTC classification using an<br />
independent BC cohort.<br />
Study design/ results: RNA from fine needle aspirates were collected<br />
in a prospective BC cohort (n=340) between 2008 and 2010 at Princess<br />
Margaret Hospital and Mount Sinai Hospital, Toronto, we included<br />
all newly diagnosed BC patients going for surgery who consented<br />
to join the study. DNA microarray analyses were carried out using<br />
genome-wide Illumina Human Ref-8 version 3 Beadarrays, which<br />
contained >24K oligonucleotide probes. After excluding tumors with<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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low RNA yield (n=8, success rate 97%), non-invasive cancers (n=27),<br />
insufficient follow-up data (n=21), CMTC divided the remaining<br />
284 BCs into 3 similar sized groups (triad). At a median followup<br />
of 32 months (range 6.3-52 months), the short-term recurrence<br />
was significantly worse (P=0.0048) in the poor prognostic groups.<br />
This result was similar to using an independent external validation<br />
cohort (n=2100) with long-term follow-up reported before, CMTC<br />
outperformed all other gene signatures in predicting prognosis and<br />
treatment response.<br />
Discussion/conclusion: This prospective validation cohort study<br />
demonstrated reproducibility of CMTC in classifying BCs into the<br />
three major treatment groups and its prognostic significance. CMTC<br />
can be used as a platform to personalize treatments: CMTC-1 BCs<br />
(ER+, low proliferation) in general can be treated with surgery and<br />
tamoxifen alone. CMTC-2 tumours (ER+, high proliferation) will<br />
require additional treatments, including chemotherapy, in addition to<br />
tamoxifen; other biologics can be prescribed based on the activities of<br />
additional oncogenic pathways. Neo-adjuvant chemotherapy should<br />
be considered for CMTC-3 tumours (triple negative and HER2+) with<br />
addition of trastuzumab in those that show activation of the HER2<br />
pathway. CMTC portfolio is being further developed into a genomic<br />
platform to guide personalized BC treatments..<br />
P2-10-35<br />
The grade of accompanying DCIS in IDC as important prognostic<br />
factor<br />
Kim JY, Moon H-G, Han WS, Noh DY. Seoul National University<br />
Hospital, <strong>Breast</strong> <strong>Cancer</strong> Center, Seoul, Korea<br />
Backgrounds: The issue of whether concomitant ductal carcinoma<br />
in situ (DCIS) affects the prognosis of with invasive breast cancer is<br />
important but studies of this have reported inconsistent results. So we<br />
aimed to assess the character and prognostic difference in infiltrating<br />
ductal carcinoma (IDC) according to accompanying DCIS status.<br />
Methods: We reviewed the medical records of the patients who<br />
underwent surgery for IDC. Male patients, patients who had received<br />
neoadjuvant chemotherapy, patients with synchronous bilateral breast<br />
cancer, follow-up periods
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Material and methods<br />
From an original cohort of 569 patients with primary breast cancer,<br />
tissue microarrays were constructed from archival tissue blocks of<br />
primary tumour (n=521), paired lymph node metastasis (n=147) and<br />
biopsies from distant metastasis (n=42). The samples were evaluated<br />
by two independent pathologists. The individual biomarker expression<br />
as well as subtype classification (Luminal A: ER+ and/or PR+, Ki67≤<br />
20% and HER2-. Luminal B: ER+ and/or PR+, Ki67> 20% and/or<br />
HER2+. HER2 type: ER/PR-, HER2+. Basal-like: ER/PR-, HER2-,<br />
CK5/6+ and/or EGFR+) were compared between primary tumour,<br />
lymph node metastasis and distant metastasis. Survival outcome<br />
were estimated using the Kaplan-Meier method and log rank test.<br />
The primary end-point was distant disease-free survival (DDFS).<br />
Results<br />
Primary tumour N (%) Lymph node N (%) Distant metastasis N(%)<br />
ER >10% 454/521 (87%) 117/147 (79%) 33/42 (79%)<br />
PR >10% 330/490 (67%) 85/146 (58%) 23/42 (55%)<br />
HER2+ (SISH) 103/510 (20%) 43/136 (32%) 18/39 (46%)<br />
Ki67 >20% 168/514 (33%) 66/144 (46%) 22/41 (54%)<br />
EGFR+ 85/517 (16%) 28/147 (19%) 9/40 (22%)<br />
CK5/6+ 127/517 (25%) 38/145 (26%) 8/42 (19%)<br />
Distribution of individual biomarker expression.<br />
Primary tumour N (%) Lymph node N (%)<br />
Distant metastasis<br />
N (%)<br />
luminal A 265 (55%) 53 (39%) 9 (23%)<br />
luminal B 160 (33%) 58 (42%) 22 (56%)<br />
HER2 type 18 (4%) 14 (10%) 4 (10%)<br />
Basal-like 33 (7%) 12 (9%) 4 (10%)<br />
Distribution according to subtype.<br />
The molecular subgroups in the primary tumours were associated<br />
with statistically significant prognostic information by log-rank<br />
test (p=0.005) validating luminal A as a subgroup with excellent<br />
prognosis. More detailed survival analysis comparing expression<br />
of biomarkers between primary tumour, lymph node metastasis and<br />
distant metastasis will be presented.<br />
Conclusion<br />
Prognostic information can be obtained by subtype classification using<br />
routine-based biomarker analysis in the primary tumour. Preliminary<br />
data suggest that the subtype distribution is associated with a worse<br />
prognostic profile in the lymph node- and distant metastasis. Detailed<br />
survival analysis will be presented at the meeting.<br />
P2-10-37<br />
Long-term prognosis of early breast cancer in a population-based<br />
cohort with a known BRCA1/2 mutation status.<br />
Nilsson MP, Werner Hartman L, Idvall I, Kristoffersson U, Olsson H,<br />
Johansson O, Borg Å, Loman N. Clinical Sciences, Lund University,<br />
Sweden; Lund University, Sweden; Landspitali University Hospital,<br />
Reykjavik, Iceland<br />
Background:<br />
The impact of germline BRCA1/2 mutations on breast cancer<br />
prognosis and treatment is currently not clear. We investigate how<br />
different factors, including BRCA1/2 mutation status, correlate with<br />
long-term outcome in early breast cancer in a population-based cohort.<br />
Methods:<br />
As previously reported, all women in the Southern Health Care Region<br />
in Sweden with breast cancer diagnosed before age 41 years between<br />
1990 and 1995 (n=262) were contacted in 1996 and offered mutation<br />
analysis of the BRCA1 and BRCA2 genes. Mutation analysis was<br />
performed on 234 of them, the others were excluded from further<br />
studies. 23 pathogenic mutations were found; 18 in BRCA1 and 5 in<br />
BRCA2. We will now present data on tumor and patient characteristics,<br />
treatment and long-term follow-up for the patients from this<br />
population-based cohort. Three patients have declined further study<br />
follow-up and were therefore excluded. Six patients had metastatic<br />
breast cancer at the time diagnosis (one of them a BRCA2 mutation<br />
carrier) and are also excluded, leaving 225 in the present analysis.<br />
Results:<br />
Among the 225 cases estrogen receptor (ER) status is known for<br />
191 (49% ER+, 51% ER-); histologic grade for 169 (24% grade I;<br />
33% grade II; 43% grade III); stage for 225 (36% stage I, 44% stage<br />
II, 20% stage III); type of surgery, adjuvant systemic treatment and<br />
postoperative radiotherapy for 225. In the cohort, 46% received<br />
adjuvant or neoadjuvant chemotherapy, whereas 15% were given<br />
adjuvant endocrine therapy. There is complete follow-up > 10 years<br />
for 205 and present vital status for 224.<br />
Of the 225 women, 128 (57%) have had a local, regional or distant<br />
recurrence of breast cancer (contralateral breast cancer not included)<br />
at the date of last follow-up. One hundred and six patients (47%)<br />
have died, 98 of whom from breast cancer and 2 from presumably<br />
radiation-induced malignancies caused by postoperative radiotherapy.<br />
Thirteen of the 22 BRCA1/2 mutation carriers (59 %) have died, all<br />
from breast cancer. Of the 9 mutation carriers that are alive today, 3<br />
have had an in-breast tumor recurrence and 3 have had a contralateral<br />
breast cancer; the 3 women that have had neither have all performed<br />
bilateral prophylactic mastectomy as well as prophylactic salpingoooforectomy.<br />
Data on how the long-term prognosis of early breast cancer is<br />
correlated to BRCA1/2 mutation status, adjuvant treatment, stage<br />
at diagnosis, histologic grade and ER status of the tumor will be<br />
presented.<br />
Conclusion:<br />
Women with early breast cancer in this cohort from the early 90ies<br />
had a poor long-term prognosis. The prognosis for women diagnosed<br />
with early breast cancer today is likely to be better, thanks to more<br />
modern chemotherapy regimens, endocrine and targeted treatments.<br />
The prognostic significance of BRCA1/2 mutation status will be<br />
further analyzed.<br />
P2-10-38<br />
Prognostic factors uPA/PAI-1: measurement in core needle<br />
biopsies<br />
Vetter M, Landstorfer B, Lantzsch T, Buchmann J, Große R, Ruschke<br />
K, Holzhausen H-J, Thomssen C, Kantelhardt E-J. Martin-Luther<br />
University Halle-Wittenberg, Halle/Saale, Germany; St. Elisabeth &<br />
St. Barbara Hospital, Halle/Saale, Germany; Martha-Maria Hospital,<br />
Halle/Saale, Germany<br />
Background<br />
The urokinase-type plasminogen activator (uPA) and its inhibitor PAI-<br />
1 are validated as prognostic factors at the highest level of evidence<br />
within the node-negative group of breast cancer patients (Harris L et<br />
al., JCO 2007; 25:5287).<br />
Usually, patients receive a core-needle biopsy before surgery. A prior<br />
feasibility study showed that the method of sampling (ex vivo from<br />
the surgical specimen using a small core needle or the larger excision<br />
specimen) doesn’t influence the uPA and PAI-1 results (Thomssen et<br />
al., J Natl <strong>Cancer</strong> 2009; 101:1028). With the current study, we assessed<br />
how well uPA and PAI-1 values obtained from the core needle biopsy<br />
(in vivo) predict the expression level of these prognostic factors in<br />
the later surgical specimen.<br />
Material and Methods<br />
Fresh frozen material of 2-3 core needle biopsies (min 10 mg each)<br />
and the corresponding tumor material (min 50 mg) removed by<br />
subsequent surgery were collected from 110 patients in two hospitals.<br />
Only areas of the surgical specimen were selected for testing that had<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
a sufficient distance to the needle biopsy defect. The uPA and PAI-1<br />
concentrations were analysed using a commercially available ELISA<br />
test (FEMTELLE TM ; American Diagnostica, Inc., Stamford, CT).<br />
The predictive values (and sensitivity/specificity) of the core-needle<br />
biopsy data were calculated to forecast the uPA and PAI-1 values of<br />
the corresponding surgical specimen results.<br />
Results<br />
Sensitivity, specificity, the positive (ppv) and negative (npv) predictive<br />
values for uPA, PAI-1 and for the combination of uPA/PAI-1 are listed<br />
in table 1. Low concentrations of uPA in the core needle biopsies<br />
correlate with low concentrations in the surgical specimens across<br />
the entire study cohort as well as in the group with an intermediate<br />
(G2, N0) risk (npv=0.91).<br />
The clinical and pathological data of the cohort and the risk assessment<br />
will be presented.<br />
Table 1. Performance of uPA/PAI-1 testing in core needle biopsies with regard to forecast surgical<br />
specimen results.<br />
uPA sensitivity specificity ppv npv<br />
all, n=110 0.91 0.65 0.66 0.91<br />
95% C.I. 0.80 - 0.98 0.52 - 0.77 0.63 - 0.77 0.79 - 0.97<br />
intermediate group 0.98 0.63 0.57 0.91<br />
95% C.I. 0.52 - 1.00 0.35 - 0.85 0.29 - 0.99 0.59 - 1.00<br />
PAI-1<br />
all, n=110 0.81 0.60 0.73 0.70<br />
95% C.I. 0.71 - 0.91 0.44 - 0.74 0.61 - 0.83 0.55 - 0.85<br />
intermediate group 0.98 0.63 0.57 0.91<br />
95% C.I. 0.52 - 1.00 0.35 - 0.85 0.29 - 0.82 0.59 - 1.00<br />
uPA/PAI-1<br />
all, n=110 0.89 0.53 0.78 0.72<br />
95% C.I. 0.81 - 0.95 0.38 - 0.67 0.68 - 0.85 0.38 - 0.67<br />
intermediate group 0.92 0.67 0.75 0.89<br />
95% C.I. 0.64 - 1.00 0.35 - 0.90 0.48 - 0.93 0.52 - 1.00<br />
Conclusion<br />
Most important, low uPA/PAI-1 results in core-needle biopsies predict<br />
low results in the surgical specimen. In some cases, core-needle<br />
biopsies and surgical specimen show discordant data. These cases<br />
do not correlate with any clinical or pathological factors such as<br />
time between needling and surgery, grading, tumor size or hospital.<br />
We assume that these discordances are caused by pre-surgical<br />
manipulations, which change expression patterns in the remaining<br />
tissue as it is reported also from multi-gene tests.<br />
P2-10-39<br />
Does E-cadherin or N-cadherin or epithelial-mesenchymal<br />
transition have a probability of clinical implication of the<br />
prognostic marker in invasive ductal carcinoma?<br />
Lee J, Yang G, Paik SS, Chung MS. Hanyang University Medical<br />
Center, Seoul, Republic of Korea<br />
Purpose Epithelial to mesenchymal transition (EMT) is widely<br />
accepted hypothesis of progression and metastasis in carcinoma.<br />
EMT can be explained as a loss of epithelial features and gain<br />
of mesenchymal properties, and in the same manner, it can be<br />
characterized by down-regulation of epithelial cellular markers,<br />
such as E-cadherin (EC) and up-regulation of mesenchymal cellular<br />
markers, such as N-cadherin (NC). <strong>Breast</strong> cancer has a diverse clinical<br />
spectrum, treatments and prognosis according to clinicopathologic<br />
characteristics and immunohistochemical features. Identifying the<br />
presence of EMT also would be able to predict the prognosis and<br />
design better and customized therapy. Our objective was to evaluate<br />
expression of the EC/NC and EMT and correlation between EMT and<br />
clinicopathologic, immunohistochemical features and to investigate<br />
clinical implication of the EC/NC and EMT as prognostic marker<br />
in breast cancer. Methods Using the clinicopathologic data of 480<br />
patients who underwent operation for invasive ductal carcinoma<br />
(IDC) during February 2001 to December 2008. 282 patients with<br />
good quality of paraffin embedded tissue block were selected. The<br />
ER and PR immunohistochemistry was scored using the Allred Score.<br />
EC and NC expression were classified on the basis of intensity of<br />
immunohistochemistry staining. The gain of a mesenchymal marker<br />
or loss of an epithelial marker was interpreted as EMT-positive. In<br />
this study, breast cancer was classified into four types according to the<br />
immunohistochemical expression of ER, PR and HER2 expression<br />
on immunohistochemical analysis and/or with HER2 gene by FISH<br />
analysis: luminal A, luminal B, HER2-enriched, and triple negative<br />
type. Results Median follow-up period was 52.6 months (range 1-113)<br />
and median age was 49 years (range 27-79). Of total 282 cases, 152<br />
(53.9%) cases were classified as luminal A, 32 (11.3%) classified as<br />
luminal B, 43 (15.2%) cases were HER2-enriched and 55 (19.5%)<br />
cases were triple negative type. Expression of a mesenchymal marker,<br />
NC was observed in 22 (7.8%) patients and loss of an epithelial<br />
marker, EC was observed in 57 (20.2%) cases. A total of 75 (26.6%)<br />
were interpreted as EMT-positive. NC score was associated with<br />
HER2-enriched, and triple negative molecular subtype (P = 0.0234).<br />
NC status was associated with HER2 positive status (P =0.0456) and<br />
HER2-enriched, triple negative molecular subtype (P =0.0029). EMT<br />
correlated with ER negative status (P = 0.0199). T stage (P < 0.001),<br />
N stage (P < 0.001) and TNM stage (P < 0.001) and ER (P = 0.0403)<br />
and PR (P = 0.0041) status significantly influenced disease-free<br />
survival (DFS). Age (P = 0.0185) and T stage (P = 0.0017), N stage (P<br />
< 0.001) and ER (P = 0.0048), and PR status (P = 0.0072), molecular<br />
subtype (P = 0.0372), significantly influenced overall survival (OS).<br />
The status of the EC/NC and EMT did not significantly affect DFS<br />
or OS. Conclusion NC status was associated with HER2 positive<br />
status and HER2-enriched, triple negative molecular subtype. And<br />
EMT correlated with ER negative status. EC/NC and EMT status<br />
have relevance to a specific molecular subtype or a probability of<br />
clinical implication of the poor prognostic marker in breast cancer.<br />
P2-10-40<br />
Correlation between expression of the prognostic marker<br />
Progranulin (GP88) with Oncotype Dx Recurrence Score in<br />
estrogen receptor positive breast tumors<br />
Serrero G, Koka M, Goicochea L, Tkaczuk KR, Fernandez KL, Logan<br />
LS, Tuttle K, Yue B, Ioffe OB. A&G Pharmaceutical Inc, Columbia,<br />
MD; University of Maryland Greenebaum <strong>Cancer</strong> Center, Baltimore,<br />
MD; Franklin Square Hospital, Baltimore, MD; Mercy Hospital,<br />
Baltimore, MD<br />
Background:<br />
GP88 (Progranulin, acrogranin) is an 88kDa glycoprotein<br />
overexpressed in breast tumors and involved in their proliferation<br />
and survival. Biological studies have shown that GP88 in ER+ breast<br />
cancer cells was associated with estrogen independence and resistance<br />
to anti-estrogen therapies and aromatase inhibitors. In addition,<br />
GP88 stimulated migration, invasion and angiogenesis, hallmarks of<br />
metastasis. Pathological studies have demonstrated that GP88 was<br />
preferentially expressed in invasive ductal carcinoma while lobular<br />
carcinoma was mostly negative. No expression was found in normal<br />
mammary tissue. Two retrospective studies totaling 530 cases of<br />
ER+ formalin-fixed paraffin-embedded invasive ductal carcinoma<br />
(IDC) established that high GP88 expression was associated with a<br />
4-fold increase in risk of recurrence and 2.5-fold increase in death<br />
when compared to low GP88 scores. Multivariate analysis showed<br />
that GP88 remains a predictor of recurrence even when adjusted for<br />
prognostic factors such as tumor size, grade, stage, lymph node status<br />
and age. High level of GP88 was also found to be elevated in the serum<br />
of breast cancer patients when compared to healthy individuals. Since<br />
GP88 tumor tissue expression appears as a prognostic factor for ER+<br />
breast cancer, we proposed to investigate whether GP88 tumor tissue<br />
www.aacrjournals.org 259s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
expression would correlated to Oncotype Dx® Recurrence Score<br />
which is now for early stage ER+ node negative breast cancer patients.<br />
Methods:<br />
Eight five cases from women ages 37-77 with ER+ invasive<br />
mammary carcinoma from three different institutions and with<br />
an available Oncotype Dx recurrence score were selected with<br />
approval from each site’s IRB. GP88 expression was determined<br />
by immunohistochemistry (IHC) using the anti-human GP88 6B3<br />
monoclonal antibody (A&G) on a Ventana automated staining<br />
platform. For all cases examined, GP88 IHC scores (0, 1+, 2+, 3+)<br />
were compared to routine clinicopathologic factors (tumor size, grade,<br />
and stage), PR, HER2/neu and Ki67 expression (by image analysis)<br />
and to their Oncotype DX® recurrence score (Genomic Health).<br />
The associations of GP88 with the parameters described above were<br />
assessed by t test or ANOVA.<br />
Results:<br />
The GP88 tissue expression correlated with Oncotype Dx Recurrence<br />
score (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
Results Through 10 years of follow-up, 80 locoregional recurrences<br />
occurred. Patients with a 70-gene signature high risk result (n = 492)<br />
had a locoregional recurrence risk of 8.8% (95%CI: 6.3-11.3) at 5<br />
years and 13.5 % (95%CI: 10.2-16.8) at 10 years, which was 2.6%<br />
(95%CI: 1.2-4.0) at 5 years and 5.7% (95%CI:3.5-7.9) at 10 years<br />
for patients with a low risk 70-gene signature (n = 561)(Logrank:<br />
p10%) were 12 cases (32.4%) which included only<br />
9 TP53 mutations. Five protein-truncating TP53 mutations were all<br />
negative staining of p53. Among BIRC5,BUB1 and PLK1 proteins,<br />
positive staining of PLK1 is the most correlated with TP53 mutations,<br />
sensitivity 0.78, specificity 0.84 and positive predictive value 0.78<br />
(p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Conclusion: These data support the hypothesis that the post<br />
chemotherapy ovary suffers both follicular and stromal dysfunction,<br />
as noted by lower Adione, which is specific to the ovarian stroma.<br />
Adione concentrations in the postmenopausal group women are<br />
similar to published reports of women post oophorectomy. This is the<br />
first longitudinal study we are aware of to evaluate ovarian stromal<br />
function in women undergoing chemotherapy. This total hormone<br />
depletion may be why women experiencing chemotherapy induced<br />
menopause report severe and distressing menopausal symptoms such<br />
as hot flashes. Estrogen is often implicated, but androgen deprivation<br />
in this population should be taken into consideration when planning<br />
interventions to improve health related quality of life.<br />
P2-11-02<br />
Perception and practice of reproductive specialists towards<br />
fertility preservation of young breast cancer patients<br />
Shimizu C, Kato T, Tamura N, Asada Y, Hiroko B, Mizota Y, Yamamoto<br />
S, Fujiwara Y. National <strong>Cancer</strong> Center Hospital, Tokyo, Japan; Asada<br />
Lady’s Clinic, Nagoya, Aichi, Japan; University of Tsukuba, Ibaragi,<br />
Japan; National <strong>Cancer</strong> Center, Tokyo, Japan<br />
Background: The potential for infertility caused by treatment is<br />
one of the important quality-of-life issues in young breast cancer<br />
(YBC) patients. Insufficient communication and partnership between<br />
oncologists and reproductive specialists has been identified as a<br />
major barrier to meeting their needs. However, the perception of<br />
reproductive specialists towards fertility preservation (FP) of YBC<br />
has not been evaluated.<br />
Objective: To investigate the perception and needs of reproductive<br />
specialists towards FP of YBC patients.<br />
Methods: A cross-sectional survey was developed and sent to 423<br />
certified reproductive specialists registered to the Japan Society for<br />
Reproductive Medicine to self-evaluate their perceptions and practices<br />
regarding FP in YBC patients.<br />
Results: Two hundred reproductive specialists (47%) responded to<br />
the survey.<br />
Demographic background of responding reproductive specialists (n=200)<br />
n (%)<br />
Age (year) mean 50 (range 35-71)<br />
Gender male 174 (87)<br />
female 42 (12)<br />
Spouse/ partner yes 190 (95)<br />
no 7 (4)<br />
Experience as a reproductive<br />
mean 25 (range 11-45)<br />
specialist (year)<br />
Experience of management of<br />
cancer patients<br />
yes 192 (96)<br />
no 4 (2)<br />
Affiliation academic hospital 75 (38)<br />
general hospital 42 (21)<br />
private clinic 77 (39)<br />
<strong>Breast</strong> Division in the same<br />
institution<br />
yes 104 (52)<br />
no 92 (46)<br />
99% responded that reproductive specialists should be engaged in<br />
FP of YBC patients. 46% responded that cancer treatment is more<br />
important than childbirth even if the patient was recurrence-free five<br />
years after primary treatment. 83% responded that they would like<br />
to treat YBC patients. Respondents affiliated with private clinics<br />
were more likely to accept both fertilized egg and unfertilized egg<br />
preservation than those affiliated with academic or general hospitals<br />
(p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
higher (worse) ACS and IOC health worry (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P2-11-06<br />
Mortality among offspring of women diagnosed with breast<br />
cancer; a population based study<br />
Verkooijen HM, Ang X, Liu J, Czene K, Salim A, Hartman M.<br />
University Medical Center Utrecht, Netherlands; National University<br />
of Singapore, Singapore; Karolinska Institute, Stockholm, Sweden;<br />
National University Hospital, Singapore, Singapore<br />
Introduction: Survival after breast cancer has improved substantially<br />
over the past decades. As a result, an increasing number of breast<br />
cancer survivors is starting or extending their family post-diagnosis.<br />
We evaluated mortality risks of offspring from women with a history<br />
of breast cancer.<br />
Methods: From the Swedish Multi-Generation Register and the<br />
<strong>Cancer</strong> Register we identified all 63,205 children whose mother had<br />
ever been diagnosed with invasive breast cancer. For these children,<br />
we calculated relative mortality risks as compared to the background<br />
population (Standardized Mortality Ratios [SMRs]). We compared<br />
SMRs according to the mother’s parity status at diagnosis and timing<br />
of birth in relation to time of diagnosis, i.e. before (>1 year before),<br />
around (between 1 year before and 1 year after) and after (>1 year<br />
after) diagnosis.<br />
Results: Children born around their mother’s breast cancer diagnosis<br />
had an increased mortality risk as compared to the background<br />
population (SMR 2.70 95% CI [1.64-4.44]). This risk was particularly<br />
high for first-born children (SMR 11.07 (95% CI [2.09-27.13]), who<br />
had an absolute excess risk of 6.4% to die before the age of 5 years.<br />
Children born more than one year before or after their mother’s<br />
breast cancer diagnosis had similar mortality risks as the background<br />
population.<br />
Conclusion: Children born around their mother’s breast cancer<br />
diagnosis have significantly increased mortality risks. Offspring of<br />
nulliparous women have a particularly high relative mortality risk,<br />
suggesting that pregnant breast cancer patients may be keen to keep<br />
their first child in spite of potential treatment toxicity.<br />
P2-11-07<br />
Endothelial progenitor cells as novel markers of anthracycline<br />
induced cardiac injury<br />
Lustberg MB, Ruppert AS, Carothers S, Bingman A, McCarthy B,<br />
Raman S, Das M, Kanji S, Lu J, Das H, Cinar-Akakin H, Gurcan<br />
MN, Berger MJ, Wesolowski R, Olson EM, Ramaswamy B, Mrozek<br />
E, Layman RM, Binkley P, Shapiro CL. The OSU <strong>Breast</strong> Program at<br />
Stefanie Spielman Comprehensive <strong>Breast</strong> Center; OSU<br />
Background: Anthracyclines including doxorubicin (DOX) cause<br />
myocardial damage that manifests as either subclinical decrements<br />
of left ventricular ejection function (LVEF) or overt cardiomyopathy.<br />
LVEF changes and cardiac risk factors are insufficient predictors<br />
of future DOX cardiotoxicity. Bone marrow derived endothelial<br />
progenitor cells (EPCs) are mobilized and are homed to sites of<br />
myocardial injury to help with repair of damaged myocardium. We<br />
hypothesized that EPC levels would be indicative of early DOX<br />
cardiotoxicity. Hence, we prospectively collected serial blood samples<br />
to evaluate functional EPCs, Troponin I (Ti) and B-natriuretic peptide<br />
(BNP), in patients (pts) receiving DOX-based chemotherapy.<br />
Methods: Eligible pts were initiating adjuvant DOX for early stage<br />
breast cancer. Pts underwent cardiac magnetic resonance (CMR), Ti,<br />
BNP, and EPC at baseline, after 1 cycle of DOX, and after completion<br />
of DOX. CD133+ progenitor cells were isolated from the peripheral<br />
blood mononuclear cells (PBMC) using AutoMACS (automated<br />
magnetic cell sorting, Miltenyi Biotech). In vitro colony forming unit<br />
(CFU) assay was performed for isolated CD133+ progenitor cells<br />
on MethoCult (Stemcell Technology). After 8 days of culture, EPC<br />
colonies were counted using a two-step image analysis algorithm.<br />
Repeated measures analysis of variance modeled changes in cardiac<br />
markers over time. Logistic regression was used to correlate variables<br />
with abnormal Ti.<br />
Results: Forty two women were enrolled. The average age was 52<br />
years (range 33-68) and stage distribution was I (14%), II (58%) and<br />
III (28%). All but one patient received peg-fligrastim after DOX.<br />
Thirty six pts had EPC/cardiac biomarkers and twenty nine pts had<br />
CMRs at all three time points. LVEF decreased 1.6% following<br />
completion of DOX (95% CI: -3.8 to 0.6, p=0.16). There was a<br />
non-linear trend in EPCs over time (p=0.05), with an initial increase<br />
followed by a decrease, with average values of 59 (95% CI: 50-70),<br />
65 (95% CI: 55-75), and 50 (95% CI: 40-60), respectively, across the<br />
three time points. By the end of treatment, 54% (95% CI: 0.37-0.71)<br />
of women had abnormal troponins (median: 0.03, range: 0.02 to<br />
0.17). Variables associated with abnormal troponins included lower<br />
baseline EPCs (p=0.095), older age (p=0.075) and initial increase in<br />
BNP post cycle 1 (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
Results: Accrual occurred during 42 clinic days between April 2011<br />
and February 2012. During that time, there were 129 postoperative<br />
appointments for patients with a diagnosis of breast cancer. 54 did not<br />
meet the eligibility requirements; 46 were DCIS, three had metastatic<br />
cancer, and five did not speak English. Of the patients who met the<br />
eligibility requirements 100% agreed to participate. Characteristics<br />
are shown in Table 1.<br />
Table 1 Enrollment Characteristics of Participants (N=73*)<br />
Age (years) 56.0 (12.7)<br />
Ethnicity (%)<br />
Non-Hispanic white 80.8<br />
African-American 4.1<br />
Hispanic 4.1<br />
Other 11.0<br />
Disease stage (%)<br />
Stage I 46.6<br />
Stage II 43.8<br />
Stage III 9.6<br />
Additional Treatment (%)<br />
None 15.9<br />
Radiation only 30.4<br />
Chemotherapy only 13.0<br />
Radiation and Chemotherapy 40.6<br />
Hormone Therapy (%)<br />
No 24.6<br />
Yes 75.4<br />
Treatment Location (%)<br />
Smilow <strong>Cancer</strong> Center 90.4<br />
Other 9.6<br />
*After further inquiry to participants were found to be pathologically DCIS and were therefore not<br />
included in analysis<br />
Only 39.4% of participants received both chemotherapy and radiation<br />
and 9.6% of our participants received their adjuvant therapy outside<br />
of Smilow <strong>Cancer</strong> Center.<br />
Conclusion: Women recently diagnosed with breast cancer are<br />
interested in receiving survivorship care plans after treatment, as<br />
demonstrated by 100% accrual rate of eligible patients approached<br />
in the postoperative visit. The postoperative visit in a surgical clinic<br />
may provide the starting point for tracking a patient through treatment.<br />
P2-11-09<br />
Weight Change and Risk of Incident Diabetes After <strong>Breast</strong> <strong>Cancer</strong><br />
Erickson KD, Patterson RE, Natarajan L, Lindsay SP, Heath D, Caan<br />
BJ. Moores UC <strong>San</strong> Diego <strong>Cancer</strong> Center, University of California,<br />
<strong>San</strong> Diego, La Jolla, CA; <strong>San</strong> Diego State University, <strong>San</strong> Diego, CA;<br />
Kaiser Permanente Northern California, Oakland, CA<br />
Weight gain after breast cancer treatment is common and may increase<br />
risk of diabetes. This analysis examined the association between<br />
weight change pattern and incident diabetes, adjusting for pre- and<br />
post-diagnosis BMI in breast cancer survivors (n=1,617) participating<br />
in the Women’s Healthy Eating & Living (WHEL) Study. Weight at 1<br />
year pre-diagnosis and ∼2 years post-diagnosis were used to calculate<br />
pre- to post-diagnosis body weight percentage change (categorized<br />
as: loss (>5%), stable (± 5%), moderate gain (>5% to
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
survivors, with a specific impact on PM. Women who complain of<br />
‘chemo fog’ should be evaluated carefully for PM deficits and their<br />
concerns should be acknowledged. An important finding from this<br />
study is the demonstration that fatigue is associated with memory<br />
deficits when memory as used in everyday life is evaluated. This<br />
finding which is suggestive of a common mechanism involved in<br />
fatigue symptoms and everyday memory disturbances raises the<br />
possibility that interventions targeted at improving fatigue may also<br />
improve memory functioning and quality of life in EBC survivors.<br />
Further longitudinal studies should be conducted to critically evaluate<br />
the role of chemotherapy by assessing PM before the initiation of<br />
chemotherapy and in EBC patients receiving only adjuvant hormonal<br />
therapy.<br />
P2-11-11<br />
Patient Reported Outcomes after <strong>Breast</strong> <strong>Cancer</strong> Surgery and<br />
Adjuvant Therapy from a German <strong>Breast</strong> <strong>Cancer</strong> Centre<br />
Feiten S, Dünnebacke J, Heymanns J, Köppler H, Thomalla J, van<br />
Roye C, Wey D, Weide R. Institute for Health Care Research in<br />
Oncology, Koblenz, Germany; Catholic Clinical Centre Koblenz-<br />
Montabaur, Koblenz, Germany; Oncology Group Practice Koblenz,<br />
Germany<br />
Objectives: Evaluation of the subjectively experienced physical,<br />
psychological, social and job-related consequences of breast cancer.<br />
Methods: Standardized paper pencil interview of patients with the<br />
initial diagnosis of breast cancer who had their primary surgery<br />
between 01/2006 and 12/2010 at an accredited breast cancer centre<br />
followed by systemic adjuvant treatment. The data collection was<br />
conducted with the help of a self-developed scanner-readable<br />
questionnaire which had been evaluated in a pretest.<br />
Results: 1260 patients were contacted, 871 completed questionnaires<br />
(return rate 72%) were analyzed. Median age of the patients (99.5%<br />
women) at the time of the interview was 65 years (30 - 91). 6%<br />
relapsed during the observation period. 91% were “satisfied” or<br />
“very satisfied” with the surgical result. 67% indicated a complete<br />
freedom of pain. 23% received lymphatic drainage at the time of the<br />
questioning (11/2011), 33% complained about limitations of arm<br />
and / or shoulder function. 76% received anti-hormonal therapy,<br />
13% stopped the anti-hormonal medication prematurely. Patients<br />
received a mean of 1.3 different anti-hormonal therapies, 54% took<br />
Tamoxifen. Psychological distress, cognitive limitations and physical<br />
consequences were rated on a scale from 1 – “not at all” to 4 – “very<br />
much”. The highest average values were found for the items sleep<br />
disturbances (2.3) and exhaustion (2.3), the lowest for depression (1.7)<br />
and word-finding difficulties (1.8). After therapy only 39% described<br />
a complete recovery of their physical capacity, 62% regained their<br />
previous mental capacity. 44% were in employment before their<br />
disease. 67% returned to their workplace but only 65% of them<br />
with their previous number of hours. 15% indicated disadvantages<br />
in their workplace due to the breast cancer disease. For 75% their<br />
partnership did not change, 12% experienced a deterioration, 13%<br />
an improvement. Before the illness 9% consulted a psychiatrist/<br />
psychotherapist, after the illness 18%. Before the diagnosis of breast<br />
cancer 13% received antipsychotic drugs, after the disease 25%.<br />
Conclusions: <strong>Breast</strong> cancer diagnosis and therapy leads to long<br />
lasting impairment of physical, psychological, social and job-related<br />
functioning in a significant number of patients.<br />
P2-11-12<br />
Proactive approach to risk reduction and early detection of breast<br />
cancer related lymphedema<br />
Fu MR, Guth A, Kleinman R, Cartwright F, Haber J, Axelrod D. New<br />
York University, New York, NY; NYU <strong>Cancer</strong> Center, New York, NY<br />
Advances in surgery and post-operative treatment continue to<br />
reduce the incidence of late effects of cancer treatment such as<br />
lymphedema. Yet, many breast cancer survivors still face considerable<br />
post-operative challenges as a result of developing lymphedema.<br />
The purpose of this study was to preliminarily evaluate a nursing<br />
educational and behavioral program “The Optimal YOU” to enhance<br />
lymphedema risk reduction, focusing on preventing inflammationinfection,<br />
promoting lymph drainage, and maintaining optimal Body<br />
Mass Index (BMI) as well as preoperative and subsequent follow-up<br />
assessment of limb volume changes and symptoms.<br />
A quasi-experimental design with repeated-measures was used.<br />
The Study outcomes included lymph volume changes by infrared<br />
perometer, lymphedema-related symptoms, and BMI by<br />
Bioimpedance at pre-operative baseline, post-operative, 6-month,<br />
and 12-month follow-up. A total of 147 patients were recruited and<br />
received the program, 141 patients completed the study (4% attrition<br />
rate).<br />
Majority (over 90%) of patients maintained preoperative limb volume<br />
and improved their symptom experience at 12-month follow-up.<br />
During the study period, only 7 patients (5%) had measurable<br />
lymphedema. At 12-month follow-up, among the 7 patients who<br />
developed measurable lymphedema, 2 patients’ limb volume<br />
returned to pre-operative level without compression therapy only<br />
by maintaining exercises of The Optimal YOU to promote daily<br />
lymph flow. About 80% of patients maintained or improved their<br />
preoperative BMI.<br />
Implementation of this nursing educational and behavioral<br />
intervention is effective to enhance lymphedema risk reduction and<br />
early detection. Findings of the study provided evidence to support<br />
the emerging policy change in lymphedema care, shifting treatmentfocus<br />
care to proactive risk reduction.<br />
P2-11-13<br />
The Effect of Positive Axillary Lymph Nodes on Symptoms,<br />
Physical Impairments, and Function<br />
Kesarwala AH, Pfalzer LA, O’Meara WP, Stout NL. National <strong>Cancer</strong><br />
Institute, Bethesda, MD; University of Michigan - Flint, MI; Lahey<br />
Clinic, Burlington, MA; Walter Reed National Military Medical<br />
Center, Bethesda, MD<br />
Purpose/Objective(s): The role of axillary lymph node (ALN)<br />
sampling in breast cancer (BC) treatment continues to evolve, and<br />
BC patients are recommended for post-operative regional nodal<br />
radiation therapy (RNRT) based on the number of positive ALN.<br />
RNRT is recommended for patients with 4 or more positive ALN,<br />
but it remains controversial in patients with 1-3 positive ALN and is<br />
rarely recommended for patients without positive ALN. Consideration<br />
of anticipated functional impairments often guides decision making.<br />
The purpose of this analysis is to investigate functional impairments<br />
in BC patients with varying numbers of positive ALN.<br />
Materials/Methods: 166 women were diagnosed with BC between<br />
2001-05 and enrolled and treated in a prospective surveillance<br />
physical therapy program. 110 had zero positive ALN, 37 had<br />
1-3 positive ALN, and 19 had 4 or more positive ALN on either<br />
sentinel LN biopsy or ALN dissection. Participants’ upper extremity<br />
(UE) range of motion, strength, and limb volume were assessed<br />
pre-operatively and at 1, 3, 6, 9, and 12+ months post-operatively<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
266s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
by a physical therapist. Limb volume was assessed using infrared<br />
optoelectronic perometry. At 12+ months, overall health status, UE<br />
symptoms and function, and physical activity levels were reported<br />
using standardized questionnaires. Chi-square tests and one-way<br />
ANOVA analyses were used to determine significance between<br />
groups (p≤0.05).<br />
Results: Of these 166 patients, 94 received mastectomy and 72<br />
received lumpectomy, while 41 received RNRT and 58 received whole<br />
breast tangent RT. No significant differences were found between<br />
groups with regard to age or race. The number of dissected LN was not<br />
significantly different between those patients with 1-3 positive ALN<br />
and 4 or more positive ALN. Rates of lymphedema and seroma were<br />
not significantly different between those patients with zero positive<br />
ALN and 1-3 positive ALN, and rates of cording were not significantly<br />
different between any of the groups. Increased lymphedema (p=0.03)<br />
and seroma (p=0.005) were seen in those patients with 4 or more<br />
positive ALN compared to those patients with zero positive ALN,<br />
but this may also be related to a significantly greater number of<br />
dissected LN in the former group. By 12+ months post-operatively,<br />
there were no differences in shoulder abduction, shoulder flexion,<br />
internal rotation, or external rotation between groups. No differences<br />
were seen between groups in self-reported fatigue, UE swelling or<br />
weakness, arm stiffness, or ability to climb stairs.<br />
Conclusions: Functional impairments represent an important category<br />
of morbidity for BC survivors and should be considered in pretreatment<br />
decision making. The number of positive ALN may not<br />
correlate with increased impairment over the first year of treatment<br />
when a prospective surveillance physical therapy program is part of<br />
the plan of care. Additional research is needed to assess longer-term<br />
changes and the impact of axillary surgery and/or radiation in the<br />
context of aggregate effects of other BC treatment modalities.<br />
P2-11-14<br />
Symptoms, Physical Impairments, and Function in <strong>Breast</strong> <strong>Cancer</strong><br />
Patients with Negative Axillary Lymph Nodes<br />
Kesarwala AH, Pfalzer LA, O’Meara WP, Stout NL. National <strong>Cancer</strong><br />
Institute, Bethesda, MD; University of Michigan - Flint, MI; Lahey<br />
Clinic, Burlington, MA; Walter Reed National Military Medical<br />
Center, Bethesda, MD<br />
Purpose/Objective(s): <strong>Breast</strong> cancer (BC) patients are recommended<br />
for post-operative regional nodal radiation therapy (RNRT) based<br />
on the number of positive axillary lymph nodes (LN). While RNRT<br />
is recommended for patients with 4 or more positive LN, it remains<br />
controversial in patients with 1-3 positive LN. For these patients,<br />
consideration of anticipated functional impairments often guides<br />
decision making, but these considerations are confounded by the<br />
inseparable effects of disease in and treatment of the axilla. The<br />
purpose of this analysis is to investigate the effect of various therapies<br />
on functional impairments in BC patients without axillary disease.<br />
Materials/Methods: 166 women were diagnosed with BC between<br />
2001-05 and enrolled and treated in a prospective surveillance<br />
physical therapy program. 110 had zero positive axillary LN on<br />
either sentinel LN biopsy or axillary LN dissection and were analyzed<br />
for this report. Participants’ upper extremity (UE) range of motion,<br />
strength, and limb volume were assessed pre-operatively and at 1,<br />
3, 6, 9, and 12+ months post-operatively by a physical therapist.<br />
Limb volume was assessed using infrared optoelectronic perometry.<br />
At 12+ months, overall health status, UE symptoms and function,<br />
and physical activity levels were reported using standardized<br />
questionnaires. Chi-square tests and one-way ANOVA analyses were<br />
used to determine significance between groups (p≤0.05).<br />
Results: Of these 110 patients, 34 received mastectomy without RT, 21<br />
received mastectomy with RNRT, 10 received lumpectomy alone, and<br />
45 received lumpectomy with whole breast tangent RT. No significant<br />
differences were found between groups with regard to stage, ER/PR<br />
status, and number of dissected LN. Rates of lymphedema, cording,<br />
and seroma were not significantly different between groups. By<br />
12+ months post-operatively, there were no differences in shoulder<br />
abduction, shoulder flexion, internal rotation, or external rotation<br />
between groups. No differences were seen between groups in selfreported<br />
fatigue, UE swelling or weakness, arm stiffness, or ability<br />
to climb stairs.<br />
Conclusions: Functional impairments represent an important<br />
category of morbidity for BC survivors and should be considered in<br />
pre-treatment decision making. In patients without axillary disease,<br />
post-operative RNRT or whole breast tangent RT may not contribute<br />
significantly to impairment over the first year of treatment when a<br />
prospective surveillance physical therapy program is part of the plan<br />
of care. Additional research is needed to assess longer-term changes<br />
and the impact of radiation in the context of the aggregate effect of<br />
disease burden combined with other BC treatment modalities.<br />
P2-11-15<br />
Development of a web-based survey tool to assess change in<br />
breast cancer (BrCa) survivor knowledge after receipt of cancer<br />
treatment summary and survivorship care plan (SCP).<br />
Custer JL, Rocque GB, Wisinski KB, Jones NR, Donohue S, Koehn<br />
TM, Champeny TL, Terhaar AR, Chen KB, Peck KA, Tun MT,<br />
Wiegmann DA, Sesto ME, Tevaarwerk AJ. University of Wisconsin,<br />
Madison, WI<br />
Intro: The Institute of Medicine advocates survivorship care plans<br />
(SCPs) as tools to improve coordination of care by improving survivor<br />
knowledge of follow-up recommendations and future risks. No<br />
evidence exists to demonstrate that SCPs impact survivor knowledge<br />
of diagnosis, treatment, or future/chronic side effects. Furthermore,<br />
there is a lack of information on existing surveys and their ability to<br />
assess survivor knowledge regarding these issues, without change<br />
over time. The purpose of this research is to report on the development<br />
of a survey assessing knowledge of diagnosis, treatment, and side<br />
effects in BrCa survivors.<br />
Methods:Using existing literature, two oncologists created 24<br />
questions addressing knowledge of diagnosis, treatment, and<br />
side effects. Content experts including breast oncology providers<br />
(representing multiple subspecialties), Survey Research Shared<br />
Service (SRSS) and patient advocates reviewed and revised the<br />
questions. Next, potential questions were administered in a group<br />
setting to BrCa survivors to evaluate clarity of instructions and survey<br />
wording. The <strong>Breast</strong> <strong>Cancer</strong> Knowledge (BreaCK) survey was further<br />
revised based on survivor feedback.<br />
For pilot testing, BrCa survivors were recruited from clinic to test<br />
BreaCK survey content and clarity. Survey 1 was administered in<br />
clinic online. SRSS conducted verbal assessments regarding content<br />
after Survey 1. Four weeks later, survivors received Survey 2 via<br />
email and answered online. Correct answers were abstracted from<br />
the medical record.<br />
Results: Nine subjects completed both surveys. Qualitatively, little<br />
intra-subject variation was seen between surveys. Subjects did not feel<br />
that the survey was burdensome or intrusive. No subject was able to<br />
correctly answer all questions. Final survey adjustments were made<br />
based on subject feedback and common incorrect answers encountered<br />
when grading the surveys. Specifically, subjects had difficulty<br />
www.aacrjournals.org 267s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
understanding “endocrine or hormone therapy.” Furthermore, subjects<br />
reported guessing in response to some questions – additional answer<br />
categories were added, including “I don’t know.”<br />
Conclusion: Survivor knowledge did not change significantly between<br />
surveys. This suggests survivor knowledge was not impacted by<br />
the survey over the four-week interval. The revised BreaCK survey<br />
may be a useful tool for assessing survivor knowledge of diagnosis,<br />
treatment and side effects. A larger cohort of BrCa survivors is being<br />
recruited, starting Summer 2012, and will be evaluated using the<br />
survey.<br />
P2-11-16<br />
Cardiac Morbidity After Adjuvant Chemotherapy (CT) for Early<br />
<strong>Breast</strong> <strong>Cancer</strong> in the Community Setting.<br />
Patt D, Espirito J, Turnwald B, Denduluri N, Wang Y, Lina A,<br />
Hoverman R, Neubauer M, Bosserman L, Busby L, Brooks B,<br />
Cartwright T, Sitarik M, Schnadig I, Winter W, Garey J, Ginsburg-<br />
Arlen A, Bergstrom K, Beveridge R. Pathways Task Force, US<br />
Oncology Network, McKesson Specialty Health, Austin, TX; Pathways<br />
Task Force, US Oncology Network, McKesson Specialty Health,<br />
The Woodlands, TX; Pathways Task Force, US Oncology Network,<br />
McKesson Specialty Health, Arlington, VA; US Oncology Network,<br />
McKesson Specialty Health, The Woodlands, TX; Kansas City <strong>Cancer</strong><br />
Center, Pathways Task Force, US Oncology Network, McKesson<br />
Specialty Health, Overland Park, KS; Pathways Task Force, US<br />
Oncology Network, McKesson Specialty Health, Rancho Cucamonga,<br />
CA; Rocky Mountain <strong>Cancer</strong> Centers, Pathways Task Force, US<br />
Oncology Network, McKesson Specialty Health, Boulder, CO;<br />
Pathways Task Force, US Oncology Network, McKesson Specialty<br />
Health, Dallas, TX; Pathways Task Force, US Oncology Network,<br />
McKesson Specialty Health, Ocala, FL; Pathways Task Force, US<br />
Oncology Network, McKesson Specialty Health, Tualatin, OR;<br />
Pathways Task Force, US Oncology Network, McKesson Specialty<br />
Health, Portland, OR<br />
Cardiac morbidity after exposure to CT is a known and previously<br />
described risk. Anthracycline exposure can be complicated by acute<br />
or chronic cardiac toxicity. Trastuzumab exposure is largely associated<br />
with acute and reversible cardiac morbidity.<br />
Methods: We retrospectively queried the electronic health record<br />
(EHR) from our network of community oncology practices,<br />
iKnowMed, for patients (pts) diagnosed with Stage I-III breast cancer<br />
(BC) from 2007-2010 with at least 5 visits and follow-up (f/u) through<br />
2012. We stratified this group by CT utilization (yes/no), regimen type,<br />
age, and characterized the incidence of cardiac disease or initiation of<br />
cardiac medication through the f/u period to determine the association<br />
of cardiac disease or treatment with CT utilization. Cardiac diseases<br />
analyzed included congestive heart failure, valvular and ischemic<br />
heart disease, arrythmias, and hypertension. Cardiac medications<br />
included beta blockers, angiotensin-converting-enzyme inhibitors,<br />
angiotensin receptor II blockers, loop and thiazide diuretics. Hazard<br />
ratios by prespecified risk parameters were then analyzed by<br />
multivariate analysis for all pts who did not have cardiac disease<br />
preceding their diagnosis of BC.<br />
Results: We identified 20,900 pts with a median f/u of 3.2 yrs (1.4-<br />
5.4). 11,295 (54%) pts received adjuvant CT and 9,605 (46%) did<br />
not. Median age at diagnosis in the CT-treated arm and non CTtreated<br />
arm was 54 and 64 yrs, respectively (p < 0.0001). Among<br />
both the non-CT and CT-treated group, the baseline prevalence of<br />
cardiac disease was 14%. Among the CT-treated group, 3475 pts or<br />
31% (95% CI, 30 % - 32%) had or developed cardiac disease within<br />
the study period. In the non-CT group, 3790 pts or 39% (95% CI,<br />
38% - 40%) had or developed cardiac disease with the study period<br />
(p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
were noted for all other cardiorespiratory fitness testing outcomes.<br />
Significant improvements from baseline to 17 weeks were seen across<br />
both groups for all measures of body composition. Lean body mass<br />
did not significantly change from baseline to 17 weeks in both groups.<br />
There were no significant between group differences for change in<br />
body composition.<br />
Cardiorespiratory fitness at baseline and 17 weeks [mean (SD)]<br />
Variable Baseline 17 Weeks Change<br />
Withing Between group<br />
group p-value p-value<br />
Standard Exercise Group<br />
(n=9) VO2 Max (mL. 24.0 (7.1) 26.3 (6.8) 2.3 (2.9) 0.05<br />
kg-1.min-1)<br />
Structured Exercise<br />
Group (n=7)<br />
VO2max(mL.kg-1.<br />
24.6 (2.9) 29.8 (3.8) 5.3 (2.6) 0.002 0.05<br />
min-1)<br />
Standard Exercise<br />
Group (n=9) Treadmill 677.2 (319.6) 813.7 (271.2) 136.4 (101.9) 0.02<br />
Duration (seconds)<br />
Structured Exercise<br />
Group (n=7) Treatdmill 794.0 (131.3) 1051.4 (68.2) 257.4 (87.1) 0.02 0.02<br />
Duration (seconds)<br />
Standard Exercise<br />
Group (n=9) Maximum<br />
Achieved Heartrate<br />
167.4 (8.4) 166.5 (8.2) -1.0 (7.1) 0.71<br />
(bpm)<br />
Structured Exercise<br />
Group (n=7) Maximum<br />
Achieved Heartrate<br />
(bpm)<br />
171.3 (11.5) 175.4 (9.8) 4.1 (7.7) 0.21 0.21<br />
Conclusion: In this study, both standard exercise and structured<br />
exercise improved CR fitness measured by VO2max, but the structured<br />
exercise group experienced significantly greater improvements.<br />
P2-12-01<br />
Prospective Evaluation of Joint Symptoms in Postmenopausal<br />
Women Initiating Aromatase Inhibitors for Early Stage <strong>Breast</strong><br />
<strong>Cancer</strong><br />
Crew KD, Chehayeb Makarem D, Awad D, Kalinsky K, Maurer M,<br />
Kranwinkel G, Brafman L, Fuentes D, Hershman DL. Columbia<br />
University Medical Center, New York, NY<br />
Background: Aromatase inhibitors (AIs) are widely prescribed to<br />
postmenopausal women for the adjuvant treatment of hormonesensitive<br />
breast cancer (BC). However, musculoskeletal complaints<br />
can lead to nonadherence and early discontinuation. The aim of<br />
this study was to characterize the natural history of the AI-induced<br />
arthralgia syndrome and determine predictors of worsening symptoms.<br />
Methods: Postmenopausal women with stage I-III BC initiating<br />
adjuvant AI therapy were enrolled. All patients completed the<br />
following questionnaires at baseline and every 3 months for a year:<br />
Modified Brief Pain Inventory-Short Form (BPI-SF), Western Ontario<br />
and McMaster Universities Osteoarthritis (WOMAC) index and the<br />
Modified Assessment of Chronic Rheumatoid Affections of the Hands<br />
(M-SACRAH). Higher scores reflect worse symptoms. Quality of life<br />
was assessed using the Functional Assessment of <strong>Cancer</strong> Therapy-<br />
Endocrine Subscale (FACT-ES). Hand grip strength was measured at<br />
each visit with a Martin dynamometer. Paired t-tests were performed<br />
to compare follow-up evaluations to baseline. Linear Regression was<br />
performed to evaluate the association between baseline symptoms<br />
and change in symptoms.<br />
Results: A total of 169 patients have been consented, 3-month data<br />
is available on 102; 6-month data on 85. Median age: 63 (42-89);<br />
White/Black/Asian/Hispanic: 61.48/30.33/3.28/25.6; median BMI<br />
(kg/m2): 28 (12-50). Compared to baseline, there was a statistically<br />
significant increase in BPI pain severity and endocrine related<br />
symptoms on the FACT-ES at 3 and 6 months. Significant changes in<br />
the BPI pain interference, M-SACRAH pain and stiffness, WOMAC<br />
function, physical well-being on the FACT-ES, trial outcome index<br />
and pinch grip strength were seen at 3 months; however these changes<br />
did not remain significant at 6 months. Logistic regression models<br />
evaluating predictors of patient reported outcome measures and grip<br />
strength were performed. Baseline score was the strongest predictor<br />
of worsening symptoms (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
but only the FACT-B social wellbeing was statistically significant<br />
at 3 months with a p=0.0164. Changes in other FACT-B and SF-36<br />
scores were not significantly different between exercise and usual care<br />
groups. There were significant improvements at 6 months in weight<br />
(p=0.0192), % body fat (p=0.0337), max strength (p=0.0029), and<br />
waist circumference (0.0359) and at 12 months in weight (p=0.0293),<br />
% body fat (p=0.0481), max strength (p=0.0097) and endurance<br />
(p=0.0037) in the exercise group compared to usual care.<br />
CONCLUSIONS: This randomized prospective study suggests<br />
benefit of exercise during chemotherapy. This benefit continued<br />
6 months beyond the completion of the exercise program with<br />
significant improvement in physical function, body composition,<br />
strength and endurance with no decline in quality of life. Regular<br />
moderate exercise may play an important role in improving function<br />
during adjuvant chemotherapy and should be further studied in a<br />
large randomized trial.<br />
P2-12-04<br />
Music Therapy Reduces Radiotherapy-Induced Fatigue in<br />
Patients with <strong>Breast</strong> or Gynecological <strong>Cancer</strong>: A Randomized<br />
Trial<br />
Freitas NMA, Silva TRMA, Freitas-Junior R, Paula Junior W,<br />
Silva DJ, Machado GDP, Ribeiro MKA, Carneiro JP. Araujo Jorge<br />
Hospital/ACCG, Goiania, Goias, Brazil; Federal University of<br />
Goias, Goiania, Goias, Brazil; Instituto Integrado de Neurociencias/<br />
IINEURO, Goiania, Goias, Brazil<br />
BACKGROUND: Fatigue is a frequent side effect of radiotherapy,<br />
and may interfere with self-esteem, social activities, and quality of<br />
life. The authors investigated the influence of music therapy (MT)<br />
on the reduction of fatigue in women with breast or gynecological<br />
malignant neoplasia during radiotherapy. METHODS: Randomized<br />
controlled trial (control group-CG and music therapy group-MTG)<br />
to assess fatigue, quality of life using the Functional Assessment of<br />
<strong>Cancer</strong> Therapy (FACT-F and FACT-G) version 4 and symptoms<br />
of depression using Beck Depression Inventory (BDI) in women<br />
undergoing radiotherapy in three distinct moments (during the first<br />
and the last week of radiotherapy, and on the week of the intermediary<br />
phase). Individual 30–40 minute sessions of music therapy were<br />
offered to participants of the MTG. RESULTS: In this study, 164<br />
women were randomized and 116 (63 CG and 53 MTG) were included<br />
in the analyses, with mean age of 52.9 years (CG) and 51.85 years<br />
(MTG). Participants in the MTG had an average of 10 MT sessions,<br />
during the study. FACT-F results were significant regarding Trial<br />
Outcome Index (TOI), synthesis of the Physical and functional wellbeing<br />
areas of FACT-F (p = 0.011), FACT-G (p = 0.005), FACT-F<br />
(p = 0.001) for MTG compared with CG. The depressive symptons<br />
were reduced to the minimum levels in the MTG (p = 0,005) with<br />
risk reduction of 74% (RR = 0,26; CI 0,10 - 0,70).<br />
Comparative analysis of categories (chi-square) during radiotherapy according to Beck Depression<br />
Inventory (BDI)<br />
Variable CG MTG P RR (CI 95%)<br />
N % N %<br />
BDI - Initial<br />
phase<br />
Minimum 36 65 34 64 0.88 1.00<br />
Mild to<br />
intense<br />
9 16 10 19<br />
BDI - Final<br />
phase<br />
Minimum 35 64 46 87 0.005 1.00<br />
Mild to<br />
intense<br />
11 20 5 9<br />
0.97 (0.65-<br />
1.44)<br />
0.26 (0.10-<br />
0.70)<br />
CG: Control Group; MTG: music therapy group; RR: relative risk; CI: confidence interval<br />
CONCLUSIONS: Individual MT sessions are effective to reduce<br />
fatigue related to cancer and symptoms of depression, as well as to<br />
improve quality of life for women with breast or gynecological cancer<br />
undergoing radiotherapy.<br />
P2-12-05<br />
Limited Absorption of Low Dose 10µg Intravaginal 17-β Estradiol<br />
(Vagifem®) in Postmenopausal Women with <strong>Breast</strong> <strong>Cancer</strong> on<br />
Aromatase Inhibitors<br />
Goldfarb SB, Dickler M, Dnistrian A, Patil S, Dunn L, Chang K,<br />
Berkowitz A, Tucker N, Carter J, Barakat R, Hudis C, Castiel M.<br />
Memorial Sloan-Kettering <strong>Cancer</strong> Center, New York, NY<br />
Background: Aromatase inhibitors (AIs) are used to treat<br />
postmenopausal women with hormone-receptor positive (HR+) breast<br />
cancer (BC). AIs block the peripheral conversion of androgens to<br />
estrogen (E), resulting in sub-physiologic levels of E that may lead<br />
to profound urogenital atrophy. Atrophic vaginitis in BC survivors<br />
is prevalent and its management is complex. An observational study<br />
(n=6) demonstrated elevated estradiol levels in 5/6 women on AIs after<br />
2 weeks (wks) of treatment with 25µg 17-β Estradiol (Vagifem ®),<br />
which raised questions regarding the safety of intravaginal estradiol<br />
in women with HR+ BC. However, the small sample size limited<br />
definitive conclusions, yet underscored the need for a clinical trial to<br />
evaluate concurrent use of AIs and intravaginal estradiol. In addition,<br />
a lower dose 17-β Estradiol (10µg) is now available and effectively<br />
treats healthy women with atrophic vaginitis. We hypothesized that<br />
the 10µg dose is effective and may have less systemic absorption<br />
than the 25µg dose. This is the first study to evaluate the 10µg dose<br />
in BC pts on AI therapy.<br />
Methods: A prospective longitudinal IRB-approved study was<br />
performed at MSKCC in postmenopausal women with stage I-III<br />
HR+ BC on adjuvant letrozole or anastrozole for at least 3 months<br />
and had urogenital atrophy. Patients on exemestane were not eligible<br />
due to cross-reactivity with the assay. All women were initiated on<br />
10µg intravaginal 17- β estradiol (Vagifem®). Serial estradiol/FSH<br />
levels were measured at baseline and wks 2, 7, 12, 18 & 24; we used<br />
a highly sensitive estradiol radioimmunoassay, ESTR-US-CT, from<br />
Cisbio US, Inc. Estradiol/FSH levels were checked approximately 12<br />
hrs after insertion, chosen to measure peak absorption. The primary<br />
endpoint was change in systemic estradiol level from baseline to<br />
wk 12. Patients also completed the Female Sexual Function Index<br />
(FSFI) and Menopausal Symptom Checklist (MSCL) at baseline<br />
and wks 12 & 24.<br />
Results: 26 pts have been treated and 18 are currently evaluable for<br />
the primary endpoint at wk 12. Wilcoxon signed rank test showed<br />
no statistically significant difference between baseline and wk 12<br />
estradiol levels (p= 0.49) or FSH levels (p= 0.28). The median change<br />
in estradiol from baseline to wk 12 was 0.3 with a range from -3 to<br />
14.6 (p=.49). Twelve wk results are anticipated for 6 additional pts on<br />
study; however 2 pts withdrew before wk 12. Based on the Wilcoxon<br />
signed rank test, estradiol levels were not elevated at wks 2 (n=17)<br />
or 7 (n=16) when compared to baseline. Graphical analysis showed<br />
a relationship with increasing estradiol coinciding with decreasing<br />
FSH, as physiologically expected. All patients reported being less<br />
bothered by menopausal symptoms on the MSCL from baseline to<br />
wk 12. Improvement in sexual function/FSFI scores was noted in all<br />
sexually active women.<br />
Conclusion: Treatment with intravaginal 10µg 17- β estradiol<br />
(Vagifem ®) did not elevate wks 2, 7 or 12 estradiol. It also provided<br />
relief of vaginal and menopausal symptoms and improvement in<br />
sexual function in postmenopausal women with HR+ BC on adjuvant<br />
AIs. This is consistent with findings in the general population.<br />
Updated data from this study will be presented for all patients treated<br />
on study.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
270s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
P2-12-06<br />
Ultra-low dose vaginal estriol and Lactobacillus acidophilus<br />
(Gynoflor®) in early breast cancer survivors on aromatase<br />
inhibitors: Pharmacokinetic, efficacy and safety results from a<br />
phase I study.<br />
Neven P, Donders G, Mögele M, Lintermans A, Bellen G, Ortmann<br />
O, Buchholz S. University Hospital Gasthuisberg Leuven, Belgium;<br />
Femicare vzw, Clinical Research for Women, Tienen, Belgium;<br />
Universitätsklinikum Regensburg, Germany<br />
Introduction: Intra-vaginal estradiol (E2) is effective to treat<br />
symptomatic vaginal atrophy. However, in postmenopausal (PM)<br />
women on aromatase inhibitors (AI), this increases serum E2 levels.<br />
We here report pharmacokinetic (PK), efficacy and safety results of<br />
a phase I study using vaginal tablets with lyophilized lactobacilli and<br />
0.03 mg estriol (E3) (Gynoflor®) in PM breast cancer (BC) survivors<br />
on AI reporting atrophic vaginitis.<br />
Patients and Methods: In this open label phase I PK study, women<br />
being treated for ≥6 months with a non-steroidal AI and reporting<br />
non-hormone treatment-resistant vaginal atrophy were recruited. The<br />
primary objective was absorption and serum concentration of estrone<br />
(E1), E2, E3, FSH, LH and SHBG during initial therapy with one<br />
vaginal tablet of Gynoflor® daily for 28 days and during subsequent<br />
maintenance therapy of a daily tablet 3x per week for another 8 weeks.<br />
The secondary objective was to evaluate clinical symptoms, changes<br />
in vaginal pH, epithelium and microflora. Patients were assessed 6<br />
times for endpoints. Blood was taken pre-insertion (baseline samples)<br />
at study entry, week 2, 4, 8, 12. At entry and week 4, multiple PK<br />
blood samples were drawn 0.5 hours pre-insertion and 0.5, 1, 2, 3, 4,<br />
6, 8, 24 hours post-insertion. Serum samples were assayed by highly<br />
sensitive GC/MS.<br />
Results: The interim results of 8 of 16 enrolled patients who have<br />
completed the 12 week study period are presented. Basline estrogen<br />
concentrations of all women were below the levels of quantitation (E3:<br />
< 10 – 20 pg/ml; E2: < 1 pg/ml; E1: < 2 pg/ml). After first insertion,<br />
E3 serum levels transiently increased in 7 of 8 women; the single<br />
maximum concentration of all women was 132 pg/ml and highest<br />
levels (12-132 pg/ml) were observed usually 3 hours post-insertion.<br />
After 4 weeks of daily application, PK results showed an increase in<br />
E3 levels as compared to baseline in only 5 of 8 women. In addition,<br />
the single maximum concentration of all women was lower, 44 pg/ml,<br />
which was only reached after 8 hours. The baseline E3 concentrations<br />
did not change over the complete period of 12 weeks and were in the<br />
range of the limit of quantitation. The serum concentrations of E2 and<br />
E1 did not increase at any time point in any of the women. Clinical<br />
symptoms, vaginal pH and maturation index improved already after<br />
2 weeks of therapy. Global efficacy and tolerability were rated by the<br />
investigators in at least 75% of the cases as (very) good, and by at<br />
least 87.5 % of the women. No serious adverse events were observed.<br />
Conclusions: Gynoflor® vaginal tablet is an effective and safe option<br />
to treat vaginal atrophy in PM patients with early BC on AI. Our data<br />
showed only a transient increase in E3 serum concentration after first<br />
application, and this increase was lower after 4 weeks. Baseline E3<br />
concentrations did not increase demonstrating that no accumulation<br />
occurred. Serum E2 and E1 concentrations did not change and were<br />
always below limit of quantitation. The clinical significance of<br />
transient vaginal E3 absorption is unknown, however the absence of<br />
elevated E2 and E1 serum levels is compatible with the desired effect<br />
for BC patients taking an AI.<br />
*The first and second author have shared first authorship.<br />
P2-12-07<br />
A review of clinical endpoints and use of quality-of-life outcomes<br />
in phase III metastatic breast cancer clinical trials<br />
Tatla R, Landaverde D, Victor C, Miles D, Verma S. University of<br />
Toronto, ON, Canada; Sunnybrook Odette <strong>Cancer</strong> Center, Toronto,<br />
ON, Canada; Dalla Lana School of Public Health, University of<br />
Toronto, ON, Canada; Mount Vernon <strong>Cancer</strong> Centre, United Kingdom<br />
Background: The management of metastatic breast cancer (MBC)<br />
is often considered to be palliative, with most interventions intended<br />
to relieve disease symptoms, minimize treatment effects and prolong<br />
patient survival. The impact of disease and treatment on a patient’s<br />
functional abilities has led to the emphasis of incorporating quality<br />
of life (QoL) measures into clinical trials. The primary objective of<br />
this study is to evaluate phase III clinical trials in MBC, and assess<br />
the inclusion of QoL as an endpoint, in addition to conventional<br />
progression and survival endpoints.<br />
Methods: A structured PubMed search was conducted to identify<br />
phase III clinical trials published between Jan. 1990 and Aug.<br />
2011, which evaluated systemic treatment in MBC patients. Data<br />
pertaining to treatment regimens, study endpoints and clinical findings<br />
were collected, with a particular focus on progression-based (PB),<br />
overall survival (OS), and QoL endpoints. The instrument(s) used in<br />
evaluating QoL were also noted (when applicable).<br />
Results: Of 520 publications identified, 122 phase III MBC clinical<br />
trials met the inclusion criteria. Of these studies, 98.4% and 95.9%<br />
included PB and OS respectively, as clinical endpoints, while QoL was<br />
assessed in only 46 (37.7%) studies. 14 instruments were identified as<br />
QoL measurement tools among these studies, with EORTC QLQ-C30<br />
and FACT-B accounting for 54.7% of the instruments used. While<br />
the inclusion of QoL was not associated with the significance of PB<br />
results, there was an association between the inclusion of QoL and<br />
OS results, with 59% of significant OS studies and 32% of nonsignificant<br />
OS studies including QoL as a clinical endpoint (p=0.016).<br />
When stratified by treatment arm, it was found that studies favouring<br />
standard therapy were more likely to include QoL (75%, p=0.045),<br />
compared to those favouring the intervention (56%), and those without<br />
significant differences (32%).<br />
Conclusions: Although the importance of QoL is often emphasized<br />
in MBC management and treatment decisions, only one-third of<br />
identified phase III clinical trials included an assessment of QoL.<br />
About half of these trials showed no statistically significant differences<br />
in QoL endpoint; of note, instruments of varying validity were utilized.<br />
There needs to be greater emphasis on the evaluation of QoL, with<br />
the use of standard and validated QoL tools in MBC clinical trials,<br />
especially as we increasingly focus on progression-based endpoints.<br />
P2-12-08<br />
Sorafenib for treatment of breast-cancer related lymphedema<br />
Zambetti M, Guidetti A, Carlo-Stella C, De Benedictis E, Tessari A,<br />
Balzarini A, Caraceni A, Gianni L, Gianni AM. IRCCS Ospedale<br />
<strong>San</strong> Raffaele, Milan, Italy; Fondazione IRCCS Istituto Nazionale<br />
Tumori, Milan, Italy; Humanitas <strong>Cancer</strong> Center, IRCCS Istituto<br />
Clinico Humanitas, Rozzano, Italy<br />
BACKGROUND Lymphedema (LE) is a common complication<br />
of breast cancer (BC) treatments conditioning disability that affects<br />
quality of life. Decongestive therapy is the most popular treatment<br />
but it determines only a transient advantage, while pharmacologic<br />
therapy didn’t impact on LE. On the basis of clinical observations<br />
of LE regression in patients treated with sorafenib with antitumoral<br />
intent, we hypothesized that sorafenib could have an anti-LE activity<br />
through inhibition of vascular permeability by suppressing VEGFRs.<br />
www.aacrjournals.org 271s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
METHODS We conducted a single-arm, monoistitutional phase II<br />
study in BC patients with treatment-acquired LE of the arm. Major<br />
or uncontrolled cardiological disease, brain metastasis, history of<br />
thromboembolism were exclusion criteria. Concomitant chemo or<br />
hormonal therapy was allowed. Pts received sorafenib 200 mg daily<br />
for a maximum of 8 weeks. The primary end-point was to evaluate<br />
the efficacy of sorafenib as reduction of LE, defined by the percentage<br />
reduction (PR) of the difference between the total arm circumference<br />
(measured as the sum of the circumference at 12 points) of the affected<br />
and the controlateral arm (Starritt, Peterk JA <strong>Cancer</strong> 2001–10):<br />
[(Initial Difference – Final Difference)/Initial Difference] x 100.<br />
Secondary end-points were safety and duration of response (DOR).<br />
The study was designed to test the null hypothesis that the PR of<br />
edema observed with this therapy was at most 20% versus the<br />
alternative hypothesis that the PR obtained by this regimen was ≥40%.<br />
RESULTS From May 2009 to April 2011, 36 BC pts were enrolled.<br />
All pts underwent axillary dissection and 29 pts had received adjuvant<br />
radiotherapy, but none on the axilla. Median time from primary breast<br />
surgery and from occurrence of edema to study enrollement was<br />
65 and 49 months, respectively. All pts are evaluable for efficacy<br />
and toxicity. Most common toxicities included grade 1-2 gastralgia<br />
(17%), hypertension (17%) and rash (43%); one patient experienced<br />
grade 3 hand-foot syndrome. Twenty-five pts completed the planned<br />
8 weeks of therapy, 11 (31%) had early treatment discontinuation<br />
after 2 (n=6), 4 (n=4) and 6 (n=1) weeks of treatment due to recurrent<br />
grade 2 toxicity or to relapse of disease (n=1). The median PR of<br />
the difference between the two arms was 34% (range, 2-100), 14<br />
pts (39%) experienced a LE reduction ≥40%. Among 25 pts who<br />
completed therapy, 12 (48%) achieved a PR ≥40%. The median<br />
difference of total circumferences between the LE and controlateral<br />
arm was significantly reduced after treatment: 37 cm (range 8–88)<br />
vs 25 cm (range 1–62) (p = 0.006). Best response was achieved after<br />
a median of 5 weeks of therapy (range 1– 6) and the median DOR<br />
was 8 weeks (range 4-15). Reduction of LE was associated with<br />
improvement of related symptoms. After discontinuation of study<br />
drug 84% pts presented a progressive increase of total circumference<br />
of LE arm and returned to values similar to baseline after a median<br />
of 7 weeks (range 2–11).<br />
CONCLUSIONS: Low dose of sorafenib has a good toxicity profile<br />
and exerts a significant anti-LE activity in BC patients. The early but<br />
transient effect observed in this study suggests exploring different<br />
schedule of administration. Further studies are warranted in order to<br />
obtain a durable benefit in term of reduction of LE and quality of life.<br />
P2-12-09<br />
A randomized controlled trial of support group intervention<br />
after breast cancer treatment: Results on sick leave, health care<br />
utilization and health economy.<br />
Granstam Björneklett H, Rosenblad A, Lindemalm C, Ojutkangas<br />
M-L, Letocha H, Strang P, Bergkvist L. Centre for Clinical Research,<br />
Västerås, Västmanland, Sweden; <strong>Cancer</strong> Center Karolinska,<br />
Karolinska, Stockhoöm, Sweden; Karolinska Institutet, Stockholm,<br />
Sweden<br />
Background<br />
More than 50% of breast cancer patients are diagnosed before the<br />
age of 65. Returning to work after treatment is, therefore, of interest<br />
for both the individual and society. The aim was, therefore, to study<br />
the effect of support group intervention on sick leave, health care<br />
utilization and health economy.<br />
Material and Methods<br />
Of 382 patients with newly diagnosed breast cancer, 191 + 191<br />
patients were randomized to an intervention group or to a routine<br />
control group respectively.<br />
The intervention group received support intervention on a residential<br />
basis for one week, followed by four days of follow-up two months<br />
later. The support intervention included informative-educational<br />
sections, relaxation training, mental visualization and non-verbal<br />
communication. Patients answered a questionnaire at baseline, 2, 6<br />
and 12 months about sick leave and health care utilization.<br />
Result There was a trend towards longer sick leave and more health<br />
care utilization in the intervention group. The difference in total costs<br />
was statistically significantly higher in the intervention group after<br />
12 months (p= 0.0036)<br />
Conclusion There was no economic benefit from intervention in its<br />
present form. In fact we saw a tendency towards longer sick leave<br />
and more health care utilization and we could show that the total cost<br />
in the intervention group was actually higher and that this difference<br />
was statistically significant after twelve months.<br />
Key words: Support intervention, breast cancer, return to work, sick<br />
leave, health care utilization, health economy<br />
P2-12-10<br />
Psycho-spiritual therapy for improving the quality of life and<br />
spiritual well-being of women with breast cancer<br />
Loghmani A, Jafari N, Zamani A, Farajzadegan Z, Bahrami F, Emami<br />
H. Isfahan University of Medical Sciences, Isfahan, Islamic Republic<br />
of Iran; University of Isfahan, Islamic Republic of Iran<br />
Objective: Psychological distress and morbidity are common<br />
consequences of diagnosis and treatment of breast cancer and<br />
associated with poor quality of life (QOL). Among several<br />
approaches, spirituality has been shown to be significantly associated<br />
with improving the quality of life of these patients. The aim of this<br />
study was to assess the role of psycho-spiritual therapy intervention<br />
in improving the quality of life and spiritual well-being of patients<br />
with breast cancer.<br />
Methods: This was a randomized controlled trial study which was<br />
conducted in the <strong>Breast</strong> <strong>Cancer</strong> Research Center, St. S. Al-Shohada<br />
hospital, Isfahan, Iran. Sixty-eight patients with breast cancer were<br />
randomized to either psycho-spiritual therapy intervention group or<br />
control group who received routine management and educational<br />
programs. Before and after 6 weeks of psycho-spiritual therapy<br />
sessions, the quality of life was evaluated using <strong>Cancer</strong> quality-oflife<br />
questionnaire (QLQ-C30) and its supplementary breast cancer<br />
questionnaire (QLQ-BR23) and Spiritual well-being was measured<br />
using the Functional Assessment of Chronic Illness Therapy Spiritual<br />
Well-being scale (FACIT-Sp12). Multivariate, repeated-measures<br />
ANOVA, T-test and Paired T-test were used for analysis using<br />
Predictive Analytic Soft Ware (PASW, version 18) for windows.<br />
Results: In all sixty five patients actually completed the six-week<br />
intervention and were evaluated for the outcomes. The mean Global<br />
health status score/QOL reached from 44.37 (SD: 13.03) to 68.63<br />
(SD: 10.86), (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
P2-12-11<br />
Use of the DigniCap System to Prevent Hair Loss in Women<br />
Receiving Chemotherapy (CTX) for Stage I <strong>Breast</strong> <strong>Cancer</strong> (BC)<br />
Rugo HS, Serrurier KM, Melisko M, Glencer A, Hwang J, D’Agostino,<br />
Jr. R, Hutchens S, Esserman LJ, Melin S. University of California<br />
<strong>San</strong> Francisco Helen Diller Comprehensive <strong>Cancer</strong> Center, <strong>San</strong><br />
Francisco, CA; Wake Forest Baptist Health Medical Center, Winston-<br />
Salem, NC<br />
Background: Alopecia is a non-life threatening complication of<br />
adjuvant CTX for early stage BC. CTX induced hair loss affects<br />
quality of life and potentially impacts decisions regarding the risks<br />
and benefits of treatment. Scalp cooling (SC), used internationally by<br />
thousands of patients (pts) including a growing number in the U.S., is<br />
thought to prevent hair loss through decreased follicular metabolic rate<br />
and vasoconstriction resulting in reduced delivery and cellular uptake<br />
of drugs. The DigniCap System is a self-contained SC system with<br />
circulating coolant. We sought to evaluate feasibility and efficacy of<br />
the DigniCap System in pts with stage I BC.<br />
Methods: We performed an initial prospective feasibility study before<br />
a planned pivotal trial. The primary endpoint was feasibility, defined<br />
as 75% HL). Pts assessed their own HL using the Dean’s<br />
scale, and pt-assessed quality of life, time to and quality of hair regrowth,<br />
and impact of HL on treatment decisions were also evaluated.<br />
Successful prevention of alopecia was defined as < grade 2 HL by the<br />
Dean’s scale. Eligibility included stage I disease and excluded use of<br />
anthracycline-taxane combination or sequential CTX.<br />
Results: 20 pts were enrolled. CTX regimens included: docetaxel and<br />
cyclophosphamide (TC) x 4-6 cycles (n=16), weekly paclitaxel and<br />
trastuzumab x 12 (n=2), and docetaxel, carboplatin, and trastuzumab<br />
(TCH) x 6 (n=2). 19 of 20 pts (95%) completed all CTX using the<br />
DigniCap System. By IP assessment, 15 pts (75%) had a maximum<br />
of ≤ grade 2 HL; 2 pts (10%) and 3 pts (15%) had a maximum grade<br />
3 or 4 HL respectively. By pt assessment, 11 pts (55%) reported<br />
≤ grade 2 HL. 68% and 32% of pts reported grade 1 or 2 toxicity,<br />
respectively, including head/scalp pain, feeling chilled, and rash. 85%<br />
of pts reported that SC made decisions about CTX easier. At a median<br />
follow-up of 15.4 months, no scalp metastases have been observed.<br />
Conclusions: Use of the DigniCap System is feasible, effective in<br />
preventing CTX-induced alopecia in the majority of users, and safe<br />
with short-term follow-up in pts with stage I BC. Additional studies<br />
should help to define potential causes for cap failure. This is the first<br />
prospective US trial to evaluate the effect of SC using an expert IP<br />
and blinded photographs to assess extent of alopecia. A larger trial is<br />
planned to confirm these results in pts with stage I/II disease.<br />
Support for this trial was provided by the Tauber Foundation (UCSF),<br />
the Madonia and Cooper Funds (WFBH), and Dignitana.<br />
P2-12-12<br />
Efficacy and safety of scalp cooling (SC) treatment for alopecia<br />
prevention in women receiving chemotherapy (CTX) for breast<br />
cancer (BC).<br />
Serrurier KM, Melisko ME, Glencer A, Esserman LJ, Rugo HS. UCSF<br />
Helen Diller Comprehensive <strong>Cancer</strong> Center<br />
Background: CTX induced hair loss (HL) is one of the most<br />
distressing side effects of BC treatment. Compared to women without<br />
CTX induced alopecia, those with alopecia have reported poorer body<br />
image, lower self-esteem and worse quality of life. In some cases,<br />
CTX induced HL may affect choice of therapy. Given the emotional<br />
impact of HL, the potential benefit of preventing CTX induced<br />
alopecia is great. We conducted a registry study tracking safety and<br />
efficacy in BC patients (pts) treated at our center who independently<br />
elected to use Penguin Cold Cap Therapy (PCCT).<br />
Methods: Pts who chose to use PCCT during CTX for early stage<br />
(ES) or advanced (M) disease signed informed consent to participate<br />
in the registry. HL was rated by practitioner assessment using the 5<br />
point Dean’s scale for HL: grade 0 (no HL), 1 (< 25% HL), 2 (25-50%<br />
HL), 3 (50-75% HL), and 4 (>75% HL), and by pt assessment using<br />
a visual analogue scale (VAS) from 0-100 where 0 = no HL and 100<br />
= 100% HL. Assessments were every 2-3 weeks at the start of each<br />
CTX cycle, and once in follow-up 1-6 months after completing CTX.<br />
Additional data collected included pt reported adverse events and pt<br />
satisfaction with the success, ease of use, and tolerability of PCCT.<br />
Results: 31 pts (29 with ES and 2 with M disease) have registered.<br />
25 have completed CTX and 20/25 are off study. 6 pts currently on<br />
CTX and 2 pts who stopped PCCT after cycle1 due to toxicity of<br />
CTX rather than issues with PCCT were excluded from the safety<br />
and efficacy analyses due to incomplete data. 2 additional pts were<br />
excluded from efficacy analysis due to beginning PCCT after the<br />
start of CTX, leaving 21 pts evaluable for efficacy and 23 pts for<br />
toxicity. CTX regimens included: docetaxel and cyclophosphamide<br />
(TC), docetaxel, carboplatin and trastuzumab (TCH), sequential<br />
doxorubicin and cyclophosphamide and paclitaxel, (AC/T), weekly<br />
nab-paclitaxel (nab). PCCT toxicities were all < grade 2 and included:<br />
15 pts (71%) with headaches and 5 (22%) with dandruff during PCCT.<br />
All pts experienced head pain, and 20 pts (95%) had scalp pain and<br />
felt chilled during the PCCT. Table 1 depicts clinician and patient<br />
reported efficacy.<br />
Table 1. Efficacy of PCCT by clinician and pt assessment<br />
Clinician reported HL by Dean’s scale<br />
CTX Regimen, N<br />
(N=pts)<br />
Pt reported HL by VAS (N=pts)<br />
Grade 0 or 1 Grade 2 Grade 3 or 4 VAS 0-25 VAS 26-50 VAS >50<br />
TC, 12 2 1 2 7 5 -<br />
TCH, 5 2 3 - 2 1 2<br />
AC/T, 2 1 - 1 - - 2<br />
Nab, 2 1 1 - - - 2<br />
Of the 20 pts assessed following completion of CTX and PCCT, 12<br />
(60%) “highly recommend” PCCT, and 8 (40%) “recommend to some<br />
degree”. No ESBC pts have worn a wig at any point.<br />
Conclusions: SC treatment (PCCT) is a viable but variably effective<br />
method of preventing HL for ESBC pts receiving CTX. The success of<br />
SC in hair preservation was dependent on the type and length of CTX<br />
regimen. Other patient factors impacting HL may exist. Short term<br />
toxicity is minimal. Given the emotional impact of CTX induced HL,<br />
ongoing study of PCCT and other SC devices, comparing different<br />
CTX regimens, is worthwhile. Ongoing studies at our center will<br />
include independently graded photographs to eliminate reporting<br />
bias by the clinician.<br />
Support for this trial was provided by the Tauber Foundation.<br />
P2-12-13<br />
Results of randomised controlled phase II study (KBCSG02 trial)<br />
of the efficiency of palonosetron, aprepitant, and dexamethasone<br />
for day1 with or without dexamethasone on days2 and 3.<br />
Kosaka Y, Sengoku N, Kikuchi M, Nishimiya H, Enomoto T, Kuranami<br />
M, Watanabe M. Kitasato University School of Medicine, Sagamihara,<br />
Japan<br />
Background: Emesis is one of the major non-hematologic toxicity<br />
caused by chemotherapy. The control of Chemotherapy Induced<br />
Nausea and Vomiting (CINV) is conducted to a life lengthening.<br />
www.aacrjournals.org 273s<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Recently, CINV is controlled by the second generation 5-HT3 receptor<br />
blocker (Palonosetron ; PALO) and a NK-1 receptor antagonist<br />
(Aprepitant ; APR). It has been shown that dexamethasone (DEX)<br />
with 5-HT3 receptor blocker improves acute / delayed CINV.<br />
However, it has not been determined the medication schedule of<br />
DEX with PALO and APR. The purpose of this study is evaluated the<br />
efficiency of palonosetron, aprepitant and dexamethasone for day1<br />
with or without dexamethasone on days2 and 3.<br />
Methods: <strong>Breast</strong> cancer patients who administered anthracyclin<br />
drug regimen have been eligible from April, 2011 to June, 2012. The<br />
patients were randomised to group A (PALO/APR/DEX one day) and<br />
group B (PALO/APR/DEX three days). Eighty patients was estimate<br />
as study samples. The primary endpoint was a complete response<br />
(CR) rate of vomiting, the secondary endpoint was a complete control<br />
(CC) rate of vomiting.<br />
Trial design<br />
Aprepitant (125 mg) (80 mg) (80 mg)<br />
Palonosetron (0.75 mg)<br />
dexamethasone (9.9 mg) (6.6 mg or placebo) (6.6 mg or placebo)<br />
Chemotherapy do<br />
days 1 2 3 4 5<br />
Results: Forty patients were enrolled in this study, and patient<br />
recruitment is continued. CR rate was no significant difference in<br />
both groups (76.9% of group A, 73.3% of group B). CC rate of group<br />
A (61.5%) did not show inferiority compared with group B (40.0%).<br />
Conclusions: In this current study, we suggest that one day<br />
dexamethasone treatment could reduce enough the emesis of high<br />
emetogenic chemotherapeutic agents.<br />
P2-12-14<br />
Use of the MD Anderson Symptom Inventory to Screen for<br />
Depression in <strong>Breast</strong> <strong>Cancer</strong><br />
Kvale EA, Azuero CB, Azuero A, Fisch M, Ritchie C. Birmingham<br />
VA Medical Center, Birmingham, AL; University of Alabama at<br />
Birmingham, AL; University of Alabama, Tuscaloosa, AL; MD<br />
Anderson <strong>Cancer</strong> Center, Houston, TX; University of California,<br />
<strong>San</strong> Francisco, CA<br />
Background: The prevalence of depression among breast cancer<br />
patients is estimated to be twice that in the general population,<br />
is linked to diminished quality of life and impaired adherence to<br />
therapy. Depression is frequently underdiagnosed or misdiagnosed<br />
in this population. Efficient screening for depression is central to<br />
patient-centered care and enhanced clinical outcomes for breast<br />
cancer patients.<br />
Purpose: To evaluate the use of a commonly utilized symptom<br />
assessment instrument as a screen to enhance identification of breast<br />
cancer patients experiencing depression.<br />
Methods: Data from a longitudinal surveillance database in outpatient<br />
supportive and palliative care were utilized, 174 breast cancer<br />
patient contacts were evaluated. Patients completed both the MD<br />
Anderson Symptom Inventory (MDASI) and the 9-item Patient Health<br />
Questionnaire (PHQ-9) as components of a routinely collected patientreported<br />
outcomes battery. Performance of the MDASI (using the 1-10<br />
Depression question) in identifying cases of depression (defined as a<br />
score ≥ 15 on the PHQ-9) was determined using receiver operating<br />
characteristic (ROC) analysis.<br />
Results: Data were available on 174 patient contacts. When scored<br />
as a continuous measure, the MDASI performed well with an area<br />
under the ROC curve of 0.87 (95% confidence interval [CI], 0.81-<br />
0.94). An MDASI cutoff score of >= 6 provided a sensitivity of 73%<br />
(95% CI, 58%-88%), a specificity of 80% (95% CI, 74%-87%), a<br />
positive predictive value (PPV) of 46%, and a negative predictive<br />
value (NPV) of 93%.<br />
Conclusion: The “depression” component of the MDASI as a<br />
screening instrument for depression in breast cancer patients yields<br />
suboptimal sensitivity and specificity for use as a screening tool.<br />
Further efforts to evaluate subsequent iterations of the MDASI<br />
and combinations of elements in the MDASI that may enhance<br />
performance are indicated.<br />
P2-12-15<br />
Understanding the complex non face-to-face interventions<br />
delivered by the clinical nurse specialists in metastatic breast<br />
cancer.<br />
Warren M, Mackie D, Leary A. Royal Marsden NHS Foundation Trust,<br />
Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation<br />
Trust, London, United Kingdom; Independent Healthcare Consultant<br />
and Research Analyst<br />
Introduction: Despite improving survival rates in breast cancer,<br />
globally one third of patients diagnosed with primary breast cancer<br />
will go onto develop metastatic breast cancer. In recent years treatment<br />
for metastatic breast cancer in the United Kingdom has moved to the<br />
ambulatory setting using treatments such as, oral chemotherapies,<br />
oral biological and bisphosphonate therapies meaning telephone<br />
consultation and clinical management, pivotal to confluent care.<br />
Research Objectives: To determine the number and complexity of<br />
incoming telephone calls, the stage of the metastatic breast cancer<br />
disease pathway for example at diagnosis, treatment, follow-up, and<br />
palliative care, the nursing interventions, outcomes and the reason<br />
for contact from patients and carers.<br />
Rationale: Previous studies demonstrate much of the clinical work<br />
of the clinical nurse specialist is delivered via the telephone. The<br />
rationale of this study was to examine the complexity of non faceto-face<br />
patient interaction with the metastatic breast cancer clinical<br />
nurse specialist.<br />
Method: A prospective study conducted over a 1 – month period at a<br />
United Kingdom National Health Service Foundation Hospital Trust.<br />
Data was collected by two clinical nurse specialists on incoming calls<br />
using Excel and a bespoke interrelational structured query database.<br />
These data were then mined using standard data mining techniques<br />
and pattern recognition techniques.<br />
Results: The study collected 28 days of data. 229 patient and carer<br />
telephone contacts were recorded. Most calls were from patients<br />
(62.5%). Incoming calls resulted in the delivery of 1282 interventions,<br />
a mean of six interventions per call (range1-8) and clustered into<br />
four areas: meeting information needs (29%), symptom management<br />
(26%), psychological/social issues (33%) and other issues (12%).<br />
The incoming telephone work accounted for 63 h which represented<br />
30% of the total working time of the clinical nurse specialist. Calls<br />
primarily originated from patients who were in the follow-up phase<br />
(43% of calls), a group usually thought to prefer self management.<br />
P2-13-01<br />
Impact of Body Mass Index (BMI) on the efficacy of aromatase<br />
inhibitors to suppress estradiol serum levels in postmenopausal<br />
patients with early breast cancer: a prospective proof of principle<br />
Pfeiler G, Königsberg R, Hadji P, Fitzal F, Maroske M, Ban G,<br />
Zellinger J, Exner R, Seifert M, Singer C, Gnant M, Dubsky P. Medical<br />
University of Vienna, Austria; Applied <strong>Cancer</strong> Research – Institution<br />
for Translational Research Vienna (ACR-ITR VIEnna)/CEADDP,<br />
Austria; Universityhospital of Giessen and Marburg GmbH, Germany<br />
Background<br />
BMI impacts on the efficacy of aromatase inhibitors (AIs) regarding<br />
disease outcome in patients with early breast cancer. We hypothesized<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
274s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
that this clinical impact of BMI is driven by the inability of AIs to<br />
suppress estradiol (E2) serum levels to the same low level in obese<br />
compared to non-obese patients.<br />
Methods<br />
68 postmenopausal ER positive patients with breast cancer, scheduled<br />
to receive anastrozole or letrozole as adjuvant endocrine treatment<br />
were prospectively included in this study. Serum was taken before<br />
(T1) and 3 months after start with aromatase inhibitors (T2). Serum<br />
levels of FSH, LH, E2, glucose and insulin were analyzed immediately<br />
in the clinical routine lab and in a dedicated central lab able to measure<br />
E2 in serum at low concentrations with high sensitivity.<br />
Results<br />
40 patients were normal - or overweight (non-obese; BMI 18.5-29.9<br />
kg/m2) and 28 patients were obese (BMI ≥ 30 kg/m2). A weak nonsignificant<br />
correlation between BMI and baseline E2 serum levels<br />
(r=0.2, p=0.2) translated into a strong negative, highly significant<br />
correlation between BMI and baseline FSH (r=-0.6, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Methods: The Oncology Services Comprehensive Electronic Records<br />
(OSCER) database was used to identify women with BC (ICD-9<br />
174), ≥1 clinic visit, and confirmed AI (anastrozole, letrozole, or<br />
exemestane) in 2011. Women with metastases (ICD-9 196-198,<br />
stage IV, or M1 disease) were excluded. OSCER captures electronic<br />
medical record data on >500,000 cancer patients since 2004 from<br />
US outpatient community and hospital affiliated oncology practices.<br />
OSCER is projected nationally through methods of direct estimations<br />
utilizing claims data (Smith et al. submitted). To identify subgroups of<br />
women at increased risk of bone loss, estimates were stratified by age<br />
and number of AIs received. Bone loss was defined by diagnosis of<br />
osteoporosis (ICD-9 733.0), osteopenia (ICD-9 733.90), or receipt of<br />
bone tx either before initiation of first AI (proxy for pre-existing bone<br />
loss) or any time before or during 2011 (proxy for current bone loss).<br />
Results: When projected to the US population, it is estimated that<br />
489,664 (95% CI 467,642—511,686) women with non-metastatic<br />
BC were treated with an AI in 2011. Of these, 52% (253,672 [95%<br />
CI 239,229—268,115]) were 65 or older. The table summarizes<br />
results for the projected cohorts. These data indicate that 19% of<br />
women receiving AIs were in the pre-/peri-/early post-menopausal<br />
age group (55 or younger), and approximately 66% of women treated<br />
with AIs did not have evidence of pre-existing bone loss (i.e., either<br />
osteoporosis diagnosis or receipt of bone tx before AI).<br />
Total Age < 45 Age 45-55 Age 56-64 Age ≥ 65<br />
Total non-metastatic BC pts on AI 489,664 11,536 80,843 143,613 253,672<br />
Pts with >1 AI Rx 438,243 11,536 69,406 129,782 227,520<br />
No evidence of bone loss before<br />
initiation of first AI<br />
322,541 10,531 67,319 97,922 146,768<br />
Evidence of bone loss before or<br />
during AI tx<br />
199,683 3,573 22,907 59,881 113,322<br />
Conclusions: This is the first study to estimate prevalence of women<br />
with non-metastatic BC treated with AIs in the US. As a large<br />
proportion of women are diagnosed with ER+ve BC and eligible<br />
for AIs (Jemal et al. 2007), a growing number will face increased<br />
subsequent risk of fractures. These findings suggest that up to 500,000<br />
women annually are treated with AIs, and over 40% have evidence<br />
of bone loss before or during AI. These women will face increased<br />
risk of fractures, highlighting the need for prevention of fractures and<br />
intervention with targeted bone tx to increase bone mass and prevent<br />
or treat osteoporosis.<br />
P2-13-04<br />
Superior efficacy of anastrozole to tamoxifen as adjuvant therapy<br />
for postmenopausal patients with hormone-responsive breast<br />
cancer. Efficacy results of long-term follow-up data from N-SAS<br />
BC 03 trial<br />
Imoto S, Osumi S, Aogi K, Hozumi Y, Mukai H, Iwata H, Yokota I,<br />
Yamaguchi T, Ohashi Y, Watanabe T, Takatsuka Y, Aihara T. School<br />
of Medicine, Kyorin University, Tokyo, Japan; National Hospital<br />
Organization Shikoku <strong>Cancer</strong> Center, Ehime, Japan; Jichi Medical<br />
University, Tochigi, Japan; National <strong>Cancer</strong> Center Hospital East,<br />
Chiba, Japan; Aichi <strong>Cancer</strong> Center Hospital, Aichi, Japan; School of<br />
Public Health, University of Tokyo, Tokyo, Japan; Tohoku University<br />
School of Medicine, Miyagi, Japan; Hamamatsu Oncology Center,<br />
Shizuoka, Japan; Kansai Rosai Hospital, Hyogo, Japan; Aihara<br />
Hospital, Osaka, Japan<br />
Background: Aromatase inhibitors have been shown to be superior<br />
to tamoxifen as adjuvant therapy in postmenopausal patients with<br />
hormone-responsive breast cancer. Here we report the efficacy results<br />
of long-term follow-up data from N-SAS BC 03 trial (UMIN CTRID:<br />
C000000056), in which anastrozole was compared to tamoxifen in<br />
hormone-responsive postmenopausal early breast cancer patients<br />
who had taken tamoxifen for 1—4 years out of a total of 5 years of<br />
treatment as adjuvant therapy.<br />
Patients and methods: Out of a total of 706 recruited patients, 696<br />
patients (tamoxifen group, n=345; anastrozole group, n=351) were<br />
used as the full analysis set for the present study. The log-rank test<br />
was used to compare the two groups in terms of disease-free survival<br />
(DFS) and relapse-free survival (RFS), Kaplan-Meier estimates were<br />
calculated. The treatment effects were estimated by Cox’s proportional<br />
hazard model and were expressed as hazard ratios, with associated<br />
95% confidence intervals (CIs).<br />
Results: After a median follow-up of 76.1 months, (range: 1.3-110<br />
months), the unadjusted hazard ratio was 0.87 (95%Cl 0.60-1.26; logrank<br />
p=0.457) for DFS and 0.77 (95%Cl 0.49-1.22; log-rank p=0.266)<br />
for RFS, both in favor of anastrozole. The estimated hazard ratio<br />
(95%CIs) for DFS and for RFS until each time point (right censored<br />
data) was as follows: until 30 months: 0.54 (0.30-0.98) and 0.48 (0.23-<br />
0.98), until 42 months; 0.65 (0.40-1.06) and 0.53 (0.29-0.97), until 54<br />
months: 0.77 (0.50-1.19) and 0.63 (0.37-1.06), until 66 months: 0.82<br />
(0.55-1.24) and 0.72 (0.44-1.17), until 78 months: 0.83 (0.57-1.23)<br />
and 0.73 (0.46-1.17), respectively. The hazard ratios (95%CIs) for<br />
DFS and for RFS until 36 months were 0.72 (95%Cl 0.43-1.22) and<br />
0.58 (95%Cl 0.30-1.12), and those after 36 months were 1.06 (95%Cl<br />
0.62-1.81) and 0.98 (95%Cl 0.51-1.88), respectively.<br />
Conclusion: Superior efficacy of anastrozole to tamoxifen in the<br />
Japanese population was suggested over a long-term follow-up<br />
period. It was the greatest early after switching from tamoxifen and<br />
then decreased thereafter.<br />
P2-13-05<br />
A pilot prospective study of adherence to aromatase inhibitor<br />
adjuvant therapy in patients with stage 1-3 breast carcinoma.<br />
Heiss B, Thompson J, Nightingale G, Tait N, Kesmodel S, Bellavance<br />
E, Chumsri S, Bao T, Goloubeva O, Feigenberg S, Tkaczuk K. Marlene<br />
and Stewart Greenebaum <strong>Cancer</strong> Center, University of Maryland,<br />
Baltimore, MD; Thomas Jefferson University, Philadelphia, PA<br />
Introduction: The most practical approach to assessment of<br />
medication adherence in clinical practice is via patient self-reporting,<br />
which can be measured using the 8-item Morisky Medication<br />
Adherence Scale (MMAS). The 8-item MMAS was developed from<br />
a previously validated 4-item scale by supplementing additional items<br />
measuring specific medication-taking behaviors to better capture<br />
barriers surrounding adherence behavior and has been determined<br />
to have better reliability than 4-item scale. Validated medication<br />
adherence surveys such as an 8-item MMAS, are untested in oncology,<br />
but have been validated in HTN, HIV, DM and other disorders in the<br />
setting of multiple chronic medications. Thus this study will serve as<br />
a pilot study of the MMAS in the oncology population. Methods:<br />
This is a prospective study conducted at the University of Maryland<br />
Greenebaum <strong>Cancer</strong> Center (UMGCC). The primary objective was<br />
to identify the adherence level (high, medium, low) to adjuvant<br />
(AI) in early stage (1-3) breast cancer (BC) patients in order to<br />
identify predictors of adherence. Subjects were stratified according<br />
to duration of therapy with AI (≤ 2 yrs or >2 yrs) at the time of the<br />
survey. The secondary objective was to identify baseline predictors<br />
for adherence. Patients received a maximum 8 points for maximum<br />
adherence to medication treatment or high adherence, 6-7 points for<br />
medium adherence and < 6 points for low adherence. Eligibility:<br />
Adult females, postmenopausal, signed consent, hormone receptorpositive<br />
BC (ER and/or PR >=1%), pathologically confirmed Stage<br />
1-3 BC, completed surgery, adjuvant chemotherapy, and/or radiation<br />
therapy, and were recommended by their medical oncologist to take<br />
adjuvant AI for 5 years. Pts received a prescription for adjuvant AIs<br />
(anastrozole, letrozole or exemestane) after completion of adjuvant<br />
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chemotherapy. Results: Patient characteristics: 73 BC pts were<br />
sequentially accrued so far at the UMGCC and filled out the selfreported<br />
questionnaire; Causcasian-62%, African American (AAF)-<br />
37%, Asian-1%, median age at diagnosis-54 (range33-84); stage<br />
1- 36%, stage 2- 47%, stage 3- 17%; mastectomy- 61%; lumpectomy-<br />
39%; local radiation therapy 62%; ER+ 95%; PR+ 78%, HER2+ 17<br />
%; tumor type ductal- 75%; lobular- 20%; mixed ductal/lobular- 5%;<br />
tumor grade-1- 46%, 2- 41%,3- 12%; adjuvant chemotherapy- 63%.<br />
Educational level- N/A- 3%, 2 years.<br />
Univariable regression models for continuous predictors and rxc<br />
contingency tables for categorical ones revealed that the adherence<br />
to AI therapy is not affected by age, marital status, education, prior<br />
cancer therapy, tumor stage, and concurrent medication. However,<br />
there was a trend for better adherence to AI therapy in Caucasian<br />
women vs. AAF (P=0.013). The study is ongoing.<br />
P2-13-06<br />
Effect of letrozole on bone and joints in collagen-induced arthritis<br />
in mice<br />
Lintermans A, Verhaeghe J, Van Bree R, Vanderschueren D,<br />
Vanderhaegen J, Braem K, Lories R, Neven P. University Hospitals<br />
Leuven, KU Leuven, Belgium; KU Leuven, Leuven, Belgium;<br />
University Hospitals Leuven, Belgium<br />
Background Aromatase inhibitors (AIs) are an established treatment<br />
modality for postmenopausal hormone-responsive breast cancer.<br />
Many of AI-treated patients experience AI-induced musculoskeletal<br />
syndrome (AIMSS), which may adversely affect quality of life and<br />
treatment adherence. The etiology underlying this syndrome remains<br />
unknown. Therefore, a well-established mouse model of human<br />
rheumatoid arthritis, collagen-induced arthritis (CIA), was used to<br />
evaluate how AIs affect bone and joints in inflammatory joint disease.<br />
Material and methods Thirty-two female DBA/1 mice were divided<br />
into 2 groups of 16 mice each; ovariectomy (OVX) or sham operation<br />
was performed at 7 weeks of age (=day 0). At day 14, arthritis was<br />
induced in all mice by injection of chicken sternal cartilage type<br />
II collagen emulsified with an equal volume of Freund’s complete<br />
adjuvant, followed by a booster injection at day 21. Afterwards,<br />
mice were treated with letrozole or vehicle during 30 days. Mice<br />
were sacrificed at day 54. Parameters analyzed included clinical<br />
CIA score of paws, dual-energy x-ray absorptiometry, microCT of<br />
femora, histopathological examination of ankles and paws and IGF-I<br />
levels. Analysis was performed with ANOVA, post-hoc tests, general<br />
linearized and mixed models.<br />
Results As expected, OVX led to an increased lean and total body<br />
weight relative to the sham group. Repeated measurements analysis<br />
with mixed models suggested interaction between weight, time and<br />
arthritis severity. Serum IGF-I concentrations were significantly<br />
higher in the OVX group compared with the sham group, but no<br />
differences were observed between letrozole treatment and controls.<br />
Collagen immunization resulted in progressive inflammation of the<br />
paws including the ankles that increased up to day 54. Over time,<br />
clinical scores for arthritis severity were highest in the OVX/vehicle<br />
group. Both letrozole groups had an intermediate course and the<br />
lowest scores were seen in the paws of the sham/vehicle group, as<br />
expected. Histopathological examination of hematoxylin and eosinstained<br />
sections were in line with these results.<br />
Subcapital BMD at the end of the arthritis experiments was<br />
significantly different between the four groups. Post-hoc test<br />
confirmed the negative effect of OVX versus sham procedure, in<br />
the presence or absence of letrozole treatment. MicroCT analysis<br />
showed that OVX induced a significant decrease in bone mineral<br />
density and content in both trabecular (volume and number) and<br />
cortical bone (volume, area, thickness and medullary area) compared<br />
to sham operation in vehicle-treated mice. In the letrozole group, only<br />
cortical bone (volume, area inside periost and medullary area) was<br />
significantly reduced following OVX. In addition, in the sham group,<br />
letrozole induced lower trabecular bone volume and less trabecular<br />
numbers compared to vehicle treatment. This was in contrast with<br />
the OVX groups; letrozole treatment resulted in significantly better<br />
trabecular bone parameters.<br />
Conclusion Not only bone loss but also severity of joint disease was<br />
increased by OVX. Remarkably, in contrast to what is observed in<br />
humans, letrozole treatment protected the bone and joints after OVX<br />
but had negative effects in its absence, thereby providing further<br />
evidence for a regulatory effect in joint and bone biology.<br />
P2-13-07<br />
Long-term follow-up data of the side effect profile of anastrozole<br />
compared with tamoxifen in Japanese women : findings from<br />
N-SAS BC03 trial.<br />
Iwata H, Ohsumi S, Aogi K, Hozumi Y, Imoto S, Mukai H, Yokota I,<br />
Yamaguchi T, Ohashi Y, Watanabe T, Takatsuka Y, Aihara T. Aichi<br />
<strong>Cancer</strong> Center Hospital, Nagoya, Aichi, Japan; NHO Shikoku<br />
<strong>Cancer</strong> Center, Matsuyama, Ehime, Japan; Jichi Medical University,<br />
Tochigi, Japan; School of Medicine, Kyorin University, Tokyo, Japan;<br />
National <strong>Cancer</strong> Center Hospital East, Chiba, Japan; School of<br />
Public Health, University of Tokyo, Tokyo, Japan; Tohoku University<br />
School of Medicine, Sendai, Japan; Hamamatsu Oncology Center,<br />
Hamamatsu, Japan; Kansai Rosai Hospital, Hyogo, Japan; Aihara<br />
Hospital, Osaka, Japan<br />
Background: Aromatase inhibitors (AIs) are standard treatment in<br />
the adjuvant setting such as initial, switch and extended treatment in<br />
postmenopausal hormone-sensitive breast cancer patients overseas.<br />
Non-steroidal AIs have usually been used as adjuvant treatment in<br />
Japanese practice. We already reported the efficacy and short term<br />
adverse events by switching therapy from tamoxifen (TAM) to<br />
anastrozole (ANA) in Japan (<strong>Breast</strong> <strong>Cancer</strong> Res Treat. 2010 ;121:379-<br />
87). However, the usage of adjuvant hormone therapy currently shows<br />
a trend to continue for a long time. Furthermore, long-term follow-up<br />
data is very important for the safe use of AIs. Off course, there are<br />
many data on safety profiles in Western countries. However, there are<br />
limited data in the Asian population. Methods: We investigated the<br />
planned analyses by using the data of a randomized adjuvant study<br />
of tamoxifen alone versus sequential tamoxifen and anastrozole in<br />
hormone-responsive postmenopausal breast cancer patients (N-SAS<br />
BC 03 trial. UMIN CTRID: C000000056). We examined the<br />
chronological changes from baseline to 36 months after randomization<br />
between the TAM arm (351 cases) and the ANA arm (345 cases)<br />
according to the case report forms (CRFs). We prospectively<br />
collected the data and compared data on hot flushes, nausea &<br />
vomiting, anorexia, fatigue, mood distress, headaches, arthralgia,<br />
leukocytopenia, liver transaminase changes, thromboembolism,<br />
vaginal bleeding, vaginal discharge, cardio-vascular events, second<br />
primary cancer and contra-lateral breast cancer between the two arms<br />
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every 3 months from baseline to 12 months, and every 6 months up<br />
to 36 months after randomization. The data were expressed as the<br />
difference in the incidence over the time course and were analyzed<br />
using chi-square tests and logistic regressions with the baseline<br />
value as a covariate via generalized estimating equation using robust<br />
standard errors. Results: The incidence of arthralgia are significantly<br />
better in the TAM arm than the ANA arm (P=0.00002). However,<br />
there are no differences concerning all events excluding arthralgia<br />
between the two arms. Ten and twelve cases of second primary<br />
cancer occurred in the TAM and ANA arms, respectively (P=0.6).<br />
Six and three cases of contralateral breast cancer occurred in the<br />
TAM and ANA arms, respectively (P=0.3). According to analyses of<br />
the chronological changes, significant changes were observed in hot<br />
flushes (P=0.001) and vaginal discharge (P.999)<br />
Conclusion: From our retrospective review, we did not observe<br />
any significant difference in the adherence to adjuvant anti-estrogen<br />
therapy in patients with EBC. The present process of discharging<br />
such patients to surgeons and family physicians for follow up does<br />
not seem to affect their compliance.<br />
P2-13-09<br />
Pharmacological impact of endoxifen in a laboratory simulation<br />
of tamoxifen therapy in postmenopausal breast cancer patients<br />
Maximov PY, McDaniel RE, Bhatta P, Brauch H, Jordan VC.<br />
Lombardi Comprehensive <strong>Cancer</strong> Center, Georgetown University<br />
Medical Center, Washington, DC; Dr. Margarete Fischer-Bosch-<br />
Institute of Clinical Pharmacology, Stuttgart, Germany<br />
Tamoxifen is a well-established adjuvant drug for the treatment and<br />
prevention of Estrogen Receptor (ER) positive breast cancer, effective<br />
in both pre- and postmenopausal women. However, the metabolic<br />
activation of tamoxifen to endoxifen by the CYP2D6 enzyme system<br />
still remains controversial to plan the treatment of patients with breast<br />
cancer. Since the discovery and description of the pharmacological<br />
properties of endoxifen, clinical trials were undertaken to determine<br />
the pharmacological relevance of endoxifen. The results of these trials,<br />
however, vary. In this study we demonstrate the pharmacological<br />
impact of endoxifen in a laboratory simulation of breast cancer<br />
therapy with tamoxifen in postmenopausal women in vitro in a<br />
panel of human breast cancer cell lines (MCF-7, T47D, ZR-75-1 and<br />
BT474). The concentrations of estrogens (E1/E2) used to simulate<br />
postmenopausal women treated with tamoxifen, were obtained<br />
from published studies, as well as the concentrations of tamoxifen<br />
and its metabolites (N-desmethyltamoxifen, 4-hydroxytamoxifen<br />
and endoxifen) based on the CYP2D6 genotype in postmenopausal<br />
breast cancer patients (Murdter TE et al, Clin Pharmacol Ther, 2011).<br />
Our results demonstrate that irrespective of CYP2D6 genotype,<br />
tamoxifen and its primary metabolites (N-desmethyltamoxifen and<br />
4-hydroxytamoxifen) are able to inhibit completely the estrogenstimulated<br />
growth of breast cancer cells in vitro. Additional endoxifen<br />
in any concentration corresponding to CYP2D6 genotype was not<br />
able to increase the antiestrogenic effect of tamoxifen and its primary<br />
metabolites. Moreover, we demonstrate that 4-hydroxytamoxifen<br />
is absolutely essentialforinhibition of estrogen action. Based on<br />
our results, we can conclude that endoxifen is pharmacologically<br />
supportive but not essential for any genotype of CYP2D6 in a<br />
postmenopausal setting. This study (PYM) was supported by Susan<br />
G. Komen for the Cure International Postdoctoral Fellowship under<br />
Award number SAC100009(VCJ), and the Department of Defense<br />
<strong>Breast</strong> Program under Award number W81XWH-06-1-0590 (VCJ).<br />
P2-13-10<br />
Prospective randomized and multicentric evaluation of cognition<br />
in menopausal breast cancer patients receiving adjuvant<br />
hormonotherapy: a phase III study (Preliminary results)<br />
Vanlemmens L, Delbeuck X, Servent V, Mailliez A, Vanlemmens L,<br />
Lefeuvre-Plesse C, Kerbrat P, Petit T, Fournier C, Vendel Y, Clisant S,<br />
Bonneterre J, Pasquier F, Le Rhun E. Centre Mémoire de Ressource<br />
et de Recherche - CHRU Lille, Lille, France; Centre Oscar Lambret,<br />
Université Lille Nord de France, Lille, France; Centre Eugène<br />
Marquis, Rennes, France; Centre Paul Strauss, Strasbourg, France;<br />
Centre Oscar Lambret, Lille, France; CHRU, Lille, France<br />
Background<br />
Cognitive impairment has been considered to be a possible adverse<br />
effect of aromatase inhibitors (AI). The aim of the study was to<br />
compare the impact of tamoxifen or AI on verbal memory (Rey<br />
auditory-verbal learning test) and other cognitive functions (memory,<br />
executive and attentional functions) after 6 months of treatment.<br />
Methods<br />
In this randomized, open-label phase III study, menopausal patients<br />
treated with adjuvant hormonotherapy for early breast cancer were<br />
enrolled at the end of the radiotherapy. Patients over 70 years, with<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
a history of cognitive disorder or with prior chemotherapy were<br />
excluded. Detailed neuropsychological assessments and quality of<br />
life evaluations were performed before the 1st administration of<br />
hormonotherapy and then 6 months later. Considering the usual norms<br />
of the auditivo-verbal Rey test, an alpha risk of 5% and a 95% power,<br />
27 patients per arm had to be included. Statistical analyses included<br />
Chi2 test and Student tests when appropriate.<br />
Results<br />
62 consecutive evaluable patients were randomized in 2 arms between<br />
March 2009 and April 2011. Patients received tamoxifen in arm A<br />
(n=31) and AI in arm B (letrozole n=17; anastrozole n=12; exemestane<br />
n= 2). Median age at inclusion was 61.4 years. The median time<br />
since menopause was 10 years. Characteristics of the breast tumor<br />
and initial neuropsychological evaluations did not differ significantly<br />
between the 2 arms. After 6 months, we observed a significant decline<br />
of the performance at the episodic memory test (immediate recall of<br />
the Rey auditory verbal learning test) (p=0.0015) in arm A only and<br />
a significant improvement on executive measures (Trail Making Test<br />
and Stroop test) (respectively p=0.03/p=0.002) in arm B. Quality of<br />
life didn’t differ after 6 months of treatment.<br />
Conclusions<br />
These preliminary results do not support that AI have a worse<br />
adverse effect on cognitive functions than tamoxifen after 6 months<br />
of treatment. A confirmation is planned after one year of treatment.<br />
P2-14-01<br />
Fulvestrant vs exemestane for treatment of metastatic breast<br />
cancer in patients with acquired resistance to non-steroidal<br />
aromatase inhibitors – a meta-analysis of EFECT and SoFEA<br />
(CRUKE/03/021 & CRUK/09/007)<br />
Johnston SRD, Chia S, Kilburn LS, Gradishar WJ, Cameron D,<br />
Dodwell D, Ellis P, Howell A, Im Y-H, Coombes G, Piccart M, Dowsett<br />
M, Bliss J, On Behalf of the SoFEA and EFECT Investigators. The<br />
Royal Marsden Hospital NHS Foundation Trust & The Institute of<br />
<strong>Cancer</strong> Research, London, United Kingdom; British Columbia <strong>Cancer</strong><br />
Agency, University of British Columbia, Vancouver, BC, Canada; The<br />
Institute of <strong>Cancer</strong> Research, Sutton, Surrey, United Kingdom; Robert<br />
H. Lurie Comprehensive <strong>Cancer</strong> Center, Feinberg School of Medicine,<br />
Northwestern University, Chicago, IL; Christie Hospital NHS<br />
Trust, Manchester, United Kingdom; Edinburgh <strong>Cancer</strong> Research<br />
Centre, University of Edinburgh and NHS Lothian, Edinburgh,<br />
United Kingdom; Leeds Teaching Hospitals NHS Trust, St. James’s<br />
University Hospital, Leeds, United Kingdom; Guy’s and St Thomas’s<br />
NHS Foundation Trust, London, United Kingdom; Samsung Medical<br />
Center, Seoul, Korea; Jules Bordet Institute, Brussels, Belgium; The<br />
Royal Marsden NHS Foundation Trust, London, United Kingdom<br />
Background: Optimal endocrine treatment (trt) for post-menopausal<br />
women with ER+ advanced breast cancer (ABC) progressing on or<br />
following a non-steroidal (NS) aromatase inhibitor (AI) is unclear.<br />
The EFECT study showed no difference in efficacy between the<br />
steroidal antiestrogen fulvestrant (F) & steroidal AI exemestane (E)<br />
in this setting (HR=0.96, 95%CI: 0.82, 1.13; p=0.65). Pre-clinical<br />
data suggest F may be more effective in a low estrogen environment.<br />
SoFEA investigated F combined with anastrozole (F+A) in patients<br />
(pts) with acquired resistance to previous AI compared with F alone<br />
& F alone vs. E. The combination of F+A was no better than F<br />
(HR=1.00, 95%CI: 0.83, 1.21; p=0.98) nor F alone better than E<br />
(HR=0.95, 95%CI: 0.79, 1.14; p=0.56); the lack of added benefit for<br />
F+A is consistent with previous 1st-line studies that have assessed<br />
this combination versus A alone (FACT & SWOG-S0226).<br />
Methods: SoFEA is a multi-center partially blinded randomized phase<br />
III study postmenopausal women were allocated to F plus A (F+A<br />
n=243), F plus placebo (n=231) or E (n=249). Similarly, EFECT is a<br />
randomized, double-blind, placebo controlled, multi-center phase III<br />
trial of F (n=351) versus E (n=342) in postmenopausal women (see<br />
table). However, given the differences in prior endocrine therapy/<br />
responsiveness within SoFEA & EFECT populations, an individual<br />
pt meta-analysis combining data from SoFEA & EFECT will be<br />
conducted enabling exploration of putative effects within specific pt<br />
subgroups to establish evidence in support, or not, of a pt subgroup<br />
sensitive to F at the dose used in these trials. Subgroups to be analysed<br />
include receptor status, visceral involvement, AI sensitivity, age,<br />
NSAI setting & time on NSAI.<br />
Results: 723 pts (480 in F & E) were enrolled from 82 UK & 4 South<br />
Korean centers (03/2004-04/2010) in SoFEA. 693 pts were enrolled<br />
from 138 centers worldwide (08/2003-11/2005) in EFECT. Trt was<br />
well tolerated in both trials; serious adverse events were rare. The<br />
meta-analysis will be conducted in July 2012 & results presented.<br />
Conclusion: Combining individual pt data from SoFEA & EFECT<br />
via meta-analysis will provide definitive clinical information on pt’s<br />
response to F at the dose used in these studies, in particular whether<br />
certain pts with acquired resistance to NSAI do experience benefit<br />
of use of this antiestrogen as opposed to E.<br />
SoFEA & EFECT trial designs:<br />
SoFEA (EBCC 2012) EFECT (JCO 2008)<br />
Pts with HR+ ABC who have<br />
progressed or recurred after Pts with HR+ ABC progressing or<br />
Population<br />
NSAI, having demonstrated recurring after NSAI<br />
prior response<br />
Prior NSAI usage (adjuvant/<br />
19% / 81% 12% / 87%<br />
metastatic)<br />
Prior AI sensitivity 100% 63%<br />
Dose<br />
F=250mg monthly (IM) after<br />
500mg loading dose; E=25mg<br />
daily; A=1mg daily<br />
F=250mg monthly (IM) after<br />
500mg loading dose; E=25mg<br />
daily<br />
Median follow-up 38 months (all pts) 13 months (alive pts)<br />
P2-14-02<br />
Preclinical Evaluation of Enzalutamide in <strong>Breast</strong> <strong>Cancer</strong> Models<br />
Cochrane DR, Bernales S, Jacobsen BM, D’Amato NC, Guerrero J,<br />
Gómez F, Protter AA, Elias AD, Richer JK. University of Colorado<br />
Anschutz Medical Campus, Aurora, CO; Medivation Inc., <strong>San</strong><br />
Francisco, CA; Fundación Ciencia & Vida, <strong>San</strong>tiago, Chile<br />
Background: The vast majority of breast cancers express the<br />
androgen receptor (AR) with ∼80% of ER+ and 30% to50% of<br />
ER- tumors being positive for AR by immunohistochemistry (IHC).<br />
Approximately 30% of breast cancer patients with estrogen receptor<br />
positive (ER+) tumors do not respond to tamoxifen or aromatase<br />
inhibitors and AR signaling has been implicated as a possible<br />
mechanism of this insensitivity. AR overexpression has also been<br />
associated with resistance to either tamoxifen or aromatase inhibitors<br />
in cell line models.<br />
Hypothesis: ER+ breast cancers can switch from estrogen to<br />
androgen-dependent growth as they become resistant to traditional<br />
endocrine therapies and AR can serve as a therapeutic target in AR+<br />
breast cancers, irrespective of ER status.<br />
Methods: The proliferative effect of dihydrotestosterone (DHT) and<br />
estradiol (E2) in the presence enzalutamide (formerly MDV3100)<br />
was examined in vitro and in xenograft studies using models of both<br />
ER+ and ER- breast cancer that express AR. Furthermore, AR and<br />
ER were examined by IHC in clinical specimens from breast cancer<br />
patients treated with neoadjuvant exemestane and adjuvant tamoxifen.<br />
Tumor tissue was compared to adjacent normal breast epithelium.<br />
Results: In ER+ models, bicalutamide and enzalutamide both<br />
inhibited DHT-mediated proliferation, while enzalutamide<br />
uniquely inhibited E2-mediated proliferation. In vivo, enzalutamide<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
significantly reduced estrogen- and androgen-mediated growth of<br />
MCF7 (ER+/AR+) xenograft tumors. Remarkably, enzalutamide<br />
demonstrated an anti-proliferative effect comparable to tamoxifen.<br />
in vitro, enzalutamide inhibits E2-stimulated tumor cell proliferation<br />
and E2 bound ER activation of genes such as PR and SDF-1, despite<br />
no observed binding of enzalutamide to ER alpha or beta. In ER-/<br />
AR+ MDA-MB-453 xenografts, enzalutamide treatment resulted in<br />
decreased nuclear AR localization, increased apoptosis and tumor<br />
growth inhibition.<br />
Conclusions: Enzalutamide demonstrated significant anti-tumor<br />
activity in preclinical models of breast cancers that express AR,<br />
regardless of ER status. When enzalutamide opposes DHT, it<br />
functions by excluding AR from the nucleus, thereby reversing the<br />
anti-apoptotic effect of AR. In contrast, when opposing E2, it causes<br />
a decrease in tumor cell proliferation. Profiling of ER+ xenografts is<br />
underway to further elucidate the mechanism by which this occurs.<br />
P2-14-03<br />
“Ethinylestradiol” is beneficial for postmenopausal advanced<br />
breast cancer patients heavily pre-treated with endocrine agents<br />
Iwase H, Yamamoto Y, Murakami K-I, Yamamoto-Ibusuki M, Tomita<br />
S, Omoto Y. Kumamoto University, Kumamoto, Japan<br />
Purpose and Methods<br />
Estrogen deprivation therapy using aromatase inhibitors is a standard<br />
therapy in postmenopausal hormone-dependent breast cancer.<br />
Paradoxically, low-dose estradiol was reported to be beneficial for<br />
the postmenopausal patients who have been heavily pre-treated with<br />
long-term sequential anti-estrogen therapies. To determine efficacy<br />
and safety of ethinylestradiol (3mg /day oral), a phase 2 study has been<br />
performed for the postmenopausal patients with advanced or recurrent<br />
breast cancer who became resistant to sequential endocrine treatments.<br />
The primary endpoint was clinical benefit rate, secondary were safety,<br />
objective response rate and time to progression. The interim data will<br />
be reported because of the extremely beneficial results.<br />
Results<br />
Eighteen cases with ER-positive tumor which showed resistance to<br />
previous sequential-endocrine therapies including SERMs and/or<br />
aromatase inhibitors were registered from Oct 2010 to May 2012.<br />
Their mean age was 62 years-old and the mean observation time was<br />
9.2 months. Nine cases were evaluated as partial response, 1 case as<br />
long NC, 3 cases as stable disease, and another 2 cases as progressive<br />
disease. In three cases of all 18 cases, the estradiol administration<br />
was withdrawn within 1 week with their early endocrine-related<br />
symptoms, such as nausea, general fatigue and fever. Duration of<br />
effect in the case of the PR (including the 4 ongoing cases) was<br />
more than 24 weeks. All of 9 responders had high ER expression<br />
in the primary or metastatic tumor and had a history of long-term<br />
endocrine therapies in metastatic setting and had response to previous<br />
endocrine therapies. Serum estradiol levels elevated as 30-100pg/mL,<br />
and FSH was suppressed below premenopausal levels in 4 weeks<br />
later administration. Although the weight gain, irregular vaginal<br />
bleeding, or endometrial thickening was observed in patients treated<br />
with long-term treatment, there was no severe adverse event, such as<br />
deep venous thrombosis or other malignancies in this series.<br />
Discussion<br />
The mechanism of low-dose estrogen treatment can be considered<br />
the estrogen-induced apoptosis. The high ER expression and the<br />
response to previous endocrine therapies might be recognized as<br />
predictive factor of this treatment. This low-dose estrogen therapy<br />
may contribute to overturn the common sense of the endocrine therapy<br />
for breast cancer.<br />
P2-14-04<br />
A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase<br />
inhibitor) in Combination with Exemestane in Patients with ER<br />
+ Metastatic <strong>Breast</strong> <strong>Cancer</strong>.<br />
Means-Powell JA, Minton SE, Mayer IA, Abramson VG, Ismail-<br />
Khan R, Arteaga CL, Ayers DA, <strong>San</strong>ders MS, Lush RM, Miele L.<br />
Vanderbilt-Ingram <strong>Cancer</strong> Center, Nashville, TN; Moffit <strong>Cancer</strong><br />
Center, Tampa, FL; University of Mississippi Health Care <strong>Cancer</strong><br />
Institute, Jackson, MS<br />
Background: RO4929097 is a potent and oral selective inhibitor of<br />
γ-secretase (GSI), producing inhibitory activity of Notch 1-4 signaling<br />
in tumor cells. Preclinical studies have demonstrated synergism<br />
of GSIs in combination with endocrine therapy, in ERα-positive<br />
xenografts. This suggests that optimal treatment of ER+ BC would<br />
benefit from an antiestrogen and GSI combination.<br />
Materials and Methods: To explore the safety, tolerability and<br />
preliminary antitumor activity of Exemestane (25 mg/d) with<br />
R04929097 combination, we conducted a Phase Ib trial in patients<br />
with ER+/ HER2- MBC, whose disease relapsed during treatment<br />
with or within 6 months of discontinuation of an adjuvant nonsteroidal<br />
aromatase inhibitor or Tamoxifen, or whose MBC progressed during<br />
treatment with 1 st or 2 nd line endocrine therapy. Goserelin (3.6 mg q28<br />
days Sub-Q) was given to all premenopausal patients. R04929097<br />
was administered orally daily for 3 consecutive days, followed by<br />
4 days off on a 21 day cycle. Doses of R04929097 were escalated<br />
on a standard 3+3 design over 5 doses (20, 30, 45, 90, and 140 mg).<br />
Patients were fully evaluated for dose limiting toxicity (DLT) for 3<br />
weeks. Patients were treated until disease progression or occurrence<br />
of unacceptable toxicity.<br />
Results: A total of 15 patients were enrolled. Median age was 56;<br />
average number of chemotherapies received in the adjuvant or<br />
metastatic setting was 3.3. Eleven patients had received adjuvant<br />
endocrine therapy. One patient received this as 1 st line endocrine<br />
therapy, eleven patients received this study as 2 nd line endocrine<br />
therapy; and three patients received this study as 3 rd line endocrine<br />
therapy in the metastatic setting. Of the 14 patients evaluable, 1<br />
had a partial response, 6 had stable disease, and 7 had progressive<br />
disease. All patients have discontinued the study at this time, 11 due<br />
to progression, 2 due to toxicity, and 1 withdrew after beginning<br />
protocol therapy. Twenty percent of patients had stable disease for six<br />
months or greater. Of the patients with stable disease for six months,<br />
one patient progressed at 9 months and 2 patients progressed at 10<br />
months. The most common toxicities were nausea (73.3%), anorexia<br />
(60%), hyperglycemia (53.3%), hypophosphatemia (46.7%), fatigue<br />
(66.7%), and cough (33.0%). Grade 3 toxicities were uncommon and<br />
included hypophosphatemia (13.0%) and rash (6.3%). There were no<br />
grade 4 toxicities. Rash was the only DLT and was seen at 140 mg.<br />
Conclusion: The combination of R04929097 and Exemestane was<br />
overall well tolerated, but MTD was not determined as access to<br />
drug ended. Further studies with GSIs in combination with endocrine<br />
therapy are warranted on the basis of a favorable safety profile and<br />
preliminary evidence of stable disease seen in patients with ER+ MBC<br />
refractory to previous endocrine therapies. PK, PD and biomarker<br />
analysis is ongoing.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
280s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
P2-14-05<br />
A phase II study of combined fulvestrant and RAD001<br />
(everolimus) in metastatic estrogen receptor (ER) positive breast<br />
cancer after aromatase inhibitor (AI) failure.<br />
Croley JJ, Black EP, Romond E, Chambers M, Waynick S, Slone<br />
S, Waynick C, Stevens M, Weiss HL, Massarweh SA. University of<br />
Kentucky and Markey <strong>Cancer</strong> Center, Lexington, KY<br />
Background: Fulvestrant is used to treat women with metastatic<br />
ER-positive breast cancer after AI failure, but has a short duration<br />
of benefit. Pi3K/mTOR signaling has been implicated in preclinical<br />
models of fulvestrant resistance and recent trials suggest that<br />
everolimus, an oral inhibitor of mTOR, can overcome resistance to<br />
other forms of endocrine therapy. We hypothesized that everolimus<br />
may delay resistance to fulvestrant and prolong time to progression<br />
(TTP).<br />
Methods: We designed a phase II clinical trial of combined fulvestrant<br />
and everolimus in postmenopausal women with ER-positive breast<br />
cancer who relapsed or experienced metastatic disease progression<br />
within 6 months of AI use. Fulvestrant was given at 500 mg<br />
IM on day1, 250 mg d14, 250 mg d28, and monthly thereafter.<br />
Everolimus was given at 10 mg po daily. Patients were required to<br />
have measurable or evaluable disease with preserved performance<br />
status and adequate organ function. Primary endpoint is TTP, and<br />
secondary endpoints are safety, response rate, clinical benefit rate,<br />
and biomarker analysis. A sample size of 40 patients was calculated<br />
to meet a median TTP of 7.0 vs. 3.7 months for fulvestrant alone<br />
as reported in the EFECT trial. Patients were followed monthly for<br />
clinical and toxicity assessment and imaging was obtained every 2<br />
months. Tumor blocks were collected when available and biopsies<br />
were offered if disease was accessible.<br />
Results: To date, 30 patients enrolled on study with a median age of 56<br />
years (range 39-85). Most common metastatic disease sites were bone<br />
in 26 patients (87%), liver in 19 (63%), and lung in 16 (53%). Prior<br />
therapy included tamoxifen in 21 patients (70%), and chemotherapy<br />
in 20 (67%), of those 17 were in the adjuvant/neoadjuvant setting.<br />
6 patients (20%) received more than one AI. 2 patients were ruled<br />
ineligible immediately after enrollment and starting study treatment,<br />
one because of a creatinine level outside the reference range and<br />
one because of the need for palliative radiation. Of the remaining<br />
28 patients, 18 discontinued therapy because of disease progression,<br />
3 because of toxicity, 2 upon patient request, and 1 because of<br />
unrelated intercurrent illness, with 4 patients currently on therapy.<br />
Most common adverse events reported were mucositis in 13 patients<br />
(43%) and rash in 11 (36%). Most common laboratory abnormalities<br />
were elevated ALT/AST in 18 patients (60%), elevated cholesterol in<br />
13 (43%), and hypokalemia in 13 (43%). The majority of toxicities<br />
were grade I/II. Most common grade III toxicities, regardless of<br />
attribution, were infection requiring hospitalization in 3 patients<br />
(10%), hypokalemia in 3 (10%) and mucositis in 2 (7.4%). There was<br />
one grade 4 toxicity reported-hypokalemia. Overall, treatment was<br />
reasonably tolerated and toxicities manageable. Efficacy findings,<br />
including the primary endpoint of TTP, will be analyzed and presented<br />
at the meeting.<br />
Conclusions: Combined everolimus with fulvestrant is feasible and<br />
has manageable toxicities in this cohort of women with metastatic<br />
ER-positive breast cancer. Detailed efficacy analysis along with<br />
updated toxicity data will be presented at the meeting.<br />
P2-14-06<br />
A phase II trial of low dose estradiol in postmenopausal women<br />
with advanced breast cancer and acquired resistance to an<br />
aromatase inhibitor.<br />
Howell SJ, Seif MW, Armstrong AC, Cope J, Wilson G, Welch RS,<br />
Misra V, Ryder D, Blowers E, Palmieri C, Wardley AM. University of<br />
Manchester, United Kingdom; The Christie NHS Foundation Trust,<br />
Manchester, United Kingdom; Imperial College, London, United<br />
Kingdom<br />
Background High dose estrogen (HDE) is an effective but toxic<br />
treatment for postmenopausal women with advanced breast<br />
cancer (ABC). In vitro, prolonged periods of estrogen deprivation<br />
(ED) sensitises cancers to the inhibitory effects of estrogen. We<br />
hypothesised that the profound ED seen with third generation<br />
aromatase inhibitor (AI) would sensitise cancers to LDE which would<br />
be better tolerated.<br />
Methods Single arm phase II study in postmenopausal women<br />
with measurable ER+ ABC and demonstrated clinical benefit (CB)<br />
with a third generation AI. Treatment: estradiol valerate 2mg daily.<br />
Primary endpoint: CB rate (CBR) was correlated with baseline and<br />
dynamic LH/FSH levels and on-treatment estradiol levels. Secondary<br />
endpoints included TTF, PFS, toxicity and QoL. If LDE was effective,<br />
retreatment with the AI on which the cancer had progressed prior<br />
to study entry was offered on progression. If LDE was ineffective<br />
HDE was offered.<br />
Results 21/50 patients were recruited before early closure due to slow<br />
accrual. 19 were assessable for efficacy and toxicity (1 ineligible; 1<br />
no LDE). CBR was 5/19 (26%; 95%CI 9.1%,51.2%). Median TTF<br />
2.8months (range 0.5-29.8). CBR durations were 11.1, 16.8, 17.3*,<br />
19.8, 29.8 months (*censored). 4 stopped treatment early due to<br />
toxicity (G4 hypercalcaemia/ G2 vaginal bleeding (VB) plus G4<br />
hyponatraemia/ G2 mucositis/ G2 headaches) 1 with SD at 3 months<br />
and 3 before response assessment. Other common toxicities were all<br />
G1/2 and mainly limitted to nausea (8/19), breast pain (7/19) and<br />
tumour flare (7/19). VB occurred in 8/11 without prior hysterectomy.<br />
Baseline LH correlated with CBR by logistic regression (p=0.01). Of<br />
3 retreated with the same AI post LDE; 1 had PR, 1 SD ≥6months<br />
and 1 PD. One woman received HDE after failure of LDE and<br />
achieved a PR.<br />
Conclusion LDE is an effective and largely well tolerated treatment<br />
in women with acquired resistance to AI. VB is common without<br />
prior hysterectomy. Rechallenge with the same AI post LDE seems<br />
effective and may offer an extra line of endocrine therapy. This should<br />
be tested in future trials.<br />
P2-14-07<br />
Evaluation of Aromatase Inhibitor failure and total healthcare<br />
expenditures among post-menopausal women with metastatic<br />
ER+/HER2- breast cancer in the US<br />
Namjoshi M, Landsman-Blumberg P, Thomson E, Chu BC. Novartis<br />
Pharmaceuticals Corporation, East Hanover, NJ; Thomson Reuters,<br />
Washington, DC<br />
Aromatase Inhibitors (AIs) have replaced tamoxifen as first-line<br />
therapy for post-menopausal women with metastatic, ER+ breast<br />
cancer (BC). However, little information is available on the realworld<br />
use of AIs. This retrospective administrative claims study<br />
compared healthcare expenditures of post-menopausal women with<br />
metastatic ER+/HER2- BC treated with AIs and experiencing 0 or<br />
≥ 1 AI failures (AIF).<br />
Women ≥ 55 years of age newly diagnosed with stage IV BC (index)<br />
were identified in the 2006-2010 Thomson Reuters MarketScan<br />
www.aacrjournals.org 281s<br />
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databases and followed until the earliest of chemotherapy,<br />
combination therapy, end of enrollment, or end of study (03/31/2011).<br />
ER+/HER2- disease was defined as any endocrine therapy (ET:<br />
tamoxifen, fulvestrant) or AI (anastrozole, letrozole, or exemestane)<br />
use and no trastuzumab, lapatinib or toremifene use anytime in the<br />
6-month pre-or variable length post-index periods. Those with postindex<br />
AI use except where use followed chemotherapy or combination<br />
therapy were retained for analysis. AIF post-index was defined as a<br />
switch to an alternative AI, ET, chemotherapy, or combination therapy.<br />
All-cause healthcare expenditures, defined as total provider payments<br />
(insurer + patient + COB) were examined by type of service and in<br />
total, and expressed as per patient per month (PPPM). A series of loggamma<br />
regressions were used to examine the relationship between<br />
AIF and PPPM expenditures as a form of cost ratios (CRs), adjusting<br />
for potential confounding factors such as patient demographic and<br />
clinical characteristics.<br />
Among 4,249 eligible patients, 36% had ≥1 AIF. At index, AIF<br />
patients were more likely to have liver (8% vs. 5%), lung (11% vs.<br />
8%), and bone metastases (60% vs. 49%), all p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 2<br />
a secondary on-line screening before contact information is passed<br />
on to the researcher for the enrollment process.<br />
Results: Over 367,000 women have signed up, including survivors<br />
and women without a history of breast cancer, ranging from ages 18<br />
to 100, representing all 50 US states and 49 countries. To date, the<br />
AOW has recruited for 65 studies, both regional and national, that<br />
vary from biomarker and circadian rhythm research to psycho-social<br />
and quality of life studies. With over 73,000 AOW members having<br />
participated in the research process, this method of recruitment has<br />
been found to be effective and efficient. The diversity of the AOW<br />
members has proved beneficial for many studies, such as those<br />
needing to enroll racial/ethnic minorities, women of varying sexual<br />
orientations, or young survivors.<br />
A secondary goal of the AOW is to assist researchers new to research<br />
with human subjects. The AOW has successfully helped researchers<br />
cross the chasm, coaching them on what it takes to transition their<br />
research from animal models to human subjects. The AOW will<br />
guide researchers through IRB submission, patient recruitment, and<br />
sample collection.<br />
Conclusions: The AOW has proved to be a successful resource for<br />
scientists to accelerate accrual, expand the number and diversity of<br />
their subject population and to obtain exactly the type of specimens<br />
they need when they need it. This partnership between women and<br />
scientists has revolutionized research and accelerated efforts to<br />
eradicate breast cancer. The public is ready and willing to partner<br />
with the research community to find the answer to urgent clinical<br />
problems. The DSLRF will launch a new initiative this fall to harness<br />
the public’s desire to be active research participants: The Health of<br />
Women (HOW) Study, an online longitudinal cohort study that will<br />
reduce participant burden with multiple short modules at regular<br />
intervals. Preliminary data from HOW will be available later this year.<br />
P2-15-02<br />
The efficacy of recruitment and retention strategies for research<br />
subjects in an early phase investigator-initiated breast cancer<br />
trial.<br />
Reichow J, Higgins D, Parker S, Childs J, Disis ML, Salazar LG.<br />
University of Washington, Seattle, WA<br />
Background: One of the biggest challenges faced by investigators is<br />
the implementation of effective strategies to improve the recruitment<br />
and retention of research participants. This is especially true for<br />
investigator-initiated, federally funded (e.g. NIH and DOD), early<br />
phase clinical trials that involve the treatment of serious diseases such<br />
as metastatic breast cancer (MBC). These studies may face additional<br />
barriers to participation since patients have often already undergone<br />
maximal treatment and are usually not in a financial position that for<br />
allows the travel and lodging necessary to receive further investigative<br />
treatment. Moreover, efficacy and toxicology in early phase clinical<br />
trials are unknown. Thus, when study budget constraints do not<br />
allow monetary incentives to participation, it is difficult to provide<br />
motivation for patients to enroll and remain adherent to the protocol<br />
requirements. However, many MBC patients are motivated to join<br />
clinical trials for altruistic purposes alone, and evidence supports that<br />
the researcher-patient relationship may be the most important factor in<br />
clinical trial participation. Recognizing that many patients are willing<br />
to participate if provided the appropriate resources despite limited<br />
monetary incentives, we developed a system to improve patient<br />
recruitment and retention to our studies, which are primarily federally<br />
funded. We report here on the strategies developed and used by our<br />
group to recruit and retain patients in a federally-funded investigatorinitiated<br />
phase I/II vaccine study in MBC patients.<br />
Methods: This study was funded by the NIH/NCI and involved<br />
infusion of HER2 specific T cells in HER2+ MBC patients after<br />
completing in vivo priming with a HER2 vaccine. It required 11 visits<br />
to Seattle, Washington. Working with agencies that offer free services<br />
to patients enrolled in clinical trials, a list of available resources was<br />
compiled and a visit flowchart with specific information on travel and<br />
lodging resources (e,g, Angel Flights and ACS sponsorship), local<br />
transportation and entertainment was developed. During screening,<br />
patients were given the list of resources and trial information. An<br />
email system was used to quickly communicate and follow-up with<br />
patients. Eligible patients were given the visit flowchart to help with<br />
their planning of study visits. An enrollment packet was provided<br />
at the first visit with a calendar to keep track of the visit schedule.<br />
Coordination of care between the patient’s primary oncologist and<br />
the research staff was maintained throughout the study.<br />
Results: 17 of 19 patients enrolled were not from Washington State.<br />
Two out-of-state patients withdrew early from the trial for reasons<br />
unrelated to disease progression or toxicity; one subject completed 8<br />
visits and enrolled in another study and the other completed 2 visits<br />
and discontinued the trial to resume chemotherapy.<br />
Conclusion: We have developed a successful system to enroll and<br />
retain patients in a trial requiring multiple study visits. Development<br />
and implementation of site-specific standard procedures are critical to<br />
improve study participation and retention, especially when patients<br />
receive no financial benefit.<br />
P2-16-01<br />
Prospective breast cancer quality evaluation application<br />
developed for native Android tablet and web browser for<br />
improving mutltidisciplinary breast cancer care<br />
Grobmyer SR, Raum N, Sposato V. University of Florida, Gainesville,<br />
FL; University of Florida, Gaineville, FL<br />
Introduction: Easy to implement, prospective and user-friendly<br />
data collection tools are needed to insure optimal breast cancer<br />
care as defined by national quality measures. Prospective quality<br />
measurement can effectively allow rapid identification of gaps in<br />
care and identification for sources of programmatic improvement in<br />
multidisciplinary care.<br />
Methods: Our group has designed a novel prospective quality<br />
assessment tool system, which consists of 3 major integrated<br />
components: 1) a web application for administration and reporting<br />
of the data, 2) a native Android tablet application for real-time data<br />
collection of breast cancer quality parameters during tumor board, and<br />
3) a backend database where parameters are stored and reported on.<br />
Results: The web application is the primary interface for the breast<br />
cancer coordinator (BCC) to enter information for the applicable<br />
Tumorboards. Quality parameters for measurement as determined<br />
by the breast program leadership are entered into the system by the<br />
BCC on the web application. The BCC will also enter medical record<br />
numbers of patients to be presented at each tumor board in the web<br />
based system. In order to maximize work flow and reduce error, the<br />
system was designed to interface with the hospital electronic medical<br />
record for retrieval of patient demographic data based on medical<br />
record number entry.<br />
The Android tablet is the interface to the system during weekly<br />
breast cancer tumor board. The tablet application facilitates real time,<br />
prospective collection of: tumor board attendance, tumor staging,<br />
tumor type, and collection of center chosen and required breast cancer<br />
quality measures. Data collected on the android system is stored in<br />
real time a central and secure database.<br />
www.aacrjournals.org 283s<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Real time quality data analysis and graphical display for user defined<br />
time periods is available on the web application and Android tablet.<br />
Required tumor hospital tumor registry data is also compiled in real<br />
time reports to faciliate communication with the hospital tumor<br />
registry.<br />
Conclusions: A novel real time Android based solution has been<br />
developed for real time breast cancer care quality and tumor registry<br />
information. Use of this technology greatly simplifies data collection<br />
required for participation national breast cancer accreditation<br />
organizations such as NAPBC as well as the American Joint<br />
Commission on <strong>Cancer</strong>. Its ease of implementation and use favor its<br />
widespread adoption. Efforts to quantify the impact of this unique<br />
tool on quality of performance in a multidisciplinary breast cancer<br />
program are underway.<br />
P2-16-02<br />
A web-based data management system for a multicenter<br />
international breast cancer oriented blood, tissue, and data<br />
biobank<br />
Margossian AL, Saadjian H, Mira A, Contreras A, Rimawi MF,<br />
Margossian ML, Scheurer M, Osborne K, Gutierrez C. <strong>Breast</strong> Center,<br />
Buenos Aires, Argentina; Dan Duncan <strong>Cancer</strong> Center/Smith <strong>Breast</strong><br />
Center, Baylor College of Medicine, Houston, TX<br />
The quality of biospecimens and associated data must be consistent<br />
and collected according to standardized methods in order to achieve<br />
international harmonization and coordination among biobanking<br />
networks.<br />
Sharing successful strategies between the Baylor College of Medicine<br />
(BCM) <strong>Cancer</strong> Center and <strong>Breast</strong> Center Buenos Aires (BCBA) is<br />
the driving force for the creation of an Argentinean <strong>Breast</strong> <strong>Cancer</strong><br />
oriented Biobank with a shared data management system.<br />
Objective: To create a bilingual web-based tool for biospecimen<br />
management, inventory, clinical and breast cancer data registration<br />
according to international standards of data security quality assurance<br />
(ISO 27001).<br />
Methods / System Characteristics: The system permits users to<br />
enter and retrieve data concerning the collection, storage, quality<br />
assurance and distribution of biospecimens, and provides clinical<br />
and other patient data for samples while maintaining strict patient<br />
confidentiality.<br />
It has a multi-tier architecture, developed using Service-Oriented<br />
Architecture (SOA) software design principles in .net 4.0, and uses a<br />
SQL server database backbone. The system allows multidimensional<br />
data analysis trough On Line Analytical Processes (OLAP) and<br />
operates with standard web clients, such as Internet Explorer.<br />
User Profiles/Access Levels:<br />
• Clinical staff (e.g., clinical research coordinator, phlebotomist,<br />
pathologist, PA, MD) conduct participant and consent registration<br />
and preregistration, epidemiological questionnaire data entry, barcode<br />
label generation, form printing, and clinical and pathological cancer<br />
data entry.<br />
• Biospecimen resource staff (e.g., lab technicians) track and store data<br />
about biospecimen collection, inventory, tracking and distribution,<br />
generate sample barcode labels, and maintain sample allocation and<br />
freezer maps for the system.<br />
• Scientists have the ability to search for biospecimens and associated<br />
data for their own translational research projects.<br />
<strong>Breast</strong> <strong>Cancer</strong> Database: Detailed clinical, pathological, treatment<br />
and follow-up breast cancer information are captured for each patient,<br />
including TNM, biopsy and definitive surgery of primary tumor and<br />
events, systemic and radiation treatment, recurrences and metastasis,<br />
follow-up. A summary screen provides a snapshot of these data to the<br />
viewer. Pathology reports and sample collection forms are attached<br />
in each corresponding biopsy or surgery screen for easy viewing and<br />
quality assurance.<br />
Conclusion: This Biobank Management System was designed by<br />
a multidisciplinary team to improve and streamline the workflow<br />
for each member of the biobank by: allowing preregistration<br />
capabilities before consenting individuals or collecting samples,<br />
automatic generation of clinical and sample ID labels, and real-time<br />
statistics with certified secure sensible information confidentiality.<br />
This system’s value is its wide range of uses, from the day-to-day<br />
management of a multicenter biobank to the storage of detailed<br />
clinical cancer-related data in a user-friendly and intuitive data entry<br />
environment.<br />
P2-16-03<br />
Creation of a “state-of-the-art” breast cancer data and biobank<br />
in Argentina<br />
Margossian AL, Gutierrez C, Saadjian H, May M, Ohanessian R,<br />
Bacigalupo S, Baravalle S, Margossian J, Osborne KC, Scheurer<br />
ME. <strong>Breast</strong> Center, Buenos Aires, Argentina; Dan Duncan <strong>Cancer</strong><br />
Center/Smith <strong>Breast</strong> Center, Baylor College of Medicine, Houston, TX<br />
Translational cancer research is highly dependent on having large<br />
series of cases with high-quality samples that were collected,<br />
processed, stored and annotated in a systematic fashion according<br />
to international standards, such as the ISBER Best Practices for<br />
Biorepositories. Sharing successful strategies between the Baylor<br />
College of Medicine (BCM) <strong>Cancer</strong> Center and <strong>Breast</strong> Center Buenos<br />
Aires (BCBA), we created this Argentinean biobank complete with<br />
breast cancer-oriented data, tumor and normal breast tissue and<br />
matched blood specimens according to best practices to facilitate<br />
international collaborative translational breast cancer research.<br />
Objective: Creation of a blood, breast tissue and tumor biobank in<br />
Argentina for research purposes with associated epidemiological,<br />
pathological, clinical, and follow-up data.<br />
Methods: Consented individuals from BCBA are classified by treating<br />
physician in four categories: 1) breast cancer; 2) benign breast disease<br />
by biopsy; 3) high-risk for breast cancer according to the Gail Model;<br />
and 4) healthy controls. Blood is collected at several time points<br />
during the breast cancer disease process: pre-surgical, pre-systemic<br />
treatment, and, if applicable, in the metastatic setting. Blood products<br />
are stored as whole blood, plasma, buffy coat, red blood cell pellet,<br />
serum and clot at -80°C or at room temperature in GenPlates. Fresh<br />
tissue and tumor sample is collected during surgical or core biopsy<br />
proceedings and stored at -80°C and paraffin embedded. Upon<br />
enrollment, participants complete an extensive epidemiological and<br />
risk factor questionnaire, which is supplemented by medical record<br />
abstraction for relevant pathological and clinical data. Participants<br />
are also re-contacted once a year for follow-up.<br />
The creation of this biobank in 2009 included the preparation and<br />
adaptation of the following processes from the Population Science<br />
Biorepository and Smith <strong>Breast</strong> Center Tumor Bank at BCM,<br />
including: 1) IRB-approved informed consent documents with specific<br />
language relevant to DNA-based research; 2) Epidemiological and<br />
risk factor questionnaires (10-page Core module and 6-page <strong>Breast</strong><br />
module); 3) Blood and tissue collection protocols, sample processing,<br />
sample bar coding and participant/sample registration system; and<br />
4) Web-based data management system, specifically designed for<br />
this biobank with encryption and data security (details presented<br />
in a separate abstract), including role-based access levels personal<br />
health information.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
284s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
Conclusion: We started our endeavor in August 2008. The<br />
development of the consent forms, two questionnaires, and biobank<br />
database prototype took one year at BCM. The translation of consents<br />
and questionnaires into Argentinean Spanish took an additional 3<br />
months. Overall the Argentinean IRB approval process, training<br />
personnel, and equipment set-up lasted for 14 months. By April 2011,<br />
the first Argentinean participant was consented into the biobank. It<br />
took nearly 3 years from inception to realization for this biobank;<br />
however, the potential benefit to translation breast cancer research is<br />
large. The overall value of this biobank will depend on the number<br />
of individuals/samples accrued and the number of years of followup<br />
attained.<br />
P2-16-04<br />
Attitudes of metastatic breast cancer patients towards research<br />
biopsies<br />
Seah DS, Scott SM, Najita J, Openshaw T, Krag KJ, Frank E, Sohl<br />
J, Stadler ZK, Garrett M, Winer EP, Come S, Lin NU. Dana-Farber<br />
<strong>Cancer</strong> Institute, Boston, MA; Beth Isreal Deaconness Medical<br />
Center, Boston, MA; <strong>Cancer</strong> Care of Maine, Brewer, ME; Mass<br />
General North Shore <strong>Cancer</strong> Center, Danvers, MA; Memorial Sloan-<br />
Kettering <strong>Cancer</strong> Center, New York, NY<br />
Background:<br />
In the era of molecularly targeted therapy, developing an understanding<br />
of the molecular basis of cancer is a principal or secondary goal of<br />
many research studies. For this reason, studies collecting tissue for<br />
research purposes are increasingly common. Understanding patients’<br />
attitudes towards research biopsies may lead to improvement in<br />
accrual to research biopsy studies.<br />
Methods:<br />
Patients with metastatic breast cancer from two academic and two<br />
community hospitals completed a self-administered paper survey<br />
consisting of 29 questions in clinic to evaluate their willingness to<br />
consider providing additional biopsies (additional biopsy performed<br />
with a clinically indicated biopsy) and research purposes only biopsies<br />
(RPOB) (research biopsy performed as a stand alone procedure).<br />
Results:<br />
160 patients (n=80 academic, n=80 community) completed the survey,<br />
with a response rate of 98%. As expected, demographic variables<br />
differed between sites, with patients from academic sites likely to<br />
be younger (P=0.01), more educated (P=0.002), employed (P=0.01),<br />
have prior trial participation (P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
1.88 (1.05-3.37) (adjusted for age, body mass index-BMI kg/m2)).<br />
Conclusion: Our study supports that insulin, IGF-1 and IGFBP-3<br />
independently, and in combination with cycling estrogen, predicts<br />
premenopausal mammographic density. These hormones may be<br />
important biomarkers in breast cancer control and clinical practice.<br />
P3-01-02<br />
Correlation of Mammographic breast density and tumor<br />
characteristics in Korean breast cancer patients<br />
Cho JY, Ahn SH, Lee JW, Yu JH, Koh BS, Kim HJ, Lee JW, Son BH,<br />
Gong G-y, Kim HH. College of Medicine, University of Ulsan, Asan<br />
Medical Center, Seoul, Republic of Korea<br />
Introduction: Western studies have demonstrated high breast density<br />
as a strong risk factor for breast cancer, it is poorly understood whether<br />
breast density affects the diverse phenotypes of breast cancer. We<br />
examined the association between various tumor characteristics and<br />
mammographic breast density in women with breast cancer. Methods:<br />
We conducted a cross-sectional analysis in 910 Korean women<br />
diagnosed with breast cancer to evaluate the associations between<br />
breast density and tumor size, lymph node status, lymphovascular<br />
invasion, histologic grade, estrogen receptor, progesterone receptor ,<br />
HER2. <strong>Breast</strong> density was classified as fatty (percent density less than<br />
50% by a computer-assisted thresholding program, named “Cumulus<br />
TM<br />
”; n = 470) or dense (percent density 50% or more; n = 440) for<br />
the cancer-free breast at the time of operation. Logistic regression<br />
was used to examine whether the relationships were modified by<br />
adjustment for body mass index, age at diagnosis, age at first birth,<br />
menopausal status, history of breast-feeding, and breast cancer<br />
staging. Results: Total 910 patients were involved, the mean age and<br />
median age at the operation was 48 years old (range 20-82), and the<br />
mean percent density was 48.09 (SD = 9.62 %: normally distributed,<br />
Kolmogorov-Smirnov test p=0.32). Crude analysis shows that tumor<br />
size over than 0.5cm were more likely to have dense breasts compared<br />
with women with a tumor size
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
differences were observed in BC staging when we compared the A<br />
and B density with C and D (p=1.0). The same occurred with the<br />
genomic classification (p=0.48).<br />
Conclusion: Our screening population has a predominance of low<br />
mammogram densities, probably due to the high body mass index<br />
observed in previous studies of this cohort. With respect to cancer<br />
cases, the absence of statistical significance results suggests that<br />
longer follow up will be necessary for definitive conclusions.<br />
Density Stage 0/I % Stage II % Stage III % Total<br />
1 0 0 3 75 1 25 4<br />
2 5 83,3 1 16,7 0 0 6<br />
3 3 50 2 33,3 1 16,7 6<br />
4 1 100 0 0 0 0 1<br />
Table 1. <strong>Cancer</strong> staging versus breast density.<br />
Density Luminal A % Luminal B %<br />
Triple<br />
Negative<br />
% HER-2 % Total<br />
1 0 0 2 50 1 25 1 25 4<br />
2 4 66,7 2 33,3 0 0 0 0 6<br />
3 2 33,3 4 66,7 0 0 0 0 6<br />
4 1 100 0 0 0 0 0 0 1<br />
Table 2. Genomic classification versus breast density.<br />
P3-01-04<br />
Surgical management of mammographic microcalcification is<br />
improved by full field digital mammography (FFDM)<br />
Bundred SM, Zhou J, Hurley E, Wilson M, Morris J, Bundred NJ.<br />
University Hospital of South Manchester; University of Manchester<br />
Background: Preoperative diagnosis of impalpable breast lesions<br />
correlates closely with the number of surgical procedures required<br />
for treatment. Correct diagnosis of mammographic microcalcification<br />
as DCIS or invasive cancer is important because lesions upgraded to<br />
malignant diagnosis at surgery require repeat surgical procedures in<br />
44% of cases (BASO Audit 2011).<br />
Methods: To determine the impact of FFDM (FFDM only since April<br />
2010) on diagnostic accuracy, positive predictive value (PPV) and<br />
surgical management of MM. Screening and symptomatic women<br />
with mammographic microcalcification (n=1125) in one visit were<br />
reviewed. Demographic information; pre and post operative diagnosis<br />
and number of surgical procedures were recorded for pre FFDM (8/<br />
2007 to 3/2010: n=710) and post FFDM (4/2010 to 5/2011: n=413).<br />
Results: Overall 299 (106 invasive) and 144 (62 invasive) malignant<br />
lesions were diagnosed before and after FFDM introduction.<br />
Mammography SFM n=711 FFDM n = 413 p<br />
Positive Predictive value 42.6% 303 34.6% 143
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P3-01-06<br />
Ultrasound as single mode of imaging may miss significant<br />
pathology in symptomatic women aged 35-39<br />
Baker EL, Masudi T, Waterworth A. Calderdale and Huddersfield NHS<br />
Foundation Trust, Huddersfield, West Yorkshire, United Kingdom<br />
Recent guidelines in the UK stipulate that symptomatic women aged<br />
under 40 with clinically benign disease do not need mammography as<br />
a standard part of their assessment. 1 Previous practice at the Calderdale<br />
and Huddersfield NHS Trust has been to perform mammography on<br />
all women over 35 years old. This study was undertaken to determine<br />
if there would be an increase in false negative assessment under the<br />
new guidelines.<br />
All female patients 35-39 years old attending symptomatic breast<br />
clinic with benign clinical examination and undergoing both<br />
ultrasound and mammogram evaluation were eligible. Patients with<br />
previous breast cancer or a clinically suspicious lump mandating<br />
mammography were excluded. The information was gathered<br />
retrospectively using patient records. 96 women were included.<br />
Mammography and ultrasound results (including M and U valves)<br />
were compared for any discrepancy. If performed, biopsy results<br />
were also reviewed.<br />
In 70% of patients there was no discrepancy between mammographic<br />
and ultrasonic evaluation (M=U). In 25% U score was one higher than<br />
M score. On further analysis this group mainly comprised of those<br />
with fibroadenomas or fibrocystic breast changes seen on ultrasound<br />
(U2) with a normal mammogram (M1).<br />
In the remaining 5%, 3 patients had U score 2 greater than M score,<br />
1 had M>U by 1 and 1 had M>U by 2. On further analysis of these<br />
discrepancies most patients had benign disease. In two patients<br />
with U5 scores and lower M scores malignancy was confirmed on<br />
biopsy. In one patient ultrasound showed benign disease (U2) but<br />
mammogram demonstrated suspicious calcifications (M4) that were<br />
confirmed as high grade DCIS on stereo-core biopsy.<br />
In conclusion for the vast majority of patients in this group<br />
mammography does not add to the evaluation on presentation at<br />
symptomatic breast clinic. However this study identified a case (1<br />
patient in 96) where significant disease could have been missed had<br />
a mammogram not been undertaken. The acceptable level of such<br />
false negative assessments with ultrasound only imaging in women<br />
under 40 must be further evaluated.<br />
1<br />
Best practice diagnostic guidelines for patients presenting with<br />
breast symptoms Alexis M Willett, Michael J Michell, Martin J R<br />
Lee, November 2010<br />
Printed by Breakthrough <strong>Breast</strong> <strong>Cancer</strong>, www.dh.gov.uk/publications<br />
P3-01-07<br />
ESTIMATED RISK OF RADIATION-INDUCED BREAST<br />
CANCER FROM MAMMOGRAPHIC SCREENING<br />
Freitas-Junior R, Correa RS, Peixoto J-E, Ferreira RS, Tanaka<br />
RMN. Federal University of Goias, Goiania, Goias, Brazil;<br />
Comissão Nacional de Energia Nuclear, Goiania, Goias, Brazil;<br />
National <strong>Cancer</strong> Institute of Brazil, Rio de Janeiro, RJ, Brazil;<br />
Superintendência de Vigilância em Saúde do Estado de Goias,<br />
Goiania, Goias, Brazil<br />
Objective: Estimate the benefit–risk balance of mammography, as<br />
number of lives saved/lost in an opportunistic screening in the state<br />
of Goiás, Brazil, in 2010, according to type of technology available<br />
and age group indicated for screening. Methods: The number of lives<br />
saved was estimated considering the gross mortality rate for breast<br />
cancer, female population living in the state, estimated mortality rate<br />
reduction due to screening programs, and mammographic coverage in<br />
the state. For number of lives lost, the model adopted by the Biological<br />
Effects of Ionizing Radiation (BEIR VII) was used. Based on the mean<br />
glandular tissue dose (Dg), the following parameters were calculated:<br />
number of radiation-induced cancer cases with one exposure, with<br />
several exposures in screening programs and over the lifetime, number<br />
of deaths caused by radiation-induced cancer at a certain age and over<br />
the lifetime. Dg of each equipment was estimated according to the<br />
European protocol, using the incident air kerma (Ki) at the simulator<br />
entrance and the half-value layer (HVL) of the X-ray beam, and<br />
table values of coefficients to convert Ki into Dg. Ki and HVL were<br />
measured in 100 equipments in operation in the state. A standard breast<br />
simulator (5.3 cm thickness and 50% glandular tissue) was used. We<br />
considered a biannual mammographic screening with an exam routine<br />
composed of a cranio-caudal and a mediolateral oblique view and<br />
40–70 and 50–70-year age groups. Results: The mean Dg was 4.28<br />
(±1.06) and 6.61 (±3.67) for conventional and digital equipments,<br />
respectively (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
Method: Conducted digitizer mammogram density assessment using<br />
quantitative rating system based on computer-assisted methods<br />
of measurement with cumulus program based on interactive<br />
thresholding. Polymorphism identification ESR1 XbaI and PvuII<br />
RFLP obtained through PCR process. The numbers of genotyped<br />
cases and controls for each marker were 50 cases and 58. Mean of<br />
density and frequencies of SNPs were compared between cases and<br />
controls to identify SNPs associated with cancer susceptibility. Using<br />
anova, independent t-test, cruskal wallis and mann whitney u test we<br />
calculated significant different between SNP genotype group.<br />
Results: The mean of mammographic density is higher in cases<br />
(52%) than in controls (0,41%) (p0,05). Women with one or two copies of the XbaI x allele had<br />
higher mean percentage density (AG/Xx and AA/xx, 49% and 47%,<br />
respectively) than those with the GG/XX genotype (32%,), AAVGG<br />
P 0.6, no distant metastasis observed at 5 years in the original 78<br />
patients with no adjuvant systemic treatment.) The aim of this study<br />
is to determine the proportion of biologically low and ultralow risk<br />
tumors among the screen-detected tumors. Second, to evaluate the<br />
impact of analog versus the more sensitive digital screening technique<br />
on the biology of tumors detected.<br />
Methods All Dutch breast cancer patients enrolled in the MINDACT<br />
trial (EORTC-10041) accrued 2007-2011, who were invited for<br />
the Dutch screening program (biennial, age 50-75), were included<br />
(n=1381). The proportions of 70-gene signature high, low and<br />
ultralow risk were calculated for patients with screen detected (n=<br />
694), interval (n=366), and symptomatic, non-screening (n=321)<br />
carcinomas, taking into account analog vs. digital technology. Covariants,<br />
such as age, tumor size, histological type, ER, progesterone<br />
receptor (PgR) and HER2/neu-oncoprotein (ERBB2) will be<br />
included in a multinominal logistic regression model to assess both<br />
confounding and effect modification by technology type; these data<br />
are pending and will be available during SABCS 2012.<br />
Results<br />
Proportion of 70-gene signature ultralow, low and high risk patients in all subgroups<br />
Ultralow risk Low risk High risk Total<br />
Chi Square<br />
Test<br />
Screen-detected carcinomas 240 (34,6%) 225 (32,4%) 229 (33%) 694 0,001<br />
Interval carcinomas 105 (28,7%) 99 (27%) 162 (44,3%) 366<br />
Non-screening related<br />
carcinomas<br />
108 (33,6%) 96 (29,9%) 117 (36,4%) 321<br />
Total 453 (32,8%) 420 (30,4%) 508 (36,8%) 1381<br />
Among the screen-detected tumors, 33% had a high risk 70-gene<br />
signature tumor and 67% had a low risk tumor (table 1). A significant<br />
difference was seen between the screen-detected carcinomas and<br />
interval carcinomas (p X 2 test = 0.001) in all 70-gene signature risk<br />
groups. Among the screen detected carcinomas, 41.5% was detected<br />
using analog mammography and 58.5% was detected using digital<br />
mammography. Analog mammography detected 26.4% high risk,<br />
31.9% low risk and 41.7% ultralow risk tumors. This is significantly<br />
different using digital mammography (p X 2 test = 0.001), which<br />
detected 37.7% high risk, 32.8% low risk and 29.6% ultralow risk<br />
tumors.<br />
Conclusion Screen detection was found to be associated with a higher<br />
likelihood of a biologically low risk tumor. Half of all screen-detected<br />
low risk tumors had an index score above 0.6, indicating an ultralow<br />
risk of distant metastasis. The transition from analog to digital<br />
mammography resulted in a decrease in detection of ultralow risk<br />
tumors and an increase in the detection of high risk tumors. Screendetected<br />
low risk biology tumors are frequent and comprehension<br />
may aid to minimize overtreatment.<br />
P3-02-02<br />
Use of contrast-enhanced computed tomography in clinical<br />
staging of asymptomatic breast cancer patients to detect<br />
asymptomatic distant metastases.<br />
Tanaka S, Sato N, Fujioka H, Takahashi Y, Kimura K, Iwamoto M,<br />
Uchiyama K. Osaka Medical College, Takatsuki City, Osaka, Japan<br />
Objective: The use of computed tomography (CT) with regards to the<br />
clinical staging of breast cancer (BC) patients has been on the increase<br />
in clinical practice. However, NCCN guidelines recommended the<br />
use of imaginng only in cases with locally advanced disease or signs<br />
of distant metastases (DM), and the benefits of routine CT have yet<br />
to be fully clarified. This study investigated the value of employing<br />
contrast-enhanced CT (CECT) to screen for DM in patients with<br />
asymptomatic BC.<br />
Methods: The clinical records of 483 patients with asymptomatic BC<br />
who underwent CECT, also in order to detect BC spread, between<br />
April 2006 and January 2011 were reviewed. The CECT results were<br />
classified into normal, true-positive (metastases) or false-positive<br />
findings.<br />
Results: Abnormal CECT findings, including true- and false-positive<br />
results, were detected in 65 patients (13.5%). Of these, 26 patients<br />
(5.4%) showed confirmed true metastatic disease, including 18 lung<br />
metastases, 11 liver metastases and 13 bone metastases. Upstaging to<br />
stage IV due to the results of the CECT was significantly associated<br />
with only larger tumos size (odds ratio, 33.4; 95% CI 12.1-92.5;<br />
P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Clinical factors associated with upstaging to stage IV by CECT.<br />
n (%)<br />
Upstaged cases (true-positive) Others (normal/false-positive) P-value<br />
Age (years)<br />
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
screen detected HER2 +ve cancers in this cohort are core grade I &<br />
II, node negative and ER +ve. Data will be presented on the systemic<br />
management and the outcome of these cases.<br />
P3-02-05<br />
Subtypes of screen-detected invasive breast cancer and<br />
symptomatic invasive breast cancer and their impact on survival<br />
Kobayashi N, Hikichi M, Miyajima S, Utsumi T. Fujita Health<br />
University, Toyoake, Aichi, Japan<br />
Background: <strong>Breast</strong> cancer is a worldwide problem which urgently<br />
requires solution, in many countries still being the most common<br />
cause of malignancy associated death. The screening program aims<br />
to detect early breast cancer to improve survival. We investigated<br />
the clinicopathrogical characteristic including intrinsic subtypes<br />
and outcome of patients with screen-detected invasive breast cancer<br />
(S-DIBC) compared with those with symptomatic invasive breast<br />
cancer (SIBC).<br />
Material and Methods: From January 2005 to December 2011 840<br />
patients with invasive breast cancer who underwent surgery at our<br />
hospital were included. There were 195 S-DIBCs and 645 SIBCs.<br />
We retrospectively reviewed the clinical and pathologic data. Ki-67<br />
LI was categorized as low ( or =15%). Tumors<br />
were classified into four groups based on the expression of ER,<br />
PgR, Ki-67 and HER2 as follows: luminal A (ER+ and/or PR+, and<br />
HER2- and Ki67 low), luminal B (ER+ and/or PR+, and HER2+ or<br />
Ki67 high), HER2 disease (ER-, PR-, HER2+), and triple negative<br />
(ER-, PR-, HER2-). Overall survival (OS) and relapse-free survival<br />
(RFS) curves were generated using the Kaplan- Meier method.<br />
Survival comparisons were made with the log-rank test, the level of<br />
significance was taken to be 0.05. SPSS 18.0 software package was<br />
used for statistical analysis.<br />
Results: S-DIBC was associated with smaller tumor size, less lymph<br />
node involvement, and earlier stage compared with SIBC (P < 0.001).<br />
Significantly more tumors were positive for hormone receptors in<br />
the S-DIBC group as compared to the SIBC group (ER+,83.5%<br />
vs.75.1%, P= 0.017; PgR+, 73.4% vs. 60.6%, P = 0.009), with a<br />
greater proportion of the luminal A subtype in the S-DIBC group<br />
(S-DIBC: Luminal A 59.0%, Luminal B 25.6%, HER2 disease 4.6%,<br />
triple negative 10.8%; SIBC group: Luminal A 46.5%, Luminal B<br />
30.0%, HER2 disease 6.6%, triple negative 16.8%). Patients with<br />
S-DIBC had better prognosis [5-year OS: 100% (S-DIBC) vs. 95.5%<br />
(SIBC), p=0.005, 5-year RFS: 98.5 vs. 92.1%, p=0.004]. Tumors<br />
detected with screening generally had more favorable outcomes than<br />
symptomatic cancers regardless of subtypes [5-year OS: (S-DIBC)<br />
Luminal A 100%, Luminal B 100%, HER2 disease 100%, triple<br />
negative 100%; (SIBC) Luminal A 95.9%, Luminal B 93.3%, HER2<br />
disease 95.5%, triple negative 84.1%)].<br />
Conclusions: Our results suggest that subtype distribution of S-DIBC<br />
differs from that of SIBC.<br />
P3-02-06<br />
Survival impact of early detection of recurrence after surgery in<br />
early breast cancer patients<br />
Hojo T, Tamura K, Masuda N, Inoue K, Kinoshita T, Fujisawa T,<br />
Hara F, Saji S, Asaga S, Anan K, Yamamoto N, Wada N, Takahashi<br />
M, Nakagami K, Kuroi K, Iwata H. National <strong>Cancer</strong> Center Hospital,<br />
Tokyo, Japan; Osaka National Hospital, Osaka, Japan; Saitama<br />
<strong>Cancer</strong> Center, Saitama, Japan; Gunma Prefectural <strong>Cancer</strong> Center,<br />
Gunma, Japan; Shikoku <strong>Cancer</strong> Cente, Shikoku, Japan; Kyoto<br />
University Graduate School of Medicine, Kyoto, Japan; Kitakyushu<br />
Municipal Medical Center, Kitakyushu, Japan; Chiba <strong>Cancer</strong> Center,<br />
Chiba, Japan; National <strong>Cancer</strong> Center Hospital East, Chiba, Japan;<br />
Hokkaido <strong>Cancer</strong> Center, Hokkaido, Japan; Shizuoka General<br />
Hospital, Shizuoka, Japan; Tokyo Metropolitan <strong>Cancer</strong> and Infectious<br />
diseases Center Komagome Hospital, Tokyo, Japan; Aichi <strong>Cancer</strong><br />
Center Hospital, Nagoya, Aichi, Japan<br />
Background and Object: Annual mammography and physical<br />
examination as the follow-up tests after surgery were recommended<br />
to early breast cancer patients based on the two randomized clinical<br />
trials (GIVIO and Rosselli Del Turco) which were reported in 1990s.<br />
Whereas, radiological imaging and blood test (serum tumor marker)<br />
for early detection of recurrence are not recommended due to the<br />
lack of evidence from clinical trial. However, the imaging techniques<br />
(helical CT, bone scan, PET/CT. MRI et al) to detect minute lesions and<br />
therapeutic options for metastatic breast cancer have been remarkably<br />
advanced since then. In fact, routine radiological examinations after<br />
surgery were performed in several Japanese hospitals for aiming early<br />
detection of recurrence as the clinical practice.<br />
We here evaluate the possible benefit of early detection of recurrence<br />
by radiological and laboratory examinations during post-operative<br />
follow-up period.<br />
Methods: Clinical information of breast cancer patients who were<br />
diagnosed as recurrence after surgery during 2005-2006 was collected<br />
from 30 hospitals in Japan. Clinical and pathological characteristics<br />
such as molecular subtype of breast cancer, survival time from<br />
initial therapy or 1 st recurrence, detection methods and symptomatic<br />
information when they diagnosed as metastasis were analyzed<br />
retrospectively.<br />
Results: As the routine examination of post-operative follow-up,<br />
serum tumor maker, chest x-ray/CT, abdominal US/CT and bone<br />
scan were done in 95%, 57%, 38%, 24% of 30 hospitals, respectively.<br />
Of the 698 patients individually evaluated in this analysis, 248 had<br />
loco-regional recurrences and 450 had distant metastases. The first<br />
distant metastatic site were 35% in bone, 30% in lung, 17% in liver<br />
and 11% in lymph node, respectively. All individual patients are<br />
divided into symptomatic (45.7%) or asymptomatic groups (54.3%) at<br />
the detection of metastases. Asymptomatic metastases were detected<br />
by serum tumor marker (26%), bone scan (18%), chest x-ray (17%),<br />
chest CT (17%), abdominal US (11%) and abdominal CT (5%),<br />
respectively. The median disease-free interval (DFI) was 3.0 years<br />
in both groups, but the median survival time after the diagnosis of<br />
recurrence to death were 3.7 years in asymptomatic patients and 3.0<br />
years in symptomatic patients, respectively. In addition, asymptomatic<br />
group had significantly superior overall survival (from primary<br />
surgery to death) than symptomatic group with oligo-metastases<br />
such as limited organ disease (P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P3-02-07<br />
Rates of <strong>Cancer</strong> Detection and Abnormal Results among Clients<br />
Recruited for Mammography through Outreach and Education<br />
Supported by the Avon <strong>Breast</strong> Health Outreach Program<br />
Rose J, Opdyke KM, Gates-Ferris K, Hurlbert M. Cicatelli Associates<br />
Inc. (CAI), New York, NY; Avon Foundation for Women, New York, NY<br />
Background:<br />
The Avon <strong>Breast</strong> Health Outreach Program (BHOP) supports<br />
community-based organizations and safety-net providers in<br />
conducting outreach and education to recruit underserved, low-income<br />
and uninsured women for breast cancer screening mammography.<br />
Funded organizations report mammography outcomes as part of<br />
routine program monitoring. NCI <strong>Breast</strong> <strong>Cancer</strong> Consortium data for<br />
2009 reported a cancer detection rate of 3.92 per 1,000 for screening<br />
mammograms and 33.21 per 1,000 for diagnostic mammograms. In<br />
CY2009, CDC’s National <strong>Breast</strong> and Cervical <strong>Cancer</strong> Early Detection<br />
Program (NBCCEDP) reported 14 percent of mammograms had<br />
abnormal results requiring further investigation, with an overall cancer<br />
detection rate of 10.2 per 1,000 mammograms.<br />
Objective:<br />
To describe reported breast cancer detection rates and rates of<br />
abnormal mammography findings among Avon BHOP-funded<br />
programs.<br />
Methods:<br />
We reviewed routinely reported program outcomes data for 98<br />
organizations funded continuously through the Avon BHOP for a<br />
three-year period from 2009 to 2011. Data for 17,839 mammograms<br />
were available in aggregate by year by grantee agency including<br />
the number of mammograms reported, number with a preliminary<br />
abnormal finding, and number of confirmed cancer diagnoses.<br />
Results:<br />
Agencies reported an average of 981 mammogram outcomes per year<br />
over 3 years (range 108 to 5,946 by agency). The average agencyspecific<br />
rate of abnormal findings across 3 years was 13.2% (median<br />
11.2%; range 0.49% to 51.0%). The average agency-specific cancer<br />
detection rate was 8.1 per 1,000 (median 6.4 per 1,000; range zero to<br />
31.7 per 1,000). 28 organizations had 3-year average cancer detection<br />
rates in excess of 10 per 1,000, and 6 had rates exceeding 20 per<br />
1,000. Large fluctuations in the proportion of mammogram outcomes<br />
reported as abnormal by a given agency year-over-year were common.<br />
Conclusion:<br />
Avon BHOP agencies reported overall abnormal and cancer detection<br />
rates similar to those of the NBCCEDP, but higher than the general<br />
population. Fluctuations in year-over-year rates were common, and<br />
may indicate changes in the way program data were reported over<br />
time, changes in screening practices (e.g. new clinical providers or<br />
new equipment), and/or differences in breast cancer risk among clients<br />
recruited for screening over time. High rates of abnormal screening<br />
results could indicate delays in obtaining results from follow-up<br />
diagnostic testing, problems with the calibration of equipment, or<br />
other quality issues.<br />
Discussion:<br />
Grantees with unusually high or low rates of abnormal or cancer<br />
outcomes or significant year-over-year rate fluctuations would benefit<br />
from technical assistance to identify and explain the underlying<br />
causes of these trends. Ensuring that all clients recruited for breast<br />
cancer screening receive high quality mammography services –<br />
including accurate imaging and reliable interpretation by experienced<br />
radiologists – is critical to minimize client anxiety and to ensure that<br />
screening results in improved health outcomes.<br />
P3-02-08<br />
Is repetition of the contralateral mammogram of patients referred<br />
from breast cancer screening for unilateral findings necessary?<br />
Castro C, Schipper R-J, van Roozendaal L, van Goethem M, Lobbes<br />
M, Smidt M. Maastricht University Medical Center, Maastricht,<br />
Netherlands; Antwerp University Hospital, Antwerp, Belgium<br />
Introduction - The Netherlands started a nationwide breast cancer<br />
screening program in 1989, including women from the age of 50 until<br />
75. Screening mammograms are performed two yearly in a mobile<br />
unit and consist of a bilateral two-view mammogram of the breast<br />
(mediolateral oblique and craniocaudal views).<br />
If indicated, patients are referred to a breast clinic for diagnostic<br />
analysis. This work-up consist of among others repeating the bilateral<br />
two-view mammogram. Since the screening is digitalized, repeating<br />
of at least the mammogram of the non suspicious side might be<br />
unnecessary.<br />
The aim of this study is to determine the additional value of repeating<br />
the contralateral mammogram in patients referred for a suspicious<br />
unilateral lesion.<br />
Material and methods – 395 patients were referred from breast<br />
screening program to our institution for unilateral findings between<br />
October 2009 and August 2011. In all patients a bilateral mammogram<br />
was repeated and analyzed by an experienced breast radiologist. In<br />
the case of breast cancer a breast magnetic resonance imaging (MRI)<br />
was performed for preoperative staging. Anonymised data concerning<br />
the date of registration of the screening mammogram, the referred<br />
side (left/right or bilateral), age, screening’s BI-RADS classification,<br />
breast density, biopsy results and breast MRI results were collected.<br />
Results - Of the 395 patients referred for a suspicious unilateral<br />
finding, a malignancy on the referred side was observed in 144 patients<br />
(36.5%). In five patients bilateral breast cancer was detected. In one<br />
patient no malignancy was detected on the referred side, though on<br />
the contralateral side. Three of these six contralateral malignancies<br />
were directly mammographically detected. All six malignancies were<br />
detected with preoperative breast MRI.<br />
Conclusion - Repetition of the two-view mammogram of the<br />
contralateral side in patients referred with a unilateral suspicious<br />
finding seems unnecessary, since all contralateral malignancies<br />
were depicted on the preoperative staging breast MRI recommended<br />
according to the EUSOBI-guidelines. Omission of the contralateral<br />
mammogram could lead to reduction of associated health care costs,<br />
radiation exposure, and patient discomfort caused by the exam.<br />
P3-02-09<br />
Cost-effectiveness of screening with additional MRI for<br />
women with familial risk for breast cancer without a genetic<br />
predisposition<br />
Saadatmand S, Heijnsdijk EA, Rutgers EJ, Hoogerbrugge N,<br />
Oosterwijk JC, Tollenaar RA, Hooning M, Obdeijn I-M, de Koning<br />
HJ, Tilanus-Linthorst MM. Erasmus Medical Center, Rotterdam,<br />
Netherlands; The Netherlands <strong>Cancer</strong> Institute, Antoni van<br />
Leeuwenhoek Hospital, Amsterdam, Netherlands; Radboud University<br />
Medical Center, Nijmegen, Netherlands; University Medical Center<br />
Groningen, Netherlands; Leiden University Medical Center, Leiden,<br />
Netherlands; Erasmus Medical Center, Netherlands<br />
Background<br />
To reduce mortality risk, women with a family history of breast<br />
cancer are often screened with mammography before 50 years of<br />
age. Additional Magnetic Resonance Imaging (MRI) can improve<br />
sensitivity. MRI screening is cost-effective for BRCA1/2 mutation<br />
carriers. However, for women with a family history of breast cancer<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
without a proven mutation cost-effectiveness is not clear. We<br />
evaluated the cost-effectiveness of additional MRI for women with<br />
a familial risk in the largest prospective MRI screening study: the<br />
Dutch MRI Screening Study (MRISC).<br />
Materials & Methods<br />
Between 1999 and 2007 a total of 1597 women (8370 women years at<br />
risk) between 25-70 years, with an estimated cumulative lifetime risk<br />
of 15-50% for breast cancer participated in the MRISC. Women were<br />
screened with clinical breast examination (CBE) every six months and<br />
annual mammography and MRI. We calculated the costs per detected<br />
breast cancer. In addition, MRISC data were incorporated into a<br />
micro simulation screening analysis model: MISCAN. This model<br />
simulates screening programs with different screening modalities and<br />
time intervals. Different screening schemes were evaluated and the<br />
cost per life-year gained (CLYG) estimated.<br />
Results<br />
Forty-seven breast cancers, including 9 Ductal Carcinoma in Situ,<br />
were detected. Screening with additional MRI leads to a cost per<br />
detected breast cancer treated of €101,962. In increasing age-cohorts<br />
the cost decreased, probably due to the higher breast cancer incidence.<br />
The cost per detected and treated breast cancer in age group 40-50<br />
years doubled in the age group >60 years. We will demonstrate these<br />
results more extensively.<br />
With MISCAN modeling we predicted that screening with this<br />
scheme from age 35 to 60 years reduces breast cancer mortality by<br />
30% at a CLYG of €119,945 (3.5% discounting), compared to 21%<br />
estimated mortality reduction at €45,707 CLYG with mammography<br />
and CBE alone.<br />
Conclusion<br />
Screening with MRI may improve survival for women with familial<br />
risk for breast cancer, but is expensive. However, it may be costeffective<br />
for a select group. We will discuss subgroups that may<br />
benefit from MRI screening and in which age category MRI was<br />
most effective in our study.<br />
P3-02-10<br />
Implementation and uptake of a provincial, population-based,<br />
organized breast screening program for high risk women in<br />
Ontario: The Ontario breast screening program (OBSP) high<br />
risk program.<br />
Eisen A, Carroll J, Chiarelli AM, Horgan M, Meschino W, Rabeneck<br />
L, Shumak R, Warner E. Sunnybrook Health Sciences Centre, Toronto,<br />
ON, Canada; University of Toronto, ON, Canada; Mount Sinai<br />
Hospital, Toronto, ON, Canada; <strong>Cancer</strong> Care Ontario, Toronto,<br />
ON, Canada; North York General Hospital, Toronto, ON, Canada<br />
Background: Genetic testing for mutations in BRCA1/2 has been<br />
clinically available in Ontario since 2000. Over 15000 individuals<br />
have been tested. Evidence from clinical trials has consistently shown<br />
that women at high risk of breast cancer (BrCa) benefit from BrCa<br />
screening that includes both magnetic resonance imaging (MRI) of<br />
the breast and mammography, yet access to MRI in Ontario was<br />
variable. In 2011, <strong>Cancer</strong> Care Ontario (CCO) established an expert<br />
panel to develop a protocol for expanding the OBSP, initially created<br />
for average risk women 50-74, to include MRI and mammography<br />
for eligible high risk women. Methods: The panel’s tasks included:<br />
1. determining high risk criteria 2. estimating the prevalence of<br />
high risk women 3. selecting a cancer risk model 4. developing a<br />
referral and assessment pathway for potentially eligible subjects 5.<br />
developing educational resources, training plan and communication<br />
strategy for relevant stakeholders 6. developing indicators for program<br />
evaluation, 7. providing guidance for post-implementation issues.<br />
Results: The program was initiated July, 2011 and now includes 28<br />
sites. Women aged 30-69 with and without a history of breast cancer<br />
are eligible if they 1. are BRCA1/2 mutation carriers or untested first<br />
degree relatives of carriers, 2. have a lifetime risk of breast cancer<br />
>=25% based on family history according to IBIS or BOADICEA<br />
risk models, or 3. received prior radiation therapy to the chest. It is<br />
estimated that 34000 high risk women in the target age group live<br />
in Ontario. Preliminary volume data for the first 9 mos are shown in<br />
Table 1. Of the 5037 women participating, 802 have been referred<br />
directly by their physician and 4,235 have been referred for genetic<br />
assessment. Of the 2,946 women who received genetic assessment,<br />
31% met the high risk criteria. To date, 729 high risk MRI scans have<br />
been performed. Conclusions: A population based organized screening<br />
program for high risk women that includes genetic risk assessment has<br />
been implemented in Ontario. Further evaluation of risk assessment<br />
and screen results are underway. To our knowledge, this is the first<br />
organized screening program for women at high risk of breast cancer.<br />
Table 1<br />
Category A* Category B ** Total<br />
# referrals to OBSP High Risk Program 802 4235 5037<br />
# women with family hx who received genetic<br />
assessment<br />
N/A N/A<br />
Counseling only 1769<br />
Counseling and BRCA1/2 testing 1177<br />
Total 2946<br />
Proportion of women with family hx determined<br />
N/A<br />
to be high risk by criteria<br />
31% N/A<br />
# women eligible for high risk screening 802 925 1727<br />
# women ineligible for high risk screening 0 2021 2021<br />
# high risk screens<br />
Mammo 649<br />
MRI 729<br />
Ultrasound (if MRI contraindicated) 6<br />
*category A: known BRCA1/2 carrier; 50% risk of being a carrier; prior XRT; known 25% lifetime<br />
breast cancer risk **category B: referred to OBSP program due to family hx without prior formal<br />
risk assessment<br />
P3-02-11<br />
Screening Magnetic Resonance Imaging (MRI) of the breast in<br />
women at increased lifetime risk for breast cancer: A retrospective<br />
single institution study.<br />
Ehsani S, Strigel R, Pettke E, Wilke L, Szalkucki L, Tevaarwerk<br />
AJ, Wisinski KB. University of Wisconsin Carbone <strong>Cancer</strong> Center,<br />
Madison, WI<br />
Background: Multiple factors are associated with an increased lifetime<br />
risk of breast cancer, including inheritance of an abnormal BRCA<br />
1/2 gene, history of lobular carcinoma in situ (LCIS) or atypical<br />
hyperplasia, family history of breast cancer or previous chest wall<br />
radiation. In 2007, the American <strong>Cancer</strong> Society released updated<br />
guidelines for breast cancer screening based on risk stratification.<br />
These guidelines added annual MRI screening to mammography<br />
for women with greater than or equal to a 20-25% lifetime risk.<br />
<strong>Breast</strong> MRI screening trials have consistently demonstrated a higher<br />
sensitivity of MRI for malignancy compared with mammography,<br />
with an additional cancer yield from MRI of approximately 3%.<br />
The purpose of this study was to evaluate MRI screening outcomes<br />
in women with an increased risk for breast cancer evaluated in<br />
an established breast subspecialty clinic within the University of<br />
Wisconsin (UW) Hospital and Clinics.<br />
Methods: Patients (Pts) were included if they were seen by a UW<br />
breast center nurse practitioner, medical or surgical oncologist<br />
between 1/1/2007 – 3/1/2011 with a diagnosis code of: family history<br />
of breast or ovarian cancer, genetic susceptibility to malignant<br />
neoplasm or genetic carrier, Hodgkin’s disease, LCIS, or atypical<br />
hyperplasia. Pts with a co-existing diagnosis of invasive breast cancer<br />
or ductal carcinoma in situ prior to initial encounter were excluded.<br />
Demographic information, breast cancer risk factors, estimated<br />
lifetime risk of breast cancer and screening recommendations<br />
www.aacrjournals.org 293s<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
were abstracted from the medical record. Results of subsequent<br />
breast imaging examinations (including breast MRI, diagnostic and<br />
screening mammography, and image-guided biopsies) were analyzed<br />
with the use of the mammography information system (PenRad).<br />
Results: Of 276 women who met the inclusion criteria, 148 underwent<br />
at least 1 screening breast MRI. The majority of MRI screened pts<br />
were premenopausal (82%) and Caucasian (96.6%) with a mean age<br />
of 42.5 (range 20-68) at their initial encounter. Eighty five percent had<br />
a first degree relative with breast cancer and 72.3% of pts undergoing<br />
MRI screening had a documented lifetime risk of breast cancer of<br />
20% or greater using a validated model. Within this MRI-screened<br />
cohort, 18.2% had a known genetic predisposition to breast cancer.<br />
Over the time assessed, 307 MRIs were performed in the 148 pts.<br />
Biopsy was recommended and performed based on the results of<br />
the MRI in 31 of 307 exams (10%). Ten cancers were detected for<br />
a positive predictive value based on biopsy performed of 32% and<br />
an overall cancer yield of 3.3% (10 of 307 MRI exams). All cancers<br />
were stage 0 - II. All pts are currently with no evidence of disease.<br />
Conclusion: <strong>Breast</strong> MRI has a high positive predictive value and<br />
cancer yield with an acceptable biopsy rate in a diverse group of high<br />
risk women undergoing breast MRI at an academic center outside<br />
of a clinical trial.<br />
P3-02-12<br />
The Cost of Mammography Screening in the United States by<br />
Screening Policy<br />
Thorsen CM, Eklund M, Ozanne EM, Esserman LJ. University of<br />
California, <strong>San</strong> Francisco, CA; Karolinska Institute, Stockholm,<br />
Sweden<br />
Background:<br />
Multiple mammography screening strategies exist; however, the<br />
resources associated with screening strategies are not well known<br />
and are rarely discussed. Many organizations recommend annual<br />
mammography for women over the age of 40, while the United States<br />
Preventative Services Task Force (USPSTF) and most countries<br />
outside the US recommend biennial screening, focusing screening<br />
efforts on women over 50 years. Additionally, some suggest risk-based<br />
approaches to improve screening. This analysis seeks to estimate<br />
the aggregate cost of mammography screening in the US in 2010<br />
and to then further compare the costs of these proposed strategies,<br />
specifically comparing annual versus biennial screening.<br />
Methods:<br />
We simulated the annual cost of mammography in the US under the<br />
following screening strategies: 1) estimate of screening that occurred<br />
in 2010 under current policy, 2) annual screening of women older<br />
than 40 years, 3) biennial screening of women 50 to 75 years, and<br />
4) biennial screening of women 50 to 75 years and high risk women<br />
40-50 years following USPSTF guidelines. The simulated 2010<br />
screening policy was based on current screening rates ranging from<br />
51% of forty-year-old women to 66% of sixty-five-year-old women.<br />
Screening strategies 2-4 simulated screening 85% of women overall,<br />
and for the USPSTF policy 20% of women 40-50 years were estimated<br />
to be high risk. The simulation was carried out using R statistical<br />
software.<br />
Results:<br />
Aggregate costs of the four screening strategies were estimated. The<br />
total cost of mammography screening in the US in 2010 was estimated<br />
to be $7.95 billion. The projected cost under an annual screening<br />
policy beginning at 40 years was $10.71 billion. The projected cost<br />
of biennial screening from 50-75 years was $5.25 billion compared to<br />
$5.33 billion following the USPSTF guidelines. The biennial USPSTF<br />
policy cost $5.38 billion less than annual screening. The largest<br />
drivers of cost were the percent of women screened, the cost of a<br />
mammogram, and the percent of women recalled after mammography.<br />
Conclusions:<br />
The costs of mammography vary greatly by strategy and are<br />
relevant to screening policy. The basic biennial strategy was the<br />
least expensive; however for a slight increase in cost, the USPSTF<br />
2009 guideline strategy screened more age appropriate women for<br />
$2.62 billion less than current policy. For less cost, the modeled<br />
USPSTF guidelines screened 85% of women compared to current<br />
policies that screen less than 65% of women. Biennial screening<br />
provides screening to more women, lowers overall false-positive<br />
rates, and improves capacity for access to high-quality equipment<br />
and well-trained mammographers. As data to support evidenced<br />
based strategies increase, resources can be better allocated toward<br />
screening a broader, larger population of women that are most likely<br />
to benefit from screening. With no evidence for adverse outcomes,<br />
a biennial screening policy enables the population of US women to<br />
benefit from mammography for less cost.<br />
P3-02-13<br />
ANALYSIS OF INFRASTRUCTURE FOR MAMMOGRAPHY<br />
SCREENING IN THE STATE OF GOIAS, BRAZIL, 2010<br />
Freitas-Junior R, Correa RS, Peixoto J-E, Rodrigues DCN, Rahal<br />
RMS. Federal University of Goias, Goiania, Goias, Brazil; Comissão<br />
Nacional de Energia Nuclear, Goiania, Goias, Brazil; National<br />
<strong>Cancer</strong> Institute of Brazil, Rio de Janeiro, RJ, Brazil<br />
Objective: Assess the infrastructure for mammography screening<br />
in the state of Goiás, Brazil, taking into consideration the quality<br />
of the image generated by the equipment and the dose received by<br />
the patients, according to the type of technology (conventional and<br />
digital mammography). Methods: Cross-sectional study in which the<br />
observational units were the diagnostic imaging services that were<br />
in operation in 2010. In an in loco visit, we collected information on<br />
the equipment and performed tests to assess quality of the image,<br />
accuracy values for tube tension, quality of X-ray beam, and dose at<br />
the simulator entrance. The percentage of mammography equipments<br />
in conformity with the parameters evaluated was calculated, and the<br />
mean glandular tissue dose (Dg) was estimated based on the dose at<br />
the simulator entrance. To assess quality of the image and the radiation<br />
dose, we used a standard breast simulator (5.3 cm thickness and 50%<br />
glandular tissue). Results: In 2010, 102 services were in operation,<br />
using 106 equipments. Among these, 100 (94.3%) – 64 conventional<br />
and 36 digital mammography equipments – had their performance<br />
and dose assessed. The visualization of fibers (p = 0.044) and the<br />
dose at the simulator entrance (p = 0.042) were the parameters that<br />
presented differences between the types of technology.<br />
Frequency of mammography equipments in conformity with the parameters used to assess the<br />
quality of the image and the equipment performance according to the type of technology, in the<br />
state of Goiás, Brazil, in 2010.<br />
Variable Conventional Digital p<br />
(n = 64) (n = 36)<br />
Quality of the image 57 89.1 31 86.1 0.752<br />
Spatial resolution 63 98.4 32 88.9 0.055<br />
Microcalcifications 55 85.9 32 88.9 0.765<br />
Fibers 64 100 33 91.7 0.044<br />
Masses 64 100 35 97.2 0.36<br />
Low Contrast disks 46 71.9 29 80.6 0.471<br />
Dose at the simulator entrance 50 78.1 21 58.3 0.042<br />
Half-value layer (HVL) 62 96.9 36 100 0.535<br />
Tension precision 46 71.9 27 75 0.817<br />
The mean dose at the simulator entrance was 9.75 mGy (± 2.46)<br />
in conventional and 14.93 mGy (± 8.39) in digital equipments (p <<br />
0.001); 12% of the conventional and 50% of the digital equipments<br />
presented Dg above the limit established by the European guidelines.<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
Conclusion: The infrastructure for mammography screening in the<br />
state of Goias, Brazil, in 2010 presented acceptable quality standard<br />
according to international guidelines. However, the radiation doses<br />
were heterogeneous between the two types of technology, with a<br />
predominance of higher doses in digital equipments.<br />
P3-02-14<br />
INTEGRATED PROGRAM FOR BREAST CANCER<br />
CONTROL: PARTIAL PRESENTATION OF THE RESULTS<br />
OBTAINED INTHE FIRST 24MONTHS OF OPERATION<br />
Blanco EC, Borges MM, Pinotti M, Gennari MB, Ribeiro IM,<br />
Nascimento CCP, <strong>San</strong>tos LFG, Sahium RC. Oswaldo Cruz Alemão<br />
Hospital, São Paulo, Brazil<br />
Introduction <strong>Breast</strong> cancer is a public health problem in Brazil. This<br />
is due to the difficulty of primary prevention (eliminating risk factors<br />
or to diagnose and treat precursor lesions), with a consequent increase<br />
in the incidence and mortality from this cancer. The current challenge<br />
arises from the lack of access to a few specialized centers, which in<br />
turn ar e not always qualified for diagnosis and prompt treatment.<br />
Objective To develop a strategic plan aimed at two management<br />
priorities: resolubility diagnostic and fast treatment of women with<br />
clinical or secondary changes to mammographic screening.<br />
Methodology The Oswaldo Cruz Alemão Hospital (OCAH) in<br />
partnership with the Ministry of Health of Brazil has developed and<br />
deployed in the region of the Mooca - City of St. Paul the Integrated<br />
Program for <strong>Breast</strong> <strong>Cancer</strong> Control (IPBCC), which begins in the<br />
primary prevention (health education and removal of factors risk),<br />
continues with the mammographic detection and early diagnosis,<br />
modern instrumental in a Center for Diagnostic Detection and<br />
Tracking (CDDT), and culminates in the surgical and radiotherapy,<br />
ad juvant chemotherapy and hormone therapy or not, according to<br />
a standardized protocol. The care is coordinated in single query by<br />
mastologists trained in resolving service, with the participation of<br />
radiologists, oncologists, social workers, psychologists, nutritionists<br />
and health educators.<br />
Results From January 2010 to December 2011 were met 12266<br />
women, mean age 58 years (range, 22-89) of which 100 were<br />
diagnosed with breast cancer and the proportion of carcinomas was of<br />
8 per 1000. The detection rate mammography, ultrasound, and by both<br />
methods were: 0.30, 0.30 and 0.25, respectively. Forty-one percent of<br />
cancers corresponded to stages Tis N0M0 (3%) and T1N0M0 (38%)<br />
predominantly in women aged less than 50 years (38% of the sample).<br />
The average time between diagnosis and recorded start of surger y or<br />
chemotherapy was 42 days (range,19 - 68 ). As for quality of care,<br />
satisfaction was 99% (n = 12143).<br />
Conclusions The experience in resolving service provided a<br />
significant increase in the number of initial cases showing detection<br />
ratesper image consistent with the age distribution of population. It<br />
is expected that the tracking time and quality of service, allow the<br />
prevalent cancers cease to be diagnosed, privileging the incidents.<br />
The median time to diagnosis and early treatment of patients with<br />
cancer was significantly lower the average of 120 days recorded in<br />
some public reference services.<br />
P3-03-01<br />
3D mapping of total choline in human breast cancer using highspeed<br />
MR spectroscopic imaging at 3T: initial experience during<br />
neoadjuvant therapy<br />
Posse S, Zhang T, Royce M, Dayao Z, Lopez S, Sillerud L, Casey L,<br />
Eberhardt S, Lomo L, Rajput A, Russell J, Lee S-j, Bolan P. University<br />
of New Mexico School of Medicine and UNM <strong>Cancer</strong> Center,<br />
Albuquerque, NM; New Mexico <strong>Cancer</strong> Center, Albuquerque, NM;<br />
University of Minnesota, Minneapolis, MN<br />
OBJECTIVE: To assess the feasibility of quantitative high-speed MR<br />
spectroscopic imaging (MRSI) of total Choline (tCho) as an adjunct<br />
to dynamic-contrast enhanced MRI to improve lesion characterization<br />
and monitor treatment response in patients undergoing neoadjuvant<br />
chemotherapy (NAC).<br />
METHODS: Twelve patients with infiltrating ductal carcinoma<br />
(Table 1) were studied using a clinical 3T MR scanner (Siemens,<br />
Erlangen, Germany) equipped with 8- and 16-channel breast array<br />
(Hologic Inc., Bedford, MA). Four patients were studied before<br />
NAC. Four patients were studied once during NAC. Two patients<br />
were studied before and within 2-7 days of treatment initiation. One<br />
of these patients participated in an additional scan after 5 months of<br />
treatment. Two additional patients were studied at 3 time points during<br />
NAC. Measurements were performed using PRESS prelocalized<br />
3D Proton-Echo-Planar-Spectroscopic-Imaging (PEPSI) using TR/<br />
TE=2000ms/135ms, matrix size up to 32×16x8, voxel size=1cc, and<br />
total acquisition time of 10 minutes (including water reference scan).<br />
Additional data were collected at TE 60 ms to enhance sensitivity<br />
for detecting tCho and J-coupled resonances. TE-averaging (8 steps,<br />
DTE: 2.5 ms) was employed to minimize gradient sideband artifacts.<br />
Quantification of tCho in reference to tissue water was performed<br />
using spectral fitting and relaxation correction.<br />
RESULTS: Strongly elevated tCho with maximum concentration<br />
up to 5.3 mmol/kg was measured in 9 patients with enhancing<br />
lesions larger than 2 cc volume (Table 2). Decreases in tCho were<br />
measured in all four patients who were followed during neoadjuvant<br />
chemotherapy. Decreases in tCho were measurable during the first<br />
week of neoadjuvant treatment in responders, consistent with previous<br />
studies. Our preliminary data also indicate that the combination of<br />
concentration and spatial extent of detectable tCho may be the most<br />
sensitive marker of treatment response.<br />
Patient/tumor characteristics<br />
Patient<br />
Age<br />
Tumor<br />
grade<br />
Tumor stage<br />
ER & PR<br />
status<br />
HER2<br />
status<br />
Lesion size (cm)<br />
1 57 2 T4bN3cM0 ER- PR- POS 4.3x7.5x8.1 6 m<br />
2 50 2 T4dN3M0 ER+ PR+ POS 5 1 y<br />
3 55 3 T2N0M0 ER- PR- NEG 3.4 x 3.5<br />
4 45 1 T2N0M0 ER+ PR+ NEG 2.5 x 2<br />
5 28 3 T3N1M0 ER- PR+ POS 6.5 4 d<br />
6 54 3 T3N1M0 ER+ PR- NEG 7 X 5.9 21 d<br />
7 60 2 T1cN0M0 ER+PR + POS 1.2<br />
8 77 1 T4N2M0 ER+ PR+ POS 16 x 17 2 m<br />
9 50 3 T2N0M0 ER+ PR- POS 3.2 x 3.6 7 d<br />
10 60 3 T3N1M0 ER+ PR+ NEG 6 x 4.5 2 d<br />
11 52 3 T3N1M0 ER- PR- NEG 6.5 x 6.2 7 d<br />
12 35 3 T2N1M0 ER- PR- NEG 2.2<br />
Treatment<br />
duration at<br />
scan 1<br />
tChol by treatment duration<br />
Patient Before 1-7 days 8-21 days 3-12 weeks 3-6 months > 6 months<br />
1 0.7/0.7/1<br />
2 ND<br />
3 1.8/1.8/1<br />
4 0.5/0.5/1<br />
5 0.8/2.4/23 1.5/3.9/21 0.8/1.2/2<br />
6 1.0/2.4/7 0.9/1.6/4 ND<br />
7 ND (Clip)<br />
8 TF<br />
9 0.6/0.7/2 0.3/0.3/2 ND<br />
10 TF 0.9/1.6/15<br />
11 1.9/4.0/87 1.9/4.2/27<br />
12 1.7/5.3/47<br />
ND - Not detected; TF - technical failure<br />
www.aacrjournals.org 295s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
CONCLUSION: This study demonstrates feasibility of quantitatively<br />
mapping tCho in invasive breast carcinoma using high-speed MRSI.<br />
The long-term goals are to utilize high-speed MRSI as an early<br />
predictor of treatment failure in women undergoing neoadjuvant<br />
therapy (i.e. chemotherapy, endocrine therapy or biologic therapy)<br />
for breast cancer and to develop an improved screening protocol for<br />
high-risk patients.<br />
P3-03-02<br />
The metastatic rate of IMLN, when IMLN metastasis is suspected<br />
with PET CT.<br />
Lee J-H, Son G-T, Choi J-E, Kang S-H, Lee S-J. Yeungnam University<br />
College of Medicine, Daegu, Republic of Korea<br />
Background<br />
Metastatic status of internal mammary lymph nodes (IMLNs) has<br />
a clinical importance in assessing stage and prognosis of breast<br />
cancer. But, when metastasis of IMLN is suspected, the management<br />
is controversial. We reviewed 29 breast cancer patients who had<br />
IMLN dissection, retrospectively, and investigated the pathologic<br />
status of IMLNs.<br />
Methods<br />
From August 2005 to December 2011, at Yeungnam University<br />
Hospital, 43 patients underwent IMLN biopsy or dissection for<br />
suspected IMLN metastasis on lymphoscintigraphy (7 patients), breast<br />
ultrasound (1 patient) or PET CT (29 patients), when diagnosed with<br />
primary or recurred breast cancer. 6 patients who had stage IV at<br />
diagnosis or had too obscure data to identify exact location of IMLN,<br />
were excluded. Among them, we reviewed clinicopathologic features<br />
of IMLN detected on PET CT and metastatic status of IMLNs was<br />
investigated.<br />
Results<br />
Total 29 patients were included in this study. 19 patients and 10<br />
patients underwent IMLN dissection when diagnosed with primary<br />
or recurred breast cancer, respectively. Unlike conventional IMLN<br />
dissections, our IMLN biopsy or dissection was done during Radical<br />
mastectomy (in 2 pts.), modified radical mastectomy (in 14 pts.),<br />
using incision of breast conserving surgery (in 3 pts.) and separated<br />
incision ( in 10 pts.), with or without resection of ribs.<br />
The mean number of IMLNs was 2.76±2.15 and total metastatic rate<br />
of IMLN was 72.4% (21/29). The sensitivity, specificity, positive<br />
predictive value, and negative predictive value of PET CT was<br />
following: 91.3%, 42.8%, 72.4% and 27.6%. Mean standard uptake<br />
value (SUV) of metastatic and non-metastatic IMLN were 3.6±2.9<br />
and 3.9±2.6 and there was no statistical difference (p-value=0.821).<br />
In PET CT, non-metastatic vs metastatic IMLN<br />
Tumor location<br />
Tumor Size<br />
(cm)<br />
Number of<br />
metastatic<br />
ALN (n)<br />
Number of<br />
IMN (n)<br />
outer central/inner<br />
Non-metastatic IMLN<br />
4 (50.0%)<br />
(8 patients)<br />
4 (50.0%) 3.81±2.08 3.50±4.98 1.75±0.70 3.91±2.62<br />
Metastatic IMLN(21<br />
patients)<br />
10 (47.6%) 11 (52.4%) 3.54±2.01 8.28±7.74 3.14±2.39 3.68±2.90<br />
P-value 1.000 0.967 0.034 0.060 0.821<br />
During IMLN dissection, besides initial approach intercostals space<br />
(ICS), some metastatic IMLN was also found in upper or lower level<br />
ICS (42.9%, 6/14). Only IMLN metastasis without axillary nodes<br />
metastasis were found in 3 patients and the tumor location of these<br />
patients was all inner or central quadrant. Chest X-ray was done<br />
postoperatively as routine procedure, and there were no other specific<br />
complications such as pneumothorax or hemothorax.<br />
Conclusion<br />
IMLN dissection without radical mastectomy can be done safely<br />
without complications due to recent advance in diagnostic and surgical<br />
skills. If SUV on IMLN is shown on the PET-CT, IMLN dissection<br />
SUV<br />
is needed, regardless of SUV. If breast cancer is located at inner<br />
quadrant, more aggressive dissection of IMLN is needed. Further<br />
follow-up and studies are needed to assess locoregional recurrence and<br />
to compare improvement in overall survival and disease free survival.<br />
P3-03-03<br />
A tri-modality imaging assessment algorithm to evaluate<br />
neoadjuvant therapy response in patients with operable breast<br />
cancer<br />
Umphrey H, Bernreuter W, Bland K, Carpenter J, Falkson C, Forero<br />
A, Keene K, Krontiras H, Meredith R, Urist M, De Los <strong>San</strong>tos J.<br />
University of Alabama at Birmingham, AL<br />
Background: To determine the negative predictive value (NPV),<br />
positive predictive value (PPV), accuracy, sensitivity and specificity of<br />
a pre-surgical tri-modality imaging assessment algorithm to determine<br />
complete pathologic response (pCR) post neoadjuvant therapy in<br />
patients with operable breast cancer.<br />
Methods: A retrospective analysis was performed on data collected<br />
from patients receiving neoadjuvant therapy and pre-surgical<br />
breast magnetic resonance imaging (MRI), ultrasound (US) and<br />
mammography between 2004 and 2010 at our institution. Tri-modality<br />
imaging was reviewed by a single blinded breast radiologist and<br />
evaluated for predetermined modality specific parameters as defined<br />
in Table 1. The NPV, PPV, accuracy, sensitivity, and specificity were<br />
calculated on the basis of the final surgical pathology report with a<br />
complete pathologic response in the breast defined as no residual<br />
invasive disease or in situ disease.<br />
Results. Eighty-three tumors in 83 patients with a mean age of 50<br />
(range 27-70) were evaluated. Twenty-three patients had a pCR.<br />
The NPV, PPV, sensitivity, specificity, and accuracy of tri-modality<br />
imaging algorithm for pCR were 0.87, 0.95, 0.95, 0.87 and 0.93<br />
utilizing a cut-point of ≤ 5 for complete response by imaging. The<br />
mean score for patients with pCR was 4.61 (range 3-10) with 3 patients<br />
scoring above 5. The mean score for patients with residual disease<br />
was 7.73 (range 5-11).<br />
Conclusions: A tri-modality imaging scoring algorithm is predictive<br />
of complete pathologic response. This algorithm will be tested in a<br />
developing prospective trial that will also assess the additive value<br />
of tumor bed biopsy in patients who achieve a score of 5 or less.<br />
Table 1<br />
Imaging Modality<br />
Imaging Parameter Score<br />
0 1 2 3<br />
MR<br />
Early peak signal intensity ≤80 >80<br />
Internal enhancement pattern Homogeneous Heterogeneous<br />
Kinetic pattern Type I Type II Type III<br />
US<br />
Mass size Resolution of mass ≤20 mm >20 mm<br />
Mammography<br />
Residual mass Absent Present<br />
Malignant calcifications Absent Present<br />
P3-04-01<br />
Protein pathway activation mapping of the I-SPY 1 biopsy<br />
specimens identifies new network focused drug targets for patients<br />
with triple negative tumors<br />
Wulfkuhle JD, Wolf D, Gallagher RI, Yau C, Calvert V, Espina V,<br />
Illi J, Wu Q, Boe M, Yan Y, I-SPY TRIAL-1 Investigators, Liotta LA,<br />
van’t Veer L, Esserman L, Petricoin EF. George Mason University,<br />
Manassas, VA; University of California, <strong>San</strong> Francisco, CA;<br />
Genentech, South <strong>San</strong> Francisco, CA<br />
Background: Identification of new therapies and predictive<br />
biomarkers is needed for patients with triple negative (TN) breast<br />
cancer. Elucidating pathway activation in cancer is critical as these<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
296s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
proteins represent targets for many of the new molecular therapeutics<br />
and companion diagnostic markers. The I-SPY TRIAL (CALGB<br />
150007/150012, ACRIN 6657) is a trial of neoadjuvant anthracyclineand<br />
taxane-based chemotherapy that provides longitudinal biopsy<br />
specimens and molecular and clinical/pathological characterization.<br />
Methods: Tumor epithelium was procured by Laser Capture<br />
Microdissection from 149 pretreatment frozen biopsy specimens<br />
(T1) and 102 frozen biopsy specimens collected 1-4 days after first<br />
chemotherapy treatment (T2). Reverse Phase Protein Microarray was<br />
used to measure the activation of 39 and 100 signaling proteins in<br />
the T1 and T2 biopsies, respectively, including drug targets for Phase<br />
I-III and FDA cleared therapeutics. Associations between pathway<br />
activation and response to chemotherapy (RCB 0/1 vs. 2/3) and<br />
relapse-free survival (RFS) were evaluated for the triple-negative<br />
(TN) patient population at each time point and for changes between<br />
T1 and T2. Significance thresholds for response and RFS were as<br />
follows: Wilcoxon rank sum test p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
positive lymph nodes). International recommendations for patients<br />
with 1-3 positive lymph nodes suggest that PMRT should be restricted<br />
to younger patients and patients with other poor prognostic features.<br />
However, large randomized trials, including the DBCG82 trials<br />
(Danish <strong>Breast</strong> <strong>Cancer</strong> Cooperative Group), have previously shown<br />
a substantial overall survival benefit after PMRT in patients with low<br />
risk of LR, and shown that the largest translation of LR reduction into<br />
breast cancer mortality reduction occurs within the most favorable<br />
prognosis group. Our hypothesis is that a more refined partitioning<br />
of patients likely to benefit from PMRT can be established through<br />
identification of genes whose transcription interacts with PMRT to<br />
modify the hazard of LR.<br />
Material and methods: The DBCG82bc cohort constitutes high risk<br />
patients (tumor size > 5 cm and/or positive nodes and/or invasion<br />
in skin or pectoral fascia) diagnosed between 1983-89, treated<br />
with mastectomy and partial axillary lymph nodes dissection and<br />
randomized to +/- PMRT. From 267 DBCG82bc patients, frozen<br />
tumor samples were available. Whole genome arrays (Applied<br />
Biosystem Human Genome Survey Microarray v2.0®, Applied<br />
Biosystem, Foster City, USA) were successful in 195 samples. Genes,<br />
whose expression levels interacted with PMRT on the association<br />
with LR, were identified through a two step Cox Proportional Hazard<br />
model with lasso penalty. 11 node negative patients were excluded<br />
from the subsequent analysis of 184 node positive patients (1-3 pos.<br />
nodes: 102 pts, ≥ 4 pos. nodes: 82 pts).<br />
Results: Seven genes were identified whose expression interact with<br />
the effect of PMRT, and a specialized index was generated based on<br />
the expression levels of these genes. Patients were ranked according<br />
to the size of the index, and divided into quartiles with 25% of the<br />
patients designated as having a “high index” and 75% a “low index”.<br />
Among patients not receiving PMRT, a low index was in both nodal<br />
groups (1-3 vs. ≥ 4 positive nodes) associated with a significantly<br />
higher risk of LR compared to patients with a high index. In both<br />
nodal groups, PMRT significantly reduced the risk of LR in patients<br />
with a low index; equalizing the risk to patients with a high index,<br />
who showed no additional LR reduction by PMRT. In the group of<br />
1-3 positive nodes, PMRT raised the local control rate (LCR) after<br />
10 years from 47.5 % to 91.8% in the low index group (p= 0.0001),<br />
whereas the change in the high index group was non-significant<br />
(92.3% vs. 100.0%). In the group of patients with ≥ 4 positive nodes,<br />
PMRT raised LCR from 16.6% to 80.0% in the low index group (p=<br />
0.0001), and no effect on LCR was seen in the high index group<br />
(83.3% vs. 87.5%, n.s.).<br />
Conclusion: A seven gene-profile attaining prognostic and predictive<br />
impact, irrespective of number of positive nodes, was identified. The<br />
profile allowed the identification of 25% of the patients not showing<br />
any additional benefit from PMRT in terms of LR. The gene-profile<br />
may provide a method to identify patients expected to benefit from<br />
PMRT.<br />
P3-04-04<br />
Identification of a “BRCAness” signature in triple negative breast<br />
cancer by Comparative Genomic Hybridization<br />
Toffoli S, Bar I, Abdulsater F, Delrée P, Hilbert P, Cavallin F, Moreau<br />
F, Clark J, Lacroix-Triki M, Campone M, Martin A-L, Roché H,<br />
Machiels J-P, Carrasco J, Canon J-L. Institute of Pathology and<br />
Genetics, Gosselies, Belgium; MDxHealth, Liège, Belgium; Institut<br />
Claudius Regaud, Toulouse, France; Institut de Cancérologie<br />
de l’Ouest-René Gauducheau, Saint-Herblain - Nantes, France;<br />
UNICANCER, Paris, France; Cliniques Universitaires Saint-Luc,<br />
Brussels, Belgium; Grand Hôpital de Charleroi (GHdC), Charleroi,<br />
Belgium<br />
Background:<br />
Triple Negative <strong>Breast</strong> <strong>Cancer</strong>s (TNBC) represent 12% to 20% of total<br />
<strong>Breast</strong> <strong>Cancer</strong>s (BC) and have a worse outcome compared with other<br />
breast cancer subtypes. TNBC often show a deficiency in DNA double<br />
strand break repair mechanisms. This deficiency is generally related<br />
to inactivation of a repair enzymatic complex involving BRCA1<br />
caused either by genetic mutations, epigenetic modifications, or by<br />
post-transcriptional regulations. The identification of BC presenting<br />
a BRCA1 deficiency could be useful to select patients that could<br />
benefit from PARP inhibitors, alkylant agents or platinum-based<br />
chemotherapy.<br />
In this study, we have identified by Comparative Genomic<br />
Hybridization array (CGH-array) a recurrent gain in 17q25.3<br />
characteristic of BRCA1 mutated or methylated TNBC.<br />
Methods:<br />
130 formalin-fixed paraffin embedded (FFPE) tumours including<br />
TNBC (unknown-BRCA1-status, BRCA1 mutated and nonmutated),<br />
Luminal A, Luminal B, Her2-neu amplified (Her2+) BC<br />
and BRCA1-mutated non-TNBC (mutated-Luminal A, Luminal B,<br />
Her2+) were obtained from our local tumour collection. DNA was<br />
extracted and genomic copy-number alterations were analysed by<br />
CGH-array (Agilent, SuperPrint G3 Human CGH 8x60K Oligo<br />
Microarrays). FISH analyses were performed on section from FFPE<br />
samples to validate some chromosomal aberrations belonging to the<br />
17q25.3 amplified region evidenced by CGH-array. The study of<br />
BRCA1 promoter methylation status in all tumours was carried out<br />
by MDxHealth (Liege,Belgium).<br />
Results:<br />
In this study, we have identified by CGH-array a genomic region<br />
(17q25.3) amplified in 90% of the BRCA1 mutated tumours (29/32).<br />
This chromosomal gain was studied in other subtypes of BC by<br />
CGH-array and it was only evidenced in 30% (6/20) of BRCA1<br />
non-mutated TNBC, 26.67% (4/15) of unknown-BRCA1-status<br />
TNBC, 13.64% (3/22) of Luminal B, 19.05% (4/21) of Her2+ and<br />
0% (0/20) of Luminal A breast cancers. FISH assays confirmed these<br />
chromosomal amplifications and evidenced like CGH array analyses<br />
a significant difference between BRCA1 mutated and non-mutated<br />
BC for the 17q25.3 gain.<br />
BRCA1 methylation was found only in TNBC (11/58) and was<br />
not found in the BRCA1-mutated BC cohort, nor in the Luninal<br />
A, Luminal B and Her2+ samples. In BRCA1 non-mutated TNBC,<br />
the methylation was found in 8 cases including 4 with 17q25.3<br />
amplification. In the unknown-BRCA1-status TNBC, 3 methylated<br />
samples were found with 1 case with co-amplification of the 17q25.3<br />
region.<br />
Recurrence of 17q25.3 amplification in BRCA1 mutated tumours as<br />
well as its detection in BC having a methylation in BRCA1 promoter<br />
suggests that the 17q25.3 gain could be a marker of the BRCA1<br />
deficiency. Identification of relevant genes whose expression is upregulated<br />
within the recurrently gained region is underway.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
298s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
Conclusions:<br />
The CGH signature observed in 17q25.3 chromosomal region and<br />
FISH assay developed in this study could allow the identification of<br />
“BRCAness” breast tumours, improving the diagnostic performance<br />
and orienting the selection of the appropriate therapy. The up-regulated<br />
genes themselves might also represent potential therapeutic targets.<br />
Acknowledgements:<br />
This work was financed through the “Plan National <strong>Cancer</strong>-Action<br />
29” (Belgium) and supported by the UNICANCER-PACS08 trial<br />
(France).<br />
P3-04-05<br />
Kinomic and phospho-proteomic analysis of breast cancer stemlike<br />
cells<br />
Leth-Larsen R, Christensen AG, Ehmsen S, Moeller M, Palmisano<br />
G, Larsen MR, Ditzel HJ. University of Southern Denmark, Odense,<br />
Denmark; Odense University Hospital, Odense, Denmark<br />
<strong>Cancer</strong> stem cells are thought to be responsible for tumorigenic<br />
potential and to possess resistance mechanisms against chemotherapyand<br />
radiation-induced cancer cell death, while the bulk of a tumor<br />
lacks these capacities. The resistance mechanisms may cause these<br />
cells to survive and become the source of later tumor recurrence,<br />
highlighting the need for therapeutic strategies that specifically target<br />
pathways central to these cancer stem cells. The CD44 hi /CD24 -/low<br />
compartment of human breast cancer is enriched in tumor-initiating<br />
cells; however the functional heterogeneity within this subpopulation<br />
remains poorly defined.<br />
From a triple-negative breast cancer cell line we isolated and<br />
cloned CD44 hi single-cells that exhibited functional heterogeneity<br />
according to cancer stem cell features, such as tumor formation<br />
in immunodeficient mice, mammosphere formation, invasion and<br />
migration abilities and sensitivity to chemotherapeutics.<br />
Quantitative proteomic analysis of these clones revealed several<br />
proteins, including kinases, exhibiting altered expression levels,<br />
while other proteins exhibited altered phosphorylation levels. The<br />
quantitative proteomic approach was based on post digestion dimethyl<br />
labeling followed by TiO 2 enrichment of phosphopeptides. Moreover,<br />
analysis of the flowthrough fraction revealed quantitative changes<br />
in the total proteome. Transcriptomic analysis using Affymetrix<br />
Human Gene 1.0 ST Arrays revealed similar alterations at the gene<br />
expression level.<br />
We used these single cell clones to further investigate the molecular<br />
mechanisms underlying the association between selected proteins,<br />
some of them phosphorylated, and cancer stem cell features.<br />
Furthermore, phosphosite-expression was investigated with<br />
NetworKIN that predicts in vivo kinase-substrate relationships.<br />
Our studies reveal pathways that are regulated by protein<br />
phosphorylation and include relevant kinase targets for drug<br />
discovery. Our results support functional heterogeneity in the breast<br />
cancer cell compartment and hold promise for further refinements of<br />
prognostic marker profiling of cells with cancer stem cell-like features.<br />
P3-04-06<br />
Higher gene expression of CSPG4 in the basal-like subtype of<br />
invasive breast cancer and its negative association with lymph<br />
node metastasis<br />
Luo C, Iida J, Chen Y, Dorchak J, Kovatich AJ, Mural RJ, Hu H,<br />
Shriver CD. Windber Research Institute, Windber, PA; Walter Reed<br />
National Military Medical Center, Bethesda, MD; MDR, Global<br />
Systems LLC, Windber, PA<br />
Background: Chondroitin sulfate proteoglycan 4 (CSPG4) was<br />
first identified as a melanoma specific antigen and demonstrated to<br />
stabilize cell-substratum interactions during early events of tumor cell<br />
spreading on endothelial cells and matrix proteins. In invasive breast<br />
cancers (IBCs), CSPG4 has been reported to be highly expressed in<br />
the triple-negative (TN) subtype. Western blotting analyses suggest<br />
that CSPG4 is expressed on TN IBC lines. Here we further explored<br />
the specific gene expression (GE) profiles associated with CSPG4<br />
using the available IBC cases from The <strong>Cancer</strong> Genome Atlas<br />
(TCGA) project towards identification of potential drug targets for<br />
patients with TN IBC.<br />
Methods: The GE data (Agilent, log2 transformed) of 459 IBC tumors<br />
were downloaded from the TCGA data portal. PAM50 classification<br />
results of all samples were obtained from the TCGA breast cancer<br />
AWG group, including 203 Luminal A (LA), 113 Luminal B (LB),<br />
51 HER2+, 84 basal-like (Basal), and 8 Normal-like (not used).<br />
Clinicopathologic data (age, race, T-, N-, and M-stages) were also<br />
obtained from the AWG group. Non-parametric Kruskal-Wallis<br />
test was used for cross-subtype analysis of CSPG4 expression,<br />
followed by Wilcoxon-Mann-Whitney test for pairwise comparison<br />
with Bonferroni adjustment. Chi-square tests were performed for<br />
categorical variation analyses. Differentially Expressed Gene (DEG)<br />
analysis was performed using the Bioconductor “samr” package for<br />
two class unpaired comparison, with p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P3-04-07<br />
Comparison of breast tumors with HER2 amplification and<br />
polysomy 17<br />
Field LA, Deyarmin B, Ellsworth RE, Shriver CD. Windber<br />
Research Institute, Windber, PA; Henry M. Jackson Foundation for<br />
the Advancement of Military Medicine, Windber, PA; Walter Reed<br />
National Military Medical Center, Bethesda, MD<br />
Background: Approximately 20% of invasive breast cancers<br />
overexpress the human epidermal growth factor receptor, Her2, and<br />
are associated with poor prognosis including decreased relapse-free<br />
and overall survival. Overexpression of the Her2 protein is primarily<br />
due to amplification of the HER2 oncogene on chromosome 17,<br />
and these patients are typically treated with targeted therapies such<br />
as trastuzumab or lapatinib. However, increased HER2 copies may<br />
also result from chromosome 17 polysomy in which the entire<br />
chromosome has been duplicated one or more times. The clinical<br />
benefit of treating patients with polysomy 17 in the absence of HER2<br />
amplification with targeted therapy remains unclear. Herein, we<br />
compared the clinical characteristics as well as the gene expression<br />
profiles of breast tumors with increased HER2 copy numbers due to<br />
HER2 amplification or chromosome 17 polysomy.<br />
Methods: Patients for this study were enrolled in the Clinical <strong>Breast</strong><br />
Care Project. HER2 and CEP17 copy numbers were determined<br />
using the PathVysion HER-2 DNA Probe Kit (Abbott Laboratories).<br />
Only those patients with at least 4 HER2 copies per cell were<br />
included in the analysis; those with a HER2/CEP17 ratio 2.2 (N=44)<br />
were considered amplified. Microarray data were generated on HG<br />
U133A 2.0 arrays (Affymetrix) for those samples with tissue available<br />
(14 polysomy and 18 amplified cases) and analyzed using Partek<br />
Genomics Suite.<br />
Results: Tumor grade and size did not differ between polysomic and<br />
amplified samples. Although amplified cases tended to be younger<br />
at diagnosis and less likely to be diagnosed with Stage I tumors, this<br />
difference did not reach statistical significance. HER2 amplified<br />
tumors were more likely to be ER negative (P=0.027) and have lymph<br />
node metastases (P=0.028) than polysomic tumors. Comparison of<br />
polysomic and amplified cases by expression microarray identified<br />
67 genes that were differentially expressed (P2) between the two groups. Thirty-nine genes were more highly<br />
expressed and 28 genes more lowly expressed in tumors with HER2<br />
gene amplification when compared to tumors from patients with<br />
chromosome 17 polysomy.<br />
Discussion: ER and lymph node status of breast tumors from women<br />
with increased HER2 copy number differed depending on whether<br />
the increased copy number was due to HER2 gene amplification or<br />
conversely, polysomy of chromosome 17. Likewise, gene expression<br />
profiles also differed depending on whether increased HER2 was<br />
due to gene amplification or chromosomal gain. Those genes with<br />
significant levels of differential expression between these two groups<br />
are involved in cell cycle control, cell adhesion and migration, cell<br />
differentiation, cytoskeleton organization, signal transduction, protein<br />
synthesis and degradation, and ion transport. Interestingly, the top<br />
4 most significant genes with higher expression in the polysomic<br />
samples, including TUBG1, CPD, BLMH, and JUP, are all located<br />
on 17q. Currently, it is not clear whether treatment with targeted<br />
Her2 therapy is beneficial in patients with chromosome 17 polysomy.<br />
However, the genes identified here may represent novel targets for<br />
developing new treatments that are effective in these women and<br />
require further study.<br />
P3-04-08<br />
Expression of hormone-responsive genes in benign breast tissue<br />
varies with menstrual cycle phase and menopausal status<br />
Hu H, Wang J, Lee O, Shidfar A, Iyer S, Ivancic D, Chatterton RT,<br />
Stearns V, Sukumar S, Khan SA. Northwestern University, Chicago,<br />
IL; Johns Hopkins University School of Medicine<br />
Background: The expression of many genes is known to be regulated<br />
by ambient hormone levels. In a preliminary study of random fineneedle<br />
aspirate (rFNA) samples from benign breast tissue, we found<br />
several genes that were highly correlated with the serum levels of<br />
progesterone (P4) and estradiol (E2). We now present data to further<br />
validate these genes as markers of menstrual cycle phase (MCP) and<br />
menopausal status (MPS) in benign breast tissue which may allow<br />
retrospective classification of archived breast samples with respect<br />
to MCP and MPS at the time of sampling.<br />
Methods: 240 rFNA samples from healthy women with recorded<br />
hormonal data at the time of sampling were analyzed. We divided<br />
these subjects by menstrual cycle phase (MCP) and menopausal<br />
status (MPS): 41 early follicular: (low circulating E2 and P4); 48<br />
mid-cycle (high E2 and low P4); 31 luteal (moderate E2 and high<br />
P4). 120 post-menopausal (low E2 and low P4). 100 ng of RNA from<br />
rFNA samples of the breast was reverse transcribed. Amplicons of<br />
interest were linearly amplified to 14 cycles for 35 genes related<br />
to hormone responsiveness. qPCR reactions were carried out<br />
using the TaqMan OpenArray (Applied Biosystems). For each<br />
gene of interest, expression levels were normalized to the average<br />
expression of GAPDH. Gene expression difference between groups<br />
were conducted using the Mann-Whitney Test. P-values from gene<br />
expression difference were adjusted via the Benjamini-Hochberg<br />
(1995) approach.<br />
Results: The mean value of TNFSF11 expression level was 13.19<br />
fold higher in luteal phase subjects than in post-menopausal subjects<br />
(P=0.0003) where there was also the biggest difference of serum<br />
P4 level between groups. The expression of DIO2 and MYBPC1<br />
was also significantly higher in luteal phase group than in the postmenopausal<br />
group (P=0.005 , P= 0.02, respectively). These 3 genes<br />
also demonstrated a higher expression pattern in luteal phase than<br />
mid-cycle and follicular phase but analysis is still ongoing. All<br />
comparisons between these groups will be presented at the meeting.<br />
Conclusion: The expression levels of TNFSF11, DIO2 and MYBPC1<br />
vary with MCP and MPS. These hormone-responsive genes are<br />
candidate MCP classifiers which could be applied to archived breast<br />
samples to assess whether biomarkers of breast cancer risk are stable<br />
across the menstrual cycle, since MCP and MPS variation is likely<br />
an important source of biological noise in studies of archived breast<br />
biopsy material.<br />
P3-04-09<br />
Withdrawn by Author<br />
P3-04-10<br />
Comparison between RNA-Seq and Affymetrix gene expression<br />
data<br />
Fumagalli D, Haibe-Kains B, Michiels S, Brown DN, Gacquer D,<br />
Majjaj S, Salgado R, Larsimont D, Detour V, Piccart M, Sotiriou<br />
C, Desmedt C. Institut Jules Bordet, Brussels, Belgium; Institut<br />
de Recherches Cliniques de Montréal, Montréal, QC, Canada;<br />
Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium<br />
Background: Microarrays have revolutionized breast cancer research<br />
by enabling gene expression comparisons on a transcriptome-wide<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
300s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
scale. They have provided clinically useful information such as the<br />
development of the intrinsic classification as well as several gene<br />
prognostic signatures. Recently, with the advent of next generation<br />
sequencing technology, RNA-Seq has emerged as a promising<br />
technology for digital read-out of the transcriptome. Here, we will<br />
present a comparison of microarray and RNA-Seq data on a series<br />
of 58 breast cancer samples.<br />
Methods: 58 tumors representing the different molecular subtypes [17<br />
triple negative (ER-, PgR-, HER2-); 14 HER2 positive (HER2+); 17<br />
luminal A (ER+, HER2-,histological grade 1), 10 luminal B (ER+,<br />
HER2-,histological grade 3)] were obtained from patients recruited<br />
between 2007 and 2011 at Jules Bordet Institute. Their RNA was<br />
profiled using the Affymetrix HG-U133 Plus 2.0 chips and sequenced<br />
with the ILLUMINA platform, producing ∼30 million 2*50 bp<br />
paired-end reads per sample. The reads alignment and expression<br />
quantification were performed using Tophat 2 and Cufflinks 2,<br />
respectively, on the basis of the Ensembl genome annotations<br />
hg19. Affymetrix microarray data were normalized using fRMA<br />
and probesets were selected using JetSet. A selection of 7 clinically<br />
relevant gene signatures was evaluated.<br />
Results: About 16000 genes were retained for analysis. Comparison<br />
of Affymetrix and RNA-Seq data revealed that 50%, 25% and 5%<br />
of these genes had a Spearman correlation superior to 0.7, 0.82 and<br />
0.92, respectively. The genes with the highest correlation coefficients<br />
between Affymetrix and RNA-Seq tended to have medium/high<br />
expression levels (median Affymetrix log2 expression of 7.5)<br />
consistent with the fact that microarrays have a limited dynamic<br />
range compared to RNA-Seq. We observed an excellent correlation<br />
between Affymetrix and RNA-Seq for the clinically relevant genes<br />
ER (0.97), PgR (0.95) and HER2 (0.90) respectively. We observed,<br />
however, a few discordances between ER and PgR quantification<br />
by immunohistochemistry and RNA-Seq/Affymetrix. We next<br />
measured the consistency of two molecular classifiers, SCMGENE<br />
(Haibe-Kains JNCI2012) and PAM50 (Parker JCO2009), between<br />
Affymetrix arrays and RNA-seq. A kappa coefficient of 0.93 (CI 0.85-<br />
1) and 0.79 (CI 0.66-0.91) was observed for SCMGENE and PAM50,<br />
respectively, with the majority of the discrepancies for PAM50<br />
concerning the HER2 subtype. The first generation proliferationbased<br />
gene expression signatures showed an excellent correlation<br />
between Affymetrix and RNA-Seq: Genomic Grade Index (0.98),<br />
Mammaprint (0.98) and Oncotype (0.97). The immune and stroma<br />
gene signatures (Desmedt et al. 2008) showed a correlation of 0.97<br />
and 0.79 respectively. The lower correlation for the stroma signature<br />
could partly be explained by the fact that RNA-Seq and Affymetrix<br />
are measuring different splice variants.<br />
Conclusions: This is to our knowledge the first study to report a<br />
systematic comparison between RNA-Seq and Affymetrix HG-<br />
U133 Plus2.0 data in breast cancer for individual genes and several<br />
prognostic gene signatures. According to these results, RNA-Seq can<br />
reliably be used for the quantification of breast cancer transcriptome.<br />
P3-04-11<br />
Systemic treatment decision making for patients with stage I and<br />
II, hormone receptor positive, her2/neu negative breast cancer<br />
Zhu X, Graham N, Paquet L, Dent S, Song X. University of Ottawa,<br />
ON, Canada; The Ottawa Hospital <strong>Cancer</strong> Centre, Ottawa, ON,<br />
Canada; Carleton University, Ottawa, ON, Canada<br />
Background: Oncotype DX is a clinically validated risk stratification<br />
tool that can predict the risk of recurrence and the benefit of adjuvant<br />
chemotherapy in women with hormone receptor positive (HR+),<br />
HER2/neu negative early stage breast cancer (EBC). This tool has<br />
been available to oncologists in Ontario since April 2010 at significant<br />
cost, yet no guidelines exist regarding their use. This retrospective<br />
chart review examined the factors that were associated with use of<br />
Oncotype DX at a tertiary care cancer centre.<br />
Materials and methods: One hundred patients (pts) diagnosed with<br />
HR+, HER2/neu negative EBC (stage I-II), who underwent Oncotype<br />
DX testing between April 1, 2010, and June 30, 2011 were included<br />
in the study. A second control group of 100 patients with similar<br />
disease characteristics but who did not receive Oncotype DX testing<br />
were randomly selected. Data collection included demographics,<br />
tumor grade and stage, and Adjuvant! Online recurrence risk scores.<br />
The distribution of patients in each category was compared using the<br />
chi-square test to detect statistically significant differences between<br />
distributions.<br />
Results: Median age in the Oncotype DX group was 58 years (r: 26-<br />
77) and 63 years (r: 30-81) in the control group. 20 patients in the<br />
Oncotype DX group were aged 35-49, 57 patients were aged 50-64,<br />
and 23 patients were aged 65 or older, while the control group had 16,<br />
43, and 41 patients, respectively (p=0.02). The Oncotype DX group<br />
had 72 pre- and perimenopausal pts and 28 postmenopausal patients,<br />
while the control group had 81 and 19 patients, respectively (p=0.13).<br />
20, 56, and 24 pts in the Oncotype DX group had grade 1, 2, and 3<br />
histology, respectively, vs. 44, 44, and 12, respectively in the control<br />
group (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Methods: We have developed a user-friendly web-based system to<br />
allow the identification and evaluation of genes that are significantly<br />
associated with disease progression and survival for breast cancer in<br />
general and also with respect to molecular subtype. The underlying<br />
algorithm combines gene expression data from multiple DNA<br />
microarray experiments and detailed clinical data to correlate<br />
outcome with gene expression levels. This algorithm integrates<br />
gene expression and survival data from 21 datasets on 10 different<br />
microarray platforms corresponding to 20,017 gene sequences across<br />
3,519 samples.<br />
Results: We demonstrate the robustness of our approach in comparison<br />
to two commercially available prognostic tests in breast cancer.<br />
Our algorithm complements these prognostic tests and is consistent<br />
with their findings. In addition, <strong>Breast</strong>Mark can act as a powerful<br />
reductionist approach to these more complex gene signatures,<br />
eliminating superfluous genes, potentially reducing the complexity<br />
and cost of these multi-index assays. We also applied the algorithm to<br />
examine expression of 58 receptor tyrosine kinases in the basal-like<br />
subtype of breast cancer, identifying seven receptor tyrosine kinases<br />
associated with poor disease-free survival and/or overall survival in<br />
this subtype (EPHA5, FGFR1, FGFR3, VEGFR1, PDGFRβ, ROS,<br />
TIE1). A web application for using this algorithm is currently available<br />
at http://glados.ucd.ie/<strong>Breast</strong>Mark/index.html.<br />
Conclusions: <strong>Breast</strong>Mark is a useful tool for examining putative<br />
prognostic markers at the RNA level in breast cancer. The value of<br />
this tool will be in the preliminary assessment of putative biomarkers<br />
in breast cancer as a whole and within its molecular subtypes. It will<br />
be of particular use to clinical and academic research groups with<br />
limited bioinformatics facilities.<br />
P3-05-01<br />
Molecular subtyping improves stratification of patients into<br />
diagnostically more meaningful risk groups<br />
Cristofanilli M, Turk M, Kaul K, Weaver J, Wesseling J, Stork-Sloots<br />
L, de Snoo F, Yao K. Fox Chase <strong>Cancer</strong> Center; NorthShore University<br />
HealthSystem; Netherlands <strong>Cancer</strong> Institute; Agendia NV<br />
Background: Microarray-based gene expression profiling<br />
demonstrated that breast cancer is a heterogeneous group of different<br />
diseases characterized by distinct molecular aberrations, rather than<br />
one disease. Improved understanding of the molecular phenotypes<br />
of the disease has already shown prognostic and predictive value<br />
and, when prospectively applied, could have dramatic implications<br />
in establishing a more personalized approach to the management<br />
of early-stage breast cancer. Combined use of MammaPrint and a<br />
molecular subtyping profile (BluePrint) identifies disease subgroups<br />
with marked differences in long-term outcome and response to neoadjuvant<br />
therapy [Glück et al. ASCO 2012]. The aim of this study<br />
was to evaluate the implication of accurate molecular subtyping using<br />
MammaPrint and BluePrint in women with early-stage breast cancer<br />
treated at US Institutions following National Comprehensive <strong>Cancer</strong><br />
Network (NCCN) standard guidelines.<br />
Methods: 208 frozen tumor samples from consecutive BC patients<br />
(TI-III, N0-Ib) were obtained from 2 US centers. Median age at<br />
diagnosis was 56 years (range 28–89 years). Between 1992 and<br />
2010 patients were treated either with breast-conserving therapy or<br />
mastectomy with axillary lymph node dissection followed by systemic<br />
adjuvant therapy when indicated. Sixty-three percent of patients<br />
received adjuvant endocrine therapy (ET), 58% received adjuvant<br />
chemotherapy (CT) and 32% received both. Hormone Receptor (HR)<br />
and HER2 status were assessed by immunohistochemistry (IHC)<br />
and fluorescent in-situ hybridization (FISH), following standard<br />
guidelines. Median follow-up was 11.3 years. Survival was assessed<br />
for patient groups according to local pathological assessment and<br />
compared with molecular classification of patients (centrally assessed<br />
full genome expression at Agendia laboratory).<br />
Results: Standard HR and HER2 status assessment revealed that<br />
57% of all tumors examined were luminal-like (ER/PR positive,<br />
HER2 negative), 20% HER2 positive and 24% triple negative.<br />
Molecular classification demonstrated discordance in the following<br />
clinical groups: 16 out of 41 patients previously identified as HER2<br />
positive were reclassified as Luminal-type, with 97% 5-year distant<br />
metastases-free survival (DMFS) for Luminal A (MammaPrint Low<br />
Risk/Luminal-type) and 98% for Luminal B (MammaPrint High<br />
Risk/Luminal-type). Ten patients identified with clinical triplenegative<br />
tumors were reclassified with molecular subtyping as HER2<br />
positive (n=6) and Luminal-type (n=4). Of the patients classified<br />
with BluePrint Basal-type tumors, 58 (28%) had a 5-year DMFS of<br />
82% (81% received adjuvant CT). Of those with HER2-type tumors,<br />
25 (12%) had a 5-year DMFS of 76% (88% received adjuvant CT<br />
without trastuzumab). Discordant cases are being centrally re-assessed<br />
for ER, PR and HER2.<br />
Conclusions: This retrospective study showed that Molecular<br />
Subtyping with BluePrint and MammaPrint leads to clinically<br />
significant prognostic and molecular stratification. The use of<br />
MammaPrint and BluePrint in the management of patients with<br />
primary breast cancer should be considered for a more accurate<br />
selection of adjuvant therapies in this era of personalized medicine.<br />
P3-05-02<br />
Pathological assessment of discordant cases for molecular<br />
(BluePrint and MammaPrint) versus clinical subtypes for breast<br />
cancer among 621 patients from the EORTC 10041/BIG 3-04<br />
(MINDACT) trial<br />
Viale G, Slaets L, de Snoo F, van’t Veer L, Rutgers E, Piccart M,<br />
Bogaerts J, van den Akker J, Stork-Sloots L, Engelen K, Russo L,<br />
Dell’Orto P, Cardoso F. European Institute of Oncology; European<br />
Organisation for Research and Treatment of <strong>Cancer</strong>; Agendia NV;<br />
Netherlands <strong>Cancer</strong> Institute; Jules Bordet Institute; Champalimaud<br />
<strong>Cancer</strong> Center<br />
Background: Biology has become the main driver of breast cancer<br />
therapy. Intrinsic biological subtypes by gene expression profiling<br />
have been identified. Pathology can be used to define surrogates<br />
of these subtypes but these are not always concordant, which may<br />
lead to different treatment plans. We investigated the concordance<br />
between BluePrint and MammaPrint (microarray-based) breast<br />
cancer subtypes and pathological surrogates (based on ER, PR,<br />
HER2 & Ki67).<br />
Methods: Using available data (centrally assessed pathology and<br />
genomics) from the MINDACT pilot phase [Rutgers et al. EJC 2011]<br />
621 tumors were analyzed. Patients were classified according to<br />
4-category based pathology (ER, PR, HER2 and Ki67); additionally,<br />
classification was performed adhering to the recent St. Gallen<br />
recommendations [Goldhirsch et al. 2011], which recognizes an<br />
additional category (Luminal B HER2+). Based on BluePrint and<br />
MammaPrint 4 subtypes are formed: Luminal A (Luminal-type/<br />
MammaPrint Low Risk); Luminal B (Luminal-type/MammaPrint<br />
High Risk); HER2-type; and Basal-type. This study is an analysis of<br />
discordant patient groups (i.e. clinical HER2+/BluePrint Luminaltype;<br />
clinical Hormone Receptor (HR)-positive/BluePrint Basal-type)<br />
providing comparison of centrally assessed tumor heterogeneity as<br />
well as comparison of quantified ER, PR and HER2 results.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
302s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
Results: Ki67 is often used as biomarker to distinguish Luminal A<br />
from Luminal B subgroups. The concordance between MammaPrint<br />
and centrally assessed Ki67 in Luminal-type patients is 71%, with<br />
a κ score of 0.35 (95% CI 0.26–0.45) indicating that Ki67 and<br />
MammaPrint cannot reliably substitute for each other. There is a<br />
relatively large group of clinical HER2+ cases that are BluePrint<br />
Luminal-type (29 out of 76; 38%) indicating that tumor expression<br />
of the Luminal profile is dominant compared with expression of the<br />
HER2 profile. These patients have high IHC ER results and fall into<br />
the group that St Gallen separately defines as Luminal B HER2-<br />
type. These patients may have lower response to trastuzumab [von<br />
Minckwitz et al. JCO 2012]. 12 out of 76 BluePrint Basal-type patients<br />
are clinical HR+. These patients have low centrally assessed IHC ER<br />
and PR expression (≥1% and
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Conclusion: The genomic variability prior to therapy was higher in<br />
the partial-responders vs. the complete responders, and the remaining<br />
tumor was even more heterogeneous after treatment than prior to<br />
treatment. Double immunoFISH is a valuable tool for visualization<br />
of both phenotypic and genomic alterations in the same cell in FFPE<br />
sections. The cohort will be expanded to explore the diversity further,<br />
and the results will be presented.<br />
P3-05-05<br />
HER2 Expression and Gene copy analysis by Immunofluorescence<br />
and Fluorescence in situ Hybridization, on a Single formalin-fixed<br />
paraffin-embedded tissue section<br />
Ha T, Seppo A, Ginty F, Kenny K, Henderson D, Kyshtoobayeva A,<br />
Gerdes M, Larriera A, Liu X, Corwin A, Zingelewicz S, Lazare M,<br />
Jun N, Kyshtoobayeva A, Chow C, Al-Kofahi Y, Hollman D, Bloom K.<br />
GE Global Research, Niskayuna, NY; Clarient Diagnostics Services,<br />
Aliso Viejo, CA<br />
Introduction<br />
<strong>Breast</strong> cancer is the most common cancer for women worldwide.<br />
HER2 expression and gene copy number are important when<br />
determining eligibility for adjuvant therapy and/or chemotherapy<br />
medications. One challenging issue for breast cancer testing is<br />
intratumoral heterogeneity of HER2 gene amplification. Intratumoral<br />
heterogeneity can make it difficult to localize target cells of interest.<br />
Serial tissue sections used for independent H&E, IHC and FISH stains<br />
also increase the difficulty to localize targets due to cellular truncation.<br />
We have developed a system to assess both HER2 expression and<br />
gene copy number on the same cell.<br />
Method<br />
Immunofluorescence (IF) and Fluorescence in situ Hybridization<br />
(FISH) were performed on tissue sections from 19 patients with<br />
invasive ductal breast carcinoma. Cases were selected based on prior<br />
HER2 FISH results (HER2:Chromosome 17 = ratio) representing<br />
unamplified (
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
were case dependent. For instance, the main cause of over-counting<br />
errors was image noise and artifacts. On the other hand, the main<br />
cause of under-counting was low image contrast, especially in highly<br />
amplified cases. These results are an early indication of the promise<br />
of automatic dot counting applied to breast cancer slides multiplexed<br />
for Her2 IF and FISH.<br />
P3-05-07<br />
Poor prognosis early breast cancer: pathological characteristics<br />
of the Unicancer-PACS08 trial including patients treated with<br />
docetaxel or ixabepilone in adjuvant setting<br />
Lacroix-Triki M, Delrée P, Filleron T, Penault-Llorca F, Bor C, Mery<br />
E, Maisongrosse V, Génin P, Jacquemier J, Reyre J, Caveriviere P,<br />
Quintyn-Ranty M-L, Escourrou G, Mesleard C, Lemonnier J, Martin<br />
A-L, Campone M. Institut Claudius Regaud, Toulouse, France;<br />
Institut de Pathologie et de Génétique, Gosselies, Belgium; Centre<br />
Jean Perrin, Clermont-Ferrand, France; Centre Francois Baclesse,<br />
Caen, France; Centre Alexis Vautrin, Vandoeuvre les Nancy, France;<br />
Institut Paoli Calmettes, Marseille, France; Laboratoire Anatomie<br />
et de Cytologie des Feuillants, Toulouse, France; CHU Rangueil,<br />
Toulouse, France; R&D Unicancer, Paris, France; ICO Centre René<br />
Gauducheau, Saint Herblain, France<br />
Background: The PACS08 trial aimed to compare adjuvant FEC100-<br />
Docetaxel regimen to FEC100-Ixabepilone (Ixa) in poor prognosis<br />
early breast cancer (BC). The study population included BC<br />
patients presenting with triple-negative (TN) [i.e. estrogen receptor<br />
(ER)-/progesterone receptor (PR)-/HER2-] or ER+/PR-/HER2-<br />
tumor, which are subgroups significantly associated with worse<br />
prognosis. Central review was performed and detailed pathological<br />
characteristics of the cohort are reported herein.<br />
Patients and method: Between 2007 and 2010, 762 patients with<br />
unilateral TNBC (n=592, 78%) or ER+/PR-/HER2- BC (n=170, 22%)<br />
were enrolled. Recruitment was interrupted due to BMS decision to<br />
stop Ixa development in adjuvant setting. As defined by inclusion<br />
criteria, TNBC were either node+ or node-, and ER+/PR-/HER2-<br />
BC only node+. Following the validation of ER, PR and HER2<br />
status on whole sections prior to inclusion, paraffin blocks (n=754)<br />
were sent for central pathology review, tissue microarray (TMA)<br />
construction and constitution of the trial collection for translational<br />
research studies. Review of the cases (n=754) was performed by a<br />
board of expert breast pathologists on a one-week working session<br />
with discussion of the difficult cases under a multihead microscope.<br />
Tumor characteristics were assessed on whole tissue sections.<br />
Immunohistochemical detection of Ki67, EGFR, cytokeratins<br />
(CK)5/6 and 14, was performed on TMAs.<br />
Results: TNBC were significantly associated with younger age at<br />
diagnosis (median age 51yr vs 57.5yr in the ER+/PR- subgroup,<br />
p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
“all-high” expression group /n=70/; 5) CLDN3-low (CLDN4, -7<br />
and ECDH-high) group /n=68/ and 6) “all-low” group /n=15/. The<br />
latter was characterised by the CLDN4-low feature as compared to<br />
the other groups.<br />
Conclusion: Expression of JPs can have prognostic relevance in breast<br />
carcinomas. The groups with low expression of ECDH have good<br />
prognosis, while gradually increasing JP expression outlines poor<br />
prognostic tumours. Strikingly the drop in all JPs expression - most<br />
likely resembling the claudin-low subtype - specifies the subgroup<br />
with the poorest outcome, which still remains an infrequent disease<br />
entity.<br />
Grant support: TÁMOP-4.2.2/B-10/1-2010-0013.<br />
P3-05-09<br />
The role of TGF-beta receptor type 3 in breast cancer progression<br />
Jovanovic B, Ashby WJ, Zijlstra A, Pietenpol JA, Moses HL.<br />
Vanderbilt University, Nashville, TN<br />
<strong>Breast</strong> cancer is a diverse group of diseases. Gene expression profiling<br />
has identified luminal A, luminal B, Her2-like, Normal breast-like<br />
and Basal-like as major classifications of breast cancer diseases.<br />
These correlate to the overall patient survival with the basal-like<br />
subtype, clinically termed as triple-negative breast cancers (TNBC),<br />
demonstrating the poorest overall outcome. The poor patient outcome<br />
is primarily due to absence of hormonal receptor targets ER, PR<br />
and HER2 which are the major drug-targets for currently available<br />
therapies. Considering that TNBC lacks well-defined molecular<br />
targets, our group pursued extensive genomic molecular and<br />
biological analysis of over 500 tumor tissues from TNBC patients.<br />
Ultimately, this led to the discovery of six, TNBC subtypes; among<br />
which are Mesenchymal-Stem Like (MSL) and Mesechymal (M).<br />
These two subtypes share a unique biological driver, the TGF-beta<br />
pathway.<br />
To gain insight into the role of the TGF-β pathway signaling in<br />
TNBC we have performed gene expression analysis on all six<br />
TNBC subtypes. A major finding was that among all TGF-β<br />
pathway-associated genes, TGF-beta receptor type 3 (TBR3) is most<br />
differentially expressed in MSL and M tumor subtypes of TNBC.<br />
Based on these findings, we are hypothesizing that TBR3 is required<br />
for maintenance of tumorigenicity in MSL and M subtypes of the<br />
triple-negative breast cancer.<br />
In order to test our hypothesis we have screened 15 TNBC cell lines<br />
for both RNA and protein levels of TBR3 and validated that TBR3<br />
is differentially expressed in M and MSL subtypes. Furthermore,<br />
we have manipulated TBR3 expression in M and MSL TNBC cell<br />
lines and tested their ‘biologies’ using both an in vitro and in vivo<br />
model systems. Preliminary results indicate that upon silencing TBR3<br />
expression, cell motility as well as ability to cluster together in 3D<br />
culture system is significantly changed. In addition, our xenograft<br />
mouse model also demonstrated a significant change in tumor onset<br />
and growth.<br />
We are interested in validating the prognostic and functional<br />
contribution of TBR3 to the breast cancer progression. The results<br />
of this study will provide insight into the potential use of the TGF-β<br />
signaling axis for prognostic or therapeutic utility in breast cancer<br />
patients.<br />
P3-06-01<br />
Hotspot mutations in PIK3CA are predictive for treatment<br />
outcome on aromatase inhibitors but not for tamoxifen<br />
Ramirez Ardila DE, Helmijr JC, Lurkin I, Look M, Ruigrok-Ritstier<br />
K, Simon I, Van Laere S, Sweep F, Span P, Linn S, Foekens J, Sleijfer<br />
S, Berns EMJJ, Jansen MPHM. Erasmus MC - Daniel den Hoed,<br />
Rotterdam, Zuid Holland, Netherlands; Agendia BV, Amsterdam,<br />
Netherlands; Antwerp University/Oncology Centre, GZA Hospitals<br />
St-Augustinus, Antwerp, Belgium; Radboud University Nijmegen<br />
Medical Center, Nijmegen, Netherlands; Netherlands <strong>Cancer</strong><br />
Institute, Amsterdam, Netherlands<br />
Introduction: PIK3CA is the most frequent (30%) mutated oncogene<br />
in breast cancer and may lead to an activation of the PI3K/AKT/<br />
mTOR-pathway. Cell lines resistant to tamoxifen have an activated<br />
PI3K-pathway. Phase III clinical trials show substantial benefit when<br />
mTOR-inhibitors are added to aromatase inhibitor treatment. On<br />
the other hand, patients with PIK3CA exon 20 mutation expression<br />
signature show better treatment outcome after adjuvant tamoxifen<br />
therapy. To address this controversy, we evaluated the PIK3CA<br />
mutation status in 1423 primary breast cancer specimens for its<br />
relationship with prognosis and treatment outcome after first-line<br />
endocrine treatment.<br />
Methods: Hotspot mutations in exon 9 and 20 of PIK3CA were<br />
detected by multiplex snapshot analyses. Mutation status in ERpositive<br />
tumors was related to metastasis free survival (MFS) in<br />
292 untreated lymph node negative (LNN) patients and time to<br />
progression (TTP) in patients with metastatic disease treated with<br />
first-line tamoxifen (N=482) or aromatase inhibitors (AIs; N=103).<br />
Whole genome mRNA and miRs expression profiling was performed<br />
in the latter patient subset to develop a PIK3CA gene signature in<br />
64 specimens. This was validated in 28 independent ER-positive<br />
specimens.<br />
Results: We could evaluate 1371 specimens and detected 437 hotspot<br />
mutations for PIK3CA (32%). Mutations in exon 20 were detected in<br />
256 patients (59%), of which 40 cases with a H1047L (16%) and 216<br />
with a H1047R (84%) mutation. Mutations in PIK3CA exon 9 were<br />
discovered in 174 patients (41%), with E542K and E545K mutations<br />
in 59 (34%) and 105 (60%) cases, respectively, as the most prevalent<br />
ones. Finally, 6 patients had PIK3CA double mutations for both exon<br />
9 and 20 and one patient had a E542K and E545K mutation.<br />
Evaluation of the untreated LNN patients for prognosis showed no<br />
relationship between MFS and PIK3CA mutations (HR= 1.07 [95%<br />
CI: 0.73-1.56]; P=0.73), neither for exon 9 nor exon 20 compared to<br />
wild-type. In the multicenter cohort of 482 patients with advanced<br />
disease treated with first-line tamoxifen no link with treatment<br />
outcome and PIK3CA mutation status was observed (HR= 1.13 [95%<br />
CI: 0.92-1.38]; P=0.24). However, patients with advanced disease<br />
treated with first-line AIs (N=64) showed a significant longer TTP<br />
for patients with a PIK3CA mutation compared to wild-types (HR=<br />
0.46 [95% CI: 0.25-0.87]; P=0.017).<br />
Expression profiles of mRNAs and miRs were integrated and<br />
resulted in signatures for PIK3CA status discovered by pathway (17<br />
genes) and expression analyses (10 genes and 9 miRs). Validation<br />
and comparison with published signatures in the 28 independent<br />
tumors showed that our 10-genes signature had the highest PIK3CA<br />
prediction accuracy (75%), with 60% sensitivity and 78% specificity.<br />
Moreover, this signature better associates with TTP (HR= 0.38 [95%<br />
CI: 0.20-0.72]; P = 0.003).<br />
Conclusion: Mutations in PIK3CA are not prognostic value in<br />
untreated ER-positive LNN patients, not predictive in ER-positive<br />
patients with advanced disease treated with first-line tamoxifen<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
therapy, however, are predictive for favourable outcome after first-line<br />
AIs. Moreover, we propose an expression signature of 10 genes as<br />
a putative biomarker to predict the PI3K status and response to AIs.<br />
P3-06-02<br />
Genetic polymorphisms from genome-wide association study<br />
associated with the metabolic and cell proliferation pathways<br />
affect the time to distant metastases of hormone receptor-positive<br />
and Her2-negative early breast cancer<br />
Huang C-S, Kuo S-H, Yang S-Y, Lien H-C, Lin C-H, Lu Y-S, Cheng<br />
A-L, Chang K-J. National Taiwan University Hospital and National<br />
Taiwan University College of Medicine, Taipei, Taiwan; College of<br />
Public Health, National Taiwan University, Taipei, Taiwan<br />
Background:<br />
Single nucleotide polymorphisms (SNPs) identified from genomewide<br />
association study (GWAS) have been found to be associated<br />
with breast cancer risk. We hypothesized that candidate genes and<br />
genes derived from GWAS involving in the Estrone/Estradiol (E2)/<br />
Tamoxifen biosynthesis may influence the adjuvant hormonal therapy<br />
effect and the survival. In this study, we sought to investigate whether<br />
these SNPs are associated with prognosis of hormone receptor (HR)-<br />
positive breast cancer patients, especially in HER2-negative patients.<br />
Patients and methods:<br />
We selected breast cancer susceptibility SNPs identified by GWAS,<br />
SNPs in tamoxifen metabolizing related genes, and SNPs in estrogen<br />
receptor genes and estrogen metabolism genes, and genotyped for<br />
variations of above genes, including ALDH3A1, CYP2C19, COMT,<br />
CYP19, MAP3K1, FGFR2, TNRC9, HCN1, ERCC4, CYP3A5,<br />
UGT1A1, ER, ABCG2, CYP2B6, CYP2D6, 5p12 in 171 hormone<br />
receptor-positive, and Her2-negative early breast cancer patients<br />
(127 with negative lymph node [LN], and 44 with 1-3 positive LN).<br />
All patients received adjuvant hormonal therapy. The associations<br />
were examined between SNPs and distance disease-free survival<br />
(DDFS), and overall survival (OS) by using the log-rank test and<br />
Cox’s proportional hazard model. Furthermore, we combined<br />
clinicopathologic features and SNPs into the risk score analysis to<br />
further validate above identified genetic markers.<br />
Results:<br />
We found that SNPs of CYP2B6 (rs3211371), FGFR2 (rs2981582),<br />
and MAP3K1 (rs889312) were significantly associated with DDFS<br />
and OS. Furthermore, in lymph node-negative patients, CYP2B6<br />
(rs3211371), FGFR2 (rs2981582), MAP3K1 (rs889312) and 5p12<br />
(rs10941679 and rs4415084) were significantly associated with DDFS<br />
and OS, while CYP3A5 (rs776746) was significantly associated with<br />
OS but not DDFS. We further assessed the associations of disease<br />
prognosis with the number of high-risk genotypes in CYP3A5,<br />
FGFR2, and MAP3K1, and showed significant dose-response<br />
relationships between the number of high-risk alleles at these 3 loci<br />
and DDFS (P = 0.005 for trend) and OS (P = 0.0008 for trend). When<br />
combining the clinicopathologic features and SNPs into the risk<br />
score analysis, patients were divided into 3 subgroups (subgroup 1,<br />
risk score1.708, n=43 [LN-positive, n=11]). We found that around 20 %<br />
of subgroup 3 patients had early development of distant metastases<br />
(DM) in the upfront 3 years (the trend of DM appeared to persist at<br />
least 10 years), and subgroup 2 patients had higher risk of DM after<br />
5 years, whereas subgroup 1 patients had no development of DM<br />
even after 12 years.<br />
Conclusion:<br />
Our results indicate that in addition to drug metabolic genes, genes<br />
related to cell proliferation, anti-apoptosis, and signaling transduction,<br />
for example, CYP3A5, CYP2B6, FGFR2, and MAP3K1 genes were<br />
associated with DDFS and OS in HR-positive/Her2-negative breast<br />
cancer patients. These findings provide additional insight that the<br />
genetic variants, or host factors, may affect the prognosis of breast<br />
cancer.<br />
P3-06-03<br />
Association between PAM50 breast cancer intrinsic subtypes and<br />
effect of gemcitabine in advanced breast cancer patients<br />
Jørgensen CLT, Nielsen TO, Bjerre KD, Liu S, Wallden B, Balslev<br />
E, Nielsen DL, Ejlertsen B. Herlev University Hospital, Herlev,<br />
Denmark; Danish <strong>Breast</strong> <strong>Cancer</strong> Cooperative Group, Copenhagen,<br />
Denmark; University of British Columbia, Vancouver, BC, Canada;<br />
NanoString Technologies, Seattle, WA<br />
Background<br />
<strong>Breast</strong> cancer can be subclassified into luminal A and B, basal-like<br />
and HER2-enriched subtypes, each with distinct biology, prognosis<br />
and response to therapy. Pre-clinical studies have suggested that a<br />
basal-like subtype is associated with responsiveness to gemcitabine.<br />
Additional data suggest that patients with highly proliferating tumors<br />
(non-luminal A) might be particularly responsive to gemcitabine.<br />
We examined these hypotheses on SBG0102, a randomized trial<br />
comparing gemcitabine plus docetaxel (GD) to single agent docetaxel<br />
(D) in patients with advanced breast cancer. Secondarily, we analyzed<br />
prognosis by PAM50 subtype, which has not previously been<br />
addressed in a metastatic setting.<br />
Patients and Methods<br />
RNA was isolated from archival formalin-fixed, paraffin-embedded<br />
primary breast tumor tissue from patients randomly assigned to<br />
GD or D, and analyzed with NanoString Technologies’ nCounter<br />
system and PAM50 intrinsic subtyping algorithm. Using time to<br />
progression (TTP) as primary endpoint, overall survival (OS) and<br />
response rate (RR) as secondary endpoints, relationships between<br />
subtypes and outcome after chemotherapy were analyzed by methods<br />
prespecified in writing as a formal prospective-retrospective clinical<br />
trial correlative study. Data analysis was performed independently<br />
by the DBCG statistical core.<br />
Results<br />
RNA from 270 patients was evaluable. 84 patients (31%) were<br />
classified as luminal A, 97 (36%) luminal B, 43 (16%) basal-like,<br />
and 46 (17%) as HER2-enriched. PAM50 intrinsic subtype was<br />
significantly associated with TTP (P=.0006) and OS (P=.0083) by<br />
Kaplan-Meier analysis. In the adjusted Cox model PAM50 remained<br />
independently prognostic. RR was not significantly different by<br />
subtype, and PAM50 was not a significant predictor of TTP by<br />
treatment arm. PAM50 was however a highly significant predictor of<br />
OS following GD compared to D (P interaction =.0008). The 43 patients<br />
with a basal-like subtype had a significant reduction in OS events<br />
(hazard ratio (HR)=0.27; 95% CI 0.14-0.52; P interaction =.0004), although<br />
TTP events were not significant by interaction test (HR=0.37; 95%<br />
CI 0.18-0.76; P interaction =.19). Kaplan-Meier estimates revealed a<br />
gain in median OS of 10 months in the doublet arm compared to<br />
the monotherapy arm (18.7 (95% CI, 12.4-23.0) v 8.5 (95% CI,<br />
4.2-11.8) months).<br />
Conclusion<br />
A significantly improved and clinical important prolongation of<br />
survival was seen from the addition of gemcitabine to docetaxel in<br />
advanced basal-like breast cancer patients. However, we could not<br />
www.aacrjournals.org 307s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
show a similar significant reduction in TTP events. These results need<br />
validation in a second similar trial or a prospective study stratified<br />
for basal-like breast cancer to obtain convincing evidence that<br />
identification of a basal-like profile may be used to direct the use of<br />
gemcitabine in combination with docetaxel.<br />
P3-06-04<br />
Role of pMAPkinase, pAKT, p27 & IGF-IR as predictive markers<br />
of response to trastuzumab in patients with HER2-positive<br />
invasive breast cancer treated with neoadjuvant chemotherapy<br />
+ trastuzumab in the REMAGUS02 trial<br />
Mathieu MC, Goubar A, Sigal B, Bertheau P, Guinebretière JM, André<br />
F, Pierga JY, Delaloge S, Giacchetti S, Brain E, Marty M. Institut<br />
Gustave Roussy - INSERM U981, Villejuif, France; Institut Curie,<br />
Paris, France; Hopital Saint-Louis, Paris, France<br />
Background: Predicting a benefit from trastuzumab in patients with<br />
HER2+ breast cancer remains an important goal. Possible mechanisms<br />
of resistance include altered receptor antibody interaction, Akt and<br />
MAPK pathways, and loss of p27. The objective of this study was to<br />
determine the correlation between pMAPkinase (pMAPK), pAKT,<br />
p27, IGF-IR protein expression and the benefit of trastuzumab for<br />
patients randomized to chemotherapy (CT) alone and CT with<br />
trastuzumab.<br />
Patients and methods: From May 2004 to October 2007, 120<br />
patients with stage II and III HER2+ breast carcinomas were<br />
enrolled in a phase II trial of neoadjuvant chemotherapy (CT) with<br />
epirubicin-cyclophosphamide (4 courses) followed by docetaxel<br />
± trastuzumab (T) (4 courses). A complete pathological response<br />
(pCR) was defined by the absence of residual invasive carcinoma<br />
in the breast and axillary lymph nodes. A tissue microarray was<br />
constructed from paraffin-embedded tumor samples collected prior to<br />
neoadjuvant chemotherapy. Patients’ tumours were scored HER2 3+<br />
immunohistochemically (IHC) or 2+ IHC with HER2 amplification<br />
by FISH. Immunohistochemical analysis of pMAPK, pAKT, p27 and<br />
IGF-IR was performed on tumor tissue microarrays before CT. The<br />
H-score (intensity x %) was evaluated. Specimens were classified<br />
as exhibiting high or low expression based on a median value as the<br />
cut-off point for each marker. A logistic regression model, including<br />
the marker and its interaction with treatment, was used to analyse the<br />
markers predictive of a treatment effect on the pCR. The independent<br />
predictive value was analysed in a multivariate logistic regression<br />
adjusting on the lymph node and ER status.<br />
Results: 117/120 (97.5%) patients had sufficient tumor for the<br />
analysis. The pCR rate was 19% in the CT arm and 25% in the CT+T<br />
arm. The median H-score was : pMAPK = 28, pAKT= 25, p27= 50 and<br />
IGF-IR = 15. No significant difference was observed in the pCR rate<br />
between the two arms according to pAKT, p27, IGF-IR expression.<br />
The pCR rate was higher in CT+T compared to CT alone in patients<br />
with high pMAPK expression (OR= 4.7 (0.9- 24.2); interaction p =<br />
0.03). No difference was observed in the pCR rate in patients with<br />
low pMAPK expression (OR= 0.5 (0.1- 1.8).<br />
Conclusions: In HER2-positive breast cancers, pMAPK expression<br />
evaluated by IHC was significantly associated with a pathological<br />
response in the arm with neoadjuvant trastuzumab. High pMAPK<br />
expression could be a predictive marker of response to trastuzumab<br />
in a CT +T regimen.<br />
P3-06-05<br />
Expression of SPARC in human breast cancer and its predictive<br />
value in the GeparTrio neoadjuvant trial.<br />
Untch M, Prinzler J, Fasching P, Müller BM, Gade S, Meinhold-<br />
Heerlein I, Huober J, Karn T, Liedtke C, Loibl S, Müller V, Rack<br />
B, Schem C, Darb-Esfahani S, von Minckwitz G, Denkert C. Helios<br />
Klinikum Berlin-Buch, Germany; Charité Universitätsmedizin<br />
Berlin, Germany; Universitätsklinikum Erlangen, Germany; German<br />
<strong>Breast</strong> Group, Germany; Universitätsklinikum Aachen, Germany;<br />
Universitätsklinikum Düsseldorf, Germany; Universitätsklinikum<br />
Frankfurt am Main, Germany; Universitätsklinikum Münster,<br />
Germany; Universitätsklinikum Hamburg-Eppendorf, Germany;<br />
Universitätsklinikum München; Universitätsklinikum Schleswig-<br />
Holstein, Germany<br />
Background: Secreted protein acidic and rich in cysteine (SPARC)<br />
is an albumin-binding protein and associated with poor prognosis in<br />
multiple cancers.<br />
The aim of this analysis was to determine the frequency of SPARC<br />
expression among different molecular breast cancer subtypes and to<br />
evaluate its predictive value for therapy response after neoadjuvant<br />
anthracycline/taxane based chemotherapy (CTX) in participants of<br />
the GeparTrio trial.<br />
Methods: We evaluated tumoral SPARC expression by<br />
immunohistochemistry on tissue microarrays (TMAs) constructed<br />
from formalin-fixed paraffin-embedded (FFPE) pre-treatment core<br />
biopsies from 667 patients (pts) of the GeparTrio trial. The details of<br />
the GeparTrio study design are described elsewhere (von Minckwitz,<br />
JNCI 2008). Cutoffs for SPARC expression were determined using the<br />
web-based software Cutoff Finder (http://molpath.charite.de/cutoff/).<br />
Results: SPARC protein expression was measurable by IHC on<br />
the TMAs and 176 (26.4 %) of 667 tumors were SPARC positive.<br />
SPARC expression was increased in pts with triple-negative breast<br />
cancer (TNBC) compared to hormone receptor or HER2 positive<br />
subtypes (p = 0.039).<br />
SPARC positivity was associated with an increased pCR rate in the<br />
overall population (p < 0.001). SPARC negative tumors had a pCR<br />
rate of 15%, which increased to 27% in SPARC positive tumors.<br />
Similarly, in TNBC the pCR rate increased from 26% in SPARC<br />
negative tumors to 47% in SPARC positive tumors (p = 0.032).<br />
In multivariate logistic regression analysis adjusted for standard<br />
clinicopathological factors, SPARC was independently predictive<br />
in the overall population (p = 0.010) as well as the subgroups of pts<br />
with TNBC (p = 0.036).<br />
Conclusions: SPARC is expressed in all biological breast cancer<br />
subtypes with TNBC revealing the highest expression rate. Our data<br />
suggest that SPARC expression may provide predictive information<br />
for response to neoadjuvant CTX.<br />
As SPARC is an albumin-binding protein and might mediate<br />
intratumoral accumulation of nab-Paclitaxel, prospective analysis of<br />
SPARC expression is planned in the GeparSepto trial.<br />
P3-06-06<br />
Lactate dehydrogenase B in breast cancer contributes to glycolytic<br />
phenotype and predicts response to neoadjuvant chemotherapy<br />
Dennison JB, Molina JR, Mitra S, Gonzalez-Angulo AM, Brown RE,<br />
Mills GB. MD Anderson <strong>Cancer</strong> Center, Houston, TX; University of<br />
Texas Health Science Center, Houston, TX<br />
Purpose: Although breast cancers are known to be molecularly<br />
heterogeneous, their metabolic heterogeneity is less well understood.<br />
This study aimed to identify and evaluate metabolic biomarkers in<br />
breast cancers and determine their ability to predict outcomes.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
308s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
Methods: mRNA microarray data from breast cancer cell lines were<br />
used to identify bimodal genes, those with the highest potential for<br />
robust high/low classification in a clinical setting. Using a panel of<br />
breast cancer cell lines, expression and activity of the highest scoring<br />
bimodal metabolism gene, lactate dehydrogenase B (LDHB), was<br />
quantified and associated with glycolytic phenotype. The contribution<br />
of LDHB to glycolysis was evaluated using MDA-MB-231 and<br />
HCC1937 cell lines with stable lentiviral knockdown of LDHB.<br />
mRNA expression of LDHB was evaluated for association with<br />
neoadjuvant chemotherapy response within clinical and PAM50-<br />
derived subtypes.<br />
Results: LDHB was highly expressed in cell lines with glycolytic,<br />
basal-like phenotypes. Knockdown of LDHB in cell lines reduced<br />
glycolytic dependence, linking LDHB expression directly to<br />
metabolic function. Using four independent patient datasets, LDHB<br />
mRNA expression was positively associated with basal subtype and<br />
negatively associated with luminal and HER2 subtypes. Furthermore,<br />
LDHB predicted basal phenotype independently of hormone-receptor<br />
(HR) clinical status (OR = 21.6 for HR-positive/HER2-negative<br />
and OR = 18.2 for triple-negative). While LDHB expression could<br />
predict basal phenotype, high LDHB expression identified aggressive<br />
breast cancer tumors that were primarily but not exclusively basal.<br />
Importantly, high LDHB expression predicted pathological complete<br />
response to neoadjuvant chemotherapy for both hormone receptor<br />
(HR) positive/HER2-negative (OR = 4.0, P = .0002) and triplenegative<br />
(OR = 3.0, P = .003) cancers. Consistent with increased<br />
response to chemotherapy, LDHB expression in basal cancers within<br />
the triple-negative group was associated with the proliferative marker<br />
CCNB1 (P < .0001).<br />
Conclusion: mRNA expression of LDHB as a single marker predicted<br />
glycolytic phenotype in cell lines and response to neoadjuvant<br />
chemotherapy in breast cancers independently of HR status. These<br />
observations support prospective clinical evaluation of LDHB as a<br />
predictive marker of response for breast cancer patients treated with<br />
neoadjuvant chemotherapy.<br />
P3-06-07<br />
Ki67 as a Predictive Marker of Response to Neoadjuvant<br />
Chemotherapy in Patients with Early-Stage <strong>Breast</strong> <strong>Cancer</strong><br />
(ESBC): A Systematic Review and Evidence Summary<br />
Lyman GH, Culakova E, Poniewierski MS, Wogu AF, Barry W,<br />
Ginsburg GS, Marcom PK, Ready N, Abernethy A, Geradts J, Hwang<br />
S, Kuderer NM. Duke University<br />
Background: Immunohistochemical (IHC) assessment of the<br />
proportion of cells staining for the KI67 nuclear antigen is being<br />
increasing utilized in the management of patients with early-stage<br />
breast cancer (ESBC). A comprehensive systematic review and<br />
evidence synthesis of biomarkers potentially predictive of response to<br />
systemic therapy was initiated as a part of an NCI-funded comparative<br />
effectiveness research program.<br />
Methods: Studies of chemotherapy response prediction based on<br />
baseline IHC assessment of Ki67 in patients with ESBC receiving<br />
neoadjuvant systemic therapy were identified. Response was specified<br />
as pathologic complete response (pCR) or clinical response (ClinR).<br />
Assay predictive performance for response was assessed on the basis<br />
of sensitivity, specificity, predictive value and predictive odds ratio<br />
(POR±95%CLs) utilizing mixed effects models. Study results were<br />
fitted in an ROC analysis based on the method of DerSimonian and<br />
Laird. Publication bias was evaluated on the basis of funnel plot<br />
asymmetry assessed by Egger’s regression intercept and Begg and<br />
Mazumdar’s rank correlation.<br />
Results: Of 469 potentially eligible studies, dual blind full text review<br />
identified 42 eligible studies reporting 44 independent cohorts with<br />
6,716 patients (21–979). While Ki67 cutpoints varied considerably,<br />
they were most commonly between 10%-30% (median 20%, range<br />
1-50%). The analysis prsented here is limited to the 30 studies of<br />
ESBC patients (N=3,343) receiving neoadjuvant therapy of which<br />
14 reported fewer than 100 patients. The proportion of patients with<br />
elevated Ki67 across studies ranged from 0.20-0.92 (median=0.54).<br />
Sensitivity and specificity for treatment response in patients with high<br />
vs. low baseline Ki67 was 0.65 [0.61, 0.68] and 0.52 [0.50, 0.54],<br />
respectively. Estimated response rates across studies in patients with<br />
high vs. low Ki67 were 31% [29%, 34%] and 19% [17%, 21%],<br />
respectively. The estimated POR for response across studies was<br />
2.82 [2.14, 3.72; P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
bead-based extraction method (STRATIFYER XTRAKT kits). Ki-67,<br />
TOP2A and RACGAP1 as well as CALM2 as a house keeping gene<br />
were measured via a multiplex quantitative RT-PCR (qPCR). Kaplan-<br />
Meier survival estimates, patitioning test and correlation analyses<br />
were performed using the SAS JMP® 9.0.0 software.<br />
Results<br />
There was only a moderate correlation between Ki-67 mRNA or<br />
Ki-67 measured by immunohistochemistry (IHC) and histologic<br />
grade (Spearman r=0.52 p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
associated with achievement of pCR in univariable analysis (OR<br />
1.01, 95% CI 0.96, 1.05) and after adjustment for hormone receptor<br />
status (HRS; OR 1.02, 95%CI 0.97, 1.07), tumor grade (OR 1.01,<br />
95%CI 0.96, 1.06), Ki67 (OR 1.02, 95%CI 0.97, 1.07) or BMI (OR<br />
1.00, 95%CI 0.96, 1.05). Vitamin D was independently associated<br />
with Ki67 (OR 0.95, 95%CI 0.91, 0.99). Vitamin D level was also<br />
not associated with 3 year RFS in univariable analysis (HR 0.98, 95%<br />
CI 0.95, 1.02), and after adjustment for HRS (HR 0.99, 95%CI 0.95,<br />
1.03), tumor grade (HR 0.99, 95%CI 0.95, 1.02), Ki-67 (HR 0.99,<br />
95%CI 0.95, 1.03), BMI (HR 0.96, 95% CI 0.92, 1.01) or pCR (HR<br />
0.99, 0.95, 1.02); no interaction was seen when stratifying on HRS<br />
(p-interaction= 0.71).<br />
Conclusions: The majority of patients in this study had insufficient<br />
vitamin D levels (2, and deletion was defined as FISH ratio
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
1. Multivariate analyses of age, nodal status, ER status, and gene<br />
expression shown below in Table 2 indicate that neither cMYC nor<br />
TOP2A status had an effect on outcome. Only nodal and ER status<br />
affected outcome.<br />
Table 1<br />
Parameter n 3-Yr DFS (%) 3-Yr OS (%)<br />
TOP2A Amplified 190 97.1 98.5<br />
Normal 130 97.6 98.5<br />
Deletion 118 94.8 97.9<br />
cMYC Amplified 99 96.8 99.00<br />
Normal 246 97.8 99.6<br />
Deletion 91 94.2 96.0<br />
ER Status Positive 320 98.3 99.4<br />
Negative 173 93.7 97.0<br />
Positive Node Yes 102 92.9 97.1<br />
No 391 97.8 98.9<br />
Table 2. Summary of Multivariate Analysis<br />
Parameter Hazard Ratio p-value<br />
Age Every Year 1.03 0.26<br />
TOP2A Amp. vs. Not-Amp 0.96 0.95<br />
cMYC Amp. vs.Not-Amp 1.01 0.99<br />
Nodes Positive vs. Negative 2.87 0.06<br />
ER Positive vs. Negative 0.33 0.05<br />
T status T2/T3 vs. T1 2.06 0.20<br />
Conclusion:<br />
Outcome (DFS + OS) in a phase II study of a nonanthracycline<br />
regimen (TC) coupled with H was unaffected by cMYC or TOP2A<br />
gene copy number status. Only ER and nodal status showed an effect<br />
in a multivariate analysis.<br />
P3-06-13<br />
Expression of Phosphorylated Activating Transcription factor<br />
2 (ATF2) is associated with sensitivity to endocrine therapy in<br />
breast cancer<br />
Palmieri C, Rudraraju B, Abdel-Fatah TMA, Moore DA, Shaw J,<br />
Green A, Ellis IO, Coombes RC, Simak A. Imperial College London,<br />
United Kingdom; Nottingham University City Hospital, Nottingham,<br />
United Kingdom; University of Leicester, United Kingdom<br />
Background<br />
The Activating Transcription Factor 2 (ATF2) gene is a member of<br />
the ATF and CREB group of bZIP transcription factors. It is involved<br />
in in transcriptional control, chromatin remodelling and the DNA<br />
damage response. Two threonine residues (Thr69 and Thr71) within<br />
the activation domain (AD) are important for its transcriptional<br />
activation and high pThr69/pThr71-ATF2 has been correlated with<br />
a well-differentiated phenotype in breast cancer (BC). In this study<br />
the protein expression of ATF2 & pThr71-ATF2 (pATF2) and its<br />
association with clinico-pathological features and outcome in a well<br />
defined BC series were studied.<br />
Methods<br />
The expression of ATF2 and pATF2 was assessed in the Nottingham<br />
Tenovus Primary <strong>Breast</strong> <strong>Cancer</strong> Series which consists of 1650 cases<br />
of primary invasive BC. ATF2 and pATF2 were correlated with<br />
clinico-pathological data as well as outcome in those high risk cases<br />
(NPI>3.4) based on exposure to tamoxifen.<br />
Results<br />
A total of 1351 tumours were suitable for analysis of both ATF2<br />
and pATF2; 436/1351 (32%) of BC co-expressed ATF2 and pATF2<br />
while 414/1351(31%) were negative for both ATF2 and pThr71-<br />
ATF2. Co-expression ATF2 and pATF2 was highly significantly<br />
associated luminal breast cancer phenotype, well differentiation,<br />
low proliferation (low mitotic index, low Ki67 and low SPAG5;<br />
ps
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
discovery cohort, the signature showed positive predictive value<br />
(PPV; i.e., cumulative relapse rate of patients predicted to relapse<br />
in 3 years) of 95.4% and negative predictive values (NPV; i.e.,<br />
relapse-free survival of patients predicted not to relapse in 3 years)<br />
of 100%. In the validation cohort, the classifier predicted correctly<br />
with PPV of 75.0% and NPV of 76.9% at 3 years. Compared with<br />
patients predicted not to relapse, those predicted to relapse had a<br />
hazard ratio of 3.37 (95% CI, 1.15-9.85) for disease recurrence or<br />
death in 3 years. In an extended validation cohort of 269 patients, our<br />
signature discriminated chemoresistant TNBC in overall cohort (PPV,<br />
52.4%; NPV, 77.7%; log rank P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
was significantly associated with higher pCR rate(19.5 vs 73.2%;<br />
p=0.026; in patients with p53- and p53+ breast cancer). In a<br />
multivariate regression analysis, after adjusting for tumor and node<br />
status, treatment administered, p53 status maintained an independent<br />
predictive role for pCR.[relative risk(RR)=6.247, 95% confidence<br />
interval (CI)=0.9-39.1] In our homogeneous patient population, pCR<br />
was not associated with initial clinical stage, nodal status as well<br />
as other clinicopathologic factors. The status of the p53, which is<br />
mutated in a high percentage of breast tumors, is a predictive factor<br />
for cytotoxic drug activity. By contrast, bcl-2 failed to be related to<br />
chemotherapy activity.<br />
P3-06-17<br />
Withdrawn by Author<br />
P3-06-18<br />
Increase of serum androgen and its metabolites in postmenopausal<br />
primary breast cancer patients with disease progression during<br />
neo-adjuvant exemestane treatment; JFMC 34-0601 TR<br />
Takada M, Saji S, Honma N, Masuda N, Yamamoto Y, Kuroi K,<br />
Yamashita H, Ohno S, Aogi K, Ueno T, Toi M. Graduate School<br />
of Medicine, Kyoto University, Kyoto, Japan; Tokyo Metropolitan<br />
Institute of Gerontology, Tokyo, Japan; Osaka National Hospital,<br />
Osaka, Japan; Kumamoto University Hospital, Kumamoto, Japan;<br />
Tokyo Metropolitan Canwithdrcer and Infectious Diseases Center,<br />
Komagome Hospital, Tokyo, Japan; Hokkaido University, Sapporo,<br />
Japan; National Hospital Organization Kyushu <strong>Cancer</strong> Center,<br />
Fukuoka, Japan; National Hospital Organization Shikoku <strong>Cancer</strong><br />
Center, Ehime, Japan<br />
BACKGROUND: We reported a positive correlation between body<br />
mass index (BMI) and clinical response to neo-adjuvant hormonal<br />
therapy (NAH) with steroidal aromatase inhibitor, exemestane, in<br />
post-menopausal breast cancer patients (Takada M et al. <strong>Breast</strong> 2012).<br />
Here, we examined the relationship between serum concentrations<br />
of sex steroids and BMI, and explored their predictive value for<br />
clinical response.<br />
PATIENTS AND METHODS: Among the 116 post-menopausal<br />
patients enrolled in the JFMC 34-0601 clinical trial of 24 weeks (wks)<br />
of NAH with exemestane, serums from 60 patients at pre-treatment,<br />
at 4wks and end of the treatment (24wks) were subjected to this<br />
study. Estradiol (E2), estrone (E1), dehydroepiandrosterone (DHEA),<br />
androstenedione (A-dione), 5-androstene-3β, 17β-diol (Aenediol),<br />
5α-androstane-3β, 17β-diol (Aanediol) were measured using LC-MS/<br />
MS analysis and E1- sulfate (E1S) was by RIA.<br />
RESULTS: There were no significant correlations between pretreatment<br />
concentrations of sex steroids and BMI, except for moderate<br />
correlation of E2 and BMI (p=0.004). In multivariate analysis, E1 was<br />
an independent predictive factor for objective response [odds 6.0, 95%<br />
confidence interval (CI) 1.5 — 34.6, p=0.011], as well as BMI. All of<br />
the estrogens decreased to under-detection levels (0.5 for E1 and E2,<br />
5 pg/assay for E1S) at 4 wks of treatment, and maintained through to<br />
the end of treatment in almost all patients independently of clinical<br />
response. The geometric mean percentage changes in androgens after<br />
NAH were: DHEA -0.2% (95%CI -15.3% — +17.6%) for patients<br />
without progressive disease (non-PD) and +44.8% (95%CI +22.1%<br />
— +71.8%) for patients with progressive disease (PD); A-dione<br />
-2.3% (95%CI -17.3% — +15.4%) for non-PD and +45.6% (95%CI<br />
+28.3% — +65.3%) for PD; Aenediol -11.5% (95%CI -20.6% —<br />
-1.4%) for non-PD and +24.9% (95%CI +1.9% — +53.0%) for PD;<br />
Aanediol +21.3% (95%CI -5.5% — +55.8%) for non-PD and +56.3%<br />
(95%CI +5.3% — +132.0%) for PD, respectively. The changes in the<br />
concentrations of both DHEA and A-dione in patients with PD were<br />
statistically significant (p=0.008 and p=0.002, respectively). In all<br />
of the PD patients, the serum concentrations of DHEA and A-dione<br />
were increased after NAH.<br />
CONCLUSION: Pretreatment serum concentration of E1 was an<br />
independent predictive factor for clinical response to NAH with<br />
exemestane. Measurement of dynamics of the serum androgen<br />
concentrations might be helpful for monitoring treatment response,<br />
and mechanism of increase of androgens has a value for further<br />
investigation. Our results should be validated using a larger dataset.<br />
(UMIN ID; C000000345)<br />
P3-06-19<br />
Ki-67 mRNA as a predictor for response to neoadjuvant<br />
chemotherapy in primary breast cancer<br />
Aigner J, Schneeweiss A, Marme F, Eidt S, Altevogt P, Sinn P, Wirtz R.<br />
National Center for Tumor Diseases, University-Hospital Heidelberg,<br />
Germany; Institut of Pathology at the St.-Elisabeth-Hospital,<br />
Cologne, Germany; German <strong>Cancer</strong> Research Center, Heidelberg,<br />
Germany; University of Heidelberg, Germany; STRATIFYER<br />
MolecularPathology GmbH, Cologne, Germany<br />
Background<br />
Stratification of molecular subtypes is of outmost importance for<br />
clinical decision making according to the 12th St Gallen Consensus<br />
conference (1). The molecular subtypes were originally identified<br />
by genome-wide mRNA analysis of fresh tissue specimen (2).<br />
Conventional immunehistochemistry assessment using ER, PR ,<br />
HER2 and Ki67 approximate these subtypes with ∼ 80% concordance<br />
(3). Here we have tested a predefined Single-Sample-Predictor for<br />
molecular subtyping based on mRNA assessment of ESR1, PGR,<br />
HER2, Ki67 and RACGAP1 in a prospective-retrospective study<br />
design.<br />
Materials and Methods<br />
Pretreatment core cut biopsies from n=100 patients with PBC treated<br />
within a randomized phase II trial (1) of anthracylin/taxane based<br />
NAC were examined. Immunohistochemistry was performed for the<br />
Ki67 antigen on an automated IHC platform (Dako Techmate 500).<br />
Ki-67 were assessed either by visual scoring (vIHC) or by quantitative<br />
image analysis (qIHC). RNA from formalin-fixed, paraffin embedded<br />
(FFPE) routine biopsies was extracted using a bead-based extraction<br />
method (STRATIFYER XTRAKT kits). Fresh tissue samokes were<br />
prepared by using Qiagen kits. ESR1, PGR, HER2, Ki-67 and<br />
RACGAP1 as well as CALM2 as a house keeping gene were measured<br />
via a multiplex quantitative RT-PCR (qPCR). Stratification into<br />
molecular subtypes was done by stepwise analysis of singular genes<br />
using predefined cut-off values. Kaplan-Meier survival estimates,<br />
patitioning test and correlation analyses were performed using the<br />
SAS JMP® 9.0.0 software.<br />
Results<br />
Concordance between RNA based and IHC-based subtyping into<br />
Luminal A, Luminal B, HER2 positive and Triple Negative breast<br />
cancer by using ESR1, PGR, HER2, Ki-67 and RACGAP1 was at<br />
85%. mRNA based analysis of fixed tumor specimen performed<br />
equally well as fresh tissue analysis. The rate of pathological complete<br />
Remission for the predefined molecular subtypes has been for Luminal<br />
A 0%, Luminal B 19%, HER2 positive 21% (without Trastuzumab)<br />
und Triple Negative Tumors 22%. qPCR from fresh tissue specimen<br />
resulted in almost identical classifications. The 5-year overall survival<br />
rate was significantly different between subtypes as expected: Luminal<br />
A 100%, Luminal B 85%, HER2 positiv 80% und triple negativ 60%.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
314s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
Luminal tumors predominantly metastasized into the bones. <strong>Cancer</strong><br />
related deaths within the first three years were restricted tot he Triple<br />
negative Tumortype.<br />
Conclusion<br />
The Single-Sample-Predictor based on assessment of only five<br />
mRNA Markers (ESR1, PGR, HER2, Ki-67 and RACGAP1) reliably<br />
stratified into molecular subtypes by using either fixed or fresh<br />
pretreatment core needle biopsies. The mRNA based assessment<br />
enables objective and highly reproducible subtyping for clinical<br />
routine diagnostics.<br />
1) Goldhirsch et al., Annals of Oncology 2011<br />
2) Perou et al., Nature 2000<br />
3) Sotiriou&Pusztai, NEJM 2009<br />
4) Schneeweiss et al, Ann Oncol 2011<br />
P3-06-20<br />
Is it possible to predict the efficacy of a combination of<br />
Panitumumab plus FEC 100 followed by docetaxel (T) for patients<br />
with triple negative breast cancer (TNBC)? Final biomarker<br />
results from a phase II neoadjuvant trial.<br />
Nabholtz J-M, Dauplat M-M, Abrial C, Weber B, Mouret-Reynier<br />
M-A, Gligorov J, Tredan O, Vanlemmens L, Petit T, Guiu S, Jouannaud<br />
C, Tubiana-Mathieu N, Kwiatkowski F, Cayre A, Uhrhammer N,<br />
Privat M, Desrichard A, Chollet P, Chalabi N, Penault-Llorca F.<br />
Centre Jean Perrin, Clermont-Ferrand, France; Centre Alexis<br />
Vautrin, Vandoeuvre les Nancy, France; Hôpital Tenon, Paris, France;<br />
Centre Leon Berard, Lyon, France; Centre Oscar Lambret, Lille,<br />
France; Centre Paul Strauss, Strasbourg, France; Centre Georges<br />
François Leclerc, Dijon, France; Institut Jean Godinot, Reims,<br />
France; CHU Dupuytren, Limoges, France<br />
Background : TNBC is an heterogeneous group of tumors for some<br />
of which the Epithelial Growth Factor Receptor pathway (EGFR)<br />
may play an important role. We evaluated the efficacy and toxicity<br />
of an anti-EGFR antibody (panitumumab) combined with a standard<br />
neoadjuvant chemotherapy in order to identify predictive biomarkers<br />
of efficacy and target biologically defined subpopulations for potential<br />
further development.<br />
Methods : Sixty patients with stage II-IIIA disease were prospectively<br />
included in this multicentre neoadjuvant study. Systemic therapy (ST)<br />
consisted of panitumumab (9 mg/kg q.3 weeks x8) combined with<br />
FEC 100 (500/100/500 mg/m 2 q.3 weeks x4) followed by 4 cycles<br />
of T (100 mg/m 2 q.3weeks x4). All patients underwent surgery at<br />
completion of ST.<br />
Paraffin-embedded and frozen samples were systematically collected<br />
before and after ST for biologic studies.<br />
Patients characteristics are as follows : mean age 50 [27-72] ; median<br />
tumor size : 40 mm [20-120] ; invasive ductal carcinoma : 96.7% ;<br />
Scarff-Bloom-Richardson Grade III : 71.7%, grade II : 28.3%.<br />
Complete pathological response (pCR) rate was 52.3% [95% IC :<br />
37.3-67.5] (Sataloff’s classification) and 46.7% [95% IC : 31.6-61.4]<br />
(Chevallier’s classification). Conservative surgery was performed in<br />
88% of cases.<br />
Skin toxicity was the main side-effect : Cutaneous toxicity grade IV<br />
: 5%, grade III : 30%, grade II : 20%. Neutropenia grade IV : 27% ;<br />
febrile neutropenia : 5%. Infection : 0%. Hand-foot syndrome grade<br />
III : 3.3%. Ungueal toxicity grade III : 1.6%, grade II : 20%.<br />
Results :<br />
We performed a ROC curve to identify the best cut-off value for<br />
KI-67, EGFR, cytokeratin 5-6 and p53 in order to predict a pCR.<br />
Tumors with more than 40% of positive cells for KI-67 and tumors<br />
with a score for EGFR greater than 70 tend to be associated with<br />
pCR according to Chevallier’s classification (p=0.06). No predictive<br />
value was identified for Cytokeratin 5-6 and p53 (p=0.61 and p=0.27,<br />
respectively).<br />
Immunohistochemistry results show that two thirds of tumors have<br />
more than 40% of positive cells for KI-67 and that two thirds of<br />
tumors present a score for EGFR greater than 70.<br />
About half of the tumors express cytokeratin 5-6 and p53 (cut off: 1%).<br />
Chi-squared tests were performed to assess relations between<br />
cutaneous toxicities and pCR.<br />
The cutaneous toxicities were not predictive of pCR (p=0.94) and no<br />
correlations were found with KI-67, EGFR, Cytokeratin 5-6 and p53.<br />
In terms of BRCA1 and BRCA2 status, 35 tumors were analysed so<br />
far: BRCA1: 6 mutations (17%); BRCA2 (30 patients): 1 mutation<br />
(3.3%).<br />
Conclusions : These results suggest the possibility to identify a<br />
subpopulation with high probability of pCR (KI-67 > 40%, EGFR<br />
score > 70).<br />
Further biological studies are ongoing and will be presented at<br />
the meeting, including EGFR polymorphisms, C-met, ALDH1,<br />
pCadherine and PTEN.<br />
This will help us further define subpopulations of TNBC patients,<br />
potential targets for antiEGFR development.<br />
P3-06-21<br />
Unique Molecular Subtypes of Triple Negative <strong>Breast</strong> Carcinomas<br />
by Routine IHC: Implications for Treatment and Prognosis<br />
Ashfaq R, Wright B, Russell K, Voss A. Caris Life Sciences, Phoenix,<br />
AZ<br />
Background: Triple negative breast cancer (TNBC) is defined by<br />
lack of expression for Estrogen Receptor, Progesterone Receptor<br />
and Her2. Recent gene expression profiling has shown that triple<br />
negative tumors are a heterogeneous group of tumors with variable<br />
prognosis. The objective of this study is to identify unique subsets<br />
of triple negative lesions based on routine IHC.<br />
Method: Previous breast cancer cases received for molecular testing<br />
by Caris Target Now (Caris Life Sciences, Phoenix, AZ) undergo<br />
standard testing for ER, PR, Her2 by IHC and Her2 FISH based<br />
on which molecular subtype is assigned (ER/PR+, Her2+ Triple<br />
Negative). Triple Negative breast carcinomas were further assessed<br />
by IHC for additional markers including CK 5/6, CK7, CK14, P53,<br />
AR, PTEN, Ki-67 and Cav-1 to help identify unique molecular<br />
subsets of TNBC.<br />
Results: Based on IHC profiles for 215 TNBC, 42% can be<br />
categorized as Basal subtype based on positivity for CK5/6.CK14<br />
and CK17, 40% are Androgen Receptor positive, 55% have loss of<br />
Caveolin , 7% of TNBC have P53 alterations. Additionally 46% of<br />
TNBC have loss of PTEN. The highest loss of PTEN occurs in the<br />
Stromal subtype (77%). PTEN loss is rarely seen in p53 positive cases.<br />
The large majority of TNBC are proliferative (90%) as assessed by<br />
Ki-67 index.<br />
Conclusions: Routine IHC markers define at least four unique<br />
subgroups of TNBC; Basal subtype, P53- Positive subtype, AR<br />
Positive subtype , Stromal subtype (Cav-1-negative), Proliferative<br />
Subtype. This study shows that with routine IHC it is possible to<br />
identify TNBC with more favorable prognosis such as AR-Positive<br />
subtype and Low proliferation TNBC versus those TNBC with poor<br />
prognosis, such as P53 and Stromal subtypes. In addition to their<br />
unique prognostic profiles, these subtypes may require different<br />
therapeutic interventions.<br />
www.aacrjournals.org 315s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P3-06-22<br />
Mechanisms behind trastuzumab resistance as neoadjuvant<br />
therapy in HER2-positive operable breast cancer<br />
Jinno H, Sato T, Hayashida T, Takahashi M, Hirose S, Kitagawa Y.<br />
Keio University School of Medicine, Shinjuku, Tokyo, Japan<br />
Background<br />
The development of trastuzumab has had a major impact in treatment<br />
of breast cancer patients with HER2 overexpression. Despite<br />
clinical usefulness, intrinsic or acquired resistance to trastuzumab<br />
is a common clinical phenomenon. However, the mechanisms of<br />
resistance to trastuzumab have not been fully elucidated. Potential<br />
mechanisms include aberrant downstream signaling caused by loss of<br />
PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R<br />
and masking with MUC4. The objective of this study was to determine<br />
the possible mechanisms of resistance to trastuzumab as neoadjuvant<br />
therapy in women with HER2-overexpressing operable breast cancer.<br />
Patients & methods<br />
Patients with operable breast cancer received 12 cycles of weekly<br />
paclitaxel (80 mg/m2 IV) plus weekly trastuzumab (4mg/kg loading<br />
dose followed by 2 mg/kg IV) for 12 weeks before surgery. All<br />
tumors were HER2-positive by immunohistochemistry (IHC)<br />
or fluorescence in situ hybridization. Expressions of ER, PgR,<br />
Ki67, PTEN, phosphorylated IGF-1R (pIGF-1R) and MUC4 were<br />
performed by IHC in core needle biopsy samples at baseline. ER<br />
and PgR status was assessed using Allred score. For Ki67 labeling<br />
index, a total of 400 cells were counted from three consecutive highpower<br />
magnifications. PTEN, pIGF-1R and MUC4 expression level<br />
was scored semiquantitatively based on staining intensity. PIK3CA<br />
mutation status was evaluated by sequencing of PIK3CA exons 9 and<br />
20 using PCR amplification and direct sequencing. pCR was defined<br />
as no residual invasive carcinoma in the breast.<br />
Results<br />
Thirty-seven patients were enrolled and assessable for clinical and<br />
pathologic responses. ER and PgR were positive in 18 (48.6%) and 16<br />
(43.2%) patients, respectively. The overall response rate was 86.5%,<br />
including a complete response in 21 patients and a partial response in<br />
11 patients. The pCR rate was 48.6% (18/37). Negative, moderate and<br />
strong membranous expression of MUC4 was observed in 3 (8.1%),<br />
18 (48.6%) and 12 (32.4%) patients, respectively. Membranous<br />
staining for pIGF1-R was negative in 24 (64.9%) patients. PTEN<br />
loss was observed in 33.3% (8/24) of the tumor examined. PIK3CA<br />
sequence analysis of the 13 tumors identified 2 mutations in exon<br />
20 and 2 mutations in exon 9, corresponding to a PIK3CA mutation<br />
frequency of 30.8%. MUC4 and pIGF1-R status did not affect the<br />
pCR rate. PTEN loss and/or PIK3CA mutation were not significantly<br />
associated with pCR rate. pCR rate was significantly correlated with<br />
PgR negativity (p=0.004) and higher Ki67 (p=0.01).<br />
Conclusions<br />
These data indicate that aberrant downstream signaling caused by<br />
loss of PTEN and/or PIK3CA mutation, alternative signaling from<br />
IGF-1R and masking with MUC4 were not important mechanisms<br />
of resistance to trastuzumab.<br />
P3-06-23<br />
Predicting response to neoadjuvant letrozole<br />
Larionov A, Turnbull A, Sims A, Renshaw L, Kay C, Harrison D, Dixon<br />
JM. University of Edinburgh, Scotland, United Kingdom<br />
Background<br />
Approximately 75% of older postmenopausal patients with large<br />
operable or locally advanced oestrogen receptor positive breast<br />
cancer respond to treatment with neoadjuvant letrozole. Prediction of<br />
response is required as approximately 25% fail to respond. The aim<br />
of this study was to design a response predicting classifier with two<br />
data sets, one published previously [1] and secondly a new dataset.<br />
Methods<br />
Patients were treated with Letrozole (Femara, 2.5 mg daily) and<br />
tissues were collected before treatment, 2 or 3 weeks on treatment,<br />
and between 3 and 5 months on treatment. Response was based on<br />
a 3D ultrasound, with response being classified as a 50% reduction<br />
in tumour volume at 3 months. To ensure biological relevance of<br />
the response groups we also separated patients into Quick Stable<br />
Responders (QSR) and Long-Term Non-responders (LNR), as<br />
summarised in Table 1.<br />
Datasets summary<br />
Dataset publication<br />
Complete triplets<br />
(Total patients)<br />
Assessable clinical responses Extreme response groups<br />
(Resp vs Non-resp)* (QSR vs LNR)*<br />
JCO-2009 [1] 57 (62) 52 (37 vs 15) 23 (16 vs 7)<br />
SABCS-2012 51 (76) 41 (31 vs 10) 24 (15 vs 9)<br />
*Responses numbers are shown for triplets only<br />
Illumina HT-12 BeadArrays were used for gene expression profiling,<br />
allowing platform-independent cross-validation with our previous<br />
study using Affymetrix HGU-133 chips [1]. The probe IDs were reannotated<br />
to Ensemble gene IDs and XPN batch correction has been<br />
applied to make the datasets directly comparable. A combination of<br />
Rank-Product, SAM and Random Forrest analyses have been used<br />
to design several alternative signatures separating extreme response<br />
groups, the patients who responded rapidly vs those who did not<br />
respond for a long time. One of the best performing signatures<br />
included 48 informative features: 24 at baseline, 12 at 2-weeks and<br />
12 changes between 0 and 2 weeks. This signature was validated on<br />
the independent previously published test set by classifying extreme<br />
responses (quick stable responders vs long term non responders)<br />
using Support vector machines (SVM) with different kernel functions.<br />
Results<br />
Are summarised in Table 2.<br />
Response prediction<br />
SVM kernel function<br />
Baseline genes 2-week genes Changed genes<br />
All features combined (48)<br />
alone (24) alone (12) alone (12)<br />
Radial 18/23 (78%)* 18/23 (78%) 19/23 (83%) 21/23 (91%)<br />
Linear 16/23 (70%) 13/25 (57%) 20/23 (87%) 21/23 (91%)<br />
*Number of correct classifications/ Total number of cases (% of correct classifications)<br />
Conclusions<br />
- A new sample series has been collected to study neo-adjuvant<br />
endocrine response. It can be used for independent validation of<br />
previous results [1] and for design of new platform-independent<br />
response predictors.<br />
- Multi-gene predictors based upon change in gene expression<br />
outperform those from baseline or 14 day measurements alone. The<br />
best classifiers include all 3 time points.<br />
- A classifier has been derived with a 91% accuracy rate of predicting<br />
extreme response group in 21 of 23 patients.<br />
References<br />
[1] Miller 2009 J Clin Oncol 27:1382.<br />
P3-06-24<br />
Early activation of IFN/STAT signaling in tumor cells of patientderived<br />
triple negative breast cancer xenografts predicts tumor<br />
sensitivity to chemotherapy<br />
Legrier M-E, Yvonnet V, Beurdeley A, Stephant G, Le Ven E, Banis<br />
S, Lassalle M, Deas O, Cairo S, Judde J-G. Xentech, Evry, Ile de<br />
France, France<br />
Triple negative breast cancer (TNBC) is a tumor subtype characterized<br />
by the absence of overexpressed estrogen receptor-alpha (ER),<br />
progesterone receptor (PR), and HER2 receptor, encoded by<br />
ERBB2, a known proto-oncogene. This type of tumors account for<br />
approximately 15-25% of breast cancers at diagnosis, and is one of<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
the most aggressive subtypes, with 77% of patients that live free of<br />
disease 5 years post-diagnosis. One of the most reliable predictive<br />
markers of patient outcome is the pathological complete response<br />
(pCR), which indicates that the surgical specimen removed after<br />
neoadjuvant chemotherapy contains no viable tumor cells detectable<br />
at histopathological level. For patients with pCR, the probability of<br />
surviving the disease is very high, however, pCR is observed only<br />
in about 20-30% of TNBC. On the other hand, for patients with no<br />
pCR the probablity of developing recurrent disease at 5 years is 50%.<br />
As pCR is strongly correlated with treatment efficacy, it is mandatory<br />
to develop methods that allow to tell as quick as possible if the<br />
treatment chosen for a given patient is efficiently working or if it<br />
should be abandoned in favor of an alternative strategy that could<br />
prove more efficacious. XenTech collection of breast cancer patientderived<br />
xenografts (PDXs) includes 25 models of TNBC that display<br />
heterogeneous response to different chemotherapy agents. We used<br />
our models to investigate if transcriptional changes could be detected<br />
in PDXs that responded well to genotoxic agents. To do this we<br />
analyzed the gene expression profile of laser-microdissected residual<br />
tumor nodules interspersed in the murine stroma upon very efficient<br />
response to Adriamycin/Cyclophosphamide (AC). When doing so,<br />
we identified several genes of the IFN/STAT1 pathway that were<br />
over-expressed when compared to untreated tumors. This activation<br />
seems to be a transient event, as it was lost in tumors relapsing after<br />
the residual tumor nodule stage.<br />
The finding that residual cells from tumors strongly responding to<br />
AC treatment over-expressed IFN/STAT1 pathway-related genes<br />
prompted us to investigate whether this effect could be detected as<br />
an early event upon tumor exposure to chemotherapy. All TNBC<br />
models tested that were good responders to AC treatment displayed<br />
over-expression of IFN/STAT1 pathway-related genes as early as 3<br />
days post-treatment, most of them reaching a plateau of intensity<br />
at day 7 post-treatment. By contrast, TNBC insensitive or low<br />
responders to AC treatment failed to show over-expression of IFN/<br />
STAT1 pathway-related genes.<br />
To verify if the selective over-expression of these genes in<br />
TNBC models sensitive to AC was independent of the treatment<br />
administered, Irinotecan and Capecitabine were used to treat TNBC<br />
models with heterogeneous response to these drugs. Again, we<br />
found that overexpression of IFN/STAT1 pathway-related genes<br />
was specifically identified at early stages only in TNBC models that<br />
responded well to these drugs.<br />
These results suggest that genes of the IFN/STAT1 pathway could be<br />
early predictors of tumor response in patients receiving neoadjuvant<br />
chemotherapy. Prospective clinical validation studies are warranted<br />
to confirm the findings from this preclinical study.<br />
P3-06-25<br />
PTEN mRNA positivity using in situ measurements is associated<br />
with better outcome in Tamoxifen treated breast cancer patients.<br />
Schalper KA, Li K, Rimm DL. Yale School of Medicine, New Haven,<br />
CT<br />
Background: Aberrant phosphatidylinositol 3-kinase (PI3K) pathway<br />
signaling occurs in a high proportion of human breast cancers and<br />
is involved in carcinogenesis, tumor progression and resistance to<br />
targeted therapies. Reduced levels of the tumor suppressor PTEN<br />
has been associated with PI3K pathway activation and is observed<br />
in ∼40% of breast carcinomas. PTEN levels have traditionally been<br />
determined in breast tumors by qualitative immunohistochemistry<br />
(IHC) and its prognostic and/or predictive value has not been<br />
clearly established. We used a novel method of quantitative in situ<br />
measurements of PTEN mRNA and protein to determine their possible<br />
prognostic and predictive value in breast cancer.<br />
Materials and methods: PTEN mRNA and protein were measured<br />
on formalin fixed paraffin embedded (FFPE) cell lines and tumor<br />
samples on tissue microarrays (TMAs) representing a retrospective<br />
cohort of 404 breast cancer cases collected from the Yale Pathology<br />
archives between 1975 and 2005. The RNAscope paired-primer<br />
method was used for PTEN mRNA in situ hybridization (ISH), with<br />
Ubiquitin C and DapB ISH probes used as positive and negative<br />
controls for each run. PTEN protein measurements were performed<br />
with monoclonal antibody 138G6 (Cell Signaling Technology).<br />
Both mRNA and protein were measured using the AQUA method of<br />
quantitative immunofluorescence.<br />
Results: Both PTEN mRNA ISH signal and protein were highly<br />
reproducible in FFPE tissues and cell lines. PTEN mRNA levels<br />
were lower in cell lines with known PTEN downregulation. In breast<br />
carcinoma samples, PTEN mRNA scores showed a positive non-linear<br />
association with protein levels. Neither PTEN mRNA nor protein<br />
showed prognostic value. However, high PTEN mRNA expression<br />
using a visually defined cutoff was associated with better outcome<br />
in a subset of Tamoxifen treated breast cancer patients.<br />
Conclusion: Initial data suggests that PTEN mRNA expression may<br />
be predictive of favorable response to endocrine therapy in breast<br />
carcinomas. However, validation in larger independent cohorts is<br />
required.<br />
P3-06-26<br />
Serum anti-p53 antibody titers predict pathological response to<br />
preoperative chemotherapy in women with HER2 positive or<br />
triple negative breast cancer.<br />
Yoshiyama T, Nakamura Y, Igawa A, Saruwatari A, Shigechi T, Ueda<br />
N, Kuba S, Ishida M, Nishimura S, Nishiyama K, Ohno S. National<br />
Kyushu <strong>Cancer</strong> Center, Fukuoka, Japan<br />
Background: In SABCS 2009, we reported that the high level<br />
of serum anti-p53 antibody titers was associated with response to<br />
preoperative chemotherapy in cases with primary breast cancer<br />
(SABCS 2009). Prognostic meaning of pathological complete<br />
response (pCR) after preoperative chemotherapy differs among<br />
various subtype, and there is a close relationship between pCR and<br />
prognosis in cases with HER2 positive or triple negative disease. The<br />
aim of this study is to evaluate the association between the high level<br />
of serum anti-p53 antibody titers and pCR in patients with HER2-<br />
positive or triple negative breast cancer.<br />
Patients and Methods: In this study, we analyzed 196 women<br />
with operable early stage breast cancer (T1-T3, N0-1) treated with<br />
preoperative chemotherapy and definitive curative surgery since 2002<br />
to 2011. All of the patients received four cycles of FEC (fluorouracil<br />
500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/<br />
m2 q3w) followed by four cycles of docetaxel (75 mg/m2 q3w).<br />
The serum anti-p53 antibody titers were assessed by ELISA with<br />
the anti-p53 EIA Kit II (MESACUP anti-53 Test: MBL) in the pretreatment<br />
serum samples. The test’s cut-off value was determined<br />
to be 1.3 IU/ml based on reference distribution in healthy control<br />
individuals. The association between serum anti-p53 antibody titers<br />
and pCR was analyzed.<br />
Results: The subtype of tumors of 196 patients were classified to<br />
86 of ER+/HER2-, 24 of ER+/HER2+, 29 of ER-/HER2+ and 57 of<br />
ER-/HER2-. The pCR was achieved 49 of 196 patients (25%). The<br />
pCR rate were 7%(6/86), 33%(8/24), 48%(14/29) and 37%(21/57)<br />
in the subtype of ER+/HER2-, ER+/HER2+, ER-/HER2+ and ER-/<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
HER2- respectively. The range of serum anti-p53 antibody titers in<br />
the serum samples of 196 patients was between 0.40 and 5610 ( the<br />
median was 0.40 and the average was 85.2). Excluding 86 cases with<br />
ER+/HER2-, relationship between serum anti-p53 antibody titers<br />
and pCR was evaluated. According to serum anti-p53 antibody titers<br />
with the patients of pCR, cut-off value of serum anti-p53 antibody<br />
titers was set to be 6 IU/ml. The pCR was observed in nine of 12<br />
cases (75%) with high serum anti-p53 antibody titers, which was<br />
significantly higher than those with low titers (35%: 34/98 ; p=0.01).<br />
Multivariate analysis showed that the only high anti-p53 antibody titer<br />
was an independent predictive factor for pCR due to preoperative<br />
chemotherapy (p=0.01).<br />
Conclusion: p53 mutation analysis using serum anti-p53 antibody<br />
titers might be a useful predictive test for response to preoperative<br />
chemotherapy in patients especially with HER2 positive or triple<br />
negative breast cancer.<br />
P3-06-27<br />
Dynamic tomographic optical breast imaging (TOBI) to monitor<br />
response to neoadjuvant therapy in breast cancer<br />
Carp SA, Wanyo CM, Specht M, Schapira L, Moy B, Finkelstein DM,<br />
Boas DA, Isakoff SJ. Massachusetts General Hospital, Charlestown,<br />
MA; Massachusetts General Hospital, Boston, MA<br />
Background: Near-infrared optical measurements have been<br />
recently shown to offer a promising non-invasive way for monitoring<br />
breast neoadjuvant chemotherapy (NAC) and predicting outcome.<br />
In particular, snapshots of tissue oxy and deoxy-hemoglobin<br />
concentration as well as water and lipid content have been<br />
demonstrated to be sensitive to therapy-induced changes. In this study,<br />
we extend optical measurements to capture additional hemodynamic<br />
and metabolic biomarkers revealed by dynamically imaging breast<br />
tissue during fractional mammographic compression. Using our<br />
dynamic tomographic optical breast imaging (TOBI) system we<br />
evaluate the early prediction performance of this advanced technology.<br />
Methods: We are conducting a pilot feasibility study in female<br />
patients with unilateral locally advanced breast cancer undergoing<br />
standard-of-care NAC. Pre-treatment and day 7 post-treatment TOBI<br />
scans are obtained, with additional (optional) scans on day 1 of each<br />
subsequent chemotherapy cycle. Both breasts are compressed in<br />
turn to 4-8 lbs of force, and optical images are acquired once every<br />
2 seconds over two minutes. Time-resolved oxy-(HbO), deoxy-<br />
(HbR), and total-(HbT) hemoglobin concentration and hemoglobin<br />
oxygen saturation (SO 2 ) are calculated. The compression-induced<br />
rate of change of HbT correlates with changes in tissue blood volume<br />
indicative of biomechanical properties. The evolution of tissue SO 2<br />
is modeled to obtain an index of the ratio of oxygen metabolism to<br />
blood flow. Therapy induced changes are quantified, and comparisons<br />
between changes in responders vs. non-responders are performed<br />
(response is defined here as >50% reduction in the largest tumor<br />
diameter).<br />
Results: We have enrolled 20 patients so far, of which 90%<br />
(N=18) completed both the day 0 and day 7 scans. 17 patients have<br />
undergone surgery at this point. We focused our initial analysis on<br />
5 HER2+ patients, of which two were non-responders, and three<br />
were responders according to our criteria. Four patients received<br />
taxol+herceptin+lapatinib, while the other received taxol+lapatinib<br />
only. In this small subgroup, the non-responders had an average<br />
increase of 1% in total hemoglobin concentration (HbT) from day<br />
0 to day 7, while the responders had an average 12% decrease in<br />
HbT, respectively. We also noted different trends in the evolution of<br />
the tissue oxygen consumption to blood flow ratio, which increased<br />
32% in non-responders from day 0 to day 7, while decreasing 11%<br />
in responders.<br />
Conclusions: The large percentage of enrolled patients that completed<br />
both initial scans demonstrates the feasibility of using dynamic optical<br />
breast tomography for breast neoadjuvant chemotherapy monitoring.<br />
Results in a small cohort of 5 HER2+ patients suggested a decreasing<br />
trend in HbT for responders as observed by previous studies. We<br />
also report for the first time an increase in the metabolic ratio of<br />
oxygen consumption to blood flow in non-responders vs. a decrease<br />
in responders. These initial results of our on-going study suggest that<br />
dynamic TOBI can detect changes due to treatment and may have<br />
predictive value for the treatment outcome and supports further studies<br />
of this non-invasive and portable tool for chemotherapy monitoring.<br />
P3-06-28<br />
Use of the MiCK drug-induced apoptosis assay improves clinical<br />
outcomes in recurrent breast cancer (BRCA)<br />
Bosserman L, Rogers K, Davidson D, Whitworth P, Karimi M,<br />
Upadhyaya G, Rutledge J, Hallquist A, Perree M, Presant C.<br />
Wilshire Oncology Medical Group-US Oncology; Nashville Oncology<br />
Associates; Tennessee Plateau Oncology; Nashville <strong>Breast</strong> Center;<br />
Data Vision; DiaTech Life Sciences<br />
Background: The microculture kinetic (MiCK) assay (Correct<br />
Chemo) correlates with outcomes in acute myelocytic leukemia<br />
and ovarian cancer (<strong>Cancer</strong> Research, in press). A prior trial suggested<br />
that its use in breast cancer could improve clinical outcomes (<strong>Cancer</strong>,<br />
in press). This study was designed to correlate MiCK assay results<br />
with clinical outcomes in recurrent or metastatic BRCA.<br />
Methods: 30 patients with recurrent or metastatic breast cancer in 4<br />
different institutions were evaluated. Each patient (pt) had a BRCA<br />
biopsy sent to a central laboratory, tumor cells were purified to over<br />
90% homogeneity, and were then cultured with individual drugs or<br />
drug combinations. The induction of apoptosis was measured every<br />
five minutes continuously for 48 hours. The amount of apoptosis<br />
was expressed in kinetic units (KU), and results were sent to the<br />
attending oncologist within 72 hours of submission. Physicians were<br />
free to choose any treatment plan for the pts, and were free to add<br />
hormonal therapy or biotherapy. Clinical results were evaluated by<br />
oncologists using clinical criteria and the results of the MiCK assay<br />
were correlated with outcomes of complete (CR) or partial (PR)<br />
response, time-to-relapse (TTR), and overall survival (OS).<br />
Results: Median age was 57 years, and number of lines of prior therapy<br />
was a median of 2 (range 1-8). Median ECOG performance status was<br />
1. The total number of drugs tested in the assay was a median of 12<br />
(range 3-31). The MiCK assay was used to help select therapy in 22<br />
pts (73%). There was change between drugs originally planned before<br />
MiCK assay and drugs used after MiCK in 15 pts (50%). The best<br />
therapy from the MiCK assay was used for treatment in 16 pts (53%).<br />
In five pts (17%), a single drug was used in place of a combination.<br />
Generic drugs were used in place of proprietary drugs in nine pts<br />
(30%). Hormonal therapy was added to drugs selected based on the<br />
MiCK assay in seven pts (23%), and bio-therapy drugs were added<br />
to chemotherapy drugs in eight pts (27%). If the MiCK results were<br />
used to help select therapy, eight pts had a CR or PR (27%), compared<br />
to 0 pts with CR or PR if MiCK was not used (p=0.04). If the MiCK<br />
assay was used to determine therapy, 17 pts (59%) had a CR, PR or<br />
stable disease compared to only 2 pts (6.9%) in whom the MiCK<br />
assay was not used (p< 0.01). The TTR was significantly longer if the<br />
MiCK assay was used to select chemotherapy, 7.4 months, compared<br />
to only 2.2 months if the MiCK assay was not used (p< 0.01). There<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
was a trend toward longer survival if the MiCK assay was used, 16.8<br />
months, compared to 13.1 months if the MiCK assay was not used,<br />
but the difference was not statistically significant (p=0.3). If the best<br />
chemotherapy from the MiCK assay was used, there were trends for<br />
increased TTR (7.3 vs 3.9 mo if best not used p=0.13) and increased<br />
rate of CR or PR or stable (54% vs 17% p=0.11).<br />
Conclusions: Use of the MiCK assay to determine chemotherapy was<br />
associated with a higher response rate and a longer time to relapse<br />
in pts with recurrent or metastatic BRCA. It is possible that OS is<br />
also improved, but longer follow up is needed. There was a trend for<br />
improved outcomes if the best chemotherapy based on the MiCK<br />
assay was used.<br />
P3-06-29<br />
Change of circulating tumor cells before and after neoadjuvant<br />
chemotherapy in patients with primary breast cancer<br />
Horiguchi J, Takata D, Rokutanda N, Nagaoka R, Tokiniwa H, Tozuka<br />
K, Sato A, Kikuchi M, Oyama T, Takeyoshi I. Gunam University<br />
Hospital, Marbashi, Gunma, Japan; Gunma University Hospital,<br />
Maebashi, Gunma, Japan<br />
Background: Circulating tumor cells (CTCs) in peripheral blood<br />
may represent the possible presence of early tumor dissemination.<br />
However, relatively few studies were designed to investigate the<br />
change of CTC status by adjuvant chemotherapy in operable breast<br />
cancer patients. Patients and methods: Peripheral blood (7.5ml)<br />
was collected from 95 patients with stage II/III breast cancer before<br />
neoadjuvant chemotherapy (NAC). NAC consisted of anthracycline<br />
and paclitaxel chemotherapy and additional trastuzumab treatment<br />
for patients with HER2-positive tumors. Results: The average age<br />
of patients was 52.6 year old (median 52.0). One or more CTCs<br />
were detected in 18 (18.9%) of 95 patients. CTCs were detected<br />
in 6 (12.0%) of 50 patients with clinical stage II disease and 12<br />
(26.7%) of 45 patients with clinical stage III disease. According to<br />
tumor subtypes, CTCs were detected in 5 (17.9%) of 28 patients<br />
with hormone receptor (HR)-positive and HER2-negative tumors<br />
(L subtype), 3 (12.5%) of 24 patients with HR-positive and HER2-<br />
positive tumors (L-H subtype), 4 (22.2%) of 18 patients with HRnegative<br />
and HER2-positive tumors (H subtype), and 6 (24.0%) of 25<br />
patients with HR-negative and HER2-negative tumors (TN subtype).<br />
After NAC, 17 (94.4%) of 18 patients who were CTC-positive before<br />
chemotherapy changed into negative status. 30 (31.6%) of 95 patients<br />
had a pathologic complete response (pCR) after NAC. There was<br />
no correlation between CTC status before NAC and pathological<br />
response. At the median follow up of 27 months, distant metastasis<br />
was observed in 9 patients (9.5%). Patients with clinical stage III, TN<br />
subtype, or non-pCR had a significantly worse disease-free survival<br />
(DFS). However, CTC status before NAC was not a significant<br />
prognostic factor. Conclusion: NAC has a significant impact on CTC<br />
status irrespective of tumor subtypes. CTC status before NAC was<br />
not a significant prognostic factor in this study. The reason of which<br />
may be that most of patients showing positive for CTCs before NAC<br />
have changed into negative after NAC.<br />
P3-06-30<br />
Predictors of Pathologic Complete Response to Chemotherapy<br />
and Antiangiotherapy in <strong>Breast</strong> <strong>Cancer</strong>.<br />
Makhoul I, Griffin RJ, Dhakal I, Raj V, Hennings L, Kadlubar SA.<br />
University of Arkansas for Medical Sciences, Little Rock, AR<br />
Vascular endothelial growth factor (VEGF) is a central mediator<br />
of angiogenesis in breast cancer. We have conducted a clinical trial<br />
using bevacizumab (B) in breast cancer in the neoadjuvant setting<br />
and showed improved pathologic complete response (pCR) when B<br />
was added to chemotherapy (CT). 41% of patients (Pts) who received<br />
B+CT achieved pCR. Blood and tumor samples were collected at<br />
baseline and serially on treatment from 39 patients who participated<br />
in the study. The correlative study was approved by the IRB and<br />
consent forms were obtained at the time of enrollment. Since patients<br />
do not equally benefit from B, it has become necessary to define the<br />
profile of patients who will benefit and those who are more likely<br />
to have major side effects from the drug. This study was conducted<br />
to evaluate for the presence of specific SNPs and CNV in the germ<br />
line and a serum protein profile that might be predictive of pCR in<br />
the neoadjuvant setting in breast cancer patients receiving B and CT.<br />
Methods: To test for the presence of functional germ line SNPs and<br />
CNVs that may influence pCR, DNA was extracted from buffy coats<br />
of study participants and SNPs/CNVs were determined using Illumina<br />
technology. To test the hypothesis that individuals who achieved<br />
pCR were those with differential expression of selected proteins<br />
in their blood, custom multiplex was performed for the following<br />
serum proteins: ANG-1, ANG-2, bFGF, IL-1a, MMP-9, PDGF-BB,<br />
PECAM-1, Tie-2, VEGF, and VEGFR2.<br />
Statistical test: The association between genotype and CNV of each<br />
SNP vs. pCR status were analyzed using Cochran-Armitage Trend<br />
Test. Differences in serum protein levels between pCR and non-pCR<br />
groups were examined by Wilcoxon rank sum test. Significance<br />
of association was evaluated in two settings of α (i) α=0.05 (ii)<br />
α=0.00001.<br />
Results: Genotype and CNV vs. pCR (n=38). In genotype vs. pCR<br />
status by SNPs tests, 131618 (∼13%) SNPs with allele frequency<br />
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
q21d demonstrated a 29% overall response rate (J Clin Oncol 29:<br />
2011 (suppl; abstr 1034)). Here we present the relationship between<br />
the dynamics of serum tumor marker CA27.29, etirinotecan pegol<br />
pharmacokinetics, and tumor response.<br />
Methods: Data from 45 pts with at least two CA27.29 measurements<br />
(pre- & post-first dose), were fitted with a PK/PD model developed<br />
to correlate CA27.29 dynamics with SN38 exposure predicted from<br />
individual pt dosing history: d[CA27.29]/dt = Kin*exp(beta*t)*(1-<br />
[SN38]/(IC50+[SN38]))-Kout*[CA27.29]. Correlation of CA27.29<br />
and RECIST response was investigated; % change of CA27.29 from<br />
baseline was also correlated with progression-free survival (PFS).<br />
Results: CA27.29 vs time profiles were well described by the model,<br />
with a population mean plasma SN38 IC50 of 1.6 ng/mL. Typical<br />
minimum/maximum SN38 concentrations during Tx were 1.5/ 3<br />
ng/mL for q14d and 0.9/ 2.4 ng/mL for q21d, indicating that both<br />
schedules resulted in SN38 exposure near the IC50. The half-life of<br />
CA27.29 decline was 15 days. 41 pts had pre- and post-Tx tumor<br />
measurements for correlation of CA27.29 response with tumor size.<br />
Of the 15 pts with RECIST CR or PR, 14 (93%) exhibited at least<br />
10% declines in CA27.29 during Tx; all 5 pts with RECIST SD ≥ 6<br />
months (mths) also manifested ≥10% declines, whereas only 45%<br />
(5/11) of pts with SD < 6 mths showed ≥10% decline in CA27.29.<br />
Among the 10 pts with RECIST progressive disease (PD), 80%<br />
showed ≥10% CA27.29 elevations during Tx. The median maximum<br />
% reduction in observed CA27.29 from baseline during the course of<br />
Tx ranged from -55% to +30% and correlated with responder status<br />
as tabulated below.<br />
Median maximum % reduction of CA27.29 from baseline by RECIST response<br />
CR (N=2) PR (N=13) SD ≥ 6 mths (N=5) SD < 6 mths (N=11) PD (N=10)<br />
-55 -55 -31 -4 30<br />
To investigate whether response in CA27.29 can serve as early<br />
indicator of Tx outcome, we assessed the impact of a reduction of<br />
≥25% after 6 weeks (wks) of Tx (2 or 3 Tx cycles for q21d and q14d<br />
schedules, respectively) on PFS. Among the 26 pts who had not<br />
had tumor progression or discontinued Tx by wk 6, median PFS for<br />
pts with ≥ 25% reduction in CA27.29 (n=9) was 12 mths. Pts with<br />
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
P3-06-33<br />
Effect of trastuzumab-based therapy on serum activin A levels<br />
in metastatic breast cancer.<br />
Zubritsky LM, Ali SM, Leitzel K, Koestler W, Fuchs E-M, Costa L,<br />
Knight R, Laadem A, Sherman ML, Lipton A. Penn State Hershey<br />
Medical Center, Hershey, PA; Lebanon VA Medical Center, Lebanon,<br />
PA; Medical University of Vienna, Austria; <strong>San</strong>ta Maria Hospital,<br />
Lisbon, Portugal; Celgene Corp., Summit, NJ; Acceleron Pharma,<br />
Cambridge, MA<br />
Background: Only half of HER2-positive metastatic breast cancer<br />
patients will respond to first-line trastuzumab-containing therapy, but<br />
of these, most will progress within a year. Trastuzumab resistance<br />
remains a continuing clinical problem, and better biomarkers and<br />
therapies are needed. Activin A is a TGF-beta superfamily member<br />
that regulates cell proliferation, apoptosis, differentiation, and immune<br />
response. We have previously reported that higher pretreatment serum<br />
activin A level predicted reduced progression-free survival (PFS) and<br />
overall survival (OS) to first-line trastuzumab, independent of age, line<br />
of therapy, CA 15-3, and hormone receptor status (ASCO Ab ID 607,<br />
2012). Methods: Serum activin A was measured using ELISA (R&D<br />
Systems, Minneapolis, MN) in 60 metastatic breast cancer patients<br />
before and 1 month after starting first-line trastuzumab-containing<br />
therapy. PFS and OS were analyzed using the Kaplan-Meier method<br />
and Cox modeling with both continuous and dichotomous (median)<br />
serum activin A analyses. Results: Pretreatment serum activin A levels<br />
had a median of 629 pg/mL and an inter-quartile range of 406 to 1791<br />
pg/mL. There was no significant change in activin A levels between<br />
pretreatment and one month after starting trastuzumab therapy.<br />
Median activin A level at one month was 655 pg/mL, with an interquartile<br />
range of 405 to 1517 pg/mL. 83% of patients who had low<br />
pretreatment activin A levels (below median) had low activin levels<br />
at one month, and 83% who had high activin levels (above median)<br />
at baseline had high activin A levels at one month. Patients who had<br />
high activin A levels at baseline and one month had the worst outcome<br />
for both PFS (HR 3.9; median 134 days vs.776 days; p Q3 25/139 22/150 0.68<br />
VEGFR-2 10.2 ng/mL ≤ median 42/291 53/296 1.27 0.0237<br />
> median 45/278 34/309 0.61<br />
Cosmetic results one year after surgery<br />
Conclusions: Unlike trials in metastatic BC (AVADO, AVEREL), in<br />
the adjuvant setting, baseline pVEGF-A concentration did not show<br />
predictive value for BEV efficacy with a median cut-off. However,<br />
analyses using the Q3 cut-off suggest a trend toward predictive<br />
value. High baseline pVEGFR-2 was associated with greater BEV<br />
treatment effect, consistent with previous results in AVADO and<br />
AVEREL. The impact of differing biology in the adjuvant setting,<br />
lower median VEGF-A concentration than in the metastatic setting<br />
(77.0 vs 127.0-129.1 pg/mL), and the possible influence of surgery<br />
immediately before treatment require further investigation. Additional<br />
exploratory analyses are ongoing to provide better understanding of<br />
the BEATRICE dataset and the complex biology of angiogenesis,<br />
including additional markers, changes over time, and combination<br />
signatures.<br />
P3-06-35<br />
Topoisomerase 1 gene copy aberrations in 52 human breast cancer<br />
cell lines and association to gene expression<br />
Stenvang J, Smid M, Nielsen S, Timmermans M, Rømer M, Nielsen<br />
D, Foekens J, Brünner N, Martens J. University of Copenhagen,<br />
Denmark; Erasmus University Medical Center/Daniel den Hoed<br />
<strong>Cancer</strong> Center, Rotterdam, Netherlands; Herlev University Hospital,<br />
Copenhagen, Denmark<br />
Background: Topoisomerase 1 (TOP1) targeting drugs, e.g.<br />
irinotecan, are included in treatment regimens for different cancer<br />
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types. Two clinical phase II studies 1,2 suggested a role for irinotecan<br />
in the treatment of metastatic breast cancer patients being refractory<br />
to anthracyclines and taxanes. Access to predictive biomarker<br />
for irinotecan would increase response rates and secure that only<br />
patients with a high likelihood of obtaining benefit will receive the<br />
drug. However, no predictive biomarkers for TOP1 targeting drugs<br />
are available.<br />
Experimental design: A TOP1/CEN-20 fluorescence in situ<br />
hybridization (FISH) probe mix 3 (Dako A/S, Denmark) was applied to<br />
analyze formalin fixed paraffin embedded (FFPE) tissue sections from<br />
52 human breast cancer cell lines 4 . The FISH data were correlated<br />
to the gene expression levels (Affymetrix u133a GeneChip) of ER,<br />
HER2, TOP2A and molecular subtypes. Furthermore, gene expression<br />
data from 8 TOP1 high copy and 8 TOP1 low copy cell lines were<br />
applied for Kegg pathway analysis.<br />
Results: To categorize the cell lines, we initially analyzed the TOP1<br />
copy number and CEN-20 counts in 100 normal breast epithelium<br />
sections and defined the normal diploid range as the mean plus/minus<br />
0.5 times the haploid gene copy number. Thereby the normal diploid<br />
range for TOP1 was defined as 1.7 (range 1.45-1.90) and for CEN-<br />
20 it was 1.6 (range 1.38-1.82). By applying these cut-off values we<br />
found that among the 52 breast cancer cell lines 61.5% had TOP1<br />
gene gains and 59.6% had increased CEN-20 copy numbers. However,<br />
the Pearson correlation between TOP1 and CEN-20 counts was<br />
0.54 resulting in only 11.5% of the cell lines having TOP1/CEN-20<br />
ratios > 1.5. A significant association exist between TOP1 gene copy<br />
number (FISH) and TOP1 copy numbers obtained from SNP array<br />
analysis (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
Patients and Methods:<br />
Using the population-based Swedish Multi-Generation and <strong>Cancer</strong><br />
Registers we selected 8,111 women diagnosed with in situ breast<br />
cancer between 1980 and 2004. We estimated the relative risks<br />
of subsequent ipsi- and contralateral invasive breast cancer or a<br />
contalateral in situ expressed as standardized incidence ratios (SIRs),<br />
in relation to age, year, time since diagnosis and family history (1 st<br />
degree relative) for breast cancer. The relative risk of death was<br />
expressed as standardized mortality ratio, (SMR).<br />
Results:<br />
Of 8,111 women identified with first in situ, 859 had a family history<br />
for breast cancer. The overall risk of a subsequent invasive breast<br />
cancer is over four fold and the risk for contralateral in situ breasts<br />
cancer was almost seven fold, compared with the risk in healthy<br />
women.<br />
Table 1. SIR of second breast event after diagnosis of first carcinoma in situ.<br />
All No family history Family history<br />
No.<br />
of SIR (95% CI)<br />
cases<br />
No.<br />
of SIR (95% CI)<br />
cases<br />
No.<br />
of SIR (95 % CI)<br />
cases<br />
Incidence<br />
Rate<br />
Ratio*<br />
(95% CI)<br />
2nd breast<br />
1.18 (0.96,<br />
886 4.34 (4.06, 4.63) 781 4.22 (3.93, 4.53) 105 5.44 (4.45, 6.59)<br />
event<br />
1.46)<br />
2nd in situ<br />
1.08 (0.61,<br />
118 6.70 (5.55, 8.02) 104 6.62 (5.41, 8.02) 14 7.41 (4.05, 12.44)<br />
contralateral 1.91)<br />
2nd invasive<br />
(ipsi- and<br />
contra<br />
latera+<br />
missing<br />
side)<br />
2nd<br />
ipsilateral<br />
invasive<br />
768 4.03 (3.75, 4.33) 677 3.92 (3.63, 4.22) 91 5.13 (4.13, 6.30)<br />
376 1.90 (1.72, 2.10) 334 1.86 (1.6, 2.08) 42 2.27 (1.63, 3.06)<br />
2nd<br />
contralateral 303 1.53 (1.36, 1.71) 262 1.46 (1.29, 1.65) 41 2.20 (1.58, 2.98)<br />
invasive<br />
1.21 (0.97,<br />
1.51)<br />
1.01 (0.73,<br />
1.40)<br />
1.49 (1.06,<br />
2.09)<br />
∗Reference group is No family history. Incidence rate ratio has been adjusted for attend age, calendar<br />
period and year of first diagnosis of carcinoma in situ and time since first diagnosis.<br />
Women with a family history had almost a 50% increased risk for<br />
a contralateral invasive breast cancer, IRR 1.49 (95% CI 1.06-<br />
2.09) compared to women without, but had no increased risk for a<br />
contralateral in situ cancer or ipsilateral invasive breast cancer.<br />
The risk for subsequent breast cancer decreased over time after<br />
diagnosis, but still 15 years after first in situ diagnosis the risk was<br />
over three times higher compared to the general population. Women<br />
below 40 years at diagnosis had the highest risk for a subsequent<br />
breast event, SIR 8.54 (95% CI 6.07-11.67).<br />
The overall mortality for women with no second invasive event was<br />
the same as for women in the general population, SIR 1.01 (95% CI<br />
0.95-1.08). Women below 50 years at first in situ diagnosis, with a<br />
second invasive cancer, had a higher mortality compare to women<br />
above 50 years, SIR 8.3 (95% CI 5.38-11.54) and SIR 1.70 (95% CI<br />
1.39-2.06) respectively.<br />
Conclusion:<br />
The risk for a subsequent invasive breast cancer, as well as mortality<br />
was substantially higher in younger women, which should be taken<br />
into account when planning their treatment and follow-up. Family<br />
history did not increase the risk for a subsequent ipsilateral invasive<br />
cancer.<br />
P3-07-04<br />
Cigarette smoking and postmenopausal breast cancer risk: results<br />
from the NIH-AARP Diet and Health Study<br />
Nyante SJ, Gierach GL, Dallal CM, Park Y, Hollenbeck AR, Brinton<br />
LA. National <strong>Cancer</strong> Institute, Rockville, MD; AARP, Washington, DC<br />
Epidemiologic evidence regarding the relationship between smoking<br />
and breast cancer risk is inconsistent. Some studies suggest that<br />
the relationship depends on interaction with other factors, such as<br />
alcohol use, body mass index (BMI), and menopausal hormone<br />
therapy (MHT). We investigated the relationship between smoking<br />
and breast cancer risk and interactions with breast cancer risk factors<br />
in the NIH-AARP Diet and Health Study, a large prospective cohort.<br />
Postmenopausal women ages 50-71 years (N=192,076) in six US<br />
states and two metropolitan areas were followed from 1995-1996<br />
through 2006. Risk factor information was self-reported at baseline.<br />
Smoking status was based on whether participants smoked ≥ 100<br />
cigarettes in their lifetime and whether they currently smoked (current<br />
- 15%, former - 40%, never - 45%). Alcohol use was estimated from<br />
a dietary questionnaire, and categorized based on drinking ≤ 5 or ><br />
5 g/day. BMI was calculated from reported height and weight and<br />
categorized as ≥ 30 or < 30 kg/m2. MHT use was categorized as<br />
current, former, or never use of any estrogen or progestin preparation.<br />
<strong>Cancer</strong> diagnosis, estrogen receptor (ER), and progesterone receptor<br />
(PR) data were reported by state registries. After a mean 9.6 years<br />
of follow-up, 7,698 women were diagnosed with primary invasive<br />
breast cancer. Multivariable-adjusted hazard ratios (HRs) and 95%<br />
confidence intervals (CIs) were calculated using Cox proportional<br />
hazards regression. Multiplicative interactions between smoking<br />
and covariates were evaluated using the likelihood ratio test (LRT).<br />
Overall, smokers were at an increased risk of breast cancer compared<br />
to women who never smoked (current HR 1.19, 95% CI 1.10, 1.28;<br />
former HR 1.08, 95% CI 1.02, 1.13). Excess risk diminished as time<br />
since quitting increased and was close to null for women who quit<br />
smoking ≥ 10 years prior to study enrollment compared to never<br />
smokers (HR 1.04, 95% CI 0.98, 1.11). Relative risks differed<br />
significantly based on alcohol use (P-LRT < 0.01), but not BMI or<br />
MHT use (P-LRT > 0.05). The HR associated with current smoking<br />
was 1.15 (95% CI 1.05, 1.25) among women who drank ≤ 5 g/day,<br />
but was higher among women who drank > 5 g/day (HR 1.41, 95% CI<br />
1.22, 1.61). The relationship for those who drank > 5 g/day persisted<br />
after adjustment for the amount of alcohol (5-10, 10-20, 20-35, >35<br />
g/day) consumed (HR 1.36, 95% CI 1.18, 1.56). Among women who<br />
drank > 5 g/day, current smoking was associated with increased risks<br />
of hormone receptor-positive tumors (ER+/PR+ HR 1.29, 95% CI<br />
1.01, 1.64; ER+/PR- HR 2.11, 95% CI 1.27, 3.50), but not ER-/PRtumors<br />
(HR 1.07, 95% CI 0.64, 1.79). In summary, we found that<br />
smoking was associated with elevated breast cancer risk which was<br />
strongest among women who drank > 5 g of alcohol per day. Among<br />
these women, smoking-associated increases in breast cancer risk were<br />
limited to hormone receptor-positive tumors, consistent with the<br />
known relationship between alcohol use and ER+ breast cancer risk.<br />
Findings were similar after additional adjustment for the amount of<br />
alcohol consumed, suggesting that the increased risks were not due to<br />
residual confounding by alcohol dose, although further analyses are<br />
needed to fully understand the interaction between these two factors.<br />
P3-07-05<br />
Bisphosphonate use after primary breast cancer and risk of<br />
contralateral breast cancer using pharmacy data<br />
Kwan M, Habel L, Song J, Weltzien E, Chung J, Sun Y, Fletcher<br />
S, Haque R. Division of Research, Kaiser Permanente Northern<br />
California; Kaiser Permanente Southern California; Harvard<br />
Medical School<br />
Background: It is not clear if bisphosphonates (BP) are associated<br />
with improved breast cancer prognosis in women with early breast<br />
cancer. Clinical trials have reported mixed results, yet BPs may be<br />
most beneficial in patients with low estrogen levels. However, BPs<br />
and risk of second (contralateral) breast cancer has been minimally<br />
studied. We examined the association of oral BP use (ever/never<br />
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and duration) on risk of contralateral breast cancer (CBC) in 17,224<br />
women with early stage breast cancer treated with tamoxifen.<br />
Materials and Methods: A cohort was assembled of women<br />
diagnosed with their first primary breast cancer (Stage 0, I, II) from<br />
1996 to 2007 on tamoxifen and followed through 31 December<br />
2009 at Kaiser Permanente Northern and Southern California.<br />
Demographic, tumor, pharmacy, and cancer treatment information<br />
was extracted from electronic medical records and SEER-affiliated<br />
cancer registries at each site. Second (contralateral) tumors were<br />
identified from the cancer registries. Detailed information on oral<br />
BP use (before and after initial breast cancer diagnosis) was obtained<br />
from pharmacy databases. A record of >90 days supply was considered<br />
the minimum exposure. Initiation and duration of post-diagnosis use<br />
was categorized as 1) non-use (≤90 days supply) and use (>90 days<br />
supply) and 2) non-use (≤90 days supply), 91 days–90<br />
days supply) was associated with a modestly lower CBC risk<br />
(HR=0.80; 95% CI: 0.61, 1.16). However, stratified analyses by age at<br />
breast cancer diagnosis (
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
patients during 2000-2009, by cancer stage (localized, regional,<br />
distant and unknown/unstaged) and race (White, Black, Other<br />
[American Indians/Alaska Natives or Asians/Pacific Islanders]).<br />
RESULTS: A total of 543,539 cases of female BC were reported to<br />
SEER during 2000-2009, with 452,047 cases among Whites (W),<br />
54,310 cases among Blacks (B), and 37,182 among other races (O).<br />
The overall incidence was highest for Whites (130.2 per 100,000<br />
population), followed by Blacks (120.1) and other races (59.6-93.2).<br />
Similarly, incidence of localized BC was highest among Whites<br />
(81.1), followed by Blacks (63.0) and other races (35.4-58.7). Blacks<br />
had the highest incidence of regional (43.6 vs. 18.8-40.1), distant (9.7<br />
vs. 3.7-6.0), and unknown stage of BC (3.8 vs. 1.6-3.0) compared<br />
to Whites and other races. Incidence of localized BC decreased<br />
slightly for Whites (average annual change -0.4%) during 2000-2009;<br />
however it increased for all other groups (1.4-1.8%). Incidence of<br />
distant BC increased for all races (W: 1.0%, B: 2.3%, O: 3.1-3.8%).<br />
Blacks had the lowest one-year and five-year survival for localized,<br />
regional and distant BC.<br />
Table 1. Survival for female breast cancer patients, by stage and race<br />
Localized Regional Distant Unknown<br />
1-year survival<br />
Whites 100% 98% 66% 79%<br />
Blacks 99% 96% 59% 80%<br />
Other 100% 99% 70% 88%<br />
5-year survival<br />
Whites 98% 84% 24% 56%<br />
Blacks 92% 70% 15% 46%<br />
Other 96% 84% 24% 59%<br />
One-year and five-year survival rates were relatively stable during<br />
2000-2009 for regional and localized BC (annual average change:<br />
-0.6% to 0.7%), for all races. For distant BC, Blacks had least<br />
improvement during 2000-2009 in one-year survival (annual average<br />
change 0.03%, vs. 0.6% for Whites and 3.6% for other races), and<br />
decreasing five-year survival (annual average change -5.4% vs. 2.2%<br />
for Whites and 1.7% for other races).<br />
CONCLUSIONS: Based on US population-based registry data,<br />
Blacks had higher incidence of more advanced breast cancer and<br />
lower long-term survival for all stages of BC. There is considerable<br />
room to improve survival rates for patients with regional and distant<br />
BC, especially among Blacks. Further studies evaluating the survival<br />
experience of later-stage BC patients based on other key factors,<br />
such as age, socioeconomic status, treatment patterns, and tumor<br />
characteristics (e.g. ER/HER2 status) are warranted.<br />
P3-07-08<br />
Recent trends in the characteristics of patients with distant stage<br />
breast cancer in the United States Surveillance, Epidemiology<br />
and End Stage Disease (SEER) program<br />
Li J, Dalvi T, Pawaskar M, Tsai K, Caspard H, Fryzek J. Medimmune,<br />
Gaithersburg, MD; Epistat Institute, Gaithersburg, MD<br />
Objectives. Even though advances in screening and contemporary<br />
diagnostic techniques have led to earlier detection, a proportion<br />
of breast cancer patients are still diagnosed with distant stage<br />
disease. The objective of this research was to describe the changing<br />
demographic and clinical characteristics of patients with distant stage<br />
breast cancer.<br />
Methods. We identified women aged 20 years or older who were<br />
diagnosed with distant stage primary breast cancer between 1995 and<br />
2009 with non-missing hormone receptor (HR) status in the SEER 18<br />
Registry (1973-2009) database. As staging systems changed across<br />
the years of the study, we opted to use the SEER historic stage in<br />
our analyses. Trends in demographic and clinical characteristics were<br />
evaluated by time period of diagnosis (1995-1999, 2000-2004, 2005-<br />
2009) and HR status (HR+ includes ER+/PR+, ER+/PR- and ER-/<br />
PR+; HR- includes ER-/PR- only). Statistically significant changes<br />
were examined using the Cochran Armitage test.<br />
Results. A total of 30,161 women with distant stage breast cancer<br />
were identified. Over the 15 years, the incidence rate (IR) of distant<br />
stage disease was stable (10.6 to 10.9 per 100,000 pys), as well as<br />
the proportion of HR+ cases (68%).<br />
Age did not vary significantly over time; 55% of the HR+ cases<br />
and 45% of the HR- cases were 60 years or older. The proportion of<br />
Black and Hispanic patients increased significantly over time (18 to<br />
24% for HR+; 24 to 33% for HR-) -as did the proportion of patients<br />
diagnosed with grades I and II cancers (44 to 54% for HR+; and 16<br />
to 20% for HR-). The proportion of ductal histologic diagnoses was<br />
stable over time, at 77% among HR+ cases and 93% among HR- cases<br />
in 2005-2009. <strong>Cancer</strong>-directed surgeries (from 63 to 47% for HR+;<br />
72 to 56% for HR-) and radiation therapies (43 to 37% for HR+; 42<br />
to 38% for HR-) became less common over the time. Information<br />
on chemotherapy/systemic therapies is unavailable in this dataset.<br />
Conclusions. Although, incidence rate of distant stage breast<br />
cancer was stable over a time, there was a higher proportion of<br />
diagnosis of grade I/II stage cancer cases potentially due to earlier<br />
cancer detections by screening programs. The growing proportion<br />
of minorities suggested that screening programs be adjusted to the<br />
changing demographics in the United States.<br />
P3-07-09<br />
Prevalence and effects of off-label use of chemotherapeutic agents<br />
in elderly breast cancer patients: estimates from Surveillance,<br />
Epidemiology and End Results-Medicare data<br />
Eaton AA, Sima CS, Panageas KS. Memorial Sloan-Kettering <strong>Cancer</strong><br />
Center, New York, NY<br />
Purpose: To gain FDA approval, drug companies submit evidence<br />
from clinical trials demonstrating that a drug is safe and efficacious<br />
in a certain setting. Current regulations allow oncologists to prescribe<br />
approved drugs for uses other than those for which the drug was<br />
approved (off-label use). While there seems to be a consensus that<br />
off-label use is common in oncology, there is a lack of published data<br />
on recent trends and on utilization in different populations.<br />
The strength of evidence demonstrating safety and efficacy varies<br />
for drugs used in the off-label setting, and patients may be at risk for<br />
unacceptable toxicity. The risk of toxicity may be higher among older<br />
patients, whose ability to tolerate chemotherapy is compromised by<br />
age-related organ decline and comorbidities. Our objective was to<br />
describe the prevalence of off-label use of chemotherapeutic agents<br />
in elderly breast cancer patients with Medicare coverage and to<br />
compare toxicity between patients using off-label drugs and patients<br />
using only approved drugs.<br />
Materials and Methods: We identified women 65 and older with a<br />
first primary breast cancer diagnosed in 2000-2007 from Surveillance,<br />
Epidemiology and End Results (SEER) cancer registry data linked<br />
with Medicare claims. Specific chemotherapeutic agents used<br />
following diagnosis were identified in Medicare claims and classified<br />
as on- or off-label use based on whether the drug was approved<br />
for breast cancer as of May 2012. Thirty-day toxicity (ER visit,<br />
hospitalization or death) was compared between patients whose first<br />
line regimen contained only approved drugs and patients whose first<br />
line regimen contained at least one off-label drug using the Cochran-<br />
Mantel-Haenszel test.<br />
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Results:<br />
Use of chemotherapy in breast cancer patients, by stage at diagnosis<br />
Stage 0/1 Stage 2 Stage 3 Stage 4 Overall<br />
N 59997 29170 7420 5237 101824<br />
Chemotherapy use<br />
Any chemotherapy 6% 36% 52% 38% 20%<br />
Any approved chemotherapy 6% 36% 52% 37% 20%<br />
Any off-label chemotherapy 0.6% 4% 8% 12% 3%<br />
30-day toxicity<br />
Approved drugs only 5% 7% 10% 15% 6%<br />
At least one off-label drug 6% 8% 16% 17% 8%<br />
The most commonly-used approved drugs were cyclophosphamide<br />
(used in 14% of patients), doxorubicin (10%), docetaxel (5%),<br />
fluorouracil (5%), and paclitaxel (5%).<br />
In total, forty-five off-label agents were used. Vinorelbine and<br />
carboplatin were each used in 1% of patients. No other off-label drug<br />
was used in more than 109 (0.11%) of patients.<br />
Toxicity was significantly higher for patients treated with off-label<br />
agents compared to patients treated with only approved drugs, after<br />
adjusting for stage at diagnosis (p=0.01).<br />
Conclusions: In this population-based cohort, rates of chemotherapy<br />
use were generally low, and rates of off-label use were even lower,<br />
with only 3% of patients treated off-label. Off-label use became more<br />
common as stage at diagnosis increased, with use increasing from 1%<br />
in stage 0/1 patients to 12% in stage 4 patients. The higher toxicity<br />
rates observed in patients treated with off-label drugs may indicate<br />
that these drugs are less safe than approved agents. This result will<br />
be confirmed in a matched analysis accounting for age, stage and<br />
comorbidities.<br />
P3-07-10<br />
Effect of lifestyle and single nucleotide polymorphisms on breast<br />
cancer risk: A case-control study in Japanese women<br />
Mizoo T, Taira N, Nishiyama K, Nogami T, Iwamoto T, Motoki T,<br />
Shien T, Matuoka J, Doihara H, Ishihara S, Kawai N, Kawasaki K,<br />
Ishibe Y, Ogasawara Y. Okayama Medical University, Okayama,<br />
Japan; Okayama Saiseikai General Hospital, Okayama, Japan;<br />
Okayama Rousai Hospital, Okayama, Japan; Kagawa Prefectural<br />
<strong>Cancer</strong> Detection Center, Takamatsu, Kagawa, Japan; Mizushima<br />
Kyodo Hospital, Kurashiki, Okayama, Japan; Kagawa Prefectural<br />
Central Hospital, Takamatsu, Kagawa, Jordan<br />
[Background] Lifestyle, including diet and physical activity, and birth/<br />
breastfeeding history are known to affect the risk for breast cancer.<br />
A correlation between single nucleotide polymorphisms (SNPs) and<br />
breast cancer risk has also been suggested in some reports, but the<br />
gene-environment interaction with breast cancer risk has not been<br />
examined widely.<br />
[Methods] The subjects were 476 breast cancer patients and 528<br />
controls who attended a health check and had no history of breast<br />
cancer. Lifestyle was examined using a questionnaire with 48<br />
questions about diet, physical activity, smoking habits, alcohol<br />
intake, and birth/breastfeeding history, etc. Based on past reports,<br />
we analyzed 6 SNPs (TNRC9-rs3803662, LSP1/11q-rs3817198,<br />
MAP3K1-rs889312, 8q24-rs13281615, 5p12-rs981782, and TGFβ1-<br />
rs1800470) using blood samples, and calculated age-adjusted odds<br />
ratios in a multiple logistic regression analysis.<br />
[Results] The study was performed from December 2010 to<br />
November 2011. Lifestyle factors (age-adjusted odds ratio, [95%<br />
confident interval]) found to have a significant correlation with<br />
development of breast cancer included BMI (1.041, [1.00 - 1.08]),<br />
smoking history (2.28, [1.45 - 3.65]), small number of births (1.18,<br />
[1.05 - 1.34]), no exercise during leisure time (1.36, [1.06 - 1.77]),<br />
low intake of green and yellow vegetables (1.69, [1.01 - 2.85]), and<br />
low intake of mushrooms (1.58, [1.05 - 2.39]). Stratified analysis<br />
based on menopause status showed that smoking history (1.85,<br />
[1.00 - 3.49]) and low intake of green and yellow vegetables (2.5,<br />
[1.03 - 5.88]) were significant risk factors before menopause, and<br />
that smoking history (2.28, [1.45 - 3.65]), low intake of green and<br />
yellow vegetables (2.24, [1.09 - 4.68]), no exercise during leisure<br />
time (1.67, [1.19 - 2.36]), small number of births (1.49, [1.25 - 1.78]),<br />
and no breastfeeding history (1.03, [1.01 - 1.06]) were significant risk<br />
factors after menopause. The results of SNP analysis suggested that<br />
TNRC9-rs3803662 was a significant risk factor in women before<br />
menopause (2.29, [1.25 - 4.25]). However, in multivariate analysis<br />
including lifestyle factors and SNPs, only smoking history emerged<br />
as a significant risk factor in women before menopause.<br />
[Conclusion] A correlation between lifestyle and breast cancer risk<br />
was found in this study, consistent with previous findings. Lifestyle<br />
and environmental factors such as births and breastfeeding may be<br />
more important than SNPs as risk factors for breast cancer.<br />
P3-07-11<br />
Retrospective database review of outcomes in invasive lobular<br />
carcinoma and invasive ductal carcinoma of the breast<br />
Shih Y-C, Dillon P. University of Virginia, Charlottesville, VA<br />
Background. Invasive lobular carcinoma (ILC) and invasive ductal<br />
carcinoma (IDC) are histologically distinct breast cancer subtypes.<br />
While ILC and IDC have similar disease-free survival (DFS) and<br />
overall survival (OS), the patterns of metastatic recurrence are<br />
suspected to differ due to differing adhesion markers.<br />
Methods. Retrospective review of a cohort of breast cancer patients<br />
treated at a tertiary academic medical center from May 1999 to April<br />
2012 was performed. Demographic, pathologic, treatment and followup<br />
data were collected from a cancer database and the institutional<br />
medical records.<br />
Results. There were 179 ILC and 358 IDC (1:2 stage-matched)<br />
patients in the study period. Mean age (59 vs. 58 years), gender,<br />
race (88% vs. 80% Caucasian), menopause state (71% vs. 66%<br />
post-menopausal), and family history (48% vs. 42% positive for<br />
breast cancer) were similar in the two groups. Median follow-up<br />
was 4.7 years. ILC patients had more negative mammograms upon<br />
diagnosis (6.8% vs. 1.4%, p=0.001), and their breast cancers were<br />
more likely to be hormone-receptor-positive/HER2-negative (90%<br />
vs. 69%, p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
P3-07-12<br />
Risk Factors for <strong>Breast</strong> <strong>Cancer</strong> in Women Served in Odete<br />
Valadares Maternity, Belo Horizonte-MG<br />
Sediyama CMNO, Peluzio MCG, Abranches MV. Universidade<br />
Federal de Viçosa, Viçosa, MG, Brazil<br />
With changes in lifestyle of the population and changes in women<br />
reproductive patterns in the last century, the profile of mortality<br />
among women has changed, today the prevailing non-infectious<br />
chronic diseases, like cancer, including breast cancer. This paper is<br />
a case-control population-based, with the objective of evaluating the<br />
risk factors and their association with breast cancer in a population of<br />
women seen in Odete Valadares Maternity, in the Hospital Foundation<br />
of the State of Minas Gerais, in Belo Horizonte, between January and<br />
July 2006. Inclusion criteria were age over 18 years and referral for<br />
mammography service. Women with abnormal mammography and<br />
confirmation of malignancy of the breast were invited to participate<br />
in the study, and those with normal mammography were invited<br />
to compose the control group. We evaluated 710 women and 456<br />
selected to participate in the study, 261 with breast cancer and 195<br />
healthy controls.<br />
Table1: Characterization of the demographic, anthropometric and reproductive patient cases and<br />
controls<br />
Variables Control Cases p<br />
Mean(SD) Median Mean(SD) Median<br />
65.55(39.80-<br />
Weight (kg) 67.12(±14.82)<br />
66.74(±14.13) 64.30(39-116) 0.27*<br />
113.68)<br />
Age (years) 47.82(±9.62) 47(16-73) 54.8(±11.93) 53(30-92) 0.8 1.191 0.715 - 1.984<br />
Alcoholism 0.5483 0.351 - 0.856#<br />
Smoking 1.084 0.694 - 1.693<br />
* A positive association. # Protective Association.<br />
This study found a positive association between physical inactivity,<br />
menopause, nulliparity, lack of breastfeeding and family history of<br />
breast cancer and the diagnosis of breast cancer, and alcohol conferred<br />
a protective effect in this population.<br />
P3-07-13<br />
Importance of socioeconomic status in relation to breast cancer<br />
risk and prognostic factors in Argentina.<br />
Croce MV, Demichelis SO, Cermignani L, Zwenger A, Segal-Eiras<br />
A, Giacomi N. Faculty of Medical Sciences, UNLP, La Plata, Buenos<br />
Aires, Argentina<br />
In Argentina, there are no studies evaluating neither breast cancer<br />
screening nor risk and prognostic factors in relation to socioeconomic<br />
status among women in metropolitan areas. Taking into account<br />
that Argentina presents social and economical disparities and that<br />
there is a mixture of features of both developed and developing<br />
societies, it is interesting to compare prognostic and risk factors<br />
in disadvantaged and advantaged women as it would clarify the<br />
influence of socioeconomic factors in breast cancer biology. The<br />
purpose of this study was to compare risk and prognostic factors of<br />
invasive breast cancer in two different Argentine populations. Study<br />
participants and data collection. A total of 625 women who had a<br />
histologically confirmed diagnosis of invasive primary breast cancer<br />
were included; 270 patients belonged to a private clinic of the city<br />
of La Plata (province of Buenos Aires) belonging to an Advantaged<br />
Population (AP) and 355 patients belonged to a public hospital of<br />
the city of Neuquén (province of Neuquén, Patagonia) belonging<br />
to a Disadvantaged Population (DP). Women of these geographical<br />
regions and first diagnosed with invasive primary breast carcinoma<br />
from 2002 until 2007 were eligible as cases. There were no racial or<br />
ethnic differences between the two groups of women; all of them were<br />
born in Argentina. Risk factors included age at diagnosis, menarche<br />
and menopause status, breastfeeding and parity, while prognostic<br />
factors were: disease stage, number of metastatic lymph nodes, tumor<br />
size, histological and nuclear grade, vascular invasion, ER, PR, and<br />
Her2neu statuses. Methods: Statistical analysis included frequency<br />
analysis and ANOVA (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P3-07-14<br />
Initial treatment and survival among elderly breast cancer<br />
patients in the United States by estrogen receptor status and<br />
cancer stage at diagnosis: an analysis of national registry data<br />
2000-2009<br />
Lang K, Huang H, Namjoshi M, Federico V, Menzin J. Boston Health<br />
Economics, Waltham, MA; Novartis Pharmaceuticals Corporation,<br />
East Hanover, NJ<br />
BACKGROUND: There are few recent studies of initial treatment<br />
and survival among elderly, newly diagnosed breast cancer (BC)<br />
patients by estrogen receptor (ER) status and cancer stage at diagnosis.<br />
METHODS: The linked Surveillance and Epidemiology End Results-<br />
Medicare (SEER-Medicare) database was used for this analysis. SEER<br />
is an epidemiologic surveillance system consisting of populationbased<br />
tumor registries designed to track cancer incidence and survival<br />
in geographically defined areas that represent approximately 25% of<br />
the US population. The SEER registry file (available through 2007)<br />
is linked to Medicare claims and enrollment data available through<br />
2009. We identified female patients newly diagnosed with Stage I, II,<br />
III, or IV breast cancer in a SEER registry between January 2002 and<br />
December 2007. Study patients were required to be aged 66+ years<br />
with no prior history of any other (non-breast) cancer. Patients were<br />
followed from the date of breast cancer diagnosis through death or<br />
December 31, 2009. Patients were identified as ER+ (ER-) if the ER<br />
assay was reported to SEER as positive/elevated (negative/normal).<br />
Demographics, initial treatment (surgery or radiation within 4 months<br />
of diagnosis), and survival (proportion of patients who died during<br />
the study period, survival at 96 months and median survival) were<br />
evaluated by ER status and cancer stage. Kaplan-Meier (KM) survival<br />
curves were estimated by ER status and stage.<br />
RESULTS: 70,845 female BC patients (59,243 ER+, and 11,602<br />
ER-) were identified. Age at diagnosis was similar for ER+ and ERpatients<br />
(mean [SD]: 75-77 [7] years; median: 74-76 years) across all<br />
stages. More ER+ patients were White (86% vs. 80% for ER-), and<br />
diagnosed at Stage I (56% vs. 39%). Fewer ER+ than ER- patients<br />
were diagnosed at Stage II (32% vs. 39%), Stage III (8% vs. 15%)<br />
and Stage IV (4% vs. 7%). Most patients had surgery in the first 4<br />
months following diagnosis (96% ER+; 94% ER-), with Stage IV<br />
patients least likely (41% ER+ vs. 47% ER-). ER+ patients were more<br />
likely to receive initial radiation than ER- patients (48% vs. 42%),<br />
with a similar trend by stage (Stage I: 54% vs. 50%; Stage II: 40%<br />
vs. 35%; Stage III: 46% vs. 44%; Stage IV: 30% vs. 29%). Fewer<br />
ER+ patients died during follow-up (23% vs. 36% of ER- patients).<br />
KM survival analyses suggest that survival rates were higher for ER+<br />
than ER- patients for the entire study period, overall (survival at 96<br />
months: 64% vs. 52%), and by stage (Stage I: 73% vs. 70%; Stage<br />
II: 60% vs. 50%; Stage III: 38% [median survival 72 months] vs.<br />
27% [median survival 41 months]; Stage IV: 12% [median survival<br />
23 months] vs. 8% [median survival 9 months]).<br />
CONCLUSIONS: Among elderly patients diagnosed with BC,<br />
those with ER+ status were diagnosed at earlier stages and had better<br />
survival outcomes. Further study of treatment patterns and outcomes<br />
by ER status is warranted.<br />
P3-08-01<br />
The prospective risk of ovarian cancer in 1433 women in a breast<br />
cancer family history clinic: no increased risk in families testing<br />
negative for BRCA1 and BRCA2.<br />
Evans DGR, Ingham SL, Sahin S, Buchan I, Warwick J, O’Hara C,<br />
Moran A, Howell A. St Mary’s Hospital, Manchester, United Kingdom;<br />
Wythenshawe Hospital, Manchester, United Kingdom; The University<br />
of Manchester, Manchester, United Kingdom; Imperial College<br />
London, United Kingdom; North West <strong>Cancer</strong> Intelligence Service,<br />
NHS Foundation Trust, Manchester, United Kingdom; Christie<br />
Hospital, Manchester, United Kingdom<br />
Since the identification of the BRCA1 and BRCA2 genes speculation<br />
has continued regarding the breast and ovarian cancer risk associated<br />
with mutations in these genes. Also, as to whether mutations in these<br />
genes account for the majority of the association between breast and<br />
ovarian cancer. Identification of RAD51C and RAD51D mutations<br />
in breast/ovarian cancer families has reawakened the debate as to<br />
whether it is safe to reassure women from BRCA negative families<br />
that they are not at increased risk of ovarian cancer. 1433 women<br />
from breast cancer families that had tested negative for BRCA1/2<br />
were followed for a total of between 0.04 and 25 years and checked<br />
against a cancer registry for ovarian cancer incidence. Data was<br />
censored at ovarian cancer diagnosis, oophorectomy or death. During<br />
16358 women years of follow up no invasive epithelial ovarian cancer<br />
occurred, although 2 borderline tumors were diagnosed. Expected<br />
rates for this cohort from cancer registry data were 2.75 epithelial<br />
ovarian tumors with 2.52 for invasive cancer and 0.23 for borderline<br />
tumors. The upper confidence limit for invasive RR was 1.3 and for<br />
borderline tumors 0.97-31. In conclusion this the largest prospective<br />
follow up of a BRCA negative cohort has demonstrated that there is<br />
no increase in risk of invasive ovarian cancer in families that have<br />
tested negative for BRCA1/2.<br />
P3-08-02<br />
Common variants at 10p14 and 1p11.2 display heterogeneity in<br />
breast cancer associations by E-cadherin tumor tissue expression<br />
in two independent datasets<br />
Horne HN, Sherman ME, Garcia-Closas M, Pharoah PD, Blows<br />
FM, Yang XR, Lissowska J, Brinton LA, Chanock SJ, Figueroa JD.<br />
National <strong>Cancer</strong> Institute, Rockville, MD; The Institute of <strong>Cancer</strong><br />
Research, Sutton, Surrey, United Kingdom; University of Cambridge,<br />
United Kingdom; M. Sklodowska-Curie Memorial <strong>Cancer</strong> Center and<br />
Institute of Oncology, Warsaw, Poland<br />
Background: E-cadherin is a tumor suppressor gene involved in<br />
cell-cell adhesion, epithelial-to-mesenchymal transitions (EMT) and<br />
invasion. Loss of E-cadherin expression is strongly associated with<br />
lobular breast cancers, which exhibit single cell patterns of infiltration<br />
and are often estrogen receptor positive. We sought to determine if<br />
relative risk estimates for 19 established breast cancer susceptibility<br />
loci were modified by E-cadherin breast tumor tissue expression.<br />
Methods: Case-control analyses included up to 1885 invasive breast<br />
cancer cases and 2366 age and site matched controls aged 20-74 years<br />
from the Polish <strong>Breast</strong> <strong>Cancer</strong> Study (PBCS), a population based casecontrol<br />
study conducted in Poland from 2000-2003. Genotyping of<br />
the 19 single nucleotide polymorphisms (SNPs) was performed using<br />
TaqMan® assays. Tissue expression of E-cadherin was assessed using<br />
immunohistochemical (IHC) staining of tissue microarrays and IHC<br />
results were scored as the product of percent positive tumor cells x<br />
intensity. Tumors having a score of
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
to estimate odds ratios (OR) and 95% confidence intervals (95% CI)<br />
for each breast cancer subtype, defined by E-cadherin expression<br />
levels, compared to controls. Case-only data from the PBCS (N = 797)<br />
and the Study of Epidemiology and Risk Factors in <strong>Cancer</strong> Heredity,<br />
SEARCH (N = 2155) was used in logistic regression models to test<br />
for heterogeneity of SNPs by E-cadherin expression.<br />
Results: Three SNPs suggested significant heterogeneity by<br />
E-cadherin expression in the PBCS: rs2046210 at 6q25.1(ESR1)<br />
[per-allele ORs (95% CI); 1.53 (1.19-1.98) for E-cadherin low tumors<br />
and 0.99 (0.86-1.14) for E-cadherin high tumors, P-heterogeneity<br />
= 0.002]; rs1045485 at 10p14 (CASP8) [per-allele ORs (95% CI);<br />
0.62 (0.41-0.93) for E-cadherin low tumors and 0.98 (0.81-1.18) for<br />
E-cadherin high tumors, P-heterogeneity = 0.04]; and rs11249433<br />
at 1p11.2 (NOTCH2/FCGR1B) [per-allele ORs (95% CI); 1.29<br />
(1.02-1.64) for E-cadherin low tumors and 1.01 (0.88-1.15) for<br />
E-cadherin high tumors, P-heterogeneity = 0.06]. Combined caseonly<br />
analysis of PBCS and SEARCH for these three SNPs showed<br />
significant heterogeneity by E-cadherin expression for rs11249433<br />
[Interaction OR (95% CI); 1.19 (1.05-1.36), P-heterogeneity =<br />
0.007] and rs1045485 [Interaction OR (95% CI); 0.69 (0.53-0.90),<br />
P-heterogeneity = 0.007]. The association with rs2046210 [Interaction<br />
OR (95% CI); 1.12 (0.61-2.03), P-heterogeneity = 0.73] did not<br />
remain significant in combined analyses.<br />
Conclusion: Our findings provide evidence that associations for<br />
breast cancer susceptibility loci vary by E-cadherin tumor tissue<br />
expression, which has not been described previously. Specifically, our<br />
results suggest that the genetic markers rs11249433 and rs1045485<br />
may preferentially modify risk for tumors with low or absent<br />
E-cadherin expression in two independent data sets.<br />
P3-08-03<br />
Urinary levels of prostaglandin E 2 metabolite and postmenopausal<br />
breast cancer<br />
Kim S, Taylor JA, <strong>San</strong>dler DP. Georgia Health Sciences University,<br />
Augusta, GA; National Institute of Environmental Health Sciences,<br />
Research Triangle Park, NC<br />
Estrogens are considered a key player in the mammary carcinogenesis.<br />
In postmenopausal women, peripheral aromatization of androgens<br />
is the predominant source of estrogens. Given that prostaglandin<br />
E 2 (PGE 2 ) is a potent activator of aromatase expression, we<br />
hypothesized that endogenous level of PGE 2 would influence estrogen<br />
bioavailability and subsequent breast cancer risk in postmenopausal<br />
women. In addition, because PGE 2 synthesis is suppressed by<br />
treatment of non-steroidal anti-inflammatory drugs (NSAIDs)<br />
via inhibition of cyclooxygenase enzyme activity, we further<br />
hypothesized that regular use of NSAIDs may modify the association<br />
between PGE 2 and postmenopausal breast cancer risk. We carried out<br />
a case-cohort analysis within the NIEHS Sister Study, a prospective<br />
cohort study of 50,884 women. Postmenopausal women who were<br />
aged 50 or older and did not report current use of hormones were<br />
eligible for the present analysis (N=11,338). Urinary levels of a major<br />
PGE 2 metabolite (PGE-M), which is generally accepted as the most<br />
accurate index of endogenous PGE 2 formation, were quantified using<br />
liquid chromatography/tandem mass spectrometry in 302 incident<br />
breast cancer cases and 305 subcohort members who were randomly<br />
selected by frequency matching for age among cases. Hazard ratios<br />
(HR) and 95% confidence intervals (95% CI) were estimated using<br />
Prentice’s pseudo-likelihood approach with Barlow’s weighting<br />
scheme. Several factors were associated with higher levels of urinary<br />
PGE-M in the multivariable analysis, including current smoking,<br />
obesity, high caloric intake from saturated fat and surgical menopause.<br />
No associations were observed for dietary intake of omega 3 fatty<br />
acids, use of vitamin supplements and physical activity. Overall, there<br />
was no association between urinary PGE-M and postmenopausal<br />
breast cancer risk. After including the interaction terms between<br />
NSAID use and urinary levels of PGE-M in the model, however, high<br />
levels of urinary PGE-M were associated with an increased risk of<br />
breast cancer in postmenopausal women who did not regularly use<br />
NSAIDs (likelihood ratio test p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
of endogenous and exogenous hormones and hormonal agents such<br />
as tamoxifen, used in the treatment of breast cancer this association<br />
may have wider implications.<br />
P3-08-05<br />
Title: Copy number variation and risk of chemotherapy-related<br />
infection.<br />
Abraham JE, Rueda OM, Chin S-F, Guo Q, Harrington P, Earl<br />
HM, Pharoah PD, Caldas C. Strangeway’s Research Laboratory,<br />
University of Cambridge, Cambridgeshire, United Kingdom;<br />
University of Cambridge NHS Foundation Hospitals, Cambridge,<br />
Cambridgeshire, United Kingdom; <strong>Cancer</strong> Research UK Cambridge<br />
Research Institute, Li Ka Shing Centre, Cambridge, Cambridgeshire,<br />
United Kingdom<br />
Background<br />
Copy-number variations (CNVs) are DNA changes that result in<br />
regions of the genome being either duplicated (copy number gains)<br />
or deleted (copy number losses). CNVs have been identified in 12%<br />
of the human genome. Although CNVs do not appear to have a major<br />
role in disease susceptibility, it is known that they are involved in drug<br />
metabolism, toxicity and response. Infection is a common dose and/or<br />
treatment limiting chemotherapy-related toxicity. Infections can be a<br />
major cause of morbidity and mortality. Although a limited number<br />
of studies have investigated the association of single nucleotide<br />
polymorphisms (SNPs) with severity of infection, no studies so<br />
far have identified CNV associations with chemotherapy-related<br />
infection. In a non-oncological setting, CNVs have been noted to be<br />
associated with altered risk of certain types of infections and severe<br />
sepsis. This study aims to evaluate whether CNV are associated<br />
with the risk of chemotherapy-related infection in a genome wide<br />
association study (GWAS) of breast cancer patients recruited to<br />
clinical trials and treated with chemotherapy regimens including<br />
paclitaxel, epirubicin, cyclophosphamide, gemcitabine, 5fluorouracil<br />
and methotrexate.<br />
Method<br />
DNA from blood and saliva samples were collected as part of the<br />
pharmacogenetics GWAS, PGSNPS. Chemotherapy-related infection<br />
was assessed using the NCI Common Toxicity Criteria (CTC).<br />
Patients (n=1921 samples) were classified as cases (NCI CTC grades<br />
2-4) or as controls (NCI CTC grades 0-1). The Affymetrix SNP6.0<br />
array, which contains more than 946,000 probes for the detection of<br />
CNVs and more than 906,600 SNPs, was used as the copy number<br />
estimation platform. DNA was segmented using DNAcopy (circular<br />
binary segmentation). CNVs were called based on their median and<br />
standard deviation. Log-ratios larger than the median plus 2 times<br />
the standard deviation were considered gains and log-ratios with<br />
values smaller than 2.5 times the standard deviation were considered<br />
as losses. Only regions with a copy number alteration present in<br />
at least a 10% of the samples were considered for the analysis.<br />
Fisher’s exact test was performed on each of these regions and the<br />
variable ‘infection’. 2-side p-values were obtained and adjusted using<br />
Benjamin-Hochberg correction.<br />
Results<br />
One CNV region (frequency of gain 0.16) showed an association<br />
with increased risk of infection (Odds Ratio=1.79, 95% Confidence<br />
Interval [1.34-2.40], P=6.37x10 -5 ). Five other CNV regions<br />
demonstrated copy number gains and three CNV regions showed<br />
copy number losses that were associated with an increased risk of<br />
infection (P=10 -4 ). All regions had a frequency of gain or loss > 0.10<br />
and were therefore not rare variants.<br />
Conclusion<br />
These data suggest that CNVs may play a role in increased risk<br />
of chemotherapy-related toxicity. The most significant CNVs<br />
associated with infection are currently undergoing validation using<br />
an independent cohort of adjuvant breast cancer patients with<br />
similar exposure to chemotherapy and comparable documentation<br />
of chemotherapy-related infection.<br />
P3-08-06<br />
Triple Negative <strong>Breast</strong> <strong>Cancer</strong> and BRCA Status: Implications<br />
for Genetic Counseling<br />
Haque R, Alvarado M, Ahmed SA, Shi JM, Chung JWL, Avila CC,<br />
Zheng CX, Tiller GE. Kaiser Permanente Southern California,<br />
Pasadena, CA<br />
BACKGROUND<br />
Controversy exists whether women newly diagnosed with triple<br />
negative breast cancer (TNBC) should be referred to genetic<br />
counseling as they may be more likely to be BRCA carriers. However,<br />
prior studies included small numbers of carriers and their results have<br />
had limited influence on practice guidelines. The objective of this<br />
study was to determine the association of breast cancer molecular<br />
subtype and BRCA status in a large group of medically insured<br />
women.<br />
METHODS<br />
We examined a cohort of 2,105 women with breast cancer history<br />
tested for BRCA mutations in a large California health plan from<br />
1997-2011. BRCA test results were recorded in the health plan’s<br />
clinical genetics registry. Of the 2,105 breast cancer patients, 249<br />
were BRCA mutation carriers (143 BRCA1 carriers, and 106 BRCA2<br />
carriers). We conducted data linkages of all patients with the health<br />
plan’s NCI-SEER affiliated tumor registry and identified ER, PR,<br />
and HER2. HER2 status was also captured from pathology reports<br />
using natural language processing. ER, PR, and HER2 status were<br />
assessed by immunohistochemical or FISH techniques. Patients were<br />
classified into four main biologic subtypes: triple negative (ER-/PR-/<br />
HER2-); luminal A (ER+ and/or PR+/HER2-); luminal B (ER+ and/or<br />
PR+/HER2+); and HER2-enriched (HER2+/ER-). We examined the<br />
association between molecular subtypes (collapsed into TNBC vs. non<br />
TNBC categories) and BRCA1/2 mutation status using contingency<br />
table analyses. P-values (two-sided) were estimated using chi-square<br />
analysis. Multivariable logistic regression was used to estimated<br />
adjusted odds ratios (OR) and 95% confidence intervals.<br />
RESULTS<br />
TNBC subtype was strongly associated with BRCA status (P
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
CONCLUSION<br />
TNBC was strongly associated with BRCA1 status, but not with<br />
BRCA2 status. Statistically significant numbers of patients with<br />
BRCA mutations have a TNBC profile. These patients should<br />
therefore be referred to clinical genetics for further evaluation and<br />
possible testing.<br />
P3-08-07<br />
HER2 positive breast carcinomas: trend in evolution between<br />
1998 and 2008 and relationship with clinico-pathological<br />
characteristics in a population based study.<br />
Beltjens F, Bertaut A, Pigeonnat S, Pouget N, Guiu S, Poillot M-L,<br />
Charon-Barra C, Coudert B, Dabakuyo S, Fumoleau P, Arveux P,<br />
Arnould L. Centre GF Leclerc, Dijon, France<br />
Background:<br />
Determination of HER2 status in invasive breast carcinomas is now<br />
mandatory for the optimal treatment of the patient. A vast majority<br />
of initial published studies described positivity in about 20 to 25<br />
% of breast carcinomas, but the proportion of HER2 positive gene<br />
expression in women with breast cancer varies in the literature<br />
from 9 to 74%. The population of the tumor analyzed (for example<br />
histologic types, stage, age), the type of the assays used and the<br />
lack of uniformity or quality controls in detection assays may partly<br />
explain these differences. Our study describes the evolution of HER2<br />
positive invasive breast cancer proportions during a period of 10<br />
years and identifies clinical and pathological characteristics of these<br />
positive tumors.<br />
Methods:<br />
Based on the regional, population-based breast cancer registry, we<br />
identify 2396 patients diagnosed with invasive breast cancer in the<br />
Côte-d’Or department and treated in a single institution between 1998<br />
and 2008. The HER2 status was determined by immunohistochemistry<br />
and by fluorescence in situ hybridization by a single team that<br />
performed regular internal quality controls and participated to<br />
multiannual external international quality control programs.<br />
Results:<br />
During the 1998-2008 period, 12.8% of invasive breast cancers<br />
were identified as HER2 positive, with no trend to annual variations<br />
(p=0.27). During the same period, despite an increase of 45% of<br />
the annual diagnosed cancers in the institution, the clinical and<br />
pathological characteristics such as age, tumor size, grade, hormonal<br />
receptors expression remain stable. We only noticed a slight but<br />
significant increase of lobular carcinomas (p=0.036). In multivariate<br />
analysis, HER2 positivity was as expected associated with : hormonal<br />
receptor negative status (OR=1.7 [IC95% : 1.2-2.4], p=0.0035),<br />
metastatic presentation at diagnosis (OR=2 [IC95% : 1.2-3.4],<br />
p=0.0092), ductal subtype (OR=1.9 [IC95% : 1.1-3.1], p=0.0178)<br />
and high SRB grade (OR=2.8 [IC95% : 1.7-4.5] for SBR II, OR=5.4<br />
[IC95% : 3.2-9.1] for SBR III, p=0.0035). Conversely, patients older<br />
than 75 years presented mostly HER2 negative tumors (OR=0.5<br />
[IC95% : 0.3-0.8], p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P3-08-09<br />
Clinical and Pathological Characteristics of <strong>Breast</strong> <strong>Cancer</strong> in<br />
Women with Neurofibromatosis Type 1<br />
Yap Y-S, Wong J, Chan M, Yong W-S, Ong K-W, Lo S-K, Ngeow J,<br />
Tan B, Madhukumar P, Tan M-H, Ang P, Teh B-T, Tan P-H, Lee AS-<br />
G. National <strong>Cancer</strong> Centre Singapore; Singapore General Hospital<br />
Background:<br />
Neurofibromatosis type 1(NF1) is an autosomal dominant genetic<br />
disorder affecting 1 in 3,000 individuals worldwide. Risk of cancer,<br />
including breast cancer, is increased, as NF1 is a tumour suppressor<br />
gene. There is limited data on the characteristics of breast cancer in<br />
individuals with NF1.<br />
Objectives:<br />
To study the clinical and pathological characteristics of breast cancer<br />
in women with NF1.<br />
Methodology:<br />
Patients with both NF1 and breast cancer were identified retrospectively<br />
from hospital records as well as prospectively when seen at National<br />
<strong>Cancer</strong> Centre Singapore (NCCS) and Singapore General Hospital<br />
(SGH). All women had histologically proven breast cancer and<br />
fulfilled at least 2 of the 7 criteria developed by the NIH Consensus<br />
Conference for clinical diagnosis of NF1. Germline NF1 mutation<br />
sequencing is being performed on patients with blood specimens<br />
available. Details on patient demographics, tumour grade, stage,<br />
receptor status and clinical outcome were evaluated. The pathological<br />
characteristics of NF1-associated breast cancer were then compared<br />
to sporadic breast cancers in our 2001-2004 cohort, with a focus on<br />
grade and HER2 positivity rate.<br />
Results:<br />
We identified 13 women with NF1 and breast cancer seen at our<br />
institutions from 2001 to present date. Average age of breast cancer<br />
diagnosis for women testing positive was 48 years (range 30-64).<br />
All 13 patients had invasive ductal carcinoma; of which 5 were<br />
stage 3 or 4 at diagnosis. To date, 4 out of 12 patients with stage<br />
1-3 breast cancer have relapsed. Grade, estrogen, progesterone and<br />
HER2 receptor status were fully available for 12 patients. Ten out<br />
of 12 tumours (83%) were grade 3, compared to 45% (705/1578)<br />
among our sporadic breast cancers (p=0.007). Eight out of 12(67%)<br />
NF1-associated breast cancers were HER2 positive (IHC 3+ or FISH<br />
positive), compared to 27% (367/1367) in sporadic cancers (p=0.002).<br />
Two other NF1-associated tumours were triple negative, and two<br />
were hormone receptor positive and HER2 negative. Six out of 12<br />
(50%) NF1-associated cancers were estrogen receptor (ER) positive,<br />
compared to 67% (1124/1689) in sporadic cancers (p=0.2).<br />
Conclusion:<br />
Our findings suggest that NF1-associated breast cancer tends to<br />
be more aggressive, with a higher frequency of grade 3 and HER2<br />
positive tumours compared to sporadic breast cancer. Further genomic<br />
profiling of these tumours (in progress) may elucidate the role of<br />
NF1 in breast cancer. This may also have implications for sporadic<br />
tumours with somatic NF1 mutations in individuals without NF1.<br />
P3-09-01<br />
Odds of the triple negative subtype and survival of stages 1-3<br />
breast cancer: Variation by race/ethnicity<br />
Parise C, Caggiano V. Sutter Institute for Medical Research,<br />
Sacramento, CA<br />
Background<br />
Triple negative (TN) breast cancer is known to be more common in<br />
black and Hispanic women and associated with poor survival. This<br />
study assesses the differences in the odds and survival of the TN<br />
versus the ER+/PR+/HER2- (the most common subtype) by race/<br />
ethnicity separately for AJCC stages 1, 2, and 3.<br />
Methods<br />
Using the California <strong>Cancer</strong> Registry for years 2000-2010, we<br />
examined 91,393 cases of stages 1-3 TN and ER+/PR+/HER2- first<br />
primary female invasive breast cancer. Race/ethnicity was defined<br />
as white, black, Hispanic, and Asian/Pacific Islander (API). Logistic<br />
regression was used to assess the association of race with odds of<br />
the TN subtype. Kaplan-Meier was used to compute 6-year survival.<br />
Cox proportional hazards was used to assess the risk of mortality of<br />
the TN subtype by race adjusting for age, grade, year of diagnosis,<br />
and socioeconomic status. All analyses were run separately for stages<br />
1, 2, and 3.<br />
Results<br />
The table shows the distribution of the TN and ER+/PR+/HER2-<br />
subtypes by stage and race/ethnicity.<br />
The distribution of the TN and ER+/PR+/HER2-subtypes by stage and race/ethnicity<br />
Stage 1 Stage 2 Stage 3 Total (%)<br />
Race/ ER+/PR+/<br />
ER+/PR+/<br />
ER+/PR+/<br />
TN<br />
TN<br />
TN<br />
ethnicity HER2-<br />
HER2-<br />
HER2-<br />
White 29,647 3,815 18,797 4,677 4,353 1,432 62,721(68.6)<br />
Black 1,438 565 1,392 987 410 377 5,169(5.7)<br />
Hispanic 4,834 977 4,283 1,771 1,409 623 13,897(15.2)<br />
API 4,086 568 3,146 834 747 225 9,606(10.5)<br />
Total (%) 40,005(43.8) 5,925(6.5) 27,618(30.2) 8,269(9.0) 6,919(7.6) 2,657(2.9) 91,393<br />
Blacks had increased odds of the TN compared with whites for stages<br />
1 (OR=2.24; 95%CI=1.96-2.56); 2 (OR=2.01; 95%CI=1.81-2.25) and<br />
3 (OR=2.00; 95%CI=1.66-2.40).<br />
Hispanics had increased odds for the TN in stages 1 (OR=1.23;<br />
95%CI=1.11-1.35) and 2(OR=1.20; 95%CI=1.11-1.31). APIs had<br />
decreased odds of the TN in stages 2 (OR=0.85; 95%CI=0.77-0.93)<br />
and 3 (OR=0.77; 95%CI=0.64-0.92).<br />
KM survival showed that APIs had the best 72 month survival for<br />
the TN in stages 1 (86%), 2 (78%), and 3(59%).<br />
Hazard ratios (HRs) indicated that all races with TN had the same risk<br />
of mortality in stage 1. Only in stage 2 did blacks have an increased<br />
risk of mortality (HR=1.17; 95%CI=1.02-1.36) while APIs had a<br />
decreased risk (HR=0.78; 95%CI=0.65-0.94). In stage 3, Hispanics<br />
(HR=0.85; 95%CI=0.72-0.99) and APIs (HR=0.70; 95%CI=0.55-<br />
0.89) had decreased risk of mortality compared with whites.<br />
Conclusions<br />
Race/ethnicity is an important factor for survival of the TN subtype:<br />
1. Although blacks and Hispanics are more likely to have the TN<br />
subtype, blacks have an increased risk of mortality compared with<br />
whites only in stage 2.<br />
2. For stage 1, all races have the same risk of mortality.<br />
3. Hispanics have decreased risk of mortality in stage 3.<br />
4. APIs have decreased risk of mortality in both stages 2 and 3.<br />
P3-09-02<br />
The HER2 –positive subtypes by stage and race/ethnicity<br />
Caggiano V, Parise C. Sutter Institute for Medical Research,<br />
Sacramento, CA<br />
HER2-positivity is often associated with poor survival. The purpose<br />
of this study is to determine if there are differences in mortality among<br />
the HER-positive subtypes when stratified by stage and race/ethnicity.<br />
Methods<br />
Using the California <strong>Cancer</strong> Registry for years 2000-2010, we<br />
examined 99,897 cases of stages 1-3 ER+/PR+/HER2- and all<br />
HER2-positive first primary female invasive breast cancers. Race/<br />
ethnicity was defined as white, black, Hispanic, and Asian/Pacific<br />
Islander (API). Kaplan-Meier (KM) and the Log-Rank test were used<br />
to compute 6-year survival. Cox proportional hazards was used to<br />
assess the risk of mortality of each of the HER2-positive subtypes<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
when compared with the ER+/PR+/HER2- subtype (the most common<br />
subtype). All analyses were adjusted for age, grade, year of diagnosis<br />
(
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
luminal B, TN, and Her2-type). Demographics (age at diagnosis,<br />
menopausal status, and BMI) were collected from medical records.<br />
Case-only odds ratios (ORs) and 95% confidence intervals (CIs) were<br />
estimated using logistic regression, adjusting for age at diagnosis.<br />
Results In all cases, the patients were Japanese. Of the 531 cases<br />
with IHC marker data, 333 (62.7%) were classified as luminal A,<br />
85 (16.0%) were luminal B, 43 (8.1%) were Her2-type, and the<br />
remaining 70 cases (13.2%) were TN. The distribution of patient<br />
demographics (age at diagnosis, menopausal status, and BMI) did<br />
not differ significantly by breast cancer tumor subtype. Case-only<br />
ORs comparing each subtype to luminal A were caluculated. Of<br />
the TN cases, postmenopausal TN cases were more likely to be<br />
underweight (OR = 3.14, 95% CI = 1.19 to 8.01). Although some<br />
epidemiological studies have reported that higher BMI was associated<br />
with premenopausal TN cases compared with luminal A cases, this<br />
association was not found among premenopausal TN cases analyzed<br />
using BMI 18.5 to 24.9 kg/m 2 as the reference in this analysis.<br />
However, there were no underweight cases (BMI < 18.5 kg/m 2 )<br />
among the premenopausal TN cases in the present study. Therefore,<br />
the association between BMI and the TN subtype was also analyzed<br />
using BMI < 25 kg/m 2 as the reference. Compared to luminal A cases,<br />
premenopausal TN cases were more likely to be obese (OR = 4.11,<br />
95% CI = 1.10 to 14.40), similar to reports from Western countries.<br />
Compared to luminal A cases, premenopausal luminal B cases were<br />
likely to be underweight (OR = 3.27, 95% CI = 0.88 to 11.39) or obese<br />
(≥ 25 kg/m 2 ) (OR = 3.32, 95% CI = 0.98 to 10.81), yet this association<br />
was of borderline significance. Compared to luminal A cases, luminal<br />
B and Her2-type cases were likely to be underweight (BMI < 18.5<br />
kg/m 2 ), yet this association was of borderline significance (luminal<br />
B: OR = 2.12, 95% CI = 0.97 to 4.46; Her2-type: OR = 2.53, 95%<br />
CI = 0.92 to 6.36).<br />
Conclusions In the present study, significant heterogeneity of<br />
associations between BMI and tumor subtypes was observed. <strong>Breast</strong><br />
cancer subtypes may have different etiologies associated with each<br />
subtype.<br />
P3-09-05<br />
The role of breast size in detection of breast cancer in asian women<br />
Lee S, <strong>San</strong>dhu H, Zheng Y. Holy Name Medical Center<br />
Introduction. Asian women typically have smaller breast sizes than<br />
those of Caucasian women and a recent survey revealed a common<br />
belief in the Korean community that smaller breast means lesser risk<br />
of developing breast cancer. However, since breast density plays<br />
a strong role in breast cancer risk in women with smaller breasts,<br />
Korean women who follow the trend of higher breast density may<br />
have increased risk of breast cancer, with smaller breast size.<br />
Materials and Methods. Mammograms from 2,050 Korean American<br />
women were obtained from Holy Name Medical Center during the<br />
years 2008 to 2011. The breast density was analyzed and compared to<br />
that reported for Caucasian women. The role of smaller breast size was<br />
further evaluated by randomly selecting 85 patients whose breast sizes<br />
were obtained by using image analysis of the mammograms using<br />
ImageJ, an image processing software developed by the National<br />
Institute of Health.<br />
Results. The data from 2050 Korean American women revealed<br />
that Korean American women have denser breast tissue than those<br />
reported for Caucasian women. In addition, 61% of these women<br />
who developed breast cancer were in high (BI-RADS 3 or 4) breast<br />
density groups. The high breast density was associated with the<br />
smallest average breast size and 50% of breast cancer patients fell<br />
into the smallest breast size category.<br />
Conclusion. This study shows that Korean women with smaller breast<br />
size follow the trend of higher breast density, and therefore increased<br />
risk of breast cancer. The association of the risk of breast cancer with<br />
smaller breast size and higher breast density needs to be addressed<br />
when counseling Asian women in the prevention of breast cancer.<br />
P3-10-01<br />
Epidemiological risk factors and normal breast tissue markers<br />
in inflammatory breast cancer<br />
Atkinson RL, Sexton KR, Ueno NT, El-Zein R, Brewster AM,<br />
Krishnamurthy SA, Woodward WA. University of Texas MD Anderson<br />
<strong>Cancer</strong> Center, Houston, TX; Dan L Duncan <strong>Cancer</strong> Center, Baylor<br />
College of Medicine, Houston, TX<br />
Background: Inflammatory breast cancer (IBC) is a rare form of<br />
aggressive breast cancer with no existing identifiers for screening or<br />
prevention strategies. Women with triple-negative (TNBC, ER–,PR–<br />
,Her2–) non-inflammatory breast cancer are less likely to breastfeed,<br />
and we have shown in adjacent normal breast tissue that this tissue<br />
has more foci of stem cells compared to non-TNBC cancers. A<br />
disproportionately higher percentage of women with IBC have TNBC<br />
relative to women with non-IBC. We hypothesized that adjacent<br />
normal tissue in TNBC IBC vs. TN non-IBC may also display unique<br />
biological features based on epidemiologic characteristics. Methods:<br />
We examined epidemiologic factors by breast cancer receptor subtype<br />
in 144 patients diagnosed with IBC in 1991–2011 at MD Anderson<br />
<strong>Cancer</strong> Center. <strong>Breast</strong> cancer risk factors including parity and<br />
breastfeeding were compared between patients with TN and non-TN<br />
IBC with chi-square or Wilcoxon rank sum tests. Normal adjacent<br />
tissues were stained for stem cell markers CD44+CD49f+CD133/2+<br />
and macrophage marker CD68. Results: The mean age at diagnosis<br />
was 52.3 years (range=23-80) and 83% of patients were non-Hispanic<br />
white, 80% were overweight or obese (BMI >25), and 36% were<br />
TN IBC. Patients with TN IBC had significantly lower frequency of<br />
breastfeeding compared with non-TN IBC, 28% vs. 55%, (p=0.01).<br />
No differences were found in the frequency of other breast cancer risk<br />
factors. All 8 IBC adjacent tissue samples showed a distinct spatial<br />
distribution of stem cell staining, not limited to the triple negative<br />
patients. Compared with 0/60 non-IBC cases, 0/8 triple negative<br />
non-IBC, (p=0.001 Pearson chi-square). Given the high BMI among<br />
IBC patients, we further examined normal tissues for the presence<br />
of CD68+ cells distributed individually or as clusters exhibiting a<br />
“crown-like” pattern (multiple CD 68+ macrophages found around<br />
dead adipocytes), and found that 7 of the 8 IBC adjacent tissues<br />
were CD68+. Benign biopsies collected from 2 patients at 10 years<br />
before diagnosis displayed similar staining, including both stem cell<br />
and CD68 staining. Compared with 12/60 non-IBC adjacent tissues<br />
were positive for CD68, with 1/8 TN non-IBC, (p=0.001 Pearson<br />
chi-square). Conclusion: We describe for the first time a stem-cell<br />
staining pattern unique to IBC present in all IBC tissues examined,<br />
including pre-cancer biopsies. Tissue samples from additional patients<br />
will be examined to further explore the relationship between stem<br />
cells and CD68 positivity with IBC subtypes.<br />
P3-10-02<br />
Modulation of mRNA and miRNAs by the novel histone<br />
deacetylase inhibitor, CG-1521 disrupts cytokinesis in SUM149PT<br />
inflammatory breast cancer cells<br />
Chatterjee N, Tenniswood MPR. University at Albany, Rensselaer, NY<br />
Inflammatory breast cancer (IBC) comprises only 2.0% of all breast<br />
cancer cases; however it accounts for 8.0% of breast cancer-specific<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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deaths. IBC is highly aggressive, appears at a younger age, and is<br />
more difficult to treat than the common forms of breast cancer. By<br />
the time the disease is diagnosed, IBC is usually stage 3 and has<br />
already metastasized to neighboring lymphatics. Though many tumors<br />
are p53 wild type and/or Her2 positive, the median overall survival<br />
among women with IBC is less than 4 years even with aggressive<br />
multimodal therapy. To develop IBC-specific therapies, we have<br />
compared the effects of two hydroxamic acid histone deacetylase<br />
(HDAC) inhibitors, Trichostatin A (TSA) and CG-1521 on the biology<br />
of the triple negative SUM149PT IBC cell line. In these cells, CG-<br />
1521 and TSA induce dose (0-10 µM) and time dependent (0-96 h)<br />
increases in the proportion of cells undergoing cell cycle arrest and<br />
cell death, in the presence or absence of 17β-estradiol. To identify<br />
the genomic targets of CG-1521, we have performed concurrent<br />
microarray analyses of mRNA and miRNA expression followed<br />
by qPCR validation. In SUM149PT cells, CG-1521 modulates the<br />
expression of approximately 935 transcripts: 341 of these transcripts<br />
are up-regulated and 594 are down-regulated after 48h of treatment.<br />
Gene ontology analysis demonstrates that many of the down-regulated<br />
mRNA transcripts encode proteins that are associated with the spindle<br />
assembly checkpoint, chromosome segregation and microtubule based<br />
processes including KIF4, PRC1, AURKB and KIF23 (MKLP-1).<br />
Strikingly, many genes in these ontologies are potentially targeted<br />
by a small number of miRNAs (miR-22, miR-1207-5p & miR-494)<br />
which are significantly up-regulated by CG-1521, suggesting that the<br />
ability of CG-1521 to down-regulate the transcripts associated with<br />
spindle formation and cytokinesis may be significantly modulated by<br />
miRNA expression. Immunofluorescence microscopy demonstrates<br />
that treatment of SUM149PT cells with CG-1521 results in the<br />
appearance of elongated midzone structures visualized by phalloidin<br />
staining, similar to the phenotype seen by others after siRNAmediated<br />
knockdown of KIF4 in HeLa cells. These data suggest<br />
that CG-1521 affects the central mitotic spindle formation, disrupts<br />
furrow formation and abscission, arresting the cells in cytokinesis<br />
ultimately leading to cell death. Whether these effects are solely<br />
mediated through transcriptional mechanisms or whether CG-1521<br />
also directly affects the activity of these proteins through acetylation<br />
remains to be determined. Nevertheless, the data show that histone<br />
deacetylase inhibitors induce cell death in IBC cells, and suggest that<br />
these small molecules may be useful addition to the armamentarium<br />
as adjuvants for the treatment of IBC.<br />
P3-10-03<br />
Bartonella henselae Infection Detected in Patients with<br />
Inflammatory <strong>Breast</strong> <strong>Cancer</strong>.<br />
Fernandez SV, Aburto L, Maggi R, Breitschwerdt EB, Cristofanilli M.<br />
Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA; North Caroline State<br />
University, Raleigh, NC<br />
Inflammatory breast cancer (IBC) is a very aggressive type of<br />
advanced breast cancer with a poor prognosis. Clinical symptoms<br />
involve a rapid onset of changes in the skin overlying the breast,<br />
including edema, redness and swelling including a wrinkled and<br />
orange peel appearance in the skin. This particular presentation is<br />
due to the invasion of the skin dermal lymphatics by breast cancer<br />
cells that obstructed the lymph channels producing the characteristic<br />
skin changes that mimic an inflammatory process. Mouse Mammary<br />
Tumor-associated Virus (MMTV) and other infectious agents have<br />
been consider as possible etiological agents of IBC particularly<br />
related to the initial description of higher incidence in women living<br />
in rural areas in North Africa. Although, the etiopathological role<br />
of bacteria in this disease has never been explored in spite of the<br />
evidence that chronic infections with certain bacteria can facilitate<br />
tumors development.<br />
Several bacterial infections promote cell proliferation and could<br />
increase the rate of cell transformation. Bartonella spp. is an emerging<br />
pathogen that can cause conditions which are characterized by<br />
the development of proliferative lesions. Bartonella might cause<br />
vasculoproliferative disorders by triggering the proliferation of<br />
endothelial cells and inducing the secretion of proliferative cytokines<br />
from infected host cells. It cause persistent infection of erythrocytes<br />
and endothelial cells in their mammalian hosts and their transmission<br />
occur mainly by blood-sucking arthropods. Bartonella are Gramnegative<br />
bacteria usually associated with cat-scratch disease, urban<br />
trench fever, bacillary angiomatosis-peliosis and endocarditis. Some<br />
reports have showed some similarities between cat scratch disease and<br />
inflammatory breast cancer (Povoski et al., <strong>Breast</strong> J 9: 497-500, 2003).<br />
Methods and Results: In the present work, we report the identification<br />
of Bartonella henselae in the pleural effusions of two patients with<br />
IBC. These patients had both estrogen-receptor negative (ER-) and<br />
progesterone-receptor negative (PR-) disease and have failed a<br />
number of previous chemotherapy regimens. Furthermore, they had<br />
metastatic disease to the pleura, skin, lymph nodes and lung. Cells<br />
from the pleural fluids of these patients stained positive for Bartonella<br />
sp. using the Warthin-Starry staining kit. Moreover, we used PCR and<br />
sequencing of the 16S-23S intergenic spacer (ITS) region to identify<br />
the etiological agent as Bartonella henselae. By immunofluorescence<br />
using an antibody that specifically recognized Bartonella henselae,<br />
the bacteria were found in the nucleus of IBC tumor cells confirming<br />
the infection and their intracellular localization.<br />
Conclusions: These results suggested that bacteria infections such<br />
as the one produced by Bartonella henselae might contribute to the<br />
clinical and pathological characteristics of IBC, associated with rapid<br />
spread of the breast tumor cells through the lymphatic system. The<br />
infection and activation of endothelial lymphatics by Bartonella might<br />
contribute to the highly metastatic process observed in IBC patients.<br />
An acute inflammatory reaction triggered by the Bartonella infected<br />
endothelium may be crucial for initiating the chronic inflammation<br />
in IBC patients and the rapid spread of tumor cells.<br />
P3-10-04<br />
Regulation of inflammatory breast cancer cell invasion through<br />
Akt1/PKBα phosphorylation of RhoC GTPase<br />
Lehman HL, Van Laere SJ, van Golen CM, Vermeulen PB, Dirix<br />
LY, van Golen KL. The University of Delaware, Newark, DE; Sint<br />
Augustine Hospital, Antwerp, Belgium; Catholic University, Leuven,<br />
Belgium; Delaware State University, Dover, DE<br />
With a 42% and 18% 5- and 10-year respective disease-free survival<br />
rate, inflammatory breast cancer (IBC) is arguably the deadliest<br />
form of breast cancer. IBC invades the dermal lymphatic vessels<br />
of the skin overlying the breast and as a consequence nearly all<br />
women have lymph node involvement and ∼1/3 have gross distant<br />
metastases at the time of diagnosis. One year after diagnosis ∼90%<br />
of patients have detectable metastases, making IBC a paradigm for<br />
lymphovascular invasion. Understanding the underlying mechanisms<br />
of the IBC metastatic phenotype is essential for new therapies. Work<br />
from our laboratory and others show distinct molecular differences<br />
between IBC and non-inflammatory breast cancers. Previously we<br />
demonstrated that RhoC GTPase is a metastatic switch responsible<br />
for the invasive phenotype of IBC. In the current study we integrate<br />
observations made in IBC patients with in vitro analysis. We<br />
demonstrate that the PI3K/Akt signaling pathway is crucial in IBC<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
invasion. Key molecules involved in cytoskeletal control and cell<br />
motility are specifically upregulated in IBC patients compared with<br />
stage and cell-type-of-origin matched non-inflammatory breast cancer<br />
patients. Distinctively, RhoC GTPase is a substrate for Akt1 and its<br />
phosphorylation is absolutely essential for IBC cell invasion. Further<br />
our data show that Akt3, not Akt1 has a role in IBC cell survival.<br />
Together our data demonstrate a unique and targetable pathway for<br />
IBC invasion and survival.<br />
P3-10-05<br />
Response to neoadjuvant systemic therapy (NST) in inflammatory<br />
breast cancer (IBC) according to estrogen receptor (ER) and<br />
HER2 expression.<br />
Masuda H, Iwamoto T, Brewer T, Hsu L, Kai K, Woodward WA,<br />
Reuben JM, Valero V, Alvarez RH, Willey J, Hortobagyi GN, Ueno<br />
NT. Morgan Welch Inflammatory <strong>Breast</strong> <strong>Cancer</strong> Research Program<br />
and Clinic, The University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX; The University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX; Okayama University Hospital, Okayama, Japan<br />
Background: Inflammatory breast cancer (IBC) is the most aggressive<br />
form breast cancer. NST, followed by local therapy (surgery and<br />
radiation therapy), is considered the current standard therapy for IBC.<br />
Among noninflammatory breast cancers, sensitivity to NST differs<br />
based on ER and HER2 status. However, whether the sensitivity<br />
to NST also differs in primary IBC based on ER status or other<br />
prognostic factors has not been studied in a large cohort.<br />
Methods: We retrospectively reviewed 1078 patients (pts) newly<br />
diagnosed with IBC from April 1989 to January 2011. Of these, 838<br />
pts met our inclusion criterion of stage III disease at diagnosis, and 713<br />
of these pts had received NST and surgery. Among this population,<br />
545 pts had information available on both ER and HER2 status. We<br />
compared pathological complete response (pCR) rates (defined as<br />
no evidence of invasive disease in the breast and ipsilateral axillary<br />
limph nodes) and clinical characteristics between ER and HER2-status<br />
subgroups and analyzed their clinical outcome. We used the Kaplan-<br />
Meier method to estimate the median recurrence-free survival (RFS)<br />
after surgery and overall survival (OS), and the Cox proportional<br />
hazards regression model to test the statistical significance of potential<br />
prognostic factors in each group.<br />
Results: Overall 177 pts had ER+HER2- tumors; 75, ER+HER2+; 134,<br />
ER-HER2+; and 159, ER-HER2-. NST consisted of anthracyclinebased<br />
[A] alone, a taxane [T] alone or with A+T; HER2 targeting<br />
therapies (H) were administered to 117 patients with HER2-positive<br />
breast cancer after 1998. Overall pCR rate was 14.7%. pCR rates<br />
are shown by marker subtype and NST received in the table below.<br />
pCR rate, nuclear grade, vascular invasion, clinical response to NST,<br />
adjuvant treatment, radiation therapy, and adjuvant hormonal therapy<br />
differed significantly among subgroups.<br />
The median RFS and OS for all patients was 19.2 and 33.2 months,<br />
respectively. In multivariate analysis, BMI, ER status, lymphatic<br />
invasion, radiation therapy, and pCR rate were associated with<br />
RFS, and ER status, vascular invasion, radiation therapy, and pCR<br />
rate were associated with OS. Except in the ER+HER2- group,<br />
pCR was associated with better prognosis compared to non-pCR.<br />
Adjuvant hormonal therapy improved RFS both in ER+HER2+ and<br />
ER+HER2- groups, but did not improve OS in the ER+HER2+ group.<br />
Among 209 patients with HER2+ IBC, 134 received HER2 targeting<br />
therapies in neoadjuvant or adjuvant chemotherapy, and had a trend<br />
to improvement in RFS compared to chemotherapy alone (P=0.082).<br />
The ER-HER2- group showed poorest outcome compared to other<br />
subgroups (P
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
P3-10-07<br />
Lymph node status and survival in inflammatory breast cancer<br />
Sieffert MR, Pedersen RC, Tereffe W, Cui H, Woods RR, Viscusi<br />
RK, LeBeau-Grasso L, Lang JE. University of Arizona College of<br />
Medicine, Tucson, AZ; University of Texas MD Anderson <strong>Cancer</strong><br />
Center, Houston, TX; University of Arizona <strong>Cancer</strong> Center, Tucson,<br />
AZ; University of Arizona Health Sciences Center, Tucson, AZ;<br />
University of Southern California Norris Comprehensive <strong>Cancer</strong><br />
Center, Los Angeles, CA<br />
Objectives: Positive lymph node status in breast cancer is known<br />
to be associated with poor outcomes when compared with nodenegative<br />
disease, but the effect of lymph node status on outcomes in<br />
inflammatory breast cancer (IBC) has not been evaluated. This study<br />
was designed to investigate the association between lymph-node status<br />
and overall survival (OS) in individuals with inflammatory breast<br />
cancer using prospective data from the Surveillance, Epidemiology,<br />
and End Results (SEER) database.<br />
Methods: We identified 750 patients in the April 2012 edition of the<br />
SEER 17 registry who had non-metastatic IBC diagnosed from 1973-<br />
2008. Patients were included only if they met a stringent definition<br />
of IBC (ICD-O-2 morphology code 8503) and their pathologic nodal<br />
status was known. Patients who did not receive mastectomy as part<br />
of their local therapy were excluded, to minimize the likelihood of<br />
inadvertently including patients with metastatic disease at or shortly<br />
after diagnosis. A total of 711 patients were deemed evaluable for<br />
analysis (145 node-negative, 566 node-positive). Survival analysis<br />
was performed using the Kaplan–Meier method. Cox proportional<br />
hazard regression was performed to evaluate univariate and<br />
multivariate associations between treatment and OS. Information<br />
regarding receipt of systemic therapy and human epidermal growth<br />
factor receptor 2 (HER2) status was not available in this version of<br />
the SEER database.<br />
Results: Positive lymph node status was associated with a significant<br />
decrease in OS (p=0.01) when compared with node negative status.<br />
In lymph node-positive patients, ER or PR positivity was associated<br />
with better OS than ER or PR negativity (adjusted HR 0.56 (p=0.005)<br />
for ER+ vs. ER-, and adjusted HR 0.55 (p=0.009) for PR+vs. PR-).<br />
In patients with positive lymph nodes, the combination of surgery<br />
and radiation therapy improved overall survival when compared with<br />
surgery alone (adjusted HR 0.56, p=0.003). In node-negative patients,<br />
the combination of surgery and radiation therapy was not clearly<br />
superior to surgery alone, possibly due to the rarity of node-negative<br />
IBC (adjusted HR 0.53, 95% CI 0.23-1.19, p=0.13).<br />
Conclusions: Our findings provide a better understanding of the<br />
characteristics of inflammatory breast cancer, and creates the<br />
opportunity for future studies to evaluate the prognostic significance<br />
and treatment implications of lymph node status in inflammatory<br />
breast cancer. Our study is limited by lack of knowledge of use of<br />
systemic therapy, the HER2 status for each patient, and information<br />
regarding locoregional recurrence. However, institutions participating<br />
in the SEER registry are likely to follow guidelines set forth by the<br />
National Comprehensive <strong>Cancer</strong> Network, recommending induction<br />
chemotherapy followed by surgery followed by radiation for IBC.<br />
Nearly 80% of the IBC patients included in this study had nodal<br />
metastasis, reflecting the inherently aggressive biology of this disease.<br />
Further studies are required to characterize the biology of IBC and<br />
guide the optimal treatment of this disease.<br />
P3-10-08<br />
A new in vitro method of growing and studying inflammatory<br />
breast cancer emboli<br />
Lehman HL, Daasner EJ, Vermeulen PB, Dirix LY, Van Laere S, van<br />
Golen KL. The University of Delaware, Newark, DE; Sint Augustine<br />
Hospital, Antwerp, Belgium; Catholic University, Leuven, Belgium<br />
Inflammatory breast cancer (IBC) is the deadliest form of breast<br />
cancer, presenting as intralymphatic emboli. Emboli within the dermal<br />
lymphatic vessels are thought to contribute to rapid metastasis. The<br />
lack of appropriate in vitro models has made it difficult to accurately<br />
study how IBC emboli metastasize. To date, attempts at creating IBC<br />
tumor emboli in vitro have used 3-dimensional culture on a solid layer<br />
of MatrigelTM, which does not resemble the physical properties of<br />
the lymphatic system. Dermal lymphatic fluid produces oscillatory<br />
fluid shear forces and is 1.5-1.7-fold more viscous than water with<br />
a pH range of 7.5-7.7. We have established a method for forming<br />
tumor emboli by culturing the IBC cell lines in suspension with<br />
either polyethylene glycol- or hyaluronic acid-containing medium<br />
and oscillatory fluid shear forces. Non-IBC cells do not form emboli<br />
under identical conditions. In vitro IBC emboli were analyzed for<br />
expression of markers associated with patient emboli and their ability<br />
to undergo amoeboid movement. In a direct comparison, the in vitro<br />
IBC emboli closely resemble IBC patient emboli with respect to<br />
size, composition and E-cadherin expression. Further, cells from the<br />
emboli are able to invade in clusters via RhoC GTPase-dependent<br />
amoeboid movement. Invasion by clusters of IBC cells is disrupted<br />
by exposure to TGFβ. This study provides a biologically relevant in<br />
vitro model to accurately grow and study inflammatory breast cancer<br />
biology and metastasis.<br />
P3-10-09<br />
Peptide-based molecular targeting of inflammatory breast cancer.<br />
Eckhardt BL, Miao RY, Cao Y, Driessen WH, Krishnamurthy S, Arap<br />
W, Ueno N, Anderson RL, Pasqualini R. The University of Texas at<br />
MD Anderson <strong>Cancer</strong> Center, Houston, TX; Stanford University<br />
School of Medicine; Trescowthick Research Laboratories, Peter<br />
MacCallum <strong>Cancer</strong> Center; The University of Texas at MD Anderson<br />
<strong>Cancer</strong> Center<br />
Inflammatory breast cancer (IBC) is a subtype of breast cancer<br />
that has a frequent association with metastatic disease and a poorer<br />
prognosis than comparative non-inflammatory breast cancers. While<br />
IBC is now considered a distinct subclass of breast cancer, the lack<br />
of molecular characterization, both at the genomic and proteomic<br />
levels, has hampered the development of rationalized and targeted<br />
therapies. Inherent receptor/ligand interactions that can occur on<br />
the surface of tumor cells can act as a dynamic molecular address<br />
that can enable targeted delivery of drugs and imaging agents to<br />
tumors. We hypothesize that such molecular addresses within IBC<br />
can be exploited for ligand-based imaging and early detection of<br />
disease sites. To this end, it is our goal to generate targeted imaging<br />
and therapeutic agents by combining ligand-directed targeting with<br />
efficient transduction of IBC cells by hybrid gene delivery vectors.<br />
Our strategy utilizes a hybrid vector with genomic elements from<br />
adeno-associated virus (AAV) and an M13-derived phage. Ligandtargeted,<br />
AAV/phage (AAVP) chimeras can display tumor-homing<br />
peptides that mediate selective internalization of viral particles<br />
through specific ligand-receptor interactions in vitro and in vivo. Such<br />
targeted vehicles are suited for the delivery of different reporter genes<br />
that can be used for imaging, diagnosis and therapy of breast cancer<br />
As a part of our ongoing studies we have identified, characterized<br />
and evaluated a peptide (WIFPWIQL, amino acid sequence) that<br />
www.aacrjournals.org 337s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
can target GRP78, a stress-response protein that is expressed in<br />
IBC tumors and elevated during metastatic progression. Indeed, we<br />
found that this GRP78-targeting peptide can bind to, and internalize<br />
within IBC cells. As a result, we sought to characterize the ability of<br />
this peptide to mediate the delivery of fluorescent-based compounds<br />
and toxic moieties in preclinical models of IBC and breast cancer<br />
metastasis. Using amine-based chemical coupling, we conjugated<br />
near-infrared dyes on both WIFPWIQL-phage and on a WIFPWIQLpeptide<br />
engrafted antibody. When these fluorescent construct<br />
were administered into mice bearing IBC or IBC-like tumors, we<br />
could visualize tumor-specific targeting of the vectors in vivo. To<br />
demonstrate efficacy of GRP78-targeted therapeutics, we conjugated<br />
the tumor-homing, GRP78 ligand to a cell-death inducing domain<br />
(creating a compound called BMTP-78, bone metastasis targeting<br />
peptide-78), which can selectively kill cells upon internalization. We<br />
show here that BMTP78 therapy in mice with established GRP78-<br />
positive tumors, but not matched GRP78-negative tumors, could<br />
effectively reduce tumor growth and metastatic burden. Finally, we<br />
demonstrate a WIFPWIQL-AAVP construct that expresses a suicide<br />
gene (HSVtk) under the control of either CMV or GRP78 promoter,<br />
could sensitize IBC tumor xenografts to the pro-drug ganciclovir.<br />
Collectively, our results demonstrate an in vivo receptor/ligand system<br />
that has the potential for imaging and therapeutic targeting of IBC<br />
and aggressive breast tumors.<br />
P3-10-10<br />
STATUS OF ANAPLASTIC LYMPHOMA KINASE (ALK)<br />
GENE IN INFLAMMATORY BREAST CARCINOMA<br />
Krishnamurthy S, Woodward W, Reuben JM, Tepperberg J, Ogura<br />
D, Niwa S, Ueno NT. MD Anderson <strong>Cancer</strong> Center, Houston, TX;<br />
LabCorp, Durham, NC; Link Genomics, Toyoka, Japan<br />
The ALK gene located on chromosome 2p23 belongs to the insulin<br />
receptor superfamily and encodes a receptor tyrosine kinase that<br />
is normally expressed in brain, testis and small intestine. There is<br />
limited data regarding ALK gene rearrangements in breast cancers. We<br />
performed a comprehensive investigation of ALK in IBC using array<br />
comparative genomic hybridization (CGH), transcriptional profiling,<br />
fluorescence in situ hybridization (FISH) and immunohistochemistry<br />
(IHC) for ALK protein expression.<br />
Materials and Methods: We used formalin fixed and paraffin<br />
embedded core biopsies of IBC for IHC and FISH and microdissected<br />
frozen tissues for array CGH and mRNA analysis. ALK protein<br />
was evaluated by IHC using primary antibody against ALK<br />
(DAKO cytomation). The Vysis ALK Break Apart FISH probe kit<br />
(Abbott Laboratories) was used to detect chromosome 2p23 gene<br />
rearrangements. Genomic DNA was applied to whole genome DNA<br />
microarray (Link Genomics) which covered the entire human genome<br />
using 12310 individually amplified bacterial artificial chromosome<br />
clones (BAC) clones. Thresholds of gains and losses were set at 1.2<br />
and 0.8 respectively. Analysis of mRNA expression was performed by<br />
labeling cRNA from the specimens to an oligo-nucleotide microarray<br />
(whole genome 4x44K Agilent technologies), scanned with an Agilent<br />
microarray scanner and analyzed with features extraction software<br />
(Agilent Technologies).<br />
Results: We performed IHC and FISH for ALK in 29 IBC patients<br />
(ER/PR +, HER2- in 12, HER2+ in 13, triple negative in 4). Array<br />
CGH and mRNA analysis was conducted in 20 of these 29 cases. All<br />
the 29 cases were negative for ALK protein expression by IHC. FISH<br />
analysis revealed intact bi-color flanking signals in all the tumor cell<br />
nuclei from the 29 specimens indicating absence of EML4-ALK gene<br />
rearrangements in any of the cases. We found mild gain of intact ALK<br />
signals in a small percentage of interphase cells in 90% of the cases.<br />
FISH for CEP2 performed in 8 specimens showed normal CEP2<br />
levels in 6/8 indicating mild amplification of the ALK gene in these<br />
cases. A total of 20 DNAs analyzed by array CGH focusing on the 2<br />
BACs that covered the ALK gene region showed no gain in 17 cases<br />
indicating no change in copy number of ALK, gain in 1 BAC in 2<br />
cases and gain of 2 BACS in 1 case. Transcriptional profiling revealed<br />
that mRNA expression of ALK was not significantly higher than the<br />
5 normal breast controls (P >0.05, t test) including the 3 patients with<br />
possible mild increase in copy numbers of ALK gene by array CGH.<br />
Conclusion: Gene rearrangements involving the ALK gene were not<br />
noted in any of the IBC patients. Mild gain of intact ALK signals<br />
as evidenced by FISH suggests low level amplification in majority<br />
of IBC patients. The lack of gain in copy numbers of ALK gene in<br />
85% of the IBC patients together with the absence of significant<br />
elevation of mRNA levels and absence of ALK protein expression<br />
by IHC suggests absence of transcription and translation of the mild<br />
amplification of the ALK gene in patients with IBC.<br />
P3-11-01<br />
Matched-pair analysis of patients with male and female breast<br />
cancer<br />
Kim M, Lee SK, Choi M-Y, Kim S, Kim J, Jung SP, Bae SY, Kil WH,<br />
Lee JE, Nam SJ. Samsung Medical Center, Sungkyunkwan University<br />
School of Medicine, Seoul, Republic of Korea<br />
Purpose: Male breast cancer (MBC) is extremely rare, accounting for<br />
less than 1% of all malignancies in men and only 1% of all breast<br />
carcinomas. The treatment and surveillance guidelines on male breast<br />
cancers are less recognized. The aim of this study is to evaluate our<br />
single institution’s experience with MBC over the past 15 years and<br />
to contrast differences between female and MBC.<br />
Methods: MBC diagnosed from 1994 to 2010 at the Department of<br />
Surgery, Samsung Medical Center (Seoul, Korea) was retrospectively<br />
analyzed. Clinical data and tumor characteristics were examined. Each<br />
MBC was matched with female counterparts by 1:N varied matching<br />
ratio that showed accordance in seven variables (year of diagnosis,<br />
age, tumor stage, nodal stage, tumor grade, estrogen receptor(ER),<br />
progesterone receptor(PR)).<br />
Results: 39 male/184 female matched-pairs were available for<br />
analysis. The median duration of follow-up was 3.8 years. The median<br />
age of MBC patients was 50 years and the median size of tumor was<br />
2.0cm. The proportion of positivity of ER and PR status was 97.4%<br />
and 84.6%, respectively. Despite of higher positive rate of hormone<br />
receptor, the rate of hormone therapy in MBC patients was significant<br />
lower than female conterpart (p=0.002). Men and women with breast<br />
cancer had similar disease-free survival (DFS) and disease-specific<br />
overall survival (DSS). Five MBC patients had a recurrence during<br />
follow up period and 4 of them were expired. The 10-years DFS was<br />
73.1% in men and 80.5% in women (p=0.348). The 10-years DSS<br />
was 74.1% in men and 87.1% in women, respectively (p=0.207).<br />
Conclusion: This study showed no disease free and overall survival<br />
differences between male and female breast cancer patients and<br />
revealed that gender is no predictor for survival in breast cancer. Male<br />
patients receive obviously less adjuvant treatment compared their<br />
female matched patients. It would be better to do more aggressive<br />
treatment in MBC to improve the survival outcome.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
Table1. Matching criteria of male and female breast cancer patients<br />
Male (n=39) Female (n=184) p<br />
Median age (range) 50 (33-74) 50 (33-75) 0.936<br />
Tumor stage pTis 4 10.3% 13 7.1%<br />
pT1 23 59.0% 111 60.3%<br />
pT2 12 30.8% 60 32.6% 0.789<br />
Nodal stage pN0 21 53.8% 99 53.8%<br />
pN1 8 20.5% 40 21.7%<br />
pN2 7 17.9% 31 16.8%<br />
pN3 2 5.1% 10 5.4%<br />
pNx 1 2.6% 4 2.2% 1.000<br />
Tumor grade G1 11 28.2% 46 25.0%<br />
G2 23 59.0% 113 61.4%<br />
G3 5 12.8% 25 13.6% 0.916<br />
ER-expression ER- 1 2.6% 1 0.5%<br />
ER+ 38 97.4% 183 99.5% 0.320<br />
PR-expression PR- 6 15.4% 26 14.1%<br />
PR+ 33 84.6% 158 85.9% 0.839<br />
Table 2. Not-matched tumor characteristics and treatment features of<br />
Male (n=39)<br />
Female<br />
(n=184)<br />
p<br />
Histology DCIS 4 10.3% 13 7.1%<br />
Invasive ductal carcinoma 28 71.8% 154 83.7%<br />
Invasive lobular carcinoma 0 0% 3 1.6%<br />
Mucinous carcinoma 6 15.4% 6 3.3%<br />
Others* 1 2.6% 8 4.3% 0.109<br />
HER2 negative 34 87.2% 165 89.7%<br />
positive 3 7.7% 18 9.8%<br />
unknown 2 5.1% 1 0.5% 0.119<br />
Operation Mastectomy 36 92.3% 68 37.0%<br />
<strong>Breast</strong> conserving surgery 3 7.7% 116 63.0% < 0.001<br />
Adjuvant<br />
radiotherapy<br />
12 30.8% 127 69.0% < 0.001<br />
Adjuvant<br />
systemic Chemotherapy 24 61.5% 125 67.9% 0.550<br />
therapy<br />
Hormone therapy 32 82.1% 177 96.2% 0.002<br />
* apocrine carcinoma, tubular carcinoma, micropapillary carcinoma, mixed<br />
P3-11-02<br />
Male breast cancer: A comparison between BRCA mutation<br />
carriers and non-carriers in Hong Kong, Southern China<br />
Kwong A, Chau WW, Wong CHN, Law FBF, Ng EKO, Suen DTK,<br />
Kurian AW, West DW, Ford JM, Ma ESK. University of Hong Kong,<br />
Pokfulam, Hong Kong; Hong Kong Hereditary <strong>Breast</strong> <strong>Cancer</strong> Family<br />
Registry, Happy Valley, Hong Kong; Stanford University School of<br />
Medicine, Stanford, CA; Hong Kong <strong>San</strong>itorium & Hospital, Happy<br />
Valley, Hong Kong<br />
Background: Male breast cancer is suggested to be biologically<br />
different from female breast cancer. The differences in clinicopathology<br />
between male and female breast cancer raise the issues of establishing<br />
specific strategies and treatment regime for male breast cancer<br />
patients. The single most significant risk factor for male breast<br />
cancer is a mutation in the BRCA2 gene. The lack of information<br />
on hereditary breast cancer in male, particularly in Asians, leaves<br />
great but forgiven research area on epidemiological studies for this<br />
group of patients.<br />
Methods: All male breast cancer patients and their family members,<br />
from a Hong Kong Hereditary and High Risk <strong>Breast</strong> <strong>Cancer</strong> Program<br />
since year 2007, were recruited in this study. All received genetic<br />
counseling and BRCA mutation testing using DNA extracted from<br />
blood samples. A questionnaire was administered at their first visit<br />
which included questions on their demographics and socioeconomic<br />
status. Other information including family history of breast cancer<br />
or other kinds of cancer, method of diagnosis, surgical strategies,<br />
pathological results, treatment regime, relapse, metastasis, and<br />
outcomes were obtained from their medical records. Descriptive<br />
analysis was performed describing the background characteristics.<br />
Chi-square test and Student’s t-test were applied to calculate the<br />
associations between BRCA mutation and risk factors. Survival<br />
analysis was performed to look for their survival patterns.<br />
Results: Thirty-six male breast cancer patients were recruited between<br />
year 2007 and 2012, while 21 were diagnosed before year 2007 (range:<br />
1996 to 2012). Mean, standard deviation, and median follow-up time<br />
were 5.75±4.31 and 5.25 years. Seven were found to carry the BRCA<br />
mutation. All were BRCA2 mutation and the mutation rate was 19.4%<br />
(N = 7). Family history of cancer was found in 52.8% (N = 19). Male<br />
BRCA mutation carriers were found to have higher risk of secondary<br />
cancer, and their first and second degree family members had higher<br />
risk of either breast cancer or other kinds of cancers. T stage in BRCA<br />
patients was significantly higher than non-BRCA patients (p = 0.028).<br />
All BRCA mutation carriers had ER positive cancers compared with<br />
96.2% who were non-carriers. Half of the male BRCA patients were<br />
PR positive compared with higher percentage in non-BRCA patients<br />
(50% vs. 80.8%, p = 0.117). Both groups had similar overall (p =<br />
0.962) and disease-free survivals (p = 0.919). The means and standard<br />
deviations of 5-year overall survival between BRCA and non-BRCA<br />
patients were 2.08±0.25 and 4.24±0.12 years respectively, and<br />
2.08±3.03 and 4.41±1.46 years for disease-free survival.<br />
Conclusions: The prevalence of male breast cancer patients with<br />
BRCA2 mutation in Hong Kong is comparable with other similar<br />
studies. Male breast cancer patients with BRCA2 mutation are<br />
suspected to have higher chance of secondary cancer and familial<br />
cancer. Although percentage of ER positive cancers are similar to the<br />
two groups, BRCA2 mutation carriers tend to have less PR positive<br />
cancers which may suggest a poorer prognosis although due to a small<br />
sample size this cannot be shown in this cohort. Further collaborative<br />
studies to better understand male breast cancer patients carrying the<br />
BRCA mutation is warranted.<br />
P3-11-03<br />
Treatment outcomes for early stage male breast cancer: a single<br />
centre retrospective case-control study<br />
Kwong A, Visram H, Graham N, Balchin K, Petrcich W, Dent S. The<br />
Ottawa Hospital, Ottawa, ON, Canada; Ottawa Hospital Research<br />
Institute, Ottawa, ON, Canada<br />
Background:<br />
Male breast cancer (BC) is a rare disease with a reported incidence of<br />
1%, and treatment strategies are therefore driven by studies conducted<br />
in the female BC population. There is also limited information<br />
with regards to treatment outcomes for men with early stage BC,<br />
particularly when compared with their female counterparts. The<br />
objective of this study is to compare the disease free survival (DFS)<br />
and overall survival (OS) of males with early stage BC compared to<br />
age and stage matched females in a single institution.<br />
Methods:<br />
A retrospective matched case-control study was conducted to compare<br />
male and female pts treated for stage 0 to IIIB BC, at the Ottawa<br />
Hospital <strong>Cancer</strong> Centre, between 1981 and 2009. Matching of male<br />
and female pts was done based on age at diagnosis (+/- 2 years),<br />
year of diagnosis (+/- 1 year), and disease stage. Data regarding<br />
surgery, adjuvant radiation, chemotherapy, and endocrine therapy was<br />
collected. Overall survival and disease-free survival were calculated<br />
using Kaplan-Meir analysis.<br />
Results:<br />
A total of 144 pts (72 female; 72 male) were eligible for this study;<br />
median age at diagnosis for both groups was 74 years (r: 30-85).<br />
Median follow-up was 54 months (r: 2-204) for males and 54<br />
months (r: 4-241) for females. All 72 men underwent mastectomy<br />
compared to 38 females (53%). Forty-four (61%) females received<br />
adjuvant radiation therapy compared to 29 (40%) males. Twenty<br />
(28%) females received adjuvant chemotherapy, compared to 23<br />
(31%) males. All female pts had estrogen receptor positive (ER+)<br />
disease, while 59 males (13 unknown) had ER+ disease. An equal<br />
number of males and females (79%) received endocrine treatment.<br />
The mean DFS for females was 127 months (25th percentile 33<br />
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<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
months; median 104 months; 75th percentile 174 months), compared<br />
to 93 months (25th percentile 46 months; median 88 months; 75th<br />
percentile 112 months) for males (p=0.62). Mean OS for females was<br />
117 months (25th percentile 40 months; median 107 months; 75th<br />
percentile 136 months), and 124 months (25th percentile 48 months;<br />
median 90 months; 75th percentile 128 months) for males (p=0.35).<br />
In multivariate analysis, the only parameter that affected both DFS<br />
and OS was stage at diagnosis (hazard ratio 0.42, 95% CI 0.18-1.00;<br />
hazard ratio 0.25, 96% CI 0.09-0.68).<br />
Conclusions:<br />
This is one of the largest case-cohort studies to report on treatment<br />
outcomes of early stage male BC pts treated in a non-trial setting. Male<br />
pts received comparable systemic therapy (chemotherapy/endocrine)<br />
as their female counterparts and DFS and OS were similar. These<br />
results add to current evidence from population studies that male sex<br />
is not a poor prognostic factor for treatment outcomes in early stage<br />
BC. The development of a national male breast cancer registry would<br />
facilitate the evaluation of modern treatment strategies and patient<br />
outcomes in this population.<br />
P3-11-04<br />
Male breast cancer: Overall survival in a single institution.<br />
Bello MA, Bergmann A, Costa CRA, Pinto RR, Millen EC, Thuler<br />
LCS, Bender PFM. Brazilian National <strong>Cancer</strong> Institute, Rio de<br />
Janeiro, Brazil<br />
Background: Male breast cancer is an uncommon disease and the<br />
therapy is mainly based on what is know from female breast cancer.<br />
Objective: To investigate the clinicopathologic characteristics of male<br />
breast cancer and the overall survival in a single institution.<br />
Methods: The clinical data and survival status of 75 male breast<br />
cancer treated in a Brazilian public cancer hospital from 2000 to<br />
2009 were collected. The association with clinicopathological<br />
characteristics and overall survival was analyzed using Kaplan-Meier<br />
curves and the Cox proportional hazards regression (enter method)<br />
was used to assess survival differences after adjusting for confounders.<br />
The study was approved by National <strong>Cancer</strong> Institute Research and<br />
Ethics Committee (number 128/11).<br />
Results: The median patient age was 64 years (range 33-86). Estrogen<br />
receptor (ER) was positive in 58 (77.3%) patients, while progesterone<br />
receptor (PR) were positive in 47 (62.7%). Histology type was<br />
ductal infiltrant carcinoma for 57 (76.0%) and 51 (68.0%) patients<br />
underwent surgery. The median follow-up period was 43,1 months<br />
(range 2.7-147.8). The median survival from the diagnosis of breast<br />
cancer was 97.0 months (95%CI 53.6 -140.4) with a 61.7% 5-year<br />
overall survival (OS). In the final Cox regression model, independent<br />
factors associated with increased risk of death were metastasis at<br />
diagnosis (HR = 18.1; 95%CI: 5.9-55.2), ≥ 65 years old (HR = 4.3;<br />
95%CI: 1.7-10.5); tumor stages ≥ IIb (HR = 3.5; 95%CI: 1.3-9.7)<br />
and smoking (HR = 1.6; 95%CI: 1.04-2.6).<br />
Conclusions: Invasive ductal carcinoma is the main pathologic type.<br />
The median survival from the diagnosis of breast cancer was 97.0<br />
months and metastasis at diagnosis, patient age, tumor stage and<br />
smoking are independent prognostic factors.<br />
P3-12-01<br />
Serum biomarkers identification using quantitative proteomics<br />
in patients (pts) with untreated brain metastases from HER2-<br />
positive breast cancer receiving capecitabine (C) and lapatinib<br />
(L) (UNICANCER LANDsCAPE trial)<br />
Gonçalves A, Camoin L, Ben Younès I, Romieu G, Campone M, Diéras<br />
V, Cropet C, Mahier Aït-Oukhatar C, Dalenc F, Le Rhun E, Labbe-<br />
Devilliers C, Borg J-P, Bachelot T. Institut Paoli Calmettes, Marseille,<br />
France; Université de la Méditerranée, Marseille, France; Centre Val<br />
d’Aurelle, Montpellier, France; Institut de Cancérologie de l’Ouest,<br />
Nantes, France; Institut Curie, Paris, France; Centre Léon Bérard,<br />
Lyon, France; Unicancer, Paris, France; Institut Claudius Regaud,<br />
Toulouse, France; Centre Oscar Lambret, Lille, France<br />
Background<br />
The LANDsCAPE phase II study showed that C+L had a significant<br />
antitumor activity in previously untreated brain metastases (BM)<br />
from HER2-positive breast cancer (BC), with a central nervous<br />
system-objective response rate (CNS-ORR) of 67% and a median<br />
time to whole-brain radiotherapy (WBRT) of 8.3 months (43 analysed<br />
pts). Thus initial C+L combination might be a viable alternative to<br />
immediate WBRT in this setting. In this study, serum samples were<br />
collected before and during treatment for proteomic-based approaches<br />
to identify predictive biomarkers of treatment response.<br />
Methods<br />
Baseline (BL) and day 21 (D21) serum samples from highly<br />
responsive (R, CNS lesions -volumetric response ≥ 75%, n=6) and<br />
non-responsive (NR, CNS-stable or progressive disease, n=6) pts were<br />
subjected to isobaric Tag for Relative and Absolute Quantification<br />
(iTRAQ)-based proteomics. Samples from each condition were<br />
pooled to constitute 4 independent mixes ((BL-R, D21-R, BL-NR<br />
and D21-NR). Each of them underwent immuno-depletion of highly<br />
abundant proteins, concentration, reduction, alkylation and tryptic<br />
digestion. Then, each mix was fractionated and subjected to iTRAQ<br />
identification and quantitation using nano-liquid chromatography<br />
(LC) and electrospray ionisation (ESI)-orbitrap tandem mass<br />
spectrometry (MS/MS) (LTQ-orbitrap, Thermofisher). Differentially<br />
expressed proteins were analysed using IPA (Ingenuity® Systems)<br />
to highlight biological functions and signalling pathways that were<br />
most significantly enriched.<br />
Results<br />
iTRAQ-based measurements identified serum proteins with significant<br />
(fold-change > 1.5 and p-value < 0.05) differential expression between<br />
BL and D21, in R- (n= 38 proteins) and NR- pts (n= 18 proteins). At<br />
baseline, 30 proteins were differentially expressed between R-and<br />
NR-pts. Among the most differentially expressed proteins, some had<br />
been previously described as involved in cancer metastases (between<br />
BL and D21 : tenascin C, neuropilin-1, Serpin A1, Cathepsin S,<br />
prostaglandin D2 synthase, melanoma cell adhesion molecules,<br />
procollagen C-endopeptidase enhancer; between R and NR: carnosine<br />
dipeptidase 1, endothelial protein C receptor, matrix metallopeptidase<br />
9, cystatin C, lumican, plexin B2, Insulin-like growth factor binding<br />
protein acid labile subunit, pro-platelet basic protein, cadherin 5,<br />
Protein S). Proteins with differential expression during treatment<br />
were involved in various biological processes, including lipid<br />
metabolism, small molecule biochemistry, molecular transport, gene<br />
expression, cellular growth and proliferation, cellular movement and<br />
cancer, as well as various canonical pathways such as acute phase<br />
response signalling, LXR/RXR activation and complement system.<br />
Interestingly, and as opposed to NR-pts, R-pts specifically showed an<br />
overall increase in proteins of acute phase response, with a significant<br />
decrease in C-reactive protein (CRP).<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
340s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
Conclusion<br />
iTRAQ-based quantitative proteomics identify serum proteins<br />
that could predict the therapeutic response to C+L combination in<br />
untreated BM from HER2-positive BC. If validated, such biomarkers<br />
may help to select the best therapeutic strategy in this setting.<br />
P3-12-02<br />
The impact of estrogen receptor status on treatment outcomes<br />
following gamma knife radiosurgery for brain metastases of<br />
primary breast cancer<br />
Cupelo EC, Aridgides PD, Bogart JA, Hahn SS, Shapiro AJ. SUNY<br />
Upstate Medical University, Syracuse, NY<br />
INTRODUCTION:<br />
Estrogen receptor (ER) status is a critical component of determining<br />
initial therapy of newly diagnosed breast cancer. Although 70% of<br />
primary breast malignancies are ER+, there remains limited data on<br />
whether ER status influences treatment outcomes for patients with<br />
brain metastases. Gamma Knife Radiosurgery (GKS) is increasingly<br />
being used in the management of brain metastases. The goal of this<br />
study is to determine the impact of ER status in patients receiving<br />
GKS for breast cancer metastases to brain.<br />
METHODS:<br />
A database of consecutive breast cancer patients receiving GKS at<br />
our institution from January 2000 to March 2012 was reviewed for<br />
hormone receptor status, dates of initial brain metastasis and GKS,<br />
presence of neurologic symptoms, and recurrence of GKS-treated<br />
lesions. The main cohort was subdivided by receptor status at initial<br />
tissue diagnosis. Progression or loss of local control of the treated<br />
lesions was defined as radiographic evidence of growth (greater than<br />
20% increase in the sum of the longest diameters) or treated lesions<br />
requiring additional treatment until death or last follow-up. Analysis<br />
for neurological symptom improvement was performed for patients<br />
with available follow-up information, with at least 1 month follow–up.<br />
Comparisons were made between subgroups using Kaplan-Meier<br />
method, Chi-square analysis and univariate comparisons with logrank<br />
test. Significance was set at p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
metastases, including its combination with trastuzumab in patients<br />
with HER2-positive disease. This trial may provide clinical evidence<br />
for the approach presented here.<br />
P3-12-04<br />
A phase 2, multi-center, open label study evaluating the efficacy<br />
and safety of GRN1005 alone or in combination with trastuzumab<br />
in patients with brain metastases from breast cancer<br />
Lin NU, Schwartzberg LS, Kesari S, Yardley DA, Verma S, Anders<br />
CK, Shih T, Shen Y, Miller K. UC <strong>San</strong> Diego, La Jolla, CA; Indiana<br />
University Melvin and Bren Simon <strong>Cancer</strong> Center, Indianapolis, IN;<br />
Sunnybrook Odette <strong>Cancer</strong> Centre, Toronto, ON, Canada; Dana-<br />
Farber <strong>Cancer</strong> Institute, Boston, MA; The West Clinic, Memphis,<br />
TN; Geron, Menlo Park, CA; University of North Carolina at Chapel<br />
Hill, NC; Sarah Cannon Research Institute, Nashville, TN; Tennessee<br />
Oncology, PLLC., Nashville, TN<br />
Rationale: Treatment of brain metastasis (BM) remains an unmet<br />
medical need due to the inability of most anti-cancer agents to<br />
effectively cross the blood-brain barrier (BBB). GRN1005 is a<br />
peptide-drug conjugate (PDC) consisting of 3 molecules of paclitaxel<br />
conjugated to a 19-amino acid peptide, Angiopep-2. GRN1005<br />
effectively penetrates the BBB by targeting the low-density<br />
lipoprotein receptor-related protein 1 (LRP1), which is expressed<br />
on the surface of the BBB and on certain neoplastic cells. In a phase<br />
1 study, GRN1005 demonstrated encouraging anti-tumor activity in<br />
breast cancer (BC) patients with BM.<br />
Methods: Up to 157 patients (pts) with measurable BM from BC,<br />
with or without extra-cranial disease, are currently being enrolled<br />
in an ongoing open label study. Prior cranial irradiation is allowed<br />
but lesions previously treated with stereotactic radiosurgery (SRS)<br />
are excluded from the efficacy analysis. All currently enrolled pts<br />
received GRN1005 at a starting dose of either 650 or 550 mg/m 2<br />
IV every three weeks, until intra-cranial disease progression (iPD),<br />
unacceptable toxicity, or initiation of non-protocol systemic therapy.<br />
HER2 positive pts received concomitant trastuzumab. The primary<br />
endpoint is intra-cranial objective response rate (iORR), as assessed<br />
by independent review using CNS RECIST 1.1. Additional endpoints<br />
include safety, duration of intra-cranial response, 3-month intracranial<br />
progression free survival (iPFS3), extra-cranial ORR, and<br />
neurocognitive function.<br />
Results: As of 4 June 2012, 24 pts (13 at 650 mg/m 2 and 11 at 550<br />
mg/m 2 ) have been treated with a median of 2 cycles of GRN1005<br />
(range 1-5). Median age was 51.5 years (34-68) and 14 (58%) pts<br />
have HER2-positive disease. Pts received a median of 6 (3-14) prior<br />
systemic regimens; 19 had received prior whole brain radiation<br />
therapy (WBRT) ± SRS and 2 had received prior SRS only (data<br />
pending on 3 pts). Six (25%) pts have discontinued treatment with<br />
GRN1005, including 2 due to iPD and 2 due to adverse events<br />
(AE). One additional pt had clinical progression and discontinued<br />
GRN1005.<br />
The AEs observed at 650 mg/m 2 are qualitatively consistent with<br />
conventional paclitaxel but are more frequent and more severe than<br />
observed with q3 week paclitaxel which led to a protocol amendment<br />
and dose reduction to 550 mg/m 2 for all subsequent pts. Among all<br />
treated pts, the most frequent AEs were neutropenia (75%), fatigue<br />
(50%), mucositis (33%), neuropathy (29%), and diarrhea (25%).<br />
Notable Grade 3-4 AEs were neutropenia in 12 pts (including 1 case<br />
of febrile), and arthralgia, fatigue, and rash in 3 pts each. Preliminary<br />
anti-tumor activity has been observed in both intra-cranial and extracranial<br />
lesions.<br />
Conclusions: GRN1005 is a promising treatment for BM associated<br />
with breast cancer and demonstrates a safety profile qualitatively<br />
similar to paclitaxel dosed every 3 weeks. Due to tolerability concerns<br />
at the 650 mg/m 2 dose, the 550 mg/m 2 dose is currently being<br />
evaluated in these heavily pretreated BC pts. Updated efficacy and<br />
safety data will be presented at the meeting.<br />
P3-12-05<br />
Clinical features and outcomes of leptomeningeal metastasis in<br />
patients with breast cancer: a single center experience<br />
Jo J-C, Kang MJ, Ahn J-H, Jung KH, Kim JE, Gong G, Kim HH,<br />
Ahn SD, Kim SS, Son BH, Ahn SH, Kim S-B. Asan Medical Center,<br />
University of Ulsan College of Medicine, Seoul, Korea<br />
Background: Leptomeningeal metastasis (LM) is one of the major<br />
problems in managing metastatic breast cancer because of LM<br />
typically carries a devastating prognosis and often represents a<br />
terminal event. We analyzed the clinical features and outcomes of<br />
LM in patients with breast cancer.<br />
Methods: We retrospectively reviewed the medical records of patients<br />
who were diagnosed with LM from breast cancer between 2002 and<br />
2012 at Asan Medical Center.<br />
Results: Of the 95 LM patients by cytologically proven (n=81)<br />
or radiologically diagnosed (n=14), 57 (60%) had an ECOG<br />
performance status (PS) ≥ 3, and the median age was 47 years<br />
(range, 26-72 years). The patients were diagnosed with LM after<br />
a median of 10.3 months (95% CI, 5.5-15.0 months) from the<br />
time of diagnosis of metastatic breast cancer. LM was present in<br />
2 patients at the time of initial diagnosis. Twenty-three patients<br />
(24.2%) had isolated CNS metastasis, and 6 (6.3%) had only LM<br />
without any detectable metastasis sites. At the time of diagnosis<br />
of LM, 46 patients (48.4%) presented with coincidental failure of<br />
systemic disease control. Seventy-eight patients (82.1%) underwent<br />
intrathecal chemotherapy (methotrexate; n=78, thiotepa; n=11),<br />
resulting in one-third of cytologic negative conversion (n=26), and<br />
41 (43.2%) received systemic chemotherapy. The overall median<br />
survival time was 3.3 months (95% CI, 2.5-4.2 months) and 7.8% of<br />
the patients survived for more than 1 year. Overall survival tended<br />
to be better in patients who achieved cytologic negative conversion<br />
to intrathecal chemotherapy than those did not (median 4.5 months<br />
versus 3.2 months, P=0.241). Overall survival was not different<br />
according to subtypes; hormone receptor (+), HER2 (+), and triple<br />
negative (median 3.6 months, 3.3 months, and 3.2 months, P=0.937).<br />
Multivariate analysis demonstrated that ECOG PS ≥ 3 (HR=2.09,<br />
95% CI 1.21-3.58, P=0.007), coincidental failure of systemic disease<br />
control at LM (HR=3.01, 95% CI 1.76-5.15, P
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
In addition, improvement in our understanding of breast cancer<br />
biology changed the treatment strategy, possibly leading to improved<br />
outcomes in patients with breast cancer and brain metastases.<br />
Object:<br />
The aim of this study was to investigate the correlation between<br />
biology of primary tumors and prognosis of patients with breast<br />
cancer metastasis to the brain.<br />
Patients and method:<br />
Among 3,171 patients with primary breast cancer undergoing<br />
surgery at out hospital from 2003 to 2010, 35 patients (1.1%) who<br />
developed brain metastases, excluding stage IV at the initial diagnosis.<br />
We reviewed 35 patients for a correlation between survival and<br />
clinicopathological variables, including stage, hormonal sensitivity,<br />
HER2 expression status, the number of brain metastases, and<br />
treatment for brain metastases.<br />
Results:<br />
The mean age of 35 patients was 52.1 years (range,22-68) and the<br />
median follow-up period was 41.0 months. The subtypes of primary<br />
tumors included triple-negative (TN) in 14 patients (40%), luminal<br />
in 11 patients (31.4%), luminal HER2-positive (luminal HER2) in<br />
2 patients (5.7%), and HER2-positive (HER2) in 2 patients (5.7%).<br />
The duration from surgery to recurrence (disease-free survival, DFS,<br />
months) was 14.7 in TN, 26.5 in luminal, 29.8 in luminal HER2, and<br />
31.0 in HER2. The duration from the first recurrence to the detection<br />
of brain metastases (months) was 7.2 in TN, 14.4 in luminal, 15.8 in<br />
luminal HER2, and 4.0 in HER2. The mean survival time after the<br />
diagnosis of brain metastases was 8.6 months (range, 0-40) with a<br />
survival time of ³ 1 year in 8/35 patients (23%) and that of < 1 year<br />
in 21/35 patients (60%). Both DFS and the duration from the first<br />
recurrence to the diagnosis of brain metastases were shorter in TN<br />
compared with other subtypes. In HER2 subtype, DFS was long but,<br />
once recurrence was detected, the duration to the development of brain<br />
metastases was short. In multivariate analysis of clinicopathological<br />
variables (age, DFS, ER, HG, HER2, the number of brain metastases<br />
(solitary versus multiple), the site of initial metastasis (brain versus<br />
other organs), and the presence or absence of chemotherapy after<br />
brain metastases, revealed solitary brain metastasis (P=0.002) and<br />
the initial metastatic site of brain (P=0.003) to be independent factors<br />
predicting survival.<br />
Table 1. Clinicopathological variables and survival in patients with breast cancer metastasis to the<br />
brain (multivariate analysis)<br />
odd ratio 95%CI p<br />
age 0.534 0.2532-1.1274 0.100<br />
DFS 1.34 0.4842-3.7451 0.568<br />
HG 0.61 0.1864-0.2354 0.430<br />
ER 0.578 0.1869-1.7897 0.342<br />
HER2 0.551 0.1878-1.1640 0.287<br />
The site of initial metastasis(Brain versus other<br />
0.164<br />
organs)<br />
1.9856-2.4003 0.003<br />
The number of brain metastases(solitary versus<br />
6.904<br />
multiple)<br />
0.0498-0.5489 0.002<br />
The presence or absence of chemotherapy after<br />
0.389<br />
brain metastases<br />
0.1192-0.2715 0.118<br />
Conclusion:<br />
The clinical outcomes of brain metastases were different among<br />
tumor subtypes. Factors predicting survival in patients with breast<br />
cancer and brain metastases may be the site of initial metastasis, the<br />
number of brain metastasis, and local treatment for brain metastases.<br />
P3-12-07<br />
Voyagers and their aids: The role of interactions between tumor<br />
and endothelial cells in brain metastasis<br />
Shah KN, Faridi JS. University of the Pacific, Stockton, CA<br />
Clinically, brain metastases are most commonly observed in breast,<br />
lung, and melanoma cancers. When a tumor cell leaves its site of<br />
origin, it enters a nearby blood vessel on a voyage to find a new tissue<br />
to invade. These circulating tumor cells will act as voyagers and they<br />
interact with a endothelial cell. For example, in the case of brain<br />
metastasis, tumor cells need to adhere to brain endothelial cells before<br />
they can invade into the surrounding brain tissue. Thus, investigating<br />
the mechanisms of tumor and endothelial cell interactions can serve<br />
as a very powerful tool to inhibit the voyage of these tumor cells<br />
and prevent the formation of metastases. In this study, we performed<br />
trans-endothelial migration assay using HBMVEC cells to study<br />
tumor-endothelial interactions. In general, HBMVEC cells were<br />
seeded to BD-Falcon cell culture inserts at a density of 2 × 105 cells<br />
and allowed to grow for 24 hours to form a confluent monolayer and<br />
GFP expressing tumor cells (MCF-7, Akt3 overexpressing MCF7,<br />
MDA-MB-231 and MDA-MB-231-BR) were incubated at suitable<br />
interval at 37°C. At the end of incubation period, cells were fixed and<br />
number of tumor cells that will penetrate the monolayer of HBMEC<br />
were counted using Phase-contrast microscope in 12 different visual<br />
fields. Transmigrating tumor cells are thought to be able to overcome<br />
the endothelial barrier by inducing changes within endothelial cells.<br />
We identified the molecular changes responsible for such adhesion<br />
and invasion by cell sorting for gene expression analysis. After coculturing<br />
the HBMEC (after transfecting with Mcherry protein) with<br />
GFP expressing tumor cells and Mcherry labeled HBMEC, we used<br />
cell sorting to separate tumor and HBMEC cells. After sorting the<br />
tumor cells and endothelial cells from co-culture, (MCF-7 monolayer<br />
vs MCF-7 co-cultured, MDA-MB-231 monolayer vs MDA-MB-231<br />
co-cultured, HBMEC monolayer vs HBMEC co-cultured) gene<br />
expression analysis was performed using SABiosciences cell adhesion<br />
assay kit to accurately capture the genetic changes that occured in the<br />
tumor and endothelial cells upon co-culture.<br />
P3-12-08<br />
Incidence, predictive factors and outcome of brain metastases<br />
(BM) in a single institution cohort of breast cancer patients.<br />
Perelló A, Alarcon J, Garcias C, Duran J, Colom B, Clemente G,<br />
Avella A, Canet R, Torrecabota J, Rifa J. Hospital Universitari Son<br />
Espases, Palma, Balearic Islands, Spain<br />
Background<br />
The aim of the study was to determine the cumulative incidence of<br />
BM, predictive factors of BM, and survival from diagnosis of BM in<br />
a cohort of breast cancer patients in a single institution.<br />
Patients and Methods<br />
We collected data from a cohort of 793 breast cancer patients between<br />
January 2000 and December 2005 in our institution. Variables<br />
recorded include age at diagnosis, hormonal receptor status (HRS),<br />
human epidermal growth factor receptor 2 status (HER2), histological<br />
grade, T stage and N stage. We analyzed the 5 and 10-year cumulative<br />
incidence of BM. Time to detection of BM and survival from BM<br />
were estimated using Kaplan-Meier method. Cox regression model<br />
was used to analyze the variables associated with time to BM<br />
Results<br />
With a median follow-up of 100 months, 49 patients went on to<br />
develop BM. The overall 5 and 10 year cumulative incidence of BM<br />
were 4.9% and 8.2% respectively. The table shows the 5 and 10 year<br />
cumulative incidence and hazard ratio (HR) of the predictive factors<br />
for the development of BM in the univariable analysis.<br />
www.aacrjournals.org 343s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
5 and 10 year cumulative incidence and hazard ratio (HR) of the predictive factors for the<br />
development of BM in the univariable analysis<br />
Variables % 5-year incidence % 10-year incidence HR (95%CI) P value<br />
HER 2 + 15.4 24.1 3.22 (1.80-5.79)
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
35 years-old (HR 2.09; 95% CI: 1.15-3.81, p=0.016) were strongly<br />
associated with higher incidence of brain metastasis. Table 1 showed<br />
the important characteritics according to different age group.<br />
Characteristics of patients according to diagnosis age<br />
Characteristics Total, N=2248 Age ≤35, N=104 Age 36-59, N=1503 Age ≥60, N=641<br />
<strong>Breast</strong> cancer subtype, N (%)<br />
Luminal A 1104 (49.1) 47 (45.2) 744 (49.5) 313 (48.8)<br />
Luminal B 448 (19.9) 24 (23.1) 299 (19.9) 125 (19.5)<br />
HER2-enriched 301 (13.4) 10 (9.6) 202 (13.4) 89 (13.9)<br />
Triple negative<br />
phenotype<br />
395 (17.6) 23 (22.1) 258 (17.2) 114 (17.8)<br />
Brain metastasis<br />
164 (7.3) 19 (18.3) 109 (7.3) 36 (5.6)<br />
event, N (%)<br />
Cumulative incidence rate of brain metastasis event, % (95% CI)<br />
At 1 year 1.2 (1.0- 1.4) 3.0 (1.3- 4.7) 1.0 (0.7- 1.3) 1.2 (0.8- 1.6)<br />
At 3 year 4.9 (4.4- 5.4) 10.4 (7.1- 13.7) 4.7 (4.1- 5.3) 4.5 (3.6- 5.4)<br />
At 5 year 8.2 (7.5- 8.9) 20.5 (15.3- 25.7) 7.8 (6.9- 8.7) 7.5 (6.1- 8.9)<br />
Luminal A= ER+ and/or PR+ and grade 1-2; Luminal B= ER+ and/or PR+ and HER2+ or grade 3;<br />
HER2- enriched= HER2+ by IHC or FISH and ER/PR -, Triple negative= ER-. PR- and HER2-<br />
Furthermore the influence of each biological subtype amoung different<br />
age group were investigated. For patient younger than 35 years-old,<br />
risk of the developement of brain metastasis was independent to<br />
biological subtype (p=0.507); while the risk of brain metastasis was<br />
influenced by biological subtype in older age groups. For patients<br />
older than 35, patients with triple negative and HER2 enriched disease<br />
had significantly increased risk for brain metastasis compared to<br />
luminal A; but for patients with luminal B disease, such incremental<br />
risk for the development brain metastasis was only observed in<br />
patients older than 60 years-old.<br />
Conclusion<br />
Our study found that each biological subtypes of breast cancer had<br />
distinct impact on the development of brain metastasis among different<br />
age group. Further studies were needed to disclose the biology<br />
underneath. Also the findings should be taken into consideration when<br />
developing strategy for brain metastasis prevention.<br />
P3-12-11<br />
Clinical outcome in patients with surgically resected brain<br />
metastases from breast cancer: prognostic considerations<br />
regarding molecular status and established prognostic<br />
classification systems.<br />
Tabouret E, Metellus P, Tallet A, Figarella-Branger D, Charaffe-<br />
Jauffret E, Viens P, Gonçalves A. Institut Paoli Calmettes, Marseille,<br />
France; APHM, Marseille, France; Insitut Paoli-Calmettes,<br />
Marseille, France<br />
Introduction: Incidence of brain metastases (BM) from breast cancer<br />
(BC) is increasing, paralleling increasing life expectancy of patients.<br />
However, biology, prognostic evaluation and treatment strategy are<br />
still a matter of debate. We analysed here a series of patients with<br />
resected brain metastases from BC to assess the actual prognostic<br />
factors in this specific population and the relevancy of widely accepted<br />
BM prognostic classification systems.<br />
Methods: we reviewed retrospectively all patients (n=49) referred to<br />
our institution between December 2001 and July 2011 with available<br />
tumor tissue from resected breast cancer brain metastases. All patients<br />
underwent initial breast tumor surgery and surgical resection of the<br />
BM. Patients, tumor and treatment characteristics were recorded.<br />
Prognostic value of ER, PR, HER2 status of BM, age, Karnofsky<br />
performance status, Mini Mental Score (MMS), clinical features,<br />
number and topography of BM, systemic disease characteristics<br />
(response, metastatic sites), delay between primary tumor and BM<br />
diagnoses and treatment after neurosurgery were analyzed using<br />
uni- and multi-variate analyses.<br />
Results: Median age was 54 years (28-75). Median KPS was 80 (50-<br />
90). MMS was abnormal for 7 pts (14.3%). At BM diagnosis, 12 pts<br />
(24.5%) did not present extracranial disease and 15 (20.6%) had only<br />
one systemic metastatic site. After surgery, 83.7% of pts benefited<br />
from whole-brain radiotherapy and 79.6% from systemic therapy.<br />
Median follow-up was 25.6 months. Median cerebral progression-free<br />
survival (C-PFS) was 11.3 months (IC95:6.0-16.6) and median overall<br />
survival (OS) was 19.4 months (IC95:16.1-22.7). By univariate<br />
analysis, neither hormonal or HER2 BM status impacted survival.<br />
Similarly, molecular subtyping by IHC approximation (“basal”,<br />
ER- and PR-/HER2-;”luminal A”, ER and/or PR+/HER2-; “luminal<br />
B”, ER and/or PR+/HER2+; “HER2”, ER and PR-/HER2+) was not<br />
significantly associated with survival(p=0.946). Abnormal MMS and<br />
multiple systemic metastases were associated with poor C-PFS (p=<br />
0.009 for both) and poor OS (p=0.006 and p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
was 34 and 8 m respectively (p=0.001). Endocrine therapy did not<br />
improve survival in ER and/or PR positive pts, (median 14 vs 20 m,<br />
p=0.437). In the entire group, median survival in RPA classes I, II<br />
and III was 24, 18 and 3 m, respectively (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
P3-13-03<br />
Molecular factors associated with bone metastases in breast<br />
cancer patients<br />
Winczura P, Sosinska-Mielcarek K, Duchnowska R, Badzio A, Lakomy<br />
J, Majewska H, Peksa R, Pieczynska B, Radecka B, Debska S, Zok J,<br />
Rogowski W, Strzelecka M, Kulma-Kreft M, Blaszczyk P, Litwiniuk<br />
M, Jesien-Lewandowicz E, Rutkowski T, Jaworska-Jankowska M,<br />
Adamowicz K, Foszczynska-Kloda M, Biernat W, Jassem J. Medical<br />
University of Gdansk, Poland; Regional Oncology Center, Gdansk,<br />
Poland; Regional Oncology Center, Opole, Poland; Military Institute<br />
of Medicine, Warsaw, Poland; Medical University of Lódz, Poland;<br />
Warmia and Masuria Oncology Center, Olsztyn, Poland; Maritime<br />
Hospital, Gdynia, Poland; Oncology Center, Bydgoszcz, Poland;<br />
Maria Sklodowska-Curie Memorial <strong>Cancer</strong> Center and Institute of<br />
Oncology, Gliwice, Poland; Regional Hospital in Wroclaw, Poland;<br />
West Pomeranian Oncology Center, Szczecin, Poland<br />
Background. Bones constitute the most frequent localization of<br />
distant failure in breast cancer patients. Treatment of bone metastases<br />
is virtually palliative, but in a proportion of patients can effectively<br />
prolong survival and improve quality of life. Currently, there are<br />
no effective strategies to prevent bone dissemination with systemic<br />
adjuvant therapies. Thus, better molecular selection and identification<br />
of patients who have particularly high risk of skeletal metastases may<br />
facilitate designing future clinical trials. In this study we analyzed<br />
expression of selected tumor proteins potentially associated with<br />
skeletal metastases in breast cancer patients.<br />
Patients and methods. The study group included 184 metastatic<br />
breast cancer patients; 113 with clinically diagnosed bone metastases<br />
and 71 with exclusively other sites of metastases, respectively. In<br />
all patients, using tissue microarrays technology, IHC expression of<br />
the following proteins was evaluated in the primary tumor: estrogen<br />
receptor (ER), progesterone receptor (PR), human epidermal<br />
growth factor receptor 2 (HER2), Ki67, cyclooxygenase 2 (COX2),<br />
chemokine receptor CXCR4, osteopontin (OPN), calcium sensing<br />
receptor (CaSR), cytokeratins 5/6 (CK5/6) and parathyroid hormonerelated<br />
protein receptor 1 (PTHrPR1). Additionally based on ER/<br />
PR, HER2 and Ki67 expression, following molecular breast cancer<br />
subtypes were selected: luminal A, luminal B HER2-negative, luminal<br />
B HER2-positive, nonluminal HER2-positive and triple negative.<br />
Results. Median survival in patients with bone vs. other site of<br />
metastases was 56 vs. 37 months respectively (p=0.0098). ER<br />
expression was more common in patients who did, compared<br />
with those who did not develop bone metastases (74.% vs. 45%<br />
respectively; p=0.0001), whereas cytoplasmic overexpression of<br />
OPN (1.9% vs. 14% respectively; p=0.002) and PTHrPR1 (16%<br />
vs. 34% respectively; p=0.007) was more common in patients with<br />
other sites of metastases. The impact of ER and cytoplasmic OPN<br />
expression on the risk of bone dissemination was confirmed in the<br />
multivariate analysis (Table 1). Luminal A breast cancer subtype<br />
(43% vs. 23% respectively; p=0.009) and luminal B HER2-positive<br />
(16% vs. 4.9%, respectively; p=0.032) were more common among<br />
patients with bone dissemination, whereas triple negative tumors<br />
prevailed in patients with other sites of metastases (16% vs. 38%;<br />
p=0.002). Median survival of patients with luminal A subtype was<br />
significantly longer than that with remaining subtypes (67 vs. 38<br />
months respectively; p=0.0004).<br />
Conclusions. These results suggest that ER expression and lack of<br />
OPN expression are independent factors predicting increased risk of<br />
bone dissemination in breast cancer patients. Bone metastases are<br />
specifically associated with luminal A and luminal B HER2-positive<br />
subtypes.<br />
Table 1. Multivariate analysis<br />
Marker Regression coefficient Standard error P 95% CI<br />
ER 0.412 0.135 0.002 0.147 - 0.677<br />
OPN cytoplasmic -0.988 0.416 0.018 -1.804 - -0.171<br />
P3-13-04<br />
Skeletal related Events and Bone Metastasis Patients with <strong>Breast</strong><br />
<strong>Cancer</strong> in Japan. A Retrospective Study<br />
Yamashiro H, Takada M, Imai S, Yamauch A, Tsuyuki S, Inamoto T,<br />
Matsutani Y, Sakata S, Wada Y, Okamura R, Harada T, Tanaka F,<br />
Moriguchi Y, Kato H, Higashide S, Kan N, Yoshibayashi H, Suwa<br />
H, Okino T, Nakayama I, Ichinose Y, Yamagami K, Hashimoto T,<br />
Nakatani E, Nagata Y, Kudo Y, Toi M. National Hospital Organization<br />
KURE Medical Center, Kure, Hiroshima, Japan; Graduate School<br />
of Medicine, Kyoto University, Kyoto, Japan; Kurashiki Central<br />
Hospital, Kurashiki, Okayama, Japan; Kitano Hospital (The Tazuke<br />
Kofukai Medical Research Institute), Osaka, Japan; Osaka Red<br />
Cross Hospital, Osaka, Japan; Tenri Hospital, Tenri, Nara, Japan;<br />
National Hospital Organization Kyoto Medical Center, Kyoto, Japan;<br />
National Hospital Organization Himeji Medical Center, Himeji,<br />
Hyogo, Japan; Yamatotakada Municipal Hospital, Yamatotakada,<br />
Nara, Japan; Osaka Saiseikai Noe Hospital, Osaka, Japan; Fukui<br />
Red Cross Hospital, Fukui, Japan; Kyoto City Hospital, Kyoto, Japan;<br />
Nagahama City Hospital, Nagahama, Shiga, Japan; Kan Norimichi<br />
Clinic, Kyoto, Japan; Japanese Red Cross Society Wakayama Medical<br />
Center, Wakayama, Wakayama, Japan; Hyogo Prefectural Tsukaguchi<br />
Hospital, Amagasaki, Hyogo, Japan; Kouga Public Hospital, Kouga,<br />
Shiga, Japan; Kyoto Min-iren Chuo Hospital, Kyoto, Japan; Takatsuki<br />
Red Cross Hospital, Takatsuki, Osaka, Japan; Shinko Hospital, Kobe,<br />
Hyogo, Japan; Hashimoto Clinic, Kobe, Hyogo, Japan; Translational<br />
Research Informatics Center, Foundation for Biomedical Research<br />
and Innovation, Kobe, Hyogo, Japan; Kobe City Medical Center<br />
General Hospital, Kobe, Hyogo, Japan<br />
Objective: Since skeletal related events (SRE) worsen QOL, the<br />
information relating to the SRE is important in the patient’s care. We<br />
have examined the incidences of bone metastasis (BM) and SRE in<br />
Japan and explored the prognostic factors which may affect the BM<br />
or SRE free period or survival.<br />
Patients and Methods: A retrospective, multicenter (21 institutes)<br />
study was performed. Patients with node positive or node negative<br />
with moderate to severe recurrence risk primary breast cancer<br />
were included. The primary endpoint was SRE-free period, and the<br />
secondary endpoints were BM-free period and the over-all survival<br />
period. By using a proportional hazard model (Cox regression),<br />
factors which affect these endpoints were examined in the population<br />
excluding stage IV patients.<br />
Results: 1,779 patients were registered and 1,708 patients’ data were<br />
used for analysis. The median follow-up duration was 5.71 years.<br />
SRE occurred in 133 (68.9%) of 193 patients who developed BM.<br />
The median SRE-free period from the initial treatment was 1,006<br />
days. The SRE-free rate and SRE-free survival rate at 5-years were<br />
92.6% and 85.4%, respectively. The median period from the initial<br />
SRE to the second one was 112 days, and the second to the third one<br />
was 147 days. The median BM-free period was 767 days. The BMfree<br />
and BM-free survival rates at 5-years were 89.2% and 83.7%,<br />
respectively. The over-all survival rate at 5-years was 89.4%. The<br />
SRE-free period was significantly affected by the number of lymph<br />
node metastasis (LN mets) (Hazard Ratio; HR [95%CI]; 1.09 [1.042-<br />
1.143], p=0.0002) and clinical stage (when stage I was assumed<br />
as reference, HR in stage II; 4.54 [1.296-15.933], stage III; 7.36<br />
[1.171-31.539], p=0.0262). SRE-free survival period was affected by<br />
the number of LN mets (HR; 1.10 [1.066-1.131], p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
(stage I as reference, HR in stage II: 2.93 [1.349-6.349], and stage<br />
III: 4.28 [1.694-10.815], p=0.008), and tumor phenotype (Luminal<br />
[L] A as reference, HR in LB; 1.89 [0.868-4.117], L-HER2: 2.81<br />
[1.334-5.923], HER2: 2.68 [1.266-5.659], Triple negative (TN);<br />
5.38 [3.031-9.537], p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 3<br />
on cancer cell migration were not observed when using osteoblasts.<br />
Together, these results suggest the functional importance of osteocytic<br />
Cx43 hemichannels in attenuating cancer cell migration and growth.<br />
P3-14-01<br />
Molecular definition of the transition of ductal carcinoma in situ<br />
(DCIS) to invasive ductal carcinoma (IDC).<br />
Colavito S, Stepansky A, Madan A, Harris LN, Hicks J, Bossuyt V,<br />
Rimm D, Lannin D, Stern DF. Yale University, New Haven, CT; Cold<br />
Spring Harbor Laboratory, Cold Spring Harbor, NY; Case Western<br />
Reserve University, Cleveland, OH<br />
Background: Ductal carcinoma in situ (DCIS) is thought to be a<br />
precursor lesion to invasive ductal carcinoma and sometimes occurs<br />
in combination with invasive disease. However, the majority of DCIS<br />
lesions do not progress to invasive disease. To date no molecular<br />
markers have been identified that associate with the potential for<br />
development to invasive disease. Our work has sought to identify<br />
molecular markers that can be used to determine the likelihood of<br />
DCIS being associated with invasive disease. Identification of such<br />
markers could be of direct therapeutic benefit, since patients with a<br />
high likelihood of associated or subsequent invasive disease could<br />
be managed more aggressively.<br />
Methods: We have compiled matched pairs, consisting of patients<br />
that have recurred with DCIS, compared to those who have DCIS plus<br />
invasive disease. Laser-capture microdissection was used to isolate in<br />
situ and invasive components of the latter, and in situ components of<br />
the former. We analyzed these samples by parallel cDNA-mediated<br />
Annealing, Selection, Extension, and Ligation (DASL) analysis of<br />
transcription, and DNA copy number analysis by resequencing. In<br />
addition, exome capture deep re-sequencing has been conducted on<br />
multiple cored in situ versus invasive components of DCIS from the<br />
same tumor sample.<br />
Results: Gene expression analysis revealed candidate genes that<br />
were specific to DCIS and others that were expressed only in the<br />
adjacent invasive component of the tissue. These genes are currently<br />
being evaluated to identify interesting candidates. Additionally,<br />
we characterized the gene expression signatures from tumors that<br />
recurred as DCIS only, to the DCIS component of those tumors that<br />
recurred with adjacent invasive disease. We identified genes that were<br />
differentially expressed between these data sets.<br />
The DNA copy number analysis of laser-captured samples indicated<br />
a single dominant clone in each DCIS. In contrast to previously<br />
reported observations, the profiles of invasive versus non-invasive<br />
lesions differ significantly from one another. Observations of noninvasive<br />
versus invasive components of adjacent disease in two of<br />
the pairs indicate that the profile of the invasive lesions differ from<br />
that of the non-invasive component, however the profiles share many<br />
individual features.<br />
Discussion: Our data identify differences between in situ and<br />
neighboring invasive tumor that may mark features associated with<br />
progression. Integration of the copy number and transcription profiling<br />
datasets will reveal the extent to which genomic alterations drive<br />
changes in gene expression. Identification of markers that distinguish<br />
indolent and aggressive subsets of DCIS that can be used to predict<br />
an association with invasive disease has the potential for near term<br />
clinical utility and may identify therapeutic targets for aggressive<br />
DCIS.<br />
P3-14-02<br />
Withdrawn by Author<br />
P3-14-03<br />
Differences in pathological and biological factors between DCIS,<br />
DCIS with microinvasion (DCIS-MI) and DCIS with concomitant<br />
invasive ductal carcinoma (DCIS-IDC).<br />
MacGrogan G, Baranzelli MC, Picquenot JM, Penault-Llorca F,<br />
Mathieu MC, Tas P, Fermeaux V, Mery E, Sagan C, Blanc-Fournier<br />
C, Brabencova E, Arnould L, Jacquemier J, Ettore F, Velasco<br />
V, Gonzalves B, Brouste V, Tunon de Lara C. Institut Bergonié,<br />
Bordeaux, France; Centre Oscar Lambret, Lille, France; Centre<br />
Henri Becquerel, Rouen, France; Centre Jean Perrin, Clermont-<br />
Ferrand, France; Institut Gustave Roussy, Villejuif, France; Centre<br />
Eugène Marquis, Rennes, France; CHU de Limoges, Limoges,<br />
France; Institut Claudius Regaud, Toulouse, France; Centre René<br />
Gauducheau, Saint Herblain, France; Centre François Baclesse,<br />
Caen, France; Institut Jean Godinot, Reims, France; Centre Georges<br />
François Leclerc, Dijon, France; Institut Paoli Calmettes, Marseille,<br />
France; Centre Antoigne Lacassagne, Nice, France<br />
Background<br />
Specific pathological and biological factors differentiating pure DCIS,<br />
DCIS with microinvasion (DCIS-MI) and DCIS with concomitant<br />
invasive ductal carcinoma (DCIS-IDC) are currently unknown.<br />
Identification of such factors would enable us to better understand<br />
the transition from an in situ to an invasive carcinoma and improve<br />
patient management for patients diagnosed with extensive DCIS.<br />
Methods<br />
We previously performed a prospective surgical study demonstrating<br />
the benefit of performing upfront sentinel lymph node (SLN) biopsy<br />
in patients with extensive DCIS or DCIS-MI undergoing mastectomy.<br />
In that study, 196 DCIS and 31 DCIS-MI diagnosed on vacuumassisted<br />
macrobiopsies underwent mastectomy and SLN biopsy. Final<br />
pathological status after mastectomy examination revealed 117 DCIS,<br />
38 DCIS-MI, 69 DCIS-IDC, and in 3 cases no residual disease was<br />
found. The mastectomy specimens of 216 cases (111 DCIS, 37 DCIS-<br />
MI, 68 DCIS-IDC) were available for central pathological review and<br />
a TMA containing DCIS lesions of 214 cases (110 DCIS, 36 DCIS-<br />
MI, 68 DCIS-IDC) was performed. DCIS morphological features<br />
(histological size, nuclear grade, comedo necrosis, inflammation)<br />
and immunohistochemical factors (ER, PR, Ki-67 and Her2) were<br />
assessed in each of the three groups and compared using Chi2 or<br />
Wilcoxon tests.<br />
Results<br />
Median histological DCIS sizes did not significantly differ<br />
between DCIS and DCIS-MI groups (70mm[4-160] and 60mm[4-<br />
180], respectively, p=0.33), nor between DCIS and DCIS-<br />
IDC(70mm[4-160] and 65mm[10-140], respectively, p=0.98). DCIS<br />
nuclear grade was significantly higher in DCIS-MI compared to DCIS<br />
(p=0.01), but there was no difference in nuclear grade between DCIS<br />
and DCIS-IDC (p=0.22). Comedo necrosis was more often present in<br />
DCIS-MI compared to DCIS (p=0.04), and no such difference was<br />
found between DCIS and DCIS-IDC (p=0.81). Stromal inflammation<br />
surrounding DCIS was more often found in DCIS-MI and DCIS-IDC<br />
compared to DCIS (p=0.03 and p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Conclusions<br />
In patients with extensive DCIS there are few morphological or<br />
current immunohistochemical factors differentiating in situ cases<br />
from those that have associated microinvasion or invasive ductal<br />
carcinoma. DCIS-MI cases have more aggressive histological features<br />
than DCIS. Stromal inflammation surrounding DCIS was the only<br />
feature distinguishing DCIS from DCIS-IDC.<br />
P3-14-04<br />
Symptomatic DCIS is a risk factor for invasion and should be<br />
managed accordingly<br />
Dimopoulos N, Williams K, Kirwan CC, Johnson R, Howe M, Bundred<br />
NJ. University Hospital of South Manchester<br />
Background: The National ABS Guidelines indicate axillary surgery<br />
is unwarranted in DCIS but should be offered to patients undergoing<br />
mastectomy. Up to 30% of pre-operatively diagnosed DCIS lesions<br />
harbour occult invasive cancers at mastectomy.<br />
Methods: To determine if DCIS mode of presentation, size (or other<br />
clinical factors such as Grade or HER2 status) predict invasion or<br />
nodal involvement, 380 patients undergoing surgery with a DCIS preoperative<br />
(B5) diagnosis were studied. In total 162 patients underwent<br />
mastectomy +/- axillary staging for DCIS and 216 conservation<br />
surgery between 2008-2011 in one unit.<br />
HER2, oestrogen receptor (ER) and progesterone receptor<br />
(PR) expression within primary DCIS were established using<br />
immunohistochemistry. HER2 was scored 0 (absent) to 3 (maximum).<br />
Scores ≥2 were taken as positive if amplified on FISH testing. ER<br />
and PR scored positive if ≥5% of cells stained.<br />
Results: In total 216 had <strong>Breast</strong> Conservation and 162 Mastectomy<br />
with 127 undergoing sentinel lymph node biopsy (111) or subsequent<br />
axillary surgery (16).<br />
Of 162 patients undergoing mastectomy for DCIS, 121 (75%)<br />
underwent axillary staging, with 9 (7%) having involved nodes.<br />
Screening mammography detected 117 (72%) but 45 (28%) presented<br />
symptomatically with a breast mass. Median age at diagnosis was<br />
57.8 years (range 29-94). Women less than 35 years of age had<br />
tumours sized greater than 4 cm in 72.3% compared to 59% in older<br />
women (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
P3-14-06<br />
The Utility of Margin Index to Predict Residual DCIS Following<br />
<strong>Breast</strong> Conserving Surgery<br />
Aneja S, Lannin DR, Killelea B, Horowitz NR, Chagpar AB. Yale<br />
University School of Medicine, New Haven, CT<br />
Background: Although breast conserving surgery (BCS) is<br />
commonly performed for ductal carcinoma in situ (DCIS), patients<br />
may require re-excision for close or positive margins to rule out<br />
residual disease. The concept of margin index (defined as margin<br />
distance/tumor size) has been found to predict residual disease in<br />
patients with invasive breast cancer, but this concept has yet to be<br />
evaluated for patients with DCIS. We sought to determine if DCIS<br />
margin index (defined as the closest margin of DCIS/extent of DCIS)<br />
was predictive of residual disease.<br />
Methods: We performed a chart review of all in situ breast cancers<br />
treated with BCS at an academic breast center in 2009. DCIS margin<br />
index was calculated as closest margin distance of DCIS (mm) / extent<br />
of DCIS (mm). Non-parametric statistical analyses were performed<br />
to evaluate the relationship between margin index and residual DCIS.<br />
Results: 177 patients with DCIS were treated with BCS in 2009.<br />
Of these, 87 (49.1%) underwent resection of additional tissue for<br />
close margins or as routine practice, and had recorded quantitative<br />
margin distances and tumor sizes such that margin index could be<br />
calculated. Of these, 18 (20.7%) had residual DCIS in the additional<br />
tissue excised. Median patient age was 60.4 years (range; 31.9-91.4).<br />
Of the 50 patients with available immunohistochemistry analysis, 42<br />
(84%) were ER-positive and 36 (72%) were PR-positive respectively.<br />
12 (13.8%) had low grade DCIS, 53 (60.9%) intermediate grade<br />
DCIS, and 22 (25.3%) high grade DCIS. Median tumor size was<br />
16mm (range; 1-80 mm); and median margin distance was 2 mm<br />
(range; 0-18 mm). Median margin index was 0.125 (range; 0 to 18).<br />
Factors correlating with residual DCIS on univariate analysis were<br />
high tumor grade (33.3% vs. 23.2%, p=0.044), PR-negativity (66.7%<br />
vs. 22.7%, p=0.044), increasing tumor size (median 27.5 mm vs.<br />
15.0 mm, p=0.003), decreasing margin distance (median 1.0 mm vs.<br />
2.1 mm, p=0.004), and lower margin index (median 0.032 vs. 0.200,<br />
p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-01-02<br />
Association of DCE-MRI texture features with molecular<br />
phenotypes and neoadjuvant therapy response in breast cancer<br />
Banerjee N, Maity S, Varadan V, Janevski A, Kamalakaran S, Sikov<br />
W, Abu-Khalaf M, Bossuyt V, Lannin D, Harris L, Cornfeld D,<br />
Dimitrova N. Philips Research North America; Yale Comprehensive<br />
<strong>Cancer</strong> Center; Warren Alpert Medical School of Brown University;<br />
Yale-New Haven Hospital; Yale <strong>Breast</strong> <strong>Cancer</strong> Program; Seidman<br />
<strong>Cancer</strong> Center<br />
Purpose: MRI imaging phenotype features such as volume and<br />
morphology are used to characterize tumor heterogeneity and tumor<br />
response. Texture-based imaging features are important in lesion<br />
characterization but their relationship to molecular phenotypes and<br />
response is unclear. Molecular stratification of breast cancer into<br />
luminal, basal, ERBB2, and normal-like can be made based on<br />
gene expression profiles. We investigate how texture-based imaging<br />
features relate to tumor biology, genetic subtypes and neoadjuvant<br />
therapy response using MRI, histopathological and RNA-sequencing<br />
data.<br />
Materials and Methods: Data from 74 Stage IIA to IIIB breast<br />
cancer patients enrolled in neo-adjuvant clinical trials NCT00617942<br />
and NCT00723125 were retrospectively reviewed. We evaluated 37<br />
gray-level co-occurrence matrix features (GLCM) on post-contrast T1<br />
fat-suppressed images of 38 HER2- tumors and 35 HER2+ tumors.<br />
The texture features included angular second moment, contrast,<br />
correlation, first diagonal moment, entropy, regularity, roughness,<br />
line likeness and other statistical summaries. We also performed<br />
RNA-sequencing on 23 tumors and compared RNAseq-based PAM50<br />
clustering with texture-based clustering. Patients with pCR and RCB<br />
class=I were determined to be responders and the rest were labeled<br />
non-responders. Wilcoxon signed rank test was used to compare<br />
luminal vs. basal, ER+ vs. ER- and PR+ vs. PR- tumors and determine<br />
the discriminative power of the texture features. We then performed<br />
hierarchical clustering on our patient data set based on the significant<br />
texture features and evaluated their association with subtypes,<br />
hormone receptor status and response. Statistical significance of<br />
clusters was determined by hypergeometric test.<br />
Results: We found five MRI texture features to be significantly<br />
associated with tumor subtypes: first diagonal moment, contrast range,<br />
correlation range and entropy range (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
[1] Arasu et al. Acad Radiol 2011;18:716-721.<br />
[2] Yankeelov & Gore. CMIR 2009;3:91-107.<br />
[3] Hylton et al. Radiology. 2012;263:663-672.<br />
P4-01-04<br />
MRI enhancement in stromal tissue surrounding breast tumors:<br />
Association with RFS following neoadjuvant chemotherapy<br />
Jones EF, Sinha SP, Newitt D, Klifa C, Kornak J, Park CC, Hylton<br />
NM. University of California, <strong>San</strong> Francisco, CA<br />
Objective: Stromal tissue surrounding breast tumors can harbor<br />
abnormalities that predict increased risk of recurrence. The purpose<br />
of this study was to evaluate low-level contrast enhancement patterns<br />
in normal appearing breast stroma surrounding tumors using dynamic<br />
contrast-enhanced magnetic resonance imaging (DCE-MRI).<br />
A secondary objective was to investigate whether enhancement<br />
patterns varied with distance from tumor and whether proximitydependent<br />
enhancement was associated with recurrence-free survival<br />
following neoadjuvant chemotherapy (NACT). Materials and<br />
Methods: Sixty-three patients with locally-advanced breast cancer<br />
were imaged with DCE-MRI before (V1) and after one cycle (V2)<br />
of adriamycin-cytoxan (AC) therapy. Normal-appearing stromal<br />
tissue on MR images was defined as fibroglandular tissue outside<br />
of tumor regions. Fibroglandular tissue was segmented from precontrast<br />
T1-weighted images using a fuzzy C-means clustering<br />
method 1 . Tumor regions were identified using a percent enhancement<br />
threshold of 70% in the first post-contrast image (PE1). Distance<br />
from tumor (proximity) was defined for each stromal voxel as the<br />
minimum three-dimensional distance from any tumor voxel. Stromal<br />
enhancement was characterized by calculating mean PE and mean<br />
signal enhancement ratio (SER=PE1/PE2) in distance shells of 5<br />
mm, from 0 to 40 mm outside of tumor tissue. Global PE and SER<br />
were calculated by averaging all stromal voxels from 5 to 40 mm<br />
from tumor. Proximity-dependent PE and SER were analyzed using<br />
a linear mixed effects model and Cox proportional hazards model for<br />
recurrence-free survival. Results: The mixed effects model displayed<br />
a decreasing radial trend in PE at both V1(estimated mean = -0.39<br />
per mm, 95% CI (-0.50, -0.29), p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
from prior studies (7 lesions). Six lesions were malignant (all IDC)<br />
and 10 were benign (5 fibroadenomas, 4 cysts, 1 papilloma). Scan<br />
time (5 minutes) and in-plane resolution were equivalent between<br />
the CUBE and FSE images while slice thickness in CUBE (2 mm)<br />
was half that of FSE (4 mm). Lesion-to-fibroglandular tissue signal<br />
ratios (S L /S F ) were calculated for both FSE and CUBE; S L is lesion<br />
signal and S F is fibroglandular tissue signal. The signal ratios were<br />
assessed with ordinary least squares linear regression. Along with<br />
lesion signal intensity with respect to surrounding tissue, depiction<br />
of lesion morphology on T2-weighted images can also contribute<br />
to differential diagnosis in breast MRI. A radiologist with breast<br />
MRI expertise evaluated the resolution difference between the two<br />
sequences based on the depiction of lesion morphology and the<br />
alignment of lesions between the T2-weighted and DCE images<br />
Results: S L /S F showed a correlation coefficient between the two<br />
methods of 0.93. Mean values of S L /S F for different methods and<br />
lesions were, FSE malignant: 1.01 ± 0.21, FSE benign: 2.05 ± 0.65,<br />
CUBE malignant 0.99 ± 0.25, CUBE benign 2.16 ± 0.62. Depiction<br />
of lesion morphology and signal intensity in small lesions improved<br />
in the CUBE images due to the reduced partial volume effect in the<br />
slice direction. Alignment of structures between T2-weighted and<br />
DCE images was facilitated with CUBE due to the higher throughplane<br />
resolution and the ability to reformat the images in orientations<br />
other than the acquisition plane.<br />
Conclusion: CUBE provides equivalent contrast and improved<br />
resolution in the breast in comparison to FSE. While T2-weighted<br />
images will continue to be an adjunct to DCE images, 3D T2-weighted<br />
sequences like CUBE have the potential to expand the contribution of<br />
T2-weighted images to the characterization of benign and malignant<br />
lesions in the breast.<br />
P4-01-07<br />
The Relationship of <strong>Breast</strong> Density in Mammography and<br />
Magnetic Resonance (MR) Imaging in a High Risk Population<br />
Chun J, Refinetti AP, Schnabel F, Leite AP, Price A, Billig J, Schwartz<br />
S, Moy L. NYU Langone Medical Center, New York, NY<br />
Background<br />
Mammographic breast density (BD) is associated with a 4 to 6-fold<br />
increased risk for developing breast cancer. Increased breast density<br />
on mammography is also known to decrease the diagnostic sensitivity<br />
of the exam, which is of great concern to women at increased risk for<br />
breast cancer. There is well-established medical literature describing<br />
the benefit of MRI in screening high risk women. A previous study has<br />
shown that background parenchymal enhancement (BPE) as measured<br />
on MRI can be correlated with breast cancer risk. The purpose of this<br />
study was to evaluate the relationship between BD, BPE, and FGT<br />
(assessment of the amount of fibroglandular tissue with contiguous<br />
MR images through both breasts) in pre and post-menopausal women<br />
who are at high risk for developing breast cancer.<br />
Methods<br />
The High Risk <strong>Breast</strong> <strong>Cancer</strong> Consortium (HRBCC) database at NYU<br />
Langone Medical Center was queried for our study population. A total<br />
of 56 women had both screening mammograms and MRIs completed<br />
at our center. Variables of interest included BD, BPE, FGT, BMI, Gail<br />
scores, and menopausal status. BD was defined by ACR classifications<br />
1-4. FGT was assessed on a similar scale 1-4. BPE was categorized<br />
as minimal, mild, moderate, or marked. BMI (kg/m2) was grouped<br />
into 4 categories: underweight (≤18), normal (19-24), overweight<br />
(25-29), and obese (≥30). Statistical analyses were performed using<br />
Spearman Correlation Coefficients.<br />
Results<br />
The median age in our cohort was 48 years (range 24-70 years). The<br />
majority of women were Caucasian (74%) with a median 5-year<br />
Gail score of 3.35. There was no correlation between BD and BPE<br />
(r=0.08) and BPE and FGT (r=0.18). However, there was a moderate<br />
positive correlation between BD and FGT (r=0.65). When we stratified<br />
by menopausal status, the correlation for BD and FGT was stronger<br />
for post-menopausal women (r=0.73) versus premenopausal women<br />
(r=0.57). When we stratified by BMI, we found a stronger positive<br />
association for BD and FGT among women who were overweight<br />
and obese (r=0.62).<br />
Clinical Characteristics<br />
VARIABLES TOTAL N=56 (%)<br />
FHBC<br />
Positive 35 (63)<br />
Negative 21 (37)<br />
BRCA 1,2<br />
Positive 17 (30)<br />
Negative 39 (70)<br />
AH, LCIS<br />
AH 18 (32)<br />
LCIS 12 (21)<br />
BD<br />
fatty 3 (5)<br />
scattered 11(20)<br />
heterogeneously dense 20 (36)<br />
dense 22 (39)<br />
BPE<br />
minimal 19 (34)<br />
mild 13 (23)<br />
moderate 14 (25)<br />
marked 10 (18)<br />
FGT<br />
fatty 10 (18)<br />
scattered 8 (14)<br />
heterogeneously dense 21 (38)<br />
dense 17 (30)<br />
BMI<br />
underweight ≤18 0 (0)<br />
normal 19-24 43 (77)<br />
overweight 25-29 9 (16)<br />
obese ≥30 4(7)<br />
Conclusions<br />
In our study cohort of patients at high risk for developing breast<br />
cancer, BD and BPE were not correlated, even after adjusting for<br />
menopausal status. This implies that BD and BPE may represent<br />
different characteristics of breast tissue and may have different<br />
implications. We found a strong correlation between BD and FGT.<br />
This association was strongest in women who were overweight and<br />
obese. FGT is a more objective and quantitative measurement of<br />
breast density and may be more useful in quantitative breast cancer<br />
risk assessment. Further studies are necessary to determine if BPE<br />
and FGT are independent risk factors for breast cancer.<br />
P4-01-08<br />
Effect of bilateral salpingo-oophrectomy on breast MRI<br />
fibroglandular volume and background parenchymal<br />
enhancement for BRCA 1/2 mutation carriers.<br />
DeLeo, III MJ, Domchek S, Kontos D, Conant E, Weinstein S. Hospital<br />
of the University of Pennsylvania, Philadelphia, PA<br />
PURPOSE: Bilateral salpingo-oophrectomy (BSO) reduces breast<br />
cancer risk in women with BRCA1/2 mutations by approximately<br />
50%. Annual screening for these high-risk women includes breast<br />
MRI and mammography. It is unknown whether BSO affects<br />
fibroglandular volume (FG) and background enhancement (BG) on<br />
breast MRI in this population. The purpose of this study is to assess<br />
the difference in FG and BG in BRCA1/2 mutation carriers before<br />
and after BSO on breast MRI.<br />
METHOD AND MATERIALS: We compared FG and BG on<br />
contrast-enhanced breast MRI before and after BSO. Two readers<br />
blinded to both clinical and imaging history scored FG according<br />
to the BI-RADS criteria from 1-4: fatty, scattered, heterogeneously<br />
dense, or extremely dense. BG was graded based on the MRI BI-<br />
RADS scale from 1-4: minimal, mild, moderate, and marked. Average<br />
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<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
BIRADS scores of each reader were used to calculate mean FG and<br />
BG (±SD) before and after BSO, and compared using a paired t-test<br />
for significance.<br />
RESULTS: We examined 60 women with BRCA1/2 mutations who<br />
underwent breast MRI before and after BSO from 2001-2011 at our<br />
institution. Five patients were excluded from the final analysis as they<br />
underwent mastectomy or bilateral radiation therapy before post-BSO<br />
MRI. Mean time to post-BSO MRI was 8.3 months ± 7 months.<br />
Mean pre- and post-operative FG were 2.64±0.78 and 2.58±0.75,<br />
respectively (p=0.622). Mean pre- and post-operative BG were<br />
2.46±0.93 and 1.87±0.81, respectively (p=0.0001). <strong>Breast</strong> cancer was<br />
detected in 8 women at a median time of 3.4 years following BSO.<br />
In these 8 women, mean pre- and post-operative FG were 3.10±0.57<br />
and 2.55±0.69, respectively. Mean pre- and post-operative BG were<br />
3.20±0.67 and 2.35±0.71, respectively.<br />
CONCLUSION: In this population of 55 BRCA1/2 mutation carriers<br />
who underwent breast MRI before and after BSO, there was a<br />
significant reduction in BG following BSO. There was no difference<br />
in FG on MRI following BSO. For the 8 patients in this cohort who<br />
were diagnosed with breast cancer after BSO, there was a trend toward<br />
higher FG and BG both before and after BSO, in comparison to the<br />
patients who were not diagnosed with breast cancer, suggesting that<br />
rates of higher FG and BG may be associated with increased risk for<br />
developing breast cancer.<br />
P4-01-09<br />
Screening breast magnetic resonance imaging (MRI) in earlystage<br />
breast cancer survivors<br />
Dowton AA, Meyer ME, Ruddy KJ, Yeh ED, Partridge AH. Dana-<br />
Farber <strong>Cancer</strong> Institute, Boston, MA; Brigham & Women’s Hospital,<br />
Boston, MA<br />
Background:<br />
Limited evidence is available regarding the value of screening breast<br />
MRI in female early stage breast cancer survivors. We sought to<br />
evaluate outcomes of index screening breast MRI in breast cancer<br />
survivors in the modern era of breast cancer treatment and imaging.<br />
Methods:<br />
Using a large prospective institutional database, we identified all<br />
women who underwent breast MRI between 7/2006 and 6/2008, were<br />
≥ 1 year and ≤ 3 years after diagnosis of stage I-IIIa breast cancer, had<br />
remaining breast tissue after treatment, and had consented to a record<br />
review protocol at our center (95% uptake rate). Sociodemographic,<br />
disease, staging and treatment information (see table 1), indications<br />
and outcomes for breast MRI, as well as disease status at 2 years after<br />
the index MRI were ascertained.<br />
Results:<br />
643 patients were identified as having undergone at least 1 MRI of the<br />
breast(s); 248 (38.5%) were diagnostic MRIs (had identified clinical<br />
indication or imaging abnormality); 12 (2%) were missing clinical<br />
data; 383 (59.5%) were screening MRIs. 338/383 (88%) patients who<br />
had screening MRI had stage I-IIIa invasive breast cancer. 220/338<br />
(65%) MRIs performed were index MRIs (index MRI defined as<br />
first MRI >1 year post diagnosis). For this preliminary analysis, we<br />
include only the 155 patients (70%) who were within 1-3 years of<br />
diagnosis at the time of index MRI (see table 1 for patient and disease<br />
characteristics).<br />
24/155 (15.5%) screening MRIs were considered not normal. Five<br />
women (21%) underwent biopsy based on abnormal MRI finding; 1<br />
resulted in the detection of a local recurrence (4.2%, 95% CI=0.1%-<br />
21.1%). 3/131 patients who had a normal index MRI were found<br />
to have local/regional recurrence or contralateral breast cancer<br />
diagnosed within 2 years of the MRI (2.3%, 95% CI=0.5%-6.6%). A<br />
statistically significant difference in the proportions was not observed<br />
based on Fisher’s test (p=0.50). 6/155 patients (3.9 %) had a systemic<br />
recurrence in the 2 years following index MRI.<br />
Table 1. Patient and Disease Characteristics<br />
Characteristic (N=155) n (%)<br />
Age at diagnosis (yrs)<br />
Median (Min-Max) 48 (28-77)<br />
0 - =70 2 (1%)<br />
Race<br />
Caucasian Non-Hispanic 144 (93%)<br />
African-American Non-Hispanic 1 (1%)<br />
Other 10 (6%)<br />
Genetic Mutation Status<br />
BRCA 1 Positive 0 (0%)<br />
BRCA 2 Positive 1 (0.6%)<br />
Indeterminate mutation of unknown significance 6 (3.9%)<br />
Negative 35 (22.6%)<br />
Not Tested 113 (72.9%)<br />
Family History of <strong>Breast</strong> <strong>Cancer</strong><br />
Yes 77 (49.7%)<br />
No 78 (50.3%)<br />
Tumor Stage<br />
I 83 (54%)<br />
IIA 34 (22%)<br />
IIB 26 (17%)<br />
IIIA 12 (8%)<br />
Type of definitive surgery<br />
BCS 92 (59%)<br />
Mastectomy 63 (41%)<br />
Hormone receptor status<br />
HR+ 125 (81%)<br />
HR- 30 (19%)<br />
HER2 status<br />
High pos 27 (17%)<br />
Negative 123 (79%)<br />
Low pos 4 (3%)<br />
Unknown 1 (1%)<br />
Conclusion:<br />
The vast majority of first screening breast MRIs obtained 1-3 years<br />
following treatment in early stage breast cancer survivors are normal,<br />
and very few detect cancer. Planned further analysis in this dataset<br />
will evaluate frequency of cancer detection in longer-term survivors.<br />
Additional research is necessary to determine the risks and benefits of<br />
screening breast MRIs being performed in this population.<br />
P4-01-10<br />
High-resolution diffusion weighted imaging for the separation<br />
of benign from malignant BI-RADS 4/5 lesions found on breast<br />
MRI at 3 Tesla<br />
Wisner DJ, Rogers N, Deshpande VS, Newitt DN, Laub GA, Porter<br />
DA, Joe BN, Hylton NM. University of California, <strong>San</strong> Francisco, CA;<br />
Siemens Medical Solutions, USA, Inc, <strong>San</strong> Francisco, CA; Siemens<br />
Medical Solutions, Erlangen, Germany<br />
Diffusion weighted imaging (DWI) has shown potential for separating<br />
malignant from benign lesions on breast MRI, theoretically improving<br />
the specificity of the breast MRI exam. However, standard DWI<br />
is hampered by multiple factors in the breast which limit utility<br />
in clinical practice. A readout segmented diffusion technique<br />
(RESOLVE)(1) permits the use of extremely short echo spacing and<br />
resamples uncorrectable data using a real-time navigator, reducing<br />
image distortion and potentially providing more accurate apparent<br />
diffusion coefficient (ADC) within lesions. In order to study the<br />
potentially utility of this method against standard diffusion, we<br />
compared ADC values from retrospectively-identified BI-RADS 4/5<br />
(suspicious) lesions with both standard single shot-spin echo EPI (ss-<br />
EPI) and RESOLVE diffusion at 3 Tesla over a 10-month period. All<br />
patients subsequently went to image-directed biopsy.<br />
The imaging parameters were as follows: TR/TE=7500-10000/60 ms<br />
(ss-EPI) and 8000-12000/64 ms (RESOLVE), averages=8 (ss-EPI)<br />
and 1 (RESOLVE), readout segmentation factor 5 with echo spacing<br />
of 0.3 ms (RESOLVE), slices = 47-50, b-values 0, 800, resolution<br />
= 1.8x1.8 x2.4 mm3, imaging times of approximately 5 minutes for<br />
both techniques. Freehand ROI’s were drawn on each suspicious<br />
lesion based on b=800 maps in close reference to the post-contrast<br />
T1 series by a board-certified radiologist who was blinded to final<br />
pathology and sequence. Similar ROI’s were drawn in normal tissue<br />
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as a control. For each lesion, mean ADC values and signal intensities<br />
at b=800 were recorded. ADC values were averaged by technique<br />
and pathologic outcome (benign or malignant). Signal intensity was<br />
normalized by dividing mean signal intensity of the lesion ROI by<br />
that of the control. Significance was determined using Wilcoxon<br />
rank-sum test for ADC, and paired t-test for signal intensity measures.<br />
Of the final cohort of 38 lesions in 31 patients, 9 were malignant<br />
and the remainder were benign. Two lesions were no longer present<br />
at breast MRI biopsy, and hence deemed benign. The lesion-tobackground<br />
signal intensity on diffusion was higher (p=0.05) on<br />
RESOLVE (1.9±0.1) compared to standard diffusion (1.7±0.1).<br />
Statistically significant differences between benign and malignant<br />
lesion were observed for mean ADC obtained by both methods<br />
(Table 1; p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
a focus or foci. Referring physicians provided information regarding<br />
the follow-up status of 88/154 (57%) lesions in noncompliant patients,<br />
of which 44/88 (50%) were followed by mammogram instead of MRI.<br />
Among compliant patients, 7/178 (3.9%) lesions seen on follow-up<br />
MRI were found to be high risk or malignant.<br />
Conclusion<br />
Compliance with follow-up MRI recommendation after core needle<br />
biopsy is low. Three characteristics were found to be associated with<br />
noncompliance with follow-up imaging: referral from non-affiliated<br />
physician, screening MRI, and a focus lesion. Moreover, patients who<br />
do not comply with recommended MRI follow-up are more likely to<br />
have follow-up mammography. Follow-up imaging among compliant<br />
patients found high-risk lesions and malignancy. Facilities performing<br />
MRI-guided core biopsies should therefore be aware of a high risk<br />
of noncompliance with follow-up.<br />
P4-01-13<br />
Practice patterns of MRI utilization for breast cancer treatment<br />
within the University of California system as part of the Athena<br />
initiative<br />
Tokin CA, Ojeda H, Mayadev JS, Hylton NM, Fowble BL, Rugo HS,<br />
Hwang S, Hurvitz S, Wells C, Blair SL. University of California, <strong>San</strong><br />
Diego; University of California, Davis; University of California, <strong>San</strong><br />
Francisco; Duke University; University of California, Los Angeles<br />
Background: The appropriate utilization of <strong>Breast</strong> MRI in breast<br />
cancer care remains controversial. As part of a quality improvement<br />
initiative for breast cancer screening and treatment, we sent out a<br />
survey to physicians who treat breast cancer patients. All respondents<br />
are participants in the ATHENA initiative, a program which unites<br />
physicians, researchers, and patients at the five University of<br />
California medical centers.<br />
Objective: To use the ATHENA infrastructure to perform a qualitative<br />
analysis of variations in breast cancer care.<br />
Methods: Surveys were sent to 50 physicians in the ATHENA network<br />
whose practices are focused on breast cancer. Respondents were<br />
presented with clinical scenarios, and asked whether they would<br />
recommend MRI always/usually or sometimes/never. Differences<br />
were compared by Chi square.<br />
Results: 39 physicians completed the survey (78% response rate).<br />
Of these physicians 29% were surgeons, 26% radiation oncologists<br />
and 45% medical oncologists. Athena physicians were more likely<br />
to order MRI for high risk screening of mutation carriers than not<br />
(85% yes vs. 15% no, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-01-15<br />
Impact of Preoperative MRI on the Surgical Treatment of <strong>Breast</strong><br />
<strong>Cancer</strong>: A SEER-Medicare Analysis<br />
Thorsen CM, Weiss JE, Kerlikowske K, Ozanne EM, Buist DS,<br />
Hubbard RA, Tosteson AN, Henderson LM, Virnig BA, Goodrich ME,<br />
Onega TL. University of California, <strong>San</strong> Francisco, CA; Dartmouth<br />
Medical School, Lebanon, NH; University of Washington, Seattle,<br />
WA; University of North Carolina, Chapel Hill, NC; University of<br />
Minnesota, Minneapolis, MN<br />
Background:<br />
Preoperative magnetic resonance imaging (MRI) use has increased<br />
for women with invasive breast cancer and ductal carcinoma in situ<br />
(DCIS). Prior studies have disputed whether preoperative MRI is<br />
associated with increased rates of mastectomy. We evaluated the<br />
rates of mastectomy versus breast conserving surgery (BCS) and their<br />
association with preoperative MRI in older women.<br />
Methods:<br />
We identified women in SEER-Medicare 66 years or older diagnosed<br />
with DCIS or invasive breast cancer between 2002 and 2007 treated<br />
within 6 months of diagnosis with mastectomy or breast conserving<br />
surgery (BCS) with or without radiotherapy (RT). Preoperative<br />
MRI was defined as MRI occurring before a woman’s first surgery<br />
after her initial diagnosis. We looked for surgical treatment (BCS or<br />
mastectomy) and radiotherapy, age at diagnosis, year of diagnosis and<br />
cancer type, overall and separately by receipt of MRI. We examined<br />
the association of surgical treatment with MRI using multivariable<br />
logistic regression adjusting for age at diagnosis, year of diagnosis,<br />
cancer type and radiotherapy.<br />
Results:<br />
Among the 70,758 women identified, 5,126 (7.2%) had a preoperative<br />
MRI. The overall use of MRI increased from 1.2% in 2002 to 18.0%<br />
in 2007 (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
P4-02-01<br />
18F-FDG PET/CT for the assessment of locoregional lymph node<br />
involvement and radiotherapy indication in stage II-III breast<br />
cancer treated with neoadjuvant chemotherapy<br />
Koolen BB, Valdés Olmos RA, Vogel WV, Vrancken Peeters M-JTFD,<br />
Rodenhuis S, Rutgers EJT, Elkhuizen PHM. Netherlands <strong>Cancer</strong><br />
Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands<br />
Background: Risk for locoregional recurrence (LRR) in breast cancer<br />
depends on tumor size and on number and location of tumor-positive<br />
locoregional nodes. Postoperative irradiation of chest wall and/or<br />
locoregional nodes is advised in patients at high risk for LRR, but<br />
remains controversial in patients at intermediate risk. Because the<br />
number of tumor-positive axillary nodes in patients treated with<br />
neoadjuvant chemotherapy (NAC) can no longer be determined from<br />
the axillary lymph node dissection (ALND) and conventional staging<br />
of N3-disease with ultrasound is inaccurate, planning of radiotherapy<br />
in these patients is hampered. The aim of the present study was to<br />
assess the accuracy of 18F-FDG PET/CT for locoregional staging in<br />
stage II-III breast cancer patients scheduled for NAC. Second, we<br />
wished to assess the value of pre-chemotherapy PET/CT in estimating<br />
the risk for LRR and determining chest wall and/or locoregional<br />
radiotherapy indication, based on the detection of ≥4 FDG-avid<br />
axillary nodes or occult N3-disease.<br />
Methods: 278 patients underwent PET/CT of the thorax in prone<br />
position. Presence and number of FDG-avid nodes were evaluated,<br />
blinded for other diagnostic procedures.<br />
First, PET/CT findings were compared with histopathology before<br />
NAC (ultrasound with fine needle aspiration and/or sentinel lymph<br />
node biopsy (SLNB)) to determine the diagnostic accuracy for<br />
detection of axillary metastases and newly discovered N3-disease.<br />
Second, risk estimation and radiotherapy planning were evaluated<br />
with and without PET/CT. Conventional locoregional staging<br />
consisted of ultrasound with fine needle aspiration before, SLNB<br />
before, and ALND after NAC. Patients were classified as low-risk<br />
(cT2N0), intermediate-risk (cT0N1, cT1N1, cT2N1, and cT3N0), or<br />
high-risk (cT3N1, cT4, cN2-3, and (y)pN2-3) for LRR. Emphasis was<br />
on the number of patients upstaged to the high-risk group by PET/<br />
CT, requiring postoperative locoregional irradiation.<br />
Results: Sensitivity, specificity, positive predictive value, and negative<br />
predictive value in the detection of axillary metastases were 80%,<br />
92%, 98%, and 53%, respectively. Occult lymph node metastases in<br />
the internal mammary chain and periclavicular area were detected in<br />
17 (6%) and 25 (9%) patients, respectively.<br />
PET/CT detected occult N3-disease in 5 (11%) of 47 low-risk patients.<br />
In 116 intermediate-risk patients, PET/CT detected ≥4 FDG-avid<br />
nodes in 14 (12%) patients and occult N3-disease in 13 (11%) patients,<br />
upstaging 25 (22%) of intermediate-risk patients. In total, 30 (18%) of<br />
278 low- and intermediate-risk patients were upstaged to the high-risk<br />
group, requiring chest wall and/or locoregional irradiation.<br />
Conclusion: In breast cancer patients scheduled for NAC, PET/CT<br />
renders pre-chemotherapy SLNB unnecessary in case of an FDGavid<br />
axillary node and detects occult N3-disease in 15% of patients.<br />
Pre-chemotherapy PET/CT is a valuable tool for selection of highrisk<br />
patients who will benefit from locoregional radiotherapy. In<br />
our population, 18% of patients had an indication for locoregional<br />
irradiation based on PET/CT information, which was missed by<br />
conventional staging.<br />
P4-02-02<br />
Comparison of 18F-FDG PET-CT and 11C-MET PET-CT for<br />
assessment of response to neoadjuvant chemotherapy in locally<br />
advanced breast carcinoma.<br />
Dinesh A, Ramteke VK, Chander J, Tripathi M, Mahajan S. Maulana<br />
Azad Medical College, New Delhi, Delhi, India; Institute of Nuclear<br />
Medicine & Allied Sciences, New Delhi, Delhi, India<br />
INTRODUCTION<br />
Neo-adjuvant chemotherapy plays an important role in treatment of<br />
breast cancer by decreasing the tumor load & it offers an opportunity<br />
to evaluate response of primary tumor to chemotherapy. This makes<br />
response monitoring crucial in the management of breast carcinoma.<br />
Standard anatomical imaging modalities are unable to accurately<br />
reflect the response to chemotherapy until several cycles of drug<br />
treatment have been completed. Metabolic imaging using tracers like<br />
18F-fluorodeoxyglucose (FDG) as a marker of glucose metabolism<br />
or amino acid tracers like L-methyl-11C methionine (MET) have<br />
potential role for the measurement of treatment response in breast<br />
cancer.<br />
AIMS AND OBJECTIVES<br />
To compare FDG PET-CT with MET PET-CT for assessment of<br />
response to neoadjuvant chemotherapy, in locally advanced breast<br />
carcinoma and to correlate it with clinico-pathological response.<br />
METHODS<br />
In our prospective study, 20 patients with histology proven locally<br />
advanced breast carcinoma were enrolled. All patients underwent<br />
clinical assessment and PET-CT imaging using FDG and MET before<br />
and after 3 cycles of neoadjuvant chemotherapy (CAF regimen).<br />
Thereafter, all patients were taken for modified radical mastectomy<br />
and the resected breast with dissected axillary nodes was sent for<br />
histo-pathological analysis. Tumor response to the neoadjuvant<br />
chemotherapy was evaluated clinically using WHO criteria and by<br />
PET-CT imaging using PERCIST criteria. Responses calculated were<br />
compared for statistical significance using paired t- test.<br />
RESULTS<br />
Mean SUV in FDG-PET for primary tumor (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
for axillary metastasis by FDG-PET and MET-PET shows higher<br />
accuracy than clinical examination. Thus, making PET-CT a valuable<br />
monitoring tool for guiding the choice of surgical management of<br />
axilla.<br />
P4-02-03<br />
FDG PET/CT for early monitoring of response to neoadjuvant<br />
chemotherapy in breast cancer patients.<br />
Andrade W, Soares F, Lima E, Maciel MdS, Toledo C, Iyeyasu H, Cruz<br />
M, Fanelli M. A. C. Camargo <strong>Cancer</strong> Hospital, São Paulo, SP, Brazil<br />
Introduction: Neoadjuvant chemotherapy (NAC), initially used only<br />
for locally advanced breast cancer, is now commonly used in patients<br />
with operable but large breast cancer or unfavorable tumor/breast size<br />
index because increases the chances of performing breast conservative<br />
surgery (BCS) instead of mastectomy in this group of patients.<br />
Patients and Methods<br />
This is a prospective unicenter trial. FDG PET/CT were performed in<br />
40 patients at baseline and after the second cycle of NAC. The level<br />
and relative changes in standardized uptake value (SUV) of FDG<br />
uptake were assessed regarding their ability to predict histopathologic<br />
response.<br />
Pathologic complete response (pCR) was defined as no malignant<br />
cells (no invasive ductal carcinoma and no ductal carcinoma in situ)<br />
identifiable in sections from the site of the tumor in the breast and in<br />
the axillary lymph node.<br />
Results<br />
This prospectively study analyzed forty patients undergoing NAC,<br />
all female, age ranged 27-64 years (mean 41.0 years and median 38<br />
years), all tumors were invasive ductal carcinoma, histological tumor<br />
grade 1, 2 and 3 were present respectively at 5%, 38.5% and 100%<br />
of the sample and nuclear grade 2 and 3 were present respectively at<br />
12.5% and 87.5%. Estrogen receptor was positive in 60% of patients<br />
and the progesterone receptor was positive in 47.5% of patients. Her<br />
2 was overexpressed in 12 patients (30%). Phenotype in this sample<br />
had the following distribution: 12.5% luminal A (5 patients), 50%<br />
Luminal B (20 patients: 14 patients with Ki-67> 14% and 6 cases<br />
with HER 2 overexpression), 15 % HER 2 (6 patients) and cases triple<br />
negative 9 (22.5%). size of the primary tumor ranged from 4.10 cm to<br />
12.0 cm (mean 7.10 cm). The size of the primary tumor ranged from<br />
had a mean of 6.7 cm and a median of 6.0 cm. This group showed<br />
great uniformity in relation to primary chemotherapy. NAC with<br />
cyclophosphamide and adriamycin were administered to 38 patients.<br />
In this study, pCR was obtained in 12 patients (30%). Baseline FDG<br />
SUV referring to pCR group was 11.26 and 7.26 in non-pCR group (p<br />
= 0.04). FDG SUV after second cycle was 2.73 in pCR group and 4.64<br />
in non-pCR group (p = 0.048). When analyzing ∆SUV (difference<br />
between baseline SUV and SUV after second cycle), pCR group<br />
had a mean reduction of 81.58% and non-pCR group had a mean<br />
reduction of 81.58% (p = 0.001). Receiver operating curve analyses<br />
were performed to deter mine optimal differentiation cut-off values<br />
of ∆SUV for differentiation of pCR and non-pCR. After two courses<br />
of NAC the optimal cutoff value to early differentiation between pCR<br />
from non-pCR were 59,1% in decrease of SUV. The sensitivity and<br />
specificity were 64,3% and 100,0%, respectively.<br />
Conclusion<br />
The optimum role of FDG PET in predicting the response of breast<br />
cancers to neoadjuvant chemotherapy is still not clearly defined and<br />
the SUV cut-off needs to be validated. FDG-PET allows for prediction<br />
of treatment response by the level of FDG uptake in terms of SUV at<br />
baseline and after two cycles of chemotherapy and FDG-PET may be<br />
helpful for individual treatment stratification in breast cancer patients.<br />
P4-02-04<br />
Tissue oxyhemoglobin dynamics measured with functional optical<br />
imaging immediately after starting chemotherapy correlates<br />
with markers of cellular proliferation and inflammation in a rat<br />
breast tumor model.<br />
Ueda S, Roblyer D, Cerussi A, Saeki T, Tromberg B. Beckman Laser<br />
Institute, University of California, Irvine, Irvine, CA; Saitama Medical<br />
University, Hidaka, Saitama, Japan<br />
We have reported that a transient increase of oxyhemoglobin level<br />
measured 24 hours after the start of neoadjuvant chemotherapy using<br />
noninvasive Diffuse Optical Spectroscopic Imaging (DOSI) may be<br />
useful in discriminating nonresponding from reponding breast cancer<br />
patients (PNAS. 2011 Aug 30;108(35):14626-31). To elucidate the<br />
underlying biological mechanism, we compared optical measured<br />
hemoglobin levels to tissue biomarkers in a rat tumor model.<br />
Method: An orthotopic mammary tumor model using Fischer 344<br />
rats and MAT3B cells was used for this experiment. 16 mg of<br />
cyclophosphamide was administered (i.p.) in 15 rats after tumors<br />
had grown to a significant size. A wide-field functional imaging<br />
device that utilizes structured near-infrared light was used to measure<br />
superficial absolute concentrations of oxyhemoglobin (ctO2Hb) and<br />
deoxyhemoglobin (ctHHb) of the tumors. Rats were imaged and<br />
sacrificed (two per timepoint) at each of the following timepoints:<br />
baseline, 2, 6, 12, 24, 48, 96 hours, and day 8 following the injection.<br />
Resected tumors were sectioned after paraffin-embedding and<br />
representative slides were used for immunohistochemistry. Cellular<br />
markers of proliferation (measured by Ki67), apoptosis (Caspase3),<br />
NK cells (ANK61), and macrophages (MAC387) were counted in<br />
each slide using Image J software.<br />
Result: Average tumors baseline values of ctO2Hb and ctHHb were<br />
81.4 µM (±9.2 SD) and 22.4 µM (±4.1 SD) respectively. In most<br />
rats, both levels gradually increased from baseline to 24 hours after<br />
the injection and reached a maximum at 48 hours and then declined<br />
until Day 8. At 24 hours, ctO2Hb was significantly higher than<br />
baseline [96.8 µM (±8.8 SD) vs. 81.4µM (±9.2 SD), p = 0.003 using<br />
Student’s t-test]. This trend was mimicked in the tissue markers of<br />
cellular proliferation and apoptosis, which peaked at 24 through 48<br />
hours and then dropped. The average NK cell count was also found<br />
to rise consistently through the course of monitoring and reached the<br />
highest at day 8, while macrophage counts reached a peak at 48 hours<br />
and then declined. The differences between baseline and 24 hours for<br />
these were statistically significant: Ki67 [294 (±107 SD) vs. 115 (±68<br />
SD), p = 0.0002], Caspase3 [2916 (±1383 SD) vs. 136 (±150 SD), p<br />
< 0.0001], NK cells [635 (±329 SD) vs. 159 (±110 SD), p = 0.0001],<br />
and macrophage markers [281 (±260 SD) vs. 39 (±31 SD), p = 0.01].<br />
Average values of hemoglobin and biological markers at baseline and after injection in 15 rats.<br />
Unit Baseline 12hrs 24hrs 48hrs 96hrs Day8<br />
ctHbO2 uM 81.4 86.6 96.8* 113.6* 71.5 57.8*<br />
ctHHb uM 22.4 22.8 25.6 30.8* 19.8 25<br />
Size mm 5.7 6.4 7.4* 8.5* 4.8 5.7<br />
Ki67 counts/HPF 115 62 294* 225* 22*<br />
Caspase3 counts/HPF 136 445* 2916* 3307* 140<br />
NK counts/HPF 159 541* 635* 587* 1380*<br />
Mac counts/HPF 39 125* 281* 1143* 171*<br />
* Significant difference between baseline and measurement time, p ≤ 0.01<br />
Conclusion: We observed an increase in oxyhemoglobin early after<br />
chemotherapy, closely linked to changes in cellular proliferation,<br />
apoptosis, NK cells and macrophage accumulation. Early optical<br />
changes may be linked to chemotherapy-induced tumor metabolic<br />
and acute inflammatory responses.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
360s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
P4-02-05<br />
A novel 64Cu-liposomal PET agent (MM-DX-929) predicts<br />
response to liposomal chemotherapeutics in preclinical breast<br />
cancer models<br />
Lee H, Zheng J, Gaddy D, Kirpotin D, Dunne M, Drummond D, Allen<br />
C, Jaffray D, Hendriks B, Wickham T. Merrimack Pharmaceuticals,<br />
Boston, MA; Princess Margaret Hospital, University Health Network,<br />
Toronto, ON, Canada; Leslie Dan Faculty of Pharmacy, University<br />
of Toronto, ON, Canada<br />
Background: Liposomal anthracyclines (such as pegylated liposomal<br />
doxorubicin (PLD) or HER2-targeted liposomal doxorubicin (MM-<br />
302)) are being used and/or evaluated for the clinical management<br />
of breast cancer, but responses vary from patient to patient. It<br />
is hypothesized that variability in the deposition of liposomal<br />
therapeutics within tumors leads to differences in drug exposure,<br />
thereby directly influencing tumor response. We have developed<br />
MM-DX-929, a novel 64Cu-liposomal PET imaging agent, as a<br />
clinically-implementable tool to investigate whether image-based<br />
quantification of liposome deposition in tumors can predict treatment<br />
response to liposomal chemotherapeutics, including PLD, MM-302<br />
and/or liposomal irinotecan (MM-398).<br />
Objectives: Our primary objective is to demonstrate that the extent<br />
of tumor uptake of MM-DX-929 is predictive of tumor response to<br />
MM-302 in preclinical breast cancer xenograft models. A secondary<br />
objective is to enable clinical translation of MM-DX-929 to enable<br />
incorporation into existing therapeutic trials.<br />
Methods: Mice bearing BT474-M3 mammary and subcutaneous<br />
tumors were injected intravenously with MM-DX-929 prior to dosing<br />
with MM-302. PET/CT imaging was performed at 16h post MM-<br />
DX-929 injection, and tumor uptake was determined. Response to<br />
treatment was quantified as tumor volume changes measured over a<br />
2-month period by MRI.<br />
Results: Tumor deposition of MM-DX-929 administration correlated<br />
well with treatment response to MM-302 (Spearman correlation<br />
coefficient of -0.891 and a p-value of 0.0004). MM-DX-929<br />
accumulation in tumors prior to the start of the MM-302 treatment<br />
successfully predicted improved tumor growth inhibition following<br />
MM-302 treatment.<br />
Conclusion: These findings support trials of MM-DX-929 as a<br />
predictive imaging agent to select patients who are most likely to<br />
respond to liposomal therapies. The clinical development of MM-<br />
DX-929 for identification of breast cancer patients likely to respond<br />
to liposomal therapeutics is currently being pursued.<br />
P4-02-06<br />
Molecular imaging with trastuzumab and pertuzumab of HER2-<br />
positive breast cancer in mice: a step towards personalized<br />
medicine<br />
Collin B, Oudot A, Vrigneaud J-M, Moreau M, Raguin O, Duchamp<br />
O, Tizon X, Denat F, Varoqueaux N, Brunotte F, Fumoleau P.<br />
Centre Georges François Leclerc, Dijon, France; Institut de<br />
Chimie Moléculaire de l’université de Bourgogne, Dijon, France;<br />
Oncodesign, Dijon, France; Roche France, Boulogne Billancourt,<br />
France<br />
Introduction<br />
The accurate and reliable assessment of HER2 status is an essential<br />
step in the diagnostic workup and selection of targeted treatment<br />
strategy in breast cancer patients. However, current ex vivo methods<br />
do not evaluate HER2 status possible discordance between primary<br />
tumor and distant metastases, nor immediate response to therapeutic<br />
intervention. Non-invasive imaging of HER2 expression could<br />
be a relevant alternative with additional benefits such as a better<br />
selection of patients for HER2-targeted therapies and the possible<br />
optimization of treatment strategies. Recent clinical trials suggest<br />
a better efficacy of trastuzumab / pertuzumab doublet but a lower<br />
activity of pertuzumab monotherapy over trastuzumab alone.<br />
Aim<br />
The aim of our study was therefore to evaluate preclinically the<br />
use of radiolabeled DOTAGA (2,2’,2’’-(10-(2,6-dioxotetrahydro-<br />
2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic<br />
acid) conjugated trastuzumab and pertuzumab for SPECT/CT (Single<br />
Photon Emission Computed Tomography/Computed Tomography)<br />
HER2 imaging purposes.<br />
Methods<br />
Trastuzumab and pertuzumab were conjugated to a new bifunctional<br />
chelating agent: DOTAGA anhydride (DOTA analog) and<br />
subsequently radiolabeled with the gamma-emitter Indium 111. The<br />
functionality of [111In]-DOTAGA-antibodies analogs was evaluated<br />
by in vitro saturation assays using HER2-overexpressing human breast<br />
cancer cell line (HCC1954). In vivo biodistribution was studied by<br />
SPECT/CT imaging at 24h, 48h and 72h after intravenous injection<br />
of [111In]-DOTAGA-antibodies in subcutaneous BT474 tumorbearing<br />
rodents.<br />
Results<br />
[111In]-DOTAGA-trastuzumab and [111In]-DOTAGA-pertuzumab<br />
showed respectively 2.6 and 2.7 DOTAGA /antibody. Both [111In]-<br />
DOTAGA-trastuzumab and [111In]-DOTAGA-pertuzumab achieved<br />
a radiochemical purity > 95%. Biological activity of [111In]-<br />
DOTAGA-trastuzumab and [111In]-DOTAGA-pertuzumab was<br />
maintained: the affinity determined on HER2 expressing HCC1954<br />
cell lines, was 5.5 and 5.6 nM. SPECT/CT imaging experiments in<br />
tumor-bearing rodents and gamma-counting of organs both showed<br />
that at 72h post-injection, more than 60 % of the activity was localized<br />
in the tumor (66.9±0.9 %ID/g for [111In]-DOTAGA-trastuzumab<br />
and 63.8±6.3 %ID/g for [111In]-DOTAGA-pertuzumab) and that<br />
an excess of non-radiolabeled corresponding antibody significantly<br />
shifted down tumor-targeting (to 17.6±2.4 %ID/g for [111In]-<br />
DOTAGA-trastuzumab and 8.7±0.8 %ID/g for [111In]-DOTAGApertuzumab.<br />
Conclusions<br />
Our results demonstrate a similar HER2 binding of trastuzumab<br />
and pertuzumab. Both radiolabeled [111In]-DOTAGA-trastuzumab<br />
and [111In]-DOTAGA-pertuzumab should be considered and<br />
might be promising tools for molecular imaging diagnosis of HER2<br />
overexpression in breast cancer.<br />
P4-02-07<br />
Early Optical Tomography Changes Predict <strong>Breast</strong> <strong>Cancer</strong><br />
Response to Neoadjuvant Chemotherapy<br />
Lim EA, Gunther JE, Flexman M, Kim HK, Hibshoosh H, Kalinsky<br />
K, Crew K, Maurer M, Taback B, Feldman S, Brown M, Refice S,<br />
Alvarez-Cid M, Hielscher A, Hershman DL. Columbia University<br />
Medical Center, New York, NY; Columbia University, New York,<br />
NY; Herbert Irving Comprehensive <strong>Cancer</strong> Center, New York, NY;<br />
Mailman School of Public Health, New York, NY<br />
Background: Pathologic complete response (pCR) or a low Residual<br />
<strong>Cancer</strong> Burden (RCB) score following neoadjuvant chemotherapy<br />
(NACT) predicts a superior survival in breast cancer (BC) patients.<br />
An early predictive marker of tumor response during NACT would<br />
provide a way to optimize treatment for non-responders; however,<br />
no ideal technology currently exists. Diffuse optical tomography<br />
www.aacrjournals.org 361s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
(DOT) is a novel, fast, safe, and low-cost technique that uses near<br />
infrared light to provide 3D data on tissue vascularity without the use<br />
of radiation, making it a promising technology for assessing early<br />
tumor response to NACT. We hypothesized that a 2-week change in<br />
DOT parameters would predict response to NACT as measured by<br />
the RCB score.<br />
Methods: Women with stage II-IIIc invasive BC scheduled to<br />
undergo NACT with 12 cycles of a weekly taxane followed by 4<br />
cycles of doxorubicin with cyclophosphamide (AC) were enrolled.<br />
Treatment with additional biologic therapies was allowed. DOT<br />
measurements were made before starting NACT, 2 weeks into<br />
treatment, and before surgery. Concentrations of oxyhemoglobin<br />
[HbO2], deoxyhemoglobin [Hb], total hemoglobin [HbT], and tissue<br />
scattering (SC) were measured by DOT. Final pathology specimens<br />
were scored for the RCB index (continuous measure), RCB class (0,<br />
1, 2, 3), and a dichotomized RCB score (RCB class 0 or 1: responders<br />
to NACT; RCB class 2 or 3: non-responders). Correlation analysis,<br />
ANOVA testing, and two sample t-tests were used to evaluate the<br />
relationship between the two-week changes in DOT parameters and<br />
the RCB score.<br />
Results: Since July 2011, we have recruited 11 pts, of whom 7 have<br />
undergone surgery. Complete data is available for 6 pts. Two of 7<br />
pts had a pCR (RCB 0), 1 had RCB 1, 3 had RCB 2, and 1 had RCB<br />
3. The Pearson correlation between the 2-week change in [Hb] and<br />
the continuous RCB index was 0.94 (p=0.0047), and that between<br />
the 2-week change in SC and the RCB index was 0.93 (p=0.0073).<br />
At 2 weeks, the [Hb] decreased by 6.7% for pts whose pathology<br />
demonstrated an RCB 0 (pCR), 1.8% for RCB 1, 0.6% for RCB 2, and<br />
increased 0.7% for RCB 3. ANOVA and Tukey testing demonstrated a<br />
significant difference in the [Hb] change for pts with RCB 0 compared<br />
to pts with RCB 1, 2, or 3 (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
Sensitivity for the detection of breast malignancy<br />
Sensitivity<br />
Mammography 72%<br />
Ultrasound 63%<br />
BSGI 82%<br />
Mammography + Ultrasound 90%<br />
Mammography + Ultrasound + BSGI 98%<br />
A subsequent breast MRI detected one of the lesions missed by the<br />
three modalities while two lesions were found by pathology alone.<br />
Conclusions<br />
Of the three imaging modalities, BSGI provided the highest<br />
independent sensitivity and when added to the diagnostic workup,<br />
BSGI detected an additional 14 malignancies, increasing the<br />
sensitivity from 90% to 98%. Although it is beyond the scope of this<br />
work, it is interesting to note that the cost of the BSGI procedure<br />
is relatively low, about $320, and that in this population the BSGI<br />
specificity was 74%. In summary, when added to the diagnostic work<br />
up of patients in the community breast cancer, BSGI can improve<br />
the detection of breast malignancy when compared to mammography<br />
and ultrasound alone.<br />
P4-02-10<br />
Molecular <strong>Breast</strong> Imaging: A multicenter clinical registry to<br />
compare breast-specific gamma imaging (BSGI) and breast MRI<br />
in the detection of breast carcinoma<br />
Weigert JM, Kieper DA, Stern LH, Böhm-Vélez M. Hampton<br />
University, Hampton, VA; Thomas Jefferson University, Methodist<br />
Division, Philadelphia, PA; Mandell and Blau MDs PC, New Britain,<br />
CT; Weinstein Imaging Associates, Pittsburgh, PA<br />
Purpose<br />
<strong>Breast</strong>-Specific Gamma Imaging (BSGI), also known as molecular<br />
breast imaging (MBI), is a diagnostic breast imaging procedure<br />
using that is becoming more common in clinical practice. In the<br />
BSGI procedure, a patient receives an intravenous injection of<br />
Tc99m-Sestamibi (MIBI) and imaging is conducted with a breastoptimized<br />
gamma camera. According to the clinical literature, the<br />
largest advantage of BSGI when compared to mammography is that<br />
the sensitivity of the examination is not influenced by breast tissue<br />
density. The goal of this work is to quantify the clinical sensitivity<br />
of BSGI against that of MRI, another diagnostic imaging modality<br />
capable of detecting mammographically occult malignancies.<br />
Methods<br />
A multi-center patient registry was maintained for all patients<br />
routinely sent to BSGI and MRI as part of their diagnostic work<br />
up. All patients who had a malignant finding on subsequent needle<br />
biopsy or surgery within 12 months post imaging were included in<br />
this analysis. The BIRADS rating schematic was used for MRI and<br />
a similar, 6-category system was used for the BSGI images. For each<br />
modality, the reports were classified as Negative: category 1 – 3 and<br />
positive: category 4 - 6.<br />
Results<br />
There were 60 patients with 63 malignant breast lesions. MRI was<br />
negative in 6 lesions (2 DCIS, 3 IDC and 1 ILC) while BSGI was<br />
negative in 6 lesions (5 IDC and one mixed IDC/DCIS). Both BSGI<br />
and MRI detected 56 of the 63 malignancies providing a sensitivity<br />
of 89% for both modalities. The combination of BSGI and MRI<br />
detected 63 of the 63 malignancies for a sensitivity of 100%.[table 1]<br />
Conclusions<br />
According to the results of this patient registry, BSGI provides equal<br />
sensitivity to that of MRI however each modality was false-negative<br />
in different patients. As a result, while each modality provided a<br />
sensitivity of 89%, the combination of BSGI and MRI provided a<br />
sensitivity of 100%.<br />
Sensitivity for BSGI/MBI, breast MRI and the combination of both modalities<br />
Sensitivity<br />
BSGI/MBI 89%<br />
MRI 89%<br />
Combined BSGI + MRI 100%<br />
The MBI/BSGI procedure does involve a relatively small dose of<br />
radiation, but this dose is less than the dose patients receive from<br />
other common diagnostic examinations such as a chest CT scan.<br />
According to RadiologyInfo.org, a website co-developed by the<br />
American College of Radiology and Radiological Society of North<br />
America, “…there are no known long-term adverse effects from such<br />
low-dose exposure.” In comparison, MRI does not involve exposure<br />
to radiation but utilizes a contrast agent that has been reported to cause<br />
adverse reactions in a very small number of patients, especially those<br />
with insufficient kidney or liver function. In addition, MRI cannot<br />
be performed in some types of patients such as those with metal<br />
implants, or those with claustrophobia. In our experience, BSGI is<br />
a low-cost imaging procedure (the procedure costing approximately<br />
1/3 that of MRI) that is well tolerated by patients and can be used in<br />
patients who for whom MRI is contraindicated or very challenging.<br />
P4-03-01<br />
Distance of breast cancer from the skin influence axillary nodal<br />
metastasis<br />
Kim EJ, Chae BJ, Song BJ, Kwak HY, Chang EY, Kim SH, Jung SS.<br />
Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul,<br />
Republic of Korea<br />
Background<br />
In breast cancer, axillary lymph node status is one of the most<br />
important prognostic variables and a crucial component to the staging<br />
system. Moreover, cancers underlying skin are willing to access to<br />
the lymphatics and cause lymphatic dissemination. Therefore, there<br />
seems an association between proximity of breast cancer to the skin<br />
and the incidence of axillary node positivity or local recurrence.<br />
The aim of this study was to determine whether distance of breast<br />
cancers from the skin affects the the clinical and pathologic features<br />
including the likelihood of axillary nodal metastases, ipsilateral breast<br />
cancer recurrence, and recurrence free survival.<br />
Methods<br />
Between January 2003 and December 2009, data were collected<br />
prospectively regarding 1005 consecutive breast cancer patients<br />
who underwent surgical treatment. The exclusion criteria were noninvasive<br />
carcinoma (e.g. Ductal Carcinoma In Situ), prior breast<br />
surgery, previous radiotherapy or neo-adjuvant chemotherapy and<br />
previous endocrine therapy. The distance of the tumor from the skin<br />
surface was measured from the skin to the most anterior hypoechoic<br />
leading edge of the lesion.<br />
Results<br />
A total of 891 patients were included in the statistical analysis,<br />
603(68%) had no axillary nodal metastasis, 288(32%) had axillary<br />
nodal metastasis. Distance of breast cancer from the skin less than<br />
3mm induced more axillary nodal metastasis (P=0.039). However,<br />
there was no statistical significant correlation between distance of<br />
breast cancer from the skin less than 3mm and ipsilateral breast<br />
tumor recurrence (P=0.788) or recurrence-free survival (P=0.353).<br />
Conclusion<br />
<strong>Breast</strong> cancers located closer to the skin have a higher incidence of<br />
axillary nodal metastasis. When evaluating a breast cancer patient<br />
and considering the risk of nodal metastasis the distance of the tumor<br />
from the skin should be considered.<br />
www.aacrjournals.org 363s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-03-02<br />
Automatic BI-RADS Diagnosis of <strong>Breast</strong> Lesions by<br />
CAD(computer-aid diagnosis)<br />
Kuo W-H, Chuang S-C, Yang S-H, Chen C-N, Chen A, Chang K-J.<br />
National Taiwan University Hospital and National Taiwan University<br />
College of Medicine, Taipei, Taiwan; Graduate Institute of Industrial<br />
Engineering, National Taiwan University, Taipei, Taiwan<br />
Objective<br />
Ultrasound is one of the most effective non-invasive tool for breast<br />
tumor detection and diagnosis. However, acquisition and observation<br />
of ultrasound images are mostly subjective and highly dependent on<br />
personal experience and judgment. The inter-observer variation often<br />
results in significantly different decisions. Objective quantification<br />
of sonographic features has become a pressing issue facing the<br />
medical staff.<br />
This research is to develop a robust, well-performing CAD system<br />
which can provide objective suggestion for BI-RADS categorization.<br />
Materials & Methods<br />
Sonographic tumor features of 264 tissue-proved BI-RADS 3<br />
to 5 breast lesions (65 cancers, 199 benign cases)were collected<br />
consecutively by well-experienced single investigator using Siemens<br />
S2000 in National Taiwan University Hospital. There are initially<br />
30 attributes extracted from only one representative view of each<br />
tumor. These attributes based on the lexicon descriptions of BI-RADS<br />
includes characters such as shape, margin irregularity, heterogeneity,<br />
boundary, acoustic shadow, flexibility. After feature selection, 9<br />
attributes, including 6 B-mode attributes and 3 elastography-related<br />
attributes are taken into practical model building. All 9 attributes<br />
used in this research are quantitative features and are computed by<br />
computer. The only necessarily manual effort is to outline the tumor<br />
lesion on the ultrasound image by investigator.<br />
We randomly take 175 cases(42 cancers, 133 benign cases), about<br />
two-third of the sample, for model training and leave 89 cases<br />
(23 cancers, 66 benign cases)as the independent test data. In both<br />
training data and independent data, the ratio between benignancy<br />
and malignancy is kept even.<br />
Using “Parameterized Three-Phased Ensemble Model”, we transform<br />
the original binary predicting result into probabilistic form so that<br />
the model can be applied to BI-RADS category which is based on<br />
malignancy probability. In each ensemble model, every component<br />
classifier (Multi-Layer FLD Classification Tree) will be assigned<br />
a weight according to its performance by AdaBoost algorithm.<br />
The classifier gives back a real value as its predicting result. The<br />
categorizing probability threshold we adopt in this research follows<br />
standard BI-RADS system: BI-RADS 3
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
represents a significant and unmet need for improved margin<br />
assessment. High reoperation rates present both increased treatment<br />
risk to patients and increased burden on healthcare systems. In the<br />
USA alone, over 150,000 lumpectomies are performed per year at<br />
an average cost between $11,000 and $19,000 USD per procedure.<br />
Assuming a relatively modest average repeat operation rate of 25%,<br />
potentially preventable repeat surgeries represent an approximate cost<br />
to the US healthcare system of $500M (USD) annually.<br />
Reducing the prevalence of repeat surgeries may be accomplished by<br />
providing faster and more accurate intraoperative tools for assessing<br />
margin widths during the time of the first surgery. One such potential<br />
technique involves the use of Optical Coherence Tomography (OCT)<br />
imaging, which uses light to produce images in much the same way<br />
that ultrasound produces images with sound. Compared to ultrasound,<br />
OCT provides decreased depth of penetration, but increased resolution<br />
capabilities. The increased resolution that OCT provides allows for the<br />
visualization of the internal cellular structure within a tissue sample<br />
and therefore, provides the potential ability to differentiate cancerous<br />
from normal or benign cells. We propose the use of an intraoperative<br />
OCT imaging system to provide near real-time imaging information<br />
about the internal structure of tissue samples excised during BCS<br />
procedures. Our hypothesis is that the overall rate of repeat operations<br />
can be reduced by providing a tool to assist surgeons with the task of<br />
margin width estimation during the time of surgery.<br />
We have developed an early stage prototype OCT imaging system<br />
that has completed laboratory phantom and preclinical studies. This<br />
paper will present the capabilities of an OCT imaging system to<br />
provide margin assessment information in biological breast tissue<br />
mimicking phantoms. The phantoms were designed to encompass<br />
imaging characteristics across a wide range of human breast densities.<br />
The paper will go on to describe preclinical imaging that was done in<br />
tumor specimens excised from human breast cancer rat models. The<br />
results obtained in the phantom and preclinical studies suggest the<br />
potential for OCT as a near-real time, intraoperative imaging tool to<br />
aid surgeons with breast lumpectomy margin width estimation. To<br />
help realize this potential, further research is required in to the use<br />
of OCT during BCS.<br />
P4-03-05<br />
The Clinical Trial of New Optical Mammography<br />
Ogura H, Yoshimoto K, Nasu H, Hosokawa Y, Matsunuma R, Ide<br />
Y, Yamaki E, Yamashita D, Suzuki T, Oda M, Ueda Y, Yamashita Y,<br />
Sakahara H. Hamamatsu University School of Medicine, Hamamatsu,<br />
Shizuoka, Japan; Hamamatsu Photonics K.K., Hamamatsu, Shizuoka,<br />
Japan<br />
Objectives: Optical mammography (O-MMG), which utilizes nearinfrared<br />
light for the detection of abnormal breast tissue, can be a<br />
potentially useful and non-invasive tool for the screening of breast<br />
cancer patients. Here we report on the preliminary results of our<br />
clinical trial using a time-resolved O-MMG system developed by<br />
Hamamatsu Photonics (Hamamatsu, Japan). In our past examination,<br />
negative results included cases with mismatch for breast cup because<br />
of small breast, lesion outside of cup because of big breast, and bad<br />
positioning. So, size and shape of a gantry was improved (3 cup sizes;<br />
S, M and L cup). We reported the initial experience of the improved<br />
O-MMG systems.<br />
Materials and Methods: In principle, the technique involves sequential<br />
irradiation of the breast tissue with a pulsed laser with a wavelength<br />
of 760, 800 and, 830nm, which is then detected by the variable<br />
capacity gantry at multiple sites after passing through the breast<br />
tissue. Measurement time has improved to about 7 minutes (a third<br />
of the conventional measurement time). The data are analyzed and<br />
tomographic images of the absorption coefficient of the breast are then<br />
reconstructed based on our tomographic reconstruction algorithm.<br />
Between October 2011 and May 2012, fifteen patients with breast<br />
cancer and one patient with fibroadenoma participated in the trial.<br />
Results: In patients with breast cancer, S cup was used for one patient,<br />
M cup for 12 patients and L cup for two patients. Five patients after<br />
neo-adjuvant chemotherapy were excluded from the analysis. The<br />
lesions were depicted as an area of high hemoglobin concentration<br />
in 7 of 10 patients with cancer. One lesion of fibroadenoma was also<br />
identified as an area of high hemoglobin concentration.<br />
Conclusion: Further examination with our new O-MMG systems<br />
will be of interest.<br />
P4-03-06<br />
Non-invasive classification of microcalcifications by the use of<br />
X-ray phase contrast mammography as a novel tool in breast<br />
diagnostics<br />
Hauser N, Wang Z, Kubik-Huch RA, Singer G, Trippel M, Roessl<br />
E, Hohl MK, Stampanoni M. Interdisciplinary <strong>Breast</strong> Center<br />
Kantonsspital Baden, Baden, Switzerland; Paul Scherrer Institut,<br />
Villigen, Switzerland; Kantonsspital Baden, Baden, Switzerland;<br />
Philips Research Laboratories, Hamburg, Germany<br />
Purpose: Phase-contrast and scattering-based x-ray imaging are<br />
known to provide additional and complementary information to<br />
conventional, absorption-based methods. The goal of this study is to<br />
evaluate this method to distinguish between benign and malignant<br />
microcalcifications with the benefit to increase accuracy of early<br />
breast cancer diagnosis. Phase-contrast mammography has been<br />
shown to increase image quality of native breast samples when<br />
compared to conventional mammography.<br />
Two major types of microcalcifications are found within breast<br />
tissue. Type I consist of calcium oxalate dehydrate and type II<br />
microcalcifications are composed of calcium phosphates. Type I is<br />
seen most frequently in benign lesions whereas type II is indicative<br />
for proliferative lesions, including carcinomas. Phase contrast<br />
mammography is shown here to distinguish between the two types of<br />
microcalcifications and therefore indicates a step forward to improve<br />
early breast cancer diagnosis.<br />
Material and Methods: Freshly dissected breast specimens (n=50)<br />
were imaged using a Talbot-Lau interferometer equipped with a<br />
conventional x-ray tube; the interferometer was operated at the fifth<br />
Talbot distance, tube voltage of 40 kVp with mean energy of 28 keV,<br />
and current of 25 mA. The device simultaneously recorded absorption,<br />
differential phase and small-angle scattering signals. These quantities<br />
were combined into novel, high-frequency-enhanced radiographic<br />
images. Histopathological analysis was performed and regions of<br />
interests correlated with the findings of phase contrast mammography.<br />
Results: Our novel imaging approach yields complementary and<br />
otherwise inaccessible information on electron density distribution<br />
and small-angle scattering power of the sample at microscopic scale.<br />
Recently we generated the world’s first phase contrast mammograms<br />
of native, not-fixed human whole breast samples. Our results<br />
indicate the superiority of the new technique with respect to image<br />
quality and lesion conspicuity. A clinical reader study is currently<br />
carried out. Exploiting the multiple, complementary information<br />
obtained by grating-based interferometry, we are able to classify<br />
microcalcifications by a non-invasive technique within the clinical<br />
environment.<br />
By considering the small-angle scattering signal as a complement<br />
to the absorption signal, our method can analyze the differences in<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
the attenuation coefficient as well as in the crystal structure of the<br />
microcalcifications. Further, the scattering signal is used to decouple<br />
the thickness parameter. We demonstrate that type I and type II<br />
microcalcifications give opposite absorption and scattering signals<br />
and in addition the small-angle scattering signal helps to determine<br />
the type of microcalcification.<br />
Conclusions: The potential clinical significance of phase-contrast<br />
enhanced mammography has been evaluated by our team. This<br />
technique yields improved diagnostic capabilities when compared<br />
with conventional mammography, can provide superior contrast,<br />
inaccessible and complementary information, and potentially<br />
also reduce dose deposition. The non-invasive classification of<br />
microcalcifications is an important step toward early diagnosis and<br />
differentiation of breast lesions.<br />
P4-03-07<br />
Angiogenic effect of bevacizumab and paclitaxel in metastatic<br />
breast cancer: evaluation by contrast-enhanced ultrasonography<br />
using Sonazoid®<br />
Ito T, Mizuno H, Iiboshi Y, Yamamura N, Fujii H, Hitora T, Fujii R,<br />
Ohashi T, Nakagawa T, Izukura M. Rinku General Medical Center,<br />
Izumisano, Osaka, Japan<br />
Agents targeting vascular endothelial growth factor (VEGF) have<br />
been validated as breast cancer therapeutics, yet efficacy can differ<br />
between tumor types and individual patients. Rapid noninvasive<br />
determination of response could provide significant benefits. We<br />
tested if response to the VEGF antibody bevacizumab and chemo<br />
drug paclitaxel could be detected using contrast-enhanced ultrasound<br />
imaging (CEUS).<br />
The objective of this study was to evaluate contrast-enhanced<br />
ultrasound (CEUS) with contrast agent Sonazoid® injection as a<br />
predictor of tumor response.<br />
Patients and methods: Ten patients with advanced and metastatic breast<br />
carcinomas treated were evaluated. Examinations were performed at<br />
baseline, after 2 and 4 weeks and every one month on antiangiogenic<br />
drug bevacizumab and chemo drug paclitaxel in tumor targets that<br />
were accessible to CEUS. Histological findings were obtained in all<br />
cases by ultrasound-guided 14 gauge core needle biopsy or 10 gauge<br />
vacuum-assisted biopsy. Each examination included a bolus injection<br />
of Sonazoid® and 40-60 seconds of raw linear data with an Aplio<br />
(Toshiba), Logiq (GE) and Ascendus (Hitachi-ALOKA) with a 8-12<br />
MHz linear transducer. A low reduced mechanical index (MI) of less<br />
than 0.24 was chosen to avoid early gas bubble destruction.<br />
The ethic committee of our institution approved this study. An<br />
informed consent was signed by each patient for the ultrasound<br />
examination and before administering for the contrast medium.<br />
Results: A total of 60 examinations were performed. Various<br />
intratumoral perfusion parameters changed over time, and the signal<br />
intensity was significantly impaired in the treated tumors before the<br />
treatment efficacy on tumor size could be observed.<br />
Conclusion: CEUS has advantages for real-time visualization and is a<br />
new noninvasive imaging technique which might be an effective tool<br />
for evaluating antiangiogenic drugs and chemo drugs in breast cancer.<br />
The use of a noninvasive ultrasound approach may allow for earlier<br />
and more effective determination of efficacy of antiangiogenic<br />
therapy.<br />
P4-03-08<br />
A new real-time image fusion technique, a coordinated sonography<br />
and MRI using magnetic position tracking system, improves the<br />
sonographic identification of enhancing lesions in breast MRI<br />
Nakano S, Fujii K, Yoshida M, Kousaka J, Mouri Y, Fukutomi T,<br />
Ishiguchi T. Aichi Medical University, Nakakute, Aichi, Japan<br />
<strong>Breast</strong> magnetic resonance imaging (MRI) is a method that can<br />
detect clinically and mammographically occult cancer foci. For<br />
lesions suspected to be malignant on the basis of breast MRI,<br />
targeted sonography can help determine whether the lesion is<br />
amenable to tissue biopsy using sonographic guidance. However,<br />
the reproducibility of sonography as well as interexaminer reliability<br />
in targeted sonography is still a clinical issue. Recently, we have<br />
developed real-time virtual sonography (RVS) that can coordinate a<br />
sonographic image and a MRI multiplanar reconstruction (MRI-MPR)<br />
of the same section in real time. Although RVS has been reported to<br />
be useful for breast cancers, only a few studies have investigated the<br />
size and positioning error between a real-time sonographic image<br />
and a MRI-MPR image. The purpose of this study was to evaluate<br />
the accuracy of RVS to sonographically identify enhancing lesions<br />
by breast MRI. Between December 2008 and May 2009, RVS was<br />
performed in 51 consecutive patients with 63 enhancing lesions.<br />
MRI was performed with the patients in the supine position using a<br />
1.5-T imager with a body surface coil to achieve the same position<br />
as with sonography. To assess the accuracy of the RVS, the following<br />
three issues were analyzed: (i) The sonographic detection rate of<br />
enhancing lesions, (ii) the comparison of the tumor size measured by<br />
sonography and the MRI-MPR and (iii) the positioning errors as the<br />
distance from the actual sonographic position to the expected MRI<br />
position in 3-D. Among the 63 enhancing lesions, 42 (67%) lesions<br />
were identified by conventional B-mode, whereas the remaining 21<br />
(33%) initial conventional B-mode occult lesions were identified<br />
by RVS alone. The sonographic size of the lesions detected by<br />
RVS alone was significantly smaller than that of lesions detected<br />
by conventional B-mode (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
value (PPV), and negative predictive value (NPV) of each imaging<br />
modality were calculated using pathologic complete response (pCR)<br />
as the outcome of interest.<br />
RESULTS:<br />
Both MRI and ultrasonography displayed higher sensitivity (77%<br />
and 79%, respectively) than specificity (38% and 25%) in predicting<br />
primary tumor response, while PET-CT was associated with higher<br />
specificity (100%) than sensitivity (68%). All three imaging<br />
modalities exhibited higher PPVs (84%, 88%, and 100%) than NPVs<br />
(31%, 14%, 40%) in relation to primary tumor response. Both MRI<br />
and PET-CT were less sensitive for predicting the response of nodal<br />
disease than of primary tumor (p < 0.001).<br />
CONCLUSIONS:<br />
Out of the three radiologic tools, examined in the present study, no<br />
single test was clearly superior in evaluating the tumor response of<br />
either the primary tumor or nodal metastases. Future investigations<br />
are warranted to identify the tumor and treatment factors which may<br />
influence the specificity, sensitivity and predictive values of each test.<br />
P4-03-10<br />
Sonographic-pathological correlation in contrast-enhanced<br />
ultrasonography in the diagnosis of breast cancers.<br />
Kato K, Miyamoto Y, Kamio M, Nogi H, Imawari Y, Mimoto R, Toriumi<br />
Y, Nakata N, Takeyama H, Uchida K. The Jikei University School of<br />
Medicine, Tokyo, Japan<br />
Background: As contrast-enhanced ultrasonography (CEUS) in<br />
the diagnosis of breast masses has been performed less frequently<br />
than other imaging modalities, it’s efficacy evaluation has not been<br />
established. CEUS with Sonazoid, which is microbubble-based<br />
contrast agent, allows visualization of the mass bloodstream, therefore<br />
the classification of enhancement patterns in CEUS could increase<br />
diagnostic yield for breast masses. To achieve this, a clear standard<br />
for the CEUS evaluation is needed. The purpose of this study was to<br />
identify CEUS findings for malignancies and clarify sonographicpathological<br />
correlation of breast cancers.<br />
Material and Method: Present study included 20 patients with<br />
invasive ductal cancer who underwent operation for primary therapy<br />
without any chemotherapy or hormonal therapy. We contrasted CEUS<br />
features with Sonazoid with surgical specimens retrospectively. As<br />
malignant findings, the presence of focal perfusion defects inside<br />
masses and enhancement of outside masses were chosen.<br />
Result: All of the 20 cases displayed focal perfusion defects. 9<br />
cases of those could be successfully assessed in the same sections<br />
histopathologically and ultrasonographically. Histopathological<br />
findings showed those defects to be fibrotic foci inside masses in<br />
7cases (77.7%). While, 6 cases of all (30%) showed stains outside<br />
tumor, and only one case was found out to be fibrotic growth with<br />
cancer cells.<br />
Conclusion: focal perfusion defects of breast masses in CEUS<br />
were considered to be specific for malignancy, and they seemed to<br />
be fibrotic foci histopathologically. Desmoplastic reaction has been<br />
observed in epithelial solid tumor biology, and if those defects reflect<br />
the desmoplasia defects could be the proof of malignancy.<br />
P4-03-11<br />
SUVmax of FDG-PET/CT is Associated with Chemotherapy<br />
Response Assay Test Results and Prognostic Factors in <strong>Breast</strong><br />
<strong>Cancer</strong> Patients<br />
Lee A, Chang J, Bang B, Lee J, Han D, Min S, Yun C, Kim BS, Lim<br />
W, Paik N, Moon B-I. Ewha Womans University Hospital, Seoul,<br />
Republic of Korea<br />
Backgrounds: 18 F-fluorodeoxyglucose positron emission tomography<br />
with computed tomography ( 18 F-FDG PET/CT) is widely used for<br />
cancer evaluation and there are several studies which suggested<br />
maximum standard uptake value (SUVmax) may reflect the cancer<br />
patients’ prognosis. Adenosine triphosphate-based chemotherapy<br />
response assay (ATP-CRA) is commonly used as a chemosensitivity<br />
assay modality for the treatment of various cancers in clinical settings<br />
and there have been several studies on its usefulness in breast cancer.<br />
We previously reported chemosensitivity (ATP-CRA) results might<br />
reflect patients’ prognosis. So we supposed that SUVmax could<br />
reflect chemosenitivity (ATP-CRA) results of patients, so performed<br />
this study to analyze the relationship between PET/CT SUVmax and<br />
chemosenstivity (ATP-CRA) results of these drugs. Furthermore, we<br />
evaluated prognostic factors for breast cancer according to SUVmax.<br />
Materials and Methods: 102 breast cancer patients, who underwent<br />
PET/CT and chemosensitive (ATP-CRA) test between December<br />
2010 and April 2012, were enrolled in this study. We analyzed,<br />
retrospectively, the correlation between SUVmax of PET/CT and<br />
chemosenitivity (ATP-CRA) results of doxorubicin/paclitaxel.<br />
SUVmax according to prognostic factors were also assessed.<br />
Results: Chemosensitivity (ATP-CRA) results of doxorubicin and<br />
paclitaxel have significant positive correlation with SUVmax. Their<br />
correlation coefficient were 0.236 (p=0.020) and 0.216 (p=0.030),<br />
respectively. Patients with larger tumor size, higher histologic and<br />
nuclear grade, estrogen receptor negative, progesterone receptor<br />
negative, HER2 positive, and Ki67 positive (≥14%) have higher<br />
mean SUVmax values (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
make pathological examination with tumor tissues removed by needle<br />
biopsy. Then we make a retrospective analysis and evaluation of<br />
patients scanned completely by qualitative and semi-quantitative<br />
methods. All patients have signed the informed consent form before<br />
the test, together with the recognition of the Ethics Committee.<br />
Results: From December 2011 to May 2012, a total of 245 patients<br />
were scanned and operated with clear paraffin pathological diagnosis<br />
by intravenous injection of 99 mTc -3PRGD 2 . Among them, a total of<br />
106 patients (167 developing lesions) were positive with radionuclide<br />
imaging results, 139 patients were negative. Diseases of 106 patients<br />
are divided into four series: breast cancer, inflammation mastitis,<br />
phyllodes tumor and partly with fibroadenoma. They have in common<br />
that there is a clear flow signal in and around lesions by color Doppler<br />
ultrasound.<br />
Discussion: After study on 245 patients, we created a molecular<br />
imaging tool to show expression of integration αvβ3 in order to<br />
assess tumor angiogenesis.Integrin αvβ3 plays an important role in<br />
physiological and pathological processes of malignant tumor, such<br />
as inflammation, tumor angiogenesis, invasion and metastasis etc.<br />
Therefore, its high expression is easy to find in cancer, mastitis, most<br />
of the phyllodes tumor and part of fiber adenoma with peripheral<br />
lesions. For patients with clear imaging, we make comprehensive<br />
analysis based on their ultrasound, mammography, MRI or CT results,<br />
which can generally contributes to the early diagnosis of disease in<br />
clinical. The detection of sentinel lymph node should be avoided<br />
for the patients with axillary lymph node imaging, who are clearly<br />
diagnosed as breast carcinoma with axillary lymph node metastases.<br />
These peptides are not only tumor receptor-targeted imaging agents<br />
with potential clinical value, but also laid a solid foundation for<br />
further development of receptor-targeted radionuclide therapy to solid<br />
tumors. The method marked with high expression of integrin αvβ3 in<br />
the tumor vascular endothelial cells by 99 mTc-3PRGD 2 and SPECT/<br />
CT imaging mode has a broad prospect in the early diagnosis of<br />
tumor, lesion detection and efficacy evaluation. In the future, we may<br />
also find the new imaging agent with more accuracy and specificity.<br />
We believe that there will be more and more breast cancer patients<br />
benefit from the technology development of ECT/CT examination.<br />
P4-04-01<br />
Combination of intratumoral CpG with systemic anti-OX40 and<br />
anti-CTLA4 mAbs eradicates established triple negative breast<br />
tumors in mice<br />
Li J, Tandon V, Levy R, Esserman L, Campbell M. University of<br />
California, <strong>San</strong> Francisco, CA; Stanford University, Stanford, CA<br />
Background: Evidence is mounting across diverse datasets and<br />
scientific techniques implicating immune dysregulation in poor<br />
outcomes of high grade and/or triple negative breast cancers.<br />
A multimodal strategy to stimulate the immune system could<br />
be an effective therapeutic approach for breast cancer. CpG<br />
oligodeoxynucleotides are single-stranded DNA that stimulate<br />
dendritic cells and B cells by binding to Toll-like receptor 9 (TLR9).<br />
OX40 (CD134) is predominantly expressed on activated T cells and<br />
the binding of OX40 with an agonistic antibody (anti-OX40) leads<br />
to the proliferation and survival of T cells. Agonistic anti-OX40<br />
antibodies can also reverse the suppressive effects of Treg cells. A<br />
third avenue is to target Cytotoxic T lymphocyte associated antigen<br />
(CTLA4) , which plays a negative regulatory role in T cell activation<br />
and is also constitutively expressed on Treg cells. Blocking CTLA4<br />
with an antagonistic antibody (anti-CTLA4) has been shown to<br />
enhance anti-tumor responses. In this study, we tested the combination<br />
of intratumoral (IT) CpG with systemic anti-OX40 plus anti-CTLA4<br />
in a mouse model of triple negative breast cancer.<br />
Methods: 4T1, an aggressive, triple-negative mammary carcinoma,<br />
was implanted orthotopically into syngeneic BALB/C mice.<br />
Treatment was initiated when tumors were ∼0.5 cm in the largest<br />
dimension. Mice were divided into 8 groups. Various combinations<br />
of PBS control, CpG, taxol, and anti-OX40+anti-CTLA4 mAbs<br />
were tested (Tables 1 and 2). CpG, 100 µg, was injected IT for 5<br />
consecutive days (days 1-5); Taxol, 16 mg/kg, was administered IP on<br />
day 1; anti-OX40 (400 µg) and anti-CTLA4 (100 µg) were given IP<br />
on days 1 and 5. Mice were sacrificed once tumors became ulcerated<br />
or reached a diameter >2 cm.<br />
Results: As shown in Table 1, CpG alone, taxol alone, or the anti-<br />
OX40 + anti-CTLA4 combination each delayed the growth of<br />
established 4T1 tumors when compared to the untreated control group.<br />
However, the majority of the mice (except one in CpG treated group)<br />
died from tumor progression. The combination of CpG + anti-OX40<br />
+ anti-CTLA4 had the best anti-tumor effects, with 4 out of 5 mice<br />
having demonstrated complete regression of their tumors (Table 2).<br />
The addition of taxol to the combination of CpG + anti-OX40 + anti-<br />
CTLA4 did not improve the anti-tumor effect, and while there was<br />
a substantial delay in growth, only one animal achieved a complete<br />
regression.<br />
Table 1: Single Agent<br />
Groups Treatments<br />
Average tumor size at the time of<br />
# of tumor free mice<br />
completion(mm3)<br />
Group 1 Control 1388 0/5<br />
Group 2 Taxol 1112 0/5<br />
Group 3 CpG 305 1/5<br />
Group 4 anti-OX40+anti-CTLA4 739 0/5<br />
Table 2: Combined Treatment<br />
Groups Treatments<br />
Average tumor size at the time of # of tumor<br />
completion(mm3)<br />
free mice<br />
Group 5 Taxol+CpG 450 0/5<br />
Group 6 Taxol+ anti-OX40+antiCTLA4 341 2/5<br />
Group 7 CpG+ anti-OX40+antiCTLA4 119 4/5<br />
Group 8 Taxol+CpG+ anti-OX40+antiCTLA4 327 1/5<br />
Conclusion: Our study demonstrated that the combination of IT CpG<br />
with systemic anti-OX40 + anti-CTLA4 mAbs can cure mice with<br />
established triple negative breast tumors, supporting the possibilities<br />
of applying immune modulation approach in human triple negative<br />
tumors. Studies are on-going to further dissect the immunological<br />
mechanisms involved.<br />
P4-04-02<br />
Tumor-initiated peripheral myeloid cell expansion is reversed<br />
by radiation therapy<br />
Gough MJ, Savage T, Bahjat KS, Redmond W, Bambina S, Kasiewicz<br />
M, Cottam B, Newell P, Crittenden MR. Earle A. Chiles Research<br />
Institute, Providence <strong>Cancer</strong> Center, Portland, OR; Providence<br />
<strong>Cancer</strong> Center, Portland, OR; The Oregon Clinic, Portland, OR<br />
Myeloid lineage cells, particularly monocytes and macrophages,<br />
have an important role in the development and progression of cancer.<br />
Within established tumors, macrophages are critical for angiogenesis,<br />
invasion, metastasis, immunosuppression and response to therapy.<br />
In addition, both transplantable and transgenic mouse models of<br />
mammary cancer are associated with myeloid expansions detectible<br />
in the tumor, spleen and peripheral blood, and these myeloid cells are<br />
able to suppress T cell activation in vitro. Reducing the tumor burden<br />
through chemotherapy and resection has been shown to control the<br />
myeloid expansion. However, chemotherapies that reduce tumor<br />
burden also have direct effects on myeloid cells, and surgical trauma<br />
has been shown to mobilize myeloid cells. Radiation therapy is the<br />
third major option to treat cancer, but the consequence of radiation<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
368s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
therapy to systemic myeloid populations has not been described. We<br />
applied tumor-specific radiation therapy to test the hypothesis that the<br />
frequency of myeloid lineage cells correlates with the primary tumor<br />
burden. We demonstrate in the MMTV-PyMT model of mammary<br />
cancer that myeloid expansion in the blood closely correlates with<br />
myeloid involvement in the tumor and with tumor progression. We<br />
demonstrate that radiation therapy of 4T1 mammary tumors leads<br />
to a decline in myeloid cell numbers in the blood and a decrease in<br />
spleen size. The frequency of myeloid cells does not decline to the<br />
level seen in tumor-free mice: we demonstrate that metastatic disease<br />
can prevent myeloid cell numbers from returning to baseline, and that<br />
tumor recurrence from residual disease correlates with re-expansion<br />
of myeloid lineage cells. Despite these changes in the frequency<br />
of myeloid lineage cells, T cell numbers in the blood and spleen<br />
remains constant. However, radiation therapy improves the myeloid<br />
cell:CD8+ T cell ratio and results in increased proliferation of T cells<br />
in the spleen. Finally, we demonstrate that T cell responses to foreign<br />
antigens are not altered by tumor burden or myeloid cell expansion,<br />
while T cell responses to tumor-associated antigens are increased<br />
after radiation therapy of the tumor. These data demonstrate that<br />
myeloid cell numbers are directly linked to primary tumor burden,<br />
that this population contracts following radiation therapy, and that<br />
radiation therapy may open a therapeutic window for immunotherapy<br />
of residual disease.<br />
P4-04-03<br />
Monocytic immature myeloid cells permit tumor immune evasion<br />
during postpartum involution<br />
Schedin P, Martinson H, Callihan E, Jindal S, Borges V. University<br />
of Colorado, Aurora, CO<br />
Young women with breast cancer diagnosed in the postpartum period,<br />
defined as up to 5 years from last child delivery, have a poorer<br />
prognosis compared to women who have never been pregnant, and<br />
represent ∼30% of all young women’s breast cancer cases. Our lab<br />
has proposed that the poor prognosis associated with postpartum<br />
breast cancer is due to gland remodeling following pregnancy,<br />
known as postpartum involution. Using rodent models and human<br />
breast tissue, it has been demonstrated recently that postpartum<br />
gland involution utilizes wound healing programs to remodel the<br />
gland to a non-secretory state. For example, macrophages with tumor<br />
promotional characteristics have been identified as essential mediators<br />
of epithelial cell death during postpartum involution. We hypothesize<br />
that the immune cells within the normal involuting gland set up an<br />
immunosuppressive environment to protect the host from negative<br />
sequel resulting from potential self-antigen exposure during epithelial<br />
cell death. A consequence would be the establishment of an immune<br />
microenvironment that favors the growth and metastasis of breast<br />
cancer cells. To characterize the role of immune cells during normal<br />
postpartum involution as well as in the promotion of mammary cancer,<br />
we developed an immunocompetent mouse model of postpartum<br />
breast cancer using the Balb/c mouse.<br />
By flow cytometry, we found that dendritic cells, GR1+ monocytic<br />
immature myeloid cells (IMCs), and T cells increase exponentially<br />
in the mammary gland during involution. Functional assays using<br />
myeloid cells from the mammary gland indicate the IMCs isolated<br />
from involuting glands are capable of suppressing T cell activation<br />
ex vivo, consistent with immune suppression in vivo. To begin to<br />
investigate whether IMCs are able to promote tumor progression in<br />
the postpartum breast cancer setting, D2A1 mammary carcinoma<br />
were injected into mammary fat pads of Balb/c mice. D2A1 cells<br />
injected into hosts with actively involuting mammary glands had a<br />
significant growth advantage over tumor cells injected into nulliparous<br />
host glands, demonstrating that mammary gland involution promotes<br />
the growth of mammary carcinoma cells in this immune competent<br />
model. T cells identified by flow cytometry are significantly lower<br />
in number systemically and within the tumors of the involutiongroup<br />
compared to the nulliparous-group, indicating systemic<br />
immunosuppression specific to the involution-group. To demonstrate<br />
immunosuppressive function, IMCs were isolated from tumors and<br />
incubated with T cells ex vivo. IMCs from involution tumors were<br />
significantly more suppressive then IMCs from nulliparous mice.<br />
These data indicate IMCs play an immunomodulatory role in the<br />
mammary gland during involution, which allows tumor cells to<br />
undergo immune evasion in the postpartum period. We are currently<br />
investigating how GR1+ IMCs suppress T cell activation and hope<br />
to determine if reprograming these cells could prevent the promotion<br />
of breast cancer during involution. (DOD-BC10904 and BC100910)<br />
P4-04-04<br />
Immunohistochemical analysis of <strong>Cancer</strong> Testis antigens and<br />
Topoisomerase 2-alpha expression in triple negative breast<br />
carcinomas: a retrospective study<br />
Juretic A, Mrklic I, Spagnoli GC, Pogorelic Z, Tomic S. Zagreb<br />
University Hospital Centre, Zagreb, Croatia; Split University Hospital<br />
Centre, Split, Croatia; University of Basel, Switzerland<br />
Aim. The aim of this study is to assess the expression of cancer testis<br />
(C/T) antigens in the TNBC group, expression of topoisomerase<br />
2-alpha (TOPO2A), basal-like (BL) immunophenotype defined by<br />
basal markers (CK5/6, CK14, and EGFR), BL morphology and<br />
conventional clinicopathologic factors as well as to demonstrate their<br />
prognostic relevance with respect to this group of tumours.<br />
Methods. The study includes 83 patients who underwent surgery<br />
between January 2003 and December 2009. Slides were stained<br />
immunohistochemically with CK5/6, CK14, EGFR, Ki-67, TOPO2A,<br />
MAGE-A1, MAGE-A10, NY-ESO and multi-MAGE. Survival-time<br />
and multivariate survival analyses were performed for the purpose<br />
of identifying prognostic markers for tumours with more aggressive<br />
behaviour.<br />
Results. Of the 83 triple negative tumours, 55 (66.3%) have BL<br />
immunophenotype and 40 (48.2%) BL morphology. MAGE-A1<br />
show the most frequent expression (69.0%), followed by multi-<br />
MAGE (58.0%), NY-ESO (27.1%) and MAGE-A10 (13, 2%).<br />
MAGE-A10 expression is significantly correlated with tumour size<br />
(p=0.026). The expressions of MAGE-A1, MAGE-A10 and multi-<br />
MAGE are significantly correlated with clinical stage (p=0.024,<br />
p=0.041, p=0.031, respectively). A significant correlation has been<br />
found between the expressions of MAGE-A10 and NY-ESO and the<br />
expression of TOPO2A (p=0.005, p=0.013). There is no significant<br />
correlation between the expression of C/T antigens and disease-free<br />
survival (DFS) or overall survival (OS).<br />
Conclusions. High expression levels of MAGE and NY-ESO<br />
observed in TNBC are of potential clinical relevance, especially in<br />
the adjuvant setting of treatment, and may be of therapeutic value<br />
as a vaccine-based treatment in the TN group of breast tumours for<br />
which therapeutic options are limited.<br />
Key words: triple negative breast cancer, basal-like breast cancer,<br />
cancer-testis antigen, topoisomerase 2-alpha, prognosis, survival<br />
analysis.<br />
www.aacrjournals.org 369s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-04-05<br />
Listeria monocytogenes-based bivalent Lm-LLO immunotherapy<br />
for the treatment of HER2/neu positive and triple negative breast<br />
cancer and its impact on immunosuppression<br />
Wallecha A, Ramos K, Malinina I, Singh R. Advaxis Inc, Princeton, NJ<br />
Overexpression of tumor associated antigens (TAA) such as HER2/<br />
neu and high molecular weight melanoma associated antigen<br />
(HMW-MAA) are associated with aggressive high-grade tumors<br />
leading to disease progression and reduced survival. HMW-MAA has<br />
been reported as a TAA in triple negative breast tumors and is also<br />
expressed at high levels by activated pericytes and pericytes in tumor<br />
angiogenic vasculature that are associated with neovascularization<br />
in vivo. Previously published reports have shown that bioengineered<br />
Listeria monocytogenes (Lm) secreting either a chimeric HER2/neu<br />
antigen (cHER2), or HMW-MAA fragment, fused to a truncated<br />
highly immunogenic fragment of the adjuvant protein listeriolysin<br />
O (LLO) were found to impact the growth of both transplantable and<br />
transgenic mouse breast tumor models. Therefore, we hypothesized<br />
that an Lm-LLO immunotherapy capable of delivering two different<br />
antigens would likely have a synergistic effect of decreasing tumor<br />
growth by targeting two independent mechanisms that support tumor<br />
growth; 1) tumor angiogenesis, and 2) tumor cell surface marker, thus<br />
improving the therapeutic efficacy of the agent. Here we report the<br />
construction of a bivalent recombinant Lm-LLO immunotherapy that<br />
expresses and secretes both the cHER2 and HMW-MAA antigens<br />
concomitantly as fusion proteins. Initial characterization of the<br />
bivalent immunotherapy indicates that both the antigens cHER2<br />
and HMW-MAA are stably expressed and secreted after two in<br />
vivo mouse passages. Preliminary studies support the hypothesis<br />
that bivalent immunotherapy causes efficient reduction of tumor<br />
growth in both HER2 expressing and triple negative breast tumors.<br />
Further, mechanistic studies demonstrate that treatment with Lm-LLO<br />
immunotherapy resulted in a decreased proportion of regulatory T<br />
cells (Tregs) as well as Myeloid Derived Suppressor Cells (MDSC)<br />
particularly in the tumor microenvironment and not in spleen, tumor<br />
draining lymph nodes, or peripheral blood. Interestingly, both residual<br />
Tregs and MDSCs isolated from the tumor microenvironment were<br />
found to have a decreased ability to suppress the division of T cells<br />
after Lm-LLO immunotherapy, a finding which warrants further<br />
investigation. We will present data on the efficacy of bivalent Lm-LLO<br />
immunotherapy and the mechanisms that are likely responsible for<br />
the observed tumor regression. Currently Lm-LLO immunotherapies<br />
are being evaluated in Phase 2 clinical trials for HPV-associated<br />
dysplasia and malignancies such as CIN2/3, cervix cancer and head<br />
& neck cancer.<br />
P4-04-06<br />
Young women’s breast cancer is characterized by increased<br />
immune suppression through circulating myeloid derived<br />
supressor cells<br />
Borges VF, Ramirez O, Borakove M, Manthey E, Diamond JR, Elias<br />
AD, Finlayson C, Kounalakis N, Jordan K. University of Colorado<br />
Denver, Aurora, CO; University of Colorado <strong>Cancer</strong> Center, Aurora,<br />
CO<br />
Background: Women age 20-40 have a higher ten-year risk for<br />
developing breast cancer than the five other leading cancers in this<br />
gender and age group combined. Women currently in their 30s have<br />
a 1/203 chance of developing breast cancer over the next ten years.<br />
Moreover, cancers diagnosed in younger women have a signficantly<br />
higher risk of death for reasons that are not fully identified. Myeloid<br />
derived suppressor cells (MDSC) have a role in suppressing antitumor<br />
immunity through Jak/Stat pathway activation by generation<br />
of reactive oxygen species (ROS) and arginase-1, and correlate<br />
preclinically with cancer progression and in human canceres with<br />
poorer prognositic features and outcomes. Our Young Women’s<br />
<strong>Breast</strong> <strong>Cancer</strong> Translational Program seeks to identify immunologic<br />
differences potentially contributing to the poorer prognosis and<br />
potential targets for development of immunomodulatory treatment.<br />
Hypothesis: We hypothesized that newly diagnosed, treatmentnaive<br />
young breast cancer cases would have higher percentage of<br />
circulating MDSC with T cell suppressive function than similar<br />
age women without breast cancer. Methods: We conducted IRB<br />
approved, prospective translational studies of women age 40 and<br />
under both affected and unaffected by breast cancer. Exclusion criteria<br />
included pregnancy, known autoimmunity or immunosuppressive<br />
medications, or other cancers. MDSC were isolated from peripheral<br />
blood and phenotyped through standard protocols. T cell suppressive<br />
abilites were tested in coculture assays for expression of activation<br />
markers CD25 and CD69, and production of gamma-interferon.<br />
Identification of mechanism of suppression was assayed through<br />
secretion of arginase-1and generation of ROS. Results: No difference<br />
in percentage of MDSC was identified between young women with<br />
breast cancer (n=61) and unaffected subjects (n=18). However, a<br />
statistically significant increase in the MDSC ability to suppress<br />
T cell activation was identified in the breast cancer cohort with<br />
diminished CD25 and CD69 expression and diminished production<br />
of gamma-interferon. MDSC from young breast cancer subjects<br />
secreted significantly more arginase-1 from MDSC. No significant<br />
difference in generation of ROS was found between the two cohorts.<br />
Conclusions: The presence of equal rather than higher numbers of<br />
circulating MDSCs between the young breast cancer versus unaffected<br />
subjects was unexpected in comparison to prior publications on<br />
MDSC in cancer. Our results may differ due to our larger sample<br />
size or the alignment by gender and age the cohorts being more<br />
representative. Also, these are the first data on MDSC in a young<br />
female population. Despite equal numbers of MDSCs, the functional<br />
analyses demonstrate MDSC isolated from breast cancer have<br />
enhanced T cell suppression capabilities compared with normal<br />
controls. These data provacatively suggest a functional difference<br />
inherent to MDSC in the young breast cancer-bearing host. Moreover,<br />
they indicate that normal young women have realtively high levels<br />
of MDSC that are available for cancer to ursurp and induce immune<br />
suppression. Identification of secretion of arginine-1 as a potential<br />
mechanism of immune supporession in young women’s breast cancer<br />
warrants further investigation.<br />
P4-04-07<br />
Tartrate-resistant Acid Phosphatase (TRAcP)-Expressed Tumor-<br />
Associated Macrophages Promote <strong>Breast</strong> <strong>Cancer</strong> Progression<br />
Dai M-S, Wu C-C, Chang P-Y, Ho C-L, Hsieh Y-F, Lo K-Y, Kao W-Y,<br />
Chao T-Y, Yu J-C. Tri-Service General Hospital, Taipei, Taiwan;<br />
Taipei Medical University, Taipei, Taiwan<br />
Purpose<br />
Tumor-associated macrophages (TAMs) can promote or dampen<br />
breast cancer progression, depending on phenotypic changes within<br />
the cancer microenvironment. Two contrasting activation states<br />
were described in the literature: the M1 anti-tumoral and M2 protumoral<br />
subtype of TAMs. In clinical observation, we analyzed the<br />
TRAcP expression in breast cancer TAM and correlated to patient’s<br />
chemotherapy responses and survival. In animal models, we aim<br />
to investigate the tumor-promoting or inhibiting properties among<br />
tartrate-resistant acid phosphatase (TRAcP) expressed TAMs.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
370s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
Methods<br />
TRAcP expression, T lymphocytes, and other macrophage relevant<br />
markers were determined by immunohistochemical staining in the<br />
human breast cancer tissue from the patients before neoadjuvant<br />
chemotherapy. The expression of TRAcP within the TAMs were<br />
calculated and correlated to the patient’s chemotherapy responsiveness<br />
and outcome. The polarized M1/M2 macrophages and breast cancer<br />
hematogenous metastasis were created in the animal model. Activated<br />
macrophages from TRAcP+/+ or TRAcP-/- mice were injected with<br />
JC (Balb/c breast cancer) cells in the metastatic model.<br />
Results<br />
The presence of Foxp3+ regulatory T cell (Treg) correlates to<br />
the tumor proliferation (Ki-67 and Her2 expression) and higher<br />
Foxp3+ Treg prevalence and tumor Ki-67 expression inferred<br />
poorer chemotherapy response. TRAcP staining within the CD68+<br />
macrophages were observed with better chemotherapy response.<br />
In animal model, M2 polarized macrophages have higher TRAcP<br />
expression, promote breast cancer metastasis, and attract Treg<br />
infiltrating in tumor, consistent with the clinical observation.<br />
Conclusion<br />
TRAcP-expressing TAMs, representing M2-polarized macrophage,<br />
demonstrat local tumor-promoting and immune-suppressive effects,<br />
and chemotherapy resistance. TRAcP expression within TAM can be<br />
a potential prognostic marker for breast cancer.<br />
P4-04-08<br />
A Potential non-viral vector to transfect dendritic cell and thereby<br />
MHC-Class I antigen presentation might be a potential use in<br />
carcinoma<br />
Shaheen S, Akita H, Souichirou I, Miura N, Harashima H. Hokkaido<br />
University, Sapporo, Hokkaido, Japan<br />
To date almost no remarkable potential non-viral vector was<br />
developed to transfect promisingly primary dendritic cell like Bone<br />
Marrow Derived Dendritic Cell (BMDC) so that it might generate<br />
antigen presentation while epitopic-plasmid was delivered. Here we<br />
have introduced a potential non-viral vector named Stearyl-KALA<br />
MEND (100-130 nm, zeta potential 35-40 mV), which expressed<br />
to date the highest transgene expression while firefly luciferase was<br />
introduced (sub-cloned), and thereby promising antigen presentation<br />
in vitro while OVA plasmid containing MHC Class-I restricted<br />
SIINFEKL epitope was introduced and co-cultured with B3Z T-cell<br />
hybridoma. On the basis of these results, we used this vector to<br />
transfect BMDC and harvested the DC to chase the corresponding<br />
EG7-OVA induced tumor ex vivo. Later we further immunized mice<br />
directly with STR-KALA MEND containing OVA plasmid and<br />
challenged against the tumor (EG7-OVA induced). In this in vivo<br />
study we found also a significant antitumor activity. To evaluate<br />
the promptness of our vector we further sub-cloned Mart-1 gene, in<br />
our sub-cloned plasmid vector and immunized the mice as before.<br />
Thereafter inserting B16F10 melanoma cells to the immunized<br />
mice we found also a significant antitumor activity after 24 days of<br />
inoculation. Thus the vector, STR-KALA MEND might be a future<br />
potential use as DNA vaccine in anti-tumor methodology.<br />
P4-05-01<br />
Oncolytic Herpes Simplex Virus Vector G47∆ Effectively Targets<br />
<strong>Breast</strong> <strong>Cancer</strong> Stem Cells<br />
Liu R, Zeng W, Hu P, Wu J, Li J, Wang J, Lei L. The Third Affiliated<br />
Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China;<br />
The Sichuan Province <strong>Cancer</strong> Hospital, Chengdu, Sichuan, China<br />
<strong>Breast</strong> tumors can be classified according to their gene-expression<br />
profiles into different molecular subtypes with distinct biological<br />
and clinical features. Moreover, different subtypes show distinct<br />
responses to different therapeutic regimens, thereby resulting in<br />
markedly different outcomes. Recently, accumulating evidence has<br />
suggested that breast cancer originates from cancer stem cells (CSCs),<br />
which comprise a small percentage of the overall tumor but are highly<br />
tumorigenic and pluripotent with unlimited proliferation potential.<br />
Furthermore, cancer stem cells are highly resistant to conventional<br />
treatment, which potentially explains certain difficulties in treating<br />
cancer with current therapy options. The use of oncolytic viruses is<br />
a relatively new strategy in cancer therapy, oncolytic herpes simplex<br />
virus (oHSV) has been shown to be a safe and effective therapeutic<br />
approach for a variety of different cancers.<br />
In this study, different types of breast cancer cell lines were cultured<br />
in anchorage-independent conditions, the cells typically form<br />
mammospheres within 10 days of anchorage-independent culture,<br />
which showed properties of CSCs. The mammospheres are capable of<br />
being passaged indefinitely and single dissociated mammosphere cells<br />
were able to regenerate spheres. Moreover, compared to the parental<br />
cell lines, mammoshpere cells were enriched for CD44 + CD24 - cells<br />
and highly expression of the alternative breast cancer stem cell<br />
marker ALDH-1.<br />
The third generation oHSV vector G47∆ effectively killed different<br />
subtypes of breast cancer cells in vitro, with more than 98% of the<br />
tumor cells killed by day 5, even at multiplicities of infection(MOI)<br />
0.01. Moreover, G47∆ equally targeted non-cancer stem cells<br />
(NCSCs) and CSCs which showed resistance to paclitaxel. We also<br />
demonstrated that G47∆ effectively replicated and spread among<br />
CSCs. Moreover, G47∆ impaired the self-renewal ability of CSCs,<br />
as the viable cells unable to form secondary tumor spheres. We<br />
also showed that G47∆ was able to induce the regression of tumor<br />
xenografts in BALB/c nude mice and demonstrated the ability of<br />
G47∆ to synergize with paclitaxel for killing both NCSCs and CSCs.<br />
This is the first report that oHSV effectively targets different breast<br />
cancer NCSCs and CSCs, thereby suggesting that oHSV may be an<br />
effective treatment modality for patients with breast cancer.<br />
P4-06-01<br />
JAK2/STAT3 activity in inflammatory breast cancer supports<br />
the investigation of JAK2 therapeutic targeting<br />
Overmoyer BA, Almendro V, Shu S, Peluffo G, Park SY, Nakhlis F,<br />
Bellon JR, Yeh ED, Jacene HA, Hirshfield-Bartek J, Polyak K. Dana<br />
Farber <strong>Cancer</strong> Institute, Harvard Medical School, Boston, MA; Seoul<br />
National University, Seoul, Korea<br />
Background: Inflammatory breast cancer (IBC) is a virulent subtype<br />
of locally advanced breast cancer that accounts for 1-5% of all breast<br />
cancers diagnosed in the United States. Conventional therapy for<br />
IBC (preoperative chemotherapy, mastectomy, radiation therapy)<br />
results in a median 5 year overall survival of 50%, which supports<br />
the need for investigation into the molecular distinctiveness of<br />
IBC, with the ultimate goal of developing effective therapeutic<br />
agents that target these molecular changes. Some of the distinctive<br />
molecular characteristics of IBC include the presence of a substantial<br />
proportion of CD44+/CD24- breast cancer cells that express stem<br />
www.aacrjournals.org 371s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
cell-like characteristics, over-expression of E-cadherin, and extensive<br />
formation of tumor emboli. Examination of breast tumors and preclinical<br />
data suggests that the JAK2/STAT3 pathway is active in<br />
CD44+/CD24- breast cancer cells, and is stimulated by various<br />
mechanisms associated with IBC, such as high IL-6 levels. We<br />
investigated the role of JAK2/STAT3 activation in IBC as preclinical<br />
evidence to pursue JAK2 targeted therapy for IBC in a clinical setting.<br />
Methods: Using de-identified breast tissue specimens from both<br />
untreated and treated IBC patients obtained on a protocol approved by<br />
our institutional review board; we performed immunohistochemical<br />
(IHC) and multicolor immunofluorescence analysis to detect the<br />
presence of CD44+/CD24- cells and the fraction of activated<br />
phospho-STAT3 (pSTAT3). The number of cells positive for pSTAT3<br />
was assessed pre and post-treatment. We also analyzed the status of<br />
CD44+/CD24- cells and pSTAT3 in SUM149 and SUM190 IBC cell<br />
lines, and an IBC xenograft model (IDC31) derived from primary<br />
tumor obtained from an IBC patient. We tested the efficacy of multiple<br />
different JAK2 inhibitors to inhibit the growth and viability of cell<br />
cultures and xenografts.<br />
Results: All IBCs were highly enriched in CD44+/CD24- cells, with<br />
approximately 80% of all cancer cells within tumors displaying this<br />
phenotype. About 85% of IBC cases show activation of pSTAT3, and<br />
a significant fraction (40%) of CD44+/CD24- cells were pSTAT3<br />
positive. Interestingly, the fraction of pSTAT3+ cells was lower in the<br />
CD44+/CD24- cells in post treatment samples from triple negative<br />
but not from luminal tumors. JAK2 inhibition significantly decreased<br />
the proliferation of pSTAT3+ IBC cells lines in vitro and the growth<br />
of pSTAT3+ xenografts including the IBC model ICD31.<br />
Discussion: Specific molecular characteristics of IBC result in a<br />
unique and virulent disease course. Based upon a predominance<br />
of CD44+/CD24- breast cancer stem cells present in IBC, we<br />
investigated the JAK2/STAT3 pathway in IBC tissue specimens, cell<br />
lines and an IBC xenograft model. Our preclinical data demonstrates<br />
a highly active JAK2/STAT3 pathway in IBC which lends itself to<br />
exploration of the efficacy of a JAK2 inhibitor in the treatment of<br />
this disease. A phase I/II study is underway to evaluate combination<br />
ruxolitinib and chemotherapy for the primary treatment of triple<br />
negative IBC.<br />
P4-06-02<br />
Identification of novel G-protein coupled receptor targets in<br />
HER2-positive breast cancer.<br />
Yadav P, Bhat RR, Chayanam S, Christiny PI, Nanda S, Hu H,<br />
Creighton C, Osborne CK, Schiff R, Trivedi MV. University of<br />
Houston, TX; Lester & Sue Smith <strong>Breast</strong> Center, Dan Duncan <strong>Cancer</strong><br />
Center, Houston, TX; Baylor College of Medicine, Houston, TX<br />
Background: HER2 is a member of human epidermal growth factor<br />
receptor (HER) superfamily and HER2-overexpressing (HER2+)<br />
breast cancer (BC) is an aggressive tumor. Despite the clinical success<br />
of anti-HER2 therapies, de novo and acquired drug resistance occur<br />
in many patients. Identification of novel drug targets to overcome<br />
anti-HER2 therapy resistance is an unmet need. Since G-protein<br />
coupled receptors (GPCRs) are known to cross-talk with the HER<br />
superfamily, it is possible that some GPCRs may signal to modulate<br />
the HER2 pathway. GPCRs are considered excellent drug targets<br />
due to their plasma membrane localization, unique ligand-binding<br />
pocket, and availability of high throughput assays for drug screening.<br />
The expression and function of the majority of GPCRs are largely<br />
unknown in HER2+ BC. The goal of this study was to identify novel<br />
GPCR targets in HER2+ BC, in the context of anti-HER2 therapy<br />
resistance.<br />
Methods: We examined the differential GPCRs expression in BC stem<br />
cells, suggested to be involved in resistance, as well as in anti-HER2<br />
treatment-resistant BT474 cell line model of HER2+ BC. BC stem<br />
cells were identified as aldehyde dehydrogenase-positive (ALDH+)<br />
cells using the Aldefluor assay. Brightly fluorescent ALDH+ cells<br />
were separated from ALDH- cells using FACS Aria II cell sorter.<br />
Anti-HER2 resistant derivatives of BT474 cells were established by<br />
long-term exposure to increasing drug concentration of trastuzumab<br />
(T), lapatinib (L), or their combination (T+L). RNA was isolated and<br />
subjected to profiling using TaqMan real time RT-PCR GPCR 384-<br />
well microarray to quantify the expression of mRNA encoding 343<br />
GPCRs from 50 different subfamilies. Only overexpressed GPCRs<br />
were considered of interest as drug targets, and the overexpression of<br />
GPCRs was verified by RT-PCR and western blotting for the selected<br />
targets. Publically available TCGA dataset for mRNA expression<br />
was also interrogated to determine differential expression of selected<br />
GPCRs in HER2+ vs. other subtypes of BC.<br />
Results: Nine GPCRs [BAI3, EDNRA, GPR110, GPR116, GPR124,<br />
MTNR1A, EDG2, EMR2, GCGR] were upregulated in ALDH+<br />
compared to ALDH- BT474 cells. In addition, 11 GPCRs [CCBP2,<br />
CCR9, F2RL1, GALR2, GPR1, GPR24, GPR87, GPR110, GPR183,<br />
LGR4, OXER1] were over-expressed in the resistant derivatives (T,<br />
L, and T+L) compared to the parental BT474 cells. Out of these, 13<br />
belong to Class A and 6 to Class B, designated by The International<br />
Union of Basic and Clinical Pharmacology (IUPHAR). GPR110<br />
was the only GPCR common to BC stem cells as well as resistant<br />
derivatives of BT474 cells. In TCGA dataset, GPR110 expression was<br />
significantly higher in HER2+ and basal subtypes of BC compared to<br />
ER+ luminal A and B subtypes. GPR110 as well as other differentially<br />
expressed GPCRs are currently being investigated as potential targets<br />
by determining the effects of their downregulation or exogenous<br />
over-expression on the growth and drug-sensitivity of these BC cells.<br />
Conclusions: We report for the first time the differential expression<br />
of a large panel of GPCRs in the BC stem cell population and in anti-<br />
HER2 resistant derivatives of the BT474 cell line model of HER2+<br />
BC. Results of the functional studies will guide novel strategies to<br />
improve the treatment for HER2+ BC.<br />
P4-06-03<br />
Zinc Finger Nuclease Genome Engineering Reveal Multiple<br />
Functions of Secretory Leukocyte Peptidase Inhibitor in<br />
Regulating Pleuripotency of <strong>Cancer</strong> Stem Cells in Inflammatory<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Robertson FM, Hibbs S, Boley KM, Chu K, Ye Z, Wright MC, Liu<br />
H, Luo AZ, Cristofanilli M, Wemhoff G. The University of Texas MD<br />
Anderson <strong>Cancer</strong> Center, Houston, TX; Sigma-Aldrich, St. Louis,<br />
MO; Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA<br />
Background: Inflammatory breast cancer (IBC) is the most aggressive<br />
and lethal variant of this disease and is known to be enriched for<br />
cells with a cancer stem cell phenotype. IBC is characterized by the<br />
presence of cell aggregates, defined as tumor emboli, that metastasize<br />
into skin and chest wall. The only documented biomarker of tumor<br />
emboli is the surface glycoprotein, E-cadherin. We previously<br />
demonstrated that IBC tumor emboli express the alarm anti-protease,<br />
secretory leukocyte peptidase inhibitor (SLPI), a metastasis related<br />
gene highly expressed in IBC patient tumors. Since the function<br />
of SLPI in IBC is unknown, the present studies used zinc finger<br />
technology to knockout (KO) copies of SLPI in the SUM149 IBC<br />
cell line to define the role of SLPI in IBC.<br />
Materials and Methods: Using CompoZr zinc finger nuclease (ZFN)<br />
technology (Sigma-Aldrich), SLPI KO cell lines were generated by<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
disrupting all alleles (3) in exon 1 of SUM149 cells derived from<br />
an IBC primary tumor with a high CD44+cell population. The<br />
target-specific ZFNs bound DNA at a sequence-specific location<br />
and created double strand breaks repaired by non-homologous end<br />
joining, resulting in deletions at the SLPI locus. Single cell SLPI KO<br />
clones were isolated and serially passaged to establish stable cell<br />
lines. Functional assays were used to assess proliferation, invasion,<br />
tube formation and clonogenicity. Global transcriptional profiling<br />
was performed to identify genes and signaling pathways directly<br />
regulated by SLPI.<br />
Results: SUM149 SLPI KO clones did not produce SLPI protein<br />
and had a significantly slower turn-over time of 75 hrs compared<br />
with 24 hrs in SUM149 wild type clones. Loss of SLPI blocked<br />
invasion by 50%, and completely inhibited formation of tube-like<br />
structures, an activity defined as vasculogenic mimicry, characteristic<br />
of IBC. The loss of only 1 SLPI allele resulted in the inability of<br />
SUM149 cells to grow as anchorage independent clones in soft agar,<br />
commonly used as a predictor of in vivo tumorigenicity. SLPI directly<br />
regulated expression of multiple genes within the embryonic stem cell<br />
pleuripotency canonical pathway, including WNT, Frizzled, PDK-1,<br />
platelet derived growth factor receptor and sphingosine-1-phosphate<br />
receptor. Studies are underway to determine the specific role of SLPI<br />
in IBC tumor growth and metastasis.<br />
Conclusions: Our previous studies demonstrated that SLPI is<br />
expressed by IBC tumor emboli and can be used as a biomarker of<br />
tumor emboli in IBC core and skin punch biopsies. SLPI was found to<br />
not only regulate critical functional activities of IBC tumor cells but<br />
also to directly regulate genes within pathways critically important<br />
to maintenance of pleuripotency of tumors with a cancer stem cell<br />
phenotype. Collectively, these studies demonstrate the power and<br />
utility of the zinc finger technology, which enables the interrogation<br />
of tumor cells to discern the direct function and role of specific genes<br />
of interest.<br />
P4-06-04<br />
Gamma-secretase inhibitors suppress the activation of NFκB<br />
and the expression of TNFα, IL-6 and IL-8 in triple negative<br />
breast cancer cells<br />
Gu J-W, King J, Makey KL, Chinchar E, Gibson J, Miele L. University<br />
of Mississippi Medical Center, Jackson, MS<br />
Background: Inflammation mediators, such as NF-kappa B (NFκB)<br />
and tumor necrosis factor alpha (TNFα), play major role in breast<br />
cancer pathogenesis, progression, and relapse. Triple negative breast<br />
cancer (TNBC) is a heterogeneous group of aggressive breast cancers<br />
and often has a poor outcome, in which Notch pathways are highly<br />
activated. However, role of crosstalk between Notch and inflammation<br />
mediators in TNBC progression and recurrence is poorly understood.<br />
The present study determines: 1) whether NFκB is highly activated<br />
in TNBC cells such as MDA-MB-231 (claudin-low-like) and MDA-<br />
MB-468 (basal-like), compared to ER-positive cells (MCF-7); 2)<br />
whether TNFα, IL-6 and IL-8 are highly expressed in TNBC cells,<br />
compared to MCF-7 cells; 3) whether Notch inhibition by gammasecretase<br />
inhibitors (GSIs) significantly decrease NFκB activation and<br />
the expression of TNFα, IL-6 and IL-8 in TNBC cells; 4) whether<br />
GSI inhibits TNBC cell migration.<br />
Material and Methods: MDA-MB-231, MDA-MB-468, MCF-7<br />
cells were cultured using RPMI 1640 media with 10% FBS. The cells<br />
were exposed to GSIs such as DAPT and RO4929097 for 18 hours.<br />
Nuclear NFκB activation was determined by using the TransAM<br />
NFκB p65 kit (Active Motif). The expressions of TNFα, IL-6, IL-<br />
8, and IFNγ were determined by the ELISA kits (R&D Systems).<br />
Migration was determined using BD BioCoat Matrigel Invasion<br />
Chamber (BD Bioscience Discovery Labware, Sedford, MA).<br />
Results: Nuclear NFκB p65 activations (A450) were 0.292±0.015,<br />
0.222±0.005, and 0.132±0.004 in cultured MDA-MB-231, MDA-<br />
MB-468, and MCF-7 cells, respectively, in which the negative<br />
control was 0.125±0.008 and the difference between the groups<br />
were significant (P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
S1 cells, suggesting that IR induces the formation of α5β1-integrin<br />
complexes leading to increased survival post-IR. Together these<br />
results provide the first evidence that NF-κB-induced β1-integrin<br />
transactivation is responsible for increased survival post IR in breast<br />
cancer. Since β1-integrin is shown to activate NF-κB, our data further<br />
suggest a loop-like β1-integrin–NF-κB–β1-integrin pathway in tumor<br />
radioresistance. This novel pathway may serve as an efficient drug<br />
target to re-sensitize radioresistant tumor cells.<br />
P4-06-06<br />
RNAi screen of the breast cancer genome identifies KIF14 and<br />
TLN1 as genes that modulate chemosensitivity in breast cancer<br />
Singel SM, Cornelius C, Batten K, Fasciani G, Wright WE, Lum L,<br />
Shay JW. University of Texas Southwestern, Dallas, TX<br />
We conducted a RNA-interference screen for genes whose loss-offunction<br />
enhanced doxorubicin and docetaxel chemosensitivity in a<br />
“triple-negative,” estrogen receptor negative, progesterone receptor<br />
negative, and Her2 negative (ER- PR- Her2-) breast cancer cell line,<br />
MDA-MB-231. From ranking chemosensitivity of 334 short-hairpin<br />
RNA (shRNA) MDA-MB-231 cell lines (targeting 134 genes with<br />
known somatic mutations in breast cancer), we focused on two genes,<br />
kinesin family member 14 (KIF14) and talin (TLN1) that not only<br />
enhanced chemosensitivity but also have oncogenic annotations.<br />
KIF14 has robust expression in breast cancer cells compared to<br />
normal mammary cells. TLN1 expression is important for migration<br />
of breast cancer cells. In TLN1-deficient cells, CK19 and ZO-1 are<br />
upregulated while CK14 and snail are downregulated, suggesting that<br />
TLN1 is important for the maintenance of epithelial-mesenchymal<br />
transition in MDA-MB-231 cells. KIF14 and TLN1 loss-of-function<br />
also enhanced chemosensitivity in 3 other triple negative breast cancer<br />
cell lines (HCC1937, HCC38, and Hs578T) but not in normal human<br />
mammary epithelial cells (HMECs). Examining protein-proteininteraction<br />
networks, we identified RIP2 as a target whose inhibition<br />
via SB203580 or PP2 can further enhance chemosensitization in<br />
KIF14-deficient cells. Knock-down of a number of other known<br />
protein-protein interaction partners of KIF14 and TLN1, including<br />
FAK, CIT, ARRB2, PSTPiP1, PRC1, SVIL, ITGA2B, ITGB3,<br />
VCL and PXN, do not significantly alter doxorubicin or docetaxel<br />
chemosensitivity in MDA-MB-231 cells. Mammary fat pad xenografts<br />
of KIF14- and TLN1- deficient MDA-MB-231 cells into NOD/SCID<br />
mice demonstrated significantly less tumor mass compared to control<br />
MDA-MB-231 cells after chemotherapy. Expressions of KIF14 and<br />
TLN1 from breast cancer expression arrays improve prognostic<br />
predictions compared to clinicopathological features alone. In<br />
summary, screenings for therapeutic targets using chemotherapy and<br />
genes with known somatic mutations in breast cancer not only provide<br />
a rational targeted screen, but also present possible up-front novel<br />
treatment combinations for patients with triple negative breast cancer.<br />
P4-06-07<br />
Isoform specific antibodies against the fibroblast growth factor<br />
receptor 2 have predictive and therapeutic implications in the<br />
treatment of human breast cancers<br />
Ettyreddy AR, Somarelli J, Bitting R, Armstrong A, Garcia Blanco<br />
MA. Duke University, Durham, NC<br />
Background: Aberrant induction of the epithelial to mesenchymal<br />
transition cascade (EMT) has a defining role in shaping cancer<br />
malignancy. Despite the complexity of this process, the alternative<br />
splicing of the fibroblast growth factor receptor 2 (FGFR2), between<br />
the epithelial-specific FGFR2-IIIb and mesenchymal-specific FGFR2-<br />
IIIc isoforms, has been shown to play a pivotal role in the EMT<br />
cascade. Aberrant splicing of FGFR2 in carcinomas has been shown<br />
to mark invasive cancerous cells that have undergone an EMT event<br />
and have gained the ability to thrive in diverse microenvironments.<br />
In addition to improper splicing patterns, overexpression of either<br />
isoform is sufficient to induce tumor formation by constitutively<br />
activating common oncogenic pathways. For example, a recent<br />
microarray analysis identified amplification of the FGFR2-IIIb locus<br />
as a common oncogenic signature in a significant number of treatmentresistant<br />
triple negative breast cancers (TNBC). Furthermore,<br />
inhibition of FGFR2 signaling in candidate TNBCs was sufficient to<br />
induce tumor regression. Due to the intimate link that exists between<br />
FGFR2 and breast cancer (BC), isoform-specific antibodies against<br />
the receptor may be able to identify tumors that possess deregulated<br />
FGFR2 signaling and subsequently inhibit their growth by blocking<br />
FGF ligand binding.<br />
Methods: To develop FGFR2-IIIb and —IIIc specific antibodies,<br />
we initially cloned and expressed the alternatively spliced region of<br />
each isoform and provided sufficient amount to ThermoScientific<br />
for rabbit immunizations. After the 72-day protocol was completed,<br />
the raw anti-IIIb/IIIc serum was passed through a column containing<br />
immobilized GST-IIIc/IIIb, respectively, to remove cross-reactive<br />
antibodies. Antibody specificity was assessed through western blotting<br />
and immunofluorescence (IF). Therapeutic validity of serum was<br />
determined by its ability to inhibit the growth of cancers in-vitro.<br />
Results: Through western blotting, we were able to demonstrate that<br />
the anti-IIIb serum was able to specifically recognize the FGFR2-<br />
IIIb isoform. However, the anti-IIIc serum exhibited substantial<br />
cross-reactivity to FGFR2-IIIb and was therefore not included in<br />
downstream studies. By IF, the anti-IIIb serum specifically recognized<br />
FGFR2-IIIb expressing cells while exhibiting background levels of<br />
reactivity to those that expressed FGFR2-IIIc, FGFR1, or FGFR4.<br />
To test the therapeutic validity of the anti-IIIb serum, we conducted<br />
cell inhibition assays using MCF-7 (FGFR2-IIIb specific), BT-549<br />
(FGFR2-IIIc specific), and PC3 (FGFR2 negative) cancer lines to<br />
test whether the growth inhibitory effects of the antibody could<br />
specifically target FGFR2-IIIb expressing cancer cell lines. After<br />
5 days of treatment with anti-IIIb or pre-immune rabbit serum, we<br />
observed potent growth inhibition of the MCF-7 BC cells (p=.02) in<br />
anti-IIIb treated wells and minimal effects on BT-549 and PC3 cells.<br />
Conclusion: Based upon the observed data, the anti-IIIb serum<br />
that we developed not only identified FGFR2-IIIb expressing cells<br />
through IF, but also inhibited their growth in vitro. Taken together,<br />
our data suggest that FGFR2-IIIb may be a promising therapeutic<br />
and predictive marker.<br />
P4-06-08<br />
Clinical utility of functional analysis of FGFR kinase family for<br />
selecting patients who may benefit from FGFR inhibitors<br />
Hoe N, Zhou J, Kuy C, Jin K, Srikrishnan R, Soundararajan A, Ma<br />
Y, Liu X, Singh S. Prometheus Labs, <strong>San</strong> Diego, CA<br />
Background:<br />
Fibroblast growth factor receptor (FGFR) family of receptor tyrosine<br />
kinases (RTKs) are currently under investigation as therapeutic<br />
targets for the treatment of breast cancer. Members of this kinase<br />
family have been associated with breast cancer progression and<br />
resistance to current therapeutics. FGFR1 amplifications range from<br />
7.5-17% in breast cancers and are associated with a shorter overall<br />
survival. FGFR1 amplified cell lines drive activation of AKT, ERK,<br />
and RSK and are highly sensitive to FGFR1 inhibition, suggesting<br />
an oncogenic addiction to FGFR1. FGFR2 is activated in lapatinibresistant,<br />
HER2-positive cells. Likewise, FGFR3 expression levels<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
are elevated in tamoxifen-resistant, ER positive patients. FGFR 4<br />
overexpression correlated with poor response to chemotherapy due<br />
to activation of MAPK and increase in B-cell lymphoma extra large<br />
(BCL-XL) levels. Using an immuno-microarray system, this study<br />
seeks to determine FGFR signal transduction pathway modulation<br />
post FGFR inhibitor treatment in breast cancer cell lines expressing<br />
varying levels of FGFR1, 2, 3 or 4.<br />
Method:<br />
FGFR 1, 2, 3, and 4 amplified cell lines (MDA-MB-134VI (KRAS),<br />
SNU16, RT112, and MDA-MB-453) were treated with varying<br />
dosages (1, 10, 100, and 1000nM) of several FGFR inhibitors<br />
(AZD4547 (pan FGFR), PD173074 (FGFR1,3) and Ponatinib-<br />
AP24534 (FGFR1)) either in presence or absence of corresponding<br />
FGF (FGF1, FGF7, FGF9, and FGF19) stimulation. Expression<br />
and activation of FGFR 1, 2, 3, and 4 and downstream signaling<br />
proteins FRS2, AKT, ERK, MEK, and RSK were measured utilizing<br />
a proximity based immuno-microarray.<br />
Results:<br />
FGFR1, 2, 3, 4 protein expression was detected in each of the<br />
corresponding four FGFR1, 2, 3, 4 amplified cell lines. Total protein<br />
levels remained unchanged with or without FGFs stimulation. Levels<br />
of FGFR1 phosphorylation increased 5 folds in MDA-MB-134VI<br />
stimulated with FGF1. FGFR2 and FGFR3 activation increased by<br />
2-3 folds in SNU16 and RT112 stimulated with FGF7, and FGF9<br />
respectively. FGFR4 activation levels in MDA-MB-453 remained<br />
unchanged due to Y367C mutation. ERK was activated in both FGF1<br />
stimulated and unstimulated group in MDA-MB134 due to the KRAS<br />
mutation. RSK activation increased in both SNU16 and RT112 when<br />
stimulated with FGF7, and FGF9 respectively. FGFR inhibitors<br />
treated data analysis is currently in progress and will be presented.<br />
Conclusion:<br />
We have demonstrated utility of specific FGFR analysis using well<br />
defined model systems. FGFR- profiling should be considered during<br />
the clinical work-up in order to select patients who may benefit from<br />
regimen containing specific FGFR inhibitors.<br />
P4-06-09<br />
Cell surface receptor CDCP1 as a potential marker of triple<br />
negative breast cancers progression<br />
Campiglio M, Sasso M, Bianchi F, De Cecco L, Turdo F, Triulzi<br />
T, Orlandi R, Morelli D, Aiello P, Ghirelli C, Agresti R, Tagliabue<br />
E. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;<br />
Fondazione IRCCS Istituto Nazionale dei Tumori<br />
The risk of recurrence and death in triple negative breast cancer<br />
(TNBC) peaks between the first and the third year after surgery and<br />
to date, there is still an urgent need to define specific markers for<br />
therapeutic targeting. Surgical wound healing process was shown<br />
to contribute to tumor recurrence since molecules release during<br />
wounding, which can contribute to create a suitable environment<br />
for tumor progression, are released into the blood and may stimulate<br />
disseminated metastatic cells. Therefore, wound-healing fluids (WHF)<br />
from breast cancer patients has been used as a tool representing the<br />
repertoire of growth factors and cytokines released after surgery<br />
able to stimulate TNBC progression. By treating TNBC cell lines<br />
with WHFs collected 24 hr post-surgery of breast cancer patients,<br />
we identified CDCP1, a cell surface receptors with CUB domain<br />
significantly up modulated by WHFs in 4 out of 5 TNBC cell lines.<br />
CDCP1, reported to be a regulator of tumor metastasization and<br />
a resistant factor to anoikis, was found highly expressed in some<br />
epithelial tumors, i.e. colon and lung and associated to a poor<br />
prognosis. By in silico analysis of gene expression public datasets of<br />
breast cancer specimens, we found a significant correlation between<br />
CDCP1 expression level and risk of relapse. Additionally, in a<br />
dataset of breast cancer cell lines we found an increased expression<br />
of CDCP1 in basal respect to luminal cancer cells. To move forward<br />
with the investigation of the CDCP1 role in the TNBC subtype, we<br />
analyzed CDCP1 protein in 12 TNBC and 8 luminal breast cancers<br />
and found a strong membrane staining in all the TNBCs, while in<br />
only 2 luminal cases faint membrane reactivity was observed. TNBC<br />
cells CDCP1-silenced by specific siRNA were not affected in their<br />
in vitro growth, while they were strongly and significantly impaired<br />
in their capability to migrate and invade; CDCP1-shRNA of TNBC<br />
cells was performed to investigate CDCP1 impact on growth and<br />
metastatization in SCID mice. In conclusion, our data suggest that<br />
CDCP1 is a new potential receptor promoting TNBC progression.<br />
Supported by AIRC (Associazione Italiana Ricerca sul Cancro).<br />
P4-06-10<br />
Epigenetic silencing of glutamine synthetase (Glul) defines<br />
glutamine depletion therapy<br />
Cavicchioli F, Shia A, O’Leary K, Haley V, Crook TR, Thompson<br />
AM, Lackner M, Lo Nigro C, Schmid P. Brighton and Sussex Medical<br />
School, University of Sussex, Brighton, United Kingdom; Ninewells<br />
Hospital, University of Dundee, United Kingdom; Genentech, Inc.,<br />
<strong>San</strong> Francisco; S. Croce General Hospital, Cuneo, Italy<br />
Background: Methylation-dependent transcriptional silencing of<br />
genes involved in amino acid synthesis can provide potential targets<br />
for novel synthetic lethality strategies. Glutamine synthetase (Glul)<br />
is the key enzyme in the biosynthesis of glutamine. We identified<br />
Glul as a novel gene subject to methylation-dependent transcriptional<br />
silencing in breast cancer cell lines using a combined functional screen<br />
with methylation reversal assays and methylation arrays.<br />
Methods: Methylation reversal assays were performed using<br />
5-aza-2-deoxycytidine and/or trichostatin treatment coupled with<br />
whole genome mRNA microarrays (Illumina HT-12 v4 Expression<br />
BeadChip Kit). Expression of Glul with and without pharmacological<br />
methylation reversal with azacytidine and/or trichostatin was<br />
validated using qRT-PCR and Western Blot. Methylation of Glul was<br />
analysed using methylation microarrays (Illumina 450K Methylation<br />
BeadChip), bisulphite sequencing and pyrosequencing. Sensitivity<br />
to glutamine deprivation was assessed using an MTT assay after<br />
culturing cells in media with various glutamine concentrations or in<br />
complete absence of glutamine. We used a panel of 55 breast cancer<br />
cell lines and formalin-fixed paraffin-embedded tissue from a series<br />
of 116 stage I-III primary breast cancers with linked mature clinical<br />
outcome data that were randomly selected from the Cuneo Tissue<br />
Bank. Tissue samples were subject to histopathological review to<br />
ensure adequate representation of cancer cells.<br />
Results: Dense methylation of the CpG-island of Glul was detected<br />
in 45% of cell lines across all subtypes. Methylation of the CpG<br />
island was linked with absent or down-regulated expression of Glul<br />
in some but not all cell lines, and Glul expression could be reactivated<br />
by azacytidine and trichostatin in these cell lines. Methylation of<br />
shore areas was detected in several cell lines but was not associated<br />
with transcriptional silencing. Cells with methylation-dependent<br />
low or absent Glul expression were highly sensitive to glutamine<br />
deprivation, whereas cell lines without Glul methylation were rescued<br />
by compensatory up-regulation of Glul. Using pyrosequencing, dense<br />
methylation of the CpG island of Glul was found in 32.8% of patients,<br />
with an additional 17.2% of patients showing partial methylation.<br />
No significant association with a specific breast cancer subtype or<br />
outcome was found.<br />
www.aacrjournals.org 375s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Conclusions: This is the first report of methylation-dependent<br />
transcriptional silencing of Glul expression in cancer. Our data<br />
demonstrate that a significant proportion of primary breast cancers<br />
show methylation of Glul and suggest that glutamine deprivation<br />
could be a novel synthetic lethality strategy for these cancers.<br />
P4-06-11<br />
Expression of genes spanning a breast cancer susceptibility locus<br />
on 6q25.1 is modulated by epigenetic modification<br />
Dunbier AK, White J, Van Huffel S. University of Otago, Dunedin,<br />
Otago, New Zealand<br />
Background:<br />
Genome wide association studies have identified single nucleotide<br />
polymorphisms around C6ORF97, an open reading frame (ORF)<br />
immediately upstream of the gene encoding ERα (ESR1) on 6q25.1,<br />
to be associated with increased risk of breast cancer 1,2 . C6ORF97<br />
and two neighbouring genes, RMND1 and C6ORF211, are also<br />
co-expressed with ESR1 in oestrogen receptor positive (ER+ve)<br />
breast cancers and C6ORF97 expression is inversely associated<br />
with proliferation and recurrence free survival in a tamoxifen-treated<br />
patient cohort 3 . Epigenetic modification represents one potential<br />
mechanism through which expression of co-localised genes could<br />
be modulated.<br />
Aim:<br />
To investigate the role of epigenetic modification in the co-expression<br />
of ESR1, RMND1, C6ORF211 and C6ORF97.<br />
Methods:<br />
Methylation status and expression of genes in the ESR1/C6ORFs locus<br />
was assessed in postmenopausal breast cancers and ER+ve cell lines.<br />
Two ER+ve cell lines, MCF7 and T47D, were cultured in oestrogendepleted<br />
media and samples were taken fortnightly for 6 months.<br />
DNA and RNA from ER+ve tumours was also analysed in addition to<br />
control ER-ve cell lines. Methylation analysis of CpG Islands within<br />
the ESR1/C6ORFs locus was carried out using methylation sensitive<br />
sequencing analysis. Expression levels of ESR1, RMND1, C6ORF211<br />
and C6ORF97 were determined using quantitative real-time PCR.<br />
Results:<br />
Variation in methylation patterns was observed at a number of key<br />
CpG islands in the ESR1/C6ORFs region. ER+ve cell lines and<br />
highly ER+ve tumours were hypomethylated. Hypomethylation was<br />
associated with increased expression of ESR1, RMND1, C6ORF211<br />
and C6ORF97. Temporal changes in methylation and expression<br />
of these genes were also observed over the period of oestrogen<br />
deprivation in both MCF7 and T47D.<br />
Conclusions:<br />
Methylation at the ESR1/C6ORFs locus is associated with expression<br />
levels of ESR1, RMND1, C6ORF211 and C6ORF97. This suggests<br />
that methylation is involved in modulating the expression of these<br />
four genes and that it could partially explain the previously observed<br />
co-expression of the genes. Our finding that hypomethylation in this<br />
region occurs in tumours with high ERα expression suggests that it<br />
could be a mechanism through which tumours increase ERα levels<br />
to maximise growth stimulation from oestradiol. Our observation<br />
that RMND1, C6ORF211 and C6ORF97 also increase in expression<br />
suggests that the proteins encoded by these genes may contribute to<br />
the phenotype exhibited by ER+ve breast tumours.<br />
References:<br />
1. Turnbull C et al. Nature Genetics 2010;42:504-7.<br />
2. Zheng W et al. Nature Genetics 2009;41:324-8.<br />
3. Dunbier A et al. PLoS Genetics 2011;7:e1001382.<br />
P4-06-12<br />
Monoclonal antibodies against nicastrin for the treatment of<br />
breast canmcer: in vitro and in vivo characterisation and function<br />
Filipovic A, Lombardo Y, Deonarain M, Giamas G, Cordingley H,<br />
Tralau-Stewart C, Coombes RC. Imperial College London, United<br />
Kingdom<br />
Nicastrin (NCT) is a crucial structural and functional constituent of the<br />
gamma-secretase (GS) enzyme which activates a range of substrates<br />
(Notch1-4, CD-44, Her-4, E-cadherin, EpCAM etc.), with a causative<br />
role in development and progression of malignant disease. Nicastrin<br />
is the only GS component with a single-pass transmembrane- and a<br />
large extracellular domain (ECD). This makes NCT a potential target<br />
for monoclonal antibody (McAb) therapy.<br />
Using genetic immunization with the NCT-ECD cDNA., we raised<br />
and cloned rat hybridomas expressing anti-NCT monoclonal Abs<br />
(McAbs) (Genovac). Four clones (NMA1-4) were taken to complete<br />
McAb production and purification, based on their ability to recognise<br />
cell surface NCT on breast cancer cells and potency to inhibit breast<br />
cancer cell invasion. We have established the binding affinities of<br />
the McAbs using non cell based and cell based assays, as well as<br />
performed competition binding experiments using surface plasmon<br />
resonance, which have revealed that the two McAbs bind distinct<br />
epitopes on NCT ECD. Although nicastrin is a heavily glycosylated<br />
protein, dyglycosylation experiments using EndoH and PNGase have<br />
revealed that the McAbs1-4 most likely bind peptide sequences of<br />
nicastrin ECD. We will also present further data from the PEPScreen<br />
experiment used to further delineate the binding epitopes of the antinicastrin<br />
McAbs. In terms of mechanism of action, we have shown<br />
that McAb2 affects the Akt pathway, while the McAb4 acts on the<br />
Cdc42-RhoGTPases signalling axis.<br />
Importantly, we have performed an in vivo mammary fat pad xenograft<br />
mouse model of triple negative breast cancer (MDA-MB-231), where<br />
the i.v. injected McAb2 inhibited tumour growth by 50% over 25<br />
days (p = 0.007). We will present the data from genome microarray<br />
analyses used to assess tumour tissues (control arm and McAb2 arm)<br />
from the mouse xenograft model.<br />
In patient samples we have previously shown (Filipovic et al, <strong>Breast</strong><br />
<strong>Cancer</strong> Research and Treatment, 2011) that nicastrin is overexpressed<br />
in breast cancer tissue compared to normal breast, (n= 1050) where it<br />
confers worse overall survival in estrogen receptor negative patients.<br />
We have now established that nicastrin can be detected in the serum<br />
of breast cancer patients by ELISA, where as a circulaing marker, its’<br />
levels are increased in mataststic patients compared to the primary<br />
BC patients.<br />
We conclude that anti-nicastrin McAb therapy may be an efficient<br />
strategy to target nicastrin expressing breast cancer.<br />
P4-06-13<br />
Effects of Statin on triple-negative breast cancer (TNBC) with<br />
Ets-1 overexpression<br />
Lee S, Jung HH, Park YH, Ahn JS, Im Y-H. Samsung Medical Center<br />
Background: Triple negative breast cancer (TNBC) is diagnosed<br />
accounting for approximately 15-20% of all breast cancer diagnoses<br />
and an aggressive clinical phenotype characterized by lack of<br />
expression of estrogen receptor (ER) and progesterone receptor (PR)<br />
as well as the absence of human epidermal growth factor receptor-2<br />
(HER-2) overexpression. Because of its expression profile, TNBC is<br />
not amenable to treatment with hormone therapy or the anti-HER2<br />
monoclonal antibody trastuzumab, and systemic treatment options<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
are limited to cytotoxic chemotherapy. At present, there is not a clear,<br />
proven effective single agent that targets a defining vulnerability in<br />
TNBC.<br />
The proto-oncogene Ets-1 is a member of the Ets family of<br />
transcription factors which share a unique DNA binding domain, the<br />
Ets domain. Ets proteins are targets for phosphorylation in response<br />
to stimulation by a variety of different growth modulators, including<br />
intracellular calcium, activators of protein kinase C pathways,<br />
growth factors and cytokines. The importance Ets genes in human<br />
carcinogenesis is supported by the observations that Ets genes<br />
have altered expression patterns, are chromosomally amplified or<br />
deleted, or are located at translocation breakpoints in leukemia and<br />
solid tumors. In model systems, increased expression of Ets-1 was<br />
found to be associated with enhanced angiogenesis and the invasive<br />
phenotype. Studies in breast cancer cell lines have implicated Ets-1<br />
in the progression of breast cancer.<br />
The present study was conducted to better understand the molecular<br />
mechanisms underlying statin-induced suppression associated with<br />
transcription factor Ets-1 overexpressed TNBC.<br />
Methods: We evaluated the anti-tumor effects of simvastatin on<br />
TNBC cells using a MTT assay, invasion assay, siRNA transfection,<br />
western blotting and xenograft study which were used to address<br />
the role of Ets-1 activity and the Erk/Akt pathway on the effect of<br />
simvastatin.<br />
Results: We demonstrated that the expression of Ets-1 was increased<br />
particular in TNBC cells among various breast cancer cell lines<br />
and the simvastatin statistically significantly enhanced antitumor<br />
activity in Ets-1 overexpressed TNBC cells. In a mouse model, the<br />
growth of Ets-1 expressed TNBC xenograft tumors was statistically<br />
significantly inhibited when simvastatin was treated. Furthermore,<br />
our data demonstrated for the first time that simvastatin inhibited the<br />
growth of TNBC cells by inhibiting Ets-1 activity via Erk and Akt<br />
pathway in a dose-dependent manner.<br />
Conclusion: Our results suggest that the inhibition of Ets-1 acitivity<br />
via Erk and Akt pathway may be a novel mechanism by which<br />
simvastatin suppresses the growth of TNBC cells. The ability of<br />
simvastatin to induce cell death via Ets-1, as well as its ability<br />
to downregulate signaling through Ras/Raf/MEK/Erk and PI3K/<br />
Akt pathway, suggested translational value. Exploitation of this<br />
activity might include a combination of Ras/Raf/MEK/Erk or PI3K/<br />
Akt/mTOR inhibitors and simvastatin to induce cell death or the<br />
combination of simvastatin in these signaling pathways. Further<br />
preclinical and clinical studies are warranted to further investigate<br />
the application of simvastatin for the treatment of TNBC.<br />
P4-06-14<br />
CD146-suppresses breast tumor invasion via a novel transcription<br />
target TIMPv<br />
Shanmuganathan S, AbdElmageed Z, Fernando A, Gaur R, Ramkumar<br />
A, Bhat S, Gupta I, Muzumdar S, Hakkim L, Ouhtit A. Sultan Qaboos<br />
University, Al-Khod, Seeb, Oman<br />
The function of the cell adhesion receptor CD146, a recently<br />
discovered marker of endothelial cells and a tumor promoter of<br />
melanoma and other cancers, is controversial in breast cancer (BC).<br />
However several lines of evidence supports its role as a tumor<br />
suppressor in BC. Further, the molecular mechanisms underpinning<br />
this suppression are unknown, neither has the ligand for CD146 been<br />
identified. Using a novel validated Enhanced Green Fluorescent<br />
Protein (EGFP)-inducible systems of CD146 expression both in vitro<br />
and in vivo, we provide here molecular and functional evidence of<br />
CD146 and its novel transcriptional target TIMPv (a variant of tissue<br />
inhibitor of metallo-proteinases) in underpinning the suppression of<br />
BC invasion.<br />
Tetracycline (tet-on) CD146 system was developed in both MCF-7<br />
and MDA-231 BC founder cell lines, and validated using time course<br />
RT-PCR and western blot analyses, and fluorescent microscopy.<br />
In functional experiments, induction of CD146 inhibited BC cell<br />
migration and invasion. TIMPv, the only endogenous protein<br />
inhibitor known for metallocarboxypeptidases, was identified by<br />
expression profiling as a novel transcriptional target of CD146-<br />
signaling, an association validated by quantitative PCR and<br />
immunoblotting experiments in a range of breast and melanoma<br />
cancer cells. However, siRNA inhibition of CD146 in the SKMel-28<br />
melanoma cell line increased TIMPv expression, suggesting that<br />
while TIMPv is a positive transcriptional target of CD146 in BC<br />
cells, it is negatively regulated in melanoma cells. Furthermore,<br />
using invasion assay, the functional relevance of TIMPv to CD146-<br />
suppressed metastasis was demonstrated by selective suppression<br />
of TIMPv in CD146-expressing BC inducible cells using RNAi.<br />
More interestingly, induction of CD146 expression in vivo, using<br />
the tet-on CD146 expression system in BC Xenograft model resulted<br />
in suppression of breast tumor growth. Further, Clinical analysis of<br />
breast tissue samples by Immunohistochemistry showed that TIMPv<br />
expression patterns paralleled those of CD44s during breast tumor<br />
progression. Pharmacological and molecular approaches revealed<br />
that the activation of NFκB via Akt pathway couples CD146 to the<br />
transcription of TIMPv in BC cells.<br />
Our study is the first report to provide a functional molecular link<br />
of a novel transcriptional target of CD146, TIMPv, to cancer via a<br />
unique axis that underpin CD146-suppressed BC progression; TIMPv<br />
is a potential target for guiding the development of novel therapeutic<br />
strategies for BC.<br />
P4-06-15<br />
Mifepristone modifies the tumor microenvironment increasing<br />
the therapeutic efficiency of low doses of Doxorubicin liposomes<br />
or paclitaxel-albumin nanoparticles in a murine model of breast<br />
cancer.<br />
Sequeira GR, Vanzulli SI, Lamb CA, Rojas PA, Lanari C. Instituto<br />
de Biología y Medicina Experimental, Ciudad Autónoma de Buenos<br />
Aires, Argentina; Academia Nacional de Medicina, Ciudad Autónoma<br />
de Buenos Aires, Argentina<br />
Chemotherapy is the standard treatment for metastatic breast cancer<br />
today. To overcome undesired side effects and improve drug efficacy in<br />
tumor cells, different nanoparticle formulations have been developed.<br />
Paclitaxel has been bound with human albumin (Nab-paclitaxel), and<br />
pegylated liposomes have been developed for doxorubicin delivery<br />
(PEG-LD). The aim of our study was to evaluate the effect of these<br />
therapeutic agents in experimental mammary carcinomas expressing<br />
different ratios of progesterone receptor (PR) isoforms and to evaluate<br />
the effect of combined treatments of chemotherapeutic agents with<br />
the antiprogestin mifepristone (MFP). Nab-paclitaxel (Abraxane,<br />
Abraxis), at a dosage of 30 and 60 mg/kg body weight administered<br />
in three doses every four days, completely inhibited the growth of the<br />
antiprogestin-resistant C4-2-HI mouse mammary carcinoma, which<br />
is associated with high levels of PR isoform B (PR-B) expression.<br />
C4-HI, an antiprogestin-responsive mouse tumor that shows high<br />
levels of PR isoform A (PR-A) expression, was not inhibited by<br />
the low Nab-paclitaxel dose. However, the combination of MFP<br />
(6 mg silastic pellet) with Nab-paclitaxel improved the efficacy of<br />
both single treatments. Similar experiments were conducted using<br />
www.aacrjournals.org 377s<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
PEG-LD (Doxopeg; Laboratorios Raffo). In this case, all tumors<br />
tested (C4-HI, CC4-3-HI, 59-2-HI and C4-2-HI) were all highly<br />
responsive to high (18 mg/kg/week) or low (9 mg/kg/week) PEG-LD<br />
doses. When PEG-LD concentrations were lowered to 4.5 mg/kg/<br />
week and they were combined with MFP, an improved response was<br />
observed with combined treatments only in tumors with high PR-A<br />
levels (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
June 2008]. After assessing how common was CRG disregulation in<br />
different epithelial cancers, via comparative genomic analysis of CRG<br />
expression patterns in tumor vs. normal tissue, we found that 34 CRGs<br />
(∼35%) were significantly disregulated in breast cancer. Because of<br />
the need for novel intervention targets in basal-like breast cancer, we<br />
focused our functional analysis there. We have tested a subset of CRGs<br />
disregulated in breast tumors for their contribution to malignancy in<br />
basal-like breast cancer cells, re-setting CRG levels toward normal<br />
cell levels by stable cDNA expression or shRNA-mediated knockdown<br />
and testing tumor formation capacity of perturbed cells. Our<br />
studies reveal that CRGs play an essential role in controlling tumor<br />
formation of basal-like breast cancer cells, with significant reductions<br />
in tumor volume, and in some cases reduced tumor incidence, upon<br />
CRG modulation. Disruption of cell behavior appears to be limited to<br />
cancer cells, as non-transformed mammary cells harboring analogous<br />
perturbations retain capacity to form acinar structures in 3D culture.<br />
Several FDA approved pharmacological agents, identified to reverse<br />
the CRG expression pattern, display inhibitory effects on basal-like<br />
breast cancer cell lines, with minimal effects on non-transformed<br />
cells. CRGs thus represent cancer cell-specific vulnerabilities in basallike<br />
breast cancer, providing novel and unexpected opportunities for<br />
intervention against this difficult-to-target disease.<br />
P4-06-19<br />
Astemizole and calcitriol: A novel targeted therapeutic strategy<br />
for breast cancer<br />
García J, García R, Villanueva O, <strong>San</strong>tos N, Barrera D, Avila E,<br />
Ordaz D, Halhali A, Camacho J, Larrea F, Díaz L. Instituto Nacional<br />
de Ciencias Médicas y Nutrición Salvador Zubirán, México, DF,<br />
Mexico; Centro de Investigación y de Estudios Avanzados del I.P.N.,<br />
México, DF, Mexico<br />
Calcitriol antiproliferative effects include inhibition of the oncogenic<br />
ether-à-go-go-1 potassium channel (Eag1), which expression and<br />
activity are necessary for cell cycle progression and tumorigenesis.<br />
Astemizole, a new promising antineoplastic drug, targets Eag1 by<br />
blocking ion currents. In vitro, we showed that astemizole synergized<br />
calcitriol antiproliferative effects by downregulating CYP24A1, the<br />
enzyme that degrades calcitriol, and upregulating the vitamin D<br />
receptor (VDR), which mediates calcitriol actions. In this study we<br />
investigated the antineoplastic effect of astemizole and calcitriol in a<br />
murine model xenografted with T-47D and invasive ductal carcinomaderived<br />
breast cancer cells (IDC). Tumor-bearing nude mice were<br />
treated with oral astemizole (50 mg/kg/day) and/or i.p. calcitriol<br />
(30 µg/kg/twice a week) during 3 weeks. Astemizole and calcitriol<br />
significantly inhibited, while the coadministration of both drugs<br />
further reduced, tumor growth compared to untreated controls. These<br />
results were supported by immunohistochemistry studies of Ki-67, a<br />
proliferation marker, which revealed less staining in tumors from mice<br />
with the co-treatment compared to controls and calcitriol or astemizole<br />
alone. In a similar manner as reported in vitro, we observed that the<br />
concomitant administration of astemizole and calcitriol upregulated<br />
VDR tumor expression (P < 0.05). Conclusion: Coadministration of<br />
calcitriol and astemizole increased the antineoplastic effects of both<br />
drugs. Our results indicate that astemizole may improve calcitriol<br />
bioactivity by upregulating tumoral VDR. In addition, the findings<br />
in this study suggest that VDR-negative tumors could be sensitized<br />
to calcitriol antineoplastic effects by concomitant administration with<br />
astemizole, which would also allow for less calcitriol dosing without<br />
sacrificing overall therapeutic efficacy. Herein we suggest a novel<br />
combined adjuvant therapy for the management of breast cancer<br />
tumors. These results provide scientific bases for further studies<br />
designed to test both compounds simultaneously in patients bearing<br />
solid or metastatic tumors.<br />
P4-07-01<br />
The Class I Selective PI3K Inhibitor GDC-0941 Enhances<br />
the Efficacy of Docetaxel in Human <strong>Breast</strong> <strong>Cancer</strong> Models by<br />
Increasing the Rate of Apoptosis<br />
Wallin JJ, Guan J, Prior WW, Lee LB, Ross L, Belmont LD, Koeppen<br />
H, Belvin M, Sampath D, Friedman LS. Genentech, Inc., South <strong>San</strong><br />
Francisco, CA<br />
Docetaxel (DTX) is commonly used as a front-line treatment option<br />
for breast cancer but many patients ultimately relapse and succumb to<br />
disease progression. Phosphatidylinositol 3-kinases (PI3K) are lipid<br />
kinases that regulate breast tumor cell growth, migration and survival.<br />
Given that phosphatidylinositol 3-kinase (PI3K) is frequently<br />
activated in breast cancer and induces chemo-resistance, it is an<br />
attractive target for combination therapy with standard of care drugs<br />
such as DTX. The current study was intended to determine if GDC-<br />
0941, an orally bioavailable class I selective PI3K inhibitor, enhances<br />
the anti-tumor activity of DTX in human breast cancer models in vitro<br />
and in vivo. A panel of 25 breast tumor cell lines representing luminal,<br />
HER2+ and basal sub-types were treated with GDC-0941, DTX or<br />
the combination of both drugs and assayed for cellular viability,<br />
modulation of PI3K pathway markers and apoptosis induction. The<br />
combination of GDC-0941 and DTX decreased the cellular viability<br />
of breast tumor cell lines in vitro but with variable drug synergy.<br />
The addition of both drugs resulted in stronger synergistic effects in<br />
a sub-set of tumor cell lines that was not predicted by breast cancer<br />
sub-type or mutations within the PI3K pathway. Human xenografts<br />
of breast cancer cell lines and patient-derived tumors were utilized<br />
to assess efficacy of GDC-0941 and DTX in vivo. In these models,<br />
the best combination efficacy was detected when the two drugs were<br />
dosed within 1 hour of each other. We also observed that GDC-0941<br />
increased the rate of apoptosis in cells arrested in mitosis upon cotreatment<br />
with DTX. Our data provides a preclinical rationale for<br />
evaluating GDC-0941 in combination with DTX for breast cancer<br />
treatment.<br />
P4-07-02<br />
Withdrawn by Author<br />
P4-07-03<br />
Rapamycin and Dalotuzumab in combination inhibit parental<br />
and endocrine resistant breast cancer cells.<br />
Beckwith H, Fettig-Anderson L, Yueh N, Douglas Y. University of<br />
Minnesota, Minneapolis, MN<br />
The PI3K/Akt/mTOR pathway is involved in breast cancer resistance<br />
to endocrine therapy. Inhibitors of mTOR have been shown to have<br />
benefit for patients with ER positive tumors that have developed<br />
endocrine therapy resistance. Inhibition of mTOR triggers a negative<br />
feedback loop resulting in enhanced phosphorylation of Akt and<br />
subsequent breast cancer cell proliferation via the IGF signaling<br />
pathway. Therefore, blockade of both IGF-1R and mTOR may be<br />
necessary to completely suppress this pathway. Our laboratory studied<br />
the effect of dual inhibition of mTOR and IGF-1R with rapamycin<br />
and dalotuzumab respectively on parental and endocrine resistant<br />
MCF-7 breast cancer cell tumorigenesis.<br />
Immunoblotting demonstrates parental MCF-7L cells treated with<br />
rapamycin alone demonstrate increased phosphorylation of Akt.<br />
www.aacrjournals.org 379s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Inhibition of phosphorylation of Akt can be achieved with combined<br />
treatment with rapamycin and dalotuzumab at concentrations of 5 nM<br />
and 2 µg/mL respectively. In addition to inhibition of pAkt, combined<br />
treatment inhibits phosphorylation of S6K1 and the translational<br />
repressor protein, 4eBP1. Furthermore, MTT proliferation assay and<br />
soft agar assay demonstrate inhibition of parental cell proliferation and<br />
colonization respectively with combined rapamycin and dalotuzumab<br />
treatment. In order to examine the effect of combination therapy in<br />
endocrine resistant cell lines, we established tamoxifen resistant<br />
(TamR) and long term estrogen deprived (LTED) cell lines. TamR<br />
cells were generated by culturing MCF-7L cells in the presence<br />
of tamoxifen for more than 1 year. LTED cells were generated by<br />
culturing MCF-7L cells in the absence of estrogen for more than 6<br />
months. Proliferation of TamR and LTED cells treated with rapamycin<br />
at a concentration of 5nM and dalotuzumab at a concentration of 2µg/<br />
mL in combination was significantly inhibited. We conclude that<br />
combination of IGF1R and mTOR inhibition might be necessary to<br />
inhibit endocrine resistant breast cancers. Ongoing clinical trials will<br />
test this combination of drugs.<br />
P4-07-04<br />
Methioninase cell-cycle synchronization potentiates chemotherapy<br />
for breast cancer<br />
Yano S, Li S, Han Q, Tan Y, Fujiwara T, Hoffman RM. Anti<strong>Cancer</strong><br />
Inc., <strong>San</strong> Diego, CA; Okayama University Graduate School of<br />
Medicine and Dentistry, Okayama, Japan; University of California,<br />
<strong>San</strong> Diego, CA<br />
Deprivation of methionine selectively arrests cancer cells during late<br />
S-phase (Proc. Natl. Acad. Sci. USA 77, 7306-7310, 1980; Biochim.<br />
Biophys. Acta, Reviews on <strong>Cancer</strong> 738, 49-87, 1984), where they<br />
are highly sensitive to chemotherapy drugs which damage DNA (J.<br />
Natl. <strong>Cancer</strong> Inst. 76, 629-639, 1986). <strong>Cancer</strong> cells, transformed to<br />
express different color fluorescent reporters during specific phases<br />
of the cell cycle (Cell 132, 487-498, 2008), were used to monitor the<br />
onset of the S/G 2 -phase block due to methionine deprivation effected<br />
by recombinant methioninase (rMETase). The S/G 2 -phase blocked<br />
cancer cells fluoresced yellow or green in contrast to cancer cells in<br />
G 1 which fluoresced red. <strong>Cancer</strong> cells, including MCF-7 breast cancer,<br />
synchronously blocked in S/G 2 -phase by rMETase, were identified<br />
by their yellow-green fluorescence and allowed to accumulate to the<br />
maximum extent. At the point of maximum yellow/green cells in<br />
the culture, the cells were administered chemotherapy drugs which<br />
interact with DNA or block DNA synthesis such as doxorubicin. We<br />
termed this procedure color-coded chemotherapy (CCC). CCC was<br />
highly effective against the cancer cells (90% cell kill). In contrast,<br />
treatment of cancer cells with drugs only, and without rMETaseeffected<br />
S/G 2 -phase synchrony, led to the majority of the cancer cell<br />
population being blocked in G 1 phase (red fluorescent) where they<br />
were resistant to the drugs (40% cell kill). CCC, which identifies,<br />
by fluorescent color, when cancer cells are blocked in S/G 2 -phase<br />
by a unique cell-cycle-blocking agent, rMETase, demonstrates<br />
the potential of cell-synchronization-based chemotherapy for<br />
breast cancer.<br />
P4-07-05<br />
MEDI3379, an antibody against HER3, is active in HER2-driven<br />
human breast tumor models<br />
Xiao Z, Rothstein R, Carrasco R, Wetzel L, Kinneer K, Chen H, Tice<br />
D, Hollingsworth R, Steiner P. MedImmune, LLC, Gaithersburg, MD<br />
HER3 (ERBB3) is a member of the EGFR/HER family of receptor<br />
tyrosine kinases (RTK), consisting of EGFR, HER2, HER3 and<br />
HER4. Unlike the other HER family members, HER3 lacks intrinsic<br />
tyrosine kinase activity and therefore needs to form heterodimers<br />
with EGFR, HER2 or other kinase-proficient RTKs to be functionally<br />
active. Dimerization is induced by overexpression of EGFR or HER2<br />
in a ligand-independent (LI) manner. In this process HER3 acts as<br />
a driver in divergent cancer types including HER2-positive breast<br />
cancer (BC) via induction of the PI3K-AKT pathway. Alternatively,<br />
heregulin (NRG1/HRG), the major HER3 ligand, induces a<br />
conformational shift in HER3 which leads to dimer formation with<br />
a partner RTK in a ligand-dependent (LD) manner.<br />
We have developed an antagonistic human monoclonal antibody<br />
against HER3, termed MEDI3379, and tested it in multiple breast<br />
cancer cell lines. We observed effective suppression of constitutive<br />
pHER3 and pAKT with MEDI3379, leading to anti-proliferation<br />
effects in cell culture models. Preclinical evaluation of MEDI3379<br />
demonstrated antitumor activity in several orthotopic BC xenografts in<br />
nude mice which did not express HRG. For example, the BC xenograft<br />
model BT474 with amplified HER2 responded to MEDI3379 (65%<br />
dTGI). In conclusion, our findings with targeting of HER3 in mouse<br />
models support continued development of MEDI3379 for cancer.<br />
P4-08-01<br />
PI3K/mTOR inhibition overcomes in vitro and in vivo trastuzumab<br />
resistance independent of feedback activation of pAKT<br />
O’Brien NA, McDonald K, Tong L, Von Euw E, Conklin D, Kalous O,<br />
Di Tomaso E, Schnell C, Linnartz R, Hurvitz SA, Finn RS, Hirawat<br />
S, Slamon DJ. UCLA, Los Angeles, CA; Novartis Pharmaceuticals,<br />
Cambridge, MA; Novartis Pharmaceuticals, Basel, Switzerland<br />
Background: Aberrant activity of the PI3K/mTOR pathway has been<br />
implicated in resistance to trastuzumab and anti-hormonal therapy for<br />
HER2-amplified and ER-positive breast cancer, respectively. Previous<br />
studies in our laboratory and others have shown that increased PI3K/<br />
mTOR signaling, either through PTEN loss or activating PIK3CA<br />
mutations, can confer resistance to trastuzumab therapy. In this study,<br />
we assessed the potential of targeting the PI3K/mTOR pathway in<br />
overcoming both de novo and acquired trastuzumab resistance.<br />
Materials and Methods: The in vitro activity of the pan-PI3K<br />
inhibitor BKM120, the mTORC1 inhibitor RAD001 and the dual<br />
PI3K/mTORC1/2 inhibitor BEZ235 were evaluated in a panel of<br />
49 human breast cancer and immortalized cell lines. The in vivo<br />
activity of these molecules was assessed in six cell line xenografts<br />
models representing, ER+/HER2- (KPL-1, ZR75-1), ER+/HER2+<br />
(UACC812, MDA361), ER-/HER2+ (SUM190), PIK3CA mutant<br />
(SUM190, MDA361), PTEN-null (ZR75-1) and trastuzumab resistant<br />
(BT-TR) breast cancer. Finally, the effect of PI3K/mTOR inhibition<br />
on feedback activation of PI3K signaling and compensatory pathways<br />
was measured by Western blot, immunohistochemistry (IHC) and<br />
reverse phase protein analysis (RPPA) of control and treated cell<br />
lysates/tumors.<br />
Results: Using a sensitivity cut-off of an IC 50 of < 1 µmol/L, 16 of<br />
the 18 HER2-amplified breast cancer cell lines and 8 of 10 cell lines<br />
with activating mutations in PIK3CA were sensitive to the pan-<br />
PI3K inhibitor BKM120. BEZ235 showed the most potent efficacy<br />
across the panel with IC 50 s < 100 nmol/L for each of the 49 cell<br />
lines tested. The HER2-amplified/PIK3CA mutant cell lines were<br />
also unexpectedly sensitive to the mTORC1 inhibitor RAD001, this<br />
was despite the silencing of mTORC1 signaling being followed by a<br />
feedback increase in phospho-AKT signaling. Furthermore, each of<br />
these molecules showed remarkable in vivo activity across the panel<br />
of xenografts models. BKM120, RAD001 and BEZ235 induced both<br />
tumor stabilization and regression independent of PTEN, PI3K, ER<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
380s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
and HER2 status. Pharmacodynamic analysis of tumor tissue revealed<br />
that BEZ235 and RAD001 both inhibited mTORC1 signaling as<br />
indicated by a reduction in the levels of phosphorylated ribosomal<br />
protein S6 (pS6). However, in contrast to BKM120 and BEZ235,<br />
RAD001 did not induce a reduction in the levels of pAKT (S473<br />
or TH308) yet showed comparable in vivo efficacy to each of these<br />
molecules. Finally, combined targeting of HER2 and PI3K/mTOR in<br />
vitro increased the anti-proliferative activity of the molecules and led<br />
to an increased induction of apoptosis. The efficacy of these molecules<br />
(alone or in combination with trastuzumab) was assessed in a model of<br />
in vivo trastuzumab resistance generated through long-term treatment<br />
of the trastuzumab sensitive BT474 cells (BT-TR). All PI3Ki induced<br />
complete inhibition of tumor proliferation in monotherapy, while the<br />
combination of trastuzumab and each of these molecules induced<br />
tumor regression in the trastuzumab resistant tumors.<br />
Discussion: These pre-clinical data indicate that targeting the PI3K/<br />
mTOR pathway either alone or in combination with trastuzumab is<br />
effective strategy for overcoming trastuzumab resistance.<br />
P4-08-02<br />
Reactivation of oncogenic signaling through mTOR inhibitorsinduced<br />
feedback adaptations.<br />
Rodrik-Outmezguine V, Chandarlapaty S, Poulikakos P, Scaltriti M,<br />
Baselga J, Rosen N. MSKCC, New York, NY; MGH, Charlestown, MA<br />
mTORC1 inhibitors (or rapalogs) relieve feedback inhibition of<br />
receptor tyrosine kinases (RTKs) and cause mTORC2-dependent<br />
phosphorylation of AKT S473 and activation of AKT kinase and<br />
signaling. The relief of feedback inhibition of mTORC2/AKT<br />
signaling has been shown to abolish the antitumor activity of rapalogs<br />
and has often been proposed as a potential mechanism of resistance<br />
to these compounds.<br />
mTOR kinase inhibitors that inhibit both mTORC1 and mTORC2<br />
complexes have now been developed to circumvent these problems.<br />
mTOR kinase inhibitors block mTORC1 and mTORC2 and thus, do<br />
not cause the mTORC2 activation of AKT observed with rapamycin.<br />
We now show, however, that these novel classes of drugs have a<br />
biphasic effect on AKT. Inhibition of mTORC2 leads to AKT S473<br />
dephosphorylation and a rapid but transient inhibition of AKT T308<br />
phosphorylation and AKT signaling. However, inhibition of mTOR<br />
kinase, as observed with rapalogs, also relieves feedback inhibition of<br />
RTKs leading to subsequent PI3K activation and rephosphorylation of<br />
AKT but only at T308, which is sufficient to reactivate AKT activity<br />
and signaling. Thus, catalytic inhibition of mTOR kinase leads to a<br />
new steady state characterized by profound inhibition of mTORC1 and<br />
accumulation of activated AKT phosphorylated on T308 but not S473.<br />
We now confirm that the reactivation of AKT signaling is a mechanism<br />
of acquired resistance to rapalogs. We observe an induction of<br />
phospho-RTKs in rapamycin-resistant cells leading to both AKT<br />
and ERK signaling pathway activation enhancing cell survival.<br />
Combined inhibition of mTOR and the induced RTKs can prevent<br />
AKT reactivation and fully abolishes AKT signaling. These results<br />
reveal the adaptive capabilities of oncogenic signaling networks,<br />
highlighting the possible need for combinatorial approaches to block<br />
feedback-regulated pathways.<br />
P4-08-03<br />
The impact of the heregulin-HER receptor signaling axis on<br />
response to HER tyrosine kinase inhibitors.<br />
Gwin WR, Liu L, Zhao S, Xia W, Spector NL. Duke University,<br />
Durham, NC<br />
Background: HER receptor tyrosine kinases (EGFR/HER1; HER2;<br />
HER3; HER4) and their soluble ligands represent a robust system<br />
involved in the regulation of a diverse array of cellular processes.<br />
Deregulation of HER receptors, notably HER2, has been linked<br />
to the initiation and progression of breast cancer and other solid<br />
tumors. Relatively less is known about the role of HER receptor<br />
soluble ligands in tumorigenesis and responsiveness to HER targeted<br />
therapies. Here we will discuss the impact of the HER3 ligand<br />
heregulin (HRG) on the sensitivity of breast cancers to HER tyrosine<br />
kinase inhibitors (TKIs), and identify TKI strategies to treat HRGdriven<br />
breast cancers. Methods: The effects of exogenous HRG<br />
(50ng/ml) on the antitumor activity of a panel of TKIs with different<br />
enzymatic properties e.g. a reversible, selective inhibitor (lapatinib)<br />
and irreversible, pan-HER inhibitors (neratinib; CI-1033) were<br />
assessed in HER2+ breast cancer (BC) cell lines. The concentration<br />
of TKIs used was in the 1-2.5 uM range, and cells were treated over<br />
a 72 hr course. Vehicle treatment alone served as controls. The impact<br />
of the above mentioned treatments on total HER receptor and specific<br />
EGFR, HER2, and HER3 phosphotyrosine sites, in addition to the<br />
phosphorylation state of components of downstream MAPK and PI3K<br />
signaling pathways was analyzed through western blot. In addition<br />
to studying the effects of exogenous HRG, the impact of TKIs on a<br />
model of triple negative BC (TNBC) known to produce HRG in an<br />
autocrine manner was also evaluated. QRT-PCR was used to assess<br />
the effects of TKIs on HER receptor mRNA levels. Results: Lapatinib<br />
inhibited proliferation and phosphorylation of EGFR, HER2, HER3,<br />
and downstream MAPK and PI3K signaling pathways in HER2+<br />
SKBR3 and BT474 cell lines. Pre-treatment with HRG abrogated the<br />
antitumor effects of a therapeutic concentration of lapatinib (1 uM),<br />
and reversed the inhibitory effects of lapatinib on the phosphorylation<br />
of HER receptors and components of their downstream signaling<br />
pathways e.g. Erk1/2 and Akt. Neratinib also blocked proliferation<br />
and phosphorylation in HER2+ BC cells. In contrast to lapatinib,<br />
the antitumor effects of neratinib were not reversed by exogenous<br />
HRG. Interestingly, treatment with neratinib and similar pan-HER<br />
irreversible TKIs, but not reversible TKIs, resulted in loss of HER2<br />
and EGFR protein expression. QRT-PCR was used to evaluate if<br />
this effect was at the level of transcription. Furthermore, neratinib<br />
inhibited cell proliferation and blocked EGFR signaling in a TNBC<br />
model driven by autocrine produced HRG. Conclusions: Our findings<br />
suggest that HRG is a mediator of therapeutic resistance to lapatinib in<br />
HER2+ and TNBC. Neratinib demonstrates profound effects on HER<br />
signaling by markedly reducing HER2 and EGFR protein expression<br />
and blocking the pro-tumorigenic effects of autocrine or paracrine<br />
expression of HRG. In contrast to HRG, we previously showed that<br />
EGF, an EGFR specific ligand did not reverse the antitumor effects of<br />
lapatinib in breast cancer cells. Thus, the selection of HER targeted<br />
therapies in a given tumor should take into account not only the<br />
HER receptor expression profile, but also the presence of autocrine<br />
or paracrine derived ligands activating HER receptors.<br />
www.aacrjournals.org 381s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-08-04<br />
Abcc10 status affects proliferation, metastases and tumor<br />
sensitivity<br />
Domanitskaya N, Paulose C, Jacobs J, Foster K, Hopper-Borge E.<br />
Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA<br />
Background: It has been proposed that therapy-induced overexpression<br />
of ATP-binding cassette (ABC) drug efflux pumps promotes resistance<br />
in many drug-treated cancers. While early studies focused on<br />
overexpression and activity of the P-glycoprotein (Pgp) pump,<br />
a structurally distinct group of ABC efflux pumps, known as the<br />
Multidrug Resistance Proteins (MRPs;ABCCs), have been gaining<br />
increasing attention as alternative sources of resistance. There are 9<br />
ABCC family members (ABCC1-6, 10-12), and we have previously<br />
shown that ABCC10 is unique because it confers resistance to a wide<br />
variety of anticancer agents including taxanes, vinca alkaloids and<br />
nucleoside-based analogs (Hopper-Borge et al, 2004, Hopper-Borge<br />
et al, 2009). Importantly we have shown that Abcc10 null mice are<br />
sensitized to taxanes (Hopper-Borge et al, <strong>Cancer</strong> Research, 2011).<br />
This is the first transporter whose loss results in in vivo tissue<br />
sensitivity to taxanes.<br />
Methods & Results: We recently bred a PyVmT mammary tumor<br />
model to our Abcc10 gene disrupted mice to investigate Abcc10’s<br />
in vivo activities regarding breast cancer resistance mechanisms.<br />
We have observed that Abcc10+/+ (WT) status limits the rate of<br />
tumorigenesis (p=0.020) and that WT tumors are more metastatic<br />
compared to Abcc10-/- (KO), (p=0.0489). To better understand the<br />
potential resistance mechanisms in this model we determined the<br />
expression levels of relevant transporters with qRT-PCR and found no<br />
significant differences between WT and KO. The PI3K-AKT-mTOR,<br />
a major signaling pathway involved in breast cancer progression has<br />
been connected to ABCCs (Tazzari, et al, 2007), and we observed<br />
upregulation of AKT in KO versus WT mammary tumor cell lines via<br />
western analyses. Therefore, we decided to ask if Abcc10 status affects<br />
proliferation, attachment, and/or migration (CyQuant, Invitrogen and<br />
xCELLigence, Roche). We showed that WT cell lines grow 3 times<br />
slower compared to KO. For migration kinetic we observed that KO<br />
cell lines were more active compared to WT.<br />
To determine the impact of Abcc10 loss in vivo we injected SCID<br />
mice with 3 WT or KO mammary tumor derived cell lines and<br />
treated tumors with docetaxel or vehicle. Tumors derived from WT<br />
and KO mice were both responsive to docetaxel (WT, p=0.003 and<br />
KO, p=0.001). However, over 21 days, the WT tumors were reduced<br />
by 50% compared to KO reduction of 86%. Kaplan-Meier survival<br />
analysis of treated/untreated SCID mice reveals that Abcc10 status is<br />
related to a poorer prognosis (KO p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
P4-08-06<br />
Notch-dependent Regulation of Novel Genes Associated with<br />
Trastuzumab Resistance<br />
Osipo C, Baumgartner A, Zlobin A, O’Toole M. Loyola University<br />
Chicago, Maywood, IL<br />
Background: We have shown previously that Notch-1 is critical for the<br />
development and maintenance of trasuzumab or lapatinib resistance<br />
in HER2 positive breast cancer cell lines. Here we sought to identify<br />
the critical genes that are regulated by Notch to promote anti-HER2<br />
targeted resistance.<br />
Methods: We measured expression of 84 known breast cancerassociated<br />
transcripts using a real-time PCR array in both trastuzumab<br />
sensitive and resistant BT474 cell lines. A 4 fold increase or decrease<br />
in transcripts levels were measured to be statisitically significant.<br />
To confirm the change in levels, we designed primers to each<br />
gene of interest and repeated the PCR at least three independent<br />
times. Furthermore, we specifically asked whether Notch-1 or<br />
it’s transcriptional mediator, CBF-1, directly regulated any of the<br />
identified genes in HER2 positive breast cancer cells using a genetic<br />
knocked down approach. An ANOVA for multiple comparisons was<br />
used to compute statistical significance.<br />
Results: We identified more than 4 fold increase in APC, ABCG2,<br />
ABCB1, Gata-3, Bcl-2, Id2, and HRG-2 transcripts in trastuzumab<br />
resistant versus sensitive cells. Conversley, Gli1 was downregulated<br />
in resistant versus sensitive cells. Interestingly, siRNA directed against<br />
Notch-1 or CBF-1 decreased ABCG2 and Gata-3, but conversely<br />
increased ABCB1 and HRG-2 in resistant cells.<br />
Conclusions: Our findings demonstrate APC, ABCG2, ABCB1,<br />
Gata-3, Bcl-2, Id2, and HRG-2 transcripts are signficantly increased<br />
in trastuzumab resistant breast cancer cells compared to sensitive<br />
cells. More importantly, Notch-1 or it’s direct transcriptional activator<br />
CBF-1 may contribute to traztuzumab resistance by directly regulating<br />
critical genes that contribute to multidrug resistance: ABCB1 and<br />
ABCG2 and/or genes associated with stem cell survival: Gata-3<br />
and HRG-2.<br />
P4-08-07<br />
Novel insight into the tumor “flare” phenomenon and lapatinib<br />
resistance<br />
Piede JA, Zhao S, Liu L, Lyerly HK, Osada T, Wang T, Xia W, Spector<br />
N. Duke University Medical Center, Durham, NC<br />
BACKGROUND: Resistance to lapatinib generally develops in<br />
approximately half of patients within one year of initiating treatment.<br />
When lapatinib is withdrawn, there is often a rapid progression of<br />
disease which is associated with high mortality rates. This “flare”<br />
phenomenon has also been observed upon discontinuation of other<br />
tyrosine kinase inhibitors (TKIs) in lung cancer, renal cell carcinoma,<br />
and gastrointestinal stromal tumors.<br />
METHODS: Using the HER2+ cell lines SKBR3 and BT474, we<br />
developed both in vitro and in vivo models demonstrating lapatinib<br />
resistance and the tumor “flare” phenomenon. Parental HER2+ cell<br />
lines were gradually exposed to increasing doses of lapatinib (100nM<br />
to 5uM) to develop a lapatinib-resistant form which was ultimately<br />
maintained in 1uM of lapatinib. Lapatinib-”released” cell lines were<br />
developed by removing lapatinib exposure from resistant cell lines<br />
and allowing the cells to grow for at least two weeks. Cell lines were<br />
grown in vitro using traditional monolayer cell culturing techniques<br />
and mammosphere technology. A comprehensive analysis of parental,<br />
lapatinib-resistant, and lapatinib-released cell lines was performed<br />
using microscopy, protein/phosphoprotein analysis, cell cycle, cancer<br />
stem cell markers by FACS, and invasion assays. Parental cells served<br />
as the control in all experiments. In vivo models were performed by<br />
injecting 10,000 cells of parental, resistant, and released cell lines in<br />
the mammary fat pads of SCID mice. Tumors were surgically resected<br />
after approximately sixty days and volume recorded. All experiments<br />
were repeated three times and calculated for statistical significance.<br />
RESULTS: Cell cycle analysis and proliferation assays demonstrate<br />
that lapatinib-resistant and released cell lines continue to proliferate<br />
despite the addition of 1uM lapatinib. Released cells also demonstrate<br />
less of a response to retreatment with lapatinib. Tumor volume of<br />
lapatinib-released cell lines were significantly larger than parental<br />
and resistant counterparts [parental: 39.9mm 3 , SD 9.48; resistant:<br />
71.8mm 3 , SD 62.33; released: 943.4mm 3 , SD 100.1] and this<br />
difference was statistically significant (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
their proliferation and arrested them at the G1 phase, by inactivating<br />
the RB/E2F pathway, decreasing the number of new origins and<br />
eventually reducing the polyploidy population.<br />
Cell survival assays after different chemotherapeutic drug treatment<br />
showed that overexpression of the exogenous HOXC10 in MCF10A<br />
led to less susceptibility to most drugs. This was partially due to a<br />
protection from apoptosis by upregulating and activating the antiapoptotic<br />
machinery such as the NF-kb pathway. Further investigation<br />
revealed the involvement of HOXC10 in DNA repair (and not initial<br />
response), especially after DNA crosslink damage. Interestingly, the<br />
binding of HOXC10 to CDK7 in a region outside its homeodomain<br />
activates CDK7 activity towards RNA polymerase II mainly in<br />
response to DNA damage. Since HOX genes are difficult to target<br />
therapeutically, one potential approach to overcome chemoresistance<br />
in HOXC10 overexpressing cells is by including CDK7 inhibitors<br />
(already in clinical trials).<br />
All these results were confirmed in the SUM159 model which stably<br />
expresses a HOXC10-shRNA.<br />
Finally, HOXC10 was found to be significantly overexpressed in<br />
MCF7 isogenic cell lines gradually selected to be resistant to some<br />
chemotherapeutic drugs. By knocking down HOXC10 in these<br />
sublines, resistance to the drug was reduced. Further, SUM159 and<br />
MDAMD231 xenografts that were treated with chemotherapy over<br />
weeks and that show partial to no response tend to have a higher<br />
expression of HOXC10.<br />
Conclusion: This study shows that HOXC10, a homeobox protein<br />
previously shown to be regulated during the cell cycle and to have a<br />
positive effect on proliferation, is overexpressed in the majority of<br />
breast cancers. This upregulation may have clinical implications since<br />
cells with higher expression of HOXC10 tend to have more genomic<br />
instability and activation of anti-apoptotic and DNA repair pathways,<br />
which eventually modulate the response to some chemotherapy drugs.<br />
P4-08-09<br />
Targeting Thyroid Receptor b in Estrogen Receptor Negative<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Gu G, Covington K, Rechoum Y, O’Malley B, Mangelsdorf D, Minna<br />
J, Webb P, Fuqua S. Baylor College of Medicine, Houston, TX; UT<br />
Southwestern Medical Center; The Methodist Hospital Research<br />
Institute<br />
Background:<br />
The treatment of estrogen receptor (ER)-negative breast cancer (BC)<br />
is a major clinical problem due to the lack of useful therapeutic targets.<br />
Nuclear receptors (NRs) are potential targets in these patients because<br />
they regulate global transcriptional events and many already have<br />
agonists/antagonists available.<br />
Material and Methods:<br />
We used microarray analysis of 227 ER-negative tumors to identify<br />
NR targets, and performed hierarchical clustering using 41 NRs.<br />
Expressed receptors were scored using prediction analysis of<br />
microarrays (PAM) across clustered groups. Cell lines were matched<br />
to subtypes using previously described data (Neve et al. 2006).<br />
Candidate gene expression levels were confirmed by qRT-PCR<br />
using TaqMan probes. pGIPZ lentiviral vectors encoding shRNA<br />
were used to knockdownselected candidates. MTT and soft agar<br />
assays were used to measure chemosensitivity and growth following<br />
treatment with Docetaxel (Doc), Doxorubicin (Dox), or Cisplatin<br />
(Cis). Statistical analysis was performed using Red-R.<br />
Results:<br />
The 41 NRs clustered tumors into 5 groups. For each group we<br />
selected genes representing the highest ranked discriminators, and<br />
examined their effects in cell lines matching each groups’ gene<br />
signature. Thyroid hormone receptor b (THRβ) was selected from<br />
group V. The expression levels of this receptor were confirmed by<br />
qRT-PCR and Western blot analysis.<br />
Knockdown of THRβ in ER-negative HCC2185 cells rendered cells<br />
more resistant to all chemotherapeutics by using MTT assay. Similar<br />
results were confirmed in ER-negative MDA-MB-453 and HCC202<br />
cells. Knockdown of THRβ enhanced colony forming potential<br />
in anchorage-independent soft agar assays in MDA-MB-453 and<br />
HCC202 cells. Statistical analysis using clinical data from Sabatier et<br />
al. (BCRT 2011) showed that patients with low THRb have a worse<br />
clinical outcome. In order to translate these findings into the clinic,<br />
we treated cells with a specific THRβ agonists, GC-1 and KB-141.<br />
GC-1 inhibited cell growth in growth assays, and synergistic effects<br />
were observed when cells were treated with GC-1 and Docetaxel in<br />
combination. Re-expression of ERα protein was observed in ERnagative<br />
cells lines after treatment with GC-1 and KB141, suggesting<br />
that modulation of THRβ may also extend hormonal therapy to this<br />
hormonally insensitive group of patients.<br />
Conclusion:<br />
Clinical targeting of NRs in ER-negative BCs is a novel strategy since<br />
receptors can be specifically targeted with ligands. Our data suggest<br />
that chemotherapy response in ER-negative patients overexpressing<br />
THRβ could be enhanced with a THRβ agonist. Similarly, functional<br />
re-activation of ERα by activating THRβ might extend hormonal<br />
therapies to these patients as well.<br />
P4-08-10<br />
Systematic expression analysis of the genes related to drugresistance<br />
in isogenic docetaxel- and adriamycin-resistance breast<br />
cancer cell lines.<br />
Tang J, Li W, Zhong S, Xu J, Zhao J. Jiangsu <strong>Cancer</strong> Hospital,<br />
Nanjing, Jiangsu, China; Jiangsu <strong>Cancer</strong> Hospital, Nnajing, Jiangsu,<br />
China<br />
Background: Docetaxel (Doc) and Adriamycin (Adr) are two of the<br />
most effective chemotherapeutic agents in the treatment of breast<br />
cancer. However, their efficacy is often limited by the emergence<br />
of multidrug resistance (MDR). The purpose of this study was to<br />
investigate MDR mechanisms through analyzing systematically the<br />
expression changes of genes related to MDR in the induction process<br />
of isogenic drug resistant MCF-7 cell lines.<br />
Material and Methods: Isogenic resistant sublines selected at 100<br />
and 200nM docetaxel (MCF-7/100nM Doc and MCF-7/200nM<br />
Doc) or at 500 and 1500 nM adriamycin (MCF-7/500nM Adr and<br />
MCF-7/1500nM) were developed from human breast cancer parental<br />
cell line MCF-7/S, by exposing MCF-7/S to gradually increasing<br />
concentrations of docetaxel or adriamycin in vitro. Flow cytometry,<br />
MTT cytotoxicity assay and cell growth curves were preformed to<br />
demonstrate the MDR characteristics developed in sublines. Some<br />
key genes on the pathways related to drug resistance (including<br />
drug-transporters: MDR1, MRP1 and BCRP; drug metabolizingenzymes:<br />
CYP3A4 and GST pi; target gene: Topo IIα and β-tubulin<br />
III; apoptosis genes: Bcl-2 and Bax) were analyzed at RNA and protein<br />
expression levels by real time RT-qPCR and western blot, respectively.<br />
Results: MCF-7/100nM Doc and MCF-7/200nM Doc was 22- and<br />
37-fold resistant to docetaxel, and 18- and 32-fold to adriamycin,<br />
respectively. MCF-7/500nM Adr and MCF-7/1500nM Adr was 61-<br />
and 274-fold resistant to adriamycin, and 3- and 12-fold to docetaxel,<br />
respectively. Meantime, they also showed cross-resistance to the other<br />
anticancer drugs in different degree. Compared to sensitive MCF-<br />
7/S, RT-qPCR and Western blot results revealed that the expression<br />
of MDR1, MRP1, BCRP, Bcl-2 were elevated in both MCF-7/<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
384s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
Doc and MCF-7/Adr, and Topo IIα, Bax were down-regulated in<br />
both the sublines, while CYP3A4 and β-tubulin III were increased<br />
only in MCF-7/Doc and GST pi was increased only in MCF-7/<br />
Adr. Furthermore, these changes above were dose-dependent, i.e.<br />
acquirement of MDR is dependent on docetaxel or adriamycin<br />
concentrations in breast carcer model resistant MCF-7 cells.<br />
Conclusions: The established MCF-7/Doc or MCF-7/Adr has the<br />
typical MDR characteristics, which can be used as the models<br />
for resistance mechanism study. The acquired process of MCF-<br />
7/S resistance to docetaxel or adriamycin is gradual, and is also<br />
complicated with the various pathways involved in. There are some<br />
common mechanisms as well as drug-special mechanisms between<br />
MCF-7/Doc and MCF-7/Adr.<br />
P4-09-01<br />
Retrospective evaluation of precision of gene-expression-based<br />
signatures of prognosis and tumor biology in replicate surgical<br />
biospecimens from patients with breast cancer<br />
Barry WT, Marcom PK, Geradts J, Datto MB. Duke University<br />
Medical Center, Durham, NC<br />
Background: Numerous gene-expression signatures have been<br />
developed for breast cancer. However, assessments of their validity<br />
continue to largely ignore the impact of intratumor heterogeneity and<br />
technical variation on clinical utility. Here, the collection of replicate<br />
specimen in Barry et al (2010) is used to evaluate a broad collection<br />
of gene-expression signatures of prognosis and tumor biology.<br />
Methods: Eighteen patients with multiple frozen cores (one patient<br />
with quadruplicate, twelve with triplicate, and five with doublet<br />
samples) were previously identified in the Duke <strong>Breast</strong> SPORE<br />
tissue repository. Cores were assessed for percent invasive cancer<br />
cellularity, and tumor size, grade, and ER/PR status. RNA was<br />
extracted and hybridized to AffymetrixH133Plus2.0 microarrays.<br />
Expression signatures of prognosis and tumor biology were developed<br />
or translated to the Affymetrix platform using routines by Prat et al.<br />
(2012) and Haibe-Keins et al. (2012). Association between signatures,<br />
and precision among replicates are evaluated using Pearson and<br />
intraclass correlation. Coefficients are reported with 95% confidence<br />
intervals.<br />
Results: Among prognostic signatures, an imputed 70-gene signature<br />
of MammaPrint had the highest level of precision (ICC=0.96, 0.91-<br />
0.98); strong concordance is seen with Affymetrix-based PAM50<br />
risk-of-relapse (ICC=0.82, 0.65-0.92); 16 of 18 patients had constant<br />
subtype calls. Substantially lower concordance was seen in the<br />
GENIUS prognostic model (ICC=0.62, 0.35-0.82). In ER+ patients<br />
(n=13), two algorithms to impute the 21-gene model of OncotypeDX<br />
recurrence score were concordant (r =0.98, ICC= 0.90 and 0.83) and<br />
distinct from the GENIUS ER+ score (average r=0.74, ICC=0.78).<br />
Imputed models for the Rotterdam 76-gene model (+ER status),<br />
GGI (+grade), and ROR-T (+tumor size) showed lower levels of<br />
correlation (0.47
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
develop prognostic signatures for other cancer types, and are using<br />
similar multiplexed algorithms to develop gene signatures able to<br />
predict response to neoadjuvant therapy.<br />
P4-09-03<br />
Withdrawn by Author<br />
P4-09-04<br />
Gene expression profile that predict outcome of Tamoxifentreated<br />
estrogen receptor-positive, high-risk, primary breast<br />
cancer patients: a DBCG study.<br />
Lyng MB, Lænkholm A-V, Tan Q, Vach W, Gravgaard KH, Knoop<br />
A, Ditzel HJ. University of Southern Denmark, Odense, Denmark;<br />
Slagelse Hospital, Slagelse, Denmark; Odense University Hospital,<br />
Odense, Denmark; University Medical Center Freiburg, Germany<br />
Background<br />
Tamoxifen significantly improves outcome for estrogen receptorpositive<br />
(ER+) breast cancer, but the 15-year recurrence rate remains<br />
30%. The aim of this study was to identify gene profiles that accurately<br />
predicted the outcome of ER+ breast cancer patients who received<br />
adjuvant Tamoxifen mono-therapy.<br />
Methods<br />
Post-menopausal breast cancer patients diagnosed no later than 2002,<br />
being ER+ as defined by >1% IHC staining and having a frozen tumor<br />
sample with >50% tumor content were included. Tumor samples<br />
from 108 patients treated with adjuvant Tamoxifen were analyzed for<br />
the expression of 59 genes using quantitative-PCR. End-point was<br />
clinically verified recurrence to distant organs or ipsilateral breast.<br />
Gene profiles were identified using a model building procedure based<br />
on conditional logistic regression and leave-one-out cross-validation,<br />
followed by a non-parametric boostrap (1000x re-sampling). The<br />
optimal profiles were further examined in 5 previously-reported<br />
datasets containing similar patient populations that were either treated<br />
with Tamoxifen or left untreated (N=623).<br />
Results<br />
Three gene profiles were identified, the strongest being a 2-gene<br />
combination of BCL2-CDKN1A exhibiting an accuracy of 75% for<br />
prediction of outcome. Independent examination using 4 previouslyreported<br />
microarray datasets of Tamoxifen-treated patient samples<br />
(N=503) confirmed the potential of BCL2-CDKN1A (average<br />
accuracy: 68%, range: 53%-85%). The predictive value was<br />
further determined by comparing the ability of the genes to predict<br />
recurrence in an additional, previously-published, cohort consisting<br />
of Tamoxifen-treated (n=58, p=0.015) and untreated patients (n=62,<br />
p=0.25).<br />
Conclusion<br />
A novel gene expression profile predictive of outcome of Tamoxifentreated<br />
patients was identified. The validation suggests that BCL2-<br />
CDKN1A exhibit strong predictive potential.<br />
P4-09-05<br />
Microarray anlyses of breast cancers identify CH25H, a<br />
cholesterol gene, as a potential marker and target for late<br />
metastatic reccurences.<br />
Saghatchian M, Mittempergher L, Michiels S, Wolf D, Canisius<br />
SV, Dessen P, Delaloge S, Lazar V, Benz SC, Roepman P, Glas AM,<br />
Tursz T, Bernards R, van’t Veer LJ. The Netherlands <strong>Cancer</strong> Institute,<br />
Amsterdam, Netherlands; Institut Jules Bordet, Brussels, Belgium;<br />
UCSF Helen Diller Family Comprehensive <strong>Cancer</strong> Center, <strong>San</strong><br />
Francisco; Institut Gustave Roussy, Villejuif, France; University of<br />
California, <strong>San</strong>ta Cruz; Agendia, Amsterdam, Netherlands<br />
Background<br />
However hormone receptor–positive, early-stage breast cancer is<br />
a disease with a long natural history and improved survival with<br />
5-year adjuvant endocrine treatments. Yet late recurrence remains<br />
an important issue in adjuvant therapy. Predictors of late recurrence<br />
are not yet well characterized.<br />
Method<br />
A total of 252 breast primary tumors were selected at the Netherlands<br />
<strong>Cancer</strong> Institute from retrospective series of ER+, HER2- breast<br />
cancer patients with a follow-up of at least 10 years. Gene expression<br />
analysis was performed using Agilent 4x44K microarrays. In order<br />
to identify genes associated to late survival differences, we used the<br />
survdiff function implemented in the R package survival and we set<br />
the parameter rho to -1 to give weight to the later part of the survival<br />
curve. The survdiff function was applied to each probe individually<br />
for DMFS time considering the probe as a covariate dichotomized<br />
into 2 groups (above and below the median expression across all<br />
samples). The parameter “strata” was used to stratify the 140 patients<br />
based on additional clinico-pathological parameters (Grade, Diameter,<br />
Lymph node status and MammaPrint), in order to find genes that add<br />
prognostic value to those parameters already known.This approach<br />
uses the distant-metastasis free survival (DMFS) time as a continuous<br />
variable.<br />
Results<br />
After univariate analysis, MammaPrint, diameter, lymph node status<br />
and grade were significantly associated to late DMFS differences<br />
(Chi-square test p-values equal to 0.016, 0.004,
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
gene a potential target for late metastasis control in breast cancer.<br />
These results warrant further prospective investigation and functional<br />
characterization of CH25H in this setting.<br />
P4-09-06<br />
miR-187 is an independent prognostic factor in lymph nodepositive<br />
breast cancer patients.<br />
O’Connor DP, Mulrane L, Brennan DJ, Madden S, Gremel G, McGee<br />
SF, McNally S, Martin FM, Crown JP, Jirstrom K, Higgins DG,<br />
Gallagher W. UCD Conway Institute, Dublin, Ireland; Molecular<br />
Therapeutics for <strong>Cancer</strong> Ireland, Dublin City University, Dublin,<br />
Ireland; St Vincent’s University Hospital, Dublin, Ireland; Lund<br />
University, Lund, Sweden<br />
Purpose<br />
MicroRNAs (miRNAs) involved in cancer progression have now<br />
become the focus of much attention as they represent a new class of<br />
biomarkers and potential drug targets. Here, we describe an integrated<br />
bioinformatics, functional analysis and translational pathology<br />
approach for the identification of novel miRNAs involved in breast<br />
cancer progression.<br />
Experimental Design<br />
Differential gene expression can, in part, be attributed to the activity<br />
of specific miRNAs. Given a database of miRNA binding site<br />
motifs and gene expression levels determined by transcriptomic<br />
profiling, correspondence analysis, between group analysis and<br />
co-inertia analysis can be combined to produce a ranked list of<br />
miRNAs associated with a specific gene signature and phenotype.<br />
Here, using two independent breast cancer cohorts, this approach<br />
was employed to produce a ranked list of miRNAs associated with<br />
disease progression. Functional studies were subsequently carried out<br />
in MCF7 cells assessing for alterations in growth, tumorigenicity and<br />
agressiveness and miRNA expression was evaluated in two cohorts<br />
of breast cancer patients by locked nucleic acid in situ hybridisation<br />
on tissue microarrays.<br />
Results<br />
CIA identified miR-187 as a key miRNA associated with poor<br />
outcome in breast cancer.<br />
Ectopic expression of miR-187 in MCF7 cells resulted in a more<br />
aggressive phenotype (evidenced by increased anchorage-independent<br />
growth, migratory and invasive potential).<br />
In a test cohort (n=117) breast cancer patients, high expression of<br />
miR-187 was associated with a trend towards reduced breast cancerspecific<br />
survival (BCSS) (p=0.058), and a significant association<br />
with reduced BCSS in lymph node-positive patients (p=0.036). In a<br />
validation cohort (n=470), high miR-187 was significantly associated<br />
with reduced BCSS in the entire cohort (p=0.021) and, again, in lymph<br />
node-positive patients (p=0.012).<br />
Multivariate cox regression analysis revealed that miR-187 is an<br />
independent prognostic factor in both TMA cohorts (Cohort 1 HR-<br />
7.369 (95% CI 2.048-26.509, p=0.002); Cohort 2 HR-2.798 (95%<br />
CI 1.518-5.157, p=0.001).<br />
Conclusions<br />
miR-187 expression in breast cancer leads to the formation of a more<br />
aggressive, invasive phenotype and acts as an independent predictor<br />
of outcome.<br />
P4-09-07<br />
ING1 Expression Measured by AQUA can be an Independent<br />
Prognostic Marker in <strong>Breast</strong> <strong>Cancer</strong><br />
Thakur S, Klimowicz A, Pohorelic B, Dean M, Konno M, Bose P,<br />
Magliocco A, Riabowol K. University of Calgary, AB, Canada; Tom<br />
Baker <strong>Cancer</strong> Center, Calgary, AB, Canada<br />
Background:<br />
<strong>Breast</strong> cancer accounts for around 45,000 cancer related deaths in<br />
North America per year. The high incidence of breast cancer observed<br />
in this region is most likely due to the availability of various screening<br />
programs used to detect breast cancer, which otherwise may never get<br />
diagnosed. There is an inverse relation between the cost of treatment<br />
and patient survival as the breast cancer progresses to higher grades.<br />
Therefore, screening and diagnosing breast cancers at earlier stages<br />
is needed which can improve patient survival.<br />
The INhibitor of Growth (ING) family of tumour suppressor proteins<br />
are implicated in diverse cellular processes including chromatin<br />
remodelling and apoptosis. ING proteins are stoichiometric members<br />
of histone acetyl transferase (HAT) and histone deacetylase (HDAC)<br />
complexes. Their expression is downregulated in several cancers,<br />
including breast carcinoma. Alternatively, ING function may be<br />
compromised by mislocalization to the cytoplasm. However, the<br />
association of expression of ING proteins and cancer specific survival<br />
has not been studied yet. In this study, we aimed to evaluate the<br />
prognostic significance of ING1 in breast cancer.<br />
Patients and Methods:<br />
This study included 443 <strong>Breast</strong> <strong>Cancer</strong> patients diagnosed in Calgary,<br />
Canada from 1985-2000. Clinical data were obtained from the Alberta<br />
<strong>Cancer</strong> Registry and chart review. Tissue microarrays (TMAs)<br />
were assembled from triplicate cores of formalin-fixed paraffinembedded<br />
tumour tissue. ING1 protein expression was quantified<br />
using fluorescent immunohistochemistry and automated quantitative<br />
analysis (AQUA) in normal breast epithelial cells and breast cancer<br />
samples. 5 year progression free survival (PFS) was analyzed using<br />
Kaplan-Meier plots and Cox proportional hazard modelling.<br />
Results:<br />
In our study, we found that ING1 expression is significantly<br />
downregulated in the breast cancer patient samples relative to<br />
normal breast epithelia. High or low ING1 cytoplasmic/nuclear<br />
(C/N) ratio results in poor 5 year PFS. Also, the low tumor/stromal<br />
(t/s) ratio of ING1 results in poor prognosis. In univariate analysis,<br />
t/s ING1 expression showed a negative correlation with tumor stage<br />
[p=0.008]; tumor grade [p=0.000]; nodal status [p=0.000] and 5 year<br />
PFS [p=0.004]. However, no correlation was observed with ER, PR<br />
or HER2 status. In multivariate analysis, t/s ING1 proved to be an<br />
independent and better prognostic marker [HR 0.582, p=0.037] than<br />
HER2 [HR 2.230, p=0.057]; Age at diagnosis [HR 2.010, p=0.205]<br />
and tumor size [HR 1.471, p=0.189].<br />
Discussion and Conclusions:<br />
This is the first study to evaluate ING1 expression in breast cancer<br />
using the AQUA technique. ING1 expression high or low in the<br />
C/N ratio might disrupt the stoichiometry of chromatin-modifying<br />
complexes and hamper ING1s extra nuclear functions, leading to poor<br />
survival. The significantly improved survival observed in patients<br />
with high t/s ING1 expression further strengthens the role of ING1<br />
as a tumor suppressor.<br />
www.aacrjournals.org 387s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-09-08<br />
HOXB9, a gene promoting tumor angiogenesis and proliferation,<br />
is significantly associated with poor clincal outcomes in ERpositive<br />
breast cancer patients<br />
Seki H, Hayashida T, Jinno H, Takahashi M, Suzuki K, Kaneda M,<br />
Hara H, Osaku M, Asanuma F, Yamada Y, Mukai M, Kitagawa Y.<br />
Kitasato University Kitasato Institute Hospital, Tokyo, Japan; Keio<br />
University School of Medicine, Tokyo, Japan; Keio University School<br />
of Medicine, Japan<br />
Background: Studies have suggested that HOXB9 expression<br />
in breast cancer cells promotes cellular invasiveness, metastatic<br />
ability, and tumor neovascularization in the surrounding tissue<br />
in in vitro and in vivo assays. These findings imply that HOXB9<br />
overexpression may alter tumor-specific cell fates and the tumor<br />
stromal microenvironment, contributing to breast cancer progression<br />
(Hayashida et al., PNAS 2010). We previously reported that clinical<br />
outcomes were significantly decreased in HOXB9-positive patients<br />
(Seki et al., Ann Surg Oncol. 2012). In this study, it was demonstrated<br />
that HER2 type and basal-like breast cancers were more associated<br />
with HOXB9 positivity than the luminal type. Therefore, it is required<br />
to identify more detail clinicopathological features most likely to<br />
be associated with HOXB9 overexpression. We investigated the<br />
correlation between HOXB9 overexpression and clinicopathological<br />
variables, and clinical outcomes in estrogen receptor (ER)-positive<br />
breast cancer patients.<br />
Patients and methods: A consecutive series of 118 ER-positive breast<br />
cancer patients who underwent surgical treatment were examined.<br />
HOXB9 expression was analyzed immunohistochemically using the<br />
anti-human HOXB9 polyclonal antibody. Immunostaining of Ki-67<br />
and CD31 were also performed to evaluate tumor proliferation and<br />
angiogenesis.<br />
Results: The median age was 59 years and median observation<br />
period was 62 months. Of 118 tumor specimens immunostained for<br />
HOXB9, 49 specimens (41.5%) were positive staining. Univariate<br />
logistic regression revealed high nuclear grade (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
P4-09-10<br />
Prospective Analysis of Fatty Acid Synthase (FASN) in <strong>Breast</strong><br />
<strong>Cancer</strong> Tissue of Early-Stage <strong>Breast</strong> <strong>Cancer</strong> Patients<br />
Puig T, Blancafort A, Casoliva G, Oliveras G, Casas M, Buxo M,<br />
Saiz E, Viñas G, Dorca J, Porta R. University of Girona and Girona<br />
Biomedical Research Institute (IDIBGi), Girona, Spain; Assistència<br />
<strong>San</strong>itària Institute, Girona, Spain; Catalan Institute of Oncology,<br />
Girona, Spain; Dr. Josep Trueta Hospital, Girona, Spain; Dr. Josep<br />
Trueta Hospital and Girona Biomedical Research Institute (IDIBGi),<br />
Girona, Spain; Health Inequalities Research Group - Employment<br />
Conditions Knowledge Network (GREDS-EMCONET), Universitat<br />
Pompeu Fabra, Barcelona, Spain; Dr. Josep Trueta Hospitaland<br />
Girona Biomedical Research Institute (IDIBGi), Girona, Spain<br />
Background: <strong>Cancer</strong> cells require nutrients to survive in the<br />
unfavorable microenvironment of primary solid tumors or metastases<br />
before angiogenesis development. Fatty acid synthase (FASN) is a<br />
multi-enzyme protein that catalyzes fatty acid synthesis. Expression<br />
levels of FASN are low or undetectable in normal human tissues<br />
except for the liver and the adipose tissue. In contrast, high levels<br />
of FASN expression have been detected in breast cancer tumors<br />
and other human carcinomas. Several reports highlight that FASN<br />
overexpression in tumor samples correlates with progression,<br />
aggressiveness and metastatic potential of the disease. In adition,<br />
some studies have suggested the same correlation with serum levels of<br />
FASN. Our aim was to analyze the association between the expression<br />
of tumor and serum levels of FASN with clinical and pathological<br />
prognostic factors in early-stage breast cancer patients.<br />
Methods: Fifty-five patients with early-stage breast cancer treated<br />
with surgery and post-operative chemotherapy were included in the<br />
study. We prospectively measured the levels of FASN in tumor and<br />
serum samples. Clinical data included demographic characteristics,<br />
menarche, pregnancy, breast feeding, menopausal status and body<br />
mass index (BMI). Pathological and molecular data included:<br />
pathological state, histological grade, estrogen and progesterone<br />
receptors, HER2 status, p53 mutation and Ki 67 levels. FASN tissue<br />
expression levels were determined by IHC and circulating FASN<br />
levels were determined by ELISA. FASN expression was graded from<br />
0 to 3+, meaning 0-1+ normal amounts of FASN protein compared<br />
to non-tumor breast tissue, 2+ moderate amounts and 3+ the highest<br />
levels of FASN expression. Baseline characteristics were summarized<br />
descriptively. Categorical variables were compared by c 2 or Fisher’s<br />
exact. For continuous variables, if the data are approximately normal,<br />
the two groups were compared using ANOVA. If the normality<br />
assumption is not warranted, then the Kruskall-Wallis test has been<br />
used.<br />
Results: Median age was 49 (rage 33-77). 51% of the patients were<br />
menopausal and median BMI was 24,75. Thirty-four percent of the<br />
patients had stage I, 51% stage II and 15% stage III. We observed a<br />
statistically significant association between FASN over expression<br />
and the lack of progesterone receptors (p=0.027) in tumor samples. In<br />
contrast, we found no relation between FASN and estrogen receptor<br />
nor between FASN and HER2 tumor expression in this setting.<br />
Menopause and age were strongly related to higher levels of FASN<br />
tumor expression (p< 0.001). Patients with higher BMI had higher<br />
levels of FASN in tumor tissue although this association was not<br />
statistically significant (p= 0.07). Finally, we observed a positive<br />
relation between breast cancer stage and the levels of FASN tumor<br />
(p=0.05). In contrast, circulating FASN levels were not associated<br />
with any pathological or clinical prognostic factor.<br />
Conclusions: Our study suggests that FASN overexpression is<br />
significantly related to age, menopausal status, more advanced stages<br />
and lack of progesterone receptor expression in early-stage breast<br />
cancer patients. However, no relation between serum levels of FASN<br />
and the clinical or molecular prognostic factors have been observed.<br />
P4-09-11<br />
Fatty Acid Synthase (FASN) expression in Triple-Negative <strong>Breast</strong><br />
<strong>Cancer</strong><br />
Viñas G, Oliveras G, Perez-Bueno F, Giro A, Blancafort A, Puig-Vives<br />
M, Marcos-Gragera R, Dorca J, Brunet J, Puig T. Catalan Institute<br />
of Oncology and Girona Biomedical Research Institute (IDIBGi),<br />
Girona, Spain; University of Girona and Biomedical Research<br />
Institute (IDIBGi), Girona, Spain; Dr. Josep Trueta Hospital and<br />
Catalan Institute of Health (ICS), Girona, Spain; Catalan Institute<br />
of Oncology, Girona, Spain; University of Girona, Spain<br />
Background:<br />
In approximately 15-20% of patients with breast cancer, the tumors<br />
do not express estrogen receptor (ER), progesterone receptor (PR)<br />
and do not have amplification of HER2. These tumors are called<br />
triple-negative breast cancer (TNBC) and patients with these tumors<br />
have a poor prognosis. There is no clinically validated, molecularly<br />
targeted therapy for TNBC patients and they can be treated only with<br />
chemotherapy. Thus, the identification of a novel targeted therapies for<br />
TNBC patients would be of great benefit. Fatty acid synthase (FASN)<br />
is a multi-enzyme protein that catalyzes fatty acid synthesis. Its main<br />
reaction is to synthesize palmitate from acetyl-CoA and malonyl-<br />
CoA, in the presence of NADPH, into long-chain saturated fatty<br />
acids. Expression levels of FASN are low or undetectable in normal<br />
human tissues except for the liver and the adipose tissue. In contrast,<br />
high levels of FASN expression have been detected in several human<br />
carcinomas. Several reports highlight that FASN overexpression<br />
in tumor samples correlates with progression, aggressiveness and<br />
metastatic potential of the disease. Previously, our group has shown<br />
that FASN activity inhibition induces apoptosis in several human<br />
cancer cells. The aim of our study was to evaluate the expression<br />
of tumor levels of FASN in triple-negative breast cancer patients.<br />
Methods:<br />
FASN tumor expression was retrospectively evaluated in 30<br />
paraffin-embedded core-biopsies of 30 patients with TNBC using<br />
the Fatty Acid Synthase polyclonal antibody (Assay design,<br />
Enzo Life Sciences, Exeter United Kingdom) and the detection<br />
kit EnVision (DAKO, Glostrup, Denmark). FASN expression<br />
levels were determined by immunohistochemistry (IHC) using the<br />
AutostainerPlus Link (DAKO). FASN expression was graded from 0<br />
to 3+, meaning 0-1+ normal amounts of FASN protein compared to<br />
non-tumor breast tissue, 2+ moderate amounts and 3+ highest levels<br />
of FASN expression. In vitro, we have determined the effect of the<br />
FASN-inhibitors, EGCG and G28UCM, on cell viability (measured by<br />
the MTT assay) and apoptosis [as assessed by cleavage of poly(ADPribose)<br />
polymerase (PARP)] of two TNBC cell lines, MDA-MB-231<br />
and MDA-MB-468.<br />
Results:<br />
From 30 patients with TNBC, 66.6% (20/30) of the patients had<br />
a high expression of FASN (FASN 3+) and 33.3% (10/30) had a<br />
moderate expression of FASN (FAS 2+). None of the tumors had lack<br />
of FASN expression analysed by immunohistochemistry. In vitro, the<br />
FASN-inhibitor G28UCM induced apoptosis and showed low IC 50<br />
values of citotoxicity in both, MDA-MB-231 and MDA-MB-468<br />
TNBC cell lines.<br />
www.aacrjournals.org 389s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Conclusions:<br />
FASN is overexpressed in triple-negative breast cancer tumors. The<br />
absence of target therapies for this breast cancer subtype and its poor<br />
prognosis lead to the exploration of FASN as therapeutic target for<br />
TNBC patients.<br />
P4-09-12<br />
TIMP-4 – Prognostic Marker and Treatment Target for Triple-<br />
Negative <strong>Breast</strong> <strong>Cancer</strong>s.<br />
Wallon UM, Sabol JL, Gilman PB, Zemba-Palko V, DuHadaway<br />
JB, Ciocca RM, Ali ZA, Carp NZ, Choy NS, Wojciechowski BS,<br />
Prendergast GC. Lankenau Medical Center, Wynnewood, PA<br />
BACKGROUND — Tissue inhibitor of metalloproteinase-4 (TIMP-<br />
4) is a secreted multi-functional protein associated with poor survival<br />
prognosis among early-stage triple-negative breast cancers (TNBC)1.<br />
Triple-negative breast cancers (TNBC) represent a highly aggressive<br />
form of this disease with few treatment options available. Current<br />
standard chemotherapy (CTX) includes taxane or adriamycin based<br />
regiments.<br />
Extracellular TIMP-4 binds to the membrane bound tetraspanin CD63<br />
and induces the activation of PI3K/AKT/mTOR survival pathway.<br />
Here we report that TIMP-4 induced aggressive tumor growth and<br />
metastasis can be adverted by targeting TIMP-4 either directly by<br />
sequestering extracellular pools of TIMP-4 or indirectly by blocking<br />
the activation of downstream survival pathways.<br />
METHODS — Prospectively collected patient samples, in accordance<br />
with the IRB approved protocol, were tested for circulating levels of<br />
TIMP-4 using a commercially available ELISA assay in samples from<br />
time of surgery and at each treatment cycle. The medical oncology<br />
staff recommended therapy without knowledge of TIMP-4 status.<br />
The role of elevated TIMP-4 in TNBC cell behavior was tested in cell<br />
culture and animal experiments using the human breast cancer line<br />
MDA-MB-468. Cells with or without TIMP-4 added to the medium<br />
were used to determine the effects on growth, clonogenic survival<br />
and response to chemotherapeutic agents such as adriamycin, Taxol,<br />
the new anti-TIMP-4 antibody and the PI3K/AKT/mTOR inhibitor<br />
GDC-0941. The same cell-line was used to induce tumor growth in<br />
nude mice with or without TIMP-4 containing slow-release pellets<br />
implanted into the mammary fatpad (mfp). Tumor growth and<br />
response to therapy was followed over a six-week period.<br />
RESULTS — Results from patient samples demonstrated that<br />
circulating TIMP-4 levels in breast cancer patients remain unaffected<br />
after surgical removal of the primary tumor. Adriamycin containing<br />
regiments was the only CTX to suppress the TIMP-4 levels<br />
independent of primary tumor size and nodal status.<br />
Adding TIMP-4 to cell culture medium or the mfp of mice resulted<br />
in an 1.5-fold increased tumor growth rate. Elevated TIMP-4 in mice<br />
also resulted in liver metastasis in 25% of animals (N=8).<br />
In cell cultures, the TIMP-4 induced effects were completely adverted<br />
by addition of GDC-0941. Adding the TIMP-4 antibody, to cell culture<br />
medium or i.p. injections to mice, resulted in a decelerated growth rate.<br />
CONCLUSIONS — On the basis of these clinical and experimental<br />
data we suggest that TIMP-4 may represent a simple prognostic and<br />
predictive marker for TNBC patients at highest risk. The presence of<br />
TIMP-4 identifies a patient population likely to recur quickly based on<br />
the continuous activation of the PI3K/AKT/mTOR pathway. Though<br />
adriamycin therapy can reduce the TIMP-4 levels, the toxicity of this<br />
agent suggests that targeted therapy of the PI3K/AKT pathway and/or<br />
a biological therapeutic approach directed against TIMP-4 may be of<br />
benefit in this subset of pts and should be further explored.<br />
a Liss, M et.al. Am. J. Pathol. 2009<br />
b Donover, P et.al. J. Cell. Biochem. 2010<br />
P4-10-01<br />
Edgetic perturbation of BRCT-mediated interactions caused by<br />
the BRCA1 H1686Q sequence variant<br />
De Nicolo A, Pathania S, Parisini E, Joukov V. Dana-Farber <strong>Cancer</strong><br />
Institute, Boston, MA; Harvard Medical School, Boston, MA; Italian<br />
Institute of Technology, Milan, Italy<br />
Background: The ever-increasing number of variants of uncertain<br />
significance (VUS) that result from BRCA1/BRCA2 genetic testing<br />
poses a challenge to healthcare providers, thus impacting clinical<br />
decision-making. Though a quantitative posterior probability model,<br />
mostly reliant on genetic data, has been developed to estimate the<br />
clinical relevance of individual VUS, indirect evidence derived from<br />
functional tests continues to be a sought-after adjunct to achieve<br />
VUS categorization. Using a multimodal approach, we previously<br />
demonstrated the deleterious effect on protein localization and<br />
function of the Italian founder sequence alteration BRCA1 V1688del,<br />
and the neutral effect of a neighboring variant, BRCA1 V1687I,<br />
identified in a patient with early onset triple negative breast cancer.<br />
Disease-causality has been suggested for the adjacent BRCA1<br />
H1686Q variant that occurs in the evolutionarily conserved THV<br />
motif of the first BRCT repeat and was described in a breast/ovarian<br />
cancer family (Giannini et al., 2008). We aimed at substantiating<br />
the predicted pathogenicity of BRCA1 H1686Q by assessing its<br />
biological significance.<br />
Methods: To investigate the structural and functional consequences<br />
of the BRCA1 H1686Q sequence alteration, we used a strategy that<br />
combined homology modeling with analysis of protein interactions<br />
(by immunoprecipitation and GST pull down techniques) and function<br />
(by a homologous recombination assay).<br />
Results: The three-dimensional model of the BRCA1 H1686Q<br />
BRCT domain suggested that the site and nature of the amino<br />
acid change could alter the interaction and relative orientation of<br />
secondary structure elements in the core region of the protein, thus<br />
possibly affecting the overall stability of the protein and triggering a<br />
long-range allosteric effect with repercussions on residues involved<br />
in phosphopeptide binding. Indeed, in transfected 293T cells, the<br />
recombinant BRCA1 H1686Q protein was less abundant than its<br />
wild-type counterpart. Moreover, while efficiently heterodimerizing,<br />
via its N-terminus, with the binding partner BARD1, the BRCA1<br />
H1686Q protein displayed a peculiar behavior with regards to<br />
C-terminal, BRCT-mediated interactions as it bound BRIP1/FANCJ<br />
and not CtIP. These results, repeatedly observed in different cell lines,<br />
were confirmed by reciprocal immunoprecipitations as well as by<br />
GST pull down experiments using a recombinant BRCA1 H1686Q<br />
BRCT domain. Notably, the BRCA1 H1686Q protein displayed a<br />
homologous recombination defect similar to that observed for the<br />
clinically ascertained BRCA1 M1775R mutant protein.<br />
Conclusions: Our data suggest that the BRCA1 H1686Q variant,<br />
by affecting the BRCT ligand recognition ability, causes an edgetic<br />
perturbation (i.e. selective disruption/retention) of BRCT-mediated<br />
interactions, which is yet sufficient to impair the homologous<br />
recombination function of the encoded protein. These findings provide<br />
valuable structure/function insights that could help elucidate the link<br />
between BRCA1 DNA repair and tumor suppression functions and aid<br />
development of functional tests for VUS screening and classification.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
390s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
P4-10-02<br />
Targeted resequencing of BRCA1 and BRCA2 in inherited breast<br />
cancer<br />
Wong-Brown MW, Li S, Wilkins M, Avery-Kiejda KA, Bowden NA,<br />
Scott RJ. University of Newcastle, NSW, Australia; University of New<br />
South Wales, Sydney, NSW, Australia; Hunter Area Pathology Service<br />
(HAPS), Newcastle, NSW, Australia<br />
<strong>Breast</strong> cancer is the leading cause of cancer-related deaths in women<br />
worldwide, affecting about 13,000 women every year in Australia.<br />
Inherited loss-of-function mutations in BRCA1 and BRCA2<br />
predispose to high risk of breast and/or ovarian cancer. Since the<br />
discovery of breast cancer susceptibility genes BRCA1 and BRCA2<br />
two decades ago, there have not been any other genes identified that<br />
play a significant role in predisposition to inherited breast cancer.<br />
A large proportion of individuals with inherited breast cancer are<br />
negative for BRCA mutations and despite numerous research efforts,<br />
further breast cancer susceptibility genes still remain elusive.<br />
We hypothesize that genetic anomalies are present in the BRCA1 and<br />
BRCA2 genes in a subset of individuals with inherited breast cancer<br />
where no genetic anomalies where identified using traditional <strong>San</strong>ger<br />
sequencing. This study aims were to identify genetic anomalies in<br />
BRCA1 and BRCA2 by completely re-sequencing 200 kilobases<br />
surrounding BRCA1 and BRCA2 using targeted massively parallel<br />
sequencing, or next-generation sequencing.<br />
For this study, DNA was used from 10 individuals referred for genetic<br />
testing after meeting the criteria for inherited breast cancer, and had<br />
been screened for BRCA1 and BRCA2 mutations by the Hunter<br />
Area Pathology Service (Newcastle, NSW, Australia). All individuals<br />
used for this study did not harbour causative genetic changes in the<br />
coding regions of BRCA1 or BRCA2. Targeted next-generation<br />
paired-end sequencing of regions containing BRCA1 and BRCA2<br />
was performed using Agilent SureSelect and an Illumina GAIIx<br />
(The Ramaciotti Centre for Gene Function Analysis). An average of<br />
50x coverage was achieved across the targeted genomic region for<br />
all samples. The sequence data was aligned to the Human Reference<br />
Sequence 37.2. Single nucleotide polymorphisms present in dbSNP<br />
or the 1000 genomes project were removed from further analyses.<br />
Genetic differences in the form of single nucleotide variants (SNVs)<br />
and insertions/deletions (indels) were identified in most individuals<br />
tested in regions that had previously remained unexplored, such as the<br />
non-coding regions of BRCA1 and BRCA2, the 5’UTR and promoter<br />
sites. Structural variations including large deletions, duplications,<br />
insertions, inversions and rearrangements were also investigated, but<br />
require further analysis and validation for confirmation.<br />
This study has comprehensively investigated BRCA1 and BRCA2 and<br />
surrounding genomic regions in a mutation negative inherited breast<br />
cancer population. The issue of accuracy of mutation detection by<br />
traditional methods, such as <strong>San</strong>ger sequencing alone, has also been<br />
addressed by this study. The outcome of this study is the increase<br />
in current knowledge of the genetic variations that results in the<br />
development and/or progression of inherited breast cancer, aid in the<br />
management of individuals with breast cancers by providing a more<br />
specific diagnosis of disease risk and provide information required<br />
for the development of personalized treatment.<br />
P4-11-01<br />
Rapid genetic counseling and testing in newly diagnosed breast<br />
cancer patients, findings from an RCT<br />
Wevers MR, Ausems MG, Bleiker EM, Rutgers EJ, Witkamp AJ, Hahn<br />
DE, Brouwer T, Kuenen MA, van der <strong>San</strong>den-Melis J, van der Luijt RB,<br />
Hogervorst FB, van Dalen T, Theunissen EB, van Ooijen B, de Roos<br />
MA, Borgstein PJ, Vrouenraets BC, Huisman JJ, Bouma WH, Rijna<br />
H, Vente JP, Valdimarsdottir H, Verhoef S, Aaronson NK. Netherlands<br />
<strong>Cancer</strong> Institute - Antoni van Leeuwenhoek Hospital, Amsterdam,<br />
Netherlands; University Medical Center, Utrecht, Netherlands;<br />
Diakonessen Hospital, Utrecht, Netherlands; St. Antonius Hospital,<br />
Nieuwegein, Netherlands; Meander Medical Center, Amersfoort,<br />
Netherlands; Rivierenland Hospital, Tiel, Netherlands; Onze Lieve<br />
Vrouwe Gasthuis, Amsterdam, Netherlands; St. Lucas Andreas<br />
Hospital, Amsterdam, Netherlands; Tergooi Hospitals, Blaricum,<br />
Netherlands; Gelre Hospitals, Apeldoorn, Netherlands; Kennemer<br />
Gasthuis, Haarlem, Netherlands; Zuwe Hofpoort Hospital, Woerden,<br />
Netherlands; Mount Sinai School of Medicine, New York<br />
Introduction<br />
Female breast cancer patients carrying a BRCA1/2 mutation have<br />
an increased risk of second primary breast and ovarian tumors.<br />
Rapid genetic counseling and testing (RGCT) may aid in making<br />
informed decisions about therapeutic and preventive surgery and<br />
adjuvant treatment. Little is known about the effects of RGCT on<br />
treatment decisions and psychosocial well-being. We have performed<br />
a randomized controlled trial to investigate these issues.<br />
Methods<br />
Newly diagnosed breast cancer patients from 12 Dutch hospitals with<br />
at least a 10% risk of carrying a BRCA1/2 mutation were randomized<br />
to an intervention group (RGCT) or a usual care control group (ratio<br />
2:1). Study outcomes included uptake of RGCT, choice of type of<br />
surgery, cancer risk perception, cancer-specific distress, quality of life<br />
and decisional satisfaction. Assessments took place at study entry,<br />
and at 6 and 12 months follow-up.<br />
Results<br />
Between 2008 and 2010, 271 patients were recruited, of whom 3<br />
subsequently withdrew. The remaining 268 patients were randomized<br />
to the intervention (n=181) or control (n=87) group. Complete<br />
questionnaire data were available for 250 (93%) and 243 (91%)<br />
patients at 6 and 12 months follow-up, respectively. Of the 181<br />
women in the intervention group, 180 (98%) underwent genetic<br />
counseling after a median of 4 days. One-hundred thirteen (63%)<br />
of them opted for accelerated DNA test procedures, of whom 72<br />
underwent rapid testing (results available in
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
control group, respectively). Data on additional surgery performed<br />
during follow-up and psychosocial outcomes will be available at the<br />
time of the conference.<br />
Conclusion<br />
The uptake of rapid genetic counseling among high-risk breast<br />
cancer patients was high, and the majority of patients underwent<br />
accelerated DNA-testing procedures. However, RGCT did not have<br />
a significant effect on choice of type of primary surgery. In part, this<br />
may be explained by the fact that surgeons and patients often did<br />
not wait for DNA test results before primary surgery. Conclusions<br />
regarding the psychosocial impact of RGCT will be presented at the<br />
time of the conference.<br />
P4-11-02<br />
Novel BRCA1 and BRCA2 genomic rearrangements in Southern<br />
Chinese breast/ovarian cancer patients<br />
Kwong A, Ng EKO, Law FBF, Wa A, Wong CLP, Wong CHN,<br />
Kurian AW, West DW, Ford JM, Ma ESK. University of Hong Kong,<br />
Pokfulam, Hong Kong; Hong Kong <strong>San</strong>itorium & Hospital, Happy<br />
Valley, Hong Kong; Hong Kong Hereditary <strong>Breast</strong> <strong>Cancer</strong> Family<br />
Registry, Happy Valley, Hong Kong; Stanford University School of<br />
Medicine, Stanford, CA<br />
Background and Aims: Germline mutations in the two breast<br />
cancer susceptibility genes, BRCA1 and BRCA2 account for a<br />
significant portion of hereditary breast/ovarian cancer. Most of the<br />
BRCA mutations reported in Southern Chinese patients were point<br />
mutations, small deletions, and insertions. The spectrum of large<br />
genomic rearrangement (LGR) is largely unknown. Here we perform<br />
the first study on the LGR of BRCA genes in a Hong Kong Chinese<br />
population. We aimed to determine the spectrum of BRCA LGRs in<br />
Southern Chinese patients with breast cancer.<br />
Methods: A total of 555 clinically high-risk breast and/or ovarian<br />
cancer patients were recruited from the Hong Kong Hereditary <strong>Breast</strong><br />
<strong>Cancer</strong> Family Registry, diagnosed from March 2007 to November<br />
2011. Multiplex ligation-dependent probe amplification (MLPA)<br />
for detecting BRCA LGRs together with comprehensive BRCA1 and<br />
BRCA2 gene sequencing of all coding exons were performed. cDNA<br />
sequencing of the LGRs was performed to locate the breakpoint of<br />
the deletions.<br />
Results: Overall BRCA1/2 mutation prevalence among this cohort<br />
was 12.4% (69/555). Among the 69 mutations identified, 4 novel<br />
LGRs (2 in BRCA1 and 2 in BRCA2) were detected only by MLPA<br />
but not full gene sequencing. Overall the LGR genes accounted for<br />
5.8% (4/69) of all BRCA mutations in our cohort, 6.9% (2/29) of all<br />
BRCA1 mutations and 5% (2/40) of all BRCA2 mutations.<br />
Conclusions: These findings highlight the LGR spectrum of BRCA1<br />
and BRCA2 genes in Southern Chinese breast cancer patients. LGR<br />
testing together with BRCA1/2 full gene sequencing is superior<br />
to other methods for comprehensive BRCA1/2 analysis in clinical<br />
settings.<br />
P4-11-03<br />
Single nucleotide polymorphism testing for breast cancer risk<br />
assessment: patient trust and willingness to pay<br />
Howe R, Omer Z, Hanoch Y, Miron-Shatz T, Thorsen C, Ozanne EM.<br />
Universiy of California <strong>San</strong> Francisco, CA; Massachusetts General<br />
Hospital, Boston, MA; Plymouth University, United Kingdom; Ono<br />
Academic College, Israel<br />
Background<br />
The field of breast cancer risk assessment is advancing rapidly<br />
with recent discoveries about risk conferring single nucleotide<br />
polymorphisms (SNPs). While these discoveries can promote<br />
personalized medicine, they are often brought to the market with<br />
direct to consumer (DTC) testing before data can support their<br />
widespread use and before reliable options for dealing with testing<br />
outcomes can be offered. In this context, and knowing that patients<br />
often misunderstand risk information, it is unclear how patients will<br />
respond to these options.<br />
Methods<br />
We surveyed high risk women’s interest in SNP testing. Participants<br />
were recruited from the <strong>Cancer</strong> Genetics Network (CGN), a national<br />
network of cancer centers that maintains a database of individuals<br />
with a family history of cancer. Participants were asked to answer<br />
questions regarding their interest in SNP testing including: whether<br />
they trust it, how much they would be willing to pay for testing, how<br />
they prefer to be tested, and how they would proceed with information<br />
identifying them as below or above average risk.<br />
Results<br />
189 women without a history of breast cancer or SNP testing<br />
completed the questionnaire. The average age of the participants was<br />
49, ranging from 30 to 65. All participants had at least one relative<br />
with breast or ovarian cancer. 13% had previously tested positive for<br />
a BRCA mutation, and 33% had received BRCA testing. Most women<br />
(90%) did not know what SNP testing was prior to the survey. Once<br />
SNP testing was described, 68% of women were interested in DTC<br />
SNP testing; at the same time, only 38% of the participants reported<br />
that they trusted DTC SNP testing.<br />
Survey Question<br />
Participant Responses<br />
Know what SNP testing is? 18 (10%)<br />
Interested in DTC SNP testing? 128 (68%)<br />
Willingness to pay for SNP testing? $125, range: $0-1000<br />
Trust DTC SNP testing? 70 (38%)<br />
Above average<br />
risk results<br />
Below average<br />
risk results<br />
How they would proceed with results<br />
Discuss with doctor 146 (77%) 112 (59%)<br />
Discuss with genetic counselor 118 (62%) 67 (35%)<br />
Research on own 74 (39%) 56 (30%)<br />
Discuss with testing company 28 (15%) 16 (8%)<br />
Skeptical of results 21 (11%) 35 (19%)<br />
No further action 2 (1%) 43 (23%)<br />
None of the above 2 (1%) 0 (0%)<br />
Intervention choices<br />
Lifestyle changes after contacting doctor 139 (74%) 90 (48%)<br />
Regular mammograms 93 (49%) 108 (57%)<br />
Surgery 69 (37%) 41 (22%)<br />
Alternative medicine 60 (32%) 33 (17%)<br />
Lifestyle changes without contacting doctor 42 (22%) 40 (21%)<br />
None 15 (8%) 70 (38%)<br />
Conclusion<br />
While our results show that women are interested in DTC SNP<br />
testing, their willingness to pay is lower than the DTC cost (∼$300).<br />
Involvement of genetic counselors and providers in SNP testing<br />
discussions may be needed to overcome the current lack of trust<br />
of DTC testing among patients. Many women showed interest in<br />
lifestyle interventions, suggesting that these interventions should be<br />
incorporated as part of standard follow-up recommendations. When<br />
identified by SNP testing as “below average” risk, women do not<br />
seem to trust the results enough to forego regular mammograms. As<br />
DTC testing becomes more common, and as more SNP tests become<br />
available, it will be necessary for the medical community to address<br />
patients’ interest in these tests and to assist in interpreting results.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
392s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
P4-11-04<br />
A Structured Genetic Risk Evaluation and Testing Program in<br />
the Community Oncology Practice Increases Identification of<br />
Individuals at Risk for BRCA Mutations<br />
Langer L, Clark L, Gress J, Patt D, Denduluri N, Wang Y, Andersen<br />
J, Solti M, Wheeler A, Delamelena T, Smith, II JW, <strong>San</strong>dbach J.<br />
Compass Oncology, Portland, OR; Texas Oncology, Austin, TX;<br />
Virginia <strong>Cancer</strong> Specialists, Arlington, VA; McKesson Specialty<br />
Health/The US Oncology Network, The Woodlands, TX<br />
Background: Genetic risk assessment is an important component of<br />
the care of the community oncology breast cancer patient. However,<br />
identification of at-risk patients is largely an ad-hoc process and<br />
practices lack a systematic approach to genetic risk evaluation. The<br />
US Oncology Network Genetic Risk Evaluation and Testing (USON<br />
GREAT) Program provides a structured approach to implementation<br />
of genetic risk evaluation, testing, and triage for appropriate<br />
intervention.<br />
Methods: In 2009, our multi-disciplinary community oncology<br />
practice implemented the USON GREAT Program. The practice’s<br />
program has a single dedicated nurse practitioner and physician lead,<br />
trained in part through a core educational curriculum and utilizing<br />
US Oncology Network-wide genetics resources (web-based MD,<br />
midlevel, and genetic counselor conferencing; discussion Portal;<br />
published guidelines and office procedures). NCCN guidelines were<br />
used to guide testing recommendations. Sequential risk evaluations<br />
were documented prospectively. We retrospectively analyzed how<br />
evaluation patterns changed over a 4 year time period. We also sought<br />
to capture descriptive characteristics of the evaluated population.<br />
Results: Overall, between 2008 and 2011, our practice evaluated<br />
1018 patients at potential risk for a BRCA mutation (mut), based on<br />
personal history of breast cancer under age 50; ovarian, fallopian or<br />
peritoneal cancer; known family history of malignancy; or known<br />
BRCA mutation in the family.<br />
Total Risk Evaluations by Year<br />
Year New Patients* Total Evaluated (% of new pt)<br />
2008 1116 71 (6%)<br />
2009 1168 270 (23%)<br />
2010 1095 353 (32%)<br />
2011 924 324 (35%)<br />
* Patients with DCIS, invasive breast cancer, ovarian/fallopian/peritoneal cancers<br />
In 2008, 6% of potential at-risk individuals were identified vs 35%<br />
in 2011. NCCN guideline exclusions for BRCA testing in invasive<br />
breast cancer were 8% in 2008 and 3% in 2010.<br />
Test Results by Diagnosis<br />
Diagnosis Number Evaluated BRCA1 BRCA2 VUS Negative<br />
Invasive <strong>Breast</strong> <strong>Cancer</strong> 655 24 32 20 477<br />
DCIS 55 2 0 1 48<br />
Ovarian/Fallopian/Peritoneal 143 16 9 5 96<br />
Unaffected 165 12 23 6 96<br />
Totals 1018 54 64 32 717<br />
150 deleterious mut and variants of uncertain significance (VUS)<br />
were identified. There was an 14.7% overall identification rate for<br />
BRCA1/2 (B1, B2) mut and VUS. Among mut and VUS identified<br />
by cancer type, B1 mut was more commonly identified in patients<br />
with a gynecologic malignancy (53% B1 vs 30% B2, 17% VUS); mut<br />
in invasive breast cancer were more likely to be in B2 (42% B2 vs<br />
32% B1, 26% VUS). 7% of all tests for individuals with malignancy<br />
were declined or cancelled due to insurance or finances, vs 37% for<br />
unaffecteds, despite their high risk of mutation carrier status.<br />
Conclusions: We report a single practice’s four-year experience with<br />
implementation of the USON GREAT Program. The results from this<br />
experience demonstrate that the USON GREAT Program results in<br />
higher rates of identification of at-risk individuals, and promotes<br />
more appropriate guidelines-based testing in the community oncology<br />
setting. The relative frequency of BRCA2 vs BRCA1 in invasive<br />
breast cancer is of unclear significance at this time and warrants further<br />
analysis. Cost of testing remains a barrier to appropriate utilization.<br />
P4-11-05<br />
Optimal age to start preventive measures in women with<br />
BRCA1/2 mutations or high familial breast cancer risk<br />
Tilanus-Linthorst MMA, Lingsma H, Evans GD, Kaas R, Manders<br />
P, Hooning MJ, van Asperen CJ, Thompson D, Eeles R, Oosterwijk<br />
JC, Leach MO, Steyerberg EJ. Erasmus University MC, Rotterdam,<br />
Netherlands; Erasmus University MC, Netherlands; University of<br />
Manchester, United Kingdom; NKI/AVL, Amsterdam, Netherlands;<br />
UMC St Radboud, Netherlands; Leiden University Medical Centre,<br />
Netherlands; Centre for <strong>Cancer</strong> Genetic Epidemiology, Cambridge,<br />
United Kingdom; Royal Marsden NHS Foundation, United Kingdom;<br />
University Medical Centre Groningen, Netherlands; Institute of<br />
<strong>Cancer</strong> Research, Royal Marsden, Sutton, United Kingdom<br />
Background<br />
Women from high risk breast cancer families consider preventive<br />
measures including screening. Guidelines on screening differ<br />
considerably regarding starting age. We investigated whether age<br />
at diagnosis in affected family members is predictive for age at<br />
diagnosis of a relative.<br />
Methods<br />
We analyzed the age of breast cancer detection of 1304 first and<br />
second degree relatives of 314 BRCA1, 164 BRCA2 and 244 highrisk<br />
participants of the Dutch MRI-SCreening study. The within<br />
and between family variance in age at diagnosis was analyzed with<br />
a random effect linear regression model. We compared the starting<br />
age of screening based on risk-group (25 years for BRCA1, 30 years<br />
for BRCA2 and 35 years for familial risk), on family history, and on<br />
the model, which combines both. The findings were validated in 63<br />
families from the UK- MARIBS study.<br />
Results<br />
Mean age at diagnosis in the family varied between families; 95%<br />
range of mean family ages was 35-55 in BRCA1 -, 41-57 in BRCA2-<br />
and 44-60 in high-risk families.14% of the variance in age at diagnosis<br />
was explained by family history, 7% by risk group.<br />
Approaches to determining start of screening based on the model<br />
and on risk-group were similar in terms of cancers missed and years<br />
of screening. The approach based on familial history only, missed<br />
more cancers and required more screening years in both the Dutch<br />
and UK datasets.<br />
Conclusion<br />
Age at breast cancer diagnosis is in part dependent on family history<br />
which may assist planning starting age for preventive measures.<br />
Keywords: BRCA1, BRCA2 , breast cancer, prevention, age at onset<br />
P4-11-06<br />
Automatic referral to genetic counseling for identification of<br />
BRCA1/2 mutations: a pilot program at Norton <strong>Cancer</strong> Institute,<br />
Louisville, KY.<br />
Lewis AL, Alabek ML, Dreher C, Goldberg JM, Brooks SE. Norton<br />
Healthcare, Louisville, KY<br />
BACKGROUND: Identifying a hereditary cancer syndrome has the<br />
potential to significantly impact a patient’s treatment and long-term<br />
management, as well as prevent future malignancies among relatives.<br />
Therefore, referral of patients appropriate for genetic counseling<br />
and testing is critical. Providers traditionally initiate patient referral;<br />
however, this can lead to inconsistent referrals and results in failure<br />
to refer more than 50% of appropriate individuals, according to recent<br />
www.aacrjournals.org 393s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
studies. In an attempt to address these quality issues, we developed<br />
an automatic referral program using the National Comprehensive<br />
<strong>Cancer</strong> Network guidelines, which was approved through our cancer<br />
committee and implemented 10/1/10. This pilot was conducted within<br />
a genetic counseling program staffed by board certified genetic<br />
counselors and associated with a private, multi-disciplinary oncology<br />
practice that is part of an American College of Surgeons accredited<br />
Network <strong>Cancer</strong> Center. Our <strong>Cancer</strong> Center is part of a five-hospital<br />
integrated healthcare system and a part of the National <strong>Cancer</strong> Institute<br />
Community <strong>Cancer</strong> Centers Program network.<br />
METHODS: We conducted weekly reviews of oncology patients<br />
scheduled for upcoming appointments to identify individuals<br />
diagnosed with breast cancer before age 50 or with ovarian, fallopian,<br />
or primary peritoneal cancer at any age. Patients previously referred<br />
to our genetic counseling program were excluded. Providers were<br />
notified weekly of their patients identified via this program, with the<br />
option to decline referral. We undertook a retrospective review of<br />
the outcomes of individuals identified from 10/1/10 through 10/1/11,<br />
with follow up as of 6/1/12. IRB approval was obtained through the<br />
University of Louisville.<br />
RESULTS: We identified 521 patients for referral, 24 (4.6%) of<br />
whom were declined by a provider, resulting in 497 referrals. Three<br />
hundred forty one (69%) referrals had breast cancer and 156 (31%)<br />
had other malignancies. Of referrals, 139 (28%) have been seen,<br />
223 (45%) have declined, and 135 (27%) are in process. Testing was<br />
pursued by 108 (78%) of referrals seen, all of whom had BRCA1/2<br />
testing and 5 (4.6%) of whom had additional testing. We identified<br />
11 (10%) individuals with a BRCA1/2 mutation. An additional 17<br />
(16%) individuals who completed testing were counseled to consider<br />
enhanced surveillance in the absence of a confirmed hereditary cancer<br />
syndrome. The total number of first degree relatives with potential to<br />
benefit from this program is 62 among individuals with a BRCA1/2<br />
mutation and 86 among individuals without a confirmed hereditary<br />
cancer syndrome.<br />
CONCLUSIONS: Initiation of an automatic genetic counseling<br />
referral program in the setting of a large oncology practice is feasible<br />
and has the potential to identify individuals with a BRCA1/2 mutation<br />
who might otherwise go undetected. Few providers object to referral,<br />
and the majority of patients are receptive to referral. The impact of this<br />
program extends beyond those identified with a BRCA1/2 mutation.<br />
This project was funded in part with federal funds: NCI, NIH Contract<br />
No. HHSN261200800001E.<br />
P4-12-01<br />
A nomogram based on clinical, imaging and histological data to<br />
predict the risk of upgrades to malignancy at surgery in biopsydiagnosed<br />
premalignant lesions of the breast<br />
Uzan C, Mazouni C, Balleyguier C, Mathieu M-C, Ferchiou M,<br />
Delaloge S. Institut Gustave Roussy, Villejuif, France<br />
Background: Population-based mammography screening has resulted<br />
in the increased detection of suspicious, non-palpable lesions that<br />
require histopathological assessment. When a “pre-malignant”<br />
lesion, such as lobular carcinoma in situ (LCIS), atypical ductal or<br />
lobular hyperplasia (ADH and ALH) or flat epithelial atypia (FEA), is<br />
discovered on the primary biopsy, a surgical excision is recommended<br />
due to the risk of underestimation of the lesion. DCIS or invasive<br />
carcinoma is finally retrieved in 10-30% of the patients, meaning a<br />
large part receive unnecessary surgery. The aim of this study was to<br />
define a nomogram integrating clinical, imaging and histological data<br />
to predict for the risk of underestimation of the lesion. Intentionally,<br />
we decided to include all the premalignant lesions which implied<br />
the same management, whereas most of the previous models of the<br />
literature are focused in only one or another type of atypia.<br />
Patients and Methods: We collected complete clinical, radiological<br />
and double-reading histological data on all patients with a diagnosis<br />
of pure atypical lesion (CLIS, ADH, ALH, FEA) on image-guided<br />
biopsy performed at the One-Stop Unjt of our breast care center<br />
from 2004 to 2011. Univariate and multivariate logistic regression<br />
analyses were used to develop a model predicting for the presence of<br />
DCIS or invasive carcinoma on the final surgical sample, and build<br />
a nomogram. This nomogram was evaluated on a training set of 205<br />
patients treated at IGR.<br />
Results: 205 patients were eligible for the study. Of these 205 patients,<br />
50 cancers (24.4%) were diagnosed at definitive surgery (21 DCIS,<br />
20 ductal and 9 lobular invasive carcinoma). Univariate analysis<br />
retrieved age (p=0.03), number of biopsy cores (p=0.02) and type<br />
of radiological anomalies (p=0.02) as factors associated with cancer<br />
at surgery. The presence of microcalcifications on biopsies of limit<br />
significance was included in the multivariate analysis (p = 0.09). The<br />
final most informative nomogram included information on patient<br />
age (p = 0.03), type of radiological anomalies (p= 0.02) and number<br />
of biopsy cores (p=0.04). The predictive accuracy of the nomogram<br />
was 0.71 and 0.68 in the training set before and after bootstrapping,<br />
respectively. The calibration of the nomogram was good. The<br />
sensitivity, specificity, positive predictive value, and negative<br />
predictive values were 68%, 73%, 45%, and 88%, respectively.<br />
Conclusion: This nomogram could help identify a subset of patients<br />
with premalignant disease for whom surgery could be spared and who<br />
would be eligible for exclusive clinical follow-up. A validation study<br />
is currently undergoing in an external dataset.<br />
P4-12-02<br />
Serum 25-hydroxyvitamin D3 is associated with decreased risk<br />
of postmenopausal breast cancer in whites: the Multiethnic<br />
Cohort Study<br />
Kim Y, Franke AA, Shvetsov YB, Wilkens LR, Lurie G, Cooney RV,<br />
Maskarinec G, Hernandez BY, Le Marchand L, Henderson B, Kolonel<br />
LN, Goodman MT. University of Hawai’i <strong>Cancer</strong> Center; University of<br />
Hawaii; Keck School of Medicine, University of Southern California<br />
Ecological studies support a positive relation of sunlight exposure to<br />
a reduced incidence of breast cancer, but findings from prospective<br />
studies of the association of circulating levels of 25-hydroxyvitamin<br />
D (25(OH)D), the established marker of vitamin D status, with the<br />
risk of breast cancer have been null. We conducted a nested casecontrol<br />
study within the Multiethnic Cohort of prediagnostic serum<br />
levels of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 among<br />
707 postmenopausal breast cancer cases and matched controls from<br />
Hawaii and Los Angeles. A 5 ng/mL increase in serum levels of<br />
25-hydroxyvitamin D3, the major component of 25(OH)D, was<br />
associated with a significant 28% decreased risk of breast cancer<br />
among white women, but not among women from other ethnic groups<br />
(pheterogeneity = 0.01). Among whites, women considered deficient<br />
in vitamin D (i.e., 25(OH)D
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
P4-12-03<br />
Towards a risk prediction model for breast cancer that utilizes<br />
breast tissue risk features<br />
Pankratz VS, Degnim AC, Visscher DW, Frank RD, Vierkant RA,<br />
Ghosh K, Aziza N, Vachon CM, Frost M, Radisky DC, Hartmann LC.<br />
Mayo Clinic, Rochester, MN; Mayo Clinic, Jacksonville, FL<br />
Background: Optimal early detection and prevention strategies for<br />
breast cancer are predicated on our ability to accurately identify<br />
women at increased risk for disease. Current breast cancer risk<br />
prediction models rely on clinical and epidemiologic features. As<br />
demonstrated with other cancers, such as those of the cervix and<br />
colon, cancer risk assessment is enhanced when the tissue at risk<br />
is examined for evidence of premalignant abnormalities. Here, we<br />
present a multivariate model for individualized breast cancer risk<br />
prediction that incorporates tissue features identified from biopsies<br />
from women with benign breast disease (BBD).<br />
Methods: We used our cohort of more than 9000 women diagnosed<br />
with BBD at the Mayo Clinic from 1967-1991, and identified a nested<br />
case:control series of 377 women who developed cancer (cases)<br />
matched with 734 women who did not (controls). We identified a set<br />
of variables that either alone or in two-way interactions contributed to<br />
a multivariable risk prediction model. We combined this relative risk<br />
model with the baseline incidence of breast cancer and the baseline<br />
hazard of death from our full BBD cohort to develop a risk prediction<br />
tool that computes absolute risk estimates for breast cancer. We<br />
calculated 5-year risk predictions for these cases and controls using<br />
our model and using the Gail model and compared c-statistics from<br />
these risk predictions. We validated our model using an independent<br />
set of 378 breast cancer cases and 728 matched controls drawn from<br />
our BBD cohort.<br />
Results: Cases and controls in the model development data set differed<br />
significantly on a number of features when examined individually.<br />
Those included in a multivariable relative risk model for breast cancer<br />
among women with BBD are shown below.<br />
Factors in risk model<br />
Variable<br />
Levels<br />
Histologic Impression<br />
Proliferative vs. not<br />
Involuted Lobules 1-74% vs.
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-12-05<br />
Enrichment of aldosterone synthase (CYP11B2) gene C-allele<br />
carriers in women at high risk in the OncoVue® polyfactorial<br />
risk model<br />
Jupe ER, Pugh TW, Knowlton NS, DeFreese DC. InterGenetics<br />
Incorporated, Oklahoma City, OK; NSK Statistical Solutions,<br />
Choctaw, OK<br />
Background: Models for accurately assessing breast cancer risk<br />
are utilized for guiding clinical decisions regarding early detection<br />
and prevention. We developed a polyfactorial risk model (PFRM;<br />
OncoVue) from analysis of a large case-control database including<br />
both functional gene polymorphism and clinical factor data. A<br />
multivariate logistic regression based statistical protocol was used<br />
to derive a single risk model consisting of 22 single nucleotide<br />
polymorphisms (SNPs) in 19 genes and 5 traditional risk factors.<br />
Several studies have shown that the PFRM is significantly improved<br />
in individualized risk estimation compared to the <strong>Breast</strong> <strong>Cancer</strong> Risk<br />
Assessment Tool (BCRAT) or Gail model. Here we have examined<br />
the genotype frequencies of women placed in the highest decile of risk<br />
by the PFRM compared to both the overall control population and to<br />
women in the control population placed at the lowest decile of risk.<br />
Materials and Methods: Analyses were performed on 1671 breast<br />
cancer cases and 3351 controls that enrolled in a case-control study<br />
conducted in six regions of the United States. DNAs were genotyped<br />
for the 22 genetic polymorphisms and combined with clinical risk<br />
factor information to calculate PFRM risk estimates for the individual<br />
participants. The PFRM lifetime scores were used to stratify the<br />
upper and lower deciles of risk. The genotype frequencies for these<br />
stratified risk groups were determined and compared to the overall<br />
control population and to each other (upper vs. lower decile). Odds<br />
Ratios (OR) were determined for the CYP11B2 genotypes because<br />
they exhibited the largest differences in frequency among the groups.<br />
Results: For CYP11B2 comparison of the genotype frequencies in<br />
the highest decile risk group to the overall genotype frequencies<br />
of controls identified significant enrichment of the C-allele carriers<br />
in the highest risk group. The OR for C-allele carriers (C/C+C/T)<br />
compared to the most common T/T genotype was 3.0 (1.9, 4.8; 95%<br />
C.I.) with a p-value
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
odds ratio was consistent across both case control studies (OR 1.25,<br />
95% CI 1.06-1.46) and cohort studies (OR 1.26, 95% CI 1.09-1.45).<br />
Heterogeneity was significant (I² = 73.40, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
mammogram history), and Correlates of <strong>Breast</strong> Health (e.g., smoking<br />
behavior, alcohol consumption), we found that clients were between<br />
3.2 and 7.2 times more likely to complete the sections via ACASI<br />
as opposed to SAPI.<br />
Rates of CIF completion by interview mode<br />
Number of items ACASI, % complete FFI, % complete SAPI, % complete<br />
in section (n=101)<br />
(n=100) (n=100)<br />
Overall CIF 34 73.3 64.0 37.0<br />
Demographics 12 82.2 85.0 59.0<br />
<strong>Breast</strong> Health<br />
Information<br />
11 94.1 93.0 80.0<br />
Correlates of <strong>Breast</strong><br />
Health<br />
11 93.1 78.0 65.0<br />
Discussion:<br />
Overall, we found that use of ACASI resulted in significantly higher<br />
rates of overall form completion and lower rates of missing data than<br />
use of SAPI or FFI, with the greatest identified disparity in form<br />
completion between ACASI and SAPI. This study has important<br />
implications for breast health specialists or any health practitioners<br />
who regularly rely on self-administered questionnaires and/or<br />
face-to-face interviews to collect important health information. We<br />
recommend that where feasible, ACASI be utilized as an effective<br />
means of collecting high quality client-level data.<br />
P4-13-03<br />
Hormone replacement therapy, is there an increased risk of in<br />
situ breast cancer ? data from a french cohort<br />
Coussy F, Giacchetti S, Hamy A-S, Porcher R, Cuvier C, Lalloum<br />
M, de Roquancourt A, Albiter M, Espié M. Hopital St Louis, Paris,<br />
France; Hôpital St Louis, Paris, France; Assistance Publique-<br />
Hôpitaux de Paris, Hôpital St Louis, Paris, France<br />
Background: Use of hormone replacement therapy (HRT) has been<br />
associated with an increased risk of breast cancer. Few studies focus<br />
on correlation between HRT and in situ breast cancer A large cohort<br />
study, the Million Women Study (Reeves GK et al. Lancet Oncol.<br />
2006) have shown that the use of HRT has been associated with<br />
an increased incidence of in situ breast cancer (RR= 1, 55 , IC=1,<br />
4-1,72, p=0,03).<br />
Purpose: We investigated the association between HRT use and<br />
duration and in situ breast cancer incidence from a data base of<br />
infraclinic breast lesions.<br />
Materials & Methods: From 2007 to 2011, 2708 patients (pts) with a<br />
non palpable breast lesion were referred to our breast disease unit for<br />
exploration (Saint Louis Hospital, Paris). Radiological abnormalities<br />
were screened by mammography and/or breast ultrasound, and/or<br />
MRI. Out of 2708 pts, 1668 had a biopsy. All biopsies were seen by<br />
an anatomopathologist dedicated to breast. Here, we focus on the<br />
1017 postmenopausal women (61%).<br />
Results: Biopsies revaled invasive breast cancers in 222 pts (22%),<br />
in situ breast cancers in 164 pts (16%) [10 lobular in situ carcinoma<br />
and 154 ductal in situ carcinoma], high risk breast lesions in 103 pts<br />
(10%) and benign breast lesions in 528 patients (52%). Characteristics<br />
of the 164 patients with in situ breast cancer: median age 62 [IQR:<br />
57 to 68], at least one pregnancy (mean number of pregnancies per<br />
woman, 1.6) 75,6%, family history of breast cancer:30,2%. Among<br />
these 164 patients, 42.6 % had used an oral contraceptive and 53%<br />
of them a HRT, with a mean duration of use of 7 years.<br />
The HRT use was not significantly associated with in situ breast<br />
cancer (p=0.66) as well as the duration of HRT.<br />
Benin In situ breast cancer p<br />
Nb of patients 528 164<br />
Median age (IQR), ys 59 (55-66) 62 (57-68) 0.008<br />
Mean nb of pregnancy (SD) 1.8 (1.4) 1.6 (1.3) 0.24<br />
Median duration of oral contraception (IQR), ys 0 (0-7) 0 (0-8) 0.97<br />
Median duration of HRT (IQS) , ys 0 (0-6) 1 (0-6) 0.66<br />
Duration of HRT, nb (%) 0.89<br />
never use 260 (49.6) 77 (47)<br />
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
TABLE 1 - Number of avoided events due to Estrogen, over 10 year follow up<br />
Estrogen- Placebo<br />
GROUP - Ages 50-59 Annualized -Annualized RR [95% C.I.]<br />
(%) (%)<br />
CHD: 0.18 0.31 0.59 [0.38-0.90] - 1,300<br />
iBrCA 0.24 0.30 0.80 [0.53-1.19] - 600<br />
All Deaths 0.35 0.48 0.73 [0.53-1.00] - 1,300<br />
GROUP - ALL AGES<br />
iBrCa 0.27 0.35 0.77 [0.62-0.95] - 800<br />
NAE / 100,000 over<br />
10 years<br />
iBrCa: Women without<br />
0.23 0.38 0.61 [0.47-0.79] - 1,500<br />
PHBBD (80% of all)<br />
CONCLUSION.<br />
1. Estrogen therapy could reduce thousands of BrCa, CHD and AC-<br />
Mortality events annually, just in North America. These gains are in<br />
addition to the established quality of life improvement for millions<br />
of women due to [E].<br />
2. Of particular importance is the [E] effect on reduction of iBrCa<br />
rates, particularly significant for women without PHBBD, confirming<br />
the new paradigm of Dual E effect for human BrCa [Ref 3].<br />
3. These substantial Public Health gains associated with [E] may<br />
justify changing policy to incorporate [E] into HRT guidelines for<br />
appropriately selected women.<br />
4. Accelerated research to optimize [E] formulations, and identifying<br />
subsets that benefit most, is urgently required for optimum HRT use<br />
in Prevention of iBrCa, CHD, and reducing AC- mortality.<br />
REFERENCES<br />
1. LaCroix AZ, et.al. Health outcomes after stopping conjugated equine<br />
estrogens among postmenopausal women with prior hysterectomy: a<br />
randomized controlled trial. JAMA 2011;305:1305-14.<br />
2. Anderson GL, et.al. Conjugated equine oestrogen and breast<br />
cancer incidence and mortality in postmenopausal women with<br />
hysterectomy: extended follow-up of the Women’s Health Initiative<br />
randomised placebo-controlled trial Lancet Oncol 2012;13:476-86.<br />
3. Ragaz J, et.al. Dual estrogen effects on breast cancer: endogenous<br />
estrogen stimulates, exogenous estrogen protects. Further investigation<br />
of estrogen chemoprevention is warranted. <strong>Cancer</strong> Res 2010;70.<br />
P4-13-05<br />
The gap between perceptions of risk and actual risk for breast<br />
cancer.<br />
Kaplan CP, Lopez M, Tice J, Pasick R, Kerlikowske K, Chen A,<br />
Karliner L. University of California, <strong>San</strong> Francisco, CA<br />
Background: Estimating a woman’s individual risk for breast cancer<br />
is essential for tailoring appropriate screening and risk reduction<br />
strategies. Prior research suggests that women often misperceive<br />
their risk as either higher or lower than it actually is. As a result,<br />
average risk women who perceive their risk to be high may experience<br />
unnecessary anxiety. In contrast, high risk women who perceive their<br />
risk to be average/low may not utilize needed screening or available<br />
risk reduction options. The overall aim of this study is to compare<br />
perception of breast cancer risk to actual risk among a sample of<br />
multi-ethnic women with a range of breast cancer risk.<br />
Methods: As part of BREASTCARE, a randomized controlled<br />
trial designed to evaluate a PC-tablet based intervention providing<br />
multi-ethnic women and their primary care physicians with<br />
tailored information about breast cancer risk, we collected baseline<br />
information regarding perception of risk. Women visiting general<br />
internal medicine primary care clinics at two sites (one academic<br />
practice and one safety net practice) during the study period, between<br />
the ages of 40 and 74, who spoke English, Spanish or Chinese, and<br />
had no personal history of breast cancer were eligible to participate.<br />
Participants were asked how concerned they were about getting breast<br />
cancer: very concerned, somewhat concerned, a little concerned, or<br />
not at all concerned. They were also asked what they believed their<br />
chances of getting breast cancer were compared to other women their<br />
age: higher, the same, or lower. We classified women as high risk if<br />
they had a positive family history based on the Referral Screening<br />
Tool (Bellcross, et al. 2009), or were in the top 5% estimated 5-year<br />
risk for their age group based on either the Gail Model (Gail et al.<br />
1999) or the <strong>Breast</strong> <strong>Cancer</strong> Surveillance Consortium Model when<br />
breast density data was available (Tice et al. 2008). We then compared<br />
women’s perception of breast cancer risk with their actual risk.<br />
Results: To date, data has been obtained for 913 participants. One<br />
third of the women were white, 23% Black, 23% Latina and 17%<br />
Asian. Twenty percent (N=182) of the women were classified as<br />
high risk. Among average risk women (N=727) 48% were very or<br />
somewhat concerned about getting breast cancer. In contrast, 35%<br />
of high risk women were a little or not at all concerned. When asked<br />
how their chances of getting breast cancer compared to other women<br />
their age, 20% of average risk women thought their risk was higher<br />
than other women their age, while 71% of those at high risk indicated<br />
that they had the same or lower risk than other women their age.<br />
Conclusions: Our results suggest that both average and high risk<br />
women have an incorrect perception of their personal breast cancer<br />
risk compared to their actual risk. Interventions that address this<br />
misunderstanding can help those at high risk to initiate appropriate risk<br />
reduction practices and those at average risk to reduce unnecessary<br />
anxiety.<br />
P4-13-06<br />
Association of Age, Obesity and Incident <strong>Breast</strong> <strong>Cancer</strong><br />
Phenotypes<br />
Scheri R, Power S, Marks J, Seewaldt V, Marcom K, Hwang S. Duke<br />
University Medical Center, Durham, NC<br />
Background: Obesity has been shown to be associated with increased<br />
risk of breast cancer in postmenopausal women. However, it is unclear<br />
whether this risk is isolated to a specific phenotype. We hypothesized<br />
that the increased levels of insulin, IGF-1 and estrogens associated<br />
with obesity preferentially drive an increased proportion of the<br />
luminal A phenotype of breast cancer.<br />
Methods: Between 2008 and 2011, 1001 women were diagnosed<br />
with invasive breast cancer at Duke University Medical Center and<br />
had weight and height recorded at the time of diagnosis. Tumor<br />
phenotypes were based on hormone receptor (HR: ER- and/or PRpositive)<br />
and Her2 testing with subtypes defined as follows: Luminal<br />
A: HR(+), Her2(-); Luminal B: HR(+), Her2(-); Her2: HR(-), Her2(+);<br />
triple negative: HR(-), Her2(-).<br />
Results: Median age of the cohort was 55.7 years; median BMI was<br />
27.7. As expected, increasing BMI was associated with older age, with<br />
BMI almost evenly distributed between three groups: ≤ 25, 25-30, and<br />
>30. In the overall group, proportion of luminal B, Her2, and triple<br />
negative subtypes did not differ by BMI; however the proportion of<br />
patients with luminal A cancer increased from 65% for the lowest<br />
BMI group to 70% for the highest BMI group. Analysis stratified by<br />
age ≤ 40, 40 to 59, and ≥60 years showed a lower proportion of the<br />
triple-negative (19% vs. 6% vs. 4%, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-13-07<br />
Meta-analysis of epidemiological studies of Insulin Glargine and<br />
<strong>Breast</strong> <strong>Cancer</strong> Risk<br />
Boyle P, Koechlin A, Boniol M, Bota M, Robertson C, Rosenstock J,<br />
Bolli GB. International Prevention Research Institute, Lyon, France;<br />
University of Strathclyde, Glasgow, United Kingdom; Dallas Diabetes<br />
and Endocrine Center, Dallas; University of Perugia, Italy<br />
After having lain dormant for a while, the association between<br />
diabetes, its risk factors and treatments, and cancer risk and death<br />
is now high on the clinical and research agenda. The microscope<br />
is currently focused on the relationships between Pioglitazone and<br />
Bladder <strong>Cancer</strong>, Exenatide and Pancreas <strong>Cancer</strong>, Liraglutide and<br />
pancreas cancer and insulin use and lung cancer. The potential<br />
association between use of insulin glargine and breast cancer risk<br />
has been the subject of recent major studies.<br />
All data regarding cancer risk and use of insulin glargine has been<br />
assembled and meta-analyses performed using state-of-the-art<br />
statistical methodology. A random effects model was employed with<br />
tests for heterogeneity (I 2 ) and publication bias. These meta-analyses<br />
are based on reports from 21 epidemiological studies involving over<br />
one million patients and 3 million person-years of observation.<br />
Based on independent estimates from these studies, the Summary<br />
Relative Risk (SRR) for all forms of cancer was (SRR=0.91, 95% CI<br />
(0.84, 0.99)), and for breast cancer SRR=1.11 (95% CI (1.00, 1.48)).<br />
For new users of glargine, the SRR for breast cancer was SRR=1.22<br />
(95% CI (1.00, 1.48)). For colorectal cancer the SRR=0.83 (95% CI<br />
(0.74, 0.94)) and for prostate cancer SRR=1.14 (95% CI (0.93, 1.39)).<br />
Overall, the risk of developing cancer among users of insulin glargine<br />
is reduced compared to the risk of users of other insulins. Similarly,<br />
the risk of colorectal cancer is reduced among users of glargine.<br />
While the lower bound of the 95% confidence interval is 1.00, the<br />
risk of breast cancer does not increase with increasing duration of<br />
use of glargine. In some studies the trend in risk with increasing<br />
duration of use goes in opposite directions. The development of a<br />
detectable breast cancer from the initial carcinogenic event depends<br />
on the tumour doubling time. The time for a de novo breast cancer to<br />
become detectable ranges from 12.3 years for a doubling time of 150<br />
days; 16.4 years for a doubling time of 200 days; and 20.5 years for a<br />
doubling time of 250 days. Most published studies have a maximum<br />
of 3-4 years of glargine use.<br />
The databases employed in these analyses were not designed for<br />
such epidemiological investigation. A major limitation is the absence<br />
of knowledge as to why a potential treatment was prescribed for<br />
an individual and why a change in therapy was indicated. Further<br />
potential limitations to this meta-analysis include that the comparison<br />
group was not the same in all studies but this could also be seen as<br />
a strength. The meta-analysis of the randomized trials had several<br />
insulin comparators and the retinopathy study had NPH as the<br />
comparator. This is not likely to invalidate the findings of this<br />
analysis nor would the fact that different adjustments were made in<br />
the individual studies.<br />
The current evidence gives no support to the hypothesis that insulin<br />
glargine is associated with an increased risk of cancer as compared<br />
to other insulins and should give reassurance to physicians and their<br />
patients. In respect to breast cancer, there is no indication of a causal<br />
association between use of insulin glargine and increased risk of<br />
breast cancer.<br />
P4-13-08<br />
Diabetes, Related Factors and <strong>Breast</strong> <strong>Cancer</strong> Risk<br />
Boyle P, Boniol M, Koechlin A, Bota M, Robertson C, Leroith D,<br />
Rosenstock J, Bolli GB, Autier P. International Prevention Research<br />
Institute, Lyon, France; University of Strathclyde, Glasgow, United<br />
Kingdom; Mt. Sinai, New York; Dallas Diabetes and Endocrine<br />
Center, Dallas; University of Perugia, Italy<br />
Diabetes and breast cancer are both extremely common conditions in<br />
women and may share common risk factors. It is natural to investigate<br />
any potential common risk factors and to seek biological clarification<br />
and improve prospects for prevention.<br />
Therefore, in order to help clarify the potential association between<br />
diabetes, related factors and breast cancer risk, a comprehensive<br />
literature review and formal meta-analysis was carried out, planned,<br />
conducted and reported following PRISMA guidelines regarding<br />
meta-analysis of observational studies. Variables studies in relation<br />
to breast cancer risk were adiposity, physical activity, glycaemic load,<br />
glycaemic index, diabetes, IGF-1, fasting glucose, fasting insulin<br />
and C-peptide, adiponectin and metformin and glargine use among<br />
patients with diabetes. For all variables except diabetes and breast<br />
cancer, only prospective studies were included in meta-analyses.<br />
Summary Relative Risks (SRR) and corresponding 95% Confidence<br />
Intervals (CI) were calculated from random effect models.<br />
For breast cancer at all ages, the calculated risks were as follows:<br />
diabetes (SRR=1.27 95% CI (1.16, 1.39); physical activity<br />
(SRR=0.88, 95% CI (0.85, 0.92)); glycaemic load (SRR=1.06,<br />
95% CI (1.00, 1.12)); glycaemic index (SRR=1.04, 95% CI (0.99,<br />
1.10)); fasting glucose (SRR=1.12, 95% CI (1.01, 1.24)); serum<br />
insulin (SRR=1.18, 95% CI (0.75, 1.85)); c-peptide (SRR=1.29,<br />
95% CI (0.91, 1.82)); adiponectin (SRR=1.16, 95% CI (0.93,<br />
1.46)); metformin (SRR=1.00, 95% CI (0.69, 1.46)); and glargine<br />
(SRR=1.11, 95% CI (1.00, 1.24)). An increase of 5 units in Body<br />
Mass Index (a weight increase if 14.5 kg in a person 1.70 metres tall)<br />
was associated in post-menopausal breast cancer (SRR=1.12, 95%<br />
CI (1.08, 1.16)) but not at pre-menopausal ages (SRR=0.83, 95%<br />
CI (0.72, 0.95)). Serum insulin was associated with breast cancer at<br />
post-menopausal ages but not at pre-menopausal ages whereas with<br />
c-peptide there was a significant association at pre-menopausal ages<br />
but not post-menopausal. For IGF-1, Hodge’s Standardised Mean<br />
Difference (HSMD) was calculated in cohort studies and there was no<br />
significant association with breast cancer at all ages (HSMD=0.003,<br />
95% CI (-0.059, 0.065)), at post-menopausal ages (HSMD=-0.014,<br />
95% CI (-0.106, 0.077)) or at pre-menopausal ages (HSMD=0.039,<br />
95% CI (-0.038, 0.117)).<br />
The risk of breast cancer is increased among post-menopausal women<br />
who have diabetes. Among those factors related to diabetes, key risk<br />
factors for breast cancer appear to be adiposity and lack of physical<br />
activity which are both related to the risk of developing diabetes.<br />
Action on these lifestyle factors should form the basis of a common<br />
prevention strategy. There is a need to re-evaluate potential biological<br />
mechanisms to explain the increased risk in post-menopausal women<br />
with diabetes.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
400s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
P4-13-09<br />
The effect of weight change on breast adipose and dense tissue<br />
Graffy HJ, Harvie MN, Warren RM, Boggis CR, Astley SM, Evans<br />
GD, Adams JE, Howell A. University Hospital of South Manchester,<br />
Manchester, United Kingdom; Addenbrooke’s Hospital, Cambridge,<br />
United Kingdom; University of Manchester, United Kingdom; Central<br />
Manchester University Hospitals NHS Foundation Trust, Manchester,<br />
United Kingdom<br />
Background Observational studies indicate that weight gain or loss<br />
alters breast cancer risk. Hormonal prevention with tamoxifen or<br />
ovarian suppression reduces mammographic breast density, but has<br />
no impact on breast adipose tissue. 1 The aim of this study was to<br />
assess whether change in weight is associated with change in breast<br />
density, breast fat or both. Methods 74 premenopausal women aged<br />
between 35 and 45 years, with a family history of breast cancer,<br />
were recruited from our Family History Clinic. 36 were allocated to<br />
a 25% calorie-restricted Mediterranean diet and exercise intervention;<br />
a further 38 women were separately recruited into a control group<br />
and given written diet and exercise advice only. At baseline and 12<br />
months breast dense and non-dense (largely adipose) components of<br />
the breast were measured: area using Cumulus 2 and volume using the<br />
Manchester ‘stepwedge’ method. 3 Visual assessment of percentage<br />
density was reported to the nearest 5%. 4 We used correlations to<br />
relate percentage change in absolute dense and non-dense (area and<br />
volume) to percentage change in: weight, total body fat (DXA),<br />
intra-abdominal and subcutaneous abdominal fat (MRI), as well<br />
as serum total IGF-I. Results At 12 months, 40 (54%) women<br />
lost >1.5% body weight, 14 (19%) gained >1.5% and 21 (28%)<br />
remained weight stable,
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
comparison of the main prognostic factors was performed to<br />
investigate differences in younger women with primary BC in contrast<br />
to older women over time.<br />
Patients and Methods: In this retrospective analysis a consecutive<br />
pts cohort of 4010 pts was analyzed. Pts were documented and treated<br />
for primary invasive breast cancer between 1963 and 2003 at two<br />
University Hospitals in Germany. To be eligible, pts were required to<br />
have identified tumor characteristics, including TNM-status. Pts with<br />
carcinoma in situ or distant metastases were excluded. The cohort<br />
was divided in two age groups, ≤40y and >40y. Furthermore to reveal<br />
trends and changes over the duration of 41 years the period of analysis<br />
was split into 3 time frames: 1963-1976, 1977-1989 and 1990-2003.<br />
We analyzed the main prognostic factors for BC including tumor<br />
size, grading, nodal status and HR-status in longitudinal comparison<br />
regarding the three time frames, respectively. During 1963-77 HRstatus<br />
was determined in just 12.6% of pts. Thus, this time frame was<br />
excluded in the analysis of HR-status.<br />
Results: In 41 yrs, 747 (18.6%) pts were treated between 1963-76,<br />
1722 pts (42.9%) in 1977-89 and 1541 pts (38.4%) in 1990-2003.<br />
Overall 358 pts were ≤40y and 3652 pts were over the age of 40.<br />
A significant reduction of tumor size (metric assessment) at primary<br />
diagnosis was observed for both age groups (pts≤40y: p=0.012;<br />
pts>40y: p40<br />
y (p=0.001) whereas no difference could be seen in pts aged ≤40 y<br />
(p=0.991).<br />
In both age groups the number of G2/3 tumors increased over the<br />
yrs (pts≤40y: p=0.001; pts>40y: p40y 38.4% and 21.7% were HR-negative,<br />
respectively (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
also collected and used to identify women at potentially increased<br />
risk. Upon enrollment, women are given the opportunity to provide<br />
a blood or saliva sample for research purposes.<br />
Women who meet Athena-defined criteria that identify them to be<br />
at increased risk receive a referral to a <strong>Breast</strong> Health Specialist<br />
(BHS). The BHS identifies individual patient needs for prevention<br />
and screening services, including genetic counseling and testing,<br />
provides referrals to a High Risk <strong>Breast</strong> Clinic or nurse practitioner,<br />
and conducts lifestyle modification counseling. BHS have special<br />
training in breast cancer risk assessment, and some are licensed<br />
genetic counselors. Primary care and/or referring providers are<br />
directly informed of risk assessment results through mailings or the<br />
electronic medical record.<br />
Results<br />
The recruitment goal enrollment for Athena is 150,000 and to date<br />
more than 17,000 women have been enrolled across the five centers.<br />
Of those enrolled, 32% indicated that they have a family history of<br />
cancer. 56% of the cohort consented to participate in research, and<br />
40% provided a biospecimen for research purposes. Across the five<br />
centers, 32 educational outreach sessions about Athena were held,<br />
reaching approximately 375 providers.<br />
Site UCLA UCI UCD UCSF UCSD Total<br />
Enrollment Period<br />
12/16/2010- 3/28/2011- 11/9/2011- 12/2/2011- 12/19/2011-<br />
5/21/2012 5/21/2012 5/21/2012 5/21/2012 5/21/2012<br />
Completed questionnaire 13,600 1,564 965 319 621 17,069<br />
Indicated a family history* 4,500 255 415 71 273 5,514 (32%)<br />
Consented to participate in<br />
7,150<br />
research<br />
1,090 841 230 315 9,626 (56%)<br />
Consented to provide<br />
biospecimen<br />
4,826 868 563 196 305 6,758 (40%)<br />
Outreach sessions 9 12 0 5 6 32<br />
Providers contacted in<br />
outreach*<br />
250 39 0 38 48 375<br />
* Includes estimates<br />
Conclusion<br />
Successful implementation of the Athena risk assessment and decision<br />
support process will enable the identification of high risk women who<br />
are most likely to benefit from tailored screening or risk reducing<br />
interventions and who otherwise may not have been referred for risk<br />
reducing measures. By identifying women at the highest risk and<br />
connecting them to screening and prevention resources, the Athena<br />
<strong>Breast</strong> Health Network aims to ultimately reduce the incidence of<br />
breast cancer in its participant cohort.<br />
P4-13-14<br />
Lung cancer after treatment of breast cancer:retrospective study<br />
from Curie Institut<br />
Sebbagh S, Cosquer M, Kirova YM, Livartowski A. Institut Curie,<br />
Paris, France; Institut Curie<br />
Background: Few studies have evaluated the effects of adjuvant<br />
radiotherapy (RT)of breast cancer(BC).The relation between the risk<br />
of lung carcinoma and radiotherapy have been controversial.<br />
Methods and materials: We retrospectively studied 127 patients<br />
treated at the Institut Curie with non metastatic breast cancer and<br />
lung carcinoma between 2000 and 2011(2/3 of BC apperead befor<br />
lung).Confirmation Diagnosis bronchial cancer obtained by: biopsy:<br />
histological data:architecture, IHC (HR, HER 2, TTF1), EGFR,<br />
Kras statut clinical and radiological Correlation. Comparison with<br />
breast tumor<br />
Results: BC: median age at diagnosis 54 years, predominatly invasive<br />
ductual carcinoma(IDC), lumpectomy 78%, mastectomy 21%. Lung<br />
cancer: median age at diagnosis: 63 years, 67 smokers. histology: 52<br />
% Adenocarcinoma, 18.1 % scamous cell carcinoma , 18.1% large<br />
cell carcinoma,13.4 % small cell carcinoma.EGFR mutation in 4.3%.<br />
109 patients underwent RT (3 cases of lung cancer befor BC):Region:<br />
internal mammary chain: 46, supracalvicular: 42 , axillary: 21.<br />
Technique: lateral decubitus position: 44 , dorsal decubitus position:<br />
57. Interval between breast and lung cancer: 0-3 years: 24.4%, 3-5<br />
years: 15%, 6-10years: 16.5%, 11-20 years: 28%, >20 years: peak of<br />
incidence of lung cancer in the 3 years of diagnosis of breast cancer:<br />
24.4 %. There was no apparent relation between treatment of BC<br />
and relative risk of developing lung carcinoma. 2nd peak between<br />
11-20 years: 32 % patients, suggest that RT may increase risk of lung<br />
carcinoma (latency period for radiation induced second malignancy).<br />
Conclusion: This study suggest that adjuvant RT is associated with<br />
a real but small risk of developing lung carcinoma.<br />
P4-14-01<br />
Incidence rate of nipple areolar complex ischemia after nipple<br />
sparing mastectomy. Analysis of the American Society of <strong>Breast</strong><br />
Surgeons Nipple Sparing Mastectomy Registry.<br />
Mitchell SD, Willey SC, Feldman SM, Beitsch PD, Unzeitig GW,<br />
Manasseh DME, Neumayer LA, Laidley AL, Grutman SB, Habal N,<br />
Busch-Devereaux E, Dupont EL, Ashikari AY. White Plains Hospital<br />
Medical Center, White Plains, NY; Georgetown, Washington, DC;<br />
Columbia University College of Physicians & Surgeons, New York,<br />
NY; Dallas <strong>Breast</strong> Center, Dallas, TX; Laredo <strong>Breast</strong> Care, Laredo,<br />
TX; Maimonides Medical Center, Brooklyn, NY; University of<br />
Utah, Salt Lake City, UT; Texas <strong>Breast</strong> Specialists, Texas Oncology,<br />
Dallas, TX; American Society of <strong>Breast</strong> Surgeons, Columbia, MD;<br />
Carolina <strong>Breast</strong> & Oncologic Surgery, Greenville, NC; <strong>Breast</strong> Surgery<br />
Associates, Greenlawn, NY; Watson Clinic, Lakeland, FL; Ashikari<br />
<strong>Breast</strong> Center, Dobbs Ferry, NY<br />
Objectives:<br />
The American Society of <strong>Breast</strong> Surgeons (ASBS) Nipple Sparing<br />
Mastectomy Registry (NSMR) is a prospective, non- randomized,<br />
IRB approved multi-center registry. The ASBS NSMR has been<br />
designed to facilitate compilation of information on metrics utilized,<br />
techniques utilized, aesthetic outcomes, as well as oncologic outcomes<br />
for the nipple sparing mastectomy. The NSMR will be ongoing for 10<br />
years with an initial N of 1000. Patient selection entails all patients<br />
undergoing a NSM at the participating institutions who have agreed<br />
to participate. We evaluated the incidence rate of nipple or nipple<br />
areolar complex ischemia after a nipple sparing mastectomy.<br />
Method:<br />
The first 173 patients entered into the ASBS NSMR (2011-2012)<br />
were analyzed for incidence rate of ischemia of the nipple or nipple<br />
areolar complex (NAC). Ischemia is defined as epidermolysis (partial<br />
thickness necrosis) or full thickness necrosis. Metrics analyzed<br />
included: postoperative NAC status, indication for surgery, patient<br />
characteristics, incision utilized, sub areolar and flap dissection<br />
technique, as well as cosmetic outcomes.<br />
Results:<br />
(Thirty-five) surgeons entered 265 NSMs on 173 patients into the<br />
ASBS NSM Registry. Indications included invasive carcinoma, DCIS,<br />
and prophylaxis. Incisions utilized included radial +/- peri -areolar<br />
extension, infra mammary fold, peri- areolar ellipse/ hemi batwing,<br />
previous lumpectomy site, and previous mastopexy incisions. Sub<br />
areolar and flap dissection technique included sharp +/- tumescent<br />
injection, electrocautery, or plasma blade. Reconstruction type<br />
included tissue expander, immediate implant, or autologous flap.<br />
Median follow-up was 5 months (range 1-16 months).<br />
The nipple or NAC in 33 (12%) of 265 mastectomies experienced<br />
some degree of ischemia. Out of a total of 265 mastectomies 3 (1%)<br />
required surgical debridement, 1 (0.3%) required surgical excision,<br />
and 29 (11%) experienced epidermolysis with full recovery (17<br />
topical treatment and 12 no treatment). No correlation in incision<br />
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type, method of dissection, utilization of separate axillary incision for<br />
SLNBx/AXLND, size or location of tumor, type of reconstruction,<br />
initial fill volume if tissue expanders utilized, previous breast surgery,<br />
previous radiation therapy, previous chemotherapy, smoking history,<br />
cup size, degree of ptosis, or indication for surgery was found in NACs<br />
undergoing ischemia versus those that did not. Cosmetic outcome<br />
assessed by the surgeon as well as patient satisfaction did not vary<br />
from the population that did not experience nipple/NAC ischemia.<br />
Cosmetic results were rated consistently as good or excellent.<br />
Conclusion:<br />
We report a 12% incidence rate of nipple or nipple areolar complex<br />
ischemia ranging from epidermolysis to full thickness necrosis: 3<br />
(1%) requiring surgical debridement, 1 (0.3%) requiring excision,<br />
and 29 (11%) exhibiting epidermolysis with full recovery. Surgical<br />
debridement or excision was rarely necessary. Epidermolysis was<br />
found to resolve with no bearing on perceived cosmetic outcome.<br />
P4-14-02<br />
National Trends and Indications for Nipple-Sparing Mastectomy:<br />
An Analysis Using the Surveillance, Epidemiology, and End<br />
Results (SEER) Database<br />
Agarwal S, Agarwal S, Agarwal J. Wayne State University, Detroit,<br />
MI; University of Michigan, Ann Arbor, MI; University of Utah, Salt<br />
Lake City, UT<br />
Introduction: Nipple-sparing mastectomy (NSM) is an evolving<br />
procedure occasionally used for breast cancer treatment. However,<br />
indications for NSM are institution-specific and lack consensus<br />
in the literature. This study uses the Surveillance, Epidemiology,<br />
and End Results (SEER) database to investigate the oncologic and<br />
demographic characteristics of breast cancer patients treated with<br />
NSM in the United States from 2005-2009.<br />
Methods: Female breast cancer patients treated from 2005-2009 with<br />
nipple-sparing/subcutaneous mastectomy (SEER code 30), defined as<br />
removal of breast tissue with preservation of nipple-areolar complex<br />
and overlying skin, were included. Variables analyzed included<br />
patient age, race, tumor stage, tumor size, lymph node status, and<br />
radiotherapy delivery.<br />
Results: A total of 449 female breast cancer patients who underwent<br />
NSM were isolated from the SEER database. The number of patients<br />
in the SEER database who underwent NSM increased steadily each<br />
year, from 66 in 2005 to 133 in 2009. Mean age was 52 years (s.d.<br />
12 years). Breakdown by race showed that 369 (82%) patients were<br />
White women, 42 (9%) were Black women, 36 (8%) were of Asian<br />
descent. A majority of patients (402) were documented to have ductal<br />
or lobular carcinoma. Documented tumor diameter was less than 3<br />
cm in 63% (284) of patients. Invasive cancer was documented in 283<br />
(63%) patients; in situ cancer was documented in 166 (37%) patients.<br />
Lymph node involvement was negative in 374 (83%) patients.<br />
Radiation therapy was delivered to 91 (20%) patients; however, 64<br />
patients receiving radiation therapy were node-negative. Radiation<br />
was delivered to 6% (10) of patients with in situ cancer and 27% (77)<br />
of patients with invasive cancer (p < 0.0001).<br />
Conclusions: The number of NSM procedures reported in SEER for<br />
breast cancer has increased from 2005-2009. However, there is a lack<br />
of consensus in the literature as to which patients may be candidates<br />
for NSM. By utilizing a national database, we are able to aggregate<br />
and report on the national experience with therapeutic NSM, to<br />
date. Patients undergoing NSM for breast cancer were characterized<br />
predominantly by tumors less than 3 cm in diameter and with negative<br />
lymph node involvement. Patients with both invasive and in situ<br />
tumors were considered suitable candidates for NSM. A majority of<br />
patients had either ductal or lobular carcinomas. A minority of patients<br />
received radiation therapy, although there was a tendency towards<br />
providing patients with invasive tumors with radiation therapy. This<br />
national data should help guide patient selection for NSM, although<br />
future studies are needed to report on the long-term oncologic safety<br />
of this procedure.<br />
Number of Reported NSM Procedures by Year<br />
Year<br />
# of NSM Procedures<br />
2005 66<br />
2006 76<br />
2007 82<br />
2008 92<br />
2009 133<br />
P4-14-03<br />
Nipple-sparing mastectomy and intra-operative nipple biopsy:<br />
To freeze or not to freeze?<br />
Guth AA, Blechman K, Samra F, Shapiro R, Axelrod D, Choi M, Karp<br />
N, Alperovich M. NYU School of Medicine, New York, NY<br />
Background: Advances in breast cancer screening and treatment have<br />
fostered the use of surgical procedures that increasingly optimize<br />
cosmetic outcome, while ensuring oncologic safety remains the<br />
primary concern of the oncologic surgeon. The role of nipple-sparing<br />
mastectomy (NSM) for risk-reducing surgery and breast cancer is<br />
evolving. It can be difficult to demonstrate involvement of the nippleareolar<br />
complex (NAC) preoperatively, and and in this report we<br />
examine the utility of intraoperative subareolar frozen section (FS).<br />
Methods: Records of patients undergoing NSM at the NYU Langone<br />
Medical Center from 2006-2011 were reviewed retrospectively. Use<br />
of subareolar FS was at surgeon’s discretion.<br />
Results: 237 NSM were performed (146 prophylacytic, 91 theraputic).<br />
FC was not utilized in 58 mastectomies (28 prophylactic), with 2 (+)<br />
on paraffin. Among the remaining 180 mastectomies, 11 biopsies<br />
were (+)(7.2%); 5 subareolar biopsies were (+) on FS and paraffin<br />
histologic slides (PS)(2.8%); 6 were negative on FS and (+) on PS.<br />
Among the 3 prophylactic NSM with (+) subareolar biopsies there<br />
was 1 (+) FS, 1 (-) FS, and 1 with no FS performed. There were no<br />
false (+) FS. Four of the 5 patients with (+)FS underwent simultaneous<br />
excision of the NAC. The 5th patient had atypia on FS and DCIS<br />
on PS, and returned to the OR during the same hospitalization for<br />
removal of NAC. The remaining patients underwent subsequent<br />
excision of the NAC either during planned 2nd stage reconstruction<br />
or following completion of chemotherapy. 8 NAC were free of disease<br />
and 5 were positive for in situ or invasive disease. There has been no<br />
local recurrence in these patients to date.<br />
Conclusions: The rate of NAC involvement is low, 5.5% in this series,<br />
and FS, while utilized in the majority of these cases, detected only<br />
46% of subareolar disease. While FS can direct intraoperative decision<br />
making, the predictive power is low, and these considerations must be<br />
addressed in preoperative patient discussions. Furthermore, among<br />
those patients with (+) subareolar biopsies, only 39% had residual<br />
disease on NAC excision. Thus, optimal oncologic management of<br />
the NAC must still be considered an unresolved issue.<br />
P4-14-04<br />
Total skin-sparing mastectomy in BRCA mutation carriers<br />
Warren Peled A, Hwang ES, Ewing CA, Alvarado M, Esserman LJ.<br />
University of California, <strong>San</strong> Francisco; Duke University Medical<br />
Center<br />
BACKGROUND: Total skin-sparing mastectomy (TSSM) with<br />
preservation of the nipple-areolar complex skin has become<br />
increasingly accepted as an oncologically safe procedure for both<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
prophylactic and therapeutic indications. The goal of this study was<br />
to evaluate the oncologic outcomes after TSSM in BRCA mutation<br />
carriers.<br />
METHODS: We identified 53 BRCA-positive patients who underwent<br />
bilateral TSSM for prophylactic (27 patients) or therapeutic (26<br />
patients) indications from 2001 to 2011. Cases were age-matched<br />
(for prophylactic cases) or age- and stage-matched (for therapeutic<br />
cases) with non-BRCA-positive patients who underwent bilateral<br />
TSSM during this time period. Outcomes included tumor involvement<br />
of the resected nipple tissue, the development of new breast cancers<br />
in patients who underwent bilateral risk-reducing TSSM, and the<br />
development of any local-regional recurrence in patients who<br />
underwent therapeutic TSSM.<br />
RESULTS: Outcomes from 212 TSSM procedures in 53 cases<br />
and 53 controls were analyzed. In patients undergoing TSSM for<br />
prophylactic indications, in situ cancer was found in 1 (1.9%) of the<br />
nipple specimens in the BRCA-positive patients vs. 2 specimens<br />
(3.7%) in the non-BRCA-positive cohort (p = 1). At a mean followup<br />
of 56 months, no new cancers developed in the BRCA-positive<br />
or the non-BRCA-positive cohorts. In patients undergoing TSSM for<br />
therapeutic indications, in situ or invasive cancer was found in 0 of<br />
the nipple specimens in the BRCA-positive patients vs. 2 specimens<br />
(3.9%) in the non-BRCA-positive cohort (p = 0.49). At a mean<br />
follow-up of 33 months, there were no local-regional recurrences in<br />
the BRCA-positive cohort.<br />
CONCLUSIONS: TSSM is an oncologically safe procedure in<br />
BRCA-positive patients, as is evidenced by the low rates of tumor<br />
involvement of the nipple tissue and local-regional recurrence after<br />
therapeutic mastectomy. In BRCA-positive patients undergoing<br />
TSSM as a risk-reducing strategy, five-year follow-up demonstrates<br />
no increased risk for the development of new breast cancers; longerterm<br />
follow-up is anticipated to further confirm its safety.<br />
P4-14-05<br />
Skin sparing mastectomy – thorough breast tissue removal leads<br />
to a low local recurrence rate of breast cancer<br />
Paily AJ, Drabble EH. Derriford Hopsital, Plymouth, Devon, United<br />
Kingdom<br />
Introduction<br />
Skin sparing mastectomy (SSM) has the dual advantage of being<br />
an acceptable treatment for breast cancer as well as preserving a<br />
skin envelope for better aesthesis and cosmesis. However, SSM and<br />
immediate breast reconstruction for early breast cancer is not based<br />
on level-1 evidence. Even though oncological recurrence is equivalent<br />
to that with skin removing mastectomies, most studies have only<br />
short term follow-ups. Local Recurrence (LR) or the threat of it is<br />
becoming an increasing issue for us as 1 in 4 will succumb from local<br />
recurrence. We present local recurrence (LR) and systemic recurrence<br />
(SR) rates and the aesthetic results following SSM with or without<br />
immediate reconstruction.<br />
Methods and materials<br />
Over a period of 10 years, 249 patients undergoing SSM with or<br />
without immediate reconstruction were identified from a prospectively<br />
recorded database and complete details of all their treatments and<br />
outcomes were assessed. The reconstructive methods employed<br />
included Transverse Rectus Abdominus Myocutaneous (TRAM)<br />
flap, Latissimus Dorsi (LD) flap in isolation or along with an implant<br />
and subpectoral implant insertion. LR and SR rates were determined.<br />
Pathological examination of biopsies from the skin flaps after SSM,<br />
were also analysed.<br />
Results<br />
Of the 249 patients who underwent SSM, only 34 did not have<br />
immediate breast reconstruction. The overall LR and SR rates<br />
were 0.4% and 4.4% respectively. 76 patients underwent SSM and<br />
TRAM flap reconstruction (1 LR and 5 SR). 33 patients had LD flap<br />
reconstruction (no LR and 1 SR). 61 patients were given LD flap<br />
reconstruction with implants (no LR and 4 SR). SSM and insertion<br />
of sub-pectoral implants was performed on 45 patients (no LR and no<br />
SR). 34 patients underwent SSM without immediate reconstruction<br />
(no LR, 1 SR). All 249 patients had no evidence of residual breast<br />
tissue in subcutaneous flap biopsies. Of the 215 patients who<br />
underwent immediate reconstruction, 140 had a good aesthetic result<br />
(65%). Individually, TRAM flap and LD flap with implant insertion<br />
each produced the best aesthetic result (74%). While reconstructions<br />
with LD flaps alone did result in a good aesthetic result in 70% of<br />
patients, it also had the poorest aesthetic result (12%) compared to<br />
the other three groups.<br />
Conclusion<br />
SSM with or without immediate breast reconstruction performed in<br />
our unit has shown a very low rate of LR compared to that in literature.<br />
In addition, flap biopsies have shown no residual breast tissue in our<br />
patients highlighting that thorough removal of breast tissue at skin<br />
sparing mastectomy leads to low LR rates. Our systemic recurrence<br />
rates are much higher than local recurrence rates, but are still as<br />
expected or slightly lower than expected. Our approach therefore<br />
achieves thorough removal of breast tissue and we believe that this<br />
leads to a low local recurrence rate, but with good aesthetic results.<br />
P4-14-06<br />
Withdrawn by Author<br />
P4-14-07<br />
Impact of preservation of the intercostobrachial nerve during<br />
axillary dissection on sensory change and health-related quality<br />
of life two years after breast cancer surgery<br />
Taira N, Shimozuma K, Ohsumi S, Kuroi K, Shiroiwa T, Watanabe<br />
T, Saito M. Okayama University Hospital, Okayama, Japan;<br />
Ritsumeikan University, Japan; National Shikoku <strong>Cancer</strong> Center,<br />
Japan; Tokyo Metropolitan <strong>Cancer</strong> and Infectious Diseases Center<br />
Komagome Hospital, Japan; Teikyo University, Japan; Sendai<br />
Medical Center, Japan; Juntendo University, Japan<br />
Background: Sensory loss or paresthesia due to division of the<br />
intercostobrachial nerve (ICBN) is a complication of axillary lymph<br />
node dissection (ALND). Preservation of the ICBN may be of value,<br />
but few prospective studies have shown an impact of preservation<br />
on sensory changes or health related quality of life (HRQOL) after<br />
breast cancer surgery.<br />
Methods: Prospective study was performed to evaluate the association<br />
of ICBN preservation with sensory change and HRQOL at 1<br />
(baseline), 6, 12 and 24 months after breast cancer surgery in 140<br />
patients. The sensory examination included dysesthesia, paresthesia,<br />
abnormal touch and pain sensation in the upper arm.<br />
Results: Division of the ICBN did not influence the frequency or<br />
severity of subjective dysesthesia and paresthesia. There was no<br />
marked difference in touch or pain sensation at baseline between<br />
patients with a preserved (group P) and divided (group D) ICBN. In<br />
group P, the percentage of patients aware of a sensory deficit or loss<br />
decreased with time, and that of patients aware of a hypersensitive<br />
sensation increased. These changes did not occur in group D, leading<br />
to a significant difference between the groups at 24 months. The main<br />
difference between the groups was the area with reduced touch or<br />
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pain sensation. This area decreased with time in group P, but not in<br />
group D. ICBN preservation or division did not influence HRQOL.<br />
Conclusion: ICBN preservation in ALND has a benefit of a reduced<br />
area with long-term axillary hypoesthesia, but has no influence on<br />
improvement of pain and HRQOL.<br />
P4-14-08<br />
Intraoperative ultrasound guidance for excision of non-palpable<br />
breast cancer<br />
Barentsz MW, van Dalen T, Gobardhan PD, Bongers V, Perre CI,<br />
Pijnappel RM, van den Bosch MA, Verkooijen HM. University Medical<br />
Center Utrecht, Netherlands; Diakonessenhuis, Utrecht, Netherlands;<br />
Amphia Hospital, Breda, Netherlands<br />
Background<br />
The effectiveness of intraoperative ultrasound (IOUS) for<br />
preoperative localization of non-palpable breast cancers within the<br />
operation theatre has not been studied extensively. In this prospective<br />
cohort study, we compared margin status, re-excision rate and excised<br />
volume of IOUS to guidewire localization (GWL).<br />
Methods<br />
A total of 258 consecutive patients with non-palpable invasive breast<br />
cancer underwent breast conserving surgery between 1999-2010.<br />
GWL was performed in 138 (54%) and IOUS in 120 (46%) patients.<br />
Tumour dimensions, resection volume, margin status and re-excision<br />
rates were compared by means of multivariate regression analysis.<br />
Calculated resection ratios, i.e. indicating the amount of excess tissue<br />
resection, were calculated by dividing the total resection volume<br />
by the optimal resection volume (the tumor diameter plus a 1.0 cm<br />
margin) and compared between the groups.<br />
Results<br />
The groups were similar in terms of age, histological subtype and<br />
presence of DCIS. Lesions in the IOUS group were larger (1.24 vs.<br />
0.98 cm), while lesions in the GWL group consisted more often of<br />
microcalcifications only (19% vs. 3%). Tumour free resection margins<br />
were obtained in more than 93% of patients (93.5% with GWL vs.<br />
93.3% with IOUS, P = .958) and re-excision was performed in 11.0%<br />
of patients undergoing GWL and 12.5% of patients undergoing IOUS<br />
(P = .684). In both groups, resection volumes were similar, but IOUS<br />
led to more optimal tissue resection (calculated resection ratio 4.33<br />
vs 3.30, P = .018). After adjustment for tumor diameter, radiological<br />
findings and presence of DCIS, the difference in calculated resection<br />
volumes was no longer significant.<br />
Conclusion<br />
For localization of non-palpable breast cancer, IOUS is a reliable<br />
alternative to GWL, as it achieves similar results in terms of complete<br />
tumour removal, re-excision rate and excised volume.<br />
P4-14-09<br />
Feasibility of liposuction for treatment of arm lymphedema from<br />
breast cancer.<br />
Doren EL, Smith PD, Sun W, Lacevic M, Fulp W, Reid R, Laronga<br />
C. University of South Florida, Tampa, FL; Moffitt <strong>Cancer</strong> Center,<br />
Tampa, FL<br />
Background: Lymphedema is a dreaded complication of breast cancer<br />
treatment affecting 20% of women having axillary node dissection.<br />
Liposuction minimizes unwanted fat in targeted areas. Our objective<br />
was to explore the feasibility of liposuction to reduce fat volume and<br />
thus arm lymphedema.<br />
Methods: An IRB-approved prospective trial was conducted of<br />
women having unilateral arm lymphedema resulting from breast<br />
cancer treatment. At enrollment there was no evidence of cancer<br />
recurrence or arm cellulitis. Arm measurements (circumferential),<br />
volumes (water displacement and geometric calculation), and muscle<br />
strength differences between the affected and unaffected arms and<br />
quality of life/functionality were measured pre-operatively and<br />
post-operatively at 6 weeks, 6 months and one year(s). Descriptive<br />
statistical analysis was performed.<br />
Results: Six breast cancer survivors underwent the liposuction<br />
procedure from 12/2008- 4/2011. Median age was 54 yrs (range: 43-<br />
60) and median volume of fat aspirated was 700mls (range: 350-700).<br />
Average volume difference between the affected and unaffected arms<br />
at baseline was 522.5 mls (176-867) (geometric) and 589.2mls (280-<br />
770) (water displacement). No immediate complications; 1 cellulitis<br />
at 4 months post-operative. Average percent volume reductions for<br />
5 of the 6 women at 6 weeks, 6 months and 1 year were 70%, 47%,<br />
71% mls geometrically and 63%, 18%, 54% by water displacement<br />
respectively. Quality of life and functionality improved in all patients.<br />
Muscle strength remained unchanged. Pain lessened. Average followup<br />
is 15.49 months (range: 1.8-24.84 months).<br />
Conclusion: Liposuction can safely reduce volume of arm<br />
lymphedema and improve functionality/quality of life. Larger studies<br />
(longer follow-up) are required to validate the durability of these<br />
early results.<br />
P4-14-10<br />
Atypical Ductal Hyperplasia diagnosed on directional vacuumassisted<br />
biopsy: is surgical excision mandatory?<br />
Chauvet M-P, Rivaux G, Farre I, Houpeau J-L, Giard S, Ceugnart<br />
L. Centre Oscar Lambret, Lille, France<br />
Background: The incidence of atypical ductal hyperplasia (ADH) is<br />
increasing due to mass screening. Because of the underestimation risk<br />
of malignancy, the management remains controversial. Our goal was<br />
to analyze clinicopathologic features of patients with ADH diagnosed<br />
on directional vacuum-assisted biopsy (DVAB). The objectives of this<br />
continuous retrospective study were to evaluate the underestimation<br />
rate of malignancy and to identify predictors of upgrade to carcinoma.<br />
Methods: Between 2003 and 2010, 3159 patients underwent<br />
stereotactic DVAB in our institute. We retrospectively evaluate<br />
clinical, mammographic and pathological features of 298 cases of<br />
ADH who underwent surgical excision in our center (93.1%). Patients<br />
with concurrent history of breast cancer, intraductal carcinoma (DCIS)<br />
associated, or with no follow-up or surgical excision on place were<br />
excluded. Histological scar of macrobiopsy was systematically<br />
searched in surgical specimens. A pathologic upgrade was defined by<br />
presence of invasive cancer or DCIS on surgical specimen. Statistical<br />
tests used were the chi-square or Fisher’s exact test.<br />
Results: Among the 298 studied DVAB, 224 ADH were isolated<br />
(75.2%), 46 associated to flat epithelial atypia (15.4%) and 28 to<br />
lobular neoplasia (9.4%). 98.4% patients presented microcalcifications<br />
at diagnosis. In 52 cases, lesions were upgraded to DCIS (n=38) or<br />
invasive cancer (n=14). The underestimated rate was 17.5%. In 67.3%<br />
cases, upgrade lesions were low or intermediate grade DCIS. Only the<br />
history of contralateral breast cancer was significantly correlated with<br />
the underestimated rate (p=0.04). There was no statistical difference<br />
between these 52 cases and the 246 others for: family history, size<br />
of calcification, sampling number, histological lesion, and quality of<br />
calcifications removal.<br />
Conclusions: In this study, DVAB may not be considered a therapeutic<br />
procedure in case of ADH, even in the case of complete removal of<br />
microcalcifications. It is still challenging to identify a subgroup of<br />
ADH cases with a low upgrade rate.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
406s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
P4-14-11<br />
Risk reducing mastectomy for women with high personal breast<br />
cancer risk<br />
Onyekwelu O, Shetty G, Baildam A. Nightingale & Genesis <strong>Breast</strong><br />
<strong>Cancer</strong> Prevention Centre, University Hospital of South Manchester,<br />
Wythenshawe, Manchester, United Kingdom; St. Bartholomew’s<br />
Hospital (Bart’s), West Smithfield, London, United Kingdom<br />
Introduction<br />
For high-risk familial history of breast cancer, risk reducing<br />
mastectomy (RRM) is now regarded as one of the management<br />
options. The aim of this study is to analyse the outcome of women<br />
undergoing RRM from 1994 to 2010 during which surgical techniques<br />
evolved and were refined.<br />
Methods<br />
A cohort of women undergoing RRM was followed from this single<br />
centre. Surgical and further details about demographics, comorbidities,<br />
and follow-up were retrieved form medical records. Analysis was<br />
carried out using the IBM®-SPSS®-Statistics-19system.<br />
Results<br />
Of 154 women 139 had bilateral RRM and 15 had unilateral surgery<br />
after earlier contralateral breast cancer. Median age at operation was<br />
39.4 years (22-63years). 54 (45.5%) women were BRCA1/2 gene<br />
mutation carriers. Most women had nipple sacrificing (86) skinsparing<br />
mastectomy with immediate reconstruction. 132 (85.7%) had<br />
submuscular expander/implant reconstruction, whilst 9 had either LD<br />
flap reconstruction or TRAM flap reconstruction.<br />
31 (20.1%) women had some complication including haematoma<br />
requiring evacuation, minor skin/nipple necrosis, but implant loss<br />
was rare (2). 52 (33.8%) women had revisional surgeries in 5 years<br />
post RRM of whom 29 had one unanticipated secondary operation.<br />
Complications were more common in the early years of the cohort.<br />
On histology, 3 women were identified with lobular carcinoma in-situ<br />
and one was associated with 1mm of microinvasion. 4 had ductal<br />
carcinoma in-situ and 2 of them were BRCA carriers. Two (1.2%)<br />
primary breast cancers were subsequently identified during a mean<br />
follow-up period of 9.82 years (2-18 years) but this was substantially<br />
less than prediction modelling. Both were BRCA gene mutation<br />
carriers - one had nipple sparing RRM and the other did not.<br />
Conclusions<br />
In asymptomatic high-risk women, RRM is safe and efficacious in<br />
reducing medium term future breast cancer incidence. Surgery carries<br />
the risk of complications and cosmetic revisions can be anticipated.<br />
P4-14-12<br />
Evaluation of the effect of pasireotide LAR administration in<br />
the lymphocele prevention after mastectomy with axillary lymph<br />
node dissection for breast cancer: results of a phase 2 randomized<br />
study.<br />
Chereau E, Uzan C, Zohar S, Bezu C, Mazouni C, Ballester M, Gouy<br />
S, Rimareix F, Garbay J-R, Darai E, Uzan S, Rouzier R. Tenon,<br />
APHP, UPMC - Paris 6, Paris, France; Institut Gustave Roussy,<br />
Villejuif, France; Hopital Saint-Louis, APHP, U444-INSERM, Paris<br />
7, Paris, France<br />
Background: Lymphocele is the principal post-operative morbidity<br />
following axillary node dissection. According to the literature, the<br />
incidence can vary from 4% to 89%. Encouraging results in terms<br />
of reducing postoperative lymphoceles as well as the volume and<br />
duration of drainage using octreotide LAR has been recently reported.<br />
Pasireotide LAR, a long acting drug designed to target multiple<br />
somatostatin receptors, was evaluated in this trial.<br />
Trial design: A phase II, two centers, randomized, double-blind,<br />
non-comparative pilot study was carried out in order to evaluate<br />
efficacy and safety of a single injection of pasireotide LAR 60 mg<br />
administered 7-10 days before scheduled mastectomy with axillary<br />
dissection surgery. This study included a parallel placebo arm to<br />
assess the natural course of the disease.<br />
Eligibility criteria: Adult female breast cancer patients planned to<br />
undergo a mastectomy (without reconstruction at the same time) and<br />
axillary node dissection .<br />
Specific aims: To assess the efficacy and safety of a single injection<br />
of pasireotide LAR 60 mg or placebo prior to mastectomy with<br />
axillary lymph node dissection surgery in reducing symptomatic<br />
lymphocele development. Symptomatic lymphocele was evaluated<br />
and was defined as: 1. total lymphocele drainage/aspiration volume<br />
(unique or iterative) >60 cc inclusive within the 28 days after surgery<br />
(excluding post-surgery drain) or; 2. a systematic aspiration volume<br />
at day 28 > 120 cc.<br />
Statistical methods: The statistical analysis was carried out<br />
sequentially after observing the absence of symptomatic lymphocele<br />
for each patient. It involves estimating the probability of a response in<br />
each group using a Bayesian design based on a beta-binomial model.<br />
The probability of response was considered random and its prior<br />
distribution was centered on 80% in the pasireotide group and 60%<br />
in the placebo group according to the investigators initial guesses.<br />
The distribution of the probability of response was updated after the<br />
observation of the patients included in the trial.<br />
Results: A total of 90 patients were included over 18 months: 42 in<br />
the treatment group and 48 in the placebo group. In the treatment<br />
group, the posterior mean estimation of the response rate (i.e. patients<br />
who did not experience a symptomatic lymphocele) was 62.4%<br />
(95% CI: 48.6%-75.3%) and 50.2% in the placebo group (95% CI:<br />
37.6%-62.8%%). In the treatment group, one serious adverse event<br />
occurred in a patient with known insulin dependent diabetes requiring<br />
hospitalization for hyperglycaemia.<br />
Conclusion: A one time injection of pasireotide LAR to prevent<br />
symptomatic lymphocele development in women undergoing<br />
mastectomy with axillary dissection is promising. Further clinical<br />
studies are warranted.<br />
P4-14-13<br />
Therapeutic mammaplasty does not cause a delay in the delivery<br />
of chemotherapy in high risk breast cancer patients<br />
Khan J, Barrett S, Stallard S, Forte C, Weiler-Mithoff E, Reid I,<br />
Winter A, Doughty J, Romics L. Victoria Infirmary, Glasgow, United<br />
Kingdom; Beatson West of Scotland <strong>Cancer</strong> Centre, Glasgow, United<br />
Kingdom; Western Infirmary, Glasgow, United Kingdom; Royal<br />
Infirmary, Glasgow, United Kingdom<br />
Introduction: oncosurgical safety of therapeutic mammaplasty (TM)<br />
is widely investigated. The interval between surgery and delivery<br />
of adjuvant chemotherapy is an integral part of overall oncological<br />
safety. Therefore, we examined the time between TM and AC, and<br />
compared it to wide local excision (WLE) and mastectomy (Mx)<br />
with or without immediate breast reconstruction (IBR), respectively.<br />
Methods: data of 174 patients who underwent TM, WLE and Mx±IBR<br />
was analyzed retrospectively. All patients were operated within three<br />
breast units of Glasgow during a period of 48 months. Time between<br />
decision to offer adjuvant chemotherpay and delivery of the first<br />
cycle of chemotherapy was analyzed. Significance was calculated<br />
with Mann-Whitney and Kruskal-Wallis tests (two and four groups<br />
compared, respectively).<br />
www.aacrjournals.org 407s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Results: median time to adjuvant chemotherapy after TM (n=36)<br />
was 29 [16-58] days, WLE (n=66) was 29.5 [15-105], Mx only<br />
(n=56) was 29 [15-57], and Mx and IBR (n=16) was 31 [15-58]<br />
days. No significant difference was found in terms of time to adjuvant<br />
chemotherpay in patients treated with TM compared to WLE<br />
(p=0.384), Mx only (p=0.828) or Mx and IBR (p=0.366). Further,<br />
there was no significant difference when a cumulative comparison<br />
of the four groups was carried out (p=0.507).<br />
Conclusions: our data indicate that oncosurgical safety of TM in terms<br />
of time to chemotherapy is similar to other high risk breast cancer<br />
patients treated WLE and Mx with or without IBR. This also suggests<br />
that there is no significant difference in postoperative complication<br />
rates after these four ways of surgical treatment of breast cancer,<br />
which would possibly be the primary cause for a delay in delivering<br />
adjuvant chemotherapy.<br />
P4-14-14<br />
Phyllodes tumour of the breast: A retrospective analysis of 87<br />
cases<br />
Walter HS, Esmail F, Krupa J, Ahmed SI. Leicester Royal Infirmary,<br />
Leicester, United Kingdom; Glenfield Hospital, Leicester, United<br />
Kingdom<br />
Background: Phyllodes tumour is a rare fibroepithelial tumour of the<br />
breast that accounts for only 0.5% of all breast neoplasms.<br />
Methods: We retrospectively reviewed the case notes of all patients<br />
with phyllodes tumour treated between 1987-2010. Clinical data was<br />
analysed with respect to pathological and treatment outcome data.<br />
Results: Between 1987-2010, 87 patients were treated for tumours,<br />
histologically classified as benign (60), borderline (10) and malignant<br />
(17). Median age at presentation was 55 years for patients with<br />
malignant phyllodes, 45 years for benign phyllodes and 48 years for<br />
patients with borderline tumours. Primary surgery for patients with<br />
benign or borderline phyllodes in 68 cases was breast conserving with<br />
2 patients undergoing mastectomy. Of those with malignant phyllodes,<br />
primary surgery for 6 patients was mastectomy and 11 patients had<br />
breast conserving surgery. 2 patients with malignant phyllodes<br />
received adjuvant radiotherapy, to the chest wall for recurrence<br />
following mastectomy in one patient and following local excision<br />
in the other patient. 2 patients with malignant phyllodes proceeded<br />
to axillary surgery, with no involvement of lymph nodes. 6 patients<br />
(8.6 %) with benign disease and 4 (23.5 %) with malignant phyllodes<br />
had a local recurrence. Of those with malignant phyllodes who had a<br />
recurrence, 2 had systemic metastases and all had had a local excision<br />
at presentation. Median time to development of metastatic disease<br />
from initial presentation was 2.5 years. 1 patient received 1 cycle of<br />
palliative doxorubicin but progressed through treatment. Relapse free<br />
survival to date for patients with benign, borderline and malignant<br />
phyllodes was 91.7 %, 90 % and 70.6 % respectively.<br />
Conclusion: Phyllodes tumours form a heterogenous group with<br />
a spectrum of behaviour in terms of risk of local recurrence and<br />
metastases. From this series, malignant phyllodes have a higher<br />
recurrence rate than benign and borderline tumours. Local excision in<br />
this group was associated with a 36.4 % local failure rate and 18.2 %<br />
risk of systemic metastasis. Treatment for malignant phyllodes should<br />
be individually based, but the greater risk of relapse both locally and<br />
systemically, should be taken into consideration and the options of<br />
mastectomy or oncoplastic techniques considered.<br />
P4-15-01<br />
Second conservative treatment for ipsilateral breast tumor<br />
recurrence: GEC-ESTRO <strong>Breast</strong> WG study<br />
Hannoun-Levi J-M, Resch A, Gal J, Niehoff P, Loessl K, Kovács G,<br />
Van Limbergen E, Polgar C. Antoine Lacassagne <strong>Cancer</strong> Center,<br />
Univerity of Nice-Sophia, Nice, France; Medical University, General<br />
Hospital of Vienna, Austria; Antoine Lacassagne <strong>Cancer</strong> Center,<br />
Nice, France; University Erlangen-Nuremberg, Erlangen, Germany;<br />
University Hospital Bernes, Switzerland; University Hospital<br />
Schleswig-Holstein Campus Lübeck, Germany; University Hospital<br />
Gasthuisberg, Leuven, Belgium; National Institute of Oncology,<br />
Budapest, Hungary<br />
For ipsilateral breast cancer tumor (IBTR), radical mastectomy<br />
represents the treatment option frequently proposed to the patient.<br />
A second conservative treatment (SCT) has been proposed using<br />
either lumpectomy alone or associated with a second irradiation of<br />
the tumor bed. However, in both clinical situations, the proof level<br />
of such therapeutic approaches remains low, based on cased-series<br />
or retrospective studies.<br />
To analyze the clinical outcome of a SCT using lumpectomy and<br />
multicatheter interstitial brachytherapy (MIB) for IBTR, the GEC-<br />
ESTRO <strong>Breast</strong> Working Group retrospectively analyzed the results of<br />
217 patients (pts) with an IBTR treated between 09/00 and 09/10 in<br />
8 European institutions by lumpectomy and MIB (low - LDR, pulse<br />
- PDR, or high-dose rate - HDR). Survival rates without 2nd local<br />
(2nd LR) and metastatic recurrence, disease free survival (DFS) and<br />
specific and overall survivals were analyzed as well as late effects<br />
and cosmetic results. Dosimetric data were reported according to the<br />
dose rate used. Univariate and multivariate analysis were performed<br />
to find local, metastatic and/or DFS progression prognostic factors.<br />
With a median follow-up of 14.5 years [3.5-38.2] and 3.9 years [1.1-<br />
10.3] from primary tumor and IBTR respectively and a median time<br />
interval of 9.4 years [1.1-35.4] between primary and IBTR, 20.7%<br />
of the local recurrence were observed at distance from the primary<br />
tumor. Median tumor sizes were 15 mm [1-60] and 11 mm [1-40]<br />
for the primary and IBTR respectively. Thirty-nine percent of the<br />
patient underwent an axillary lymph node dissection at the time of<br />
IBTR. Median radiotherapy dose for the primary was 56 Gy [30-<br />
69.6]. Positive hormonal receptor status for IBCR was 72.8% while<br />
65% and 19.8% received hormonal and chemotherapy respectively<br />
as adjuvant therapy for the IBTR. Five and 10-year actuarial 2nd LR<br />
rates were 5.6% [1.5-9.5] and 7.2% [2.1-12.1] respectively. Five and<br />
10-year actuarial metastatic recurrence rates were 9.6% [5.7-15.2]<br />
and 19.1% [7.8-28.3] respectively. Five and 10-year actuarial DFS<br />
rates were 84.6% [78.9-90.6] and 77.2% [67.5-88.3] respectively. Five<br />
and 10-year actuarial overall/specific survival (OS) rates were 88.7%<br />
[83.1-94.8] and 76.4% [66.9-87.3] respectively. 141 pts developed<br />
193 complications. Fibrosis was the most frequent complication with<br />
11% of G3-4 complications. Cosmetic result was jugged as excellent/<br />
good in 85%. Focusing on multivariate analysis, prognostic factors<br />
for 2nd LR, metastatic recurrence and DFS are reported.<br />
MVA results<br />
IBTR 2nd LR Distant mets DFS<br />
Age 0.09 - -<br />
Grade 0.02 - -<br />
pT - 0.01 0.001<br />
HR - - 0.003<br />
pT: tumor size; HR: hormone status<br />
The results of this study suggest that in case of IBTR, a SCT<br />
combining lumpectomy plus MIB is feasible with an overall survival<br />
rate at least equivalent to those obtain after salvage mastectomy. The<br />
rate of complication remains acceptable with encouraging cosmetic<br />
results.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
408s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
The literature analysis suggests that the rate of 2nd LR is 10% [3-<br />
32], 25% [7-36] and 10% [2-26], after salvage mastectomy, salvage<br />
lumpectomy alone or combined with a second irradiation respectively.<br />
However, the 5-y OS rates after salvage mastectomy and SCT seem<br />
to be equivalent (75%) mainly influenced by distant metastatic<br />
progression.<br />
P4-15-02<br />
Timing of infectious complications following breast conserving<br />
therapy with catheter-based accelerated partial breast irradiation<br />
Haynes AB, Bloom ES, Bedrosian I, Kuerer HM, Hwang RF, Caudle<br />
AS, Hunt KK, Graviss L, Chemaly RF, Tereffe W, Shaitelman SF,<br />
Babiera GV. University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX<br />
Background:<br />
Accelerated partial breast irradiation (APBI) has been introduced<br />
as an alternative to whole breast irradiation as part of breast<br />
conserving therapy for selected patients. The long-term outcomes<br />
remain under investigation. Previous publications have emphasized<br />
early postoperative infections with APBI with less focus on delayed<br />
infection. In the current study, we evaluated patients enrolled on a<br />
prospective registry trial for infectious complications after treatment<br />
with catheter-based APBI.<br />
Methods:<br />
Patients who underwent single-entry catheter-based APBI were<br />
identified from a single-institution prospective registry from 2009 to<br />
2011. Data regarding treatment, patient comorbidities, complications,<br />
and outcomes were obtained from registry and retrospective chart<br />
review. Infectious complications were assessed from the date of APBI<br />
catheter insertion and were classified as early (≤30 days) or delayed<br />
(>30 days). All patients were maintained on oral antibiotics while<br />
the catheter was in place.<br />
Results:<br />
A total of 91 patients with 92 cases of primary breast cancer were<br />
enrolled on a prospective registry at a comprehensive cancer center<br />
between 2009 and 2011 and treated with single-entry catheter-based<br />
APBI. The median follow-up time was 76.2 weeks. A temporary<br />
catheter was placed at the time of initial operation in 40 cases (43.5%)<br />
and left in place a median of 6 days prior to definitive catheter<br />
insertion. There were 20 patients (21.7%) who required re-excision.<br />
Overall, breast infection occurred in 13 (14.1%) patients. Three (3.3%)<br />
patients had infection within 30 days of catheter placement and 10<br />
(10.9%) occurred more than 30 days after catheter insertion (median<br />
112.5 days, interquartile range 51-154). Eight patients were managed<br />
with oral antibiotics alone on an outpatient basis. The remainder<br />
required a combination of admission, intravenous antibiotics, and<br />
aspiration of abscess. One patient underwent operative drainage.<br />
Conclusion:<br />
We found an overall infection rate of 14.1% in patients treated with<br />
catheter-based APBI. This is consistent with other reports; however,<br />
we found that the majority of infections occurred more than 30<br />
days after definitive catheter placement. Vigilance for infectious<br />
complications must continue beyond the immediate treatment<br />
period in patients undergoing catheter-based APBI. Most infections<br />
following APBI can be managed on an outpatient basis without<br />
operative intervention.<br />
P4-15-03<br />
Patterns of relapse following re-irradiation of the breast using<br />
partial breast brachytherapy (PBB)<br />
Chadha M, Boachie-Adjei K, Boolbol SK, Kirstein L, Osborne MP,<br />
Tarter P, Harrison LB. Beth Israel Medical Center, New York, NY<br />
Purpose: This study is undertaken to evaluate the patterns of relapse<br />
among patients with a prior history of irradiation where the RT field<br />
included the breast, and who received re-irradiation using PBB for<br />
a localized second cancer event in the breast using partial breast.<br />
Materials and Methods: Twenty-seven patients were enrolled in an<br />
IRB approved study. Nineteen patients had prior history of breast<br />
cancer treated with lumpectomy and external beam therapy (ERT),<br />
and 8 patients had prior history of mantle RT. All patients underwent<br />
lumpectomy with negative margins and received a median dose of<br />
45Gy PBB. The median time interval between the primary breast<br />
cancer diagnosis and the second cancer event in the ipsilateral breast<br />
is 94-months (range 28-months to 211-months). The median time<br />
between mantle RT and the breast cancer is 245 months.<br />
Results: At a median follow up of 73 months following lumpectomy<br />
and PBB 14.8 % (4/27) patients developed a local recurrence and were<br />
salvaged by mastectomy. The 5-year Kaplan Meier local disease-free<br />
survival and mastectomy-free survival is 100% and 81%, respectively.<br />
Remarkably, one third of patients with prior history of mantle RT<br />
developed third primary cancers (pancreas, lung and renal). All<br />
patients with the third primary cancers died free of any relapse from<br />
the breast cancer. None of the patients with prior history of breast<br />
cancer developed a second malignancy, and 3/21 developed distant<br />
metastases.<br />
Conclusions: In appropriately selected patients with prior history<br />
of lumpectomy and ERT for breast cancer we observed a high rate<br />
of local control and freedom from mastectomy. Patterns of relapse<br />
among patients with prior mantle RT suggest that breast conservation<br />
and PBB was appropriate for treating early stage disease. <strong>Breast</strong><br />
conservation therapy did not have a detrimental effect on breast cancer<br />
specific outcome and eventual patient survival. Patients motivated<br />
for breast conservation may have an alternative to mastectomy at<br />
initial diagnosis.<br />
P4-15-04<br />
Impact of awake brest cancer surgery on postoperative<br />
lymphocyte responses<br />
Vanni G, De Felice V, Buonomo C, Esser A, Petrella G, Buonomo<br />
OC. Tor Vergata University, Rome, Italy<br />
Background. Surgical stress and general anesthesia can have a<br />
detrimental effects on postoperative immune system. We sought<br />
to evaluate comparatively postoperative lymphocytes response in<br />
patients undergoing quadrantectomy and lymph node sentinel biopsy<br />
(LNSB) under local or general anesthesia.<br />
Methods. Between December 2011 and May 2012, 50 patients<br />
with breast cancer were randomized by computer to undergo<br />
quadrantectomy and LNSB under local anesthesia (awake group,<br />
n=25) or general anesthesia (control group, n=25). In both groups,<br />
assessment of total lymphocytes count and changes in proportion of<br />
specific lymphocyte-subsets including CD19+, CD3+, CD4+/CD8+<br />
ratio, CD4+, CD8+ and CD16+CD56+ (Natural-killer) were evaluated<br />
at baseline and on postoperative day 1, 2 and 3.<br />
Results. Study groups were well matched in baseline and surgical<br />
data. On postoperative day 1, a significantly higher amount of<br />
Natural-Killer proportion was found in the awake group versus the<br />
control group (median: 12 Vs 4, P=0.002); this difference was still<br />
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<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
significant on postoperative day 2 (median: 11 Vs 7, P=0.02). Yet, in<br />
awake group there was a higher CD4+/CD8+ ratio on postoperative<br />
day 1 (median: 2.6 Vs 1.6, P=0.05). No difference was found among<br />
groups in the remaining lymphocyte subsets. On postoperative day<br />
3, total lymphocytes count was significantly decreased from baseline<br />
value in the control group only (median-∆: 460/mm3, P=0.01) while<br />
it remained unchanged in the awake group.<br />
Conclusions. In this study, quadrantectomy and LNSB under local<br />
anesthesia resulted in a lesser impact on postoperative lymphocyte<br />
responses when compared to the equivalent procedure performed<br />
under general anesthesia.<br />
P4-15-05<br />
Long-term outcome of breast cancer patients treated with<br />
radiofrequency ablation<br />
Earashi M, Noguchi M, Motoyoshi A, Komiya H, Fujii H. Yatsuo<br />
General Hospital, Toyama, Japan; Kanazawa Medical University<br />
Hospital, Uchinada-Daigaku, Ishikawa, Japan<br />
Background: Radiofrequency ablation (RFA) is considered to be the<br />
most promising non-surgical ablation technique for the treatment<br />
of small breast cancer. In feasibility studies, the ablated tumor was<br />
surgically removed after RFA, and the tumor cell viability were<br />
assessed by histological and/or immunohistological examinations.<br />
However, these assessments of tumor viability do not take the place<br />
of long-term follow-up in patients treated with RFA alone, because<br />
they do not allow for them to be followed up for recurrence after<br />
RFA, or to determine if there were any undesirable complications of<br />
this procedure. At present, few data are available regarding long-term<br />
follow-up of patients treated with this modality.<br />
Methods: Since 2005, we have performed RFA and sentinel lymph<br />
node (SLN) biopsy in 19 cases with invasive breast cancer less than<br />
2.0 cm in greatest diameter. After SLN biopsy, a primary electrode<br />
(seven-array model 70 Starburst needle electrode; RITA Medical<br />
Systems, Mountain View, CA) was inserted into the tumor under<br />
real-time US guidance. Then, the prongs of the needle electrode<br />
were deployed over a distance of 3 cm in all cases, and the RF<br />
generator (RITA model 1500) was activated and set to automatic,<br />
with power at 20 W, temperature of 95°C, and an ablation time of<br />
15 min. Axillary lymph node dissection (ALND) was performed in<br />
patients with positive SLNs. Several months after RFA therapy, the<br />
ablated tumor tissue was excised by multiple mammotome biopsy<br />
and examined histologically or immunohistochemically with H&E<br />
staining, nicotinamide adenine dinucleotide (NADH)-diaphorase<br />
staining, and single-stranded (ss) DNA staining. All cases were<br />
followed-up after breast radiation and systemic therapies.<br />
Results: The mean tumor size based on the ultrasonographic maximum<br />
dimension was 1.3 cm (range: 0.5 – 2.0 cm). Although complete<br />
response was histologically confirmed in only 8 cases, NADHdiaphorase<br />
and ssDNA staining did not demonstrate any viable tumor<br />
cells in any of the ablated lesions. At a mean follow-up of 60 months<br />
(follow-up range, 37 – 82 months), there were no cases of in-breast<br />
recurrence, although one patient died due to hepatic metastases.<br />
Cosmesis of the conserved breast was excellent or good in all of the<br />
cases, but a hard lump was persistent after RFA in half of the cases.<br />
Conclusions: The long-term outcome of patients treated with RFA<br />
is encouraging with regard to cosmesis and local control. However,<br />
a persisted lump can cause patient discomfort, anxiety and fear.<br />
Therefore, further studies are needed to establish the optimal<br />
technique. Moreover, a prospective study will be required to determine<br />
the equivalency in local recurrence rates between the RFA therapy<br />
and conventional breast-conserving treatment.<br />
P4-16-01<br />
Accelerated hypofractionated whole breast radiotherapy for<br />
localized breast cancer: the effect of a boost on patient reported<br />
long-term cosmetic outcome<br />
Chan EK, Tabarsi N, Tyldesley S, Khan M, Woods R, Speers C, Weir<br />
L. British Columbia <strong>Cancer</strong> Agency, Vancouver Centre, Vancouver,<br />
BC, Canada; University of British Columbia, Vancouver, BC, Canada<br />
PURPOSE<br />
Equivalent long-term local control and cosmetic outcomes between<br />
conventional and accelerated, hypofractionated whole breast<br />
radiotherapy (AWBRT) for early-stage breast cancer have been<br />
demonstrated. However, there is uncertainty about the long-term<br />
cosmetic outcome of a boost to the tumor bed following AWBRT<br />
(AWBRT+B). The primary outcome of this study was to evaluate<br />
the cosmetic effect of a boost using a patient reported questionnaire.<br />
The cosmetic subscale in the questionnaire was used to compare the<br />
appearance of the treated versus non treated breast between the boost<br />
and non-boost groups.<br />
MATERIALS AND METHODS<br />
Between 2000 and 2005, 4392 women 75 years and under with<br />
unilateral early-stage breast cancer received AWBRT alone or<br />
AWBRT+B. Random samples of 800 women treated with AWBRT<br />
alone and 800 women treated with AWBRT+B were identified from<br />
the 3960 women still alive at least 5 years after treatment without<br />
contralateral disease. The women were contacted by mail to complete<br />
a questionnaire based on the <strong>Breast</strong> <strong>Cancer</strong> Treatment Outcomes Scale<br />
(22 questions regarding cosmetic, pain and functional outcomes).<br />
Cochrane-Armitage (CA) trend test and Wilcoxon Rank-sum (WR)<br />
were used to compare baseline patient and treatment variables to<br />
long-term cosmetic outcomes between the two treatment groups.<br />
RESULTS<br />
312 women (154 received AWBRT alone and 158 received<br />
AWBRT+B) completed the questionnaire. The median (range) age<br />
of respondents was 57 (40-75) years in the AWBRT alone group and<br />
52 (32-75) years in the AWBRT+B group (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
CONCLUSION<br />
Similar to conventionally fractionated WBRT, patients who receive<br />
a boost after AWBRT self-report long-term slightly worse cosmetic<br />
and pain outcomes compared AWBRT alone.<br />
P4-16-02<br />
A survival benefit from locoregional radiotherapy for nodepositive<br />
and CMF treated breast cancer is most significant in<br />
Luminal A tumors<br />
Voduc D, Cheang MCU, Tyldesley S, Chia S, Gelmon K, Speers C,<br />
Nielsen TO. BC <strong>Cancer</strong> Agency, Vancouver, BC, Canada; University<br />
of British Columbia, Vancouver, BC, Canada<br />
Background: Between 1978-1986, 318 premenopausal women<br />
treated with mastectomy for lymph node positive breast cancer, were<br />
randomized to CMF chemotherapy alone vs. CMF chemotherapy<br />
and adjuvant radiotherapy (RT) to the chest wall and regional<br />
lymph nodes. After 15 years of follow-up, post-mastectomy RT was<br />
associated with a statistically significant 29% relative risk reduction in<br />
mortality. Recent evidence suggests that Luminal A tumors, identified<br />
using hormone receptors and Ki67, have a particularly favorable<br />
prognosis. We retrospectively identified the Luminal A tumors from<br />
this clinical trial cohort to determine if the response to postmastectomy<br />
RT differed among Luminal A and non-Luminal A tumors.<br />
Methods: 203 archival breast tumor samples from this study were used<br />
to construct a tissue microarray. Luminal A tumors were identified<br />
using an immunopanel consisting of: estrogen receptor, progestorone<br />
receptor, Her2, and Ki67. Luminal A tumors were defined as either<br />
ER or PR positive, Her2 negative, and Ki67 < 14%. Kaplan-Meier<br />
estimates and the log-rank test were used to test the differences in<br />
locoregional relapse free survival (LRFS) and breast cancer specific<br />
survival (BCSS). Interaction between treatment and Luminal A/Nonluminal<br />
A were tested using Cox regression analysis.<br />
Results: The intrinsic subtype was successfully determined in 144<br />
breast tumors, and 49 were classified as Luminal A (34%). Survival<br />
outcomes at 10 years are summarized in Table 1:<br />
Table 1: Survival outcomes at 10 years<br />
<strong>Breast</strong> <strong>Cancer</strong> Specific Survival Luminal A Non-Luminal A<br />
RT 82% 54%<br />
No RT 36% 49%<br />
Log-rank p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P4-16-04<br />
Outcome of stage II/III breast cancer treated with neoadjuvant<br />
versus adjuvant radiotherapy in British Columbia.<br />
Lohmann AE, Voduc D, Speers C, Chia S. British Columbia <strong>Cancer</strong><br />
Agency, Vancouver, BC, Canada<br />
Backgroud: Neoadjuvant radiotherapy (NRT) is generally<br />
recommended after systemic therapy for inoperable stage III breast<br />
cancer. At the BCCA, neoadjuvant radiation is also frequently offered<br />
for patients with operable node positive disease after neoadjuvant<br />
chemotherapy. There is a lack of randomised trial data comparing<br />
outcomes in stage II/III breast cancer when radiation therapy is<br />
delivered neoadjuvantly versus adjuvantly.<br />
Aim: The primary objective of this study is to assess the clinical<br />
outcomes, as measured by relapse-free survival (RFS), overall<br />
survival (OS), and breast cancer-specific survival (BCSS), of women<br />
with stage II/III breast cancer treated with neoadjuvant chemotherapy<br />
and either neoadjuvant or adjuvant radiotherapy.<br />
Methods: Patients were identified by linking the <strong>Breast</strong> <strong>Cancer</strong><br />
Outcomes Unit (BCOU) with the British Columbia <strong>Cancer</strong> Agency<br />
Pharmacy data repository. Inclusion criteria included: Female,<br />
referred to BCCA with newly diagnosed disease, clinical stage II or<br />
III breast cancer, neoadjuvant chemotherapy, breast surgery performed<br />
as part of the initial treatment plan, RT (given adjuvantly or neoadjuvantly<br />
to the breast/chest wall +/- regional nodes). Patients were<br />
excluded if they had a previous or synchronous in situ or invasive<br />
breast cancer. Demographic data, treatment characteristics, ER, PR<br />
and HER-2 status (when available) were extracted. Data was analyzed<br />
using descriptive statistics and Kaplan Méier curves survival analyses<br />
were produced using SPSS, V. 14.<br />
Results: Between Jan 1, 1995 and Dec 31, 2008, 687 patients with<br />
stage II/III disease were identified. 394 patients received neo-adjuvant<br />
and 293 patients received adjuvant radiation. Patients treated with<br />
neoadjuvant vs. adjuvant RT differed in age (median: 51yrs vs.<br />
49yrs, p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
P4-16-06<br />
Radiotherapy to the Primary Tumor Is Associated with Improved<br />
Survival in Stage IV <strong>Breast</strong> <strong>Cancer</strong><br />
Morgan SC, Caudrelier J-M, Clemons MJ. University of Ottawa, ON,<br />
Canada; The Ottawa Hospital <strong>Cancer</strong> Centre, Ottawa, ON, Canada<br />
Background: In patients found to have metastatic disease at the time<br />
of breast cancer diagnosis, the role of local therapy is undefined.<br />
Numerous retrospective analyses have suggested that surgery and/<br />
or external beam radiotherapy (EBRT) directed at the primary tumor<br />
may improve overall survival (OS). All these analyses, however, are<br />
subject to significant selection bias. The current retrospective analysis<br />
of a large registry dataset attempts to limit the effect of this bias.<br />
Methods: The study population consisted of women in the<br />
Surveillance, Epidemiology, and End Results (SEER) program<br />
database diagnosed with stage IV breast cancer between 1988 and<br />
2009. Only those patients for whom surgery to the primary tumor<br />
was recommended but was not undertaken (due to patient refusal<br />
or other uncategorized reasons) were included. In this population<br />
of patients deemed candidates for surgery, the association between<br />
receipt of primary tumor-directed EBRT and overall survival was<br />
studied. Descriptive statistics were used to characterize the study<br />
population. OS was estimated using the Kaplan-Meier (KM) method.<br />
Univariate and multivariate Cox regression were used to identify<br />
factors associated with OS.<br />
Results: A total of 3,529 cases were analyzed. EBRT was received in<br />
768 cases. Median age at diagnosis was 68 years (IQR, 56-79 years).<br />
Median follow-up by reverse KM estimate was 98 months (range,<br />
0-252 months). On univariate analysis, EBRT was associated with<br />
improved OS (hazard ratio 0.80, 95% CI 0.74-0.87, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
With a mean follow-up of 49 months (range 31-66 months), only one<br />
case of local recurrence has been reported. The observed toxicity was<br />
considered acceptable.<br />
As to cosmetic results, at 6 months after the end of IORT, 71/226<br />
patients (31.4.%) had a score of 2 for symmetry and contour<br />
(asymmetry exhibited by 1/3 or less of volume breast), while 19/226<br />
(8.4%) had a score 3 (asymmetry greater than 1/3 of breast volume).<br />
These findings remained unchanged at the following examinations. No<br />
breast oedema, discoloration at site or scar prominence were observed.<br />
Discussion<br />
IOERT has significant advantages compared to other post-operative<br />
APBI approaches. The surgical re-approximation of the tumor bed,<br />
combined with the high quality of electron beam radiation, generates<br />
substantially more uniform dose distributions.<br />
IOERT offers the advantage of an excellent delineation of the tumor<br />
bed under visual control and high sparing of normal tissue, including<br />
the skin. IOERT delivers a very high biologically dose at the time of<br />
the surgery, when residual tumor cells are more rapidly proliferating.<br />
IOERT is insensitive to chemotherapy sequencing since all of the<br />
radiation is given during the surgery. IOERT offers low-risk women<br />
the possibility of a one-day procedure to treat their cancer and<br />
preserve their breast.<br />
The results of our study are very encouraging compared with other<br />
series with IOERT or APBI. The absolute recurrence rate of 0.4%<br />
and the recurrence rate per year of 0.2% of the present study are<br />
lower compared to the ones from the largest series with IOERT ever<br />
published (3.6% and 1.2%, respectively) (1).<br />
Conclusion<br />
APBI using a single dose of IOERT can be delivered safely in women<br />
with early, low risk breast cancer. A longer follow-up is needed to<br />
ascertain its efficacy compared to that of the current standard treatment<br />
of whole breast irradiation.<br />
References<br />
1. Veronesi U, Orecchia R, Luini A, et al. Intraoperative radiotherapy<br />
during breast conserving surgery: a study on 1,822 cases treated with<br />
electrons. <strong>Breast</strong> <strong>Cancer</strong> Res Treat 2010; 124:141-151.<br />
P4-16-09<br />
Dosimetric feasibility and acute toxicity in a prospective trial of<br />
ultra-short course accelerated partial breast irradiation (APBI)<br />
using a multi-lumen balloon brachytherapy device<br />
Khan AJ, Vicini FA, Brown S, Haffty BG, Kearney T, Dale R, Arthur<br />
DW. <strong>Cancer</strong> Institute of New Jersey, New Brunswick, NJ; Michigan<br />
Healthcare Professionals, Farmington Hills, MI; Wellstar Kennestone<br />
Hospital, Marietta, GA; Imperial College London, United Kingdom;<br />
Virginia Commonwealth University, Massey <strong>Cancer</strong> Center,<br />
Richmond, VA<br />
Background:<br />
Shorter courses of APBI with novel fractionation schedules are being<br />
investigated; a large randomized trial from Europe has recently shown<br />
the safety and efficacy of a single-fraction adjuvant approach (with<br />
limited follow-up). We designed a prospective trial to identify and<br />
address the potential radiobiological and logistical limitations of<br />
single-fraction, intraoperative APBI.<br />
Methods:<br />
We designed a single-arm, multi-institutional, prospective phase<br />
II trial that sequentially treats three cohorts of women (each n=30)<br />
with three progressively hypofractionated schedules. Eligible women<br />
were age ≥ 50 years with unifocal invasive or in situ tumors ≤ 3.0<br />
cm, excised with negative margins, and with negative lymph nodes<br />
and positive hormone-receptors. Using a reference schedule of 60 Gy<br />
delivered in 2 Gy fractions, and assuming tumor parameters: a/b = 4<br />
Gy; a = 0.27 Gy-1, and repopulation parameters of: Teff = 26 days;<br />
delay time = 0 days, the reference tumor BED is ∼ 86 Gy4. We began<br />
with a schedule of 4 fractions of 7 Gy delivered twice-daily using<br />
a Contura MLB multi-lumen device. We defined very conservative<br />
dosimetric criteria for acceptability: maximum skin and rib dose to not<br />
exceed 100% of prescription dose, and V150 and V200 to not exceed<br />
40 cc and 10 cc, respectively. Subsequent schedules are 3 fractions<br />
of 8.25 Gy and 2 fractions of 10.25 Gy, both delivered over 2 days.<br />
The primary endpoint is to exclude a local failure rate exceeding 10%<br />
with the upper limit of a 95% confidence interval.<br />
Results:<br />
A total of 30 patients have been enrolled at the 7 Gy x 4 fractions<br />
dose-level and followed for a minimum of 6 months. The median<br />
skin dose as a percent of prescription dose (PD) was 84% (40-100)<br />
and the median rib dose was 71% (16-119). 96% of the PTV_eval<br />
received a median of 95% of PD (range 85-103). The V150 (range<br />
14-48cc) and V200 (range 0-29cc) criteria were met in all cases. One<br />
breast infection occurred and was treated; 2 cases of symptomatic<br />
fat necrosis and 2 cases of symptomatic seromas occurred. No acute<br />
toxicities greater than CTCAE grade 2 have been observed.<br />
Conclusion:<br />
Short-course APBI is dosimetrically feasible using the Contura MLB<br />
and appears to be tolerable in terms of acute toxicities. Our approach<br />
is based on well-defined radiobiological parameters and allows for<br />
an abbreviated course of treatment that is guided by full pathological<br />
review and the ability to objectively achieve and validate acceptable<br />
dosimetric criteria in each case. We have opened enrollment to the<br />
next schedule of 8.25 Gy for three fractions.<br />
P4-16-10<br />
Positive sentinel lymph nodes (SLNs) without axillary dissection<br />
in breast cancer: the tangent fields of irradiation may not allow<br />
optimal coverage and dose distribution in level I and II of the<br />
axilla<br />
Qiong P, Khodari W, Bigorie V, Bosc R, Dao TH, Totobenazara J-L,<br />
Assaf E, Caillet P, Diana C, Lagrange J-L, Calitchi E, Belkacemi<br />
Y. APHP GH Henri Mondor et Université de Paris-Est, Créteil,<br />
France; APHP GH Henri Mondor, Créteil, France; Association of<br />
Radiotherapy and Oncology of the Mediterranean Area, France;<br />
French <strong>Breast</strong> Intergroup, France<br />
Purpose<br />
The recent Z0011 trial demonstrated equivalent survival in patients<br />
(pts) with breast cancer (BC) and 1 to 2 positive SLNs who were<br />
randomly assigned to SLN biopsy (SLNB) alone or followed by<br />
axillary lymph node dissection (ALND). More importantly, regional<br />
recurrence with SLNB alone was less than 1%, despite the fact that an<br />
estimated 27% of patients had additional metastases in the undissected<br />
axillary nodes. Currently, many teams do not recommend anymore<br />
ALND when the pts receive systemic therapy and whole breast<br />
irradiation (WBI). However, the optimal design of radiation fields for<br />
patients with positive SLNs who do not undergo ALND is uncertain.<br />
This prospective study was designed to define the dose distribution<br />
and coverage of level I and II of the axilla using only tangent fields<br />
after conservative surgery (CS) or total mastectomy (TM).<br />
Methods and Materials<br />
Thirty four pts were included in this analysis. 5 (14.7%) had TM and<br />
29 (85.3%) had CS. Median age was 54 (30-90) years. All pts had<br />
3D conformal RT. The level I/II/III axillary volumes were contoured<br />
using the RTOG contouring atlas. The total dose delivered was 50Gy<br />
in 25 fractions (n=11) or the same dose (D) followed by a boost of<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
414s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
10 to 16Gy (n=23). Pts were analyzed according to the total dose<br />
delivered in these 2 groups: group 1 (50Gy; n=11), group 2 (60 to<br />
66Gy; n=23). A subgroup analysis was also performed in the group<br />
2 regarding the initial tumor site and delivered dose: 66Gy to the<br />
upper quadrant (n=14 group 2a) vs the lower quadrant (n=4; group<br />
2b) vs 60Gy to the upper quadrant (n=5, group 2c). All dose-volumehistograms<br />
were analyzed. Mean, median values derived from level I<br />
and level II volumes were compared using t-test. Level of significance<br />
was set at p-value=0.05.<br />
Results<br />
In the whole population, the median D delivered to level I and II<br />
was 16.2 and 1.7 Gy, respectively. The mean D at these levels were<br />
21.2 Gy (rang: 1.0 – 48.1) and 5.0 Gy (0.1 – 40.9), respectively. The<br />
volume of 95% and 50%-isodose coverage were 0 cm 3 and 17.2 cm 3<br />
for level I and 0 cm 3 for level II. The mean values for level I and II<br />
volumes were 1.4 cm 3 and 21.9 cm 3 , respectively.<br />
According to the total D delivered (with or without boost), no<br />
difference was found between group 1 and group 2 in terms mean,<br />
median, and minimal D delivered to axilla levels (p = 0.5 and 0.9).<br />
Conversely, the difference was statistically significant for maximal D<br />
(p = 0.01). Furthermore, there was no difference according to tumor<br />
site and total dose between group 2a and 2b and group 2c (p = 0.07<br />
and 0.7). In addition, no difference was observed between irradiation<br />
of whole breast or chest wall at 50Gy (p = 0.3 and 0.7).<br />
Conclusion<br />
In patients undergoing conservative surgery or post-mastectomy<br />
radiotherapy, tangent fields provide a limited coverage of level I and<br />
II of the axilla as defined by the RTOG contouring atlas. In addition,<br />
these regions were mainly underdosed with au total dose < 30Gy even<br />
for pts who received 66Gy at the upper quadrant. These data should be<br />
considered when only tangent fields are planed to target the axilla in<br />
patients with metastases in SLNB positive without axillary dissection.<br />
P4-16-11<br />
Impact of receptor status on prognosis among breast cancer<br />
patients with brain metastases treated with Cyberknife<br />
radiosurgery<br />
Fasola CE, Gibbs IC, Soltys SG, Horst KC. Stanford <strong>Cancer</strong> Center,<br />
Stanford, CA<br />
Purpose: Stereotactic radiosurgery (SRS) is increasingly used in the<br />
management of brain metastases. Receptor status is an important<br />
prognostic factor among women with breast cancer. The aim of this<br />
study was to evaluate the effect of receptor status on clinical outcomes<br />
in breast cancer patients with brain metastases treated with SRS.<br />
Materials and Methods: We performed a retrospective review of<br />
102 primary breast cancer patients with brain metastases treated<br />
with Cyberknife radiosurgery at Stanford University Medical Center<br />
between 2004 and 2011. The clinical characteristics, pathologic<br />
features, treatment details and clinical outcomes were reviewed.<br />
Median follow-up time was 18 months from the date of treatment<br />
with Cyberknife radiosurgery. All analyses were performed using<br />
SAS software, version 9.3 (SAS Institute, Cary, NC).<br />
Results: Patients with Her-2/neu positive receptor status treated with<br />
trastuzumab had a significantly improved median overall survival after<br />
treatment with stereotactic radiosurgery compared to patients with<br />
Her-2/neu negative receptor status (27 months vs 7 months, p=0.002)<br />
or patients with Her-2/neu positive receptor status who did not<br />
receive trastuzumab (27 months vs 12 months, p=0.04). In contrast,<br />
patients with estrogen receptor, progesterone receptor and Her-2/<br />
neu negative receptor status had significantly worse median overall<br />
survival after treatment with stereotactic radiosurgery compared to<br />
patients with at least one positive receptor (8 months vs 17 months,<br />
p=0.02). On multivariable analysis, Her-2/neu status emerged as the<br />
only significant predictor of survival (p=0.01).<br />
Conclusions: Her-2/neu receptor status was found to be a significant<br />
prognostic factor influencing survival among breast cancer patients<br />
with brain metastases treated with SRS. Importantly, the addition<br />
of treatment with trastuzumab among Her-2 neu positive patients<br />
significantly improved clinical outcomes.<br />
P4-16-12<br />
Outcomes of low- risk Ductal Carcinoma in situ in South East<br />
Asian women treated with breast conservation surgery.<br />
Wong FY, Wang FQ, Chen JJ, Tan CH, Tan PH. National <strong>Cancer</strong><br />
Centre Singapore; Singapore General Hospital, Singapore, Singapore<br />
Background<br />
Singapore is the first South East Asian country to establish a<br />
nationwide breast cancer screening programme in 2002. Since then,<br />
the incidence of breast cancer and pre-invasive disease, in particular,<br />
has increased tremendously. Ductal carcinoma in situ (DCIS)<br />
constitutes over a quarter of all screen-detected cancers.<br />
In Singapore, most patients with DCIS are managed with breast<br />
conserving surgery (BCS). In almost all cases, this is followed by<br />
adjuvant radiotherapy (RT) to the whole breast. However, the optimum<br />
management of low-risk DCIS remains contentious. Non-randomized<br />
data in Caucasian women suggests benefits in the reduction of local<br />
recurrence despite already low recurrence rates. Similar information<br />
in Asian women is lacking. We examined the outcomes of South East<br />
Asian women with low-risk DCIS treated with BCS.<br />
Methods<br />
Retrospective chart reviews of patients treated with BCS for DCIS<br />
from 1995 to 2011 was performed. Patients meeting the pathological<br />
criteria from ECOG 5194 were included: Low-Intermediate grade<br />
(LG) DCIS ≥0.3cm but ≤2.5cm excised with final margins ≥3mm<br />
and High grade (HG) DCIS ≥3mm but ≤1.0cm.<br />
Most patients received adjuvant RT consisting of whole breast RT to<br />
50Gy followed by a 10Gy boost to the tumour bed. Patients deemed<br />
to have especially low recurrence risks did not receive RT and some<br />
patient declined adjuvant RT. Patients who are oestrogen receptor<br />
positive were offered 5 years of tamoxifen.<br />
Results<br />
A total of 744 patients with pathological diagnosis of pure DCIS were<br />
identified, of which 273 meets the selection criteria: LG (N=219);<br />
HG (N=54). Median follow-up for these patients is 60 months.<br />
Median age at diagnosis is 50 years old. About 70% of patients were<br />
screen detected; only 21 of which (7.7%) were diagnosed before the<br />
introduction of breast screening.<br />
There were 8 ipsilateral breast tumour recurrences (IBTR) in total;<br />
7 of which were DCIS. The estimated actuarial IBTR rates at 5- and<br />
10-year for the entire cohort are 1.8% and 4.3% respectively. In<br />
comparison, 10 contralateral new breast primaries were diagnosed in<br />
this cohort, giving 5- and 10-year contralateral relapse rates of 1.9%<br />
and 7.2% respectively.<br />
All patients with LG DCIS received RT except for 9. There were<br />
7 recurrences in this group, two among the 9 patients who did not<br />
receive RT. The estimated IBTR rates at 5- and 10-year are 2.3% and<br />
4.2% respectively. All patients with HG DCIS received RT. There<br />
was only 1 IBTR occurring beyond 5 years giving an estimated IBTR<br />
rate of 4.5% at 10-year. These results compare favourably with the<br />
www.aacrjournals.org 415s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
5-year IBTR rates of 6.1% and 15.3% in the LG and HG patients<br />
respectively in the ECOG 5194 study where patients were managed<br />
with BCS alone.<br />
One patient died of metastatic breast cancer from the contralateral<br />
breast giving a 10-year overall survival of 98.5%.<br />
Conclusions<br />
South East Asian women with screen detected DCIS have exceedingly<br />
low rates of IBTR after breast conservation therapy. The addition<br />
of adjuvant RT approximately halved the IBTR rates in our study<br />
patients. The high proportion of recurrence in the small group of<br />
patients who did not receive RT warns of the potential hazards of<br />
managing even these low-risk patients without radiation.<br />
P4-16-13<br />
Relationship between coverage of axillary lymph nodes, with<br />
tangential breast irradiation, and body mass index<br />
Inokuchi M, Furukawa H, Fujimura T, Ohta T, Ohashi S, Takanaka<br />
T. Kanazawa University Hospital, Kanazawa, Ishikawa, Japan<br />
Background:<br />
The ACOSOG Z0011 trial confirmed axillary clearance is not<br />
necessary in select, clinically lymph node-negative women with<br />
positive sentinel lymph node biopsies (SLNBs) who undergo breastconserving<br />
surgery(BCS) or receive whole-breast radiotherapy(RT)<br />
and systemic therapy. The results suggested that the receipt of adjuvant<br />
breast RT and systemic therapy is adequate for loco-regional control.<br />
But it was unknown whether the low regional recurrence rates in<br />
these patients were caused by the treatment of a portion of the axilla<br />
with the tangent fields. In any case, axillary lymph node dose with<br />
tangential breast irradiation differs for each patient. It could depend<br />
on the proportions or body mass index(BMI) of each patient. If the<br />
difference of BMI impacts axillary coverage in breast RT, it could<br />
also influence loco-regional control. The purpose of this study was<br />
the dosimetric analyses of the axillary coverage with standard breast<br />
tangential irradiation, by BMI categories.<br />
Methods and materials:<br />
Between April 2007 and September 2011, 256 breast cancer patients<br />
were treated with breast tangential irradiation after BCS. They were<br />
classified using BMI categories as follows: underweight (
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 4<br />
were deceased or developed distant metastasis, 5 patients were alive<br />
with no evidence of disease, 3 patients had partial tumour response<br />
with surgery pending.<br />
Conclusions: Patients with locally advanced, triple-negative breast<br />
cancer who progressed during or shortly after NAC had a high clinical<br />
response rate when treated with salvage XRT+ CDDP. In patients<br />
who underwent surgery after salvage treatment, 50% achieved pCR.<br />
Salvage treatments appeared to be relatively well tolerated and safe.<br />
This subset of patients is at very high risk for tumour recurrence.<br />
Prospective, multi-centre studies of concurrent cisplatin and<br />
radiotherapy in the setting of locally advanced, triple negative breast<br />
cancer are needed to further assess efficacy and toxicity.<br />
P4-16-15<br />
Withdrawn by Author<br />
P4-17-01<br />
The effect of body mass index on breast reconstruction outcomes.<br />
Lopez JJ, Laronga C, Doren EL, Sun W, Fulp WJ, Smith PD.<br />
University of South Florida, Tampa, FL; H. Lee Moffitt <strong>Cancer</strong><br />
Center, Tampa, FL<br />
Introduction<br />
With increasing numbers of women choosing mastectomy for breast<br />
cancer treatment, breast reconstruction is consequentially on the rise.<br />
Obesity, a known predictor for wound healing complications, is also<br />
on the rise. Our objective is to review our institutional experience<br />
with the association between Body Mass Index (BMI) and breast<br />
reconstruction complications.<br />
Methods<br />
An IRB approved retrospective review of prospectively gathered<br />
patients having mastectomy with reconstruction was conducted.<br />
Data including patient demographics, stage at diagnosis, adjuvant<br />
treatment, type of mastectomy, type of reconstruction, and<br />
complications were collected. Patients were stratified by BMI into<br />
two categories: Normal weight (BMI 18.5 – 24.9), and overweight/<br />
obese (BMI 25 or greater). The statistical analysis was preformed<br />
using Wilcoxon Rank-Sum Test and Chi Squared Test, both using<br />
exact method with Monte Carlo estimation.<br />
Results<br />
From 06/1996 to 08/2011, 443 patients were identified having<br />
mastectomy and reconstruction. Of these, 218 patients had a normal<br />
weight at the time of mastectomy; 225 patients were overweight/<br />
obese. The overall median age was 49 years (range: 18 - 82). 780<br />
mastectomies with reconstruction (106 unilateral, 337 bilateral) were<br />
performed. The most common reconstruction types included 477<br />
tissue expander with implant reconstructions (62.8% of breasts), 106<br />
latissimus flap with prosthesis (14.0%), and 103 pedicled TRAM flaps<br />
(13.6%). 245 patients (55.3%) experienced at least one complication;<br />
the most common complications were fat necrosis (80 patients, 18.1%<br />
of patients), infection (57, 12.9%), epidermolysis (41, 9.3%), and<br />
skin necrosis (39, 8.8%).<br />
The overweight/obese group had a significantly higher prevalence<br />
of diabetes (6.3% vs. 0.9%, p = 0.0036) and hypertension (26.7%<br />
vs. 11.1%, p < 0.0001) and was more likely to receive neoadjuvant<br />
chemotherapy (16.2% vs. 4.8% p = 0.0005), possibly due to<br />
presentation at a later stage, but no significant differences were<br />
identified. Other comorbid conditions, including smoking, history of<br />
breast cancer, adjuvant chemotherapy, and history of or postsurgical<br />
radiation, were similar between the two groups. One significant<br />
difference was that the overweight/obese group was significantly<br />
older than the normal weight group (p = 0.0005).<br />
There were no significant differences identified in the incidence of any<br />
individual complication between the two BMI groups. Additionally,<br />
the incidence of a patient having any complication was similar<br />
between the two groups (128 overweight/obese patients for 56.9%<br />
and 117 normal weight patients for 53.7%, p = 0.4918). When using<br />
breasts instead of patients as the unit of measure, when an overweight/<br />
obese patient had a complication they were significantly more likely<br />
to require an unanticipated return to the OR (93/160 breasts with a<br />
complication for 58.1% vs. 67/154 for 43.5%, p = 0.0124).<br />
Conclusion<br />
Obesity does not increase the risk of breast reconstruction<br />
complications, but increases the severity of complications if one<br />
should arise. This supports the continued use of breast reconstruction<br />
in patients regardless of their weight, and emphasizes that when<br />
the correct procedure is selected for an overweight/obese patient,<br />
outcomes can be similar to patients that are of a normal weight.<br />
P4-17-02<br />
Radiation therapy and expander-implant breast reconstruction:<br />
an analysis of timing and comparison of complications<br />
Lentz RB, Higgins SA, Matthew MK, Kwei SL. Yale University School<br />
of Medicine, New Haven, CT<br />
Background: The optimal timing of expander/implant exchange in<br />
the setting of post mastectomy radiation (PMRT) remains unclear.<br />
Studies investigating the sequencing of reconstruction and PMRT<br />
are inconclusive, with some reporting exchange prior to PMRT<br />
results in fewer complications, while others report no difference.<br />
When the exchange follows PMRT, most reconstructive surgeons<br />
wait between 3-6 months, however, little is known about the optimal<br />
time for exchange. The primary aim of the study was to characterize<br />
complications associated with sequencing expander/implant breast<br />
reconstruction before or after PMRT. The secondary aim was to<br />
compare the outcomes between early (4<br />
months) expander/implant exchange in the subset of patients who<br />
received PMRT prior to exchange.<br />
Materials and Methods: The medical records of all patients<br />
undergoing PMRT in the setting of expander/implant breast<br />
reconstruction between June 2004-June 2011 at our institution were<br />
reviewed retrospectively. For aim 1, patients were classified as having<br />
undergone exchange prior to the initiation of PMRT (group I) or after<br />
completion of PMRT (group II). For aim 2, patients who underwent<br />
exchange after PMRT were then classified as having undergone<br />
exchange less than 4 months after PMRT (group III) or more than 4<br />
months after PMRT (group IV). Complications requiring additional<br />
surgery or hospitalization were recorded. Statistical analysis was<br />
performed using students t test and Fischer exact test.<br />
Results: Fifty-five eligible patients were identified having undergone<br />
56 two-stage tissue expander/implant breast reconstructions by 6<br />
different plastic surgeons, 22 in group I and 34 in group II. There<br />
was no significant difference in overall complication (54.55% vs<br />
47.06%, p = 0.584) or reconstruction failure rates (13.64% vs 20.59%,<br />
p = 0.724). The most commonly encountered complications were<br />
infection, wound dehiscence and capsular contracture. There was<br />
no significant difference in rate of infection (18.18% vs 23.53%, p =<br />
0.746) or wound dehiscence (4.55% vs 14.71%, p = 0.386). Group<br />
I did experience a higher rate of capsular contracture (40.91% vs<br />
11.76%, p = 0.021). From the 34 breast reconstructions that underwent<br />
expander/implant exchange following PMRT, 20 were in group III<br />
and 14 were in group IV. There was no significant difference in<br />
overall complication (40% vs 57.14%, p = 0.487) or reconstruction<br />
failure rate (25% vs 14.29%, p = 0.672). Trends suggest a higher rate<br />
www.aacrjournals.org 417s<br />
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of infection in group III (30% vs 14.29%, p = 0.422) and a higher<br />
rate of capsular contracture in group IV (5% vs 21.43%, p = 0.283),<br />
however statistical significance was not reached.<br />
Conclusions: Our findings suggest that neither the sequencing nor<br />
timing of expander/implant exchange in the setting of PMRT has<br />
an impact on overall complication or reconstruction failure rate.<br />
Patients who underwent exchange prior to PMRT, thus radiating<br />
their permanent implants, experienced a higher incidence of capsular<br />
contracture. With respect to optimal timing following PMRT, our<br />
results suggest that implant exchange can occur earlier without<br />
resulting in an increase in complications, however there may be an<br />
association between timing and type of complication.<br />
P4-17-03<br />
Towards the standardisation of outcome reporting in<br />
reconstructive breast surgery: Initial results of the BRAVO<br />
(<strong>Breast</strong> Reconstruction and Valid Outcome) Study–A multicentre<br />
consensus process to develop a core outcome set for reconstructive<br />
breast surgery<br />
Potter S, Ward J, Cawthorn S, Holcombe C, Warr R, Wilson S, Tillett<br />
R, Weiler-Mithoff E, Winters Z, Barker J, Oates C, Harcourt D,<br />
Brookes S, Blazeby J. University of Bristol, United Kingdom; North<br />
Bristol NHS Trust, Bristol, United Kingdom; Linda McCartney <strong>Breast</strong><br />
Centre, Royal Liverpool and Broadgreen University Hospitals NHS<br />
Trust, Liverpool, United Kingdom; NHS Greater Glasgow and Clyde,<br />
Glasgow, United Kingdom; University of the West of England, Bristol,<br />
United Kingdom<br />
Introduction: Appropriate outcome selection is essential if research<br />
is to guide decision-making for patients, professionals and policy<br />
makers. Systematic reviews evaluating the clinical, cosmetic and<br />
patient-reported outcomes of breast reconstruction, however, have<br />
demonstrated marked heterogeneity of outcome reporting such that<br />
results from individual studies cannot be compared or combined.<br />
Standardising end-points by developing and using core outcome<br />
sets - an agreed minimum set of outcomes that should be measured<br />
and reported in all research and audit studies – is one way by which<br />
outcome reporting may be improved. We therefore report the initial<br />
results of the BRAVO (<strong>Breast</strong> Reconstruction and Valid Outcomes)<br />
Study which aims to use a scientifically rigorous Delphi consensus<br />
process to develop a core outcome set for reconstructive breast<br />
surgery.<br />
Methods: The Delphi process involves the sequential completion of<br />
questionnaires to allow stakeholder opinions to be synthesised using<br />
item responses to prioritise outcome domains.<br />
The questionnaire was developed from a long list of 148 outcomes<br />
generated from literature reviews and qualitative work with<br />
stakeholders. The outcomes were categorised into 34 domains in six<br />
categories (short-term complications; late complications; symptoms;<br />
psychosocial issues; practical issues and cosmesis) and each domain<br />
operationalised.<br />
Key stakeholders were identified as patients, surgeons, specialist<br />
nurses and psychologists and participants were sampled purposively<br />
to ensure a breadth of perspectives. Each participant was sent a<br />
questionnaire and asked to prioritise the outcomes on a nine-point<br />
likert scale from 1(not important) to 9(extremely important).<br />
The number of respondents in each group rating each outcome as not<br />
important(scores 1-3); equivocal(scores 4-6) or very important(score<br />
7-9) were calculated for each item and compared between groups. The<br />
proportions of respondents rating each item as very important(score<br />
7-9) was used to rank the items.<br />
Results: 213 of the 430 questionnaires were returned(126/274 patients<br />
and 87/156 professionals) giving a response rate of 49.5%.<br />
Patient participants had a median age of 53.4 years(range 34-76)<br />
and had undergone a full range of reconstructive procedures. The<br />
professional group included 39 breast surgeons, 20 plastic surgeons<br />
and 18 clinical nurse specialists.<br />
There was agreement between 7 of the 10 outcomes that each group<br />
rated most highly. Items with consensus included patient-reported<br />
cosmesis,cosmetic satisfaction and early complications. Patients, but<br />
not professionals, considered generic complications such as bleeding<br />
to be important while professionals valued psychosocial issues such<br />
as self-esteem more highly than patients.<br />
Conclusions: Patients and professionals prioritise similar<br />
outcomes, but areas of discrepancy with regard to complications<br />
and psychosocial outcomes remain. A further Delphi round asking<br />
participants to re-prioritise outcomes and a consensus meeting to<br />
ratify the final decisions will be necessary to determine a final core<br />
outcome set for reconstructive breast surgery.<br />
P4-17-04<br />
BRECONDA: Development and acceptability of an interactive<br />
decisional support tool for women considering breast<br />
reconstruction<br />
Sherman KA, Harcourt D, Lam T, Boyages J. Macquarie University,<br />
Sydney, NSW, Australia; Westmead Hospital, University of Sydney,<br />
Westmead, NSW, Australia; University of the West of England, Bristol,<br />
United Kingdom<br />
Introduction<br />
Women needing a mastectomy for breast cancer, or cancer<br />
prophylaxis, are faced with the difficult decision regarding whether,<br />
and how, to restore breast shape after surgery. To a large extent<br />
this decision is based on personal preferences and values. In view<br />
of limited support resources available in this context, we have<br />
developed an online interactive decision aid, BRECONDA, to assist<br />
with decision-making. BRECONDA uses a multi-media platform to<br />
provide up-to-date information about surgical choices, interactive<br />
decision sheets encouraging women to weigh-up perceived benefits<br />
and risks and identify personal values and preferences, and video<br />
recorded patient stories. Since psychological stress can hamper<br />
decision-making, BRECONDA also demonstrates videoed stress<br />
management relaxation techniques. The aim of this study was to<br />
assess the user acceptability of this intervention.<br />
Methods<br />
Following diagnosis, and prior to surgery, 54 women with breast<br />
cancer who were eligible for breast reconstruction following<br />
mastectomy were randomly assigned into one of two conditions: 1)<br />
Intervention group which received access to the BRECONDA program<br />
as well as a standard information booklet about breast surgery given<br />
to all such patients; and, 2) Control/Usual care group which received<br />
the standard information booklet alone. User ratings of satisfaction<br />
and reactions to BRECONDA were documented at 6-week followup<br />
for the Intervention group through quantitative measures and<br />
telephone interviews. Additionally, perceived decisional conflict,<br />
distress (intrusive and avoidant thoughts), knowledge and satisfaction<br />
with information at the 6-week assessment were documented for<br />
all participants. ANCOVAs were used to identify between group<br />
differences on these key variables at follow-up.<br />
Results<br />
Intervention participants’ ratings of BRECONDA demonstrated<br />
high user acceptability, with high scores on perceived usefulness,<br />
ease of use and provision of sufficient information. Interview data<br />
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indicated that Intervention participants perceived BRECONDA to be<br />
well-balanced, informative, and beneficial to the decision making<br />
process and that it helped them feel more secure in their decision<br />
and to prepare questions for their surgeon. Interactive decision<br />
sheets, patient testimonials and photo galleries were highly valued<br />
by all interviewees. At follow-up, 40% of participants had undergone<br />
immediate reconstruction, with fewer Intervention participants<br />
electing this surgery. Furthermore, Intervention participants reported<br />
lower decisional conflict compared with Usual Care participants at<br />
follow-up (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Results: 237 patients underwent implant/expander reconstruction.<br />
Median time from implant placement until last follow-up was 173<br />
days. 21.5% developed major complications (needing operative time<br />
or infection needing intravenous treatment). Diabetes was the most<br />
consistent factor associated with major complications (46.7 vs 20.1%,<br />
p = 0.02 and p = 0.009 in multivariable analysis). Radiation was linked<br />
to capsular contractures (18.6 vs 10.1%, p = 0.02). Chemotherapy<br />
(25.0 vs 19.0%, p = 0.26) or radiation (26.3 vs 19.1%, p = 0.21) did<br />
not predict major complications. Among patients receiving PMRT<br />
(80 patients), 26.2% had major complications, 34 had immediate<br />
PMRT on the expander and 44 had PMRT to the chest wall, followed<br />
by delayed reconstruction with expander/implant placement. In<br />
these, delayed reconstruction increased dehiscence (0 vs 18.2%, p =<br />
0.009) compared to immediate reconstruction, with a trend for higher<br />
incidence of major complications in the delayed reconstruction group<br />
(14.7 vs 34.1%, p = 0.05). 40 Gy/16 versus 50-50.4 Gy/25-28 (28 vs<br />
24%, p = 0.78) was not associated with major complications. Diabetes<br />
and smoking were associated with several complications.<br />
Conclusions: Diabetes is associated with a higher rate of major<br />
complications after expander/implant reconstruction while radiation<br />
increases capsular contractures. If PMRT is indicated, putting in<br />
an expander before radiation results in less morbidity than delayed<br />
reconstruction. Also, 40 Gy/16 versus 50-50.4 Gy/25-28 do not differ<br />
much in terms of complication rates.<br />
P4-17-09<br />
Efficacy and safety of lipomodelling and adipose tissue derived<br />
degenerative stem cells(ADRC) for breast reconstruction –<br />
Medium term follow up<br />
Noor L, Bhaskar P, Hennessy C. University Hospital of North Tees,<br />
Cleveland, United Kingdom<br />
Background: Past and current literature support Lipomodelling as<br />
a tool for breast reconstruction. Lipomodelling with Adipose tissue<br />
Derived Regenerative Stem Cells dramatically improves the graft<br />
survival through both adipogenesis and angiogenesis. Literature<br />
regarding safety of this procedure for breast reconstruction is limited.<br />
Our aim was to assess the safety and efficacy of ADRC-enriched fat<br />
grafts for breast reconstruction.<br />
Material & Methods: A prospective study from September 2008<br />
– April 2012 at a District General Hospital UK including patients<br />
operated by two breast surgeons. The indications and the fat grafting<br />
procedures used are analyzed (Cytori Celution 800/CRS or Cytori<br />
pure graft system). Patients with benign indications were followed<br />
for 1 year and those with cancer were followed for 5 years according<br />
to regional guide lines with breast imaging.<br />
Results: Out of total 50 patients, 10 had benign diagnosis while 40<br />
had breast cancer treatment. 30 patients had correction after breast<br />
conservation, 17 had revision of reconstruction (8 TRAM, 4 LD<br />
and 5 implant based reconstruction) while 3 had other procedures.<br />
19/40 had history of breast irradiation as adjuvant treatment after<br />
surgery for breast cancer. Median age was 52 years with range 18-<br />
72 years. ADRC enriched fat grafting was done in 40 cases and pure<br />
graft in10 patients. Graft volume injected was 80-420 mls (average<br />
247 mls). 90% patients are satisfied with outcome of surgery with<br />
good to excellent cosmetic outcome. Only 4 patients had noticeable<br />
fat resorption, 3 underwent redo grafting. At average follow up of<br />
21 months (1-48 months) no significant complications were seen,<br />
imaging showed fat necrosis in 3 and oil cyst in 1 patient though no<br />
one required biopsy. No patient developed local recurrence, although<br />
4 subsequently found to have metastatic disease.<br />
Conclusion: We found it a useful, safe and effective technique for<br />
breast reconstruction with high patient satisfaction. We recommend<br />
a central database of all patients with this procedure to substantiate<br />
findings of this study and as recommended by Association of <strong>Breast</strong><br />
Surgery (ABS) & British Association of Plastic Reconstructive &<br />
Aesthetic Surgeons (BAPRAS).<br />
P5-01-01<br />
Predicting OncoDX Recurrence Scores with Immunohistochemical<br />
Markers<br />
Bradshaw SH, Gravel DH, Song X, Marginean EC, Robertson SJ.<br />
The Ottawa Hospital, Ottawa, ON, Canada<br />
Background: Standard immunohistochemistry (IHC) performed for<br />
invasive breast carcinoma includes ER, PR and Her2/Neu status, and<br />
these markers are used in conjunction with other patient and tumour<br />
factors to determine prognosis and guide treatment. Many, but not<br />
all, low stage, lymph node (LN) negative, ER positive patients have<br />
a good prognosis without chemotherapy. Thus a demand exists for<br />
predictive tools to stratify patient risk within this subgroup. It has<br />
been reported that, for a subset of ER positive Her2/Neu negative<br />
patients, the 21 gene OncotypeDX recurrence score (Onco-RS) adds<br />
independent prognostic information to that obtained from these<br />
standard IHC markers (1). As several genes analyzed for the Onco-RS<br />
relate to ER, PR, HER2/neu and proliferative status, it is reasonable<br />
to try to incorporate clinical-pathological variables and these IHC<br />
scores into a predictive model. Indeed, recent studies suggest that most<br />
of the additional information provided by the OncoDX-RS may be<br />
obtained more cost effectively using the Ki-67 IHC based proliferation<br />
percentage combined with a semi-quantitative assessment of standard<br />
IHC markers including ER and PR and Her2/neu (2). The aim of this<br />
study is to assess the ability of a simple combined IHC recurrence<br />
score (IHC-RS) to predict Onco-RS. The IHC-RS was derived from<br />
a simple semi-quantitative assessment of ER and PR combined with<br />
Ki-67 proliferation percentage.<br />
Design: A cohort of 159 women aged 27-78 with ER positive, HER2/<br />
neu negative breast cancer completed Oncodx testing between March<br />
2010 and May 2012. This sample reflects the population selected at<br />
our institution for Oncotype testing. The variables investigated for<br />
inclusion in a model to predict RS score included tumor grade, stage,<br />
patient age, Allred ER & PR and Ki-67 percentage.<br />
Results and Discussion: A predictive model was developed to<br />
generate a recurrence score (IHC-RS) using stepwise multiple<br />
regression incorporating Allred ER score, Allred PR score and Ki-<br />
67 percentage. The best subset model (Schwartz BIC) accounted<br />
for 60.7% of the Onco-RS variability (adjusted R 2 =60.7, p = 0.05).<br />
In addition, analysis of individual cases where the IHC-RS was not<br />
in agreement with the Onco-RS reveals that the Onco-RS, although<br />
technically highly reproducible, may suffer from sampling error.<br />
The IHC-RS is more robust with respect to sampling error, owing to<br />
the retention of tumor architecture inherent in IHC. IHC, however,<br />
can lack the technical reproducibility and transportability inherent<br />
in the Onco-RS methodology. There are clearly advantages to an<br />
ICH derived multi-score such as IHC-4 (3) or the simpler IHC-RS<br />
proposed in this study. Full utility of any IHC-based recurrence score<br />
will require standardization of testing and scoring both within and<br />
across different testing laboratories. In addition, full utility of any IHC<br />
based model will require direct correlation to patient outcome, rather<br />
than to a surrogate marker such as the Onco-RS used in this study.<br />
1 - M Dowsett et al. J Clin Oncol. 2010 Apr 10; 1829-1834<br />
2 – Cuzick J et al. J Clin Oncol. 2011 Nov 10;4273-8.<br />
3 –S Barton et al. British Journal of <strong>Cancer</strong> (2012) 106, 1760–1765.<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
P5-01-02<br />
Inter-observer concordance of Ki-67 labeling index in breast<br />
cancer: Japan <strong>Breast</strong> <strong>Cancer</strong> Research Group (JBCRG) Ki-67<br />
Ring Study<br />
Ueno T, Mikami Y, Yoshimura K, Tsuda H, Kurosumi M, Masuda S,<br />
Horii R, Toi M, Sasano H. Kyoto University Hospital, Kyoto, Japan;<br />
National <strong>Cancer</strong> Center Hospital, Tokyo, Japan; Saitama <strong>Cancer</strong><br />
Center, Saitama, Japan; Nihon University School of Medicine, Tokyo,<br />
Japan; The <strong>Cancer</strong> Institute Hospital of the Japanese Foundation<br />
for <strong>Cancer</strong> Research, Tokyo, Japan; Tohoku University School of<br />
Medicine, Sendai, Japan<br />
Background: The standardized assessment of Ki-67 labeling index<br />
(LI) plays pivotal roles in identifying the patients (pts) with primary<br />
breast cancer who could benefit from systemic chemotherapy, in<br />
particular among pts with estrogen receptor(ER)-positive cancers.<br />
Therefore, in this study, we evaluated the inter-observer concordance<br />
of the assessment of Ki-67 LI in archival materials.<br />
Methods: Six surgical pathologists specializing in breast pathology<br />
from different Japanese institutions participated in this study. All<br />
slides were prepared from archival tissues of breast cancer fixed<br />
in 10% buffered formalin for 24 hours in a single institution (KU).<br />
Three independent studies were conducted. Study 1) Six consecutive<br />
slides were prepared from 5 cases. A slide from each case was stained<br />
with MIB-1 (DAKO, Denmark) in each institution according to their<br />
routine methods. Total of 30 stained slides were assessed for Ki-67<br />
LI by each pathologist using two different modes of assessment. One<br />
is the scoring system in which the rate of positive cells was scored<br />
from 1 (0 – 9 %) to 10 (90 – 100%) without counting the cell number.<br />
The second one is the counting system in which approximately 1000<br />
cells in total were counted in the hot spots and the positive rate was<br />
calculated. Study 2) Twenty tumors with Ki-67 LI ranging from 5 to<br />
25 (15 ± 10) %, stained in a single institution (KU) were assessed by<br />
each pathologist by the counting system. Study 3) In order to avoid<br />
variations by assessment in varied microscopic fields and to further<br />
evaluate the variation of threshold of immunointensity interpreted<br />
as positive by different pathologists, fifteen printed photographs of<br />
Ki-67-stained slides were sent and assessed for Ki-67 LI by each<br />
participating breast pathologist.<br />
Results:<br />
Study 1) The counting system demonstrated a better correlation<br />
of Ki-67 LI among six pathologists than the scoring system {the<br />
intraclass correlation coefficient (ICC), 0.66 (95% confidence interval<br />
0.52-0.78) for the counting system, 0.57 (0.42-0.72) for the scoring<br />
system}. The two assessment systems showed a moderate correlation<br />
{ICC, 0.68 (0.60-0.75)}. Study 2) The assessment of Ki-67 LI in 20<br />
slides with Ki-67 LI of 5 to 25 % demonstrated a correlation similar<br />
to that in the specimens with an unrestricted range of Ki-67 LI in<br />
the study 1 {ICC, 0.68 (0.50-0.81) for the study 2, 0.66 (0.52-0.78)<br />
for the study 1}. Study 3) The assessment of Ki-67 LI in the same<br />
photographs yielded a considerably significant concordance among<br />
six pathologists {ICC, 0.94 (0.88-0.97)}.<br />
Conclusion:<br />
The counting system turned out better than the scoring system in<br />
terms of the inter-observer agreement of the Ki-67 LI assessment.<br />
The degree of concordance was by no means influenced by the range<br />
of Ki-67 LI. The concordance of the Ki-67 LI assessment among six<br />
participating pathologists was significantly high when the assessed<br />
field was fixed using the same photographs for evaluation, suggesting<br />
that the selection of the fields for evaluation is critical. These results<br />
suggest that identification of hot spots for evaluation is pivotal for<br />
obtaining the accurate Ki-67 LI of breast cancer and still images of<br />
these hot spots could provide reproducible results.<br />
P5-01-03<br />
Discordant Estrogen and Progesterone Receptor Status in <strong>Breast</strong><br />
<strong>Cancer</strong><br />
Hefti MM, Hu R, Knoblauch N, Collins L, Tamimi RM, Beck AH.<br />
Beth Israel Deaconess Medical Center, Boston, MA; Brigham and<br />
Women’s Hospital, Boston, MA<br />
Introduction: Hormone receptor status is used to guide clinical<br />
therapy in breast cancer. Estrogen receptor (ER) assays from<br />
pathology reports have been shown to be in agreement with ER<br />
measured by a centralized laboratory on tissue microarray 87% of<br />
the time (Kappa = 0.64); however, little is known of reproducibility<br />
within subsets of patients defined by ER/PR status (1).<br />
Methods: We computed percent agreement and Kappa statistics for<br />
ER/PR status as reported in pathology reports from Nurse’s Health<br />
Study (NHS) participants with breast cancer from 1976 to 2000, and<br />
as scored by immunohistochemistry (IHC) on tissue microarrays at a<br />
central laboratory (n=2011). Statistics were computed separately for 4<br />
subsets of patients stratified by ER/PR status as defined by pathology<br />
reports (ER+/PR+, ER+/PR-, ER-/PR+, ER-/PR-). We also used a<br />
curated compilation of publicly available gene expression data sets<br />
providing both IHC and microarray data on ER and PR expression<br />
(n=1236).<br />
Results: We observed significant heterogeneity in Kappa values<br />
across the four groups of patients, with ER+/PR+ and ER-/PRshowing<br />
the strongest agreement, ER+/PR- showing fair agreement,<br />
and ER-/PR+ showing no significant agreement: 89.1% of ER+/PR+<br />
cases from medical record were ER+/PR+ by TMA (κ=.60), 69.4% of<br />
ER-/PR- cases from medical record were ER-/PR- by TMA (κ=.63),<br />
42% of ER+/PR- cases from medical record were ER+/PR- by TMA<br />
(κ=.37), and only 6% of cases of ER-/PR+ cases from medical record<br />
were ER-/PR+ by TMA (κ=.06). Using publicly available microarray<br />
data, we observed similar results comparing IHC to gene expression<br />
data in the same samples. Expression values were scaled across<br />
patients, and a patient was classified as positive for the marker by<br />
microarray if the scaled expression value was greater than zero. The<br />
agreement between IHC data and gene expression-based classification<br />
was 50.0% (k=.50), 80.8% (κ=.54), 42.0% (κ=.15), and 7.2% (κ=-<br />
.006) for ER+/PR+, ER-/PR-, ER+/PR-, and ER-/PR+, respectively.<br />
Conclusion: ER-/PR+ is by far the most rare and least reproducible<br />
subset of breast cancer cases. Given the lack of reproducibility of<br />
the ER-/PR+ group and the minimal reported benefit from hormonal<br />
therapy in these patients (2), these data question the clinical utility<br />
of assessment of PR, particularly in ER- breast cancer.<br />
1. Collins LC, Marotti JD, Baer HJ, Tamimi RM. Comparison of<br />
estrogen receptor results from pathology reports with results from<br />
central laboratory testing. Journal of the National <strong>Cancer</strong> Institute.<br />
2008;100(3):218-21.<br />
2. Anderson H, Hills M, Zabaglo L, A’Hern R, Leary AF, Haynes BP,<br />
et al. Relationship between estrogen receptor, progesterone receptor,<br />
HER-2 and Ki67 expression and efficacy of aromatase inhibitors in<br />
advanced breast cancer. Annals of oncology: official journal of the<br />
European Society for Medical Oncology/ESMO. 2011;22(8):1770-6.<br />
P5-01-04<br />
Clinico-pathological features of low-grade triple negative early<br />
breast cancers.<br />
Nourieh M, Furhmann L, Feron J-G, Caly M, Diéras V, Sastre-Garau<br />
X, Chavrier P, Vincent-Salomon A. Institut Curie, Paris, France<br />
Aims: To characterize clinico-pathological features and clinical<br />
outcome of low grade triple negative early breast carcinomas.<br />
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Material and methods: Between January 2005 and December 2006,<br />
300 tumours were classified as triple negative (ER-ve, PR-ve, HER2<br />
0/1+) out of 3000 patients treated for a breast cancer at the Institut<br />
curie. Patients with a low-grade (grade 1 and 2 according to Ellis<br />
and Elston) T1 and small T2 (< 3cm) breast carcinoma treated with<br />
surgery first were considered in our study. Immunohistochemistry<br />
was performed with ER, PR, Androgen Receptor (AR), HER2,<br />
Ki67, EGFR, CK5/6, CK14 and CK8/18 antibodies for all tumours;<br />
GCDFP15 for invasive lobular carcinomas (ILC) and invasive ductal<br />
carcinoma (IDC) with apocrine features, and CA15-3 to assess the<br />
inverted polarity if needed.<br />
Results: We identified 36 low-grade carcinomas out of 186 triple<br />
negative breast carcinomas (19%). Thirty-two tumours were grade<br />
2 and four tumours grade 1 and associated with a low or a moderate<br />
mitotic score. Ki67 proliferation index was high (≥20%) in 22 cases<br />
(61%) (median: 22%-mean: 29%). Thirty-one (86%) tumours showed<br />
a basal- like phenotype (EGFR+ or CK5/6+ or CK14 +). Interestingly,<br />
the five “nul” (non basal-like) triple negative tumours demonstrated<br />
a low proliferation index (Ki67 ≤20%). All but one tumors expressed<br />
CK8/18. The tumour’s size varied between 3 and 37 mm (mean =<br />
17.2). Lympho- vascular invasion was present in 10 cases (27%).<br />
High and intermediate grade ductal carcinoma in situ component was<br />
associated in 28 cases (77%). Stroma was abundant and associated<br />
with a lymphocytic infiltrate in all cases. Various histological types<br />
were observed: 16 IDC (44%), 7 ILC (19%), 5 IDC with apocrine<br />
differentiation, 2 micropapillary, 1 papillary, 1 mucinous, 3 adenoid<br />
cystic and one low grade adeno-squamous carcinomas. Three out of<br />
16 IDC showed a week nuclear positivity with AR. Five and six out<br />
of the seven ILC were positive for AR and GCDFP15 respectively.<br />
All carcinomas with apocrine differentiation were AR and CGDFP15<br />
positive. Conversely, all micropapillary, papillary and mucinous<br />
carcinomas were AR negative. The mean age of patients was 61.6<br />
years. Distant metastases occurred in five patients. Thirty-three (91%)<br />
women were alive and 29 (80%) of them without evidence of cancer<br />
at 6 years of follow-up.<br />
Conclusion: Low grade invasive carcinomas represent 19% of the<br />
cases in our series of 186 triple negative early breast carcinomas and<br />
were diagnosed in patients older than 60 years. These cases were<br />
of various histological types, were all associated with a marked<br />
lymphocytic infiltrate and in the majority of the cases with high grade<br />
ductal carcinomas in situ. Despite a low mitotic activity, proliferation<br />
index was generally higher than 20% except for “nul” non-basal<br />
cases. However, patient’s overall survival seemed to be better than<br />
that reported for high grade triple negative breast cancer. Histological<br />
types, proliferation and age should be taken into account for treatment<br />
decision in triple negative early breast carcinoma patients.<br />
P5-01-05<br />
Could c-myc amplification replace Cahan’s criterias to<br />
discriminate secondary from primary angiosarcoma of the<br />
breast?<br />
Laé M, Hamel F, Hadj-Hamou S, Malfoy B, Kirova YM. Institut<br />
Curie, Paris, France<br />
Background: Angiosarcomas (AS) are a relatively rare histological<br />
subtype of sarcomas. Despite their rarity, AS display remarkable<br />
clinical heterogeneity. These tumors can occur in any location in the<br />
body, but the breast AS are important part of these tumours. Cahan et<br />
al. defined the criteria for the diagnosis of radiation induced sarcomas<br />
(RIS), used since 1948: i) prior history of RT; ii) asymptomatic<br />
latent period of several years; iii) the occurrence of a sarcoma<br />
within a previously irradiated field; iiii) histological confirmation of<br />
sarcomatous nature of the post-irradiation lesion.<br />
Purpose: The aim of this study is to show a new biological data which<br />
can help us to recognize these rare tumors.<br />
Material and Methods: Forty-one breast AS were studied<br />
(pathological review, clinical and follow-up information obtained),<br />
as well as the transcriptome signatures of the radiation tumorigenesis.<br />
For all RIS, the patients’ radiotherapy plans and hospital records were<br />
reviewed and their radiation related nature was confirmed if they<br />
respected the classic Cahan’s criteria. Interphase FISH was performed<br />
by hybridization of probes covering C-MYC (chromosome 8q24.21)<br />
and CEP8 on tissue sections from each of the forty-one tumors.<br />
Results: Among forty-one breast AS, thirty one were secondary<br />
tumors and ten primary tumors. Amplification (5 to 20 fold) of the<br />
MYC oncogene was found in all breast secondary AS (31 cases) but<br />
in none of the 10 primary AS except one. The relationships between<br />
clinical, pathological and biological features are studied. These data<br />
point the pathways preferentially involved in the pathogenesis of<br />
secondary AS of the breast and may provide the basis for an additional<br />
targeted therapy.<br />
Conclusion: The presence of c-myc amplification on biopsy<br />
or surgical specimen represents an important additional tool to<br />
discriminate secondary from primary angiosarcoma of the breast<br />
when radiotherapy data are not available.<br />
P5-01-06<br />
Differences in FGF1 and FGFR2 expression in BRCA1-associated,<br />
BRCA2-associated, and sporadic breast carcinomas<br />
Vos S, van der Wall E, van Diest PJ, van der Groep P. University<br />
Medical Center Utrecht, Netherlands<br />
Introduction. In contrast to BRCA1-associated breast cancer, a<br />
distinctive phenotype for BRCA2-associated carcinomas has not<br />
been identified yet as there is no clear distinction between BRCA2-<br />
and non-BRCA mutation related or sporadic carcinomas. Recently,<br />
studies suggest overexpression of fibroblast growth factor 1 (FGF1)<br />
and fibroblast growth factor receptor 2 (FGFR2) in BRCA2 related<br />
cancers. The aim of the study was therefore to investigate whether<br />
there is differential expression of FGF1 and/or FGFR2 between<br />
BRCA2 related and sporadic and BRCA1 related cancers. This would<br />
reveal the usefulness of FGF1 and FGFR2 immunohistochemistry in<br />
daily pathology practise.<br />
Method. Invasive breast carcinomas of 33 BRCA1 and 22 BRCA2<br />
germline mutation carriers and a tissue microarray containing 104<br />
sporadic invasive breast carcinomas were immunohistochemically<br />
stained for FGF1, FGFR2, estrogen receptor (ER), progesterone<br />
receptor (PR), HER2, epidermal growth factor receptor 1 (EGFR),<br />
cytokeratin (CK) 5/6 and CK14.<br />
Results. FGFR2 expression was seen in 68.2% and 79.0% of BRCA2-<br />
associated and sporadic carcinomas respectively, in contrast to 22.6%<br />
of BRCA1-associated tumors (p = 0.000). FGF1 expression was seen<br />
in 72.7% of BRCA2-associated carcinomas and in 45.2% and 41.8% in<br />
BRCA1-associated and sporadic carcinomas, respectively (p = 0.032).<br />
Conclusion. FGFR2 expression differs significantly between BRCA1-<br />
and BRCA2 associated breast carcinomas but not between BRCA2<br />
and sporadic cancers. FGF1 expression differs significantly between<br />
BRCA2-associated and sporadic carcinomas and could be used as a<br />
BRCA2-specific biomarker.<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
P5-01-07<br />
Fibroadenomatoid changes are more prevalent in middle-aged<br />
women and have a positive association with invasive breast cancer<br />
Chen Y, Bekhash A, Kovatich AJ, Hooke JA, Kvecher L, Mitchell EP,<br />
Rui H, Mural RJ, Shriver CD, Hu H. Windber Research Institute,<br />
Windber, PA; Walter Reed National Military Medical Center,<br />
Bethesda, MD; MDR, Global Systems LLC, Windber, PA; Thomas<br />
Jefferson University, Philadelphia, PA<br />
Background: The role of benign breast diseases (BBDs) in the<br />
development of invasive breast cancers (IBCs) has been studied for<br />
many years. Some BBDs have been studied comprehensively (e.g.,<br />
fibrocystic changes (FCC)) while less is known about other BBDs<br />
(e.g., fiboadenomatoid changes (FAC)). FAC has been considered by<br />
some researchers as a precursor of fibroadenoma (FA). Conclusions<br />
from different studies vary, partially due to different interpretation<br />
methods and diagnostic criteria when multiple hospitals and<br />
pathologists were involved. In this study, we used subjects in the<br />
Clinical <strong>Breast</strong> Care Project (CBCP) from a military medical center<br />
where pathology slides were reviewed by a single breast pathologist<br />
to study FAC, FA, and FCC in comparison to the published literature.<br />
Methods: Subjects were enrolled in the study following IRBapproved,<br />
HIPAA-compliant protocols. All the clinicopathologic<br />
data are available from the CBCP data warehouse (DW4TR). In the<br />
CBCP, FCC is composed of 4 components: stromal fibrosis, cysts,<br />
apocrine metaplasia, and sclerosing adenosis. Two modeling studies<br />
were performed. i) For the BBDs and IBC association study, two<br />
groups of subjects were identified: 1136 subjects diagnosed with<br />
“Benign” or “Atypical” diseases, and 619 cases diagnosed with<br />
IBCs. A logistic regression model was developed for the prediction<br />
of IBCs by the 3 BBDs and 2 well-established risk factors (RF): age<br />
(younger, 60) and race (Caucasian,<br />
African American, Asian, and other). ii) For the RF association study<br />
with the BBDs, 6 additional RFs reported to be associated with<br />
these BBDs were identified from the literature: current use of oral<br />
contraceptives, number of live births, education, body mass index,<br />
hormonal replacement therapy, and IBC family history. These 8 RFs<br />
were used to develop a logistic regression model for each of the BBDs.<br />
The analyses were performed in SAS.<br />
Results: In the first study, age and race were confirmed as RFs<br />
for IBCs. FAC was positively associated with IBC (OR=3.04,<br />
95%CI=2.06 to 4.50). FA was negatively associated with IBC,<br />
and the level of the association was stronger in women without<br />
FCC (OR=0.15, 95%CI=0.08 to 0.28), compared to women with<br />
FCC (OR=0.40, 95%CI=0.24 to 0.65). FCC was not significantly<br />
associated with IBC. Results from the second study indicated that,<br />
age was significantly associated with FAC (p=0.015), specifically<br />
the middle-aged women were more likely to have FAC compared<br />
to younger women (OR=2.03, 95%CI=1.23 to 3.34), while the<br />
older women were at a non-significantly increased risk. Trends of<br />
association with FAC were also noted for the number of live birth<br />
(p=0.095), ethnicity (p=0.096), and current oral contraceptive pill use<br />
(p=0.077). The FCC model results were in general consistent with the<br />
literature, and we also confirmed that age was negatively associated<br />
with the diagnosis of FA.<br />
Discussion: Our study was consistent with FCC findings in the<br />
literature. We observed that FAC was positively associated with IBC,<br />
whereas FA was negatively associated. Also, FAC occurred more<br />
often in middle-aged women while FAs occurrence was higher in<br />
younger women. Our results suggest that FAC and FA may be two<br />
different diseases.<br />
P5-01-08<br />
Complex fibroadenoma is not an independent risk marker for<br />
breast cancer<br />
Nassar A, Visscher DW, Degnim AC, Frank RD, Vierkant RA,<br />
Hartmann LC, Frost MH, Ghosh K. Mayo Clinic, Rochester, MN<br />
Background: Fibroadenoma (FA) is a relatively common benign<br />
breast tumor that can occur in women of any age, with a peak<br />
incidence during the second and third decades. The only previous<br />
study of this lesion reported that FAs are associated with a 2.2 times<br />
increased risk of developing invasive breast cancer (BC) compared<br />
to matched controls [1]. This relative risk may increase to 3.1 among<br />
patients with complex FA, and remains elevated for decades after<br />
diagnosis. However, this study did not thoroughly account for other<br />
forms of concomitant risk factors. Our investigative team sought to<br />
examine breast cancer risk among women with non-complex and<br />
complex FA, overall and stratified by other BC risk factors.<br />
Materials and Methods: The study cohort included women between<br />
ages 18 to 85 in the Mayo Benign <strong>Breast</strong> Disease (BBD) Cohort who<br />
underwent excisional breast biopsy between 1967and1991 and were<br />
found to have a FA. FA was defined histologically as a combination<br />
of epithelial and stromal proliferation. Complex FA was defined as<br />
FA associated with any of the following features: sclerosing adenosis,<br />
epithelial calcifications, papillary apocrine change, and microcysts<br />
greater than 3.0 mm. The primary endpoint was a diagnosis of<br />
BC, determined using the Mayo medical record and questionnaire<br />
information from study participants. A single breast pathologist,<br />
blinded to the initial diagnosis and clinical outcome, performed<br />
pathology review. Observed vs. expected BC risk across levels of<br />
FA was assessed via standardized incidence ratios (SIRs), using agestratified<br />
incidence rates from the Iowa Surveillance, Epidemiology,<br />
and End Results (SEER) registry. Analyses were carried out overall<br />
and within subgroups of involution status (none, partial, complete)<br />
and overall histology (non-proliferative disease [NP], proliferative<br />
disease without atypia [PDWA] or atypical hyperplasia [AH]).<br />
Results: Of 9097 women in the Mayo BBD Cohort, FA were identified<br />
in 2139- non-complex in 1903 (20.9%) and complex in 236 (2.6%).<br />
The greatest proportion of FA occurred in the 40-69 age range. The<br />
mean ages for women with non-complex FA and complex FA were<br />
45.7 and 50.2 years respectively. The SIR of breast cancer in the<br />
overall BBD cohort was 1.5 (95% CI [1.4-1.6]). The SIR among<br />
women with non-complex FA was 1.5 (95% CI [1.3-1.8]), and for<br />
complex FA increased to 2.41 (95% CI [1.7-3.4]). However, women<br />
with complex FA were more likely to have other concomitant highrisk<br />
histologic features such as PDWA and incomplete involution.<br />
In stratified analyses accounting for involution status and PDWA,<br />
complex FA did not demonstrate an independent increase in BC risk.<br />
Conclusion: Complex FA does not confer an increased risk for BC<br />
beyond other established histologic features. Therefore, women with<br />
complex FA should be managed based upon a risk level consistent<br />
with the major histologic category of PDWA and/or AH.<br />
P5-01-09<br />
Identification of Molecular Apocrine Triple Negative <strong>Breast</strong><br />
<strong>Cancer</strong> Using a Novel 2-Gene Assay and Comparison with<br />
Androgen Receptor Protein Expression and Gene Expression<br />
Profiling by DASL<br />
Alvarez J, Schaffer M, Karkera J, Martinez G, Gaffney D, Bell<br />
K, Sharp M, Wong J, Hertzog B, Ricci D, Platero S. Janssen<br />
Pharmaceuticals<br />
Background: The molecular apocrine (MA) subtype of breast cancer<br />
is identified by gene expression profiling. MA tumors are estrogen<br />
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receptor (ER) negative and progesterone receptor (PR) negative, but<br />
still express estrogen responsive genes. The androgen receptor (AR)<br />
pathway may be driving growth in these tumors because androgen<br />
responsive genes are expressed in tumors with the MA gene signature.<br />
The MA gene signature is identified in approximately 10% of triple<br />
negative breast cancer (TNBC) and may predict patients with<br />
tumors responsive to agents that inhibit the AR pathway. AR protein<br />
expression, measured by immunohistochemistry (IHC), may be a<br />
surrogate for the MA gene signature, but to date, a careful comparison<br />
of gene expression profiles and AR protein expression has not been<br />
conducted. In this study, cohorts of TNBCs were assessed for the<br />
MA gene signature and these results were compared with AR IHC<br />
expression and with a novel gene expression assay that may predict<br />
tumors with the MA gene signature.<br />
Methods: Formalin fixed, paraffin-embedded (FFPE) TNBC samples<br />
were commercially obtained. ER, PR and HER2 status of these<br />
samples was confirmed by IHC. AR expression was detected by<br />
IHC using two different antibody clones. Both staining intensity<br />
and percent positive cells were recorded for each sample. Gene<br />
expression data was collected from a cohort of TNBC FFPE samples<br />
using cDNA-mediated Annealing, Selection, extension, and Ligation<br />
(DASL) technology. A 2-gene classifier of the MA gene expression<br />
signature was derived by interrogating publically available gene<br />
expression data from ER-negative breast cancers. A reversetranscriptase<br />
polymerase chain reaction (RT-PCR) assay to detect<br />
the 2-gene classifier was developed. Cell lines predicted to have the<br />
MA gene signature by the 2-gene assay were tested for sensitivity<br />
to R-1881 in vitro.<br />
Results: Using computational approaches and publically available<br />
datasets, we confirmed the validity of the MA gene signature and<br />
estimated the prevalence to be between 12% and 37% in ER-negative<br />
breast tumors. The 2-gene classifier was 100% specific in determining<br />
MA tumors in a training set using gene expression data as a standard.<br />
In a validation set, the 2-gene assay was 66% correlative with AR<br />
IHC positivity when the IHC cut-off was set at 10% positive tumor<br />
cells. Cell lines predicted to express the MA gene signature by the<br />
2-gene classifier proliferated in response to androgen. This effect was<br />
blocked by Flutamide.<br />
Conclusions: These results indicate that AR IHC using a 10% cut-off<br />
may not completely correlate with the MA gene signature. Further<br />
refinement of AR IHC scoring criteria may produce greater specificity.<br />
Cell proliferation data suggests the 2-gene assay can predict tumors<br />
that will proliferate in response to androgen. Work is ongoing to<br />
determine the correlation between the 2-gene assay results, AR IHC<br />
and DASL gene expression data to fully understand the predictability<br />
of this assay. Understanding this correlation may allow use of simple<br />
clinical assays to accurately select patients responsive to agents that<br />
block AR signaling.<br />
P5-01-10<br />
Clinical-pathological features and outcomes of Invasive lobular<br />
(ILC) vs Invasive ductal (IDC) breast cancer (BC): a monoinstitutional<br />
series.<br />
Ferro A, Eccher C, Triolo R, Caldara A, Di Pasquale MC, Russo LM,<br />
De Carli NL, Cuorvo LV, Barbareschi M, Gasperetti F, Berlanda G,<br />
Pellegrini M, Moroso S, Galligioni E. S Chiara Hospital, Trento,<br />
Italy; FBK, Trento, Italy<br />
Purpose:<br />
The aim of our study was to investigate different clinico-biological<br />
behavior associated to ILC compared to IDC evaluating implications<br />
on survival outcomes<br />
Methods: We analyzed data from 3749 cases of IBC treated from<br />
1995 to 2008 and categorized as having ILC, IDC and mixed/other.<br />
Associations between clinical-pathological variables and the ILC/<br />
IDC histotype were assessed using a χ 2 test. Log-rank test and Cox<br />
regression model were performed to evaluate the impact of hystologic<br />
types on overall survival (OS), Event Free Survival (EFS) and Post-<br />
Progression Survival (PPS).<br />
Results: We identified 445 (12%) ILC, 3021 (80.5%) IDC, 149<br />
mixed (ductal-lobular) BC (3.9%) and 134 other hystotypes (3.6%).<br />
Median age was 61 (25-97) years. Compared with IDC, ILC occurred<br />
significantly (p3 ILC pts, in whom a trend of worse prognosis (55.6<br />
vs 60.2%) was observed.<br />
Conclusions: Despite the quite favorable biological pattern, ILC did<br />
not show a better outcomes than IDC.<br />
P5-01-11<br />
‘Same-day diagnosis’ of women suspected of breast cancer:<br />
success rate and impact on diagnostic quality and patients’<br />
anxiety levels<br />
Barentsz MW, Wessels H, van Diest PJ, Pijnappel RM, van der Pol<br />
CC, Witkamp AJ, van den Bosch MA, Verkooijen HM. University<br />
Medical Center Utrecht<br />
Introduction:<br />
Uncertainty about a breast cancer diagnosis is a stressful event. As<br />
such, many initiatives have been undertaken to reduce the time of<br />
uncertainty by providing ‘same-day diagnosis’ for patients suspected<br />
of breast cancer. However, only few studies have evaluated the<br />
feasibility of ‘same-day diagnosis’ diagnosis, while the impact of<br />
‘same-day diagnosis’ on diagnostic accuracy and patient anxiety has<br />
hardly been studied at all. This study aims to evaluates feasibility,<br />
diagnostic accuracy and impact on patients’ anxiety of ‘same-day<br />
diagnosis’ of patients suspected of breast cancer.<br />
Materials and Methods:<br />
In November 2011, the ‘same-day diagnosis’ system was implemented<br />
in our hospital. This system consists of completing the following<br />
items on the day of the first visit:<br />
1. Clinical examination, imaging (mammography, ultrasound), and<br />
(if necessary) FNA or core needle biopsy<br />
2. High speed processing of biopsy specimens using Leica Peloris<br />
tissue processor<br />
3. Multidisciplinary evaluation of clinical, imaging and histological<br />
findings<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
4. Communication of the final diagnosis and treatment plan to the<br />
patient<br />
All patients presenting for ‘same-day diagnosis’ are entered<br />
prospectively in a database. Feasibility of ‘same-day diagnosis’ is<br />
evaluated, and reasons for failure are scrutinized. Diagnostic quality<br />
of ‘same-day diagnosis’ is evaluated by linking all patients to PALGA<br />
(Dutch National Pathology Database) six months following the day<br />
of diagnosis, in order to identify false negative results (i.e. missed<br />
cancers) and false positive results (i.e. ‘cancers’ turned out to be<br />
benign during further work-up). Impact of ‘same-day diagnosis’<br />
on patient anxiety is measured by the 4-item State Trait Anxiety<br />
Inventory, which is filled out by patients on several occasions on<br />
the day of diagnosis as well as during the first seven days following<br />
diagnosis.<br />
Results<br />
Between November 2011 and May 2012, 266 women were eligible<br />
for ‘same-day diagnosis’. Fifty-eight patients (22%) were diagnosed<br />
with breast cancer. Overall, 80% of the patients received a final<br />
diagnosis within one day. For patients with cancer, this proportion<br />
was somewhat lower, i.e. 71%. Accuracy of ‘same-day diagnosis’ and<br />
impact on patients’ anxiety are currently under study.<br />
Conclusion<br />
’Same-day diagnosis’ is feasible for the far majority of patients<br />
suspected of breast cancer. Evaluation of implementation of ‘sameday<br />
diagnosis’ on diagnostic quality and impact on patient anxiety is<br />
crucial. Updated results will be presented in December 2012.<br />
P5-01-12<br />
Over- and Undergrading of <strong>Breast</strong> <strong>Cancer</strong> on Core Biopsies in<br />
Comparison to Surgical Specimens<br />
Decker T, Focke CM, Gläser D, Finsterbusch K. Bonhoeffer Medical<br />
Center, Neubrandenburg, Germany<br />
Background<br />
In numerous studies histological grade (HG) remained an independent<br />
prognostic factor for ER positive tumours even after the inclusion<br />
of gene signatures in the multivariate models. Moreover, grade 3 is<br />
judged as clear argument in favour of chemotherapy. Therefore, there<br />
are many reasons to provide patients and doctors with HG as important<br />
prognostic and predictive information already preoperatively. To<br />
evaluate the relevance of histological grading (HG) based on core<br />
biopsies (CB) for clinical decision making in breast cancer (BC) we<br />
evaluated the concordance with HG from surgical specimen (SSP)<br />
and the reasons for under- or overgrading.<br />
Methods<br />
CB and related SSP of 398 BCs were prospectively graded according<br />
to the Nottingham grading system (SSP: 65 G1, 162 G2 and 171<br />
G3). CB/SSP agreement rates and positive predictive values (PPV)<br />
of CB based HG were calculated. Rates of over- and underestimation<br />
of glandular differentiation (GD), nuclear pleomorphism (NP) and<br />
mitotic activity (MA) were calculated.<br />
Results<br />
CB/SSP agreement rates came out with 95% for G1, 73% for G2, and<br />
56 % for G3. The PPVs of CB based HG were 56% for G1, 61% for<br />
G2 and 100% for G3. The overgrading and undergrading rates on CB<br />
were 1% and 37%, respectively. Main causes for undergrading in CB<br />
were underestimated MA (40%) and a combination of underestimated<br />
NP and MA (32%).<br />
Conclusions<br />
Whereas overgrading on CB is an exception, undergrading derives<br />
largely from underestimation of proliferation. G3 assessed on<br />
CB came out with the highest PPV, providing a reliable base for<br />
preoperative decisions i.e. about primary chemotherapy. Reversely,<br />
because of the relative low PPV of G1 on CB one has to be aware of<br />
potential upgrading on surgical specimen later on.<br />
P5-01-13<br />
Flat Epithelial Atypia: Management and outcome in three Dutch<br />
teaching hospitals<br />
Ghuijs PM, de Vries B, Strobbe LJA, van Deurzen CHM, Heuts EM,<br />
Keymeulen KBMI, Lobbes MBI, Wauters CAP, Van de Vijver KKBT,<br />
Smidt ML. Maastricht University Medical Centre, Maastricht,<br />
Netherlands; Canisius-Wilhelmina Hospital, Nijmegen, Netherlands;<br />
Erasmus Medical Centre, Rotterdam, Netherlands<br />
Background: Flat Epithelial Atypia (FEA) is a presumably<br />
neoplastic alteration of terminal duct-lobular units, characterized<br />
by the replacement of native luminal epithelium by ductal cells<br />
demonstrating low-grade cytologic atypia. The architecture shows<br />
stratification of epithelial cells. FEA is often accompanied by<br />
microcalcifications and therefore discovered in biopsies following<br />
screening mammography. FEA is frequently seen in association with<br />
ADH (atypical ductal hyperplasia), DCIS (ductal carcinoma in situ),<br />
lobular neoplasia and invasive tubular carcinomas. There is emerging<br />
evidence suggesting FEA may represent a precursor to DCIS. The<br />
risk of subsequent breast carcinoma remains to be defined. The aim of<br />
this study is therefore to inventorise the management and outcome of<br />
solitary FEA in histological biopsies in three Dutch teaching hospitals.<br />
Materials and Methods: Data of this retrospective multicentre<br />
study were collected in a database. Local pathology databases were<br />
screened with the terms: ‘FEA’, ‘Flat Epithelial Atypia’, ‘columnar<br />
atypia’ and Dutch equivalents. Results were manually screened, only<br />
including solitary FEA.<br />
Patient files were viewed for information on presentation,<br />
mammography, ultrasound and management: surgery vs follow-up.<br />
In case of excision, definitive pathology was added.<br />
Results: We included 103 patients showing only solitary FEA in the<br />
primary biopsy. Management of these patients consisted of followup<br />
for 60 patients (58,3%) and surgery for 43 patients (41,7%, 49<br />
excisions): lumpectomy (42) or mastectomy (7). Reason for choosing<br />
mastectomy was preventive in case of contralateral breast cancer or<br />
increased familial or genetic risk.<br />
Definitive pathology of lumpectomy or mastectomy showed no<br />
abnormalities or solitary FEA in 31 patients; other findings were<br />
ADH in 7, LCIS in 4 and DCIS in 7 patients. Some patients showed<br />
more than one finding. Invasive breast cancer (IBC) was detected in<br />
3 patients. Only one mastectomy showed invasive disease, located<br />
in a different lobe, however.<br />
No incidents occurred in the follow-up group.<br />
Conclusions: No consistent management exists concerning solitary<br />
FEA in these three hospitals. Also, one hospital used the diagnosis<br />
of FEA inconsistently and interchangingly with other terms. Lack of<br />
this study is the retrospective gathering of data, making it difficult<br />
to detect the reasons for the chosen management. DCIS or IBC was<br />
discovered in 20,4% of all surgical specimens. It was concluded that<br />
FEA should be seen as a red flag, indicating the possible presence of<br />
a more malignant lesion. Additional research is warranted concerning<br />
long term follow-up for this patient group.<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-01-14<br />
Discrepancy between routine and expert pathologists in<br />
histological assessment of early stage non palpable breast cancer<br />
and its impact on loco regional and systemic treatment<br />
Postma EL, Verkooijen HM, van Diest PJ, Willems SM, van den Bosch<br />
MA, van Hillegersberg R. UMC Utrecht<br />
Background<br />
Histopathological parameters are essential for deciding on further<br />
adjuvant treatment in patients with breast cancer after surgery.<br />
Here, we assessed the impact of inter observer variability on further<br />
treatment strategy in patients with clinically node negative, non<br />
palpable breast carcinomas.<br />
Methods<br />
Clinical and histopathological data of 314 patients with clinically<br />
node negative non palpable invasive breast cancer were analysed.<br />
Histological assessment of the primary tumour and sentinel nodes was<br />
first performed in a routine setting, subsequently central review took<br />
place. In cases of discordance between local en central assessment,<br />
we determined the impact on locoregional and systemic treatment<br />
strategy.<br />
Results<br />
Discordance between local and central review was seen in 13%<br />
of the patients (kappa 0.60 95% CI 0.50-0.71) for type, in 12%<br />
(k=0.796 95% CI 0.73-0.86) for grade, in 1% for ER status (k=0.898<br />
95% CI 0.80-1.0), in 2% for PR status(0.940 95% CI 0.89-0.99).<br />
Discrepancy in the assessment of the sentinel node(s) was seen in<br />
2% of the patients. (k=0.954 95% CI 0.92-0.98). Practising current<br />
Dutch Guidelines, loco regional treatment would be affected in 2%<br />
(7/310), systemic treatment in 5% (16/310) and both in 1% (2/310)<br />
of the patients.<br />
For patients in whom central review would have led to additional<br />
systemic treatment (3%), the 10 years mortality and recurrence rate<br />
would decrease with a median of 4.6% and 15% respectively.<br />
Conclusion<br />
Inter observer variation in the histopathological assessment of nonpalpable<br />
breast carcinoma specimens and sentinel nodes results in<br />
a different loco regional or systemic treatment advice in 8% of the<br />
patients.<br />
P5-01-15<br />
Anti-ER monoclonal antibody SP1 seems more sensitive in the<br />
identification of ER alpha positive breast cancer cases than anti-<br />
ER monoclonal antibody 1D5<br />
Madeira KP, Daltoé RD, Sirtoli GM, Rezende LCD, Carvalho AA,<br />
Silva IV, Rangel LBA. Universidade Federal do Espírito <strong>San</strong>to,<br />
Vitória, ES, Brazil<br />
Background:<br />
Accurate pathological analysis of biopsies is crucial for conclusive<br />
and precise disease diagnosis, prognosis and therapeutic guidelines.<br />
Evaluation of estrogen receptor (ER) expression in breast cancer<br />
(BC) is imperative in determining the disease prognosis, and patients’<br />
eligibility for hormonotherapy. Herein, ER alpha status was evaluated<br />
in 61 BC cases using two different anti-ER alpha monoclonal<br />
antibodies, SP1 (rabbit) and 1D5 (mouse).<br />
Methods:<br />
Primary BC cases registered in two reference hospitals, with<br />
correspondent written informed consent, were used to generate in<br />
house tissue microarray platforms. ER alpha expression was accessed<br />
by immunohistochemistry using the monoclonal antibodies anti-ER<br />
alpha, SP1 and 1D5. Staining scoring followed the Allred method (PS,<br />
proportion score or percentage of stained cells; IS, intensity score).<br />
Concordance and correlation parameters were calculated using Kappa<br />
factor; Pearson, Spearman’s, or intraclass correlation coefficient (CF).<br />
Staining patterns were compared by paired T-Test and Wilcoxon test.<br />
Findings:<br />
SP1 and 1D5 provided equivalent results (Concordance rate,<br />
96.7%; Kappa factor, 0.921), whereas SP1 was more prone for<br />
positive results than 1D5 (2 samples diverged). Total concordance<br />
of PS was obtained (Pearson and intraclass CF, 0.7351 and 0.6193,<br />
respectively); however, concordance between the antibodies seems<br />
more accurate in higher PS values. Excellent SI correlation between<br />
antibodies was observed throughout the population (Spearman’s<br />
CF, ρ=0.9150). Following the Allred score, 17 out of 42 positive<br />
BC samples diverged; always pointing 1D5 to weaker staining than<br />
SP1. When calculating Spearman’s CF of Total Score (TS) within<br />
the population, excellent correlation between both the antibodies<br />
(ρ=0.9238) was noted; nonetheless, results were less concordant<br />
result among the BC positive cases (ρ=0.7743). Indeed, 20 samples<br />
were differentially classified using the antibodies (only 3 had higher<br />
TS with 1D5). Considering the mean TS of all samples, or of invasive<br />
ductal carcinoma, SP1 provided higher scores than 1D5 (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
microscope show a regular shape. In fibroadenoma, phyllodes tumor<br />
and mastitis team, they shows unobviously sonographic features and<br />
the cell morphology contrast with breast cancer are quite different.<br />
Conclusions :Ultrasonography appearance of breast masses is related<br />
to pathologic characteristics and can be a predictor of histopathologic<br />
pattern preoperatively.<br />
P5-02-01<br />
Discrepancy between CT and FDG-PET/CT in the staging of<br />
patients with inflammatory breast cancer: Implications for<br />
radiation therapy treatment planning<br />
Jacene H, DiPiro P, Bellon J, Nakhlis F, Hirshfield-Bartek J, Yeh<br />
E, Overmoyer B. Dana-Farber <strong>Cancer</strong> Institute, Harvard Medical<br />
School, Boston, MA<br />
Background: To compare suspected areas of cancer involvement based<br />
on the findings of CT and FDG-PET/CT in patients with inflammatory<br />
breast cancer (IBC) and to determine if discrepancies would modify<br />
radiation therapy treatment fields.<br />
Methods: This is a retrospective study of 29 consecutive female<br />
patients with IBC (median age 49 years, range 28-78) who had both<br />
CT and PET/CT scans prior to the initiation of systemic therapy.<br />
CT and PET/CT scans were obtained within a median of 3 days<br />
(range 0-64). CT and PET/CT scans were independently reviewed<br />
by a board-certified radiologist (PD) and a board-certified nuclear<br />
medicine physician (HJ), respectively. Findings were recorded by<br />
anatomic site and graded as negative, equivocal or positive for<br />
malignancy. Radiation fields were then determined by a breast<br />
radiation oncologist (JB) after separately reviewing the CT and PET/<br />
CT images. Discrepancies between the two modalities were recorded.<br />
The study was approved by the hospital institutional review board.<br />
Results: Seven of 29 patients (24%) had discrepant findings that<br />
likely would have resulted in a modification of radiation treatment<br />
fields and/or radiation dose. In four patients, internal mammary<br />
nodal involvement was suspected on PET/CT but not on CT. In<br />
two of these four patients, PET/CT also detected additional disease<br />
(supraclavicular in one patient and chest wall in the other) that<br />
likely would have required a change in radiation field and/or dose.<br />
Another patient had subpectoral adenopathy on PET/CT that was not<br />
considered abnormal on CT. One patient had equivocal findings in<br />
the infraclavicular region on CT which was negative on PET/CT. In<br />
one patient, body habitus limited the CT evaluation; more extensive<br />
infiltrative soft tissue and nodal disease was seen on PET/CT.<br />
In four patients, there were discrepant findings for distant disease<br />
that likely would have resulted in a change in management or<br />
additional imaging studies. In two of these cases, PET/CT showed a<br />
clearly positive finding that was negative or equivocal on CT. In an<br />
additional two cases, equivocal PET/CT findings would have resulted<br />
in additional testing that would not have been recommended by CT<br />
alone. In another 4 cases, metastatic disease was suspected based<br />
on CT, but additional sites (all in bone and not seen on CT) were<br />
suspected on PET/CT.<br />
Conclusions: Inflammatory breast cancer patients have a high<br />
probability of presenting with extensive local/regional disease and<br />
distant metastases. In our IBC population, PET/CT imaging would<br />
have likely resulted in a change of radiation field or dose in 7 of 29<br />
(24%) patients. Additionally, in four instances PET/CT suspected<br />
additional metastatic disease (14%). These discrepancies most<br />
commonly involved inclusion of an internal mammary nodal radiation<br />
field and identification of distant metastases. Pathologic verification<br />
of abnormal findings is necessary to verify these results. PET/CT<br />
imaging should be considered a standard component of radiographic<br />
staging for patients with IBC.<br />
P5-02-02<br />
Factors influencing time to seeking medical advice and start of<br />
treatment in breast cancer (BC) patients – an International survey<br />
Jassem J, Ozmen V, Bacanu F, Drobniene M, Eglitis J, Kahan Z,<br />
Lakshmaiah K, Mardiak J, Pienkowski T, Semiglazova T, Stamatovic<br />
L, Timcheva C, Vasovics S, Vrbanec D, Zaborek P. Medical University<br />
of Gdansk, Poland; University of Istanbul, Turkey; Sf Maria Hospital,<br />
Bucharest, Romania; Institute of Oncology, Vilnius University, Vilnus,<br />
Lithuania; Riga East University Hospital, Riga, Latvia; University of<br />
Szeged, Hungary; Kidwai Memorial Institute of Oncology, Bangaluru,<br />
India; National <strong>Cancer</strong> Institute and Medical School of Comenius<br />
University, Bratislava, Slovakia (Slovak Republic); Medical Center<br />
of Postgraduate Education, ECZ, Otwock, Poland; Petrov Research<br />
Institute of Oncology, St. Petersburg, Russian Federation; Institute of<br />
Oncology and Radiology, Belgrade, Serbia; Chemiotherapy Clinic,<br />
Sofia, Bulgaria; Zagreb University Hospital Center, Zagreb, Croatia;<br />
Warsaw School of Economics, Warsaw, Poland<br />
Background. We earlier reported patient-related factors influencing<br />
the delay in first medical advice for signs of BC in selected countries (J<br />
Clin Oncol 2012;30[15S]:578s). The present analysis, which includes<br />
additional countries, addresses the factors influencing time from first<br />
symptoms of BC to initiation of treatment (Total Delay Time; TDT).<br />
Methods. A total of 6,588 female BC patients from 11 countries<br />
were surveyed using a uniform questionnaire translated into local<br />
languages. TDT was determined using 8 individual scales, including<br />
one pertaining to patient delay and 7 related to subsequent steps in<br />
a typical diagnostic process. Regression models were constructed<br />
using 18 variables concerning diverse contextual and personal patient<br />
characteristics. Due to expected differences in the relevant sets of<br />
predictors, time between first symptoms and first medical visit (Patient<br />
Delay Time; PDT) and time between first medical visit and start of<br />
therapy (System Delay Time; SDT) were modeled separately, with<br />
multilevel regression.<br />
Results. Mean TDT varied in individual countries from 11.5 to 29.4<br />
weeks (grand mean of 14.3 weeks; see table), with 43% of cases<br />
with a delay of >12 weeks. Multilevel regression equation indicated<br />
that factors significantly correlated with longer PDT were distrust in<br />
the medical system and ignoring disease. Patients with fear of the<br />
disease, stronger self-examination habits, at least secondary education,<br />
being employed, reporting more support from friends and family, and<br />
living in cities of >100,000 inhabitants had shorter PDT. Predictors<br />
of shorter SDT included being diagnosed by an oncologist vs. other<br />
physician, having at least secondary education, being older than 60<br />
years, having a history of cancer in female relatives and having breast<br />
lump vs. other BC symptoms. Indicators of longer SDT were PDT >4<br />
weeks, more than one BC symptom detected by patient, distrust in<br />
the medical system, disregard of BC signs, less support from friends<br />
and family, and having first medical examination in a public vs.<br />
private medical center. Individual countries differed significantly with<br />
regard to intercept of the multilevel models and slopes of regression<br />
coefficients for selected psychological and behavioral attributes.<br />
Conclusions. An extensive set of variables potentially impacting<br />
delay times, mainly related to psychological and behavioral patient<br />
attributes, was examined. Several of them strongly determined<br />
both PDT and SDT, but their strength differed between individual<br />
countries. Both models (for PDT and SDT), although statistically<br />
significant, accounted for approximately 20% of variance in time;<br />
www.aacrjournals.org 427s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
therefore other variables, e.g. related to the differences in national<br />
healthcare systems (not addressed in this study) might have a stronger<br />
impact on delays in the initiation of BC therapy and warrant further<br />
analyses.<br />
Country Number of patients Mean PDT (weeks) Mean SDT (weeks) Mean TDT (weeks)<br />
Poland 1000 3.6 9.5 11.5<br />
Lithuania 458 4.9 8.3 12.2<br />
Serbia 800 4.5 9.3 12.9<br />
Slovakia 253 4.0 10.7 13.2<br />
Croatia 250 4.9 10.2 13.4<br />
Turkey 1031 4.8 10.5 13.8<br />
Russia 1059 4.8 12.4 15.7<br />
Bulgaria 644 4.8 12.5 15.9<br />
Latvia 156 6.2 13.1 17.5<br />
Romania 319 6.0 20.4 25.5<br />
India 268 6.1 24.7 29.4<br />
P5-02-03<br />
Large-scale genomic instability consistently identifies BRCA1/2<br />
inactivation in breast cancers<br />
Stern M-H, Popova T, Manié E, Dubois T, Sigal-Zafrani B, Bollet M,<br />
Sastre-Garau X, Vincent-Salomon A, Houdayer C, Stoppa-Lyonnet<br />
D. Institut Curie, Paris, France<br />
The goal of this study was to identify genomic markers predicting<br />
actual BRCA1/2 inactivation in breast cancers. By comparing<br />
genomic profiles of BRCA1/2 mutated and wildtype basal-like<br />
carcinomas (BLC) we developed a signature of BRCAness. The<br />
signature accounts for the level of the large scale genomic instability<br />
and was demonstrated to predict BRCA1/2 impairment with 100%<br />
sensitivity and 90% specificity in the large series of BLCs. We<br />
introduced a bioinformatics procedure evaluating the number of large<br />
scale rearrangements (denoted as Large Scale Transition or LST)<br />
in the genome and showed that the number of LSTs discriminate<br />
homologous recombination deficient and proficient tumors (Popova<br />
et al, <strong>Cancer</strong> Research 2012 Aug).<br />
The efficiency of the signature of BRCAness represented by the<br />
number of LSTs was then evaluated for the luminal breast tumors and<br />
ovarian carcinomas. Luminal breast tumors and ovarian carcinomas<br />
could be stratified into two groups according to the number of LSTs.<br />
The performance of the LST signature in all types of breast cancers<br />
will be presented.<br />
Measurement of LST is a highly reliable, simple and cost effective<br />
method to identify patients who should benefit of a BRCA1/2 testing,<br />
and to select tumors which may respond to treatment targeting DNA<br />
repair deficiencies (platinium salts, PARP inhibitors).<br />
P5-03-01<br />
<strong>Cancer</strong> stem cells predict engraftment and poor prognosis of<br />
primary breast tumors<br />
Charaffe-Jauffret E, Ginestier C, Bertucci F, Cabaud O, Wicinski<br />
J, Finetti p, Josselin E, Adelaide J, Nguyen T-T, Monville F,<br />
Jacquemier J, Thomassin-Piana J, Pinna G, Jalaguier A, Lambaudie<br />
E, Houvenaeghel G, Xerri l, Harel-bellan A, Chaffanet M, Viens P,<br />
Birnbaum D. CRCM-IPC; CEA<br />
<strong>Breast</strong> cancer is a major health problem and heterogeneity of the<br />
disease has been considered as a strong limitation to find the best<br />
therapies to cure cancer, overcome recurrences and metastases. The<br />
establishment of models that reflect tumor biology and metastatic<br />
progression is critical to develop successful new therapeutic strategies.<br />
In the breast, orthotopic xenografts currently appear as the best models<br />
to study tumor growth, metastasis and develop tools for prognosis<br />
prediction. Furthermore, mouse transplant assays have been used to<br />
assess cancer stem cell (CSC) activity and demonstrate that leukemia<br />
and many solid tumors are organized along a hierarchical model.<br />
Despite the promise of the CSC model sustained by mouse<br />
transplantation assays, the clinical relevance of xenografts studies to<br />
identify determinants of stemness able to influence clinical outcome<br />
remains challenging. In breast cancer, transcriptional programs from<br />
functionally validated CSC populations remain to be deciphered.<br />
Here, we report the establishment of a bank of primary breast tumorderived<br />
xenografts (xenobank). We showed that the xenografts retain<br />
the main features of primary tumors, that engraftment is correlated<br />
with the presence of CSC in tumors, and that engraftment in the<br />
mouse is able to predict prognosis in patients. This suggests that<br />
CSCs may govern breast cancer prognosis. We established the gene<br />
expression profiles of functionally validated ALDEFLUOR-positive<br />
CSC populations (breast CSC-GES) and demonstrated their clinical<br />
relevance. Among 2609 patients with breast cancers, we validated<br />
that he expression of the breast CSC-GES is correlated with poor<br />
outcome and metastasis in uni-and multivariate analysis (5-year<br />
MFS was 70% CI95 [67-74] in the breast CSC-positive class and<br />
80% (CI95 [77-83]) in the breast CSC-negative class (p=5.5E-04<br />
with log-rank test). Furthermore, we identified a core of 19 genes<br />
commonly expressed in breast CSC, murine embryonic, neural and<br />
hematopoietic stem cells programs and demonstrated for each gene<br />
its ability to modulate breast CSC population, being implicated in<br />
self-renewing or differentiation programs. We found that the core of<br />
genes in common between four stem cell gene expression studies<br />
(CE-BCSC-3SC) displayed an adverse prognostic impact for patients<br />
with breast cancer. The core contained genes implicated in oxidative<br />
phosphorylation, detoxification, lipid metabolism, and genomic<br />
stability, and these shared determinants of stemness influenced<br />
clinical outcome.<br />
Thus, we show ed that CSCs from orthotopically engrafted primary<br />
breast tumors have clinical and biological relevance. This functionally<br />
validated CSC population is highly correlated with survival and<br />
express genes governing main stem cell functions, substantiating a<br />
major prediction of the CSC model and opening further promises for<br />
new CSC therapies using valid preclinical models.<br />
P5-03-02<br />
Targeting mRNA Translation to Enhance the Radiosensitivity of<br />
Inflammatory <strong>Breast</strong> <strong>Cancer</strong> Stem Cells<br />
Silvera D, Connolly EP, Volta V, Arju R, Venuto T, Schneider RJ.<br />
NYU School of Medicine, New York, NY; NYU <strong>Cancer</strong> Institute, NYU<br />
School of Medicine, New York, NY; Columbia University College of<br />
Physicians and Surgeons, New York, NY<br />
Purpose/Objective(s): Inflammatory breast cancer (IBC) is a highly<br />
aggressive and radiation resistant malignancy with a dismal prognosis<br />
despite multimodality therapy, including ionizing radiation. We have<br />
previously shown that the unique pathogenic properties of IBC result<br />
in part from over-expression of translation initiation factor eIF4G1,<br />
which is part of the eIF4F translation initiation complex, along with<br />
eIF4E and eIF4A. eIF4F is regulated by mTOR, providing a promising<br />
target for anti-cancer therapeutics. We demonstrated that protein<br />
synthesis is highly regulated during IR by the DNA-damage response<br />
(DDR) pathway through mTOR signaling. Many key proteins required<br />
for the DDR pathway are encoded by mRNAs that require high levels<br />
of the eIF4F complex and mTOR activity for their efficient translation.<br />
We hypothesized that upregulation of eIF4F in IBC plays a crucial<br />
role in the radio-resistance of disease.<br />
Materials/Methods: Experiments were conducted in IBC SUM149<br />
cells. eIF4G1, eIF4E and eIF4A were silenced through the generation<br />
of stable cell lines that express tetracycline-inducible shRNAs. eIF4A<br />
was also inhibited using the pharmacologic investigational inhibitor<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
428s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
DAMD-PatA. Radiation sensitivity in vitro was determined by cell<br />
survival assay. Tumor xenografts were generated by the injection<br />
of stable shRNA inducible cell lines into nude mice. IBC SUM149<br />
cancer stem cells (CSC) from both in vitro and in vivo experiments<br />
were analyzed by a combination of cell surface marker analysis,<br />
mammosphere formation and Aldefluor assays.<br />
Results: We show that moderate inhibition by silencing of individual<br />
components (or by pharmacologic inhibition of eIF4A) of the<br />
eIF4F complex prevents IBC xenograft tumor growth and strongly<br />
enhances radiosensitivity. In contrast to results obtained for nontransformed<br />
breast epithelial cells, reducing the high levels of eIF4G1<br />
in epithelial IBC cells in 2D cultures provides no enhancement in<br />
radiation sensitivity. Rather, SUM149 IBC cells harbor a substantial<br />
population of CSCs, which are the cells that are strongly dependent<br />
on high levels of eIF4G1, and which are selectively radio-sensitized<br />
as a result of eIF4G1-silencing. CSCs also require eIF4E and eIF4A<br />
activity in order to survive radiation treatment. We also demonstrate<br />
that silencing of eIF4G1 radio-sensitizes the stem cell population<br />
within IBC tumor xenografts. Radio-resistance of IBC cells is likely<br />
mediated by differential responses to the DDR in the stem-cell<br />
populations and by selective mRNA translation of proteins involved<br />
in the DDR pathway.<br />
Conclusions: Our results demonstrate that regulation of mRNA<br />
translation plays an important role in conferring radio-resistance to<br />
advanced breast cancers, particularly by allowing the survival of the<br />
CSC compartment. While inhibition of eIF4F enhances radiation<br />
sensitivity in non-transformed cells, this process is abrogated in<br />
IBC due to enrichment of a radiation resistant CSC population,<br />
demonstrating translational control of the breast cancer stem cell<br />
population, and providing a novel understanding of the role of the<br />
regulation of mRNA translation in radiation resistance of breast<br />
cancer.<br />
P5-03-03<br />
Antitumor Activity and <strong>Cancer</strong> Stem Cells Effect of Cetuximab<br />
in Combination with Ixabepilone in Triple Negative <strong>Breast</strong><br />
<strong>Cancer</strong>s (TNBC)<br />
Tanei T, Rodriguez AA, Dobrolecki L, Choi DS, Landis M, Chang JC.<br />
The Methodist Hospital Research Institute and Weill Cornell Medical<br />
School, Houston, TX<br />
Purpose: The ErbB family, including EGFR, has been demonstrated to<br />
play key roles in metastasis, tumorigenesis, cell proliferation, and drug<br />
resistance. Recently, these characteristics have been linked to a small<br />
subpopulation of cells classified as cancer stem cells (CSCs) which<br />
are believed to be responsible for tumor initiation and maintenance.<br />
Ixabepilone is the microtubule-stabilizing agent has been expected<br />
to be more sensitive than the conventional taxanes. The aim of this<br />
study was to investigate whether the EGFR monoclonocal antibody<br />
cetuximab, in combination with ixabepilone is a more effective<br />
treatment, and kill cancer stem cells more effectively as compared<br />
to chemotherapy alone in TNBC.<br />
Experimental Design and Results: <strong>Breast</strong> CSC populations were<br />
evaluated with FACS analysis (CD44+ and CD24-/low, or Aldefluor+)<br />
and mammosphere formation efficiency (MSFE). In vitro, we<br />
demonstrated that in triple negative cell lines (MDA-MB-231 and<br />
SUM159), cancer stem cell populations were decreased after treatment<br />
of cetuximab, or cetuximab plus ixabepilone. In vivo, cetuximab in<br />
combination with ixabepilone treatment caused significant tumor<br />
regression (cetuximab vs. cetuximab+ ixabepilone; tumor volume<br />
fold change P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-03-05<br />
Histone deacetylase (HDAC)-inhibitor mediated reprogramming<br />
drives cancer cells to the pentose phosphate metabolic pathway<br />
Debeb BG, Larson RA, Lacerda L, Xu W, Smith DL, Ueno NT, Reuben<br />
JM, Gilcrease M, Krishnamurthy S, Buchholz TA, Woodward WA. MD<br />
Anderson <strong>Cancer</strong> Center, Houston, TX<br />
Recent studies have shown that energy metabolism in human<br />
pluripotent cells contrasts sharply with energy metabolism in<br />
differentiated cell types. Specifically, it has been shown that nuclear<br />
reprogramming from somatic cells to induced pluripotent stem cells<br />
is associated with a switch from oxidative to glycolytic metabolism.<br />
Whether a metabolic switch also occurs in reprogrammed/<br />
dedifferentiated breast cancer cells is unknown. Moreover, the<br />
function of the metabolic state in stemness is poorly understood and<br />
no data are available on whether breast cancer stem cells (CSCs)<br />
are metabolically different from committed cancer cells. Herein we<br />
demonstrated that HDAC inhibitors reprogram committed single<br />
aldefluor negative breast cancer cells into aldefluor positive cells<br />
(10.3 ± 2.8 vs 21.3 ±3.7% untreated vs treated P
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
paclitaxel (ip on days 1, 4 and 8) or both drugs when tumors reached<br />
0.5 cm 2 . Statistical analysis was performed using one-way ANOVA<br />
with the Bonferroni multiple comparison test. RESULTS: Activity of<br />
the HH measured by the expression of Gli1 was increased in BCSC<br />
cell lines as compared to E cell line (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
HIF-1α DN construct. Moreover, SUM-149 cells expressing the HIF-<br />
1α DN construct exhibited delayed tumor growth in vivo (p = 0.05).<br />
Standard clonogenic assays demonstrated that PyMT HIF-1α KO<br />
cells and SUM-149 cells expressing the HIF-1α DN construct were<br />
more sensitive to radiation therapy (SF6 of PyMT, HIF-1α:Control,<br />
0.016:0.087), but that the PyMT KO and SUM-149 mammospheres<br />
that persisted after radiation were completely radioresistant (SF6<br />
of PyMT, HIF-1 α: Control, 0.48:0.44). In contrast, MCF-7 cells<br />
were not radiosensitized in either standard or mammosphere assays.<br />
Interestingly, in HIF-1α DN MCF-7 cells, molecular features of<br />
IBC were observed, such as the increased expression of E-Cadherin<br />
and loss of Wisp3. But, Notch1 protein expression was unchanged<br />
between HIF-1α DN MCF7 or SUM149 cells. Moreover, concurrent<br />
radiation in the presence of a gamma secretase inhibitor or with<br />
a p53-MDM2 inhibitor nutlin failed to radiosensitize HIF KO<br />
mammosphere clonogens. We conclude that downregulation of HIF-1<br />
activity selectively radiosensitizes IBC clonogenic cells but fails to<br />
radiosensitize the residual mammospheres. These data suggest that<br />
the known HIF-1α mediated mechanisms that favor radiosensitivity,<br />
such as the promotion of glycolysis and proliferation under stress,<br />
may predominate in mammospheres, which ultimately leads to<br />
radioresistance in residual mammospheres after HIF inhibition.<br />
P5-03-11<br />
Possible role for cancer stem cells: results from a pilot neoadjuvant<br />
trial of HER-2 positive breast cancer patients treated with a<br />
combination of (Nab)-paclitaxel and lapatinib.<br />
Siziopikou KP, Gradishar WJ, Kaklamani VG. Northwestern<br />
University Feinberg School of Medicine, Chicago, IL<br />
Background: Lapatinib, a dual kinase inhibitor against both<br />
epidermal growth factor (EGFR) and human epidermal factor 2<br />
(HER-2) and nanoparticle albumin bound (nab) paclitaxel was<br />
recently used by our group in a pilot study of early stage HER-2<br />
positive breast cancer. We reported that the combination was well<br />
tolerated and showed good efficiency in this patient group. <strong>Cancer</strong><br />
stem cells were recently identified in solid tumors including breast<br />
carcinomas. These tumor initiating stem cells are reported to be<br />
increased in HER-2 positive breast cancers. Lapatininb is postulated<br />
to reduce the percentage of breast cancer stem cells following HER-<br />
2 inhibition. This study aimed to investigate such an effect in this<br />
patient population of early stage HER-2 positive breast cancer cases<br />
uniquely treated by a combination of nab-paclitaxel and lapatininb.<br />
Design: 30 patients with stage I-III HER-2 positive breast cancer<br />
were treated in a neoadjuvant setting with lapatinib 1,000mg/day and<br />
nab-paclitaxel 260 mg/m2 every 2 weeks for 4 cycles. The expression<br />
of the stem cell markers aldehyde dehydroganase (ALDH1) (BD),<br />
CD24 and CD44 (both <strong>San</strong>ta Cruz Biotechnology) was assessed<br />
immunohistochemically in breast cancer specimens prior to treatment<br />
and at the time of definitive surgery. Staining was considered negative<br />
if < or = 1%, and positive if >1%.<br />
Results: Of the 30 patients, 28 underwent surgery and were evaluated<br />
for pathologic response. Complete pathologic response (pCR) was<br />
observed in 5/28 (17.9%) of the patients. Of the 17 patients for whom<br />
pre-treatment material was available 13 (76.5%) were positive for<br />
ALDH1 expression and 4 (23.5%) were negative. Of the 22 patients<br />
with material available for testing at the time of surgery, 5 showed<br />
pCR, 3 were negative and 14 (63.6%) were positive for ALDH-A1<br />
expression. The CD44+/CD24- phenotype was variable and showed<br />
no difference between groups.<br />
Conclusions: 1. Combination of lapatinib and nab-paclitaxel resulted<br />
in a complete pathologic response in almost 1/5 of the HER-2 positive<br />
early stage breast cancer patients. 2. Overall, there is a reduction in<br />
the number cancer stem cells following neoadjuvant treatment with<br />
lapatinib and nab-paclitaxel. Our results support the hypothesis that<br />
lapatinib may have an effect in manipulating the numbers of cancer<br />
stem cells in patients with HER-2 positive breast cancer. Additional<br />
studies are currently under way to further characterize these findings.<br />
P5-03-12<br />
Targeting breast cancer stem cells using the autopahgy inhibitor<br />
N-Acetyl cysteine<br />
Dave B, Granados S, Mitra S, Chang JC. Methodist Hostpital<br />
Research Institute, Houston, TX<br />
Introduction: One in eight women is diagnosed with breast cancer<br />
in the United States. The most aggressive form of breast cancer is<br />
the “triple negative breast cancer” (TNBCs), where there is a lack<br />
of expression of all three receptors, namely ER, PR and HER2 and<br />
a lack of targeted therapies lead to the highest relapse rate in breast<br />
cancer. This makes it imperative to identify and target the mechanism<br />
of relapse of this cancer. We have recently identified autophagy<br />
as a mechanism of tumor resistant cell survival in breast cancer.<br />
We have demonstrated an increase in autophagy in chemotherapy<br />
treated patients. Further, we have shown that addition of a stem<br />
cell inhibitor against NOTCH reduces autophagy and stem cells<br />
population. In order to eliminate these tumor resistant cells from<br />
surviving chemotherapy, we plan to target the cell survival pathway of<br />
autophagy using N-acetyl csyteine as a novel inhibitor. Materials and<br />
Methods: We treated three triple negative cell lines (SUM159, BT549<br />
and MDA-MB231) with varying concentrations of N-acetyl cysteine<br />
and determined its impact on tumor initiating cells via mammosphere<br />
formation and FACS sorting of CD44hi/CD24low cells. N-acetyl<br />
cysteine affects mitochondrial metabolism so we tested its impact<br />
on mitochondrial DNA mass. Results: N-acetyl cysteine significantly<br />
decreased TIC population as evidenced by the remarkable reduction<br />
in mammosphere formation efficiency and levels of CD44hi/24low<br />
cells at 1 and 10uM in all three cell lines. In two cells lines we have<br />
demonstrated that there is a significant increase in mitochondrial mass<br />
upon treatment of NAC. Conclusion: We have currently determined<br />
that N-acetyl cysteine works via autophagy and eliminates tumor<br />
initiating cell population. We have also demonstrated that this<br />
involves changing the mitochondrial mass and overall changes in the<br />
metabolism of these cells. This novel interlink between mitochondrial<br />
metabolism and autophagy provided a new insight into the role of<br />
tumor initiating cells in breast cancer and possible new approaches<br />
to treat therapy resistance in triple negative breast cancer.<br />
P5-03-13<br />
Detection of tumor initiating cells (TIC) among the peripherally<br />
circulating epithelial tumor cells from patients with breast cancer<br />
Pachmann K, Zimon D, Pizon M, Carl S, Rabenstein C, Camara<br />
O, Pachmann U. University Hospital Jena, Germany; Transfusion<br />
Center, Bayreuth, Germany<br />
Background: The detection of tumor cells circulating in the peripheral<br />
blood of patients with breast cancer is a sign that cells have been able<br />
to leave the primary tumor and survive in the circulation. However,<br />
in order to form metastases they require additional properties such<br />
as the ability to adhere, self renew and grow. Here we present data<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
432s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
that a variable fraction among the circulating tumor cells detected by<br />
the maintrac® approach express mRNA of the stem cell gene nanog<br />
and of the adhesion molecule vimentin and are capable of forming<br />
tumor spheres a property ascribed to TIC.<br />
Patients and methods: Between 10 to 50 circulating epithelial antigen<br />
positive cells detected by the maintrac® approach were selected<br />
randomly from each of 20 patients with breast cancer before and<br />
after surgery and isolated using automated capillary aspiration and<br />
deposited individually onto slides for expression profiling. In addition,<br />
the circulating tumor cells were cultured without isolation among the<br />
white blood cells from 5 patients with breast cancer in different stages<br />
of disease using culture methods favoring growth of epithelial cells.<br />
Results: Although no EpCAM mRNA positive cells expressing stem<br />
cell genes or the adhesion molecule vimentin were detected before<br />
surgery, 10 to 20% of the cells were found to be positive for mRNA<br />
of these genes after surgery. Most surprisingly, it was possible to grow<br />
tumor spheres (Fig 1) from these circulating cells without previous<br />
isolation in all patients in a fraction comprising between 1% of the<br />
epithelial antigen positive cells in patients with newly diagnosed<br />
tumor up to 10% in a patient with advanced breast cancer.<br />
Conclusion: We here show, that among the peripherally circulating<br />
tumor cells a variable fraction is able to express stem cell and adhesion<br />
properties and can be grown into tumor spheres, a property ascribed<br />
to cells capable of initiating tumors and metastases.<br />
P5-03-14<br />
Expression of ALDH1 in metastasizing axillary lymphnodes in<br />
breast cancer<br />
Shi A, Dong Y, Bi L, Xu N, Fan Z, Li S, Yang H, Li Y. First Hospital of<br />
Bethune Medical College, Jilin University, Changchun, Jilin, China;<br />
Lester & Sue Smith <strong>Breast</strong> Center, Baylor College of Medicine,<br />
Houston, TX<br />
Background: There is increasing evidences that a wide variety of<br />
malignancies, including breast cancer, may be driven by a small subset<br />
of ‘tumor-initiating cells’ or ‘cancer stem cells’ (CSC) which are able<br />
to form tumors in immunocompromised mice as well as to generate<br />
the phenotypic heterogeneity of the initial tumor. Enzyme aldehyde<br />
dehydrogenase (ALDH1) has been reported as a possible marker<br />
for mammary CSC. These cells are a source of tumor recurrence<br />
and metastasis, and are resistant to chemotherapy, radiotherapy and<br />
hormone therapy.<br />
Objective: Assuming that the detection of CSC in axillary lymph<br />
nodes is more effective to predicting cancer outcome than the widely<br />
used detection of cancer cells in axillary lymph nodes, we measure<br />
ALDH1 levels to predict their presence into axillary lymph nodes on<br />
development of cancer and anticipate outcomes.<br />
Methods: ALDH1 protein was detected by an immunohistochemical<br />
technique in 229 cases of breast cancer diagnosed from 2002 to 2011<br />
Follow-up ranged from 11.5 months to 96.9 months, with a mean of<br />
73.9 months. A survival assay was used to determine the relationship<br />
between distant metastatic rate and survival rate.<br />
Results: ALDHl expression was detected in 79cases and the Positive<br />
rate in metastatic axillary lymph nodes was 34.5%. Negative ER,<br />
PR status were related to the ALDH1 positive cases(P= 0.012). See<br />
Table 1. Mortality rate between ALDH1 positive cases (50.8%) and<br />
negative cases (28.8%) were significantly different (P= 0.001). See<br />
Table 2. Further, survival analysis of recurrence-free survivals (RFS)<br />
and survival rate decreased significantly between ALDHl positive and<br />
negative cases (P =0.001) (see table 2) and COX analysis shows that<br />
ALDH1 expression is an independent predictor of poor outcome in<br />
breast cancer(P =0.011).<br />
Discussion<br />
What cancer stem cells migrate to the axillary nodes have more<br />
important prediction than that the matastesis of normal cancar cells<br />
in axillary node. It might be a role resulting in dying in breast cancer.<br />
table1 Relationship between ALDH1 expression and clinicopathological parameters.<br />
clinical parameters ALDH+ ALDH- P VALUE<br />
All cases 79 150<br />
Age(years) 0.719<br />
≤50 42 76<br />
>50 37 74<br />
Menopause status 0.622<br />
pre 43 77<br />
post 34 70<br />
tumor size(cm) 0.384<br />
≤2 16 27<br />
2-5 50 106<br />
>5 13 16<br />
The number of 0.843<br />
≤3 36 73<br />
4-9 31 53<br />
>9 12 24<br />
STAGE(II, III, IV) 0.137<br />
II(Iia,Iib) 29 73<br />
III (IIIa, IIIb, IIIc) 47 75<br />
IV 3 2<br />
ER 0.012<br />
positive 46 113<br />
negative 31 36<br />
PR 0.139<br />
positive 49 109<br />
negative 28 40<br />
Her-2 0.192<br />
positive 22 31<br />
negative 55 118<br />
table 2 Relationship between ALDH1 expression and status.<br />
Status ALDH1+ ALDH1- P-VALUE<br />
Alive(group1) 48 121 0.001<br />
Death(group2) 31 29<br />
P5-04-01<br />
Expression of epithelial-mesenchymal transition (EMT)-related<br />
markers in primary tumors and matched lymph node metastases<br />
in breast cancer patients<br />
Zaczek AJ, Ahrends T, Markiewicz A, Seroczynska B, Szade J,<br />
Welnicka-Jaskiewicz M, Jassem J. Intercollegiate Faculty of<br />
Biotechnology, University of Gdansk and Medical University of<br />
Gdansk, Gdansk, Poland; Medical University of Gdansk, Pomorskie,<br />
Poland<br />
Background. Malignant tumors may include multiple cancer cell<br />
populations with various metastatic potential. More aggressive<br />
subpopulations might easier be captured in lymph nodes metastases<br />
(LNM) than in primary tumors (PT). We evaluated mRNA and protein<br />
levels of master EMT regulators: TWIST1, SNAIL and SLUG,<br />
protein levels of EMT-related markers: E-cadherin, vimentin, and<br />
expression of classical breast cancer receptors: HER2, ER and PR<br />
in PT and corresponding LNM. The results were correlated with<br />
clinicopathological data and patient outcomes.<br />
Methods. Formalin-fixed paraffin-embedded (FFPE) samples from<br />
PT and matched LNM from 42 stage II-III breast cancer patients<br />
were examined. Expression of TWIST1, SNAIL and SLUG was<br />
measured by RT-qPCR, with median as cut off for positive result.<br />
Protein expression was examined by immunohistochemistry on tissue<br />
microarrays. For TWIST1, SNAIL, SLUG, E-cadherin and vimentin<br />
>10% of positively stained cells defined positive result. ER and PR<br />
were scored according to Allred system, and HER2 - according to<br />
HercepTest criteria. Results were considered concordant if PT and<br />
LNM were both positive or both negative. Concordance was measured<br />
by estimating Cohen’s kappa coefficient (κ), with κ value equal 1<br />
indicating perfect agreement. Disease-free survival (DFS) and overall<br />
survival (OS) were compared using F-Cox test. Hazard ratios (HRs)<br />
with 95% confidence intervals (95% CI) were computed using Cox<br />
regression analysis.<br />
www.aacrjournals.org 433s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Results. On average, expression of TWIST1, SNAIL and SLUG<br />
was significantly higher in LNM compared to PT (P
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
cancers with adjacent DCIS, expression of mesenchymal markers<br />
was increased in invasive component compared to DCIS component.<br />
CONCLUSIONS: Our study confirmed that EMT is an intrinsic<br />
characteristic of basal-like subtype and is associated with breast<br />
cancer with stem cell phenotype. However, increased expression of<br />
EMT-related markers in invasive carcinoma compared to pure DCIS,<br />
especially in basal-like subtype, and in the invasive component of<br />
basal-like invasive carcinoma with DCIS component also suggests<br />
a role of EMT in the transition of in situ- to invasive carcinoma in<br />
basal-like breast cancer.<br />
P5-04-04<br />
Significance of PELP1/HDAC2/microRNA-200 regulatory<br />
network in EMT and metastasis of breast cancer<br />
Roy SS, Gonugunta VK, Bandyopadhyay AM, Rao M, Goodall G, Sun<br />
L, Tekmal RR, Vadlamudi RK. UTHSCSA, <strong>San</strong> <strong>Antonio</strong>, TX; Centre<br />
for <strong>Cancer</strong> Biology, Adelaide, Australia<br />
Tumor metastasis remains a significant clinical problem and is the<br />
leading cause of death among breast cancer patients. Estrogen receptor<br />
(ER)-coregulators play an essential role in cancer progression and<br />
metastatic tumors express increased levels of coregulators. Proline<br />
glutamic acid rich protein (PELP1) is an ER coregulator, its expression<br />
is upregulated during breast cancer progression to metastasis and is an<br />
independent prognostic predictor of shorter survival of breast cancer<br />
patients. MicroRNA (miR) mediated regulation of tumorigenesis<br />
is emerging as a new paradigm in cancer biology and widespread<br />
misexpression of miRs has been reported in breast cancer. The<br />
objective of this study is to examine the mechanism and therapeutic<br />
significance of PELP1 regulation of miRs leading to breast cancer<br />
metastasis. We have used both ER+ve (ZR75, MCF7) and ER-ve<br />
(MDAMB231, MDAMB468) models that either stably overexpress<br />
PELP1 or PELP1shRNA. Boyden chamber, and invasion assays<br />
demonstrated that PELP1 down regulation significantly affect<br />
migration of both ER+ve and ER-ve cells. Epithelial to Mesenchymal<br />
Transition (EMT) real time qPCR Array studies identified PELP1<br />
modulate expression of EMT genes Snail, Twist, ZEB1, ZEB2,<br />
Vimentin and MMPs. Importantly, whole genome microRNA array<br />
analysis using PELP1 model cells revealed that miR200a and miR141<br />
were significantly upregulated in cells expressing PELP1-shRNA<br />
compared to control cells. Accordingly, over expression of PELP1<br />
in low metastatic model cells decreased expression of miR200a and<br />
miR141. PELP1 regulation of miRs was further confirmed by ZEB1<br />
and ZEB2 3’UTR luciferase reporter assays. ChIP analysis revealed<br />
recruitment of PELP1 to the proximal promoter region of miR-200a<br />
and miR141 and promoter reporter assays further confirmed PELP1<br />
regulation of miRs. Interestingly, PELP1 down regulated expression<br />
of miR200a and miR141 by promoting repressive chromatin<br />
modifications via HDAC2. Supporting this, HDAC inhibitors reversed<br />
PELP1 driven repressive effects. Further, ectopic expression of<br />
miR200a and miR141 mimetic decreased PELP1 mediated invasion/<br />
metastatic functions. Prognostic significance of PELP1-miRNA<br />
axis was determined using Tissue micro-array (TMA) and in situ<br />
hybridization (ISH assays) of Locked Nucleic Acid (LNA)-based<br />
microarray approach in 102 human breast tumors. To test therapeutic<br />
potential in vivo, we have generated ZR-PELP1- and MCF7-PELP1-<br />
shMIMIC of miR200a and miR141 stable cells. In vitro gene<br />
expression and Boyden chamber assays using these model cells<br />
revealed that shMIMIC of miR200a and miR141 reversed PELP1<br />
mediated alterations in gene expression and reduced PELP1 driven<br />
migration/invasion. Proof of principle studies using IVIS imaging<br />
of nude mice based assays of GFP-Luc labeled cells demonstrated<br />
therapeutic efficacy of miRIDIAN shMIMIC of miR200a and<br />
miR141 on PELP1 driven in vivo metastasis. Collectively, these<br />
novel findings demonstrate for the first time a previously unknown<br />
role for PELP1 in epigenetically controlling the functions of tumor<br />
metastasis suppressor miR-200a and miR141. These results suggest<br />
that PELP1-miR axis may be crucial stimulus for promoting EMT and<br />
breast cancer metastasis. This study is funded by NIH T32CA148724<br />
Postdoc Fellowship Grant.<br />
P5-04-05<br />
E-Cadherin is Required for In Vivo Growth of Inflammatory<br />
<strong>Breast</strong> <strong>Cancer</strong>: Importance of Mesenchymal-Epithelial Transition<br />
(MET) and Role of HIF1α<br />
Chu K, Boley KM, Cristofanilli M, Robertson FM. The University of<br />
Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX; Fox Chase <strong>Cancer</strong><br />
Center, Philadelphia, PA<br />
Background: Inflammatory breast cancer (IBC) is the most aggressive<br />
and deadly form of breast cancer and is phenotypically distinct from<br />
other forms of locally advanced breast cancer. The 5-year survival for<br />
IBC patients (40%) has not improved even with the implementation<br />
of multi-disciplinary care and targeted therapies (e.g. anti-HER2 or<br />
anti-estrogen therapies). Lymph node involvement is common at first<br />
diagnosis and the accelerated metastasis program that characterizes<br />
IBC account for a disproportionate number of the 40,000 women<br />
who will die from breast cancer. The most common molecular<br />
marker for IBC is the cell adhesion surface glycoprotein, E-Cadherin.<br />
Classically, E-Cadherin is thought to be a tumor suppressor and its<br />
loss is associated with the epithelial-mesenchymal transition (EMT)<br />
and acquisition of an invasive phenotype. The importance of EMT in<br />
metastasis is well accepted in numerous tumor models although the<br />
presence of EMT in patient samples is rarely demonstrated. Given<br />
the propensity of IBC to metastasize, one would expect a strong EMT<br />
signature in IBC cell lines, however the persistent robust expression<br />
of E-Cadherin in IBC patient tumors and in IBC cell lines, with a<br />
lack of expression of ZEB1, a transcriptional repressor of E-cadherin<br />
and diminished expression of genes within the transforming growth<br />
factor beta signaling pathway, suggests otherwise.<br />
Methods: To further define the role of E-Cadherin in IBC, we used<br />
the SUM149 IBC cell line to manipulate E-Cadherin via shRNA<br />
knockdown and by overexpression of ZEB1 a known transcriptional<br />
repressor of E-cadherin.<br />
Results: While the lack of E-Cadherin or ZEB1 overexpression in<br />
SUM149 cells led to an EMT phenotype in vitro, E-Cadherin was<br />
required for in vivo growth of SUM149 tumor cells. Gene profiling<br />
identified novel E-Cadherin signaling pathways including an hypoxia<br />
gene signature through HIF1a as well as cytokine responsive<br />
pathways. The requirement of HIF-1a for in vivo growth of SUM149<br />
cells was confirmed by shRNA knockdown of HIF-1a.<br />
Conclusions: The absolute requirement for E-Cadherin and<br />
maintenance of the mesenchymal-epithelial transition in IBC<br />
tumor growth is demonstrated. Furthermore, a novel functional link<br />
between E-Cadherin and HIF-1a and in their critical role in survival<br />
of IBC tumors is identified for the first time and warrants further<br />
investigation.<br />
Supported in part by The Susan G Komen Organization Promise<br />
Grant KG081287 (FMR and MC)<br />
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<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-04-06<br />
Soluble factors from activated immune cells induce epithelial<br />
mesenchymal transition in inflammatory breast cancer cells<br />
Cohen EN, Gao H, Anfossi S, Giordano A, Tin S, Wu Q, Lee B-N,<br />
Luthra R, Krishnamurthy S, Hortobagyi GN, Ueno NT, Woodward WA,<br />
Reuben JM. The University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX; The University of Texas at Houston Health Science<br />
Center, Houston, TX; The Morgan Welch Inflammatory <strong>Breast</strong> <strong>Cancer</strong><br />
Research Program and Clinic, The University of Texas MD Anderson<br />
<strong>Cancer</strong> Center, Houston, TX<br />
Rationale:<br />
Inflammatory breast cancer (IBC) is the most insidious form of<br />
locally advanced disease. Emerging evidence suggests that host<br />
factors in the microenviromement may interact with underlying IBC<br />
genetics to promote the aggressive nature of the tumor. An integral<br />
part of the metastatic process involves epithelial to mesenchymal<br />
transition (EMT) where primary breast cancer cells gain motility and<br />
stem cell features that allow distant seeding. Interestingly, the IBC<br />
consortium microarray data found no clear evidence for EMT in IBC<br />
tumor tissues. However, it is unknown if soluble factors secreted by<br />
activated immune cells mediate EMT in the IBC microenvironment<br />
that may account for the absence of EMT in studies of the tumor cells<br />
themselves. Therefore, we tested whether the conditioned media of<br />
activated immune cells were capable of inducing EMT in IBC cells.<br />
Methods:<br />
Conditioned media (CM) were generated using healthy donor<br />
peripheral blood mononuclear cells that were activated with anti-CD3<br />
antibody immobilized to plastic and soluble anti-CD28 antibody to<br />
activate T cells through the T-cell receptor (TCR) or left unstimulated<br />
for 48 hours. Thereafter, CM from each of the cultures was harvested<br />
and filtered. Next, 48-hour pre-seeded SUM149 IBC cells were grown<br />
in culture medium consisting of 25% CM and 75% IBC culture<br />
medium for an additional 2 days. Unconditioned media and TGF-β<br />
were used as negative and positive controls, respectively for EMT.<br />
Following treatment with CM, RNA was extracted from the target<br />
cells and analyzed for the presence of EMT-related transcription<br />
factors (EMT-TF) and markers of epithelial and mesenchymal states<br />
by TaqMan® qRT-PCR. Subsequently, a panel of 24 genes was tested<br />
on 4 IBC cell lines (SUM149, SUM190, KPL4 and IBC-3) and 5<br />
non-IBC cell lines (MCF-10a, MCF-7, MDA-231, and MDA-453)<br />
treated with immune-activated CM using the Fluidigm® Dynamic<br />
Array integrated fluidic circuit (“chip”) gene expression platform<br />
which allows for the simultaneous quantification of 2,304 data points<br />
using TaqMan® assays. Formalin-fixed, paraffin embedded blocks<br />
were prepared from trypsinized cells for immunohistochemical (IHC)<br />
staining to detect E-cadherin and vimentin expression.<br />
Results:<br />
SUM149 cells cultured in the presence of TCR-activated CM for two<br />
days showed upregulation in EMT-TFs (SNAIL1, ZEB1, and TG2),<br />
vimentin and fibronectin by qRT-PCR. IHC staining showed increases<br />
in both vimentin and E-cadherin expression after 48-hour exposure to<br />
anti-TCR CM. Fluidigm® gene expression analysis of multiple cell<br />
lines exposed to anti-TCR CM showed that E-cadherin expression<br />
was unchanged or slightly decreased in non-IBC cell lines, whereas<br />
3 of 4 IBC cell lines showed an increase in E-cadherin.<br />
Discussion:<br />
These data suggest that soluble factors secreted by activated immune<br />
cells are capable of inducing EMT in IBC cells and may mediate the<br />
persistent E-cadherin expression observed in IBC. Such processes<br />
may contribute to the highly aggressive nature of the disease; however,<br />
an immune competent in vivo model is warranted to fully understand<br />
the implications of these findings.<br />
P5-04-07<br />
Epithelial-mesenchymal transition phenotype in breast cancers<br />
is associated with clinicopathologic factors indicating aggressive<br />
biologic behavior and poor clinical outcome<br />
Bae YK, Kim A, Choi JE, Kang SH, Lee SJ. Yeungnam University<br />
College of Medicine, Daegu, Korea<br />
Epithelial-mesenchymal transition (EMT) is defined by the loss<br />
of epithelial characteristics and the acquisition of a mesenchymal<br />
phenotype. EMT in epithelial tumors is a reversible process and<br />
expected to be involved in invasion, metastasis and chemoresistance<br />
of cancer cells. EMT-inducing factors down-regulate E-cadherin and<br />
up-regulate extracellular matrix proteins such as fibronectin. <strong>Cancer</strong><br />
tissue may display a wide spectrum of expression phenotypes of<br />
EMT-related proteins. However, little is known about the clinical<br />
significance of the different EMT phenotypes in breast cancers. We<br />
investigated expression pattern of EMT-related proteins, E-cadherin<br />
and fibronectin in 1,498 invasive breast carcinomas by using<br />
immunohistochemistry on tissue microarrays. EMT phenotypes were<br />
divided into complete type (E-cadherin-negative and fibronectinpositive);<br />
incomplete type, including hybrid (E-cadherin-positive and<br />
fibronectin-positive) and null (E-cadherin-negative and fibronectinnegative)<br />
types; and a wild type (E-cadherin-positive and fibronectinnegative).<br />
We correlated EMT phenotype with clinicopathologic<br />
characteristics and patients survival. Loss of E-cadherin was observed<br />
in 140 (9.3%) cases and fibronectin was expressed in cancer cells of<br />
320 (21.4%) cases. Twenty three (1.5%) cases were categorized as<br />
complete type, 414 (27.6%) as incomplete type (hybrid type, 297;<br />
null type, 117), and 1,061 (70.8%) as wild type. Complete EMT<br />
phenotype was significantly associated with advanced pT stage,<br />
lymph node metastasis, high histological grade, and triple negativity<br />
(p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
increased expression of some EMT transcriptional regulators, such<br />
as ZEB1, Snail and Slug, which suggested our selected kinases may<br />
regulate EMT through these transcription factors. Interestingly,<br />
FACS analysis also showed a substantial increase in CD44 hi CD24 -<br />
population in these kinase-transducted HMLER cells. The increase<br />
of CD44 hi CD24 - mesenchymal phenotype could be attributed to<br />
increase of standard form CD44 (CD44s) and decrease of the variant<br />
form CD44 (CD44v8-10). And this alternation was associated with<br />
down-regulation of ESRP1 and ESRP2, two splicing factors that<br />
regulate CD44 splicing and EMT. Therefore, these selected kinases<br />
may be considered as novel regulators of EMT, and may aid the<br />
development of new prognostic markers or drug targets for breast<br />
cancer progression.<br />
P5-04-09<br />
Squamous Cell Carcinoma Antigen 1 (SCCA1) Upregulation<br />
Causes Epithelial to Mesenchymal Transition (EMT) and<br />
Promotes Mammary Tumorigenesis<br />
Sheshadri N, Ullman E, Catanzaro J, Chen E, Zong W-X. Stony Brook<br />
University, Stony Brook, NY<br />
SCCA1, a member of the family of serine protease inhibitors, was first<br />
identified as a serological marker for cervical cancer but has since been<br />
shown to be upregulated in several other cancers including lung, head<br />
and neck, liver, skin, and breast. SCCA1 is believed to protect cells<br />
from unscheduled cathepsin release and activation upon lysosomal<br />
injury. In order to understand the molecular role of SCCA in cancer,<br />
we ectopically expressed it in the immortalized yet non-tumorigenic<br />
mammary epithelial cell line MCF10A. Expression of SCCA1 impairs<br />
the efficiency of lysosomal as well as proteasomal protein degradation<br />
pathways. Transcriptional profiling of SCCA expressing cells by<br />
microarray demonstrates an altered gene expression pattern that<br />
resembles EMT. Phenotypically, SCCA1 expression leads to spindle<br />
shaped cell morphology, increased migratory potential, resistance<br />
to anoikis, and the ability to form colonies in soft agar. SCCA1-<br />
expressing MCF10A cells can form tumors when injected into the<br />
mammary fat pad of immune-compromised mice. Correlative to the<br />
transforming activity, SCCA1 expressing cells have enhanced Erk and<br />
Akt signaling pathways, and have bypassed the requirement of growth<br />
factors and hormones that are essential for proliferation of MCF10A<br />
cells. In a transgenic mouse model, where SCCA1 is conditionally<br />
expressed in mammary epithelial cells under the control of MMTV<br />
promoter, increased mammary gland ductal branching and hyperplasia<br />
are observed. These findings indicate a previously unknown role of<br />
SCCA1 in promoting EMT and tumorigenesis, possibly by inducing<br />
chronic misfolded protein stress that contributes to enhance tumorpromoting<br />
signaling.<br />
P5-05-01<br />
Catalogued phospho-sensing peptides identifying active,<br />
oncogenic kinase signatures<br />
Mori M, Chen Z, Boudreau A, van’t Veer L, Coppé J-P. University<br />
of California, <strong>San</strong> Francisco, CA; Kinogea Inc., Shanghai, China;<br />
Lawrence Berkeley National Laboratory, Berkeley, CA<br />
Background: Phospho-signaling networks represent one of the most<br />
clinically and therapeutically important frontiers of biology and<br />
medicine. Yet, measuring the phospho-catalytic activity of kinases,<br />
and monitoring the functionality of the entire kinome network at once<br />
remains largely unexplored. In particular, a highly convenient tool<br />
would be the advent of a microarray-like chip to comprehensively map<br />
phosphorylation networks to identify kinase signatures underlying<br />
cancer types and guide therapeutic interventions. In order to create<br />
such a kinase-sensing platform, we developed a library of peptide<br />
probes capable of reporting on the catalytic activity of kinases. The<br />
well-studied EGFR and SRC kinase network measurements serve<br />
as proof of concept.<br />
Methods: We developed a human kinase protein and peptide<br />
repertoire from thousands of publications and >30 public databases<br />
computationally curated, filtered and merged, suitable to act as peptide<br />
beacons to evaluate enzymes’ activity. Our database catalogues 916<br />
kinase enzymes, 1913 substrate proteins, 6173 distinctive kinasesubstrate<br />
active nodes, and compiles 2702 unique biological kinase<br />
peptide targets that all represent biologically relevant, latent nanosensors<br />
usable to comprehensively track kinase signaling networks.<br />
Here, a representative set of 33 out of 417 peptides predicted to be<br />
specifically targeted by EGFR and SRC tyrosine kinase families<br />
and 17 control peptides, is tested for their potential kinase-activity<br />
reporting ability using a common luminescence ATP-consumption<br />
assay. We further validated the peptide screen in biological extracts<br />
using an isogenic culture model of basal like breast cancer (HMT-<br />
3522 S1 and T4-2).<br />
Results: The differential phosphorylation activity of recombinant,<br />
active kinase enzymes (EGFR, ERBB2, SRC, HCK, FYN, FRK, LYN,<br />
LCK) was successfully detected by ATP-consumption measurement<br />
using the 50 peptides in time course experiments (0.25-4 hours) with<br />
evidence of selectively. Subsets of these data were confirmed by SRC<br />
kinase inhibitor treatments and dilution assays (0.1-5ng/ul kinase<br />
enzymes). Increased presence of activated SRC kinase in biological<br />
extracts from T4-2 breast cancer cells compared to nonmalignant<br />
S1 cells was shown by significantly elevated phosphorylation of 10<br />
tested peptides (maximum elevation was shown with a SRC -specific<br />
reporting peptide and increased from 4 to 73% ATP consumption in<br />
S1 versus T4-2 cells, respectively).<br />
Conclusion: These data demonstrate that the tested peptides can<br />
monitor kinases’ activity. The peptide database can serve as a resource<br />
to provide sensitive and specific phospho-sensing probes, used to<br />
directly and specifically evaluate the activity of kinases, and can<br />
potentially support the identification of the entire, active, oncogenic<br />
kinome. Using this resource, we were able to identify peptides with<br />
evidence of specificity in in vitro and ex culture assays. Our efforts<br />
now concentrate on expanding this approach into a functional<br />
kinomic-screening platform in multiplex array format. Ultimately, we<br />
hope to translate such device into the clinic, and map phosphorylation<br />
signatures that cause breast malignancies and to guide tailor-made<br />
therapies.<br />
P5-05-02<br />
The role of cellular heterogeneity on the therapeutic response<br />
of breast cancer: Clinical insights from a hybrid multiscale<br />
computational model<br />
Powathil GG, Thompson A, Chaplain MAJ. University of Dundee,<br />
Scotland, United Kingdom; Dundee <strong>Cancer</strong> Centre, University of<br />
Dundee, Scotland, United Kingdom<br />
Background:<br />
The therapeutic control of cancer progression critically depends on<br />
the responses of the individual cells that constitute the entire tumor<br />
mass. A key reason for poor therapeutic responses is the emergence<br />
of drug resistance due to intracellular and extracellular cellular<br />
heterogeneity that seriously impair the efficacy of chemotherapy<br />
and radiation therapy.<br />
Method:<br />
We have developed a hybrid multiscale computational model of breast<br />
cancer growth and treatment that incorporates individual cell-cycle<br />
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dynamics and the effects of a changing microenvironment through<br />
the oxygen dynamics to consider optimum treatment protocols<br />
for breast cancer. In this model, the internal cell-cycle dynamics<br />
determine the growth strategy of the cancer cells, making the model<br />
more biologically relevant. This also helps classify the cancer cells<br />
according to their cell-cycle state and to analyse the effect of various<br />
cell-cycle-dependent chemotherapeutic drugs. The incorporation of<br />
oxygen dynamics within this hybrid model allows study of the effects<br />
of the microenvironment in cell-cycle regulation and drug resistance<br />
due to a hypoxia-induced quiescence (G0/G1 arrest) of the cancer<br />
cells. Furthermore, the effects of radiation therapy are included in<br />
the model using a modified linear quadratic model for the radiation<br />
damage, incorporating the effects of hypoxia and cell-cycle in<br />
determining the cell based radiosensitivity. The model is then used to<br />
study various combinations of multiple doses of cell-cycle-dependent<br />
chemotherapies and radiation therapy given that radiation may work<br />
better by the partial synchronisation of cells in a radiosensitive phase<br />
of the cell-cycle.<br />
Results:<br />
Using this computational model, we have shown that the cytotoxic<br />
effect of combination therapy is very much dependent on the timing of<br />
drug delivery, the time delay between the doses of chemotherapeutic<br />
drug and cell-cycle heterogeneity. The effectiveness of the drugs is<br />
also dependent on the spatial distribution of the tumor cell mass as<br />
this greatly influences the surrounding tumor microenvironment and<br />
drug distribution. After each dose of the chemotherapeutic drug, the<br />
changing spatial dynamics of the tumor cells redistributes the tissue<br />
oxygen and subsequently delivered drug doses within the tumor.<br />
Moreover, the cell-cycle phase-based chemotherapy also helps in<br />
favor of radiation therapy through the partial synchronisation of cells<br />
in the most radiosensitive phase of the cell-cycle.<br />
Conclusions:<br />
The incorporation of the spatial distribution of the breast cancer cells<br />
along with the internal and external cellular heterogeneity is critical<br />
to optimising scheduling strategies for chemotherapy and combined<br />
chemotherapy and radiation therapy. Overall, the computational<br />
simulation results highlight the potential usefulness of the model in<br />
developing patient-specific optimal treatment strategies.<br />
P5-05-03<br />
The 5p12 breast cancer susceptibility locus is associated with<br />
MRPS30 expression in estrogen receptor - positive tumors<br />
Quigley DA, Van Loo P, Alnæs GG, Tost J, Zelenika D, Balmain<br />
A, Børresen-Dale A-L, Kristensen VN. Institute for <strong>Cancer</strong><br />
Research, Oslo University Hospital, Oslo, Norway; Wellcome Trust<br />
<strong>San</strong>ger Institute, Hinxton, United Kingdom; Helen Diller Family<br />
Comprehensive <strong>Cancer</strong> Center, University of California, <strong>San</strong><br />
Francisco, CA; CEA - Institut de Génomique, Evry, France<br />
Genome-wide association studies (GWAS) have identified numerous<br />
loci linked to breast cancer susceptibility, but few of these loci have<br />
been convincingly linked to causal variants. We identified genes<br />
whose mRNA expression is linked to germline variation in normal<br />
mammary tissue and breast tumors by performing a genome-wide<br />
expression Quantitative Trait Locus (eQTL) analysis in 97 samples<br />
of normal mammary tissue and 286 breast adenocarcinomas. In the<br />
tumors we found 164 cis-acting loci, which affect expression of<br />
nearby genes. Twenty nine of these loci are previously unreported<br />
in other eQTL studies, including a cis-acting locus at 5p12 affecting<br />
expression of the mitochondrial ribosomal 28S subunit protein<br />
MRPS30 in estrogen receptor-positive but not estrogen receptornegative<br />
tumors. This locus has been associated with susceptibility<br />
to estrogen receptor-positive breast cancer in several GWAS, with<br />
MRPS30 being the suggested candidate gene. One of these studies<br />
found that the rs771660 variant was most significantly associated<br />
with breast cancer in the 5p12 region, and we found that rs771660<br />
was most strongly associated with MRPS30 gene expression. We<br />
provide the first evidence that this breast cancer susceptibility locus<br />
affects MRPS30 expression specifically in estrogen receptor-positive<br />
tumors and suggest a mechanism for estrogen activation of MRPS30<br />
via proteins in the AP-1 complex.<br />
P5-05-04<br />
Intraductal delivery of RNAi-based therapeutics to gene targets<br />
identified through computational systems modeling<br />
Brock A, Krause S, Li H, Kowalski M, Collins J, Ingber D. Wyss<br />
Institute, Harvard University, Boston, MA; Boston Children’s<br />
Hospital, Boston, MA<br />
We utilize a computational systems biology approach to identify<br />
gene targets with the potential to serve as targets for therapeutic<br />
RNAi. Inferred gene regulatory network models were constructed<br />
using whole transcriptome expression profiling for progressive<br />
stages of mammary tumorigenesis in FVB C3(1)-SV40Tag mice.<br />
These computational models predicted key mediator transcription<br />
factors that are critical for hyperplasia and ductal filling in the early<br />
stages of disease progression. Putative mediator transcription factors<br />
were targeted by RNAi first in a mammary spheroid assay. Based<br />
on their ability to restore lumen formation and normal apical-basal<br />
polarization to mammary tumor cells, two transcription factors, Hoxa1<br />
and Hoxb13, were selected for validation in vivo. siRNA targeting<br />
each of these transcription factors was formulated with lipidoid<br />
nanoparticles and delivered to the mammary gland via intraductal<br />
injection. Silencing Hoxa1 resulted in a significant reduction in tumor<br />
incidence in FVB C3(1)-SV40Tag. This represents a novel strategy<br />
to achieve localized silencing of a target gene in the mammary<br />
epithelium.<br />
P5-05-05<br />
Computational modeling of breast cancer growth and spread:<br />
the role of matrix degrading enzymes<br />
Deakin NE, Thompson AM, Chaplain MAJ. University of Dundee,<br />
United Kingdom; Dundee <strong>Cancer</strong> Centre, University of Dundee,<br />
United Kingdom<br />
Background<br />
A “hallmark” of cancer growth and metastatic spread is the process of<br />
local invasion of the surrounding tissue. <strong>Cancer</strong> cells achieve this by<br />
the secretion of enzymes involved in proteolysis (tissue degradation)<br />
including matrix metalloproteinases (MMPs). These over-expressed<br />
proteolytic enzymes then proceed to degrade the host tissue allowing<br />
the cancer cells to disseminate throughout the microenvironment by<br />
active migration and interaction with components of the extracellular<br />
matrix such as collagen. The implications of MMP-2 activation by<br />
MMP-14 and the tissue inhibitor of metalloproteinases-2 (TIMP2) can<br />
be considered alongside the suitability of the matrix to be invaded.<br />
The suitability of the matrix incorporates pore size, since in some<br />
highly dense collagen structures such as breast tissue, the cancer<br />
cells are unable to physically fit through a porous region and rely on<br />
membrane-bound MMPs to forge a path through which degradation<br />
by other MMPs and movement of cancer cells can occur.<br />
Method<br />
We have developed a multi-scale mathematical model of breast<br />
cancer cell invasion of host tissue by combining both micro- (cell)<br />
and macro- (tissue) scale dynamics. The model considers cancer cells<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
and two matrix-degrading enzymes from the MMP family of differing<br />
mechanistic actions, namely MMP-2 and the membrane bound MMP-<br />
14 (also called MT1-MMP), and their interaction with, and effect on,<br />
the extracellular matrix (ECM) in a 2-D spatial domain.<br />
For the macro-scale we use a system of reaction-diffusion-taxis<br />
partial differential equations to capture the qualitative dynamics of<br />
the migratory response of the cancer cells. The micro-scale operates<br />
over a smaller spatial and temporal scale, and as such allows us<br />
to explicitly examine the stochastic role which is inherent within<br />
the region of enzyme operation. Computational simulations of the<br />
equations predict the spatio-temporal evolution of the cancer cell<br />
density, the concentration levels of the various enzymes and the<br />
density of the extracellular matrix.<br />
Results<br />
The model exhibits a rich range of dynamic and heterogeneous<br />
spatio-temporal solutions, which qualitatively match experimental<br />
and clinically observed results for aggressive breast carcinoma<br />
invasion and can be used to determine the speed of invasion through<br />
a variety of structured mediums such as the highly dense collagen<br />
constitution of some peritumoral stroma. Using the “worst case”<br />
scenario, an estimate for the maximum region of invasion over time<br />
from the initial data can be obtained suggesting the likely extent of<br />
breast cancer cell invasion into the surrounding tissue.<br />
Conclusion<br />
This modeling is most relevant to and informs the biological processes<br />
occurring in early stage breast cancer, in which local invasion is a<br />
crucial aspect of tumor behavior.<br />
P5-05-06<br />
Spatio-temporal computational modeling of the p53-Mdm2<br />
pathway<br />
Sturrock M, Thompson AM, Chaplain MAJ. University of Dundee,<br />
United Kingdom; Dundee <strong>Cancer</strong> Centre, University of Dundee,<br />
United Kingdom<br />
Background<br />
The p53 transcription factor is a well-established regulator of the cell<br />
cycle and key to preventing cancer. In response to a variety of cellular<br />
stresses (e.g., DNA damage or oncogene activation) p53 is activated<br />
and translocates to the nucleus where it activates transcription of target<br />
genes which can induce cell cycle arrest, senescence or apoptosis. One<br />
of the target genes for p53 is the gene for Mdm2, a negative regulator<br />
of p53 function in cells. Mdm2 represses p53 function through two<br />
main mechanisms: by promoting p53 ubiquitination and proteasomal<br />
degradation and, through direct inhibition of p53 transcriptional<br />
activity. Experimental data have revealed that in response to gamma<br />
irradiation, p53 and Mdm2 concentrations exhibit spatial and temporal<br />
oscillatory dynamics in individual MCF7 breast cancer cells. The<br />
precise function of these oscillations is still under investigation.<br />
Method<br />
Using in vitro laboratory data, we have developed a computational<br />
model to study the spatio-temporal evolution of the p53-Mdm2<br />
pathway. The model comprises a system of coupled nonlinear<br />
partial differential equations, including transport terms and reaction<br />
kinetics. The transport is assumed to include both random (diffusion)<br />
and active mechanisms with proteins convected in the cytoplasm<br />
toward the nucleus, modeling transport along microtubules. Internal<br />
structures such as ribosomes and the nuclear membrane are also<br />
explicitly modeled.<br />
Results<br />
Using computational simulations we have found ranges of values<br />
for the model parameters such that sustained oscillatory dynamics<br />
occur, consistent with available experimental measurements. To<br />
bridge the gap between in vitro and in silico experiments realistic<br />
cell geometries using imported images of cells have informed our<br />
computational domain. The effects of microtubule-disrupting drugs,<br />
proteasome inhibitor drugs, and mutations in the DNA binding site<br />
of p53, have been modeled yielding data in agreement with published<br />
experimental laboratory studies.<br />
Conclusions<br />
This mathematical computational model enables us to compare the<br />
effects of clinically relevant therapeutic approaches at the single cell<br />
level. In particular, the precise temporal and spatial distributions of<br />
p53 can be determined and the cellular consequences modeled.<br />
P5-06-01<br />
Active pak6 induces aneuploidy in breast cancer cells.<br />
Paul BA, Lu ML. University of Miami Miller School of Medicine,<br />
Miami, FL; Florida Atlantic University, Boca Raton, FL<br />
The natural history of breast cancer remains largely undefined. More<br />
than 50% of clinical specimens exhibit aneuploidy. Among these<br />
aneuploid cancers, nearly half have chromosome copy numbers<br />
approaching tetraploid. The high incidence of aneuploidy in advanced<br />
breast cancer is thought to be a byproduct of chromosome missegregation<br />
resulting from mutations in tumor suppressor genes<br />
regulating cell cycle checkpoints and corresponding to disease<br />
progression. However, recent large-scale sequencing projects have<br />
revealed that most tumors contain approximately 14-20 different<br />
mutant genes, suggesting heterogeneity exists throughout the genomes<br />
of cancer cells. This notion revives the concept that aneuploidy<br />
resulting from chromosome mis-segregation or other similar<br />
mechanisms may play an active role leading to transformation and<br />
disease progression.<br />
A novel p21-activated kinase 6 (PAK6) was recently identified to be<br />
an androgen receptor (AR) and estrogen receptor (ER) interacting<br />
protein. An estrogen-stimulated PAK6 activation was observed in<br />
BT474 breast cancer cells. This activation is mediated by estrogenstimulated<br />
activation of PKA. At the cellular level, active PAK6<br />
promotes transformation to metastatic phenotypes in MCF7 breast<br />
cancer cells as evidenced by increases in cell motility, matrigel<br />
invasion, and soft agar growth. Further characterization of MCF7<br />
cells expressing a constitutively active PAK6 mutant revealed an<br />
accumulation of cells with higher ploidy as compared to that of<br />
parental cells. Using a proteomic approach to determine the PAK6<br />
downstream target, we identified that Cdt1, a DNA pre-replicative<br />
complex subunit, is overexpressed in response to PAK6 activation.<br />
In eukaryotes, the expression and stability of Cdt1 are strictly<br />
regulated to ensure only one round of DNA replication in each cell<br />
cycle. Deregulated overexpression of Cdt1 has previously been<br />
demonstrated to induce aneuploidy and malignant transformation<br />
due to re-initiation of DNA replication within the same S-phase. The<br />
identification of Cdt1 overexpression in response to PAK6 activation<br />
provides a plausible mechanism for the observed accumulation of<br />
higher ploidy cells in MCF7 cells expressing active PAK6. Taken<br />
together these findings suggest a direct link between hormonal signals,<br />
DNA replication, and maintenance of genomic integrity.<br />
P5-06-02<br />
The Role of <strong>Breast</strong> Tumor Kinase (Brk) in Cell Cycle Control<br />
Nimnual AS, Chan E. Stony Brook University, Stony Brook, NY<br />
Brk promotes cell proliferation and has been associated with multiple<br />
mitogenic pathways. However, the role of Brk in the cell cycle is still<br />
elusive. Here, we present a mechanism of Brk-induced cell cycle<br />
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progression. Brk downregulates the cell cycle inhibitor p27 by altering<br />
its transcription factor FoxO3a subcellular localization. p27 is a key<br />
component of the G1/S cell cycle checkpoint and downregulation of<br />
p27 promotes S phase entry. The progression of the cell from G1 to<br />
S phase, induced by Brk, is independent of growth factors suggesting<br />
a role for Brk in malignant transformation. FoxO3a appears to be a<br />
major component in p27 down-regulation by Brk as the effect of Brk<br />
on p27 expression is significantly abrogated in cells transfected with<br />
siRNA targeting FoxO3a. The induction of FoxO3a nuclear exclusion<br />
by Brk is inhibited by LY294002 indicating that the mechanism is<br />
mediated by the PI3-kinase/Akt pathway. The mechanism underlying<br />
PI3-kinase mediated Brk function is still under investigation with<br />
evidence suggesting the involvement of the translocation of epidermal<br />
growth factor receptor. These data suggest that perturbation of p27<br />
expression induced by Brk causes S phase entrance. Deregulation of<br />
the cell cycle is a key event in neoplasia, and thus, the mechanism<br />
presented here likely contributes to breast cancer development.<br />
P5-07-01<br />
Defining the mechanism of breast cancer growth by chemokine<br />
receptor CXCR7 and Epidermal Growth Factor Receptor<br />
coupling interaction.<br />
Salazar N, Muñoz D, Singh RK, Lokeshwar BL. University of Miami<br />
Miller School of Medicine, Miami, FL; Miami VA Medical Center,<br />
Miami, FL; Dow Corning Inc., Midland, MI<br />
Introduction: <strong>Breast</strong> cancer (BrCa) ranks second in both incidence<br />
and cancer deaths for women in the USA. Recent advances have<br />
revealed a significant contribution of chemokines and their receptors<br />
in tumor growth, survival after chemotherapy, and organ-specific<br />
metastasis. CXCR7 is the latest CXC-chemokine receptor implicated<br />
in BrCa growth. It is endogenously over expressed in BrCa, but<br />
its mechanism of tumor growth enhancement is still not clearly<br />
defined. CXCR7 heterodimerizes with CXCR4 and binds to SDF-1<br />
(CXCL12) and CXCL11. No direct ligand mediated physiological<br />
action has been implicated for CXCR7 in BrCa other than facilitating<br />
CXCR4-mediated cell motility, however, studies in other cancers have<br />
implicated CXCR7 in cell proliferation, anti-apoptotic activity and<br />
cell-cell adhesion. The expression pattern of CXCR7 in BrCa tissues<br />
and its potential contribution in BrCa cell proliferation and survival<br />
were investigated in representative BrCa cell lines using knock down<br />
and knock-in experiments.<br />
Results: CXCR7 was only expressed in ER-α positive BrCa cells<br />
(e.g., MCF-7) and was not found in BrCa cells with known metastatic<br />
potential (MDA-MB231 and SKBr3). Depletion of CXCR7 in MCF-7<br />
BrCa cells by both siRNA and shRNA decreased cell proliferation<br />
and caused cell cycle arrest. Since CXCR7 is an atypical G-protein<br />
coupled receptor where ligand activation does not elicit conventional<br />
intracellular signaling, we hypothesized that CXCR7 regulates<br />
BrCa proliferation through interaction with EGFR or activating<br />
other potential targets of MAP-kinase activation. CXCR7 depletion<br />
reduced site-specific phosphorylation of EGFR at Tyrosine 1110 after<br />
EGF-stimulation. CXCR7 depletion also reduced phosphorylation of<br />
ERK-1/2, indicating a potentially direct interaction with mitogenic<br />
signaling in MCF-7 cells. We tested for direct interaction of CXCR7<br />
with EGFR by co-immunoprecipitation and immunofluorescence<br />
studies. We found EGFR and CXCR7 co-immunoprecipitate and<br />
co-localize as demonstrated by confocal microscopy. Interestingly,<br />
our results also demonstrate CXCR7 and EGFR are co-localized<br />
before EGF stimulation. Further corroboration of CXCR7-EGFR<br />
interaction was established using the proximity ligation assay (PLA)<br />
technique that allowed us to visualize CXCR7-EGFR co-localization<br />
both in cell culture and in human normal and breast cancer tissue.<br />
Conclusion: This data demonstrates an important role for CXCR7 in<br />
BrCa growth and explores the mechanism of action of direct coupling<br />
of EGFR with CXCR7.<br />
P5-07-02<br />
Analysis of a novel synergistic relationship between the FK506<br />
binding protein FKBP52 and beta catenin in androgen receptor<br />
signaling pathways<br />
Storer CL, Olivares K, Fletterick RJ, Webb P, Cox MB. The University<br />
of Texas at El Paso, El Paso, TX; The University of California, <strong>San</strong><br />
Francisco, CA; The Methodist Hospital Research Institute, Houston,<br />
TX<br />
Hormone-dependent cancers depend largely on folding and regulation<br />
by a chaperone-steroid receptor complex. The final stage of the<br />
receptor-chaperone complex consists of a receptor, a heat shock<br />
protein 90 (Hsp90) dimer, p23, and an immunophilin. Hormonedependent<br />
prostate cancer progresses due to key interactions between<br />
the androgen receptor complex and the ligand dihydrotestosterone.<br />
While current treatments block androgen receptor-ligand interactions,<br />
these therapies are no longer effective in advanced stage, hormone<br />
independent prostate cancer (HRPC), when the receptor is activated<br />
even in miniscule levels of hormone. Therefore, we are interested<br />
in targeting other members of the androgen receptor complex and<br />
signaling cascade, namely the immunophilin FK506 binding protein<br />
(FKBP52) and the Wnt cell signaling protein β-catenin. FKBP52 has<br />
the ability to potentiate activity of the androgen, progesterone, and<br />
glucocorticoid receptors and is a prostate cancer biomarker. β-catenin<br />
is a member of the cellular adhesion complex with E-cadherin in<br />
healthy cells, but in aberrant situations, β-catenin actively promotes<br />
progression and invasion in a number of cancers. Our data from<br />
FKBP52 knockout mouse embryonic fibroblast cell lines suggests<br />
that FKBP52 and β-catenin work in tandem to synergize androgen<br />
receptor (AR) transcriptional activity with the probasin promoter.<br />
When AR, FKBP52, and β-catenin are co-transfected, a synergistic<br />
up-regulation of AR signaling is observed, as assessed by luciferase<br />
reporter assays. According to pull down assays, FKBP52 and<br />
β-catenin can interact in the absence of other proteins. Luciferase<br />
assays of mutant FKBP52 proteins suggest that FKBP52’s binding<br />
to β-catenin involves the FKBP52 proline-rich loop and may act<br />
independently of Hsp90 binding. Interestingly, it appears that this<br />
synergistic effect is promoter-specific, suggesting that regulation by<br />
these proteins occurs at the transcriptional level. We have successfully<br />
abrogated the synergism of these proteins using the FKBP52-specific<br />
inhibitor MJC13, a small molecule developed for use in our laboratory.<br />
According to surface plasmon resonance studies, this molecule binds<br />
the androgen receptor at the BF-3 regulatory surface, the interaction<br />
surface for FKBP52 regulation of receptor. According to recent<br />
findings, AR, Wnt, and Human Epidermal Growth Factor Receptor<br />
2 signaling pathways are linked in molecular apocrine breast cancer<br />
progression. We therefore hypothesize that our findings could be<br />
relevant to breast cancer as well as prostate cancer.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
440s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
P5-07-03<br />
Gallotannins and Gallic acid From Mango Fruit (Mangifera<br />
Indica L) Suppress <strong>Breast</strong> <strong>Cancer</strong> Tumor Growth by Targeting<br />
Phosphatidylinositol3-kinase (PI3K)-Akt-NF-kB Pathway and<br />
Associated microRNAs<br />
Banerjee N, Kim H, Krenek K, Talcott S, Talcott SM. Texas A&M<br />
University, College Station, TX<br />
The cytotoxic and anti-inflammatory properties of polyphenolics have<br />
been demonstrated in numerous types of cancer and the objective<br />
of this research was to understand the post-transcriptional targets<br />
involved in anti-inflammatory and pro-apoptotic pathways in the<br />
breast cancer cell line BT474, treated with a polyphenolic extract<br />
(2.5-40µg/ml) rich in gallotannins and gallic acid from mango fruit<br />
in vitro and in athymic nude mice bearing BT474 cells as xenografts.<br />
Results show that cell proliferation as well as tumor size and weight<br />
in vivo was decreased by polyphenolics 60% and 70% in vitro and<br />
vivo, respectively. NF-kB protein and mRNA expression as well as<br />
activation were decreased in a dose-dependent manner (0.6 fold).<br />
The extract also inhibited PI3K-dependent phosphorylation of AKT<br />
and expression and this was accompanied by down-regulation of<br />
miRNA 126 of BT474 (2.25 fold) and in vivo. NFκB-dependent<br />
genes involved in apoptosis-inhibition, metastasis and angiogenesis,<br />
such as survivin, VCAM-1, and VEGF were also decreased, in vitro<br />
and in vivo.<br />
A microRNA-array was also used to investigate whether microRNAs<br />
with target regions within affected genes were affected by the<br />
polyphenolic extract and results show that in addition to miR-126,<br />
miR-let-7a and miR-let-7b among others were significantly increased<br />
by the extract.<br />
In summary the anti-carcinogenic and anti-inflammatory activity of<br />
mango polyphenolics in breast cancer cells were at least in part due<br />
to targeting miR-126 -Phosphatidylinositol 3-kinase (PI3K)-Akt-NFkB<br />
which plays an important role in the proliferative/ inflammatory<br />
phenotype exhibited in this breast cancer cell line.<br />
P5-07-04<br />
Aurora kinase regulates PKC-mediated MMP-9 expression and<br />
invasion in MCF-7 breast cancer cells<br />
Kim JS, Noh EM, Lee YR, Hwang B-M, Jung SH, Youn HJ, Lee SJ.<br />
Institute for Medical Sciences Chonbuk National University Medical<br />
School, Jeonju, Republic of Korea; Chonbuk National University<br />
Medical School, Jeonju, Republic of Korea; School of Dentistry,<br />
Wonkwang University, Iksan, Republic of Korea; College of Phamacy,<br />
Ewha Womans University, Seoul, Republic of Korea<br />
Aurora kinase is a novel family of serine/threonine kinases. Elevated<br />
expression of aurora kinase A and B is observed in many tumor cells,<br />
and dysregulation of aurora kinase has been linked to tumorigenesis.<br />
Therefore, a number of studies focused in their oncogene activities<br />
as anti-tumor targets. Matrix metalloproteinase-9 (MMP-9), which<br />
degrades the extracellular matrix (ECM) and it is important process for<br />
breast cancer cell invasion. MMP-9 can be stimulated by activation of<br />
various cellular signaling pathways including protein kinase C (PKC),<br />
and mitogen-activated protein kinase (MAPKs), activator protein-1<br />
(AP-1) and nuclear factor-kappaB (NF-κB) signaling pathways.<br />
Here, we show that 12-O-tetradecanoylphorbol-13-acetate (TPA), a<br />
directly PKC activator stimulation resulted in an up-regulation and<br />
phosphorlyation of aurora kinases in MCF-7 breast cancer cells.<br />
Also, Results showed that inhibition of the aurora kinases suppressed<br />
TPA-induced MMP-9 secretion/expression and cell invasion through<br />
suppression of NF-κB, AP-1, and MAPKs in MCF-7 breast cancer<br />
cell. In conclusion, this study provides new insight into the novel role<br />
of aurora kinase for expression of MMP-9 by TPA and regulation of<br />
aurora kinase by TPA through MAPKs signaling pathway.<br />
P5-07-05<br />
Insulin-like growth factor binding protein-3 is a key component<br />
of the breast cancer cell response to DNA-damaging therapy<br />
Baxter RC, Lin MZ, Marzec KA, Martin JL. University of Sydney,<br />
Sydney, NSW, Australia<br />
Introduction. <strong>Breast</strong> cancer cells frequently develop resistance to<br />
DNA-damaging therapies, such as radiation and the cytotoxic drugs<br />
doxorubicin and etoposide, and activation of the epidermal growth<br />
factor receptor (EGFR) may play an important role in this process.<br />
However many estrogen receptor (ER)-negative breast tumors<br />
respond poorly to DNA-damaging drugs even when combined with<br />
an EGFR inhibitor. EGFR can modulate the repair of DNA double<br />
strand breaks (DSB) by non-homologous end-joining (NHEJ), by<br />
forming protein complexes that include the catalytic subunit of<br />
DNA-dependent protein kinase (DNA-PKcs). In previous studies we<br />
have shown that the growth-regulatory protein, insulin-like growth<br />
factor binding protein-3 (IGFBP-3), can translocate to the nucleus,<br />
is a substrate for DNA-PKcs, and can transactivate EGFR. The aim<br />
of this study was to delineate the role of IGFBP-3 in the response of<br />
breast cancer cells to DSB-inducing chemotherapeutic agents.<br />
Results. In the triple-negative breast cancer cell lines MDA-MB-468<br />
and Hs578T, which express IGFBP-3 highly, nuclear localization<br />
of EGFR and IGFBP-3, and of their complex as measured by<br />
coimmunoprecipitation (coIP), was enhanced by exposure to<br />
etoposide or doxorubicin, peaking 2 h after etoposide treatment.<br />
This effect was blocked by the EGFR kinase inhibitor gefitinib.<br />
Concomitantly, the co-location of EGFR-IGFBP-3 complexes with<br />
lipid rafts, visualized by proximity ligation assay (PLA) and confocal<br />
microscopy, decreased in response to drug treatment, consistent<br />
with the loss of this complex from the plasma membrane. Similar<br />
to the nuclear DNA-PKcs-EGFR complex, the nuclear DNA-PKcs-<br />
IGFBP-3 complex (seen by both coIP and PLA) was greatest 4 h<br />
after treatment. DNA-PKcs activation at serine-2056, required for<br />
the repair of DNA DSB and stimulated by etoposide treatment, was<br />
decreased by IGFBP-3 downregulation using two separate siRNAs,<br />
and this treatment also attenuated the enhanced DNA-PKcs-EGFR<br />
complexes seen in response to etoposide. Collectively these data<br />
suggest that IGFBP-3 has an obligatory role in the DNA repair<br />
response to DNA-damaging therapy through its interactions with<br />
EGFR and DNA-PKcs.<br />
Conclusion. IGFBP-3 co-translocation to the nucleus of breast<br />
cancer cells and its complex formation with DNA-PKcs and EGFR<br />
in response to DNA damage demonstrate its previously unrecognized<br />
involvement in the regulation of DNA DSB repair by NHEJ. These<br />
novel findings suggests the possibility of a therapeutic approach for<br />
sensitizing ER-negative breast cancers to chemo- or radiotherapy<br />
by targeting the DNA repair function of IGFBP-3. Supported by the<br />
Australian Research Council.<br />
www.aacrjournals.org 441s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-07-06<br />
Triple negative receptor status is associated with low DNA repair<br />
capacity in women with breast cancer<br />
Matta J, Ortiz C, Vargas W, Echenique M, <strong>San</strong>chez F, Ramirez<br />
E, Torres A, Ortiz J, Bolaños G, Gonzalez J, Laboy J, Barnes R,<br />
<strong>San</strong>tiago S, Romero A, Martinez R, Alvarez-Garriga C, Bayona M.<br />
Ponce School of Medicne and Health Sciences, Ponce, Puerto Rico;<br />
Auxilio Mutuo Hospital, <strong>San</strong> Juan, Puerto Rico; Ponce School of<br />
Medicine and Health Sciences and Damas Hospital, Ponce, Puerto<br />
Rico; Private Office, Ponce, Puerto Rico; Ponce School of Medicine<br />
and Health Sciences and Private Practice, Ponce, Puerto Rico; Ponce<br />
School of Medicine and Health Sciences and <strong>San</strong> Lucas Hospital,<br />
Ponce, Puerto Rico; Ponce School of Medicine and Health Sciences,<br />
Ponce, Puerto Rico; Dr. Pila Hospital, Ponce, Puerto Rico; Food and<br />
Drug Administration, Silver Spring, MD<br />
BACKGROUND: <strong>Breast</strong> cancer (BC) is a heterogeneous disease that<br />
manifests different etiologies based on its hormone-receptor status,<br />
which is used to determine BC risk, prognosis, and therapy. Although<br />
many studies have shown important associations between hormone<br />
receptor status and BC, it is unknown how or whether DNA repair<br />
capacity (DRC) correlates with, or is influenced by hormone receptor<br />
status Even though diminished DNA repair capacity is recognized as<br />
a risk factor for BC, no studies to date have evaluated the relationship<br />
of DRC and hormone receptor status. OBJECTIVE: The objective<br />
of this study was to evaluate the association between estrogen,<br />
progesterone, and HER2/neu receptors and DRC measured in<br />
lymphocytes of breast cancer patients. METHODS: Study participants<br />
were pre and post-menopausal women histopathologically confirmed<br />
BC (n =271) were recruited over the last 6 years, primarily through<br />
clinicians from the cities of Ponce, <strong>San</strong> Juan, and Yauco, and other<br />
selected cities throughout Puerto Rico. We recruited only patients<br />
who (1) were recently diagnosed histopathologically with primary<br />
breast cancer and (2) were treatment-naïve (i.e., had not received<br />
chemotherapy, blood transfusions, or radiotherapy). All participants<br />
signed informed consent forms for interviewing, drawing blood<br />
samples, and obtaining tumor material and pathology reports. DRC<br />
was measured in purified lymphocytes with a host cell reactivation<br />
assay and a luciferase reporter gene. Hormone receptor status for ER,<br />
PR and Her2neu, were determined through immunohistochemistry.<br />
DRC levels were dichotomized in ?high? and ?low? using the median<br />
as a cutoff point (2.0% DRC level). <strong>Breast</strong> cancer cases with high<br />
and low DRC were compared to receptor status and other selected<br />
variables such as age, BMI, multivitamin use, that were adjusted for<br />
potential confounding. Crude and multiple logistic regression adjusted<br />
odds ratios were used to assess the associations between low DRC<br />
and each of the receptors and selected variables after adjusting for<br />
age, overweight and obesity, age at menopause, multivitamin use.<br />
RESULTS: Pre-menopausal- Triple negative BC patients were more<br />
likely to have a low DRC (p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
P5-09-01<br />
Evaluation of BCL2 sequence variant in Iranian women patients<br />
with <strong>Breast</strong> cancer<br />
Motahari B, Ghaffarpour M, Javadi GH, Houshmand M. Science and<br />
Research branch, Islamic Azad University, Tehran, Islamic Republic<br />
of Iran; National Institute of Genetic Engineering and Biotechnology,<br />
Tehran, Islamic Republic of Iran; Iranian Research Organization for<br />
Science and Technology, Tehran, Islamic Republic of Iran; Special<br />
Medical Center, Tehran, Islamic Republic of Iran<br />
Introduction:<br />
Despite recent advancements in the treatment and management of<br />
cancers, <strong>Breast</strong> cancer still remains the most common malignancy and<br />
second leading cause of cancer-related deaths among women in Iran.<br />
Apoptosis and cellular proliferation play role an important role during<br />
normal mammary development and carcinogenesis of the mammary<br />
gland. In normal tissues, the homeostasis between apoptosis and cell<br />
proliferation is regulated by Bcl-2 family proteins. Tumor cells tend to<br />
interfere with the mechanism of Apoptosis by activating anti apoptotic<br />
genes such as bcl-2. BCL-2 gene, located at 18q21.3 and consists of<br />
three exons and two promoters (P1 and P2), which have different<br />
functions. The second promoter, P2, is located 1,400 bp upstream of<br />
the translation initiation site and functions as a negative regulatory<br />
element to the P1 promoter. Bcl-2 is the one of the most important<br />
anti apoptotic genes.It has been shown that the -938AA genotype s<br />
associated with higher Bcl-2 expression levels in B-CLL and poor<br />
prognosis. Bcl2 gene has been also demonstrated with breast cancer<br />
development and a single nucleotide polymorphism (SNP-938C >A)<br />
has been identified recently and can provide a susceptible factor for<br />
causing breast cancer.<br />
The main objective of this study was to evaluation of the frequency of<br />
specific genetic alterations in the BCL-2 gene (-938,-758 and 21) and<br />
the risk of breast cancer in Iranian women patients with <strong>Breast</strong> cancer.<br />
Materials and Methods:<br />
Patients; 27 paired Fresh tumor and adjacent normal samples were<br />
obtained from consecutive patients with BC who underwent surgery<br />
for mama mastroctomy from IRANIAN National Tumor Bank,<br />
National <strong>Cancer</strong> Institute, Imam Khomeini Hospital Complexes,<br />
Medical Tehran University, Tehran, Iran. Histopathological<br />
examinations were performed, and all tumors were confirmed as<br />
adenocarcinoma.<br />
Mutational analysis: Fresh tumors and their adjacent were extracted<br />
for genomic DNA using the QIA amp Mini Kit according to the<br />
manufacturer’s instructions. We searched DNA samples of Iranian<br />
patients for identification of SNP; -938C>A, - 758T insertion in the<br />
inhibitory P2 promoter and 21A/G in exon 2 of the BCL-2 gene by<br />
means of PCR sequencing.<br />
Results and conclusions:<br />
In All cases, the frequency of genetic alterations in the BCL-2<br />
gene (-938,-758 and 21) was 16 of27 (59.29%) heterozygous in-<br />
938(C, A) and 5 of 27(18.51%) SNP-938 C >A ,0 of 27(0%)and 8<br />
of 23(34.78%)heterozygous in +21(A,G)and 2 of 23(8.69%)SNP<br />
21A>G respectively. According to our findings, point mutation in<br />
-938C and 21A alleles displayed a positive relation with increasing<br />
tumorgenesis in breast cancer. Our result indicated that the regulatory<br />
BCL2 promoter polymorphism (-938C, A) and coding BCl2 gene<br />
(21A, G) may be useful as a tumor marker for increasing tumorgenesis<br />
in Iranian women breast cancer.<br />
P5-10-01<br />
MicroRNAs -181 and -135a modulate tumour infiltrating immune<br />
cell programs in distinct molecular breast cancer subtypes<br />
Paladini L, Truglia M, Arcangeli A, De Mattos Aruda L, Bianchini<br />
G, Iwamoto T, Bottai G, Pusztai L, Calin GA, Di Leo A, <strong>San</strong>tarpia<br />
L. Istituto Toscano Tumori, Prato, Italy; Istituto Toscano Tumori -<br />
Hospital of Prato, Prato, Italy; University of Florence, Italy; Vall<br />
d’Hebron Institute of Oncology, Vall d’Hebron University Hospital,<br />
Barcelona, Spain; Fondazione Centro <strong>San</strong> Raffaele del Monte Tabor,<br />
Milan, Italy; Okayama University Hospital, Okayama, Japan; The<br />
University of Texas M.D. Anderson <strong>Cancer</strong> Center, Houston<br />
Background and Aims: MicroRNAs (miRNAs) are short noncoding<br />
RNA whose expression levels have diagnostic and prognostic<br />
implications in cancer. However, the relevance of aberrantly expressed<br />
miRNAs to breast tumour-immune response has not been established.<br />
We aimed to assess the association between deregulated miRNAs<br />
and tumour immune response in breast molecular cancer subtypes.<br />
Methods: One hundred and seventy ductal infiltrating breast<br />
carcinomas (BC) (ER+/HER2- n=85, HER2+ n=40, ER-/HER2-<br />
n=45) were evaluated for the presence of cellular immune components<br />
by IHC assay. CD3, CD20 were used as markers for T lymphocytes<br />
infiltration (TIL), and B lymphocytes infiltration (BIL), respectively,<br />
whereas CD68 for the presence of tumour-associated macrophage<br />
(TAM). Total RNA (including miRNA) was extracted from all<br />
tumours and 32 highly specific miRNAs and 276 immune genes were<br />
evaluated by array and qRT-PCR assays. We derived an integrated<br />
immune miRNA-regulatory gene profile to tease out relationships<br />
of these genes as potential targets of specific miRNAs. In vitro<br />
experiments on BC cell lines were performed to confirm potential<br />
links between deregulated miRNAs and immune genes.<br />
Results: Lymphocytes infiltration (LI) was most common in HER2+<br />
and ER-/HER2- BC samples (P < .004 and < .001) although B<br />
and T cells components were differently distributed in these 2 BC<br />
groups. TAM was a frequent event in ER-/HER2- BC subtype (P<br />
< .005). By gene and integration analyses we identified important<br />
miRNA immune-modulated target genes associated with prognostic<br />
factors and with molecular BC subtypes. We focused our studies<br />
on miR-181 and miR-135a that were significantly associated with<br />
ER-/HER2- (P < .001) and HER2+ BC (P < .002), respectively.<br />
BCs with abnormal expression of miR-181 and miR-135a showed<br />
an important association with distinct TIL and TAM components<br />
and specific immune genes. Importantly, preclinical data on BC cell<br />
lines demonstrated that miR-181 and miR-135a were able to regulate<br />
important cell immune-modulators such as SEMA3B and STAT6<br />
signalling pathways, respectively. These 2 cellular pathways in turn<br />
were capable to regulate specific cascades of immune gene networks.<br />
Conclusion: We identified specific miRNAs associated with immune<br />
cellular components and immune-related tumour response in the 3<br />
main molecular BC subtypes (ER+/HER2-, HER2+ and ER-/HER2).<br />
Aberrant expression of miR-181 and miR-135a can contribute to BC<br />
tumour immune response programs by regulating important gene<br />
targets such as SEMA3B and STAT6 signalling pathways in ER-/<br />
HER2- and HER2+ tumours, respectively. Modulation of miRNAs<br />
activating tumour immune response programs may have important<br />
implications for novel therapeutic strategies in BC.<br />
www.aacrjournals.org 443s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-10-02<br />
High serum levels of miR-19a are associated with poor outcome<br />
in metastatic inflammatory breast cancer<br />
Anfossi S, Giordano A, Cohen EN, Gao H, Woodward W, Ueno NT,<br />
Valero V, Alvarez RH, Hortobagyi GN, Lee B-N, Cristofanilli M,<br />
Reuben JM. The University of Texas MD Anderson <strong>Cancer</strong> Center;<br />
Morgan Welch Inflammatory <strong>Breast</strong> <strong>Cancer</strong> Research Program and<br />
Clinic, The University of Texas MD Anderson <strong>Cancer</strong> Center; Fox<br />
Chase <strong>Cancer</strong> Center<br />
Background: Increased expression of miR-19a plays an important<br />
role in tumor progression by regulating angiogenesis and apoptosis.<br />
As miRs can be a valuable diagnostic and prognostic serum biomarker,<br />
we assessed if high serum levels of miR-19a were associated with the<br />
shorter overall survival (OS) of patients with metastatic inflammatory<br />
breast cancer (MIBC) and metastatic non-inflammatory breast cancer<br />
(MNIBC).<br />
Methods: We analyzed 27 MNIBC (10 HER2 normal [HER2 - ] and<br />
17 HER2 amplified [HER2 + ]), 37 MIBC (18 HER2 - and 19 HER2 + )<br />
patients, and 30 healthy donors (HDs). Patients’ sera were collected<br />
before starting a new line of treatment. MiR-19a levels were measured<br />
in patients’ sera and cell lines (MCF-7, SKBR3, MA-231, KPL-4,<br />
SUM-149) by qRT-PCR to assess differences in expression levels<br />
between IBC and non-IBC. MiR-192 and U6 snRNA were used<br />
to normalize miR-19a expression levels in serum and cell lines,<br />
respectively. Fold-changes in expression of miR-19a were calculated<br />
using the 2 -DCt method. Mann-Whitney U test, ROC curve analysis,<br />
Kaplan-Meier, and Student’s t-test were used for statistical analysis.<br />
Results: Median levels of miR-19a were higher in sera of<br />
both MNIBC and MIBC patients than in HDs (p=.001, p1.62) had a shorter<br />
median OS than MNIBC patients with HER2 - tumors (n=9) and low<br />
serum level of miR-19a ( 1.62) and HER2 + MNIBC patients with low<br />
miR-19a (
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
P5-10-04<br />
Metformin mediated upregulation of microRNA-193 triggers<br />
apoptosis by decreasing fatty acid synthase<br />
Cochrane DR, Wahdan-Alaswad RS, Edgerton SM, Terrell KL,<br />
Spoelstra NS, Thor AD, Anderson SM, Richer JK. University of<br />
Colorado Denver School of Medicine, Aurora, CO<br />
Background: We have previously shown that the anti-diabetic drug<br />
metformin kills triple negative (TN) breast cancer cells lines via<br />
apoptosis, at lower IC50 than luminal and HER2 subtypes (presented<br />
at ENDO, manuscript in preparation). Metformin reportedly shows<br />
greater efficacy against stem cells than differentiated cells, reducing<br />
mammosphere formation in in non-adherent culture. Fatty acid<br />
synthase (FASN) is an enzyme critical for de novo fatty acid synthesis<br />
that is overexpressed in breast cancer.<br />
Hypothesis: We hypothesized that miRNAs might be involved in<br />
the ability of metformin to preferentially kill TN cell lines at a lower<br />
IC50 than luminal A lines.<br />
Methods: TN and luminal A (LA) breast cancer cell lines (MDA-<br />
468, HCC70 and MCF7, T47D, respectively) were used to study<br />
the effects of 10mM metformin action in vitro, at physiological and<br />
hyperglycemic culture conditions. Affymetrix chips Human Gene<br />
1.1 and the miRNA 2.0 were utilized to profile gene and miRNA<br />
expression at 6 and 24 hrs. Mimics and lentiviral expression vectors<br />
were utilized to manipulate miRNA expression and a luciferase<br />
reporter was used to confirm miR-193 direct targeting of the FASN<br />
3’UTR.<br />
Results: miR-193 is significantly higher in untreated LA as compared<br />
to TN cells. MiR-193 increases 2-4 fold within 6 hrs of metformin<br />
treatment in both TN, but not LA cell lines. A predicted target of miR-<br />
193, fatty acid synthase (FASN), is decreased by 8 fold following 24<br />
hrs 10mM metformin treatment of the TN breast cancer cells. miR-193<br />
directly targets FASN via a binding site in the 3’UTR, downregulating<br />
gene expression. Restoration of miR-193 to TN lines, causes a<br />
dramatic decrease in FASN protein in a dose dependent fashion.<br />
Conclusions and future directions: Metformin stimulates an increase<br />
in mature miR-193, which mediates the dramatic downregulation of<br />
FASN. This occurs coincident with apoptotic cell death. It remains to<br />
be determined if FASN is the only relevant direct target of miR-193<br />
in TN cell lines. The addition of exogenous non-targetable FASN,<br />
lacking its 3’UTR, will demonstrate whether this pathway is a primary<br />
mechanism of metformin action in TN cells. Future studies will<br />
investigate the ability of metformin to inhibit FASN in non-adherent<br />
mammosphere (stem cell-like) subpopulations, the role of fatty acid<br />
metabolism in mammosphere maintenance and anoikis resistance.<br />
Supported by Komen <strong>Breast</strong> <strong>Cancer</strong> Foundation Grants KG100575<br />
(ADT, JKR, SME, NSS) and KG090415 (JKR, DRC)<br />
P5-10-05<br />
Novel Mechanisms of Metformin Action in TN <strong>Breast</strong> <strong>Cancer</strong>:<br />
Upregulation of miRNA 141 and 192, are Associated with a<br />
Decrease in Targets GRB2 and MSN Involved in Signaling and<br />
Motility Respectively<br />
Edgerton SM, Richer JK, Fan Z, Spoelstra NS, Wahdan-Alsawad RS,<br />
Arnadottir SS, Thor AD. University of Colorado Denver School of<br />
Medicine, Aurora, CO; Aarhus University, Aarhus, Denmark<br />
BACKGROUND: We have previously shown that the anti-diabetic<br />
agent, metformin, inhibits cellular proliferation, colony formation and<br />
cell signaling, with an induction of S-phase arrest and apoptosis in<br />
triple negative (TN) breast cancer cell lines in vitro, and cell outgrowth<br />
and proliferation in vivo. These changes are associated with profound<br />
shifts in phosphorylated cell signaling intermediates, including EGFR,<br />
IGF-1R, Akt, MAPK and others (Liu, et al Cell Cycle 2009). We<br />
have also shown that Stat3 activity (via phosphorylation at serine and<br />
tyrosine sites) is critical to the effects of metformin against TN cells<br />
(Deng, et al Cell Cycle 2012). In unpublished studies, we have noted<br />
that metformin significantly inhibits cellular motility in vitro. In this<br />
study we focus on mechanisms underlying the effects of metformin<br />
in TN cancer cell signaling and motility.<br />
METHODS: TN breast cancer cell lines MDA-MB-468 and MDA-<br />
MB-231were used to study mechanisms of metformin action in vitro.<br />
Invasion chamber and motility assays were used to quantitate the<br />
effects of metformin as compared to untreated controls, with and<br />
without a variety of inhibitors at normal or supraphysiological glucose<br />
concentrations. Affymetrix chips Human Gene 1.1 and miRNA 2.0<br />
were used to identify genes and miRNA up or down regulated by<br />
metformin treatment at 6 and 24 hr at glucose concentrations of 5, 10<br />
or 17 mM. Appropriate primers and antibodies were used to validate<br />
these data at the transcript and protein levels respectively by qRT-<br />
PCR and western blot analyses. Lentiviral expression vectors and<br />
mimics were used to manipulate miRNA expression levels. Direct<br />
targeting of the GRB2 and MSN 3’UTR’s were performed using<br />
luciferase reporters.<br />
RESULTS: TargetScan and Diana miR-Path analysis of miRNA’s<br />
up-regulated at 6 hr following metformin treatmetns identified genes<br />
that were down regulated with metformin treatment such as GRB2<br />
(a predicted target of miR-141) and MSN (a predicted target of miR-<br />
192), as possible mechanisms of drug action. GRB2 regulated the<br />
phosphorylation of numerous receptor tyrosine kinase (RTK) gene<br />
pathway intermediates, including those downstream of EGFR, IGF-<br />
1R and MAPK. Knock-down of miR-141 by an antagomir showed<br />
that miR-141 regulated GRB2. Invasion chamber and motility assays<br />
confirm that the metformin associated reduction in TN cell motility<br />
and invasion capacity involved miR-193 and MSN.<br />
CONCLUSIONS: Metformin acts by diverse molecular mechanisms;<br />
some of these may be cell type specific. In TN breast cancer cells,<br />
metformin causes a rapid increase in miR-141, which targets GRB2, a<br />
gene that encodes a critical regulator upstream of many growth factors.<br />
Metformin treatment also upregulates miR-192, which represses MSN<br />
to reduce motility and invasion.<br />
Supported by Komen <strong>Breast</strong> <strong>Cancer</strong> Foundation Grant KG100575<br />
(SME, JKR, ZF, NSS, ADT)<br />
P5-10-06<br />
A functional role for miR-150 in breast cancer<br />
D’Amato NC, Gu H, Lee M, Heinz R, Spoelstra NS, Jean A, Cochrane<br />
DR, Richer JK. University of Colorado Anschutz Medical Campus,<br />
Aurora, CO<br />
Background: During mammary gland development, massive<br />
coordinated changes in protein expression govern the progression<br />
through pregnancy to lactation and involution. These dramatic<br />
changes are likely regulated in part at the translational level by<br />
changes in microRNAs (miRNAs). We profiled miRNA expression<br />
in mammary epithelial cells (MECs) isolated from mice at pregnancy<br />
day 14 (P14) or lactation day 2 (L2) and found that miR-150 is the<br />
most significantly downregulated miRNA between pregnancy and<br />
lactation. Interestingly, miR-150 was recently discovered to be<br />
decreased in mouse mammary tumors compared to normal mammary<br />
tissue in numerous transgenic models. However, a causal role for<br />
miR-150 has yet to be studied in human breast cancer and little is<br />
known about its functional role and relevant targets in the normal<br />
breast or breast cancer.<br />
www.aacrjournals.org 445s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Hypothesis: We hypothesized that miR-150 may be a tumor<br />
suppressor whose loss in breast cancer cells is an important event that<br />
allows for expression of multiple pro-tumorigenic genes.<br />
Methods: miR-150 levels in human breast cancers were evaluated in<br />
specimens of both ER+ and triple-negative breast cancer (TNBC) as<br />
compared to adjacent, non-involved normal breast epithelium by in<br />
situ hybridization. miR-150 levels were also measured by qRT-PCR<br />
in cell lines representative of multiple breast cancer subtypes. We<br />
stably restored miR-150 in TNBC cell lines by lentiviral infection<br />
and evaluated its effects on clonogenicity, growth in 3D culture,<br />
migration/invasion, and tumorigenicity. Expression of predicted<br />
miR-150 targets was assessed by immunoblot. Crossing of miR-<br />
150 fl/fl mice with BLG-Cre or MMTV/NIC transgenic mice will be<br />
utilized to determine the effects of MEC-specific loss of this miRNA<br />
on mammary tumorigenesis.<br />
Results: In clinical samples, in situ hybridization reveals that<br />
miR-150 levels are lower in both ER+ and TNBC tumor specimens<br />
compared to adjacent normal epithelium, with triple-negative tumors<br />
having the lowest expression. All breast cancer cell lines tested also<br />
have low miR-150 expression as compared to normal mammary<br />
epithelial tissue, with TNBC cell lines expressing the lowest levels.<br />
Exogenous expression of miR-150 in breast cancer cell lines caused<br />
a dramatic decrease in migration and invasion in vitro, and we are<br />
testing predicted miR-150 targets for their role in this phenotype.<br />
Experiments with transgenic models will determine if loss of miR-150<br />
in mammary epithelial cells in the MMTV/NIC mouse model results<br />
in decreased latency or increased tumor formation and metastasis, or<br />
if miR-150 loss during pregnancy results in alterations in lactation,<br />
hyperplasia, or tumor formation.<br />
Conclusions: TNBC specimens and cell lines have the lowest<br />
expression of miR-150, though decreased miR-150 expression<br />
compared to normal mammary epithelium is a common feature of<br />
breast cancers regardless of subtype. miR-150 expression dramatically<br />
inhibits breast cancer cell migration and invasion in vitro, and ongoing<br />
experiments will determine the relevant target genes.<br />
Supported by Susan G. Komen Grant KG090415 and NIH NICHD<br />
P01 PAR-10-245 (Project 3) to JKR<br />
P5-10-07<br />
Luminal A breast cancer: identification of novel circulating<br />
miRNA biomarkers<br />
McDermott AM, Miller N, Ball G, Sweeney KJ, Kerin MJ. National<br />
University of Ireland, Galway, Galway, Ireland; Nottingham Trent<br />
University, Nottingham, United Kingdom<br />
Introduction<br />
<strong>Breast</strong> cancer is a prevalent disease in need of a reliable circulating<br />
biomarker with a role in combination with mammography to facilitate<br />
early diagnosis. Mi(cro)RNAs are a group of small molecules with<br />
ideal biomarker characteristics. The knowledge that miRNAs are<br />
aberrantly expressed in cancer, and can be detected in the circulation<br />
supports their potential role in minimally invasive cancer diagnostics.<br />
Intrinsic breast cancer subtypes provide well characterized phenotypes<br />
to study the biomarker potential of miRNAs. The aim of this study<br />
was to identify systemic miRNAs differentially expressed in Luminal<br />
A (ER+PR+HER2/neu-) breast cancer, and to study their utility as<br />
oncologic biomarkers in the clinical setting.<br />
Material and Method<br />
Whole blood samples were collected prospectively from women<br />
diagnosed with Luminal A breast cancer (n=57) and healthy controls<br />
(n=57). Luminal A phenotype was confirmed by immunohistochemistry<br />
and fluorescence in situ hybridization (FISH). RNA was extracted,<br />
reverse transcribed and a Taqman Low-Density Array (TLDA,<br />
microarray) conducted on a test cohort (10 Luminal A; 10 Control).<br />
Differentially expressed miRNAs were identified using Artificial<br />
Neural Networks (ANN). Expression of specific miRNAs were<br />
validated using RQ-PCR on an independent whole blood cohort (n=47<br />
Luminal A; n=47 Control) and tissue (n=30). Results were analyzed<br />
using Q-Base and Minitab V16.0.<br />
Results<br />
The microarray performed on the test cohort identified 77 differentially<br />
expressed miRNAs. Artificial Neural Networking highlighted seven<br />
miRNAs for further analysis (Table 1).<br />
Table 1: Top 7 Ranked miRNAs<br />
Rank-Order* miRNA Median-Train-Performance** p-value***<br />
1 miR-181a 0.75 0.005<br />
2 miR-301a 0.833333 0.116<br />
3 miR-182 0.75 0.551<br />
4 miR-423-5p 0.75 0.08<br />
5 miR-93 0.708333 0.924<br />
6 miR-652 0.75 0.001<br />
*Ranked according to ANN ** Based on Test Cohort *** Based on Validation Cohort, obtained<br />
using 2-sample t-test<br />
RQ-PCR quantification of expression of these seven candidate<br />
miRNAs in the validation group confirmed the biomarker potential<br />
of two miRNAs. MiR-181a and miR-652 were significantly<br />
under-expressed in the cancer group compared to the control<br />
group (p=0.005 and p=0.001 respectively). Circulating miR-181a<br />
expression correlated with invasive tumour size (r=-0.592, p=0.008).<br />
Furthermore, a combination of these two miRNAs provided a<br />
sensitivity and specificity for detection of Luminal A breast cancer<br />
of 70% and 65%, respectively (Area Under the Curve, AUC=0.77).<br />
MiR-181a and miR-652 were also under-expressed in Luminal A<br />
tumor tissue compared to Tumor Associated Normal (TAN, p=0.019<br />
and p=0.001, respectively).<br />
Conclusion<br />
This study provides insight into the underlying molecular portrait<br />
of the Luminal A subtype by identifying 77 miRNAs with altered<br />
systemic expression levels. Two novel miRNA oncologic biomarkers<br />
are identified, which are altered in both the tumor and circulation.<br />
These miRNAs may have a role in combination with mammography<br />
to facilitate accurate subtype-specific breast tumor detection.<br />
P5-10-08<br />
Hyperactive MAPK signaling alters expression of miR-221/222<br />
and miR-30 families, which impacts multiple pathways and<br />
contributes to breast cancer aggressiveness and progression<br />
Miller P, El-Ashry D. University of Miami, FL<br />
We have previously identified a patient-derived microRNA signature<br />
indicative of hyperactive MAPK (hMAPK) signaling in breast<br />
cancer. This signature associates with reduced estrogen receptor<br />
(ER) expression, and altered protein expression of a multitude of<br />
genes associated with breast cancer aggressiveness and progression.<br />
Additionally, this signature predicts poor clinical outcome with<br />
reduced disease free survival and overall survival in all comers, and<br />
especially among patients with ER+ tumors. Many of the proteins<br />
whose expression is altered in tumors with this hMAPK-miRNA<br />
signature are predicted or validated targets of miRNAs within<br />
the signature. We hypothesize that alterations in expression of<br />
hMAPK-miRNAs directly affect post-transcriptional regulation of<br />
a subset of these proteins. Using a hMAPK cell line model of breast<br />
cancer generated from an MCF-7 background, we investigated the<br />
involvement of hMAPK-miRNAs in post-transcriptional regulation<br />
and resulting dynamics of expression of several proteins identified<br />
as being differentially expressed between hMAPK-tumors and nothMAPK-tumors.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
446s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
Here we have investigated the hMAPK regulation of one<br />
miRNA family that is upregulated and one miRNA family that is<br />
downregulated in the hMAPK signature. Each of these families has<br />
key validated targets important in breast cancer, and many other<br />
putative gene targets. The miR-221/222 family is upregulated in the<br />
hMAPK-miRNA signature, and is a negative regulator of ER and the<br />
cell cycle regulator p27. In our breast cancer cell line model, we have<br />
previously demonstrated that miR-221/222 are upregulated and ER<br />
and p27 are downregulated in hMAPK cells vs control transfected<br />
MCF-7 cells. We now show that inhibiting MAPK signaling with<br />
pharmacological inhibitors reduces the expression of miR-221/222,<br />
and results in enhanced expression of ER and p27; we confirm that<br />
this regulation occurs at the post-transcriptional level using a dualluciferase<br />
reporter construct containing the ER 3’UTR. Additionally,<br />
stimulation of MAPK signaling dynamically increases the expression<br />
of miR-221/222 and decreases ER and p27 expression. These results<br />
indicate that hMAPK signaling directly alters expression of ER and<br />
p27 by altering miRNA expression. Members of the miR-30 family are<br />
downregulated in the hMAPK-miRNA signature, and several proteins<br />
that upregulated in hMAPK-miRNA tumors vs not-hMAPK-miRNA<br />
tumors, including SNAIL, NOTCH1, and FOXO3, are all targets<br />
of the miR-30 family. Using our cell line model, we have shown<br />
that members of the miR-30 family are downregulated by hMAPK<br />
signaling, that SNAIL is upregulated, and that abrogation of hMAPK<br />
signaling reverses these changes.<br />
It is known that SNAIL and ER exhibit inverse expression in breast<br />
cancer cells, and these data suggest that this is due to hMAPK<br />
mediated miRNA activity. Thus, hMAPK signaling may contribute<br />
to increased EMT, ER-negativity, and poor clinical outcome observed<br />
in breast tumors with this hMAPK-miRNA signature via the direct<br />
action of these hMAPK-regulated miRNAs. These results suggest<br />
novel mechanisms by which hMAPK signaling may contribute to<br />
breast cancer disease aggressiveness and progression.<br />
P5-10-09<br />
Prediction of Trastuzumab treatment response for HER2-positive<br />
breast cancer by microRNA profiling<br />
Sato F, Wang Z, Ueno T, Myomoto A, Takizawa S, Masuda N, Mikami<br />
Y, Shimizu K, Tsujimoto G, Toi M. Graduate School of Medicine, Kyoto<br />
University, Kyoto, Japan; Toray Industry, Kamakura, Kanagawa,<br />
Japan; Kyoto University Hospital, Kyoto, Japan; Graduate School<br />
of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan<br />
[Background and Aim] Although Trastuzumab has been used for<br />
HER2(+) breast cancer, the treatment response of Trastuzumab<br />
therapy depends on unknown mechanisms among individual cases.<br />
In order to avoid unnecessary adverse events and to lighten financial<br />
burden for patients, pre-treatment prediction of trastuzumab treatment<br />
response would be beneficial for patients. Thus, in this study, we<br />
develop a prediction algorithm using microRNA expression profile<br />
of breast cancer tissues. [Materials and Methods] Eighty-three breast<br />
cancer patients who underwent trastuzumab-chemo combined therapy<br />
before operations were enrolled with written informed consent.<br />
FFPE specimens of pre-treatment core needle biopsy samples were<br />
collected, and regions containing cancer and adjacent stromal cells<br />
were laser-microdissected. Total RNA samples extracted from the<br />
microdissected specimens were subjected for microRNA microarray<br />
(3D-Gene®, Toray, Japan) analysis. Among these 83 patients, 39 cases<br />
had pCR (complete response in IDC regions regardless presense of<br />
DCIS without lymphnode metastasis), and the other 44 cases did not.<br />
According to the pCR/non-pCR information, we develop a prediction<br />
model using 35 signature microRNAs by a SVM technique. Prediction<br />
accuracy assessed by Leave-one-out validation was AUROC=0.889.<br />
The 35 signature microRNAs for trastuzumab treatment response<br />
included 7 out of 8 let-7 family members and miR-125a-5p/b-5p.<br />
[Conclusion] microRNA profile could predict treatment response of<br />
trastuzumab-chemo combined therapy for HER2(+) breast cancer,<br />
and the developed prediction algorithm might be a useful tool for<br />
clinical decision making.<br />
P5-10-10<br />
The miR-34a is down-regulated in breast cancer and breast stem<br />
cells and a potential to eradicating breast cancer via a systemic<br />
delivery of a VISA –miR-34a nanoparticle system<br />
Xie X, Li L, Xie X, Wei W, Kong Y, Wu M, Yang L, Gao J, Xiao X, Tang<br />
J, Xie Z, Wang X, Liu P, Li X, Guo J. Sun Yat-Sen University <strong>Cancer</strong><br />
Center, Guangzhou, China<br />
<strong>Breast</strong> cancer is the most common disease in women around the world<br />
and the current treatment strategies are not potent enough for the<br />
patients, especially those who are the triple-negative type of molecular<br />
classifications. Therefore, novel and more effective treatments are<br />
pressingly needed. Of the current methods, target therapy, which<br />
not only retains cancer-specific expression but also limits toxicity,<br />
is a new strategy for treatment of cancers. In this study, it was to<br />
investigate miR-34a expression in breast caner specimen and its<br />
relationship with patient’s clinical status, and develop targeted miR-<br />
34a delivery system as a potential method for breast cancer therapy.<br />
miR-34a expression was investigated by qRT-PCR and related to<br />
clinicopathologic significance and found to be down-regulated in<br />
breast cancer as compared with normal adjacent tissues and involved<br />
in breast cancer stem cell through down-regulation of CD44, ZEB1,<br />
and Bmi1. We designed targeted miR-34a expression using T-VISA<br />
system (hTERT promoter driven VP16-Gal4-WPRE Integrated<br />
Systemic Amplifier) liposomed-based nanoparticles and evaluated<br />
the antitumor effect in breast cancer cells in vitro and in orthotopic<br />
animal model as well as its systemic toxicity. The T-VISA-miR-34a<br />
system robust targeted to breast cancer cells and breast cancer stem<br />
cells and prolonged duration expression of miR-34a. Furthermore, a<br />
systemic delivery of a VISA –miR-34a nanoparticle system targeted<br />
efficiently expression of miR-34a to tumors and could significantly<br />
inhibit tumor growth and prolong mouse survival in multiple living<br />
imaging xenograft and syngeneic models of orthotopic breast cancer<br />
and without toxicity in intact mice. Our study demonstrated that<br />
miR-34a expression was down-regulated in breast cancer and breast<br />
cancer stem cells through down-regulation of CD44, ZEB1, and Bmi1.<br />
The T-VISA-miR-34a nanoparticle system showed robust antitumor<br />
effects in breast cancer and could be a potential therapeutic approach<br />
to eradicating breast cancer.<br />
P5-10-11<br />
Clinical significance of microRNA expression as a prognostic<br />
factor in early N+ breast cancer (BC)<br />
Ciruelos EM, de Velasco GA, Castañeda C, Rodriguez-Peralto JL,<br />
Gamez A, Sepúlveda JM, Cortés-Funes H, Castellano DE, Fresno<br />
JA. Hospital Universitario 12 de Octubre, Madrid, Spain; Instituto<br />
de Enfermedades Neoplásicas, Lima, Peru; Hospital Universitario<br />
La Paz, Madrid, Spain<br />
Background: microRNAs (miRNAs) are small noncoding RNA<br />
molecules that post-transcriptionally regulate gene expression. In the<br />
present study, we describe miRNA expression in early node-positive<br />
BC and identify a 8-miRNA score that could contribute to prognosis<br />
assessment.<br />
www.aacrjournals.org 447s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Methods: First, microarray analysis was performed using RNA<br />
samples extracted from primary breast cancer. The expression of<br />
miRNAs was analyzed by RT-qPCR using the TaqMan Arrays<br />
from Applied Biosystems. After a suitable normalization of the 677<br />
miRNAs analyzed, 123 presented a good correlation between their<br />
levels of expression in frozen tissue and paraffin tissue. A supervised<br />
analysis was done in order to identify MIR that could predict relapse.<br />
Results: 172 patients with node-positive chemotherapy-treated early<br />
BC were included in the present study. The median age at diagnosis<br />
was (53.7) years, 128 cases (74.4%) had positive estrogen receptor,<br />
and 163 patients ( 94,7%) received adjuvant chemotherapy. After a<br />
median follow up of 8,1 years, 71p (41.2%) relapsed. Supervised<br />
analyses identified 8 microRNAs (has miR-30e, miR-30a, miR-21,<br />
miR-210, miR-93, miR-150, miR-99b, miR-572) associated with<br />
higher risk of relapse (5 year PFS 50% vs 90%, HR 3.75, 95% CI<br />
2.27 – 6.19) and with estimated overall survival (median not reached,<br />
HR 4.51, 95% CI 2.36 – 8.61). Interestingly, miRNAs defined 2<br />
prognostic groups (high and low risk) regardless of type of adjuvant<br />
chemotherapy (with or without anthracyclines) and histological<br />
subtype (luminal A, B or triple negative).<br />
DFS and OS in the global population clasiffied as 8miRNA-low and high risk<br />
8miRNA<br />
DFS OS<br />
risk (n)<br />
median (years) HR (95% CI) p median (years) HR (95% CI) p<br />
Low (103) not reached 3.7 (2.27 - 6.19)
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
comparisons between means and ANOVA followed by post-hoc test<br />
to compare the mean response between subject factors of interest. All<br />
tests were 2-tailed; statistical significance was set at p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
that are differentially expressed between chemo-resistant and sensitive<br />
breast cancer cells. In particular, through high-throughput miRNA<br />
inhibitor library screens, we have identified miRNA inhibitors that<br />
sensitize resistant TNBC cells to paclitaxel, a drug commonly used to<br />
treat triple negative breast cancers. Interestingly, our studies revealed<br />
that specific miRNAs including miR-185 (patent pending) that<br />
sensitize resistant TNBCs to paclitaxel are expressed at significantly<br />
lower levels in relapsed metastatic TNBC patient sera compared to<br />
sera from their healthy siblings. Furthermore, using liposome- or<br />
biocompatible PLGA nanoparticle-based approaches, we show that<br />
systemic delivery of one of the sensitizer miRNAs suppresses breast<br />
cancer lung metastasis without any hepatotoxicity in preclinical mouse<br />
tumor models. Importantly, we show that one of the mechanisms<br />
by which sensitizer miRNAs regulate paclitaxel sensitivity is by<br />
targeting Stathmin, a microtubule destabilizer protein that can bind<br />
to tubulin dimers and stimulate microtubule destabilization. These<br />
findings suggest that tumor-specific miRNAs render selective cell<br />
cytotoxicity in a drug-specific manner, that these miRNAs may serve<br />
as detection markers for identifying patients who might benefit most<br />
from specific drug treatment, and that these miRNAs may represent<br />
novel therapeutic tools for the treatment of the TNBCs. Since<br />
miRNAs are endogenously expressed and can be easily manipulated<br />
using synthetic oligoribonucleotides, we believe that they represent<br />
more attractive targets than the single gene or gene product targeted<br />
by conventional cancer treatments that are typically prone to drug<br />
resistance. Since paclitaxel is used for the treatment of many cancers,<br />
the long-term implications of this study are likely not limited to breast<br />
cancer alone but may apply to other tumor types.<br />
P5-10-17<br />
Radiotherapy-induced miR expression influences the formation<br />
of local recurrence in breast cancer<br />
Fabris L, Berton S, Massarut S, D’Andrea S, Roncadin M, Perin T,<br />
Calin G, Belletti B, Baldassarre G. CRO, National <strong>Cancer</strong> Institute;<br />
MD Anderson <strong>Cancer</strong> Center<br />
In early breast cancer (EBC) patients, local disease relapse occurs<br />
at the site of the original primary tumor in 90% of cases and the<br />
addition of external beam radiotherapy (EBRT) after surgery is<br />
necessary to reduce recurrence rate. This observation suggested that<br />
surgery itself could represent a perturbing factor, possibly by altering<br />
the local microenvironment by inducing a wound healing response.<br />
Recent evidences indicate that, in selected EBC patients, 5 weeks<br />
of EBRT can be successfully replaced by a single dose of Targeted<br />
Intraoperative Radiotherapy (TARGIT). Interestingly, TARGIT acts<br />
not only affecting tumor cell survival itself, but is also able to alter<br />
the tumor microenvironment, by modifying cytokines secretion and<br />
activation of several intracellular pathways in breast cancer cells.<br />
In order to understand the significance of these modifications in<br />
breast tumor microenvironment after exposure to TARGIT we set<br />
up a mouse model of TARGIT treatment. Our results highlighted<br />
that the act of surgery alone strongly stimulates breast cancer cell<br />
growth and the addition of local irradiation completely reverses the<br />
surgery-induced breast cancer cell growth. Moreover, we evaluated<br />
the impact of TARGIT by analyzing microRNA (miR) expression<br />
both in our mouse model and in human specimens. To this aim, we<br />
collected paired specimens of peri-tumoral mammary tissues from 30<br />
early breast cancer (EBC) patients, before and after treatment with<br />
TARGIT. Microarray approach followed by qRT-PCR validation<br />
revealed the presence of specific TARGIT-regulated miRs. Among<br />
the others, miR-223 was the most highly and significantly modified.<br />
In silico analyses indicated that epidermal growth factor (EGF) is a<br />
potential candidate of mR-223 regulation. In vitro experiments, using<br />
both normal and tumor derived cell lines validated the bioinformatic<br />
prediction, demonstrating that the 3’UTR of EGF is a target of miR-<br />
223 and this binding results in the control of EGF production by<br />
the cells. Importantly, miR-223 overexpression was able to impair,<br />
at least in part, the wound-induced growth of normal and tumor<br />
derived breast-cancer cells, eventually influencing breast cancer cell<br />
proliferation and survival.<br />
Our results suggest that the effects of radiotherapy in the wounded<br />
tissue go far beyond the mere killing of residual tumor cells and is able<br />
to balance the negative effects of the wound healing process, both in<br />
human and mouse breast tissue. TARGIT-induced microenvironment<br />
modifications, in particular miR-223 up-regulation, significantly<br />
impair breast cancer response to surgery-induced inflammation<br />
eventually resulting in recurrence control. Our experimental findings<br />
strongly support the notion that the timely application of radiotherapy<br />
to the tumor bed, immediately after tumor removal, is critical to<br />
counteract the effects of surgery and wound healing process on<br />
residual breast cancer cells and normal peri-tumoral breast tissue.<br />
P5-11-01<br />
Extending breast conservation choices for women with breast<br />
cancer<br />
Egbeare DM, Chan HY. Cheltenham General Hospital, Cheltenham,<br />
Gloucestershire, United Kingdom<br />
Introduction<br />
Long term outcomes for women treated with breast conserving surgery<br />
are similar to women having mastectomy. The adoption of modern<br />
oncoplastic techniques (e.g. volume displacement) has increased the<br />
proportion of women having breast conserving surgery compared<br />
with mastectomy. The widespread use of therapeutic reduction<br />
mammoplasty (TRM) can further reduce the need for mastectomy<br />
in a modern oncoplastic breast unit. We analyse if the introduction of<br />
TRM has led to an increase in breast conservation and more choice<br />
for women treated at our unit.<br />
Methods<br />
Operative logbooks were reviewed. The two-year period April 2007<br />
- April 2009 (before widespread adoption of TRM) was compared to<br />
April 2010 - April 2012. Length of stay, re-admission rates, additional<br />
operative procedures and cancer recurrences were analysed.<br />
Results<br />
During the 2007-2009 time period, a single surgeon undertook<br />
209 primary operations for breast cancer. 64 women underwent<br />
mastectomy (30.6%). Of these, 26 (40.6%)had an immediate<br />
reconstruction with latissimus dorsi flap (+/- an implant). 4 women<br />
in this period had a TRM as their primary surgery for breast cancer<br />
(1.9%).<br />
During the 2010-2012 period, the same surgeon undertook 201 primary<br />
operations for breast cancer. 55 women underwent mastectomy<br />
(27.4%): 27 had immediate latissimus dorsi reconstruction; 13 had<br />
implant based reconstruction (overall reconstruction rate 72%). 32<br />
patients underwent TRM as their primary breast cancer operation<br />
(15.9%), all with simultaneous contralateral breast reduction.<br />
Of the immediate reconstruction group in 2007-09, 11 women (42%)<br />
have undergone another operative procedure – nipple reconstruction,<br />
contralateral breast operations, capsulectomy or “tidying-up”<br />
procedures. One patient has had a recurrence of her breast cancer and<br />
one patient has died of breast cancer in the 5 year follow-up period.<br />
One patient has developed contralateral breast cancer.<br />
In the 2010-12 TRM group, 6 patients (18.8%) underwent a second<br />
operation – 3 re-excisions of positive margins and 3 axillary<br />
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clearances (positive sentinel lymph node biopsy at first operation).<br />
The median length of stay for women treated with TRM was 1 day<br />
compared to a median stay of 6 days for patients undergoing latissimus<br />
dorsi reconstruction.<br />
Conclusions<br />
Our unit already had high breast conserving surgery rates and a<br />
high reconstruction:mastectomy ratio. Introduction of TRM became<br />
widespread approximately 2 years ago. Using a TRM technique 25-<br />
50% of the breast volume can be removed. This enables some patients<br />
who would have been advised mastectomy to be offered a choice<br />
of breast conserving surgery; hence the further modest reduction in<br />
mastectomy rate seen.<br />
TRM enables breast (and nipple) conservation and a quicker recovery<br />
period. TRM may appeal to women thinking about breast reduction<br />
before a breast cancer diagnosis. It is useful after neoadjuvant<br />
treatment, for multifocal tumours and in women where a high tumour<br />
volume:breast volume ratio would make good cosmetic results<br />
difficult to achieve with traditional breast conservation techniques.<br />
A further advantage of TRM is the simultaneous contralateral breast<br />
reduction; thus reducing re-operation rates.<br />
In conclusion, most importantly, TRM extends breast conserving<br />
surgery choices for women with breast cancer.<br />
P5-11-02<br />
<strong>Breast</strong> <strong>Cancer</strong> Radiation Therapy and the Risk of Developing<br />
Bronchiolitis Obliterans Organizing Pneumonia (BOOP):<br />
Communication of BOOP Risk by <strong>Breast</strong> <strong>Cancer</strong> Information<br />
Websites and General Medical Information Websites<br />
Kelly EM. Kelly Consulting, Smithtown, NY<br />
Background: BOOP is an inflammatory pulmonary disorder<br />
consisting of organized polypoid granulation tissue in the distal<br />
airways extending into the alveolar ducts and alveoli. Clinical<br />
manifestations of BOOP include fever, cough, dyspnea on exertion,<br />
and fatigue. Patients with severe BOOP require hospitalization. The<br />
mainstay of BOOP treatment is high dose corticosteroids. Many<br />
patients relapse and require long term corticosteroids, often in<br />
combination with another immunosuppressant. Significant morbidity<br />
and disability may be associated with both the diagnosis of BOOP<br />
and the toxicities of treatment. The mortality rate of BOOP has been<br />
estimated to be about 5%.<br />
Radiation Therapy (RT) is an important component in the treatment<br />
of breast cancer (<strong>Breast</strong> Ca). Beginning in 1995, reports of BOOP<br />
occurring in <strong>Breast</strong> Ca RT patients began to appear in the medical<br />
literature. From 1995 to the present, 43 case study reports described<br />
121 <strong>Breast</strong> Ca RT patients who developed BOOP within one year of<br />
their RT. From 1999 to 2011, seven epidemiological studies were<br />
published that suggested that the incidence of BOOP in <strong>Breast</strong> Ca<br />
RT patients was in the range of 2% to 3%.<br />
Objectives: The primary objective of this study was to determine<br />
if internet sources of <strong>Breast</strong> Ca information targeted to <strong>Breast</strong> Ca<br />
patients include BOOP information in their description of RT risks.<br />
The secondary objective was to determine if general medical websites<br />
conveyed BOOP/<strong>Breast</strong> Ca RT risk information.<br />
Methods: Eight websites specifically targeted to <strong>Breast</strong> Ca patients<br />
were reviewed. Sponsors of these websites included the US<br />
government, <strong>Breast</strong> Ca advocacy groups, and medical organizations.<br />
Seven general medical websites that contained BOOP/<strong>Breast</strong> Ca RT<br />
information were also reviewed.<br />
Results: There was no mention of BOOP in any of the websites<br />
targeted to <strong>Breast</strong> Ca patients. The websites included those from<br />
the National <strong>Cancer</strong> Institute, American <strong>Cancer</strong> Society, American<br />
Society of Therapeutic Radiology and Oncology, Susan G. Komen,<br />
and <strong>Breast</strong><strong>Cancer</strong>.Org. The internet search identified seven general<br />
medical websites that did include information about the risk of BOOP<br />
from <strong>Breast</strong> Ca RT.<br />
Discussion: It is perplexing that none of the eight website sources<br />
for <strong>Breast</strong> Ca patients included any mention of the risk of BOOP<br />
associated with <strong>Breast</strong> Ca RT, whereas seven general medical internet<br />
sources did disclose this information. This disparity raises important<br />
issues and questions. The majority of BOOP/<strong>Breast</strong> Ca RT reports<br />
were published in pulmonology journals. Is this information being<br />
disseminated to providers of <strong>Breast</strong> Ca treatment? Many of the <strong>Breast</strong><br />
Ca information websites stated that their information was up to date<br />
and was reviewed by leading <strong>Breast</strong> Ca physicians, so it remains an<br />
enigma that the BOOP/RT association was not disclosed. The lack of<br />
any information about BOOP and <strong>Breast</strong> Ca RT may indicate <strong>Breast</strong><br />
Ca physician unawareness. An alternative explanation for this finding<br />
may be that these physicans are aware of the BOOP/RT association,<br />
but they believe that the rarity of BOOP diagnoses justifies omitting<br />
this information in internet-based information sources.<br />
P5-12-01<br />
ARE WEB-BASED RESOURCES THE BREAST? : AN<br />
EVALUATION OF THE QUALITY OF ONLINE RESOURCES<br />
FOR BREAST CANCER PATIENTS<br />
Nguyen S, Regehr G, Brar B, Lin J, Ingledew P. British Columbia<br />
<strong>Cancer</strong> Centre, Fraser Valley <strong>Cancer</strong> Centre, Surrey, BC, Canada;<br />
Centre for Health Education Scholarship, Vancouver, BC, Canada;<br />
UBC, Vancouver, BC, Canada<br />
Background: <strong>Cancer</strong> patients are increasingly using the internet to<br />
seek disease specific information. Our prior studies indicate that a<br />
majority of breast cancer patients use the internet to aid decision<br />
making and to inform themselves about their disease. Although<br />
there is a substantial amount of information available on the internet<br />
regarding breast cancer, there are no comprehensive studies evaluating<br />
the quality of this information and whether it is adequate to support<br />
patients’ decision making. The purpose of this study was to apply a<br />
validated evaluation tool to evaluate the quality of online breast cancer<br />
patient information. Methods: Using the principles of design-based<br />
research, an evaluation tool was developed and validated for the<br />
purposes of evaluation of web-based patient information. To review<br />
the quality of breast cancer information, a list of the top 100 breast<br />
cancer websites was systematically compiled using the meta-search<br />
engines Yippy and Dogpile, and the search engine Google. The<br />
websites were assessed for administration, accountability, authorship,<br />
organization, readability, and content. Inter-rater reliability was<br />
evaluated. Results were analyzed using descriptive statistics. Results:<br />
Over 2000 hits were initially obtained using the search term “breast<br />
cancer” (the most common search term according to our previous<br />
studies) in the three search engines. After applying the pre-specified<br />
inclusion and exclusion criteria the “top 100” breast cancer sites were<br />
evaluated. The majority of breast cancer websites were administered<br />
by commercial businesses (47%) and non-profit organizations<br />
(33%). 86% of the websites disclosed ownership, sponsorship, and/<br />
or advertising. Only 34% of websites identified the author and 39%<br />
cited sources. The average readability of websites was a grade 9 level.<br />
The majority of the information was out of date and only 27% of<br />
websites had updated their content within the last two years. While<br />
88% of the websites sufficiently covered breast cancer, only 18%<br />
addressed prognosis. Conclusions: While a majority of breast cancer<br />
patients use the internet to obtain information on their diagnosis and<br />
treatment options, this study demonstrates that web-based information<br />
www.aacrjournals.org 451s<br />
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is variable and there are distressing gaps in the information available.<br />
Although the assessed websites were mostly accurate, there were<br />
significant deficits in authorship, attribution, and currency. Of<br />
concern, our research has previously demonstrated that patients use<br />
authorship and attribution to determine the reliability of web-based<br />
information. Additionally, very few websites provided information<br />
regarding prognosis, an area research has identified as an important<br />
topic sought by breast cancer patients. The results of this study can<br />
be used to counsel patients on the strengths and weaknesses of webbased<br />
breast cancer information and to empower patients to choose<br />
sites likely to enhance their personal knowledge.<br />
P5-12-02<br />
Tangled in the <strong>Breast</strong> <strong>Cancer</strong> Web: An Evaluation of the Usage<br />
of Web-based Information Resources by <strong>Breast</strong> <strong>Cancer</strong> Patients<br />
Nguyen SKA, Ingledew P. British Columbia <strong>Cancer</strong> Agency, FVCC,<br />
Surrey, BC, Canada<br />
Background: Increasingly cancer patients are researching web-based<br />
information to inform their clinical encounter with physicians. The use<br />
of the internet by breast cancer patients is incompletely characterized<br />
in the literature. The purpose of this study was to characterize the<br />
use of the internet by breast cancer patients describing the way they<br />
search for, and the impact of, web-based information on the clinical<br />
encounter.<br />
Methods: From September 2011 to January 2012, breast cancer<br />
patients presenting at a tertiary cancer centre waiting to see their<br />
oncologist completed a written 23-question survey. Answers were<br />
closed and open-ended. Mixed-methods were used to interpret the<br />
quantitative and qualitative data.<br />
Results: 81 patients were approached and 56 completed the survey.<br />
Forty-five (80%) respondents used the internet and of those, 32 (71%)<br />
respondents searched for breast cancer information. Patients who<br />
searched for internet breast cancer information (users) were younger<br />
than those who did not use the internet (p = 0.01). All respondents<br />
used Google as their principal search engine and “breast cancer” was<br />
the most commonly used search term. Twenty (62%) users accessed<br />
sites from a reputable source and 19 (59%) users viewed top search<br />
engine hits. To evaluate quality, 15 (47%) users referred to website<br />
author credentials and 13 (41%) users examined references. All<br />
users sought information with respect to treatment and three-quarters<br />
sought information on prognosis. The internet influenced treatment<br />
decision making for 30 (66%) users. Twenty-six (80%) users felt<br />
the information increased their knowledge of breast cancer and it<br />
influenced treatment decision making for 16 (53%) patients.<br />
Conclusions: This study highlights search patterns and factors<br />
used by patients in seeking web-based breast cancer information.<br />
Physicians must appreciate that breast cancer patients use the internet<br />
for information and address discrepancies between the information<br />
sought and that which is available.<br />
P5-12-03<br />
Developing the ePromotora: Increasing Promotora’s Access to<br />
<strong>Breast</strong> <strong>Cancer</strong> Electronic Resources<br />
Lopez AM, Ryan J, Valencia A, El-Khayat Y, Nunez A. University of<br />
Arizona, Tucson, AZ<br />
Background: Disparities in breast cancer screening and survival have<br />
been attributed to multiple factors including limited access to breast<br />
health education. Innovative information technologies facilitate health<br />
education; however, access to information technology is not uniform.<br />
The resultant systematic gap in health knowledge has led to a new<br />
health disparity where higher socioeconomic individuals acquire<br />
health information electronically more easily than the disadvantaged.<br />
Promotoras or Community Health Workers (CHWs) facilitate access<br />
to culturally appropriate cancer health information, screening and care.<br />
Hypothesis: An electronic asynchronous breast cancer educational<br />
intervention developed by the Arizona Telemedicine Program and<br />
the Arizona Health Sciences Library will improve CHW computer<br />
literacy and will enhance health education communication. Specific<br />
Aims: to develop, implement and assess a 6-session e-promotora<br />
training curriculum with a focus on breast health.<br />
Methods: The first step in developing a training curriculum was a<br />
needs assessment and a computer literacy assessment. This assessment<br />
served as the foundation for the computer literacy curriculum which<br />
focused on breast health content. The educational intervention was<br />
delivered as a combination of on-line, webinar, and face-to-face<br />
seminars. To meet the needs of the participants all sessions were<br />
delivered bilingually, Spanish and English. Program evaluation<br />
included pre and post knowledge assessments, session assignments,<br />
program satisfaction and 6-month follow up focus groups or structured<br />
interviews to evaluate the utility, implementation and dissemination<br />
of knowledge gained.<br />
Results: 26 CHWs have completed the training. All participants<br />
identified as Latinas, average age--51 years of age and educational<br />
attainment--58% (15/26) reported high school or less. Pre and post<br />
assessment data reveal high program satisfaction scores, increased<br />
participant knowledge and confidence in knowledge, consistent and<br />
ongoing use of information learned and computer skills gained and<br />
effective dissemination of health information gained.<br />
Conclusions: The e-promotora training curriculum effectively<br />
improves CHW computer literacy, facilitates dissemination of<br />
electronic health information and helps address the disparities in<br />
electronic health information.<br />
P5-13-01<br />
Does empowering patients improve accrual to breast cancer<br />
trials?<br />
Arnaout A, Kuchuk I, Bouganim N, Verma S, Clemons M. Ottawa<br />
Hospital, Ottawa, ON, Canada; Mcgill University and Segal <strong>Cancer</strong><br />
Centre, Jewish General Hospital, Montreal, QC, Canada<br />
BACKGROUND Many international oncology professional and<br />
patient advocacy groups recommend that a minimum of 5% of eligible<br />
new patients should be entered into a clinical trial. Unfortunately,<br />
physician and patient related barriers translates to a much lower<br />
accrual rate in reality. We performed a prospective single arm pilot<br />
study evaluating the efficacy of implementing various physician and<br />
patient related strategies in enhancing clinical trial accrual.<br />
METHODS All patients with newly diagnosed breast cancer seen<br />
at the breast surgery clinic were eligible for the study. Patients were<br />
offered information packages by their surgeons on non-surgical<br />
clinical trials that they might be eligible for, prior to their initial<br />
oncologist visit. Oncologists were informed of the information given<br />
to the prospective patient consultation via email and chart flagging.<br />
Patient were then given a questionnaire assessing the feedback on this<br />
method of introducing clinical trials. The primary outcome was the<br />
number of patients consenting to clinical trials. Secondary outcomes<br />
included the number of patients actually enrolling in clinical trials,<br />
screen failure rate, and overall patient satisfaction with this method<br />
of potentially enhancing accrual to clinical trials.<br />
RESULTS 36 patients consented to this pilot study. 51% of<br />
oncologists mentioned the clinical trials to the patients. For those<br />
patients with which clinical trials were discussed, 72% went on to<br />
consent for a trial of which 31% were ultimately found to be ineligible<br />
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(screen failure rate). The overall 14% clinical trial enrolment was<br />
significantly higher than our historical average of 7%. 100% of the<br />
patients found that the information package very helpful and was<br />
noted to reduce anxiety (39%) and empower (31%) the patients. 19%<br />
of the patients felt that this information should have been offered by<br />
the oncologist during the initial consultation as opposed to the surgeon<br />
prior to the oncology visit.<br />
CONCLUSIONS The findings of this study could have a major<br />
impact on the way that cancer centres across the world approach<br />
patients for clinical trial options. Physicians remain an important<br />
barrier to trial accrual. The results of this study demonstrate that<br />
combined patient and physician centered approach to clinical trial<br />
enrolment may be the most effective.<br />
P5-13-02<br />
Decision making from multidisciplinary team meetings to<br />
bedside: factors predicting for physicians’ and breast cancer<br />
patients’ acceptance of clinical trials proposed by MTMs<br />
Deneuve J, Mazouni C, Arnedos M, Prenois F, Saghatchian M, André<br />
F, Bourrgier C, Delaloge S. Institut Gustave Roussy, Villejuif, France<br />
Background: In University hospitals or Comprehensive <strong>Cancer</strong><br />
Centers (CCC), breast cancer (BC) patients have a theoretically large<br />
access to clinical trials as part of the management and treatment of<br />
their localized or advanced disease. Though, most patients are not<br />
proposed inclusion into suitable trials or studies or do not accept<br />
them. We aimed at determining the factors that influence physicians<br />
and patient’s choice to respectively propose or enter clinical trials for<br />
which the patients were considered eligible by MTM.<br />
Methods: Patients who were considered eligible for a clinical trial<br />
by a BC-specific multidisciplinary team meeting (MTM) assessing<br />
their cases were prospectively registered during a 6 months period.<br />
The complete files of these patients were prospectively registered<br />
following initial written proposal by the MTM. The 27 clinical trials<br />
proposed were classified in 5 categories: cognitive studies, imaging,<br />
radiation therapy, diagnostic/prognostic biology, or interventional<br />
therapeutic studies. Detailed analysis of factors predicting physician’s<br />
proposal and patient’s final inclusion was conducted. Candidate<br />
factors were age, socio-demographic characteristics, PS, type of<br />
clinician, time intervals, stage of disease, type of disease, type of<br />
study, single vs multiple study proposal.<br />
Results: MTM proposed 547 inclusions into clinical trials for<br />
397 patients between March 3rd and Sept 21 st , 2011. 267 pts were<br />
considered eligible for 1 trial, 100 for 2, 25 for 3, 4 for 4 and 1 for<br />
5 trials; 211 for cognitive studies, 13 for imaging, 71 for radiation<br />
therapy, 136 for diagnostic/prognostic biology, 116 for interventional<br />
therapeutic studies. Upon referral physician’s visit, the trial was<br />
only proposed in 39.3% and pts were finally included in 29.1% of<br />
the cases. Reasons for non inclusion were patients’ refusal in only<br />
5-11%, but absence of proposal by physician in 45-81%, according to<br />
the types of studies. The only factor predicting both proposal by the<br />
referral physician’s and final inclusion into trials was type of study<br />
(both p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Results: We are planning to enroll 480 participants for the quantitative<br />
survey portion and 48 participants for in-depth qualitative data<br />
collection, including audio-recorded patient-physician interactions<br />
and in-depth patient interviews, along with 8 in-depth provider<br />
interviews. Data collection is ongoing and results will be presented.<br />
Acknowledgement: This research was supported by a grant from the<br />
National <strong>Cancer</strong> Institute (2P50CA106743)<br />
P5-14-01<br />
Withdrawn by Author<br />
P5-14-02<br />
Women’s responses to changes in US Preventive Services Task<br />
Force mammography screening guidelines: results from focus<br />
groups among ethnically diverse women<br />
Bluethmann SM, Allen JD, Hernandez C, Opdyke KM, Gates-Ferris K,<br />
Hurlbert M, Harden E. University of Texas School of Public Health;<br />
Dana Farber <strong>Cancer</strong> Institute; Avon Foundation for <strong>Breast</strong> <strong>Cancer</strong><br />
Crusade; Cicatelli and Associates<br />
Introduction: In 2009, the US Preventive Services Task Force<br />
(USPSTF) changed its recommendations on the age and frequency for<br />
routine mammography. To this point, responses to this change among<br />
ethnically diverse women have been not been well examined. The<br />
objective of this qualitative study is to describe women’s awareness<br />
of the change in mammography screening guidelines by the U.S.<br />
Preventive Services Task Force and to describe their attitudes toward<br />
this change.<br />
Methods: White, Black and Hispanic women ages 40-49 years<br />
were recruited from a variety of community settings in the Greater<br />
Boston, MA area to participate in focus groups (k=10; N=73).<br />
Groups were segmented by race/ethnicity (Black=29%; White=29%;<br />
Hispanic=15%). Women were asked if they were aware of the change<br />
in USPSTF guidelines, and if so, their understanding about reasons<br />
for this change and intention to comply. Focus groups were audiotaped<br />
and transcribed verbatim. Thematic content analysis was used<br />
to cull recurring discussion themes.<br />
Results: Most women in this study were not aware of changes in the<br />
USPSTF mammography screening guidelines. Those who were aware<br />
of the guideline change were highly suspicious that it was motivated<br />
by a desire for cost savings on the part of insurance companies and/or<br />
providers. Concerns regarding the accuracy of mammography, pain<br />
associated with screening, and fear of receiving positive test results<br />
were prevalent. Nevertheless, most said that they did not intend<br />
to comply with changes in guidelines; many believed that regular<br />
(yearly) mammography should start at a young age (40 or before)<br />
and continue indefinitely.<br />
Conclusion: Most women in this sample were unaware about changes<br />
in mammography screening guidelines and lacked understanding<br />
regarding underlying reasons for the change. Communication about<br />
the rationale for changes in mammography screening guidelines has<br />
left many women unconvinced about the potential downsides of<br />
screening and has generated a high degree of mistrust of insurance<br />
companies and medical providers.<br />
P5-14-03<br />
<strong>Breast</strong> cancer screening and follow-up of abnormal mammogram<br />
results: A population-based study comparing results from an<br />
urban university cancer center to a national database.<br />
Mitchell EP, Avery TP, Jaslow RC, Berger AC, Lee SY, Vaughan-Briggs<br />
C, Bonat J. Thomas Jefferson University, Philadelphia, PA<br />
Background: To improve access to screening, the National <strong>Breast</strong><br />
and Cervical <strong>Cancer</strong> Early Detection Program (NBCCEDP) was<br />
developed through the Centers for Disease Control and Prevention<br />
(CDC) to provide low-income, and uninsured underserved women<br />
access to timely breast and cervical cancer screening and diagnostic<br />
services. This population-based study investigates the demographics<br />
and diagnostic outcomes of women who underwent breast cancer<br />
screening through this program established at an urban university<br />
cancer center compared to data obtained from the national program<br />
database.<br />
Methods: The Kimmel <strong>Cancer</strong> Center at Jefferson (KCC) launched<br />
its screening program with resources from the CDC, the State of<br />
Pennsylvania, and the Susan G. Komen Foundation in 2008. The<br />
core of the program is staff lead by a Social Worker/Navigator who<br />
connects patients to education and screening services, institutional<br />
information and guidance, and follow-up to minimize barriers<br />
to access, lessen dropout, and ensure follow-through for timely<br />
diagnosis and treatment. Working with our Community-Based partner<br />
organizations, uninsured and underinsured women in Philadelphia<br />
are able to seamlessly travel from education and screening through<br />
to treatment and support. All KCC patients evaluated through this<br />
program from 2008-2011 were included and records of the NBCCDP<br />
database 2006-2010 for this study and analyses.<br />
Results: KCC has a substantially larger African American (54.44%<br />
vs. 13.8%), smaller Hispanic (8.59% vs. 27.6%), larger percentage<br />
of abnormal mammograms (25.96% vs. 14%), higher breast cancer<br />
diagnosed per mammogram (2.13 vs 1.0) and a much younger<br />
population than the national cohort. Fewer than 1% of KCC patients<br />
have been lost to follow-up.<br />
Conclusions: The KCC <strong>Breast</strong> and Cervical Screening and Treatment<br />
Program Services reaches a highly vulnerable and at-risk population,<br />
has a higher abnormal mammogram and breast cancer detection rate,<br />
and a higher continued participation rate than the national cohort. The<br />
Social/Worker/Navigator has a distinct role in providing follow-up<br />
for abnormal findings to minimize no-shows by providing creative<br />
problem-solving, support, counseling, finding resources to minimize<br />
barriers, and contributes significantly to the ease of operation and the<br />
continued participation of patients in the program.<br />
P5-14-04<br />
Alleviate the pain in the system: Using process improvement and<br />
systems design tools to strive for a high quality breast healthcare<br />
system in the District of Columbia metro area.<br />
Brousseau MK, Graham L, Kaye P, Nolan T, Moraras N. Primary<br />
Care Coalition of Montgomery County, Maryland, Silver Spring,<br />
MD; Regional Primary Care Coalition, Washington, DC; Associates<br />
in Process Improvement, Silver Spring, MD<br />
Background: Throughout the District of Columbia Metro Area,<br />
breast cancer mortality rates are higher than the national average due<br />
in part to limited service coordination and lack of access to breast<br />
health services along the continuum. The Primary Care Coalition of<br />
Montgomery County (PCC) and the Regional Primary Care Coalition<br />
(RPCC) are collaborating to improve the efficiency and effectiveness<br />
of breast cancer screening, referral, and follow-up so that jurisdictions<br />
and clinics in the DC metro area are better positioned to provide<br />
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100% low-income women residents with access to breast healthcare.<br />
The Regional Initiative builds upon the successes of the PCC <strong>Breast</strong><br />
Healthcare Process Improvement Project.<br />
Objectives: 1) Adopt the Primary Care-Based Model in three clinics<br />
in three other jurisdictions and implement process improvement<br />
approaches to show improvements in breast cancer screening,<br />
referral, and follow-up; and 2) Develop a cross-jurisdiction learning<br />
community to enhance spread throughout the Region.<br />
Methods: The Regional Initiative employs a multi-tiered learning<br />
community framework to share data, address systems level<br />
barriers, and design new systems for the provision of high-quality<br />
care regardless of insurance status. Partners use the Model for<br />
Improvement to improve processes at the micro-system level and<br />
system design theory drives larger systems changes.<br />
Results:<br />
Objective 1: The three adaptation sites represent Prince Georges<br />
County, Maryland, Washington, DC, and Fairfax Virginia. After a<br />
year of focused process improvement, partnership development, and<br />
data collection, initial analysis demonstrates:<br />
- All three clinics show increased screening rates approaching 65%,<br />
representing the 90th percentile performance in the Healthcare<br />
Effectiveness Data and Information Set (HEDIS) for Medicaid breast<br />
cancer screening.<br />
- At Greater Baden Medical Services in Prince Georges County,<br />
Maryland, cycle time between referral and mammography screening<br />
decreased from 48 to 27 days.<br />
- The Community Health Care Network, Fairfax County, Virginia,<br />
worked closely with one mammography provider to decrease the<br />
no-show rate for mammography appointments from 26% to 6%.<br />
- The Project Team developed a change package to share<br />
recommended interventions and successful strategies that have been<br />
tested and documented, and can be used by clinics certified as primary<br />
care medical homes or in the process of adopting those standards.<br />
Objective 2: The Cross-Jurisdiction Learning Collaborative brings<br />
representatives from each jurisdiction together to share breast health<br />
measures, success stories, and plan/discuss process improvement<br />
activities from a regional perspective. Participants include over 50<br />
breast health providers from around the region:<br />
- 17 safety-net clinics<br />
- 11 hospital and/or mammography providers<br />
- All County and/or State National <strong>Breast</strong> and Cervical <strong>Cancer</strong> Early<br />
Detection Programs in the Region<br />
Next Steps: Spread learnings regionally and nationally to foster<br />
collaboration, replicate the PCC Primary Care-Based Model using<br />
the change package, and further improve breast health outcomes for<br />
the safety-net population.<br />
P5-14-05<br />
Compliance with radiation therapy in breast cancer patients in<br />
Southeastern Kentucky<br />
Elsoueidi R, Adane E, Dignan M. Appalachian Regional Healthcare,<br />
Hazard, KY; University of Kentucky, Lexington, KY<br />
Background: Nearly a quarter of Americans live in rural areas,<br />
which consistently report higher cancer mortality rates than urban<br />
and suburban areas. The worse outcome for cancer patients in<br />
these areas has been attributed in part to compliance with treatment<br />
recommendations. Southeastern Kentucky is a rural area with a low<br />
income population and barriers such as distance and lack of public<br />
transportation to access health care and compliance with treatment<br />
is a major concern.<br />
Methods: Data on patients with breast cancer treated with radiation<br />
therapy at Appalachian Regional Healthcare cancer center which<br />
serves the area of Southeastern Kentucky were collected. Age,<br />
economic status (measured by availability of medical insurance),<br />
distance of patient’s residence from the hospital, were evaluated as<br />
potential predictors of compliance with recommendations to obtain<br />
radiation therapy. Data were analyzed with Fisher’s exact test.<br />
Results: A total of 80 patients with breast cancer received adjuvant<br />
radiation treatment from 2008 to 2011. Of these 80 patients, 24 (30%)<br />
had Medicaid, 31 (39%) had Medicare, and 25 (31%) had commercial<br />
health insurance. Only two (2.5%) patients did not complete treatment<br />
due to transportation. An additional 10 patients (13%) had treatment<br />
interruption due to weather, transportation or other financial reasons.<br />
In patients who completed treatment, a total of 2640 days of treatment<br />
were provided. A total of 55 (2.1%) days of treatment were missed.<br />
Of the 10 patients who had interruption, 5 of them had Medicaid and<br />
the number of missed days by the Medicaid patients was (37/55),<br />
which is 67% of the total days missed. No statistically significant<br />
difference was detected in the number of patients missing treatment<br />
between Medicaid and other insurance types (p=0.16). None of the<br />
factors evaluated predicted patient compliance, although a trend<br />
toward lower compliance was noted in patients who had Medicaid.<br />
Conclusion: Despite being a rural area with multiple barriers to access<br />
healthcare, the rate of full compliance (defined as completion of the<br />
entire course of radiation therapy) with adjuvant radiation therapy in<br />
breast cancer patients in Southeastern Kentucky was 97.5%, which is<br />
similar to the rates in clinical trials that generally exceed 90%. A trend<br />
toward lower compliance was noted in patients who had Medicaid<br />
although it was not statistically significant.<br />
P5-14-06<br />
Analysis of test-therapy concordance for biomarkers uPA and<br />
PAI-1 in primary breast cancer in clinical hospital routine:<br />
Results of a prospective multi-center study at Certified <strong>Breast</strong><br />
<strong>Cancer</strong>s in Germany<br />
Jacobs VR, Augustin D, Wischnik A, Kiechle M, Hoess C, Steinkohl O,<br />
Rack B, Kapitza T, Krase P. Paracelsus Medical University, Salzburg,<br />
Austria; Klinikum Deggendorf, Deggendorf; Klinikum Augsburg,<br />
Augsburg, Germany; Technical University Munich (TUM), Germany;<br />
Cooperative <strong>Breast</strong> Center Ebersberg-Rosenheim. Kreisklinikum<br />
Ebersberg, Ebersberg, Germany; Klinikum Dritter Orden, Munich,<br />
Germany; Ludwig-Maximilian-University (LMU), Munich, Germany;<br />
Top-Expertise, Germering/Munich, Germany; AOK Bayern, Munich<br />
Objective: Biomarkers uPA and PAI-1 are guideline recommended<br />
by ASCO, USA, and AGO, Germany, to be used in primary breast<br />
cancer to avoid unnecessary CTX in medium risk recurrence patients<br />
[G2, N-, HR+, Her2neu-, >35 years]. For quality assurance of uPA/<br />
PAI-1 testing an analysis of test-therapy concordance was performed.<br />
Methods: Prospective, non-interventional, multi-center study<br />
over two years among six Certified <strong>Breast</strong> Centers in Germany to<br />
analyze application of uPA/PAI-1 and use of the result in consecutive<br />
decision making in Tumor Board decision and actual therapy in the<br />
clinical setting for AOK Bayern-insured patients. Concordance and<br />
discordance rates of uPA/PAI-1 testing in daily clinical setting were<br />
calculated and individual reasons for decision making analyzed.<br />
Results: Among n=93 uPA/PAI-1 tests evaluated n=42/93 (45.2%)<br />
were uPA+PAI-1 negative and n=51/93 (54.8%) uPA and/or PAI-1<br />
positive. In the group of uPA+PAI-1 negative test result in n=35/42<br />
(83.3%) CTX was avoided and and in n=7/42 (16.7%) CTX<br />
performed. In the group of uPA and/or PAI-1 positive test result<br />
in n=26/51 (51.0%) CTX was performed and in n=25/51 (49.0%)<br />
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not. Concordance of uPA/PAI-1 test result vs. consecutive therapy<br />
was (35+26)/93=65.6% and discordance of uPA/PAI-1 test-therapy<br />
(7+25)/93 = 34.4%. However, discordance of uPA/PAI-1 test result vs.<br />
Tumor Board recommendation was only n=21/93 (22.6%). As reasons<br />
for discordance a variety of influencing and/or interference factors<br />
were indentified, affecting use of test and test results or even changing<br />
therapy decision, e.g. individual therapy decision by physician,<br />
parallel use of competitive biomarkers, study participation, missing<br />
CTX therapy option in advance (like advanced age), wrong target<br />
group, timing of uPA/PAI-1 test too early, test result in contradiction<br />
of physicians’ expectations (expected negative result) and rejection of<br />
CTX recommended by patients despite uPA/PAI-1 test-proven benefit.<br />
Conclusions: Individual process optimization of uPA/PAI-1 test<br />
indication, performance and result assessment could improve quality<br />
of care, reduce costs and lead to an improved application of uPA/PAI-1<br />
test results as well as more stringency and consistency of test-therapy<br />
decisions in daily clinical setting.<br />
P5-15-01<br />
Cost-effectiveness of gene expression profiling for ductal<br />
carcinoma in-situ (Oncotype DCIS Score)<br />
Alvarado MD, Harrison BL, Solin LJ, Ozanne EM. University of<br />
California, <strong>San</strong> Francisco, CA; Albert Einstein Medical Center,<br />
Philadelphia, PA<br />
BACKGROUND: Ductal carcinoma in-situ (DCIS) affects nearly<br />
50,000 women each year. More than 75% of women who receive<br />
lumpectomy (BCS) for DCIS undergo whole breast radiation (XRT),<br />
which is known to prevent local recurrences. A molecular assay for<br />
DCIS has recently been validated, that identifies low-risk biology<br />
and may give insight into the need for adjuvant XRT. We sought to<br />
determine the cost-effectiveness of the Oncotype DCIS Score for<br />
risk stratification in newly diagnosed DCIS.<br />
METHODS: We conducted a cost-effectiveness analysis of using<br />
this molecular assay (validated in the E5194 study) compared to<br />
standard clinical assessment to determine treatment recommendation<br />
for XRT. A Markov model was developed in TreeAge Pro 2011 and<br />
simulated relevant outcomes over a lifetime horizon for 55-year-old<br />
women. For those in the intervention arm who are stratified by the<br />
assay, it was assumed that 75% of women (low DCIS score) did not<br />
receive XRT and had local risk of recurrence (LRR) of 12%; 25%<br />
were intermediate or high risk by the DCIS score (LRR of 26%) and<br />
received 6 weeks of XRT with an assumed LRR of 13%. For those<br />
in the standard care arm who are stratified by clinical assessment,<br />
an assumed 25% did not receive XRT and had LRR of 15.4%; 75%<br />
received 6 weeks of XRT with an estimated LRR of 7.7%. Recurrence<br />
rates were based on ECOG 5194 and assumed 50% reduction with<br />
XRT. Utilities were derived from literature. Direct medical costs<br />
were obtained from Medicare fee schedule; indirect costs (time and<br />
transportation for XRT) were ascertained.<br />
RESULTS: On average, the intervention (assay) strategy was less<br />
costly than the clinical assessment strategy by approximately $1000/<br />
patient, with similar life expectancies (17.15 vs 17.11, respectively)<br />
and quality-adjusted life-years (QALYs) (16.777 vs 16.789). The<br />
incremental cost-effectiveness ratio (ICER) for changing strategy<br />
from the assay to clinical assessment was approximately $95,000/<br />
QALY, at the upper limit of the societal accepted willingness-to-pay<br />
threshold.<br />
CONCLUSIONS: Based on the conservative assumptions that the<br />
benefit of XRT is independent of biology and that at least 75% of<br />
patients in E5194 would typically be offered XRT, the assay strategy<br />
is more cost-effective than standard clinical assessment. Additional<br />
research is needed to better understand health state utilities associated<br />
with less treatment as it pertains to risk of recurrence. Further<br />
validation studies of the assay are needed to accurately assess radiation<br />
benefit across all risk groups.<br />
P5-15-02<br />
The benefit of targeted therapeutics in medical oncology since<br />
the development of trastuzumab<br />
Conter HJ, Conter D, Wolff RA, Valero V, Zwelling L. University of<br />
Texas M.D. Anderson <strong>Cancer</strong> Center, Houston, TX; Huron College,<br />
London, ON, Canada<br />
Background:<br />
Trastuzumab has achieved widespread approval and funding across<br />
much of the developed world for metastatic and, later, adjuvant<br />
HER2/neu positive breast cancer. This success may be attributed<br />
to a favorable therapeutic index and incremental cost-effectiveness<br />
ratio (ICER). Has the success of trastuzumab been replicated by<br />
newer therapeutics?<br />
Methods:<br />
The societal marginal benefit gained from a new drug can be estimated<br />
by calculating the difference between the incremental quality-adjusted<br />
life-years gained (QALY) and the maximum willingness-to-pay<br />
(WTP) for the increase in health by society. A systematic review was<br />
employed to amass all English-language cost-effectiveness analyses<br />
(CEA) on small-molecule inhibitors and monoclonal antibodies<br />
approved for the treatment of solid malignancies. Searches of<br />
PubMed and EMBASE provided citations published between 1995<br />
and February 5, 2012. Two reviewers each independently assessed<br />
the eligibility of all abstracts and subsequently abstracted data<br />
from published abstracts and manuscripts. CEAs comparing two<br />
experimental treatments to each other were excluded. Incremental<br />
costs and ICERs were converted from their native currency to U.S.<br />
dollars according to their average exchange-rates since publication.<br />
Results:<br />
Of the 1,576 citations identified, 60 were included in the final<br />
analysis. Tumor-types studied included breast, colorectal, gastric,<br />
gastrointestinal stromal, head and neck, non-small cell lung, ovarian,<br />
hepatocellular, and renal cancers, and pancreatic neuro-endocrine<br />
tumor. Studies originated from USA (14%), continental Europe<br />
(37%), England (12%), Canada (12%), Asia (11%), and Latin America<br />
(12%). Median WTP was $65,000 (range $30,000-$297,000). 92%<br />
of all CEAs included considered to be cost-effective by the CEA’s<br />
authors. Trastuzumab was studied for breast cancer treatment by 13<br />
CEAs in the adjuvant setting and by 3 CEAs in the metastatic setting.<br />
Trastuzumab is significantly more cost-effective than other targeted<br />
treatments (mean ICER $32,000 vs. $108,000, p=0.001). 84% of<br />
trastuzumab studies found its ICER
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
can be made or future therapies produce greater incremental clinical<br />
benefits for the same cost, it seems unlikely that the societal success<br />
of trastuzumab will be replicated. However, this analysis assumes<br />
that maximizing societal health, not profit, is of primary concern.<br />
P5-15-03<br />
Cost-effectiveness of ‘radioguided occult lesion localization’<br />
(ROLL) versus ‘wire-guided localization’ (WGL) in breast<br />
conserving surgery for non-palpable breast cancer: results from<br />
a randomized controlled multicentre trial<br />
Postma EL, Koffijberg E, Verkooijen HM, Witkamp AJ, van den Bosch<br />
MA, van Hillegersberg R. UMC Utrecht; Julius Center Utrecht<br />
Background<br />
Accurate pre-operative localization of non-palpable breast cancer is<br />
essential to achieve complete resection. Radio-guided occult lesion<br />
localization (ROLL) has been introduced as an alternative for wireguided<br />
localization (WGL). Although efficacy of ROLL has been<br />
established in a RCT, cost-effectiveness of ROLL compared with<br />
WGL is not yet known.<br />
Objective. To determine whether ROLL has acceptable costeffectiveness<br />
compared with WGL.<br />
Methods. An economic evaluation was performed alongside<br />
a randomized controlled trial (ClinicalTrials.gov, number<br />
NCT00539474). Women (>18 years) with histologically proven nonpalpable<br />
breast cancer and eligible for breast conserving treatment<br />
with sentinel node procedure were randomized to ROLL(n=162) or<br />
WGL (n=152). Empirical data on direct medical costs was collected,<br />
and changes in quality of life were measured over a 6 months period.<br />
Bootstrapping was used to assess uncertainty in cost-effectiveness<br />
estimates, and sensitivity of the results to the missing data approach<br />
was investigated.<br />
Results. In total, 314 patients with 316 invasive breast cancers were<br />
enrolled. On average ROLL required the same time as WGL for<br />
the initial procedure (119 vs. 118 min.), resulted in a 7% higher reinterventions<br />
risk (27% vs. 20%, p=0.163), a 13% higher complication<br />
risk (30% vs. 17%, p=0.006) but showed similar health effects<br />
(difference 0.00 QALYs 95%CI (-0.04 to 0.05). Total costs were also<br />
similar for ROLL and WGL (+ €26 per patient 95% CI -250 to 311).<br />
Conclusion. ROLL is comparable to WGL with respect to both costs<br />
and quality of life, and will therefore not lead to more cost-effective<br />
medical care.<br />
P5-15-04<br />
CTX and CTX-related direct medication costs saved by testing<br />
biomarkers uPA and PAI-1 in primary breast cancer: Results<br />
of a prospective multi-center study at Certified <strong>Breast</strong> Centers<br />
in Germany<br />
Jacobs VR, Augustin D, Wischnik A, Kiechle M, Hoess C, Steinkohl O,<br />
Rack B, Kapitza T, Krase P. Paracelsus Medical University, Salzburg,<br />
Austria; Klinikum Deggendorf, Deggendorf, Germany; Klinikum<br />
Augsburg, Augsburg, Germany; Technical University Munich<br />
(TUM), Germany; Cooperative <strong>Breast</strong> Center Ebersberg-Rosenheim.<br />
Kreisklinikum Ebersberg, Ebersberg, Germany; Klinikum Dritter<br />
Orden, Munich, Germany; Ludwig-Maximilian-University (LMU),<br />
Munich, Germany; Top Expertise, Germering/Munich, Germany;<br />
AOK Bayern, Munich, Germany<br />
Background: Biomarkers uPA and PAI-1 are guideline recommended<br />
by ASCO, USA, and AGO, Germany, to be used in primary breast<br />
cancer to avoid unnecessary CTX in medium risk recurrence patients<br />
[G2, N-, HR+, HER2neu-, >35 years]. This study was performed to<br />
verify in normal clinical settings how many CTX cycles and how<br />
much CTX-related direct medication costs can be avoided by uPA/<br />
PAI-1 testing.<br />
Methods: Prospective, non-interventional, multi-center study over<br />
two years among six Certified <strong>Breast</strong> Centers in Germany to analyze<br />
application of uPA/PAI-1 and consecutive decision making in the<br />
clinical setting for AOK Bayern-insured patients. CTX regimen<br />
and cycles avoided were identified for each case and direct costs for<br />
CTX and CTX-related medication costs for concomitant medication<br />
calculated for each patient individually according to body weight<br />
and body surface as well as potential FN prophylaxis according<br />
to physicians’ decision. All medication costs were taken from the<br />
pharmaceutical price list for Germany Rote Liste of 2012. EURO [€]<br />
to US Dollar conversion rate as of June 12 2012: € 1.00 = US$ 1.25.<br />
Results: In n=93 breast cancers n=35 CTX (37.6%; FEC n=25,<br />
FEC+DOC n=8 and TC n=2) were avoided according to uPA/PAI-<br />
1 test result. Consecutively 210 CTX cycles or 12.1 years of CTX<br />
application were saved improving patients’ quality of life. uPA/<br />
PAI-1 testing saved direct medication costs for avoided CTX of US$<br />
221.816, CTX-related concomitant medication of US$ 34.353 and<br />
G-CSF prophylaxis of US$ 25.749, overall US$ 281.918. At process<br />
costs for a single uPA/PAI-1 test calculated at US$ 359, uPA/PAI-<br />
1 testing resulted in additional costs of US$ 33.387 for all breast<br />
cancer cases. Overall, testing of uPA/PAI-1 has been proven to be<br />
cost-effective regarding direct medication costs alone at a returnon-investment<br />
ratio of 8.4:1. Indirect cost savings further increase<br />
this ROI.<br />
Conclusions: Innovative and individual cancer diagnostics like<br />
biomarkers uPA/PAI-1 can decrease need of CTX and increase<br />
patients’ quality of life and thereby reduce costs for health care<br />
systems. Since application of this test is inadequate at present time<br />
measures are suggested to fully implement such cost-effective<br />
diagnostics.<br />
P5-15-05<br />
Budget impact analysis of everolimus for estrogen receptor<br />
positive, human epidermal growth factor receptor-2 negative<br />
metastatic breast cancer patients in the United States<br />
Xie J, Diener M, De G, Yang H, Wu EQ, Namjoshi M. Analysis Group,<br />
Inc., New York, NY; Analysis Group, Inc., Boston, MA; Novartis<br />
Pharmaceuticals Corporation, East Hanover, NJ<br />
BACKGROUND: A phase III randomized clinical trial demonstrated<br />
significantly longer progression-free survival of everolimus and<br />
exemestane combination therapy compared to exemestane alone in<br />
postmenopausal women with estrogen receptor positive (ER+), human<br />
epidermal growth factor receptor-2 negative (HER2-) metastatic<br />
breast cancer (MBC) who failed letrozole or anastrozole. This study<br />
estimates the budget impact of adding everolimus as the first or second<br />
treatment after failure of letrozole or anastrozole for post-menopausal,<br />
ER+ HER2- MBC patients from a third-party payer perspective in<br />
the United States.<br />
METHODS: Pharmacy and medical budget impacts were estimated<br />
over the first year of everolimus use in this indication. Published<br />
epidemiology data were used to estimate target population size. Market<br />
share was assumed to be divided between exemestane, fulvestrant<br />
and tamoxifen before everolimus entry based on market research<br />
data on file. Market share of combination therapy of everolimus and<br />
exemestane was assumed to increase linearly during the one-year<br />
period and replace 10% of overall market share by the end of the year,<br />
proportional to the pre-entry market share distribution of the other<br />
three treatments. Pharmacy budget inputs (wholesale acquisition cost<br />
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of the therapies, daily dose, treatment duration, dispensing fee and<br />
copayment) were obtained from published and unpublished sources.<br />
Patients were assumed to be on treatment until progression or death.<br />
Medical costs were estimated as the average costs before and after<br />
progression, weighted by time in each state and adjusted for survival.<br />
Pre- and post-progression costs, time to progression and survival rates<br />
were derived from published literature. Compliance was assumed to<br />
be 100% until progression and adverse events were not considered.<br />
All costs were reported in 2011 US dollars.<br />
RESULTS: In a hypothetical health plan with 1 million members,<br />
there would be 72 patients expected to use one of the study drugs<br />
(exemestane, tamoxifen, fulvestrant or everolimus+exemestane) as<br />
the first treatment option immediately after letrozole or anastrozole<br />
failure, and 159 expected to use one of the study drugs as the second<br />
treatment option after letrozole or anastrozole failure. For the first<br />
treatment option after letrozole or anastrozole failure, total budget<br />
impact was $0.013 per member per month (PMPM), including a<br />
$0.017 PMPM increase to the pharmacy budget and $0.004 PMPM<br />
decrease to the medical budget one year after everolimus entry. For<br />
the second treatment option after letrozole or anastrozole failure, total<br />
budget impact was $0.029 PMPM, including a $0.037 PMPM increase<br />
to the pharmacy budget and $0.009 PMPM decrease to the medical<br />
budget one year after everolimus entry. Total budget impact was<br />
$0.042 PMPM, including a $0.055 PMPM increase to the pharmacy<br />
budget and $0.013 PMPM decrease to the medical budget one year<br />
after everolimus entry.<br />
CONCLUSION: Use of everolimus for ER+, HER2- MBC is<br />
expected to reduce the medical budget due to improved efficacy<br />
but increase the pharmacy budget due to higher drug cost. The total<br />
budget impact is relatively small.<br />
P5-15-06<br />
Societal economics of the 21-gene Recurrence Score® in estrogenreceptor-positive<br />
early-stage breast cancer in Japan<br />
Yamauchi H, Nakagawa C, Yamashige S, Takei H, Yagata H, Yoshida<br />
A, Hayashi N, Hornberger J, Yu T, Chien R, Chao C, Yoshizawa C,<br />
Nakamura S. St. Luke’s International Hospital, Chu-o-ku, Tokyo,<br />
Japan; Hitotsubashi University, Tokyo, Japan; Saitama <strong>Cancer</strong><br />
Center, Saitama, Japan; Cedar Associates LLC, Menlo Park, CA;<br />
Stanford University School of Medicine, Stanford, CA; Mailman<br />
School of Public Health, Columbia University, New York, NY;<br />
Genomic Health, Inc., Redwood City, CA; Showa University, Tokyo,<br />
Japan<br />
Background: <strong>Breast</strong> cancer incidence and breast-cancer mortality<br />
have been increasing in Japan. In estrogen-receptor-positive breast<br />
cancer, adding chemotherapy as adjuvant treatment is not definitive<br />
benefit for all women. Primary data on the clinical validity and<br />
decision impact of the 21-gene Recurrence Score for guiding the<br />
use of adjuvant chemotherapy has been studied among a Japanese<br />
population.<br />
Objective: The cost-effectiveness of the clinically validated 21-<br />
gene Recurrence Score for estrogen-receptor-positive, lymph-nodenegative,<br />
early-stage breast cancer (ESBC) was assessed from a<br />
Japanese societal perspective.<br />
Method: The proportion of patients with low, intermediate, and high<br />
risk of recurrence by the 21-gene Recurrence Score and the influence<br />
of the Recurrence Score on use of adjuvant chemotherapy were<br />
obtained in a study of 104 patients. A Markov model was used to<br />
track time until distant recurrence and time from distant recurrence to<br />
death. Effect of adjuvant chemotherapy based on 21-gene Recurrence<br />
Score was based on published clinical validation studies. Direct and<br />
indirect medical costs were obtained from the referral center. Utilities<br />
associated with progression and adverse events associated with<br />
chemotherapy were extracted from the literature. Sensitivity analyses<br />
were performed to assess the key drivers of cost-effectiveness and<br />
the robustness of the findings to variations in the input estimates.<br />
Results: Forty-eight percent of patients were identified by the<br />
21-gene Recurrence Score as low-risk, 36% as intermediate-risk,<br />
and 16% as high-risk. In treatment decision by using the 21-gene<br />
Recurrence Score, chemotherapy use overall decreased by 19%,<br />
resulting in an average increase of 0.235 QALYs. Testing with the<br />
21-gene Recurrence Score cost ¥350,000 per patient with ¥153,490<br />
lower acute costs because fewer women were treated with adjuvant<br />
chemotherapy. Eighteen percent more women who were identified as<br />
high risk were recommended adjuvant chemotherapy, which results<br />
in longer progression-free survival. On average across all risk groups,<br />
cost of monitoring until recurrence per patient increased by ¥3,572<br />
and costs associated with recurrence declined by ¥43,687. Use of the<br />
21-gene Recurrence Score resulted in a net cost of ¥665,455 ($8,386)<br />
per QALY gained.<br />
Conclusions: The change in decisions resulting from use of the 21-<br />
gene Recurrence Score in women with estrogen-receptor-positive,<br />
lymph-node-negative, ESBC is projected to be societally costeffective<br />
in Japan.<br />
P5-15-07<br />
Time savings with trastuzumab subcutaneous (SC) injection<br />
vs. trastuzumab intravenous (IV) infusion: First results from a<br />
Time-and-Motion study (T&M)<br />
de Cock E, Tao S, Alexa U, Pivot X, Knoop A. United Biosource<br />
Corporation, Barcelona, Spain; United Biosource Corporation,<br />
Montreal, Canada; F Hoffmann-La Roche Ltd, Basel, Switzerland;<br />
CHU Jean Minjoz, Besancon, France; Odense University Hospital,<br />
Odense, Denmark<br />
Objective:<br />
To quantify resource utilization in terms of “active” health care<br />
professional (HCP) time and consumables, as well as associated costs,<br />
related to trastuzumab (TRA) SC injection and TRA IV infusion in<br />
the treatment of patients with HER2-positive EBC within the PrefHer<br />
trial setting. Using time and resource use inputs, we will estimate<br />
average time and cost for SC and IV processes on a per patient and<br />
per site basis, as well as estimate potential time and cost savings with<br />
a switch from IV to SC administration route per site and per country.<br />
Methods:<br />
This is a multi-country (6 countries), multi-centre (17 centres),<br />
prospective, T&M study, run as a sub-study to the PrefHer trial<br />
(ClinicalTrials.gov identifier NCT01401166). Using a structured<br />
questionnaire, we conducted on-site interviews with a nurse and<br />
pharmacy member in each centre to elicit practice pattern flow and<br />
to obtain time estimates for trastuzumab-related tasks for both IV and<br />
SC processes. The information served to tailor generic Case Report<br />
Forms (CRFs) to reflect centre-specific practices. For each task we<br />
defined adequate “start” and “stop” descriptions for pre-specified<br />
tasks to ensure accurate and unbiased collection of T&M data. Data<br />
collection is performed by trained observers who measure time<br />
using a stop watch and record onto paper CRFs. This is a descriptive<br />
non-comparative study with convenience-based sample sizes<br />
ranging between 10-30 observations per process per site. While data<br />
collection is currently ongoing (final data expected during Q4 2012<br />
and are planned to be reported at the meeting), first results presented<br />
in this abstract are based on interview data and for SC process on<br />
preliminary data from the T&M study (in the absence of staff-elicited<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
458s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
time estimates for SC process due to lack of experience). Estimated<br />
total time is calculated as the sum of individual task times and results<br />
are pooled across all sites.<br />
Results:<br />
Patient hospital arrival/registration, blood sampling, and physician<br />
visit account for a median 39 minutes (min) and are expected to be<br />
similar for both processes (i.e. “non-observed” time; not included<br />
in T&M data collection). Median total HCP time for tasks included<br />
in the T&M study (i.e. “observed” time) is estimated at 59 and 20<br />
min, respectively (estimated 66% reduction with SC). For IV, the<br />
majority of “observed” task time is for account of TRA pharmacy<br />
reconstitution (25%) and infusion initiation (17%), with the remaining<br />
58% distributed across other care unit tasks. For SC, injection<br />
(35%) and TRA pharmacy dispensing (30%) constitute the bulk of<br />
“observed” task time, with 35% for other care unit tasks. Time savings<br />
are expected because of avoiding time related mainly to infusion line<br />
(dis)connection, and IV pharmacy reconstitution, tasks which are only<br />
partially being replaced by SC injection and discarding.<br />
Conclusion: A switch from IV to SC TRA may result in important<br />
care unit and pharmacy time savings to be reinvested in improving<br />
overall patient care. Patients could potentially be moved out of<br />
the chemotherapy care unit to receive SC administration in other<br />
settings and free up valuable chair time, thereby increasing the unit’s<br />
throughput and overall efficiency.<br />
P5-16-01<br />
Survival advantage in patients with metastatic breast cancer<br />
receiving endocrine therapy plus Sialyl Tn-KLH vaccine: post<br />
hoc analysis of a large randomized trial<br />
Ibrahim NK, Murray JL, Zhou D, Mittendorf EA, Sample D, Tautchin<br />
M, Miles D. University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX; Biomira, Inc., AB, Canada; Mount Vernon <strong>Cancer</strong><br />
Center, Northwood, Middlesex, United Kingdom<br />
Background<br />
A multicenter, double blinded, randomized phase III trial of<br />
the therapeutic cancer vaccine STn-KLH was completed in an<br />
international cohort of 1,028 women with metastatic breast cancer who<br />
had either no evidence of disease or nonprogressive disease following<br />
first-line chemotherapy. This trial is registered with ClinicalTrials.<br />
gov (No. NCT00003638). The outcomes showed that STn-KLH<br />
was safe and relatively well tolerated but had neither a positive nor<br />
negative effect on time to progression (TTP) or overall survival (OS)<br />
duration in the intent-to-treat population when compared with KLH<br />
control alone. The purpose of this post hoc analysis is to explore the<br />
potential benefit of combining an antiestrogen with MUC1 vaccines<br />
in metastatic breast cancer patients.<br />
Methods<br />
The data were further explored to determine if a retrospective,<br />
reassigned endocrine subset patient stratification produces subgroups<br />
that may have experienced benefit in TTP or survival compared with<br />
the phase III trial ITT analysis.<br />
Results<br />
Women treated with concomitant endocrine therapy, a pre stratified<br />
subset comprising approximately one third of the original study<br />
population, achieved a clinical benefit both in terms of TTP and<br />
survival compared with women who did not receive endocrine<br />
therapy. Moreover, women in the endocrine-treatment subset who<br />
mounted a median or greater antibody response (titer >1:320 toward<br />
bovine submaxillary mucin) to the STn-KLH vaccine experienced<br />
significantly longer median survival than their trial counterparts who<br />
mounted a below-median antibody response.<br />
Conclusion<br />
Unlike maintenance chemotherapy, with its associated cumulative<br />
toxicity, the combination of endocrine and STn-KLH therapy may<br />
offer clinical benefit with few adverse effects for women with<br />
metastatic breast cancer.<br />
P5-16-02<br />
Final Results of the Phase I/II Trials of the E75 Adjuvant <strong>Breast</strong><br />
<strong>Cancer</strong> Vaccine<br />
Vreeland TJ, Clifton GT, Hale DF, Sears AK, Patil R, Holmes JP,<br />
Ponniah S, Mittendorf EA, Peoples GE. <strong>San</strong> <strong>Antonio</strong> Military Medical<br />
Center, <strong>San</strong> <strong>Antonio</strong>, TX; Joyce Murtha <strong>Breast</strong> Care Center, Windber,<br />
PA; Redwood Regional Medical Group, <strong>San</strong>ta Rosa Memorial<br />
Hospital, <strong>San</strong>ta Rosa, CA; Uniform Services University of Health<br />
Sciences, Bethesda, MD; MD Anderson <strong>Cancer</strong> Center, Houston, TX<br />
Background: We have completed phase I/II clinical trials vaccinating<br />
breast cancer patients (pts) with E75, a HLA-A2/A3-restricted HER2/<br />
neu (HER2) peptide vaccine. The vaccine was administered in the<br />
adjuvant setting to prevent recurrences in high risk patients rendered<br />
disease-free with standard of care therapy. We have previously<br />
reported preliminary results indicating that the vaccine (including<br />
booster inoculations) is safe and effective in stimulating an antitumor<br />
immune response. Here, we report the final 5 year results<br />
from these trials.<br />
Methods: The phase I/II trials were performed as dose-escalation/<br />
schedule-optimization trials enrolling node positive and high-risk,<br />
node negative breast cancer patients with tumors expressing any level<br />
of HER2. HLA-A2/A3+ pts were enrolled into the vaccine group<br />
(VG) while HLA-A2/A3- pts were followed prospectively as the<br />
untreated control group (CG). The VG pts were given 4-6 monthly<br />
intradermal inoculations of E75 with GM-CSF during the primary<br />
vaccine series (PVS). In addition, a voluntary booster program was<br />
initiated during the trial, with booster inoculations being offered every<br />
6 months after completion of the PVS. Patients were monitored for<br />
local and systemic toxicity (graded by NCI Common Terminology<br />
Criteria for Adverse Events). In vivo immune response was assessed<br />
in the VG by delayed type hypersensitivity (DTH) reactions to both<br />
E75 and saline, pre- and post-PVS. VG and CG pts were followed<br />
for 60 months (mo) and recurrences were documented. Demographic<br />
differences were compared with the Fisher’s exact test and diseasefree<br />
survival was determined using the Kaplan-Meier method and<br />
compared by log-rank test.<br />
Results: 195 pts were enrolled, 6 withdrew (2 from VG, 4 from CG),<br />
1 was lost to follow-up prior to vaccination, and 1 was found to be<br />
ineligible, leaving 187 evaluable pts; 108 in the VG and 79 in the<br />
CG. 53 pts volunteered for the booster program and received at least<br />
one booster inoculation. The VG and CG were well-matched with the<br />
only statistically significant difference being ER-/PR- status (31.1%<br />
in VG vs 17.7% in CG, p=0.04). Vaccination was well tolerated<br />
(maximum local toxicity: 73.1% Grade 1, 26.9% Grade 2, 0% Grade<br />
3; maximum systemic toxicity: 72.2% Grade 1, 15.7% Grade 2, and<br />
2.8% Grade 3). In the VG, pre- to post-PVS E75 DTH significantly<br />
increased (mean 3.8 ±1.0 vs 14.8±1.4, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
At the end of the 5 year follow-up period, the E75 vaccine shows a<br />
strong trend toward preventing breast cancer recurrence in vaccinated<br />
patients. To investigate this vaccine (now known as NeuVax) further,<br />
the PRESENT trial, a prospective, randomized, double-blind, placebocontrolled,<br />
multi-center phase III registration trial has been initiated<br />
and is actively enrolling.<br />
P5-16-03<br />
Phase II study of autologous dendritic cell vaccination in patients<br />
with HER2 negative breast cancer combined with neoadjuvant<br />
chemotherapy<br />
Castillo A, Salgado E, Inoges S, Arevalo E, Castañon E, López Díaz<br />
de Cerio A, Sola JJ, Pina L, Nuñez J, Rodriguez-Spiteri N, Espinós<br />
J, Aramendia JM, Fernandez Hidalgo OA, <strong>San</strong>tisteban M. Clínica<br />
Universidad de Navarra, Pamplona, Navarra, Spain; Complejo<br />
Hospitalario de Navarra, Pamplona, Navarra, Spain; Universidad de<br />
Navarra, Pamplona, Navarra, Spain; Clínica Universidad de Navarra<br />
Background The limited efficacy of neoadjuvant schedules to obtain<br />
pCR in breast cancer together with a prompt relapse of triple negative<br />
breast cancers has opened up the development of new strategies<br />
involving the immune system, which is essential in cancer control.<br />
We have elaborated an autologous vaccine with dendritic cells loaded<br />
with patients’ own tumor antigens. Based on the synergistic effect<br />
between immunotherapy and chemotherapy our hypothesis is that the<br />
combination of both strategies could improve pCR with an excellent<br />
tolerance and could increase DFS and OS. Methods Two centers are<br />
enrolling patients from February 2011. Twenty-one patients with<br />
stage II-III HER2 negative breast cancer have started on sequential<br />
neoadjuvant chemotherapy based on dose dense antracyclines (E<br />
100mg/m 2 and C 600 mgr/m 2 ) x4 cycles plus GM-CSF followed by<br />
taxanes (DOC 75-100 mgr/m 2 ) x4 cycles plus vaccination. Vaccine<br />
calendar was started after the 4 th EC and alternated with taxane<br />
schedule and after chemotherapy up to a maximum of a 2 year-period.<br />
SNB biopsy was performed before neoadjuvant chemotherapy.<br />
pCR in the breast and the axilla is the main endpoint, measured by<br />
Miller&Paine classification. Data were analyzed using SPSS and<br />
alpha was set at 0.05 (two-tailed). We have compared these results in<br />
the vaccinated cohort (V) with our historic cohort (C) of 19 patients<br />
treated in the same way but without the vaccine. Results Both cohorts<br />
(V and C) were well balanced for age, histologyc type, differentiation<br />
grade, Ki67>15%, tumor size ≤ 5 cm, stage and expression of hormone<br />
receptors. All patients except one in the vaccine cohort achieved 8<br />
cycles of chemotherapy. According to grade ¾ toxicities we did not<br />
find significant differences except for hand-foot syndrome in the V<br />
cohort (19% vs 0%; p=0.04) and vomiting in the C cohort (0% vs<br />
21%; p=0.02). Lymphopenia was the most common adverse event<br />
(81% in V vs 89.5% in C; p= 0.45). Other toxicities were anemia (0%<br />
vs 5.3%; p=0.28), thrombopenia (0% vs 10% p=0.12), leukopenia<br />
(9.5% vs 15.8% p=0.55) and neutropenia (14% vs 21%, p=0.57).<br />
Gastrointestinal toxicity was similar in both groups: mucositis (0%<br />
vs 5.3%, p=0.28); gastritis (5% in both cohorts), nausea (19% vs<br />
16%, p= 0.78), diarrhea (5% in both cohorts), constipation (0% vs<br />
15% in C, p=0.06). Myalgias were seen in 19% in V vs 11% in C<br />
(p=0.45). We did not see any local grade ¾ toxicity related to the<br />
intradermal vaccines. Regarding efficacy data, clinical complete<br />
response by MRI was shown in 38% in the V as compared to 16% in<br />
the C (p=0.06). <strong>Breast</strong>-conserving surgery was more common in the<br />
V cohort (62% vs 53%, p=0.55). Total pCR (T plus N) was superior<br />
with the addition of the vaccine (24% vs 5% p=0.014). Moreover<br />
in three more patients in the V group we find isolated tumor cells in<br />
the breast (T itc) . Conclusions The addition of autologous dendritic<br />
cell vaccines to neoadjuvant chemotherapy significantly increased<br />
the rate of pathological complete responses among patients with<br />
HER2-negative breast cancer. Vaccination does not seem to add any<br />
toxicity to the schedule.<br />
P5-16-04<br />
A phase I study of a DNA plasmid based vaccine encoding the<br />
HER-2/neu intracellular domain in subjects with HER2+ breast<br />
cancer.<br />
Salazar LG, Slota M, Higgens D, Coveler A, Dang Y, Childs J, Bates<br />
N, Guthrie K, Waisman J, Disis ML. University of Washington, Seattle,<br />
WA; BREASTLINK, Hawthorne, CA<br />
HER2+ breast cancer (BC) is associated with early disease relapse,<br />
usually to distant sites. This would suggest relapse is due to residual<br />
microscopic disease. Generation of vaccine-induced HER2-specific<br />
CD4+ T helper immunity (Th1) may result in immunologic<br />
eradication of residual HER2+ tumor cells and subsequent<br />
development of immunologic memory and epitope spreading (ES),<br />
which has been associated with a survival benefit in vaccinated BC<br />
patients. We have shown HER2 peptide-based vaccines can generate<br />
immunity in BC however, more recently we developed a plasmid<br />
DNA based vaccine (pNGVL3-hICD) which may have additional<br />
advantages over synthetic peptides. DNA vaccines offer a strategy<br />
to immunize against multiple tumor antigens and are able to elicit<br />
both CTL and Th1 immunity. Plasmid DNA can also remain at the<br />
vaccine site, providing a constant source of antigen. Intradermal<br />
(i.d.) delivery of DNA vaccines with GM-CSF as adjuvant may<br />
enhance immunogenicity due to local influx of dermal Langerhans<br />
cells. We have recently completed a phase I trial utilizing pNGVL3-<br />
hICD in optimally treated stage III and IV HER2+ BC patients and<br />
have defined vaccine safety profile, optimal dose and schedule; and<br />
demonstrated vaccine biologic activity.<br />
Methods: A total of 66 subjects with stage III and IV HER2+ BC in<br />
complete remission were enrolled sequentially into 1 of 3 pNGVL3-<br />
hICD dose arms (22 subjects/arm): Arm 1=10µg, Arm 2=100 µg, and<br />
Arm 3 =500µg. All vaccines were admixed with 100µg GM-CSF and<br />
given i.d. monthly for a total of 3 vaccines. Toxicity was assessed at<br />
baseline, during vaccination and at follow-up. Immune responses to<br />
HER ICD and ECD were assessed with IFN-γ ELISPOT at baseline<br />
and serially through week 60 post-vaccination. Linear regression<br />
analysis was used to compare differences in immune responses from<br />
baseline over the whole study period between dose arms. Vaccine site<br />
skin biopsies and peripheral lymphocytes were serially analyzed for<br />
plasmid persistence via RT-PCR.<br />
Results: 64 subjects (20 in Arm 1; 22 in Arm 2; 22 in Arm 3)<br />
completed 3 vaccines. Age, stage/status, number of previous<br />
chemotherapy regimens, and use of bisphosphonate and trastuzumab<br />
therapies was similar across dose arms. Vaccine-related toxicity was<br />
primarily Grade 1/2 injection site reactions, myalgias, arthralgias<br />
and not significantly different between arms; no cardiac or grade<br />
IV toxicity was observed. Immune responses to HER2 ICD were<br />
significantly better in Arms 2 and 3 vs Arm 1 (p=0.001 and 0.002,<br />
respectively) but not statistically different between Arms 2 and 3. 38<br />
patients had DNA plasmid persistence at the vaccination site with no<br />
difference between arms. There has been no detection of DNA plasmid<br />
in lymphocytes from patients in all arms. Analyses of survival and ES<br />
(HER ECD immune responses) are on-going and will be presented.<br />
Conclusions: pNGVL3-hICD was safe and effectively induced<br />
persistent HER2 ICD specific Th1 immunity without increased cardiac<br />
toxicity. Moreover, immunity was present more than 1 year after end<br />
of vaccination, indicative of vaccine-induced immunologic memory.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
460s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
P5-16-05<br />
The combination of trastuzumab and HER2-directed peptide<br />
vaccines is safe in HER2-expressing breast cancer patients<br />
Hale DF, Vreeland TJ, Perez SA, Berry JS, Ardavanis A, Trappey<br />
AF, Tzonis P, Sears AK, Clifton GT, Shumway NM, Papamichail<br />
M, Ponniah S, Peoples GE, Mittendorf EA. Brooke Army Medical<br />
Center, <strong>San</strong> <strong>Antonio</strong>, TX; <strong>Cancer</strong> Immunology and Immunotherapy<br />
Center, Athens, Greece; MD Anderson <strong>Cancer</strong> Center, Houston, TX;<br />
Uniformed Services University of the Health Sciences, Bethesda, MD<br />
Background: Cardiotoxicity is the most concerning toxicity associated<br />
with the commonly used HER2-directed immunotherapy, trastuzumab<br />
(Tz). In general, a significant decline of left ventricular ejection<br />
fraction (EF) in asymptomatic patients is accepted as a decrease of<br />
at least 10% or an absolute value of below 50%. We are currently<br />
conducting multiple trials of HER2-directed peptide vaccines, often<br />
given either concurrently or in close temporal proximity to Tz. This<br />
has raised the issue that combining therapies could increase the risk<br />
of cardio-toxicity. Here, we present safety data from multiple trials<br />
in which the combination of these HER2-directed therapies was<br />
administered.<br />
Methods: Phase I and II trials were conducted in disease-free breast<br />
cancer patients after completion of chemotherapy when indicated.<br />
Patients (pts) who were determined by treating oncologists to qualify<br />
for Tz received this therapy per standard-of-care. These pts were<br />
enrolled onto HER2-directed peptide vaccine trials per each trial’s<br />
inclusion criteria, with vaccinated (VG) pts receiving peptide + GM-<br />
CSF and control (CG) pts receiving GM-CSF alone. All patients were<br />
monitored for local and systemic toxicity to peptide inoculations<br />
(graded by the NCI’s Common Terminology Criteria for Adverse<br />
Events). In addition, patients who received Tz had EF tracked<br />
through either echocardiogram or MUGA according to local standard<br />
of practice. Our database was queried for patients who received Tz<br />
and peptide, and had documented measures of EF pre-vaccine (Pre),<br />
during vaccine (D) and post-vaccine (Post). These pts were then<br />
placed in two groups based on the timing of Tz and vaccine therapy:<br />
concurrent(C) group and sequential(S) group. Mean EF at each time<br />
point was compared using a t-test.<br />
Results: Overall, the peptide vaccines were well tolerated (max local<br />
tox: 1% Grade 0, 65% Gr 1, 33% Gr 2, 1% Gr 3; max systemic tox:<br />
19% Gr 0, 63% Gr 1, 18% Gr 2, 0% Gr 3). These toxicities are likely<br />
secondary to the GM-CSF immunoadjuvant as control pts receiving<br />
GM-CSF alone have similar toxicity profiles (max local tox: 0%<br />
Gr 0, 76% Gr 1, 23% Gr 2, 1% Gr 3; max systemic tox: 20% Gr 0,<br />
65% Gr 1, 15% Gr 2, 0% Gr 3). There have been no serious or nonserious<br />
cardiac-related adverse events in our trials. In total, 71 pts<br />
treated with Tz and enrolled in a vaccine trial had EF measurements<br />
available for analysis; 54 in the S group (35 VG, 19 CG) and 17 in<br />
the C group (10 VG, 7 CG). Overall, neither VG nor CG pts had<br />
significant changes in EF (VG Pre: 65±0.8%, D: 63±0.9%, Post:<br />
64±0.3%; CG Pre: 63±1.2%, D: 64±1.8%, Post: 63±1.1%). Separating<br />
VG pts into C and S pts, there were again no significant changes in<br />
EF, (C Pre: 65±1.0%, D: 63±1.0%, Post: 63±1.4%; S Pre: 65±1.7%,<br />
D: 61±1.3%, Post: 65±1.8%).<br />
Conclusions: HER2-directed peptide vaccines are safe and well<br />
tolerated. Initial data indicate that the combination of Tz and HER2-<br />
directed peptide vaccines, whether concurrent or sequential, does not<br />
cause significant cardiac toxicities as measured by changes in the EF<br />
during and after therapy. We will continue to track this safety data<br />
to confirm early findings as we pursue additional combination trials.<br />
P5-16-06<br />
A phase 2 randomized trial of docetaxel (DOC) alone or in<br />
combination with therapeutic cancer vaccine, CEA-, MUC-1-<br />
TRICOM (PANVAC)<br />
Heery CR, Ibrahim NK, Mohebtash M, Madan RA, Arlen PM, Bilusic<br />
M, Kim JW, Singh NK, Hodge S, McMahon S, Steinberg SM, Hodge<br />
JW, Schlom J, Gulley JL.<br />
Background<br />
A previous phase 1/2 trial of PANVAC, a poxviral based cancer<br />
vaccine, suggested clinical efficacy in some patients (pts) with breast<br />
and ovarian cancer and evidence of immunologic activity. Preclinical<br />
data showed DOC can modify tumor phenotype, making tumor cells<br />
more amenable to T-cell mediated killing. The goal was to determine<br />
if DOC and PANVAC could synergize and improve clinical outcomes<br />
compared with DOC alone.<br />
Methods<br />
This is an open-label randomized phase 2 multi-center trial designed<br />
to enroll 48 pts with metastatic breast cancer to receive DOC in<br />
combination with PANVAC (A) or alone (B). Cross-over was<br />
allowed so that pts randomized to B could receive the vaccine upon<br />
progression. Eligibility included ECOG performance status
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-17-01<br />
Bevacizumab (B) in the adjuvant treatment of breast cancer -<br />
first toxicity results from Eastern Cooperative Oncology Group<br />
trial E5103.<br />
Miller KD, O’Neill A, Dang C, Northfelt D, Gradishar W, Sledge GW.<br />
Indiana University Melvin and Bren Simon <strong>Cancer</strong> Center; Dana<br />
Farber <strong>Cancer</strong> Institute; Memorial Sloan Kettering <strong>Cancer</strong> Center;<br />
Mayo Clinic; Northwestern University<br />
Background: A previous feasibility trial (E2104 – Ann Oncol<br />
23(2):331-7,2012) suggested incorporation of B into anthracyclinecontaining<br />
adjuvant therapy was feasible but ongoing cardiac<br />
monitoring was required to define the true impact of B on cardiac<br />
function. Methods: Patients (pts) were assigned 1:2:2 to one of three<br />
treatment arms. In addition to doxorubicin and cyclophosphamide<br />
followed by weekly paclitaxel, patients received either placebo (Arm<br />
A – AC>T) or B during chemotherapy (Arm B - BAC>BT), or B<br />
during chemotherapy followed by B monotherapy (15 mg/kg q3wk)<br />
for an additional 10 cycles (Arm C – BAC>BT>B). Randomization<br />
was stratified and B dose adjusted for choice of AC schedule (classical<br />
q3wk - 15 mg/kg; dose dense(dd) q2 wk - 10 mg/kg). When indicated,<br />
radiation and hormonal therapy were administered concurrently<br />
with B (for Arm C pts). The primary cardiac endpoint was the<br />
incidence of clinically apparent cardiac dysfunction (CHF)defined<br />
as symptomatic decline in left ventricular ejection fraction (LVEF)<br />
to below the lower limit of normal (LLN) or symptomatic diastolic<br />
dysfunction as assessed by independent review. Cumulative toxicity<br />
data as of Jan 23, 2012 are presented. Results: From 11.07 to 2.11,<br />
4994 pts were enrolled. Median age was 52; 80% received ddAC.<br />
Chemotherapy associated toxicities including myelosuppression<br />
(Grade 4 neutropenia 16/20/19%) and neuropathy (Grade ≥ 3<br />
8/8/8%) were similar across all arms. Grade ≥ 3 hypertension/<br />
thrombosis/proteinuria/hemorrhage was reported by 7/3/10% & LVEF < LLN 1% 2% 2%<br />
Post C8 LVEF Arm A Arm B Arm C<br />
Baseline and post Cycle 8 LVEF available 847 1685 1674<br />
Median post Cycle 8 LVEF 61 60 60<br />
% with post Cycle 8 LVEF decline > 10% 12% 18% 18%<br />
% with post Cycle 8 drop >10% & LVEF < LLN 2% 6% 6%<br />
Conclusion: Incorporation of B into anthracycline and taxane<br />
containing adjuvant therapy results in a significant but small increase<br />
in clinical CHF. The rate of clinical CHF is similar to that predicted<br />
by E2104 (2.5-2.9%) and reported In the FDA label for anthracycline<br />
pre-treated pts(3.8%). No unexpected toxicities were encountered.<br />
P5-17-02<br />
Withdrawn by Author<br />
P5-17-03<br />
Quality of life (QoL) results from the TURANDOT trial<br />
comparing two bevacizumab (BEV)-containing regimens as firstline<br />
treatment for HER2-negative metastatic breast cancer (mBC)<br />
Láng I, Inbar MJ, Kahan Z, Greil R, Beslija S, Stemmer SM,<br />
Kaufman B, Ahlers S, Brodowicz T, Zielinski C. National Institute of<br />
Oncology, Budapest, Hungary; Tel Aviv Sourasky Medical Centre,<br />
Tel Aviv, Israel; University of Szeged, Hungary; Paracelsus Medical<br />
University, Salzburg, Austria; Institute of Oncology, Sarajevo, Bosnia<br />
and Herzegowina; Rabin Medical Center, Petah-Tikva, Israel;<br />
Sheba Medical Center, Ramat Gan, Israel; IST GmbH Mannheim,<br />
Mannheim, Germany; Medical University of Vienna and Central<br />
European Cooperative Oncology Group (CECOG), Vienna, Austria<br />
Background: BEV has been shown to significantly improve the<br />
efficacy of both paclitaxel (PAC) and capecitabine (CAP) as firstline<br />
therapy for HER2-negative mBC. TURANDOT, a randomized<br />
phase III trial comparing BEV-PAC vs BEV-CAP, includes extensive<br />
QoL evaluation.<br />
Methods: Patients (pts) with HER2-negative mBC who had received<br />
no prior chemotherapy for mBC were randomized to receive either<br />
BEV-PAC (BEV 10 mg/kg d1 & 15 + PAC 90 mg/m 2 d1, 8, & 15<br />
q4w) or BEV-CAP (BEV 15 mg/kg d1 + CAP 1000 mg/m 2 bid d1-14<br />
q3w) until disease progression, unacceptable toxicity, or withdrawal of<br />
consent. The primary endpoint is overall survival (OS); QoL, assessed<br />
using the EORTC QLQ-C30, is a secondary endpoint. Pts were asked<br />
to complete QLQ-C30 at baseline, q12w during study therapy, at the<br />
end of treatment, and 28 days after discontinuing from the study.<br />
Results: On-treatment QoL questionnaires were available from all 561<br />
of the treated pts at baseline, 394 at week 12, 266 at week 24, 186 at<br />
week 36, 129 at week 48, and 50 pts ranged from +1.5 to +2.6. In the BEV-CAP arm, mean<br />
baseline score was 56.0; the mean score remained above the baseline<br />
mean score until week 96. Mean change from baseline ranged from<br />
-3.9 at week 84 to +4.9 at week 96. Mean scores for most individual<br />
symptom scales were low (typically
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
P5-17-04<br />
Management of Antiangiogenics’ Renovascular Safety in breast<br />
cancer. Subgroup and intermediate results of the MARS Study.<br />
Launay-Vacher V, Janus N, Daniel C, Rey J-B, Ray-Coquard I,<br />
Gligorov J, Spano J-P, Thery J-C, Jouannaud C, Goldwasser F, Mir<br />
O, Morere J-F, Oudard S, Azizi M, Dorent R, Deray G, Beuzeboc P.<br />
Institut Curie, Paris, France; Hôpital de la Pitié-Salpêtrière, Paris,<br />
France; Institut Jean Godinot, Reims, France; Centre Léon Bérard,<br />
Lyon, France; Hôpital Tenon, Paris, France; Hôpital Cochin, Paris,<br />
France; Hôpital Avicenne, Bobigny, France; Hôpital Européen<br />
Georges Pompidou, Paris, France<br />
Background:<br />
Hypertension (HTN) and proteinuria (Pu) are class-side-effects<br />
of anti-VEGF drugs (AVD), related to the inhibition of the VEGF<br />
pathway. The MARS study has been conducted to assess the<br />
renovascular tolerance of these drugs in the clinical setting.<br />
Methods:<br />
The MARS study is a multicentric prospective observational study of<br />
the renovascular safety of AVD in AVD-naive patients. in 7 centres<br />
from 2009 to 2011. There was no intervention on the choice of the<br />
AVD. Data collected included: gender, age, serum creatinine (SCr),<br />
diabetes, HTN, hematuria (Hu) and dipstick Pu. This sub-group<br />
analysis presents the intermediate results for the first 184 patients<br />
with breast cancer (BC) receiving bevacizumab who completed the<br />
1-year follow-up (f/u) (out of 337 BC patients in total).<br />
Results:<br />
All these 184 patients received bevacizumab (mean and median<br />
durations of treatment: 7.8 and 8 months, respectively). Median age<br />
at inclusion was 60 years. Bone, visceral and cerebral metastasis<br />
frequencies were 75.0, 52.2 and 7.1%, respectively. Diabetes and<br />
HTN prevalences were 4.3% and 10.3%, respectively. Baseline<br />
renal assessment retrieved: Pu 13.0%, Hu 8.2%, mean aMDRD<br />
98.8 ml/min/1.73m 2 and 1.1% had aMDRD
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-17-06<br />
The deficient eNOS c.894G>T genotype is not associated with<br />
increased severity of hypertension and proteinuria in breast<br />
cancer patients receiving bevacizumab<br />
Del Re M, Ferrarini I, Fontana A, <strong>San</strong>toro M, Bona E, Del Re I, Stasi<br />
I, Bertolini I, Laurà F, Landucci E, Salvadori B, Falcone A, Danesi<br />
R. University Hospital, Pisa, Italy<br />
Background. Tumor angiogenesis is a complex process involving a<br />
wide array of effector molecules and stromal cells. In tumor tissue,<br />
vasculature is structurally and functionally abnormal, causing<br />
elevated interstitial pressure and irregular perfusion. The expression<br />
of vascular endothelial growth factor (VEGF), the most important<br />
angiogenic factor, is enhanced in many tumors. VEGF may induce<br />
nitric oxide (NO) production via up-regulation of the endothelial NO<br />
synthase (eNOS, NOS3) and the resultant overproduction of NO is<br />
associated with vasodilation and edema within tumors (Goel S et al.<br />
Physiol Rev 2011;91:1071). eNOS plays an important physiologic<br />
role in maintaining blood pressure homeostasis and vascular<br />
integrity by providing constitutive release of NO in endothelial<br />
cells. Functional variants of the eNOS gene, including the singlenucleotide<br />
polymorphism rs1799983 (c.894G>T, p.Asp298Glu) at<br />
codon 298, have been associated with reduced function of eNOS<br />
and higher incidence of hypertension (HT) (Niu W, Qi Y. PLoS One<br />
2011;6:e24266).<br />
Purpose. Since suppression of VEGF-eNOS axis by anti-angiogenic<br />
therapies is considered a causative factor of HT in patients, the<br />
purpose of this study was to examine whether the major eNOS nonsynonymous<br />
variant c.894G>T may be associated with increased<br />
risk of developing hypertension (HT) and proteinuria (PU) in breast<br />
cancer patients treated with bevacizumab.<br />
Patients and methods. Forty-one metastatic breast cancer patients<br />
given bevacizumab as per standard of care were enrolled. Main<br />
characteristics were: median age 49.5 years (range 29-73) at first<br />
diagnosis, 53 years (range 34-74) at metastatic disease; PS 0-1 in all<br />
patients; 4 subjects with hypertension and 1 patient with compensated<br />
cardiovascular disease at diagnosis. Twenty-six subjects had received<br />
neoadjuvant or adjuvant chemotherapy based on anthracycline and<br />
taxane; first-line chemotherapy for metastatic disease was paclitaxel<br />
plus bevacizumab for all patients; 14 subjects received hormonetherapy<br />
for metastatic disease (range 1-5 lines). Germline DNA was<br />
extracted from peripheral blood and used to screen patients for eNOS<br />
c.894G>T variant by automatic sequencing. The study was approved<br />
by the local Ethics Committee.<br />
Results. Three patients (7.3%) were homozygous variant c.894TT,<br />
12 (29.3%) homozygous wild-type c.894GG and the remaining 26<br />
(63.4%) were heterozygous c.894GT. The c.894TT patients had no HT<br />
or PU at baseline and developed grade (G) 1, 2, 2 HT, respectively,<br />
and in one case PU during treatment. G1, 2 and 3 HT developed in 4, 5<br />
and 2 c.894GG subjects, respectively, while PU was observed in 7/12<br />
(58%) patients. The full range of HT grades and PU were observed<br />
in heterozygous subjects. Thirty-seven patients achieved one of the<br />
following: partial remission, minimal response or stable disease upon<br />
treatment with bevacizumab in combination with chemotherapy; 3<br />
subjects had progressive disease and 1 was not evaluable.<br />
Conclusions. The presence of the mutant T allele of c.894G>T is<br />
not associated with increased severity of HT and PU; therefore,<br />
bevacizumab can be administered at no increased risk in TT patients<br />
with respect to the wild-type GG population.<br />
P5-17-07<br />
Influence of bevacizumab on local-regional recurrence in triple<br />
negative breast cancer<br />
Prendergast BM, De Los <strong>San</strong>tos JF, Barrett OC, Forero A, Falkson<br />
CI, Urist MM, Krontiras H, Bland KI, Meredith RF, Keene KS, You<br />
Z, Carpenter JT. University of Alabama Birmingham, AL<br />
Background:<br />
Triple negative breast cancer (TNBC) comprises 15-20% of newly<br />
diagnosed invasive breast cancers and has been associated with an<br />
elevated risk of both local-regional recurrence (LRR) as well as distant<br />
failure. Bevacizumab (BEV) has been shown to improve pathologic<br />
complete response rates in the setting of neoadjuvant chemotherapy<br />
(NCT), but its effect on LRR remains undefined. This study reports<br />
the impact of adding BEV to standard breast cancer therapy in TNBC<br />
patients treated at a single institution.<br />
Methods:<br />
One hundred and eighty-five consecutive TNBC patients treated at the<br />
University of Alabama Birmingham from May 2005 to August 2010<br />
were reviewed. Thirty-one TNBC patients treated with chemotherapy<br />
(CT) and BEV on prospective studies were matched (1:2) with 62<br />
TNBC patients treated with CT alone, controlling for age, stage, and<br />
use of radiation (RT). The Kaplan-Meier method was used to estimate<br />
LRR, distant metastasis-free survival (DMFS), and overall survival<br />
(OS), and cohorts were compared using Cox proportional hazards<br />
models and the 2-sided log-rank test.<br />
Results:<br />
Mean age was 47 and 46 years in the cohorts with and without BEV,<br />
respectively. Stage in each cohort was as follows: 32% stage I, 61%<br />
stage II, and 7% stage III. Use of adjuvant RT was 81% in each cohort<br />
(25/31 BEV, 50/62 no BEV). BEV was delivered with NCT in 17<br />
patients (55%) and with adjuvant CT in the remaining 14 patients<br />
(45%). Eleven patients (35%) completed an additional 1 year of<br />
maintenance therapy with BEV. LRR occurred in 2 (6%) patients<br />
treated with BEV vs. 16 (26%) treated with CT alone (HR=0.25,<br />
95% CI 0.06-1.07, p=0.04). Distant recurrence occurred in 3 (10%)<br />
patients treated with BEV vs. 11 (18%) patients in the CT group<br />
HR=0.6, 95% CI 0.2-1.8, p=0.48). There were 2 (6%) deaths in the<br />
BEV group vs. 12 (19%) in the CT alone group (HR=0.55, 95% CI<br />
0.13-2.3, p=0.19).<br />
Conclusions:<br />
In a matched-pair analysis of TNBC patients, the addition of BEV<br />
to conventional breast cancer management was associated with a<br />
reduction in LRR. Further prospective study is necessary to examine<br />
the impact of BEV on local-regional control in TNBC.<br />
P5-18-01<br />
Pertuzumab (P) in combination with trastuzumab (T) and<br />
docetaxel (D) in elderly patients with HER2-positive metastatic<br />
breast cancer in the CLEOPATRA study<br />
Miles D, Baselga J, Amadori D, Sunpaweravong P, Semiglazov V,<br />
Knott A, Clark E, Ross G, Swain SM. Mount Vernon <strong>Cancer</strong> Centre,<br />
Middlesex, United Kingdom; Massachusetts General Hospital <strong>Cancer</strong><br />
Center and Harvard Medical School, Boston, MA; Istituto Scientifico<br />
Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy;<br />
Songklanagarind Hospital, Prince of Songkla University, Hat Yai,<br />
Thailand; NN Petrov Research Institute of Oncology, St Petersburg,<br />
Russian Federation; Roche Products Limited, Welwyn, United<br />
Kingdom; MedStar Washington Hospital Center, Washington, DC<br />
Background: The incidence of cancer increases with age as does<br />
the risk of treatment-related adverse events (AEs) due to underlying<br />
comorbidities. A better understanding of cancer therapy-related AEs<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
464s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
in elderly pts may help identify the optimal therapy by balancing<br />
treatment benefit and risk. CLEOPATRA, a double-blind Phase III<br />
trial, compared placebo (Pla)+T+D with P+T+D in pts with HER2-<br />
positive 1L MBC (Baselga 2012). Here we report safety and efficacy<br />
by age group.<br />
Methods: P/Pla: 840 mg initial dose, 420 mg q3w iv; T: 8 mg/kg<br />
initial dose, 6 mg/kg q3w iv; D: 75 mg/m 2 q3w iv, escalating to 100<br />
mg/m 2 if tolerated. P/Pla+T were given until progressive disease (PD)<br />
or unacceptable toxicity. At least 6 cycles of D were recommended; 6 cycles were<br />
allowed at investigators’ discretion. At baseline, pts were required<br />
to have ECOG PS of 0 or 1, LVEF ≥50% and no decline to
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
The issues related to the ITT and dependent censored analyses will be<br />
reviewed and discussed. Alternative analytic approaches designed to<br />
estimate the treatment effect that would have been observed had there<br />
been no selective crossover will be presented. The methods include<br />
the inverse probability of censoring weighted (IPCW) approach,<br />
and randomization-based estimators under the accelerated failure<br />
time model.<br />
HERA data to about 8y MFU (available fall 2012) will be used to<br />
illustrate approaches.<br />
CONCLUSION: Alternative methods addressing selective crossover<br />
are required to estimate the trastuzumab effect for updated analyses<br />
of DFS and OS for HERA, and for any other large randomized trial<br />
with positive interim results.<br />
P5-18-03<br />
Clinicopathological features among patients with HER2-positive<br />
breast cancer with prolonged response to trastuzumab based<br />
therapy<br />
Vaz-Luis I, Seah D, Olson E, Metzger O, Wagle N, Sohl J, Litsas G,<br />
Burstein H, Krop I, Winer E, Lin NU. Dana Farber <strong>Cancer</strong> Institute,<br />
Boston, MA; Ohio State University<br />
Background: HER2-positivity is a predictor of benefit from<br />
trastuzumab (TRZ), but fails to depict the observed interpatient<br />
variability in terms of treatment (tx) duration. In this study we<br />
described the relationship between clinicopathological features and<br />
TRZ tx duration.<br />
Methods: A retrospective consecutive series of 343 HER2+ breast<br />
cancer (BC) patients (pts) treated with TRZ at the Dana-Farber <strong>Cancer</strong><br />
Institute from 1999-2008 was identified. 139 pts treated with 1st line<br />
TRZ-based tx were selected for analysis. Pts who received any non-<br />
TRZ prior tx for metastatic disease were excluded. TRZ tx duration<br />
was defined as time from start of 1st line therapy to the 1st day of 2nd<br />
line therapy or death. Central nervous system (CNS) progression with<br />
TRZ maintenance was not considered change of tx. Pts were divided<br />
equally into 3 groups based on the duration of 1st line tx distribution.<br />
Short-term responders (STR) were on the 1st line tx for 15m. An additional group of extremely LTR (ELTR) was defined<br />
as being in the 90th percentile of tx duration (>37m). Descriptive<br />
analysis was performed; fisher exact test, Kruskal-Wallis and logistic<br />
regression methods were used to compare groups.<br />
Results: Median follow-up time since metastatic diagnosis was 4 years<br />
(y) (range 0-11). Median age at diagnosis was 47y (22-83), 25% of<br />
stage I-III pts at diagnosis received adjuvant/neoadjuvant TRZ. The<br />
median disease free interval (DFI) was 20m (0-172), median number<br />
of metastatic sites was 2(1-5), 68% of pts had visceral disease. Median<br />
duration of 1st line tx was 10m (2-105). TRZ was given with CT<br />
in 86%, hormone tx in 6% and as monotherapy in 9%. 25% of pts<br />
developed CNS progression and continued tx. There were only small<br />
absolute differences for clinicopathological characteristics among<br />
STR, IR and LTR.<br />
(N) STR(46) IR (46) LTR (47) p<br />
Duration of 1st line tx(median; range) 3; 2-7 10; 7-14 25; 15-105<br />
HR(n;%) 0.10<br />
Positive 18; 39 28; 61 26; 55<br />
Negative 28; 61 18; 39 21; 45<br />
Stage I-III(n;%) 37; 80 36; 78 33; 70 0.54<br />
Adjuv/neoadjuv TRZ(n;%) 12; 32 9; 25 6; 18 0.40<br />
DFI(median; range) 21; 0-172 17; 0-153 23; 0-161 0.88<br />
Number of sites of 1st<br />
2.5; 1-5 2; 1-4 2; 1-5 0.94<br />
recurrence(median; range)<br />
Sites of 1st recurrence: Visceral(n;%) 32; 70 26; 57 36; 77 0.11<br />
Type of 1st line tx(n;%) 0.10<br />
TRZ monotherapy 7; 15 1; 2 4; 9<br />
TRZ-hormone tx 1; 2 5; 11 2; 4<br />
TRZ-chemotherapy 38; 83 40; 87 41; 87<br />
Complete response(n;%) 0; 0 3; 7 2; 4 0.19<br />
CNS progression during 1st line tx;<br />
non-CNS disease controlled(n;%)<br />
3; 7 6; 13 25; 53
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
Results: Eight patients enrolled in the phase I trial and received a<br />
median of 5 (range 1-24) cycles of therapy. All patients had received<br />
trastuzumab and a median of 5 (range 2-12) prior lines of therapy.<br />
Grade 3 diarrhea was the dose-limiting toxicity. The MTD was<br />
determined to be T at 8 mg IV weekly with neratinib at 240 mg<br />
daily. As of June 1, 2012, nineteen patients (target accrual thirty-four<br />
patients) have enrolled in the phase II trial and received a median<br />
of 2 (range 1-8) cycles of therapy. Among the 25 patients treated at<br />
the MTD (phase I n=6; phase II n=19), the most frequent treatmentrelated<br />
grade 2/3 events were diarrhea (gr 2 44%/gr 3 24%), mucositis<br />
(20%/12%), hyperglycemia (24%8%), and rash (20%/0%). Twenty<br />
patients treated at the MTD are evaluable for response; 11 patients<br />
had PR (8 confirmed PRs) and 1 had SD≥6 months for a RR of<br />
40%. Molecular analyses revealed a set of patients with more than<br />
1 mutation in the HER2-PI3K-AKT-mTOR pathway had prolonged<br />
responses to T-N therapy.<br />
Conclusions: Temsirolimus and neratinib is a tolerable regimen that<br />
has clinical activity in trastuzumab-refractory HER2+ MBC patients.<br />
The phase II study is ongoing and additional efficacy, safety, and<br />
biomarker data will be presented.<br />
P5-18-05<br />
Interim Results from a Phase 1b/2a Study of Trastuzumab<br />
Emtansine and Docetaxel, With and Without Pertuzumab, in<br />
Patients With HER2-Positive Locally Advanced or Metastatic<br />
<strong>Breast</strong> <strong>Cancer</strong><br />
Martin M, García-Sáenz JÁ, Dewar JA, Albanell J, Limentani<br />
SA, Strasak A, Patre M, Branle F, Fumoleau P. Hospital General<br />
Universitario Gregorio Marañón; Hospital <strong>San</strong> Carlos; Ninewells<br />
Hospital; Hospital del Mar; Levine <strong>Cancer</strong> Institute; F. Hoffmann-La<br />
Roche Limited; Centre Georges François Leclerc<br />
Introduction<br />
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate<br />
comprising trastuzumab, a stable linker, and DM1 (a microtubule<br />
inhibitor). In 2 randomized trials in patients (pts) with HER2-positive<br />
metastatic breast cancer (MBC), T-DM1 significantly prolonged<br />
progression-free survival (PFS) compared with standard therapy<br />
(Hurvitz, ESMO 2011; Blackwell, ASCO 2012). The combination<br />
of T-DM1 and docetaxel (D) or pertuzumab (P) has shown enhanced<br />
antitumor activity in preclinical models of HER2-positive BC (Lewis<br />
Phillips, AACR 2008; Fields, AACR 2010).<br />
Methods<br />
This phase 1b/2a dose-escalation study examines the safety,<br />
tolerability, efficacy, and pharmacokinetics (PK) of T-DM1 (starting<br />
dose 2.4 mg/kg every 3 weeks [q3w]) combined with D (starting<br />
dose 75 mg/m 2 q3w) in pts with MBC, and T-DM1 with D±P (840<br />
mg loading dose, then 420 mg q3w) in pts with newly diagnosed<br />
locally advanced BC (LABC; clinical stage IIa-IIIc). The maximum<br />
tolerated dose (MTD) for T-DM1+D is established in pts with MBC<br />
and used as the starting dose for feasibility of T-DM1+D±P (up to 6<br />
cycles) in pts with LABC. Eligibility criteria include HER2-positive<br />
MBC (locally assessed) or LABC (centrally confirmed). This interim<br />
report includes data from pts who completed at least 1 treatment<br />
cycle in phase 1b.<br />
Results<br />
During MBC feasibility, 21 pts were enrolled; median age was 47.0<br />
years (yr; range, 33–70); median number of prior lines of MBC<br />
therapy was 2 (range, 0–10). Four pts experienced 6 DLTs (Table 1).<br />
The MTD was T-DM1 3.6 mg/kg q3w + D 60 mg/m 2 q3w. Common<br />
grade (G) 3/4 adverse events (AEs): neutropenia (81%), leukopenia<br />
(52%), and thrombocytopenia (29%). ORR was 76.2% (16/21);<br />
median PFS was 11.8 months (range, 1.6–26.9). In LABC feasibility,<br />
18 pts were enrolled; median age was 49.5 yr (range, 34–74). Four<br />
pts experienced 4 DLTs (Table 2). The MTD for T-DM1+D was 3.6<br />
mg/kg q3w + 75 mg/m 2 q3w; MTD for T-DM1+D+P was 3.6 mg/kg<br />
q3w + 75 mg/m 2 q3w + 840 mg (with G-CSF primary prophylaxis).<br />
Common G3/4 AEs: T-DM1+D, neutropenia (2/9; 22%), increased<br />
alanine aminotransferase (ALT; 2/9; 22%), thrombocytopenia (TCP;<br />
1/9; 11%); T-DM1+D+P, neutropenia (5/9; 56%), TCP (2/9; 22%),<br />
increased ALT (2/9; 22%), and cytolytic hepatitis (1/9; 11%). With<br />
9 pts enrolled in the T-DM1+D LABC cohorts and 8 pts currently<br />
evaluable, pCR rate (ypT0N0) is 87.5%.<br />
Table 1. MBC Feasibility<br />
Cohort 1 (n=6) Cohort 2 (n=6) Cohort 3 (n=3) Cohort 4 (n=6)<br />
T-DM1 dose, mg/kg 2.4 (day 2) 2.4 (day 2) 2.4 (day 1) 3.6 (day 1)<br />
Docetaxel dose, mg/m 2 75 (day 1) 60 (day 1) 60 (day 1) 60 (day 1)<br />
DLTs<br />
G3 hepatitis (n=2); G3<br />
febrile neutropenia; G3 hepatitis<br />
G4 TCP<br />
None<br />
G3 increased<br />
aspartate<br />
aminotransferase<br />
Table 2. LABC Feasibility<br />
Cohort 1<br />
(n=3)<br />
Cohort 2<br />
(n=3)<br />
Cohort 3 (n=3) Cohort 4 (n=3) Cohort 5 (n=6)<br />
T-DM1 dose, mg/kg 3.6 3.6 3.6 3.6 3.6<br />
Docetaxel dose, mg/m 2 60 75 100 60 75<br />
Pertuzumab dose, mg — — — 840 840<br />
DLTs None None<br />
G4 TCP; G3<br />
G4 TCP; G4<br />
mucosal None<br />
neutropenia<br />
inflammation<br />
Conclusions<br />
Full-dose T-DM1 can be safely combined with D in pts with MBC,<br />
and with D±P in pts with LABC. G-CSF is needed with higher doses<br />
of D. Pathological assessment for all LABC patients and PK analyses<br />
will be available for the full presentation.<br />
P5-18-06<br />
Trastuzumab emtansine in HER2-positive metastatic breast<br />
cancer: pooled safety analysis from seven studies<br />
Diéras V, Harbeck N, Budd GT, Greenson JK, Guardino E, Samant<br />
M, Chernyukhin N, Smitt M, Krop IE. Institut Curie; <strong>Breast</strong> Center,<br />
University of Munich; Cleveland Clinic, Lerner College of Medicine;<br />
University of Michigan; Genentech, Inc.; Dana-Farber <strong>Cancer</strong><br />
Institute<br />
Background<br />
The antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM1)<br />
combines the antitumor activities of trastuzumab with intracellular<br />
delivery of the cytotoxic agent DM1 and represents a new approach<br />
to therapy for HER2-positive MBC. Recently, the first phase 3 data<br />
have been reported with significant improvements in PFS (9.6 vs<br />
6.4 months; HR=0.650; P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Results<br />
Among all pts (N=882), median age was 53 years (range 25–85 years);<br />
52.7% had ≥3 metastatic sites; 81.7% had received prior treatment<br />
for MBC; and the median number of prior non-endocrine agents for<br />
MBC was 3.0 (range 0–19). All-grade AEs occurring in ≥25% of<br />
patients were fatigue (45.4%), nausea (42.3%), headache (28.7%),<br />
thrombocytopenia (28.7%), and constipation (25.5%). Grade ≥3 AEs<br />
occurring in ≥2% were thrombocytopenia, increased AST, increased<br />
ALT, fatigue, hypokalemia, and anemia. Table 1 describes the grade<br />
≥3 incidence of these AEs, as well as selected AEs with known<br />
association to T-DM1 or potential risk based on the components of<br />
T-DM1 or on preclinical data.<br />
Table 1: Incidence of grade ≥3 adverse events by NCI CTCAE, v 3.0 in T-DM1-treated patients<br />
EMILIA (prior<br />
treatment with<br />
taxane,<br />
All T-DM1<br />
exposed patients<br />
(N=882)<br />
Single-arm trials<br />
(prior MBC<br />
treatment)<br />
(n=288)<br />
TDM4450g<br />
(no prior MBC<br />
treatment) (n=69)<br />
trastuzumab)<br />
(n=490)<br />
Adverse event Grade ≥3, % Grade ≥3, % Grade ≥3, % Grade ≥3, %<br />
Thrombocytopenia 10.2 7.6 7.2 12.9<br />
Increased AST 4.1 3.1 8.7 4.3<br />
Fatigue 3.2 3.8 4.3 2.4<br />
Hypokalemia 2.9 4.2 2.9 2.2<br />
Increased ALT 2.8 1.4 10.1 2.9<br />
Anemia 2.5 2.4 2.9 2.7<br />
Peripheral neuropathy 1.2 1.0 0 1.6<br />
Nausea 1.0 1.0 2.9 0.8<br />
Constipation 0.6 0.3 1.4 0.4<br />
Headache 0.6 0.3 0 0.8<br />
Epistaxis 0.5 1.0 0 0.2<br />
Cardiac dysfunction a 0.2 0.3 1.4 0<br />
Eye disorders a 0.1 0.3 0 0<br />
Nodular regenerative<br />
hyperplasia of the liver<br />
0.2 0.3 0 0.2<br />
Pneumonitis a 0.2 0.3 1.4 0<br />
Infusion-related reactions 0.1 0.3 0 0<br />
a<br />
AE basket defined based on MedDRA SMQ.<br />
Conclusions<br />
The safety profile of T-DM1 3.6 mg/kg q3w was consistent across<br />
the studies and the different patient populations with HER2-positive<br />
MBC. Additional analyses on hepatic transaminase increases and<br />
those exploring potential associations between thrombocytopenia<br />
and hemorrhage will be presented.<br />
P5-18-07<br />
Completed SN33 Trial: 60 month follow-up of Early Stage Node<br />
Positive HER2 Negative patients with NeuVax (E75) and<br />
sargramostim.<br />
Mazanet R, Schwartz MW, Ramadan D, Lavin PT. Galena Biopharma,<br />
Lake Oswego, OR; Aptiv Solutions, Southborough, MA<br />
Background: Despite recent advances in adjuvant treatment, the<br />
prognosis for HER2 negative patients has not improved. Unlike<br />
HER2 positive patients, the benefit of Herceptin has not been shown.<br />
Here we present the final 60-month results of a phase 1/I2 clinical<br />
trial vaccinating early stage node positive breast cancer patients with<br />
NeuVax (E75) and sargramostim following adjuvant chemotherapy<br />
and radiation. Previously, data reported from this trial was combined<br />
with a node negative trial that used the same treatment schema. Those<br />
reports showed the vaccine was safe, and effective at stimulating<br />
HER2-specific immunity. We report safety and efficacy (Disease Free<br />
Survival, DFS) data through 60 months. Methods: Eligible patients<br />
had excised early stage node-positive breast cancer with any level of<br />
HER2 expression. After completion of standard of care chemotherapy<br />
and radiation, patients were enrolled but not randomized: patients<br />
were assigned to the vaccine group (VG) only if they were HLA<br />
A2/A3+. The non-treated patients were followed as a control group<br />
(CG). Hormone receptor positive patients received appropriate<br />
adjuvant therapy concomitant with vaccine. The phase I/II trial was<br />
performed with phase 1 as a dose escalation/schedule optimization<br />
where VG was given 3-6 monthly inoculations of NeuVax (E75) with<br />
the immunoadjuvant, sargramostim. The phase 2 portion utilized<br />
the optimal dose and schedule carried forward. Herceptin became<br />
commercially available during the conduct of the trial, and HER2<br />
positive patients were offered this treatment but remained on trial.<br />
DFS was summarized by Kaplan-Meier lifetables and analyzed<br />
by the log-rank test. Due to waning immunity after the scheduled<br />
monthly vaccinations, a voluntary booster program was initiated to<br />
be integrated into the trial process. Results: 97 patients were enrolled;<br />
53 in the VG and 44 in the CG. The VG and CG were well-matched<br />
with the only difference being trastuzumab therapy (18.5% in VG<br />
vs. 4.8% in CG, p=0.03). There were no HER2 0 patients in the VG.<br />
Vaccination was well tolerated with primarily grade 1 and grade 2<br />
toxicity. No VG patients relapsed during the vaccination period. ITT<br />
patients in this phase 1/2 trial favored VG in DFS at 24 months (VG<br />
90.6%, CG 79.5%, p=0.1194); at 60 months, the VG continues to have<br />
fewer recurrences than the CG (VG 84.5% vs. 77.1%, p=0.3046).<br />
In the patients who were treated at the optimum (Phase 2) dose, the<br />
difference in the DFS at 24 months observed was (VG 96.2%, CG<br />
79.5%, p=0.0597); at 60 months, the VG continues to have fewer<br />
recurrences than the CG (92.3% vs. 77.1%). When the HER2 positive<br />
patients were removed from the population, the Phase 2 HER2<br />
Negative VG had a significantly improved DFS at 24 months (100%<br />
vs. 80.6%, p=0.045); at 60 months, VG retains a 17% difference (VG<br />
94.7% vs. CG 77.4%). Conclusions: NeuVax (E75) and sargramostim<br />
vaccine is safe and well–tolerated in early stage breast cancer patients.<br />
With follow-up at 60 months, the vaccine used as adjuvant therapy<br />
continues to reduce relapses in node positive HER2 negative patients<br />
treated at an optimal dose. A phase 3 multicenter, multinational<br />
double-blind trial is underway.<br />
P5-18-08<br />
Identification of ErbB2 function in the heart: implication for<br />
anti-ErbB2 therapy in breast cancer<br />
Perry M-C, Eichner LJ, Dufour CR, Muller WJ, Giguère V. Rosalind<br />
and Morris Goodman <strong>Cancer</strong> Research Centre, McGill University,<br />
Montréal, QC, Canada; McGill University, Montréal, QC, Canada<br />
The ErbB2 receptor tyrosine kinase is essential for cardiac<br />
development during embryogenesis. The importance of its signaling in<br />
the adult heart was revealed by an unexpected cardiotoxic side effect<br />
of trastuzumab, a monoclonal antibody against ErbB2 used in the<br />
treatment of breast cancer. Considering that trastuzumab-associated<br />
cardiotoxicity is usually largely reversible, we hypothesized that<br />
ErbB2 signaling in the heart is important to maintain cardiac<br />
homeostasis.<br />
As genetic experiments showed that ErbB2-deficient embryos die at<br />
mid-gestation, whereas conditional inactivation of ErbB2 in the heart<br />
leads to early and severe cardiac dysfunction, the role of ErbB2 in<br />
the mature heart can not be analyzed in those animal models. Thus,<br />
we chose an ErbB2 hypomorph (HP) mouse model in which ErbB2<br />
is expressed at only 10% of its endogenous level to study the role<br />
of ErbB2 in the adult heart. Histopathological analyses of the heart<br />
in this model revealed that at birth, the ErbB2 HP mice have similar<br />
heart mass and cardiomyocite size as the control animals. However,<br />
we found that the rapid growth of the heart during early postnatal<br />
development is impaired in ErbB2 HP mice, indicating that the heart<br />
is unable to increase cell size in order to adapt to the pressure overload<br />
that mice face following birth. This incapacity of the ErbB2 HP heart<br />
to maintain homeostasis eventually leads to the development of<br />
cardiac dysfunction in this model, as characterized by a decrease of<br />
the left ventricular function. Microarray and ChIP-seq analyses were<br />
applied to identify the ErbB2-responsive pathways which may explain<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
468s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
the phenotype observed. Taken together, our results demonstrate that<br />
ErbB2 signaling is required for the physiological adaptive response<br />
of the mature heart to pressure burden. The results generated by this<br />
study reveal the biological function of Erbb2 in the adult heart, but<br />
also provide important information for devising strategies to prevent<br />
and mitigate the cardiotoxic effects of Trastuzumab treatment,<br />
allowing for the potential use of this drug to treat all cancer patients<br />
overexpressing ErbB2.<br />
P5-18-09<br />
A Phase I Study of MM-302, a HER2-targeted Liposomal<br />
Doxorubicin, in Patients with Advanced, HER@- Positive <strong>Breast</strong><br />
<strong>Cancer</strong><br />
Wickham T, Futch K. Merrimack Pharmmaceuticals; Merrimack<br />
Pharmaceuticals<br />
Background: Anthracyclines have been an effective backbone of<br />
breast cancer therapies for decades. However, cardiotoxicity issues<br />
associated with free anthracyclines have limited their effective<br />
use. While liposomal doxorubicin formulations have succeeded in<br />
reducing cardiotoxicity, they have failed to demonstrate clear-cut<br />
efficacy advantages. To address these safety and efficacy limitations,<br />
we have designed a pegylated liposomal doxorubicin formulation,<br />
MM-302, with anti-HER2 antibody fragments coupled to its surface.<br />
MM-302 specifically targets tumor cells overexpressing HER2 with<br />
minimal uptake into normal cells such as cardiomyocytes which<br />
express low levels of HER2. This first-in-human Phase 1 study<br />
evaluates the safety of MM-302 in patients with HER2+ advanced<br />
breast cancer (ABC). Methods: Patients aged > 18 years with<br />
histologically confirmed HER2+ advanced breast cancer that have<br />
progressed or recurred on standard therapy or for which no standard<br />
therapy exists who have adequate performance status, bone marrow<br />
reserve, and organ function, were eligible for the study. A standard 3 +<br />
3 dose escalation design is used to determine the maximum tolerated<br />
dose (MTD) followed by expansion arms to evaluate activity. The<br />
primary endpoint is determination of the MTD. Secondary endpoints<br />
included determination of dose-limiting toxicity, adverse event(s),<br />
and pharmacokinetic and immunogenicity profiles of MM-302, as<br />
well as overall response and clinical benefit rates of MM-302. MM-<br />
302 is administered intravenously weekly in 4-week cycles. Results:<br />
We report current findings containing data from four cohorts (8, 16,<br />
30 and 40 mg/m2 Q4W). 14 patients have been enrolled in these<br />
cohorts; median age 55 (range 34-65), median cycles 2 (range 1-6).<br />
The most frequent AEs were constipation (53.8%), Fatigue (69.2%)<br />
and decreased appetite (46.2%). Five patients have achieved SD and<br />
one patient has achieved a PR. A pharmacokinetic analysis indicates<br />
a half-life of approximately 50 hours. Conclusions: To date, results<br />
suggest that single agent MM-302 administered to patients with ABC<br />
is tolerable, without cardiotoxicity, in patients up to 40 mg/m2 Q4W.<br />
Updated data on additional dosing cohorts and expansion arms will<br />
be presented.<br />
P5-18-10<br />
Chemotherapy can enhance trastuzumab-mediated ADCC<br />
Tagliabue E, Sfondrini L, Regondi V, Casalini P, Pupa SM, Sommariva<br />
M, Balsari A, Triulzi T. Fondazione IRCCS Istituto Nazionale dei<br />
Tumori; Università degli Studi di Milano<br />
Trastuzumab, a recombinant humanized monoclonal antibody<br />
directed to the HER2 protein, has shown survival benefits in<br />
women with HER2-positive breast cancer, and treatment is now<br />
FDA-approved in combination with chemotherapy. However, some<br />
patients do not respond clinically to trastuzumab, pointing to the need<br />
for further definition of trastuzumab killing activity on tumor cells<br />
to optimize this therapy. Recent clinical data indicate a synergistic<br />
therapeutic effect between trastuzumab and taxanes in HER2-positive<br />
breast cancer patients, but the mechanism(s) underlying this synergy<br />
remains unclear. Because drug-stressed cells can dynamically<br />
regulate factors that favor activity of immune effector cells, and<br />
because trastuzumab-mediated ADCC is crucially dependent on<br />
NK cell activity, we hypothesize that this synergy reflects enhanced<br />
trastuzumab-mediated ADCC on tumor cells due to improved rather<br />
than impaired participation of immune effectors resulting from druginduced<br />
stress. To test this hypothesis, we investigated the effect of<br />
chemotherapy in HER2-positive breast carcinoma models on NK<br />
receptor ligands and correlated the changes in these molecules with<br />
the ability of trastuzumab to mediate ADCC.<br />
Flow cytometry revealed a 4-fold upmodulated surface expression of<br />
NKG2D (MICA, MICB, ULBP1, ULBP2) and DNAM-1 (CD112 and<br />
CD155) ligands in HER2-positive breast carcinoma cell lines BT474<br />
and MDA-MB-361 treated for 6 hr with taxotere at a 72-hr IC 50 dose,<br />
consistent with results of Western blot analysis using soluble lysates<br />
obtained from chemotherapy-treated HER2-positive breast carcinoma<br />
xenografts. The enhanced expression of NKG2D and DNAM-1<br />
ligands in breast carcinoma cells was accompanied by about a 50%<br />
increase in trastuzumab-mediated in vitro ADCC in chemotherapytreated<br />
versus untreated cells. Antibodies blocking NKG2D and<br />
DNAM-1, but not control monoclonal antibody, abolished the<br />
chemotherapy-induced increase of in vitro trastuzumab-dependent<br />
ADCC. Increased expression of NK ligands in taxotere-treated BT474<br />
cells was associated with cytoskeletal damage assessed by confocal<br />
microscopy; at 72 hr after chemotherapy, NK ligands returned to<br />
basal levels, pointing to the importance of duration of NK ligand<br />
enhancement for the chemotherapy-induced trastuzumab-mediated<br />
ADCC.<br />
Together, our results indicate that chemotherapy can modulate<br />
expression levels of NK-activating ligands on human breast carcinoma<br />
cells in correlation with trastuzumab-mediated ADCC, raising the<br />
possibility of identifying optimal chemotherapy administration<br />
schedules to maximize activity of trastuzumab-mediated ADCC<br />
effectors. (Partially supported by AIRC)<br />
P5-18-11<br />
Pharmacokinetics and exposure-efficacy relationship of<br />
trastuzumab emtansine in EMILIA, a phase 3 study of<br />
trastuzumab emtansine vs capecitabine and lapatinib in HER2-<br />
positive locally advanced or metastatic breast cancer<br />
Wang B, Jin J, Wada R, Fang L, Saad O, Olsen S, Althaus B, Swain<br />
S, Untch M, Girish S. Genentech, Inc.; Quantitative Solutions;<br />
Washington Hospital Center; HELIOS Hospital Berlin-Buch<br />
Background<br />
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate<br />
composed of trastuzumab (T), the cytotoxic agent DM1, and a<br />
stable thioether linker; it is being evaluated for the treatment (tx) of<br />
HER2-positive cancer. EMILIA is a randomized, multicenter, openlabel<br />
phase 3 study assessing the efficacy and safety of T-DM1 vs<br />
capecitabine (X) and lapatinib (L) in pts with HER2-positive locally<br />
advanced or metastatic breast cancer (MBC) previously treated with<br />
T and a taxane. We report the pharmacokinetics (PK) of T-DM1 in<br />
EMILIA and compare these data with historical data of single-agent<br />
T-DM1. The effects of T-DM1 exposure on efficacy outcomes in<br />
EMILIA are also reported.<br />
www.aacrjournals.org 469s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Methods<br />
In EMILIA, pts were randomized 1:1 to receive T-DM1 3.6 mg/kg<br />
q3w (n=495) or X + L (n=496) in 21-day cycles. At least 1 PK sample<br />
was collected from 350 pts in the T-DM1 arm; 307 of these had<br />
adequate PK profiles for the estimation of ≥1 PK parameter in cycle<br />
1. PK parameters were estimated by noncompartmental analysis for<br />
serum T-DM1, serum total T (conjugated and unconjugated T), and<br />
plasma DM1. A logistic regression model was used to evaluate the<br />
relationship between T-DM1 exposure (ie, T-DM1 AUC and DM1<br />
C max ) and objective response rates (ORR). Analyses of progressionfree<br />
survival (PFS) and overall survival (OS), stratified by T-DM1<br />
exposure, were conducted. Cox regression was used to evaluate the<br />
effect of T-DM1 exposure and other potential covariates on PFS<br />
and OS.<br />
Results<br />
The PK parameters for T-DM1, total T, and DM1 in EMILIA and<br />
other studies of single-agent T-DM1 are summarized in Table 1.<br />
The PK parameters appear similar regardless of prior tx for MBC.<br />
No significant differences in mean serum T-DM1 AUC (P=0.091)<br />
or plasma DM1 C max (P=0.812) were observed between responders<br />
and non-responders following T-DM1 tx. Furthermore, variability in<br />
T-DM1 AUC and DM1 C max does not appear to affect the probability<br />
of response to therapy (P=0.23 for T-DM1 AUC and P=0.74 for DM1<br />
C max ). Based on Cox proportional hazards analysis, no significant<br />
exposure-efficacy relationship was observed between T-DM1 AUC<br />
(P=0.23 for PFS and P=0.53 for OS) or DM1 C max (P=0.96 for PFS<br />
and P=0.34 for OS) and PFS or OS, respectively.<br />
Table 1. PK parameters of single-agent T-DM1<br />
T-DM1 T-DM1 T-DM1 T-DM1 T-DM1 Total T DM1<br />
Mean (SD)<br />
AUC ,<br />
Study<br />
inf<br />
CL, mL/<br />
C max , µg/mL day •µg/ t ½ , day V ss , mL/kg<br />
day/kg<br />
mL<br />
C max , µg/mL C max , ng/mL<br />
EMILIA (n=307) 83.4 (16.5) 489 (122) 3.68 (0.886) 29.5 (14.6) 7.81 (2.18) 86.3 (20.1) 4.61 (1.61)<br />
TDM4450g (no prior<br />
MBC tx) (n=64)<br />
84.9 (30.6) 476 (119) 3.58 (0.666) 30.0 (8.21) 8.09 (2.50) 81.5 (20.6) 5.08 (2.41)<br />
TDM4258g (prior T for<br />
MBC) (n=101)<br />
80.9 (20.7) 457 (129) 3.53 (0.714) 28.4 (12.9) 8.51 (2.69) 88.0 (30.2) 5.35 (2.03)<br />
TDM4374g (prior T and<br />
L for MBC) (n=105)<br />
79.5 (21.1) 486 (141) 3.96 (0.964) 31.2 (10.9) 8.04 (2.97) 89.9 (31.3) 5.36 (2.56)<br />
Conclusions<br />
T-DM1 PK data in EMILIA pts were similar to those observed in<br />
previous phase 2 studies, which include pts who have and have not<br />
received prior therapy for MBC. Variation in T-DM1 exposure among<br />
pts who received T-DM1 3.6 mg/kg q3w had no significant impact on<br />
ORR, PFS, or OS. Detailed analyses will be presented.<br />
P5-18-12<br />
Comparison of treatment patterns and outcomes in metastatic<br />
breast cancer patients initiated on trastuzumab vs. lapatinib; a<br />
retrospective analysis<br />
Gauthier G, Guérin A, Styles AL, Wu EQ, Masaquel A, Brammer<br />
MG, Lalla D. Analysis Group Inc., Boston, MA; Genentech, Inc.,<br />
South <strong>San</strong> Francisco, CA<br />
Background: Trastuzumab-or lapatinib-based therapies are<br />
recommended by the National Comprehensive <strong>Cancer</strong> Network<br />
(NCCN) guidelines as preferred agents for metastatic HER2-positive<br />
breast cancer. Few studies have compared treatment patterns,<br />
healthcare resource utilization (HRU), and costs in metastatic breast<br />
cancer (MBC) patients receiving trastuzumab vs. lapatinib. The<br />
objective of this study was to compare discontinuation rates, HRU,<br />
and costs in MBC patients (pts) initiated on trastuzumab vs. lapatinib.<br />
Methods: MBC adult women initiated on trastuzumab or lapatinib on/<br />
after 03/13/2007 (lapatinib FDA-approval date) were selected from the<br />
US-based PharMetrics® Integrated Database (2000-2011). Selected<br />
pts were required to be continuously eligible in their healthcare plan<br />
≥6 months prior to and ≥30 days following trastuzumab or lapatinib<br />
initiation date. Pts were observed over the period spanning from<br />
trastuzumab or lapatinib initiation date (without restriction on line<br />
of therapy) up to the end of continuous health plan enrollment or<br />
data availability, whichever occurred first. Trastuzumab or lapatinib<br />
discontinuation rates (gap ≥45 consecutive days) were compared<br />
using multivariate Cox proportional-hazards models and reported<br />
as hazard ratios (HRs). Incremental HRU was estimated using<br />
negative binomial regression models and reported as incidence rate<br />
ratios (IRRs). Monthly cost difference (2010 USD; measured from<br />
a payer perspective) were estimated using multivariate generalized<br />
linear or two-part models. Since a large proportion of lapatinib users<br />
were previously treated with trastuzumab, a sensitivity analysis was<br />
conducted to control for the impact of prior trastuzumab use.<br />
Results: Among the 643 pts selected, 381 and 262 pts were initiated<br />
on trastuzumab and lapatinib, respectively. Of the 262 pts initiated<br />
on lapatinib, 171 (65%) were previously treated with trastuzumab.<br />
After adjustment for confounders (demographics, index year, prior<br />
MBC therapies, comorbidities, baseline HRU, and MBC duration),<br />
compared to trastuzumab users, lapatinib users had a higher rate of<br />
treatment discontinuation (HR=1.57; p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
(n=10), capecitabine (n=8), T-DM1 (n=6), and pertuzumab (n=1).<br />
Therapy was well tolerated; no treatment related grade 4 toxicities<br />
were observed. Myelosuppression was limited to one pt with Grade<br />
2 anemia and one each with Grade 2/3 thrombocytopenia. MTD was<br />
not reached. There were no objective responses; 2 pts. in cohort 3<br />
had SD. Serial tumor biopsies and bone marrow aspirates have been<br />
analyzed for 7 pts (cohort 1: 001-004; cohort 2: 005-007; cohort 3:<br />
analysis ongoing). Tumor hTERT (p=ns) and phosphorylated HER2<br />
(p=0.03) decreased after treatment in nearly all pts. Bone marrow<br />
S-phase did not change consistently with treatment.<br />
Relative pHER2<br />
Relative hTERT<br />
Patient Baseline Pre-cycle 2 Baseline Pre-cycle 2<br />
001 0.109 0.089 0.380 0.867<br />
002* 0 0 0.924 0<br />
003 0.302 0.131 0.574 0.366<br />
004 0.290 0,158 0.224 0.014<br />
005 1.709 0.418 0.806 0.583<br />
006 0.890 0.244 1.017 0.314<br />
007 0.945 0.388 0.253 0.191<br />
*Her2+ at diagnosis but baseline sample at study entry HER2-.<br />
Conclusion: The combination of trastuzumab + imetelstat is well<br />
tolerated and results in decreases in HER2 phosphorylation similar<br />
to that seen in preclinical models. Additional biologic correlates and<br />
PK analyses are ongoing. Further study of this combination in less<br />
heavily pre-treated patients is planned.<br />
P5-18-14<br />
Cardiac monitoring during adjuvant trastuzumab therapy for<br />
breast cancer<br />
Ng D, Ferrusi I, Khong H, Earle C, Trudeau M, Marshall D, Leighl N.<br />
University of Toronto, ON, Canada; McMaster University, Hamilton,<br />
ON, Canada; University of Calgary, AB, Canada; Ontario Institute<br />
for <strong>Cancer</strong> Research, Toronto, ON, Canada<br />
Background: Adjuvant trastuzumab improves survival in HER2+<br />
breast cancer. Cardiac toxicity is an important potential side effect.<br />
We report real world practice patterns in cardiac monitoring and<br />
outcomes during adjuvant trastuzumab therapy in Ontario. Methods:<br />
A cohort of female patients diagnosed with early breast cancer from<br />
Jan 1, 2006 to Dec 31, 2007 and who received trastuzumab was<br />
identified retrospectively through linkage of provincial administrative<br />
and registry databases. Demographic, pathology, treatment, hospital<br />
admissions, claims for cardiac tests (MUGA or echo), and outcomes<br />
were extracted for individuals. Pre-existing cardiac disease (CHF,<br />
MI, angina, valve disorder, arrhythmia, cardiomyopathy) and risk<br />
factors (diabetes, lipid disorder, hypertension) were classified using<br />
ICD-10 codes. Appropriate cardiac monitoring definitions were<br />
based on published trials and expert opinion. Symptomatic cardiac<br />
toxicity was defined as a physician claim or hospital admission with<br />
a cardiac diagnosis occurring within 2 years of the first trastuzumab<br />
dose. Asymptomatic cardiac toxicity was defined as temporary or<br />
permanent cessation of trastuzumab with additional cardiac tests.<br />
Patients were categorized into treatment groups: G1 received at<br />
least 17 doses (standard 3-weekly administration for 51 weeks)<br />
with no complications; G2 stopped early for non-cardiac reasons<br />
(no additional cardiac tests); G3 had symptomatic or asymptomatic<br />
cardiac toxicity. Analyses of patient, treatment and system factors<br />
possibly affecting cardiac monitoring and toxicity were performed.<br />
Results: 1,357 patients diagnosed with early breast cancer between<br />
2006-7 received trastuzumab (median=18 doses). 77% received<br />
anthracyclines; 4.1% had at least 1 cardiac risk factor. The majority<br />
(91%) had a baseline cardiac test, including 96% of those with<br />
cardiac risks. Geographic region was associated with baseline testing,<br />
but multivariable analysis of other factors including urbanicity,<br />
left lateral radiation, age, income, and anthracycline use, did not<br />
explain the variation in baseline testing patterns. The majority,<br />
81%, had ≥3 cardiac tests, 62.2% had ≥4. Cardiac monitoring was<br />
deemed appropriate in 80.7% of patients without cardiac events, and<br />
73.4% in those with symptomatic or asymptomatic cardiac events.<br />
Multivariable analysis revealed duration of trastuzumab to be the<br />
most significant factor associated with appropriateness of cardiac<br />
monitoring (G1 - OR 0.62, p=0.018, 95% CI 0.45-0.92; G3 - OR<br />
4.56, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-18-16<br />
A Multicenter Phase 2 Study (JO22997) Evaluating the Efficacy<br />
and Safety of Trastuzumab Emtansine in Japanese Patients With<br />
Heavily Pretreated HER2-Positive Metastatic <strong>Breast</strong> <strong>Cancer</strong><br />
Masuda N, Ito Y, Takao S, Doihara H, Rai Y, Horiguchi J, Kohno<br />
N, Fujiwara Y, Tokuda Y, Watanabe J, Iwata H, Ishiguro H, Miyoshi<br />
Y, Matsubara M, Kashiwaba M. NHO Osaka National Hospital,<br />
Osaka, Japan; The <strong>Cancer</strong> Institute Hospital of JFCR, Tokyo, Japan;<br />
Hyogo <strong>Cancer</strong> Center, Akashi, Japan; Okayama University Hospital,<br />
Okayama, Japan; Sagara Hospital, Kagoshima, Japan; Gunma<br />
University, Maebashi, Japan; Tokyo Medical University, Tokyo,<br />
Japan; National <strong>Cancer</strong> Center Central Hospital, Tokyo, Japan;<br />
Tokai University, Isehara, Japan; Shizuoka <strong>Cancer</strong> Center, Sunto-gun,<br />
Japan; Aichi <strong>Cancer</strong> Center, Nagoya, Japan; Kyoto University, Kyoto,<br />
Japan; Hyogo College of Medicine, Nishinomiya, Japan; Chugai<br />
Pharmaceutical Co.,Ltd., Tokyo, Japan; Iwate Medical University,<br />
Morioka, Japan<br />
Background: Trastuzumab emtansine (T-DM1) is an anti-human<br />
epidermal growth factor receptor 2 (HER2) antibody-drug conjugate<br />
in development for the treatment of HER2-positive recurrent, locally<br />
advanced or metastatic breast cancer (MBC). T-DM1 comprises<br />
trastuzumab, DM1—a microtubule inhibitory cytotoxic agent derived<br />
from maytansine—and the stable linker ([N-maleimidomethyl]<br />
cyclohexane-1-carboxylate) that conjugates DM1 and trastuzumab. A<br />
phase 1 study in Japanese patients determined a maximum tolerated<br />
dose for T-DM1 of 3.6 mg/kg every 3 weeks (q3w), which was<br />
identical to that reported in Western populations (TDM3569g). Singleagent<br />
T-DM1 has demonstrated robust clinical efficacy in Western<br />
phase 2 and phase 3 clinical studies (TDM4258g, TDM4374g and<br />
EMILIA). Since the efficacy of T-DM1 in Japanese patients has not<br />
previously been investigated, this study examined the efficacy and<br />
safety of T-DM1 in Japanese patients with pretreated HER2-positive<br />
MBC.<br />
Methods: JO22997 is a phase 2, multicenter, single arm clinical<br />
study assessing the efficacy and safety of single-agent T-DM1<br />
given at 3.6 mg/kg q3w to patients with HER2-positive MBC. Key<br />
eligibility criteria were prior treatment with trastuzumab and at least<br />
1 chemotherapy, ECOG performance status (PS) of ≤2, and adequate<br />
organ function. Patients were required to have target lesions according<br />
to the guidelines of the Response Evaluation Criteria In Solid Tumors,<br />
v1.1. The primary objective of the study was to assess the objective<br />
response rate (ORR) by independent review committee (IRC);<br />
secondary objectives were progression-free survival (PFS), safety,<br />
and to obtain pharmacokinetic data in Japanese patients.<br />
Results: 73 patients received T-DM1. Median age was 58 years<br />
(range, 36–82 years); 61 (83.6%), 10 (13.7%), and 2 (2.7%) patients<br />
had ECOG PS of 0, 1, and 2, respectively; 39 (53.4%) patients had<br />
tumors that were estrogen receptor– and/or progesterone receptor–<br />
positive. The median number of prior chemotherapy regimens for<br />
MBC was 3 (range, 1–8) including lapatinib in 43 (58.9%) patients.<br />
Median duration of treatment with T-DM1 was 23.1 weeks (range,<br />
0.1–63.3 weeks). The ORR by IRC was 38.4% (90% confidence<br />
interval [CI], 28.8%–48.6%; partial response only), and clinical<br />
benefit rate (partial response + stable disease ≥24 weeks) was 45.2%<br />
(95% CI, 33.5%–57.3%). Median PFS by IRC was 5.6 months<br />
(95% CI, 4.6–8.2 months). The most frequently observed grade ≥3<br />
adverse events were thrombocytopenia (21.9%), increased aspartate<br />
aminotransferase (13.7%), increased alanine aminotransferase (8.2%)<br />
and vomiting (5.5%). One patient (1.4%) discontinued treatment due<br />
to thrombocytopenia. No patient received platelet transfusion. Grade<br />
3/4 hemorrhage was observed in one patient (1.4%). PK parameters<br />
for T-DM1 and its metabolites were consistent with previous phase<br />
I results.<br />
Conclusion: Single-agent T-DM1 has promising activity in Japanese<br />
patients with previously treated HER2-positive MBC and was well<br />
tolerated. Although the incidence of grade 3/4 thrombocytopenia<br />
tends to be higher than in Western studies, this was not associated<br />
with clinically important manifestations. (JapicCTI-101277)<br />
P5-18-17<br />
Impact of compliance with National Comprehensive <strong>Cancer</strong><br />
Network guidelines on adjuvant trastuzumab administration for<br />
patients with HER2-positive breast cancer.<br />
Mullins DN, Maly J, Abdel-Rasoul M, Shapiro CL, Olson EM.<br />
Comprehensive <strong>Cancer</strong> Center, The Ohio State University Wexner<br />
Medical Center, Arthur G. James <strong>Cancer</strong> Hospital and Richard J.<br />
Solove Research Institute, Columbus, OH; The Ohio State University<br />
Wexner Medical Center, Columbus, OH; The Ohio State University,<br />
Columbus, OH<br />
Background:<br />
The National Comprehensive <strong>Cancer</strong> Network (NCCN) breast cancer<br />
guidelines recommend trastuzumab as a component of adjuvant<br />
therapy for patients with stage I-III HER2-positive breast cancer.<br />
Reasons for noncompliance with adjuvant trastuzumab therapy and<br />
the impact of noncompliance with national guidelines are unknown.<br />
Methods:<br />
We retrospectively identified 331 patients with stage I-III HER2<br />
-positive breast cancer treated at the Ohio State University James<br />
<strong>Cancer</strong> Hospital 2005-2011 who were eligible for adjuvant<br />
trastuzumab. Medical records were reviewed to obtain age at<br />
diagnosis, race, co-morbidity score, stage, hormone positivity, type<br />
of therapy administered, date of disease recurrence, vital status and<br />
date of last follow up. Available clinician-documented reasons for not<br />
administering adjuvant trastuzumab were also recorded. Multivariate<br />
logistic regression modeling was used to examine the effect of these<br />
variables on completion of 1 year of adjuvant trastuzumab. Cox<br />
regression modeling was used to estimate the effect of completing 1<br />
year of trastuzumab on disease-free and overall survival, respectively.<br />
Results:<br />
Median follow up was 39.9 months (range 12.0-85.1). Of the 331<br />
patients, the majority of (289; 87%) received at least 1 dose of<br />
trastuzumab while 251 (76%) patients completed the recommended 1<br />
year of trastuzumab therapy. In multivariate modeling, age ≥ 70 years<br />
(Odds Ratio 0.18, 95% CI 0.07 to 0.47; p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
Conclusion:<br />
Age ≥ 70 years and stage I disease are predictors of noncompliance<br />
with NCCN guidelines recommending administration of adjuvant<br />
trastuzumab therapy for one year. Failure to complete one year<br />
of adjuvant trastuzumab is significantly associated with disease<br />
recurrence and worse overall survival in patients with stage I-III<br />
HER2-amplified breast cancer.<br />
P5-18-18<br />
Lapatinib versus trastuzumab, or both, added to preoperative<br />
chemotherapy for breast cancer: A meta-analysis of randomized<br />
evidence<br />
Valachis A, Nearchou A, Lind P. University of Uppsala, Sweden;<br />
Mälarsjukhuset, Eskilstuna, Sweden; Karolinska Institute, Stockholm,<br />
Sweden<br />
Purpose: We compared the efficacy and safety of the addition of<br />
lapatinib versus trastuzumab, or the combination, to neoadjuvant<br />
chemotherapy in HER2-positive breast cancer.<br />
Methods: Potentially eligible trials were identified through PubMed<br />
and Cochrane Library searches and abstracts of major international<br />
conferences. The endpoints that we assessed were pathologic<br />
complete response (pCR) rate and toxicity. Pooled relative risks<br />
(RR) were estimated for each endpoint with fixed or random effects<br />
models, depending on between-studies heterogeneity.<br />
Results: Six trials were identified with 1494 eligible patients. The<br />
probability to achieve pCR was higher for the trastuzumab plus<br />
chemotherapy arm than lapatinib plus chemotherapy (RR 1.25, 95%<br />
Confidence Interval (CI): 1.08-1.43; p-value = 0.003) (6 trials; 1494<br />
patients). Furthermore, the probability for pCR was significantly<br />
higher in the group given both lapatinib and trastuzumab than in<br />
the group given trastuzumab alone (RR 1.39, 95% CI: 1.20-1.63;<br />
p-value < 0.001) (4 trials; 779 patients). Diarrhea and dermatologic<br />
toxicities were statistically more frequent in patients receiving<br />
lapatinib than trastuzumab. The combination was associated with a<br />
higher rate of diarrhea than trastuzumab alone. No differences were<br />
observed regarding cardiac adverse events among patients receiving<br />
trastuzumab, lapatinib, or the combination.<br />
Conclusion: These data support the superiority of a dual-HER2<br />
inhibition for the treatment of HER2-positive breast cancer in the<br />
neoadjuvant setting. The direct comparison of trastuzumab and<br />
lapatinib demonstrated that lapatinib is inferior in terms of pCR and<br />
toxicity.<br />
P5-18-19<br />
The 2006 Adjuvant Trastuzumab Convention in Belgium: 5<br />
years later<br />
Vanderhaegen J, Paridaens R, Piccart M, Lalami Y, Machiels J-P,<br />
Louis E, Borms M, Mebis J, Dirix L, Lintermans A, Brouckaert O,<br />
Neven P. University Hospital Leuven, Belgium; University Hospital<br />
Leuven/Catholic University Leuven, Belgium; Institut Jules Bordet,<br />
Brussels, Belgium; Cliniques Universitaires St-Luc, Brussels,<br />
Belgium; CHU de Liège, Liege, Belgium; AZ Groeninge, Kortrijk,<br />
Belgium; Limburgs Oncologisch Centrum, Limburg, Belgium; St<br />
Augustinus Hospital, Wilrijk, Belgium<br />
Background: Outside clinical trials, long term follow-up data from<br />
large series of women treated with adjuvant trastuzumab are lacking.<br />
We here report such data from a Belgian cohort for premature<br />
trastuzumab discontinuation and 5 year outcome.<br />
Patients and Methods: A year prior to its reimbursement (June 1 st<br />
2007), the Belgian health authorities offered adjuvant trastuzumab<br />
to women with a HER-2 amplified breast cancer as given in HERA:<br />
following completion of loco-regional therapy, at least 4 cycles<br />
of chemotherapy (CT) (neo-adjuvant or adjuvant) or radiotherapy<br />
whichever was last. Demographics, histopathologic features, baseline<br />
(≥55%) and follow-up left ventricular ejection fraction (LVEF)<br />
together with 5 yr breast cancer related events (BCRE) were centrally<br />
recorded. Outcome was reported by grade (< or > grade 3), lymph<br />
node (pN) status (neg/pos), hormone receptor (HR) status (neg/pos)<br />
and timing of CT (adjuvant/neo-adjuvant).<br />
Results: 917 pts were included. Files on histopathology, demographics,<br />
LVEF and therapy are available for 887 (97%) pts, outcome for<br />
738 (80%). Median age at diagnosis was 53 years (25-81); 56%<br />
of tumors were >pT1, 57% pN+, 72% grade 3, 59% HR-positive<br />
for estrogen receptor (ER) and/or progesterone receptor (PR). CT<br />
was neo-adjuvant in 20% and adjuvant in 80%. Radiotherapy and<br />
endocrine therapy were given respectively in 86% and 50%. Median<br />
follow-up was 63 (range 8-90) months. Premature (
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-18-20<br />
Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel<br />
in patients with metastatic HER2-overexpressing metastatic<br />
breast cancer.<br />
Datko F, D’Andrea G, Dickler M, Theodoulou M, Goldfarb S, Lake<br />
D, Fornier M, Modi S, Sklarin N, Comen E, Fasano J, Gajria D,<br />
Drullinsky P, Gilewski T, Murphy C, Syldor A, Lau A, Hamilton N,<br />
Patil S, Liu J, Chandarlapaty S, Hudis C, Dang C. Memorial Sloan-<br />
Kettering <strong>Cancer</strong> Center, New York, NY; Bon Secours Hospital,<br />
Cork, Ireland<br />
Background: Pertuzumab (P) is a monoclonal antibody which binds<br />
to extracellular domain II of HER2 distally from trastuzumab (H),<br />
disrupting HER2 dimerization and signaling. The CLEOPATRA<br />
phase III trial showed that HP + docetaxel in HER2+ metastatic breast<br />
cancer (MBC) prolonged progression-free survival (PFS) compared<br />
to placebo + H + docetaxel. We report preliminary results of a phase<br />
II study to evaluate the safety and efficacy of weekly paclitaxel with<br />
HP (THP).<br />
Methods: Patients (pts) with HER2+ MBC with 0-1 prior treatment<br />
(Rx) are eligible. Pts receive weekly (w) paclitaxel (80mg/m 2 ), q3w<br />
trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab<br />
(flat loading dose 840mg → flat dose 420mg). The primary endpoint is<br />
PFS at 6 months (mo). Secondary endpoints include response, safety<br />
(including cardiac events), and tolerability. Evaluable pts are those<br />
who have started study Rx and are assessed at 6 mo for PFS. Left<br />
ventricular ejection fraction (LVEF) is monitored by echocardiogram<br />
every 3 mo. Cardiac events are defined as symptomatic LV systolic<br />
dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac<br />
death.<br />
Results: As of 6-1-12, 38 of the planned 69 pts were enrolled and<br />
20 pts were evaluable at 6 mo. Median age is 52 years (range 32 to<br />
72). A total of 11 pts (55%) previously received trastuzumab in the<br />
adjuvant or metastatic setting, and 8 pts (40%) were being treated<br />
in the second-line metastatic setting. Of the 20 evaluable pts, G 3/4<br />
toxicities were sepsis (1 pt, 5%), cholecystitis (1 pt, 5%), fatigue (1<br />
pt, 5%), skin ulceration (1 pt, 5%) and cystic macular degeneration<br />
(1 pt with prior prolonged Rx with paclitaxel, 5%). Common G 1/2<br />
toxicities included alopecia (20 pts, 100%), peripheral neuropathy<br />
(20 pts, 100%), fatigue (18 pts, 90%), ALT/AST elevation (17 pts,<br />
85%), diarrhea (15 pts, 75%), rash (13 pts, 65%), nail changes (10<br />
pts, 50%), mucositis (9 pts, 45%), dry skin (8 pts, 40%), and nausea<br />
(8 pts, 40%). Median LVEF was 64% at baseline (range 50% to 69%),<br />
60% at 3mo (range 50% to 73%), and 60% at 6mo (range 49% to<br />
67%). There were no cardiac events. At 6 mo, 15/20 pts (75%) were<br />
progression-free (2 CR, 8 PR and 5 SD); 5 pts had progressed. The 6<br />
mo PFS results for all 38 enrolled patients will be updated.<br />
Conclusions: Our single-center phase II study continues to accrue,<br />
with no clinically significant diarrhea or signal of increased cardiac<br />
toxicity to date. Pertuzumab was recently FDA-approved in<br />
combination with trastuzumab and docetaxel. If the estimate of safety<br />
and activity is similar to results with docetaxel in CLEOPATRA, this<br />
study will provide support for weekly paclitaxel as an alternative<br />
option in combination with trastuzumab and pertuzumab in this<br />
setting.<br />
P5-18-21<br />
A Phase II randomized trial of lapatinib with either vinorelbine<br />
or capecitabine as first- and second-line therapy for ErbB2-<br />
overexpressing metastatic breast cancer (MBC)<br />
Janni W, Sarosiek T, Pikiel J, Karaszewska B, Staroslawska E,<br />
Salat C, Caglevic C, Potemski P, Brain E, Briggs K, de Silvio<br />
M, Sapunar F, Papadimitriou C. Klinikum der Heinrich-Heine-<br />
Universität Düsseldorf, Düsseldorf, Germany; Centrum Medyczne<br />
Ostrobramska, NZOZ Magodent, Warsaw, Poland; Wojewodzkie<br />
Centrum Onkologii, Centrum Badan Klinicznych, Gdansk, Poland;<br />
Przychodnia Lekarska NZOZ “KOMED”, Konin, Poland; Centrum<br />
Onkologii Ziemii Lubelskiej, Lublin, Poland; Hämato-Onkologische<br />
Gemeinschaftspraxis, München, Germany; Mariano <strong>San</strong>chez<br />
Fontecilla, Las Condes, Chile; Wojewodzki Szpital Specjalistyczny,<br />
Kopernika, Poland; Institut Curie - Hôpital René Huguenin, Saint-<br />
Cloud, France; GlaxoSmithKline Oncology, Uxbridge, Middlesex,<br />
United Kingdom; GlaxoSmithKline Oncology, Collegeville, PA;<br />
Therapeutic Clinic, General Hospital of Athens, Greece<br />
Background: Lapatinib (L), a dual kinase inhibitor of epidermal<br />
growth factor receptor and ErbB2, is effective in the treatment of<br />
ErbB2+ MBC in combination with capecitabine (C) following<br />
progression after trastuzumab, anthracyclines, and taxanes.<br />
Vinorelbine (V) is an important chemotherapy option in MBC, and<br />
multiple Phase II trials have been conducted in combination with<br />
trastuzumab. This randomized, open-label, multicenter, Phase II<br />
study (LAP112620, VITAL) evaluated the efficacy and safety of L<br />
with either V or C in women with ErbB2+ MBC.<br />
Methods: Patients with MBC who had received ≤1 chemotherapy<br />
regimen in the metastatic setting were randomized 2:1 to either L<br />
1250 mg orally once daily (QD) continuously plus V 20 mg/m2<br />
intravenously on Days 1 and 8, every third week, or L 1250 mg<br />
orally QD continuously plus C 2000 mg/m2/day orally in 2 doses 12<br />
hours apart on Days 1-14 every third week. Patients were stratified<br />
by prior receipt of therapy for MBC (Y/N) and site of metastatic<br />
disease (visceral/soft tissue or bone-only). The primary endpoint<br />
of progression-free survival (PFS) was assessed once all subjects<br />
had been followed for a minimum of 6 months or had otherwise<br />
progressed, died or withdrawn, if sooner. The primary focus was to<br />
evaluate PFS in the L plus V arm with a descriptive intent only. Other<br />
endpoints included overall response rate, overall survival, and safety.<br />
Patients progressing on one treatment arm were given the option of<br />
crossing over to the other arm.<br />
Results: 112 patients were randomized. The results and conclusions<br />
sections will be updated once the primary analysis has been completed<br />
in September 2012.<br />
clinicaltrials.gov - NCT01013740<br />
P5-18-22<br />
Long-term survival of patients with HER2 metastatic breast<br />
cancer treated by targeted therapies.<br />
Fiteni F, Villanueva C, Bazan F, Chaigneau L, Cals L, Dobi E,<br />
Montcuquet P, Nerich V, Limat S, Pivot X. Besançon University<br />
Hospital, Besançon, Doubs, France<br />
Purpose<br />
HER2 targeted therapies have substantially improved outcomes of<br />
patients with HER2 positive metastatic breast cancer (MBC). Medical<br />
records of patients with HER2 positive MBC achieving long survival<br />
were reviewed to describe their clinical characteristics and to assess<br />
whether curability is possible.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
474s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
Patients and methods<br />
One thousand and seven hundred patients with MBC were treated<br />
between 01/01/2003 and 31/05/2012 in the 5 hospitals from the<br />
Franche-Comte region. All 217 patients with HER2 positive MBC<br />
region were retrospectively studied.<br />
Results<br />
Among this population of HER2 positive MBC, 56 patients (26%)<br />
survived longer than 5 years. The characteristics of these long<br />
survivors were the following: median age at diagnosis was 55 years<br />
old (range, 33-87); 20 patients (35,7%) were metastatic at presentation;<br />
20 patients (35,7%) had received adjuvant chemotherapy; the<br />
median disease-free interval was 17 months; brain, liver, lung, bone<br />
metastases were observed in 4 (7%), 19 (34%), 13 (23%), 23 (41%)<br />
in cases at occurrence of metastatic disease, respectively; tumours<br />
were hormonal receptors positive in 39 cases (70%) of these patients.<br />
A total of 16 (29%), 7 (12,5%), 7 (12,5%) and 26 (46%) cases had<br />
received 1, 2, 3 or more lines of chemotherapy at metastatic setting.<br />
The proportion of HER2 targeted treatment was 79%, 61%, 50%<br />
in first, second and third line, respectively. All patients received<br />
trastuzumab or lapatinib for their disease and 18 patients (32%) were<br />
given an anthracycline containing regimen.<br />
There were 7 complete response (CR), there were all observed after<br />
one line of chemotherapy based on trastuzumab combined with a<br />
taxane in all cases. Among these 7 patients, all continued trastuzumab<br />
after CR and all RH+ patients received hormonotherapy after CR.<br />
Among these 56 patients, 35 (62,5%) were still alive at the date<br />
cutoff in 31/05/2012.<br />
Conclusion<br />
A significant proportion of patients with HER2 positive MBC were<br />
long survivors. Prospective clinical trials in this subset of patients<br />
should take into account this high number of patients with favorable<br />
outcome to achieve conclusion in term of survival. Can one consider<br />
the curabiblity of some MBC patients with HER2 overexpression?<br />
P5-18-23<br />
The prognosis of T1a, T1b N0 M0, HER2+ patients in Korea.<br />
Lee JW, Moon H-G, Han W, Noh D-Y. Seoul National University<br />
Hospital, Seoul, Korea<br />
Backgrounds: Increased expression of HER-2 or amplification of<br />
the HER-2/neu gene has been associated with a worse prognosis<br />
than with other breast cancer phenotypes. Especially in cases of size<br />
of 0.5∼1cm and node-negative status, adjuvant chemotherapy with<br />
or without Trastuzumab treatment is suggested by recent National<br />
Comprehensive <strong>Cancer</strong> Network(NCCN) guidelines. In Korea, the<br />
breast cancer patient pool is more younger than western data, and<br />
there could be some ethnic differences.<br />
Methods: The Korean <strong>Breast</strong> <strong>Cancer</strong> Society (KBCS) has been<br />
collaborating with the Korean Central <strong>Cancer</strong> Registry (KCCR) to<br />
improve the completeness and validity of the breast cancer registry<br />
and the mortality data. Data of T1a,bN0M0 breast cancer patients<br />
from 1999 to 2006 from KBCS on-line registry was obtained, and a<br />
total of 2,962 patients were included for survival analysis.<br />
Results: 711 patients (24.0%) was HER-2 positive. Hormone receptor<br />
and HER2 status was used to classify 4 molecular subtypes; Hormone<br />
receptor(HR)+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-. The<br />
median follow-up was for 55.82 month (±24.196). <strong>Breast</strong> cancer<br />
specific survival rate was lowest at HR-/HER2+ subtype(97.9%).<br />
It’s 1.0∼1.8% lower than other subtypes. Between all T1N0M0 cases,<br />
especially T1b HR-/HER2+ cases showed lowest survival of 96.4%.<br />
Conclusion: This study calculated the nationwide survival rates of<br />
Korean breast cancer patients with T1a,bN0M0 disease for the first<br />
time. HER2 gene positivity was associated with worse prognosis<br />
and it’s concordant with western studies. But prognosis of T1N0M0<br />
lesion is much better than that of other nations. So, the usage of<br />
chemotherapy and Trastuzumab treatment should be considered more<br />
carefully in Korea. Further analysis of the long-term survival and a<br />
nationwide collaborative study should be performed to estimate the<br />
survival trend of Korean breast cancer patients.<br />
P5-18-24<br />
Population pharmacokinetics of trastuzumab emtansine, a HER2-<br />
targeted antibody-drug conjugate, in patients with HER2-positive<br />
metastatic breast cancer: clinical implications of the effect of<br />
various covariates<br />
Lu D, Girish S, Gao Y, Wang B, Yi J-H, Guardino E, Samant M,<br />
Cobleigh M, Rimawi M, Conte P, Jin J. Genentech, Inc.; Quantitative<br />
Solutions; Rush University Medical Center; Baylor College of<br />
Medicine; University of Modena and Reggio Emilia<br />
Background<br />
Trastuzumab emtansine (T-DM1) is a HER2-targeted antibodydrug<br />
conjugate composed of the humanized monoclonal antibody<br />
trastuzumab, the potent cytotoxic agent DM1 (a microtubule inhibitor),<br />
and a stable thioether linker. To estimate typical pharmacokinetic<br />
(PK) parameter values and interpatient variability, a population PK<br />
model for T-DM1 was previously developed from 1 phase 1 (0.3 to<br />
4.8 mg/kg in qw or q3w regimens) and 2 phase 2 (3.6 mg/kg q3w)<br />
trials (Gupta, J Clin Pharmacol 2012). The model reported here has<br />
been updated with additional data from 2 randomized trials (phase 2<br />
TDM4450g and phase 3 EMILIA, 3.6 mg/kg q3w). Another phase 2<br />
trial (TDM4688g) was used for external validation of the model. The<br />
effect of demographic and pathophysiological covariates on the PK<br />
of T-DM1 was explored to better understand the clinical factors that<br />
might affect exposure and clinical outcome for individual patients.<br />
Methods<br />
For the current analysis, 9934 T-DM1 serum concentration-time<br />
data points from 671 patients were simultaneously fitted using<br />
NONMEM® software. T-DM1 concentration-time data to date are<br />
best described using a 2-compartment linear model. All relevant<br />
and plausible covariates likely to have an effect on T-DM1 systemic<br />
exposure, or likely to have clinical relevance, were explored for<br />
possible correlation with the key T-DM1 PK parameters of clearance<br />
(CL) and central volume of distribution (V c ). These covariates include<br />
those related to demographics, renal and hepatic function, disease<br />
status, and treatment history.<br />
Results<br />
The estimated CL for T-DM1 is 0.68 L/day, V c is 3.13 L, and the<br />
terminal half-life is 3.94 days. Interindividual variability (IIV) of<br />
the base model is 25.6% and 17.5% for CL and V c , respectively.<br />
Patients with greater body weight, sum of longest dimension of target<br />
lesions, serum concentration of shed HER2 extracellular domain, and<br />
aspartate aminotransferase concentrations, as well as patients with<br />
lower serum albumin and baseline trastuzumab concentrations, have<br />
statistically faster CL. Patients with greater body weight also have<br />
statistically larger V c . Incorporation of these covariates (P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Conclusions<br />
A relatively small IIV for the estimated T-DM1 PK parameters of CL<br />
and V c was observed. None of the evaluated covariates had a clinically<br />
meaningful magnitude of effect on T-DM1 exposure (
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
between arms. Causes of death remained unchanged from the first<br />
interim OS analysis, with the most common cause being progressive<br />
disease. Adverse events leading to death were rare and balanced<br />
between arms.<br />
Conclusions: Treatment of pts with HER2-positive 1L MBC with<br />
P+T+D compared with Pla+T+D was associated with an improvement<br />
in OS, which was both statistically significant and clinically<br />
meaningful. These results show that combined HER2 blockade and<br />
chemotherapy using the P+T+D regimen can be considered a standard<br />
of care for pts with HER2-positive MBC in the 1L setting.<br />
P5-19-01<br />
Targeting the HER3-phosphatidyl inositol-3 kinase pathway in<br />
breast cancers<br />
Cook RS, Morrison MM, Arteaga CL, Perou CM. Vanderbilt<br />
University, Nashville, TN; University of North Carolina<br />
Background: Using a mouse model of HER3 ablation in the mammary<br />
epithelium, we previously showed that HER3 is required for the<br />
genesis of transgenic HER2-overexpressing breast cancers. However,<br />
increasing evidence suggests that transgenic models of HER2<br />
overexpression result in luminal B-like mammary tumors, which<br />
resemble human breast tumors that express estrogen receptor (ER)<br />
but are often not responsive to endocrine therapy. Furthermore, we<br />
found that HER3 is required in the untransformed mouse mammary<br />
epithelium for differentiation and survival of luminal cells, but not<br />
basal cells. Herein we report that HER3 drives growth and survival of<br />
luminal breast cancers in a manner that parallels its role in maintaining<br />
the untransformed luminal epithelium in the breast.<br />
Results: Expression profiling of a large human breast cancer dataset<br />
demonstrated that HER3 expression was highest in Luminal breast<br />
cancers as compared to different molecular subtypes of breast cancers,<br />
including HER2-enriched, claudin-low, and basal-like breast cancers.<br />
In luminal breast cancer cell lines MCF7, ZR75-1, and MDA-MB-361,<br />
HER3 targeting using siRNA or a monoclonal antibody against HER3<br />
decreased Akt, S6, and Erk1/2 phosphorylation, cell growth and cell<br />
survival under conditions of estrogen deprivation. Luminal breast<br />
tumor xenografts treated with U3-1287, a humanized monoclonal<br />
anti-ErbB3 antibody, or EZN-3920, an anti-sense oligonucleotide<br />
against ErbB3, decreased tumor growth and phosphatidyl inositol-3<br />
kinase (PI3K)/mTOR signaling in vivo. Interestingly, luminal breast<br />
tumor xenografts responded to the ER inhibitor fulvestrant with<br />
increased HER3 expression and phosphorylation, and with increased<br />
PI3K/mTOR signaling as shown by enhanced S6 phosphorylation.<br />
Fulvestrant-mediated upregulation of HER3 was also seen in matched<br />
clinical breast tumor specimens harvested before treatment and after<br />
21 days of fulvestrant treatment.AMG-888 blocked fulvestrantinduced<br />
HER3 and phospho-S6 upregulation in vivo, resulting in<br />
regression of luminal breast tumor xenografts.<br />
Conclusions: These data suggest that HER3 targeting may improve the<br />
outcome of luminal breast cancers treated with endocrine therapy, and<br />
are consistent with our findings that a HER3-dependent expression<br />
signature positively correlates with relapse in tamoxifen-treated<br />
patients. Taken together, these results define a novel role for HER3<br />
in luminal breast cancer cells, and support future investigations into<br />
therapeutic strategies to target HER3 in luminal breast cancers.<br />
P5-19-02<br />
Selective PI3K and dual PI3K/mTOR inhibitors enhance the<br />
efficacy of endocrine therapies in breast cancer models<br />
Friedman L, Ross LB, Wallin J, Guan J, Prior WW, Wu E, Nannini<br />
M, Sampath D. Genentech, Inc., South <strong>San</strong> Francisco, CA<br />
Purpose: Phosphoinositide 3-kinases (PI3K) are lipid kinases that can<br />
regulate breast tumor cell growth, migration and survival. Standard<br />
of care drugs such as estrogen receptor (ER) antagonists including<br />
fulvestrant and tamoxifen, and aromatase inhibitors such as letrozole<br />
are indicated for the treatment of hormone receptor positive breast<br />
cancer. The current study is focused on investigating preclinical<br />
activity in breast cancer models, for GDC-0941, a class I PI3K<br />
inhibitor, GDC-0032, a PI3K inhibitor, and GDC-0980, a dual mTOR<br />
kinase and class I PI3K inhibitor. Investigation into PI3K inhibitor<br />
efficacy in combination with endocrine therapies is also explored.<br />
Experimental Design: A panel of ER+ breast cancer cell lines were<br />
treated with GDC-0941, GDC-0032 and GDC-0980 either as single<br />
agents or in combination with fulvestrant or tamoxifen and assayed for<br />
cellular effects. MCF-7 cells ectopically expressing aromatase were<br />
utilized to test the efficacy of aromatase inhibitors in combination<br />
with PI3K inhibitors in vitro. In addition, human xenografts of breast<br />
cancer cell lines were employed to assess combination efficacy of<br />
PI3K inhibitors with fulvestrant and tamoxifen in vivo.<br />
Results: Combination of GDC-0941, GDC-0032 or GDC-0980 with<br />
endocrine therapies resulted in a decrease in cellular viability and<br />
an increase in cell death. Synergy of PI3K inhibitor combinations<br />
with fulvestrant or tamoxifen was assessed using Combination<br />
Index (C.I.), and C.I. values as low as 0.1 indicated strong synergy<br />
in some contexts. Combination activity of PI3K inhibitors and<br />
letrozole was also observed in MCF7 cells expressing aromatase.<br />
In MCF-7 xenografts, the combination of GDC-0980, GDC-0032<br />
and GDC-0941 enhanced activity of fulvestrant resulting in tumor<br />
regressions and tumor growth delay (116% tumor growth inhibition<br />
(TGI) for GDC-0980 and 91% TGI for GDC-0941 and GDC-0032). In<br />
addition, the combination of GDC-0941 or GDC-0032 with tamoxifen<br />
enhanced the efficacy of tamoxifen in vivo (83%TGI for GDC-0941<br />
and 102%TGI for GDC-0032). Mechanism of action and biomarker<br />
studies are underway.<br />
Conclusion: Collectively, the non-clinical efficacy data provide a<br />
strong rationale to evaluate the combination of PI3K inhibitors with<br />
anti-estrogen therapy in hormone receptor positive breast cancer.<br />
P5-19-03<br />
Olaparib plus carboplatin in combination with vandetanib<br />
inhibited the growth of BRCA-wt triple negative breast tumors<br />
in mice: Outside BRCA-box<br />
Dey N, Sun Y, De P, Leyland-Jones B. <strong>San</strong>ford Research/USD, Sioux<br />
Falls, SD<br />
Introduction: PARP inhibition has emerged as one of the most<br />
exciting and promising ‘targeted’ therapeutic strategies in the<br />
treatment of advanced triple negative breast cancer (TNBC) – the<br />
intended ‘target,’ being DNA repair (Anders CK, 2010). Although<br />
olaparib is known to have antitumor activity in BRCA-related TNBC<br />
cells, a limited number of preclinical and clinical studies have shown<br />
antitumor efficacy of olaparib in non-BRCA-related BC (Shimo<br />
T, 2012). Understanding the biology of TNBC cells has identified<br />
molecular targets including RTK(s), such as EGFR.<br />
Purpose: Here we tested the combination of a PARP inhibitor,<br />
olaparib (O) (AstraZeneca) plus carboplatin (C) with the EGFR/<br />
VEGFR inhibitor, vandetanib (V) (AstraZeneca) in a BRCA-wt<br />
TNBC model.<br />
www.aacrjournals.org 477s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Methods: Athymic mice bearing TNBC (BRCA-wt VEGFR<br />
expressing MDA-MB231& MDA-MB468 [EGFR amplified/<br />
overexpressed]) xenograft tumors (200 mm 3 ) were treated with O<br />
plus C in combination with V (Arms: vehicle control 1, vehicle<br />
control 2, C+O, V, C+O+V). In vitro effects of V in combination<br />
with O plus C (or temozolomide) on clonogenic growth (3D on-TOP<br />
assay), proliferation (MTT and CelltiterGLO), apoptosis (Apoptosis<br />
Array), cell signaling marker(s) (Western Blot), and tumor cell<br />
phenotypes (fibronectin-directed migration, matrigel-invasion, and<br />
vascular mimicry) were investigated in a panel of five BRCA-wt and<br />
BRCA-mutated TNBC cell lines. The effects of V were tested on (a)<br />
cell signaling marker(s), (b) angiogenesis marker (HIF-1alpha), and<br />
(c) angiogenesis related phenotypes (vitronectin-directed migration,<br />
and cord formation) in HUVEC.<br />
Results: (1) O plus C in combination with V caused a regression of<br />
the in vivo growth of established tumors by 50% which was evident<br />
in both the BRCA-wt TNBC models tested. Interestingly, a marked<br />
suppression of the progression of tumor-growth was observed in the<br />
O plus C arm. (2) In vitro, V alone (10 µM) inhibited baseline as<br />
well as EGF-induced phosphorylation of AKT (S473 / T308), S6RP,<br />
4EBP1 and ERK. (3) TNBC cells exhibited higher sensitivity to V in<br />
clonogenic assays when combined with a 10 µM fixed dose of O and<br />
C / temozolomide. (4) A combination of V with O plus C increased<br />
cleaved caspase-3, PARP cleavage, and pro-apoptotic signals, while<br />
inhibiting vascular mimicry, migration, and invasion in MDA-MB231,<br />
MDA-MB468, and SUM149 cells. (5) Treatment with V blocked<br />
cord formation, migration, EGF-induced HIF-1α accumulation, and<br />
phosphorylation of AKT, 4EBP1, and ERK in HUVEC.<br />
Conclusion: A profound anti-tumor efficacy of O plus C in<br />
combination with V in BRCA-wt TNBC model can be explained by<br />
a significant anti-proliferative/pro-apoptotic and anti-migratory/antiinvasive<br />
actions of the drugs (alone or in combination), as observed<br />
both in tumor cells as well as in endothelial compartments. The<br />
combination of O plus C plus V merits further investigation in TNBC.<br />
P5-20-01<br />
A randomized double-blind phase II study of the combination<br />
of oral WX-671 plus capecitabine vs. capecitabine monotherapy<br />
in first-line HER2- negative metastatic breast cancer (MBC).<br />
Goldstein LJ, Oliveria CT, Heinrich B, Stemmer SM, Mala C, Selder<br />
S, Bevan P, Harbeck N. Fox Chase <strong>Cancer</strong> Center, Philadelphia,<br />
PA; Instituto Brasilerio Controle <strong>Cancer</strong>, Sao Paulo, Brazil;<br />
Hamatologisch-Onkologische-Praxis Augsburg, Augsburg, Germany;<br />
Rabin Medical Center, Petah Tikva, Israel; Wilex, Munich, Germany;<br />
Univeristy of Munich, Munich, Germany<br />
Background: uPA and its inhibitor PAI-1 play a key role in tumor<br />
invasion, metastasis and tumor growth. High levels of uPA and PAI-<br />
1 in breast tumors are statistically significant prognostic factors of<br />
disease-free (DFS) and overall survival (OS), which were validated<br />
at the highest level of evidence, as well as predictors for benefit<br />
of adjuvant chemotherapy. WX-UK1 is an active site competitive<br />
inhibitor of uPA with an inhibition constant in the submicromolar<br />
range. WX-671 (upamostat) is an oral prodrug of WX-UK1. In<br />
preclinical animal tumor models, both WX-UK1 and WX-671 have<br />
been shown to reduce the growth rate of implanted tumors, to inhibit<br />
invasion, and reduce metastases. This current proof of concept study<br />
is designed to substantiate the anti-metastatic properties of upamostat<br />
for patients appropriate for first line therapy for MBC.<br />
Methods: Female patients aged >18, with HER2 negative MBC<br />
appropriate for first line monotherapy with capecitabine, with<br />
adequate performance status, organ function, bone marrow reserve<br />
without brain metastases were eligible. Patients were randomized in a<br />
double-blind fashion to receive upamostat (200mg orally daily for 21<br />
days) plus capecitabine (1000 mg/m2 orally twice daily for 14 days)<br />
vs. capecitabine (1000 mg/m2 orally twice daily for 14 days) in 3 week<br />
treatment cycles until progressive disease or unacceptable toxicity.<br />
The primary endpoint is to evaluate the efficacy of the combination<br />
of upamostat plus capecitabine compared to monotherapy as assessed<br />
by comparison of progression free survival. The secondary objectives<br />
are OS, objective response rates, safety and tolerability, and to assess<br />
the pharmacokinetics (PK) of upamostat and capecitabine when<br />
combined.<br />
Results: Between August 2008 and April 2011,132 patients were<br />
enrolled. 17 patients are still receiving treatment. 26% of the patients<br />
are characterized as triple negative, 13% as only Estrogen Receptor<br />
(ER) positive and 4% as only Progesteron Receptor (PR) positive.<br />
57 % of the patients are ER and PR positive.<br />
Conclusions: Progression free survival, response rates and safety<br />
will be reported. This abstract is being submitted as a placeholder. A<br />
completed abstract will be submitted when the analyses are completed.<br />
P5-20-02<br />
Predictors of long-term survival in a large cohort of patients<br />
with HER2-positive (HER2+) metastatic breast cancer (MBC).<br />
Chavez Mac Gregor M, Lei X, Giordano SH, Valero V, Esteva F,<br />
Mittendorf EA, Gonzalez-Angulo AM, Hortobagyi GN. University<br />
of Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX<br />
Background: Numerous studies have examined prognostic factors for<br />
survival in breast cancer patients (pts), but few have focused on longterm<br />
survival among pts with HER2+ MBC receiving HER2-targeted<br />
therapy. In this study we sought to evaluate the clinical characteristics<br />
and predictive factors of long-term survival in this group of pts.<br />
Methods: All pts with HER2+ MBC treated with HER2-directed<br />
therapy at MD Anderson <strong>Cancer</strong> Center were identified by<br />
retrospective review of the Institutional <strong>Breast</strong> Medical Oncology<br />
database. HER2 status was determined by IHC or FISH. Patient<br />
characteristics were analyzed using descriptive statistics. Overall<br />
survival (OS) was measured from the date of diagnosis of the first<br />
distant metastasis to the date of death or last contact. Pts were grouped<br />
according to OS and categorized as long term-survivors (LTS, OS<br />
≥5 years), or non-long term survivors (non-LTS, OS 50, p=0.005);<br />
stage at diagnosis (25% for stage I-III vs. 36% for stage IV de novo,<br />
p
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
breast surgery among pts with stage IV de novo (OR=2.88; 95% CI<br />
1.47-5.66) were significantly associated with long-term survival.<br />
Conclusions: Some patients with HER2+positive MBC have an<br />
excellent outcome, particularly younger pts with HR-positive<br />
tumors, low burden of disease and non-visceral metastases in which<br />
multidisciplinary treatment is favored. In the era of HER2-targeted<br />
therapies, 14.5% of the patients are long-term survivors. To our<br />
knowledge this is the largest series identifying the characteristics of<br />
this group of patients.<br />
P5-20-03<br />
A phase 2, double-blind, randomized, placebo-controlled, dosefinding<br />
study of sotatercept for the treatment of patients with<br />
chemotherapy-induced anemia and metastatic breast cancer.<br />
Auerbach M, Osborne CRC, Klesczewski K, Laadem A, Sherman<br />
ML, Bianca R. Auerbach Hematology/Oncology, Baltimore, MD;<br />
Texas Oncology, P.A., Sammons <strong>Cancer</strong> Center, Dallas, TX; Celgene<br />
Corporation, Summit, NJ; Acceleron Pharma, Cambridge, MA<br />
Background: Sotatercept is a recombinant activin receptor IIA<br />
(ActRIIA) ligand trap and is comprised of the extracellular domain<br />
of ActRIIA linked to the Fc domain of human IgG1 (ActRIIA-IgG1).<br />
Results of preclinical and early clinical studies provide evidence that<br />
sotatercept increases the concentration of hemoglobin (Hb) in blood<br />
and may constitute a novel treatment for chemotherapy-induced<br />
anemia (CIA), a condition that results in significant morbidity.<br />
Methods: This study evaluated the safety of, and hematopoietic<br />
response to, sotatercept in patients with CIA and metastatic breast<br />
cancer (MBC). Response was defined as increase in Hb ≥1 g/dL for<br />
≥28 consecutive days during treatment or ≤2 months following the last<br />
dose, in the absence of red blood cell (RBC) transfusion or treatment<br />
with an erythropoiesis stimulating agent (ESA). If RBC transfusion<br />
or treatment with an ESA was required, no Hb measurements within<br />
28 days of the RBC transfusion or administration of ESA were<br />
used to determine the Hb response. Subjects were randomized to<br />
subcutaneous injection of sotatercept (0.1, 0.3, or 0.5 mg/kg) or<br />
placebo and were treated on day 1 of each of four 28-day cycles.<br />
Results: Thirty (30) subjects were enrolled and treated (5 placebo,<br />
25 sotatercept). Increases in mean Hb in the 0.3 and 0.5 mg/kg<br />
groups were greater than in 0.1 mg/kg and placebo groups. Increases<br />
peaked approximately 15 days following treatment and declined<br />
over the remaining interval between treatments. Among 23 subjects<br />
with confirmed CIA and administered ≥1 dose and followed for ≥57<br />
days (per-protocol analysis), 5/18 (28%) administered sotatercept<br />
responded (0/5 [0%] at 0.1 mg/kg; 3/9 [33%] at 0.3 mg/kg; 2/4<br />
[50%] at 0.5 mg/kg) vs 1/5 [20%] administered placebo. Among 13<br />
nonresponders administered sotatercept, 5 (39%) experienced ≥1<br />
dose interruption/reduction, as per protocol, due to elevated Hb. The<br />
incidence of adverse events (AEs) was consistent with that reported<br />
in patients with MBC. No dose-limiting or dose-related toxicity was<br />
observed.<br />
Conclusions: Sotatercept demonstrated dose-dependent hematopoietic<br />
activity in subjects with CIA and MBC. The safety findings were<br />
generally consistent with the known safety profile of sotatercept.<br />
These data suggest that a greater dose of sotatercept or a dose<br />
interval
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-20-05<br />
A Phase 2 trial of RAD 001 and Carboplatin in patients with triple<br />
negative metastatic breast cancer<br />
Singh JC, Volm M, Novik Y, Speyer J, Adams S, Omene CO, Meyers<br />
M, Smith JA, Schneider R, Formenti S, Goldberg JD, Li X, Davis S,<br />
Beardslee B, Tiersten A. New York University, New York, NY<br />
BACKGROUND: RAD001 is an oral mTOR inhibitor that has<br />
exhibited activity in breast cancer. Triple negative breast cancer<br />
cells are unable to repair double stranded DNA breaks and hence<br />
have sensitivity to platinum agents that cause interstrand crosslinks.<br />
Rapamycin acts synergistically with platinum agents to induce<br />
apoptosis and inhibit proliferation in at least two different breast<br />
cancer cell lines (including ER/PR negative cell lines). We propose<br />
that combination RAD001 and carboplatin may have activity in<br />
triple-negative breast cancer.<br />
MATERIALS AND METHODS: The primary objective of the study<br />
is to determine clinical benefit (complete remission (CR) + partial<br />
remission (PR) + stable disease (SD more than 6 months)) and the<br />
toxicity of this combination in triple negative metastatic breast cancer<br />
who have had 0-3 prior chemotherapy regimens for metastatic disease.<br />
Twenty-five subjects were to be entered in this Phase II study. This<br />
design has greater than 80% power to test the null hypothesis that the<br />
clinical benefit rate is less than or equal to 10% versus the alternative<br />
hypothesis that clinical benefit rate is greater than or equal to 30%.<br />
Prior carboplatin is allowed. Women with treated brain metastasis<br />
are eligible. Secondary objectives are to determine progression free<br />
survival and relationship between pretreatment sensitivity (biopsy<br />
at baseline) and clinical response (biopsy post 2 cycles) using IHC<br />
staining for abundance of key proteins in the Akt-mTOR pathway and<br />
their activity using surrogate phosphorylation site-specific antibodies.<br />
According to the original study plan, carboplatin AUC 6, was to be<br />
given intravenously every three weeks. Five mg of RAD001 was<br />
to be given daily with a 3 patient run-in and then 10 mg daily if<br />
there were no dose-limiting toxicities. Due to a surprising amount<br />
of thrombocytopenia with this combination the dose of carboplatin<br />
was first amended to AUC 5 and most recently to AUC 4 with 5 mg<br />
of RAD001 (and no plan to escalate to 10 mg).<br />
RESULTS: 23 patients of a planned 25 have been recruited thus far.<br />
Median age is 59. Of the 20 patients assessable for response at this<br />
time, there have been 1 CR, 5 PRs, 8 SDs and 6 PDs. One SD was<br />
achieved in a patient progressing on single agent Carboplatin at study<br />
entry. Median duration of CR+ SD +PR thus far is 13 weeks (range:<br />
6-74 weeks). 5 of 22 patients assessable for toxicity had grade 3/4<br />
thrombocytopenia and 4 patients had grade 3 neutropenia (no febrile<br />
neutropenia). 13 out of eighteen patients have had treatment held and/<br />
or dose reductions secondary to hematological toxicity, however, since<br />
amendment for starting dose of Carboplatin to AUC 4 the regimen<br />
has been very well tolerated with only 1 out of eleven patients with<br />
grade 3 neutropenia and grade 3 thrombocytopenia. 1 patient suffered<br />
from grade 3 dehydration. The estimated clinical benefit rate is 45%<br />
(95% confidence interval: 23%, 67%). Median time to progression<br />
or death is 85 days from start of treatment.<br />
CONCLUSIONS: Our study has met the primary end point of<br />
demonstrating clinical benefit in triple negative metastatic breast<br />
cancer. Dose limiting thrombocytopenia was an unexpected side<br />
effect requiring protocol amendment. We continue to accrue study<br />
subjects at the amended dosing.<br />
P5-20-06<br />
RAD001 (Everolimus) in combination with Letrozole in the<br />
treatment of postmenopausal women with estrogen receptor<br />
positive Metastatic <strong>Breast</strong> cancer after failure of hormonal<br />
therapy – a phase II study<br />
Safra T, Kaufman B, Ben Baruch N, Kadouri-Sonenfeld L, Nisenbaum<br />
B, Greenberg J, Ryvo L, Yerushalmi R, Evron E. Tel Aviv Sourasky<br />
MC, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;<br />
Sheba Medical Center, Ramat Gan, Israel; Kaplan Medical Center,<br />
Rehovot, Israel; Hadassah Ein Karem Medical Center, Jerusalem,<br />
Israel; Meir Kfar Saba Medical Center, Kfar Saba, Israel; Rabin<br />
Medical Center Belinson Campus, Petach Tikva, Israel; Assaf<br />
Harofeh Medical Center, Assaf Harofeh, Israel<br />
Background and Objectives: Approximately 70% of postmenopausal<br />
women (PMW) present with hormone receptor positive Metastatic<br />
<strong>Breast</strong> cancer (MBC) and there is a need for new treatment modalities<br />
after failure of prior endocrine therapy. Activation of the mTOR<br />
pathway is a key adaptive change driving endocrine resistance. Preclinical<br />
and early clinical data suggest synergistic effect between<br />
RAD001 (Everolimus, a Novartis mTOR inhibitor) and Letrozole<br />
results in more profound effects on proliferation arrest and induction<br />
of tumor cell kill.<br />
Our objectives are to assess overall response rate (ORR) as well as<br />
progression free survival (PFS), overall survival (OS) and safety<br />
profile with treatment of Letrozole and RAD001 in PMW with MBC<br />
after failure of endocrine therapies.<br />
Methods and materials: A multi-center, Israeli phase II open label<br />
study evaluating treatment of RAD001 (10 mg daily) combined with<br />
Letrozole (2.5 mg daily) in PMW with MBC after recurrence or<br />
progression on Tamoxifen and/or Anastrozole and/or Letrozole and/<br />
or Fulvestarnt and/or Exemestane.<br />
Sixty five patients were enrolled in 7 institutes. This abstract presents<br />
data and preliminary results of 24 patients in 2 of the study centers.<br />
Median age was 65.5 (54-80) years. Hormonal status were: 50% of<br />
the patients had ER+/PR+, 40% ER+/PR- and 10% ER-/PR+. All<br />
had MBC with 1 to 3 metastatic sites i.e. bones (90%), liver (30%),<br />
lung (12%) and skin (12%).<br />
Patients were previously exposed to a median of 1 (1-3) therapy line<br />
for MBC, all previously treated with hormonal therapy for MBC<br />
and the majority were also exposed to adjuvant hormonal therapy.<br />
Results: With a median follow up of 4 months (range 3-12), partial<br />
response was observed in 22%, stable disease in 28% and progressive<br />
disease in 50% of patients. Median time to progression (TTP) was 4<br />
months (3-11) with 65% still on treatment. Median OS is too early<br />
to evaluate (all but 2 are still alive).<br />
Grade III bone marrow toxicity was observed in about 5%. Nonhematological<br />
toxicities were: grade I fatigue in about 90%, rash and<br />
irritation(grade I-II) in about 70%, glucose level, liver function tests,<br />
blood cholesterol and triglycerides increased and/or renal function<br />
alterations (grade I-III) in about 80%, all the above disappeared after<br />
treatment delays or dose reduction, 5% developed non-inflammatory<br />
pneumonitis.<br />
The 2 most common toxicities were mucositis; 30% grade I and 50%<br />
grade II and significant weight loss (5-10% weight reduction) in 90%.<br />
Conclusions: Our study shows significant activity with the<br />
combination of RAD001 and Letrozole in MBC previously treated<br />
several lines of hormonal treatment with an acceptable toxicity.<br />
Combining RAD001 with Letrozolein the treatment of MBC,<br />
potentially inhibit tumor cell growth\proliferation and act as anti<br />
angiogenesis while at the same time potentially preventing the<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
480s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
development of Letrozole resistance. Longer follow-up and further<br />
evaluation is warranted, additional data will be collected and provided<br />
towards the 2012 SABCS.<br />
P5-20-07<br />
Phase II Trial of Dasatinib in Combination With Weekly<br />
Paclitaxel for Patients with Metastatic <strong>Breast</strong> Carcinoma<br />
Morris PG, Lake D, McArthur HL, Gilewski T, Dang C, Chaim J,<br />
Patl S, Lim K, Norton L, Hudis CA, Fornier MN. Memorial Sloan-<br />
Kettering <strong>Cancer</strong> Center, New York<br />
Background: Src kinase plays an important role in proliferation,<br />
survival, angiogenesis and metastasis in several malignancies<br />
including breast cancer. Therefore, inhibition of Src and other<br />
tyrosine kinases (TKs) represents a novel therapeutic approach.<br />
Dasatinib is a potent inhibitor of 5 oncogenic TKs, inhibits VEGFstimulated<br />
proliferation, has potent bone anti-resorptive activity and<br />
selectively inhibits basal-type breast cancer growth. Preclinically,<br />
the combination of dasatinib and paclitaxel had superior antitumor<br />
activity to either agent alone. In a previous phase I study, we<br />
determined that, in combination with weekly paclitaxel, the optimum<br />
dose of dasatinib was 120mg. Of note, 4/9 (44%) patients treated at<br />
or above this dasatinib dose level had objective tumor response. We<br />
now present results from the phase II trial of this combination.<br />
Methods: Patients with MBC, ECOG PS 0-1, normal hepatic, renal,<br />
marrow function were eligible. Patients had measurable, HER2-<br />
negative metastatic breast cancer (MBC), ≤2 prior therapies for MBC.<br />
Treatment consisted of weekly paclitaxel 80 mg/m 2 IV 3/4 weeks +<br />
Dasatinib 120mg orally daily. Response was assessed by RECIST<br />
after every 8 weeks of therapy. Simon’s two-stage optimal design<br />
was used to test the null hypothesis of a 15% response rate (RR)<br />
against the alternative of a 30% RR. In stage I, planned enrollment<br />
was 23 patients based on Type I and Type II errors of 10%. If 4 or<br />
more responses are observed, enrollment will be extended to 55<br />
patients. Exploratory correlative biomarkers of clinical benefit include<br />
Src phosphorylation (p-Src) in peripheral blood mononuclear cells,<br />
plasma levels of VEGFR2 and collagen Type IV, circulating tumor<br />
cells (CTCs) and tumor gene expression profiling.<br />
Results: 21 patients (19 females, 2 male) have enrolled; median<br />
age 48 (range 30-79). Patients received a median of 1 prior therapy<br />
for MBC (range 0-2). 6 patients are not assessable for response: 1<br />
has received 15% of pts included anemia<br />
(45%), neutropenia (32%), nausea (51%), vomiting (32%) diarrhea<br />
(51%), fatigue (53%), anorexia (25%) dysgeusia (32%), headache<br />
(28%), peripheral neuropathy (34%) cough (28%) alopecia (21%)<br />
and hypokalemia (19%). Grade 3/4 adverse events occurred in 30<br />
patients, with only four experiencing grade 4 AEs, three neutropenia<br />
and one chest pain. No grade 3/4 febrile neutropenia occurred. Grade<br />
3 AEs of interest included two pts with peripheral neuropathy and 1<br />
with pleural effusion.<br />
Conclusions: The combination of Ixabepilone weekly + Dasatinib<br />
orally daily is an active and well tolerated regimen in pretreated MBC<br />
with manageable toxicity. Updated results will be reported.<br />
www.aacrjournals.org 481s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P5-20-09<br />
Tumor mutational analysis and therapy outcomes for patients<br />
(pts) with metastatic/unresectable locally advanced myoepithelial/<br />
metaplastic breast cancer treated with PI3K targeted therapy<br />
Moulder S, Wheler J, Albarracin C, Gilcrease M, Falchook G, Naing<br />
A, Hong D, Fu S, Piha-Paul S, Tsimberidou A, Janku F, Kurzrock R.<br />
University of Texas, MD Anderson <strong>Cancer</strong> Center<br />
Background: Metaplastic breast cancers are considered a<br />
chemorefractory subset of triple negative breast cancers. Molecular<br />
profiling has demonstrated that metaplastic tumors are enriched for<br />
epithelial-to-mesenchymal transition (EMT), frequently express<br />
myoepithelial differentiation, make up a component of the ‘claudinlow’<br />
subtype, and harbor relatively high rates of mutations/activation<br />
of the PI3kinase pathway (Hennessy, <strong>Cancer</strong> Research, 2009; Prat,<br />
<strong>Breast</strong> <strong>Cancer</strong> Res, 2010).<br />
Methods: Data from pts with myoepithelial/metaplastic breast cancer<br />
treated within the Center for Targeted Therapy using regimens with<br />
known inhibitors of the PI3K pathway were evaluated to determine<br />
response to therapy. Mutational analyses were performed in archived<br />
tumor samples when available.<br />
Results: 23 pts have been treated using 6 different therapy regimens<br />
and one pt was treated on two separate clinical trials for a total<br />
of 24 analyzable outcomes. Patients were treated with liposomal<br />
doxorubicin, bevacizumab and the mTOR inhibitor, temsirolimus<br />
(DAT, n=17); liposomal doxorubicin and temsirolimus (DT, n=1);<br />
paclitaxel, bevacizumab and temsirolimus (TAT, n=3); paclitaxel<br />
and temsirolimus (TT, n=1), paclitaxel in combination with an<br />
experimental PI3K inhibitor (TEx, n=1), or temsirolimus alone<br />
(tem, n=1). Response was measured every two cycles using RECIST<br />
criteria. Most pts had received prior chemotherapy, median of 2<br />
prior regimens (range 0-7). Three patients were not evaluated for<br />
response, one who died of pneumonia during cycle 2 (DAT) and<br />
two who have not yet completed 2 cycles of therapy (DAT, TEx).<br />
Response rate (CR+PR) was 35% (CR=2, PR=4, SD≥6 months=2,<br />
SD
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
P5-20-11<br />
Bevacizumab in metastatic breast cancer: a retrospective<br />
matched-pair analysis.<br />
Gampenrieder SP, Romeder F, Muß C, Pircher M, Ressler S,<br />
Rinnerthaler G, Bartsch R, Sattlberger C, Mlineritsch B, Greil R.<br />
Paracelsus Medical University, Salzburg, Austria; Comprehensive<br />
<strong>Cancer</strong> Center Vienna, Medical University of Vienna, Austria;<br />
Hospital of Vöcklabruck, Vöcklabruck, Austria<br />
Background: In November 2011 the FDA withdrew accelerated<br />
approval of the breast cancer indication for bevacizumab, because “the<br />
drug has not been shown to be safe and effective for this use” (FDA<br />
Commissioner M. A. Hamburg, MD). The objective of this analysis<br />
was to evaluate efficacy and safety of bevacizumab in non-selected<br />
patients with stage IV breast cancer.<br />
Patients and methods: All patients with metastatic breast cancer<br />
treated with bevacizumab in combination with chemotherapy in our<br />
institution between 2005 and 2011 were retrospectively analysed.<br />
At least 1 cycle of bevacizumab was required for safety analysis, 3<br />
applications for efficacy evaluation. A control group was matched<br />
according to the following criteria: receptor status, line of treatment,<br />
chemotherapy backbone, visceral or non-visceral disease and age.<br />
Results: A total of 213 patients fulfilled the inclusion criteria. All<br />
of them were evaluable for toxicity, 199 for response. 503 potential<br />
controls allowed a complete matching for 103 patients. Fifty-eight<br />
percent of patients received first-line, 15% second-line and 27%<br />
of patients beyond second-line treatment. Visceral metastases<br />
were present in 69% of patients in both groups. The most common<br />
chemotherapy backbones were paclitaxel, capecitabine and docetaxel<br />
with 44%, 32% and 19%, respectively.<br />
Control group (n = 103) Bevacizumab group (n = 103) p-value<br />
PFS [mo] 6.0 (95 % CI 4.0-7.9) 8.9 (95 % CI 7.5-10.4) .009<br />
OS [mo] 24.4 (95 % CI 21.1-27.8) 25.4 (95 % CI 15.9-34.8) .498<br />
ORR (CR+PR) 37 (36%) 47 (46%), RR 1.26 (95% CI .88-1.80) .170<br />
CBR (ORR+SD) 68 (67%) 87 (85%), RR 1.27 (95% CI 1.07-1.47) .003<br />
Most common grade 3/4 toxicities related to bevacizumab were<br />
hypertension (27%), proteinuria (1%), thromboembolism (9%) and<br />
bleeding events (1%). Interestingly, patients developing hypertension<br />
during bevacizumab treatment had a more favourable outcome (PSF<br />
11.7 vs. 5.7 months, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Methods: This is a single center, open-label study to evaluate the<br />
safety and tolerability of every other week entinostat in combination<br />
with a 28-day cycle of Lapatinib. Patients with metastatic breast<br />
cancer in whom trastuzumab has failed were included. The phase<br />
I portion of the study is a conventional 3+3 dose-escalation design.<br />
Dose levels include 0 (starting dose) Entinostat 10 mg orally every<br />
other week, I Entinostat 12 mg, and II Entinostat 15 mg. Lapatinib<br />
1,250 mg orally is given every day without dose escalation. Toxicities<br />
are evaluated at the end of each cycle.<br />
Results: Here we report the phase I portion of the study. To date, 9<br />
patients were enrolled, 3 were in level 0, and 6 were in level I. In Level<br />
0, 2 patients were taken off study due to disease progression (PD) at<br />
the end of cycle one and 1 patient was taken off study due to PD at<br />
the end of cycle two. In Level I, 1 patient was taken off study due to<br />
PD at the end of cycle one and 2 patients were taken off study due<br />
to PD at the end of cycle 2. 1 patient had stable disease. The median<br />
age is 41 (range, 26 – 69). Seven of the nine patients are evaluable for<br />
toxicity. Most common toxicities reported by the patients are nausea<br />
grade 3 (1), fatigue grade 3 (1), muscle aches/pain grade 2 (3), skin<br />
rash grade 3 (1), paresthesias grade 2 (2), heartburn grade 1 (4), and<br />
diarrhea Grade 2 (1). Lapatinib dose was reduced in 2 patients. The<br />
most common hematological toxicities were neutropenia grade 1 (3),<br />
anemia grade 2 (1), and thrombocytopenia grade 4 (1).<br />
Conclusions: Overall, patients have tolerated the combination<br />
regimen relatively well. We have not reached the maximum tolerated<br />
dose, so patient enrollment will continue until the phase I portion of<br />
the study is complete, most likely in July 2012. We plan to proceed<br />
with phase II portion in two parallel cohorts (HER2+ inflammatory<br />
and non-inflammatory metastatic breast cancer).<br />
P5-21-01<br />
pT1a,bpN0M0 breast cancer: clinicopathological characteristics<br />
and their impact on treatment decision. Central review of the<br />
prospective ODISSEE cohort<br />
Lacroix-Triki M, Radosevic-Robin N, Louis B, Roche-Comet I,<br />
Soubeyrand M-S, Bourgeois H, Chauvet M-P, Fourrier-Réglat A,<br />
Gligorov J, Peyrat J-P, Dalenc F, Belkacemi Y, Penault-Llorca F.<br />
Institut Claudius Regaud, Toulouse, France; Centre Jean Perrin,<br />
Clermont-Ferrand, France; Laboratoire d’Anatomie et Cytologie<br />
Pathologiques, Strasbourg, France; Institut Histo-Cyto-Pathologie,<br />
Le Bouscat, France; Cabinet CY-PATH, Villeurbanne, France;<br />
Clinique Victor Hugo, Le Mans, France; Centre Oscar Lambret,<br />
Lyon, France; Université Victor Segalen, Bordeaux, France; Hôpital<br />
Tenon, Paris, France; CHU Henri Mondor-UPEC, Créteil, France<br />
Background: The incidence of infra-centimetric breast cancer (BC)<br />
is increasing due to mass screening. The management remains<br />
controversial opposing locoregional treatment only based on low<br />
stage and potentially aggressive tumor biology (especially for triple<br />
negative and HER2 positive tumors). The objectives of the prospective<br />
multicenter ODISSEE study were i) to describe daily practice<br />
management of pT1ab BC, ii) to identify potential new biomarkers<br />
and iii) to describe long term outcome (10-year follow up).<br />
Methods: 616 patients with unifocal pT1a,b pN0M0 BC were included<br />
after surgery from May 2009 to March 2010 in 116 centers. Paraffin<br />
blocks were available for central pathology review in 350 patients.<br />
Due to the small tumor size, tissue microarray (TMA) construction<br />
was finally achieved for 287 cases. Collection of additional tumor<br />
blocks is ongoing. Review of the cases was performed independently<br />
by two pathologists and discordant cases were reviewed under a<br />
multihead microscope. Histological characteristics (histological<br />
type, tumor size and grade, presence of in situ component, presence<br />
of lymphovascular invasion) were assessed on whole tissue sections.<br />
Immunohistochemical detection of ER, PR, HER2, Ki67, EGFR,<br />
cytokeratin 5/6, Bcl-2 was performed on TMAs.<br />
Results: Clinicopathological characteristics of the 287 centrally<br />
reviewed cases were similar to those of the 616 patients included in<br />
the cohort. Median age: 60.1 years (range [31–89] years). Median<br />
tumor size: 7.8 mm (range [1–10] mm) with 11% pT1a and 89%<br />
pT1b. Histological types: 72% ductal, 11% lobular and 17% other<br />
types (among which 53% of tubular). Minor in situ component was<br />
found in 36% of the cases, and invasive carcinoma with an extensive<br />
in situ component in 1.9%. Most of tumors were histological grade I<br />
and II (52% and 40% respectively), 8% were grade III. Proliferation<br />
was low as assessed by mitotic count (low 82%, intermediate 13%<br />
and high 5%) or by Ki67 index (
December 4-8, 2012 <strong>Abstract</strong>s: Poster Session 5<br />
(63%), these HER2+ pts do not differ from the general BC population.<br />
Both hormone receptor types are positive in 47%, while ER+ only or<br />
PR+ only was detected in 13% and 3%, respectively. Adjuvant ET<br />
of any type, starting before or during T treatment, was given in 87%<br />
of HR+ and in 3% of HR- pts. 6% of HR+ pts received T and ET<br />
without concomitant CT. Details on the adjuvant treatment options<br />
are provided in the table:<br />
Concomitant adjuvant<br />
treatment<br />
HER2+/HR- HER2+/HR+ Total<br />
CT and ET 3% 81% 52%<br />
ET only 0% (4 pts) 6% 4%<br />
CT only 92% 12% 41%<br />
Trastuzumab single drug therapy 5% 1% 3%<br />
Anthracycline 87%* 88%* 88%*<br />
Taxane 66%* 63%* 64%*<br />
CT simultaneous to trastuzumab 16%* 16%* 16%*<br />
* of pts receiving CT<br />
After a median follow-up of 26.4 months and the observation of a<br />
total of 296 relapse events (9%; HR-: 12%; HR+: 7%) relapse-free<br />
survival (RFS) was significantly shorter in the HR- compared to the<br />
HR+ group (at 3 years: 86 vs 92%, hazard ratio = 0.56 , p < 0.0001).<br />
Conclusion: The vast majority of HER2+ BC pts receives concomitant<br />
endocrine therapy in case of a positive HR status. Regardless of the<br />
regulatory status in Germany, a small proportion of patients with<br />
co-positive early BC received T and ET without concomitant CT.<br />
No differences between receptor subgroups could be detected with<br />
respect to type of CT and its onset relative to T. HR status remains<br />
a paramount prognostic factor in this HER2+ sub-population of BC<br />
pts, with risk of early relapse (after a median follow-up of 2 years)<br />
almost twice as high in HR- tumors.<br />
P5-21-03<br />
Concurrent loco-regional radiotherapy and trastuzumab in<br />
early-stage breast cancer: Long term results of prospective<br />
single-institution study<br />
Jacob J, Belin L, Pierga J-Y, Vincent-Salomon A, Dendale R, Beuzeboc<br />
P, Cottu P-H, Campana F, Fourquet A, Kirova YM. Institut Curie,<br />
Paris, France<br />
Purpose: To evaluate the early and late heart and skin toxicities, as<br />
well as the efficacy of concurrent adjuvant trastuzumab-radiotherapy<br />
(RT) for breast cancer (BC), with group with internal mammary<br />
chain (IMC) RT.<br />
Material and methods: Prospective study of 308 patients (pts)<br />
treated between 2000 and 2009 by concurrent trastuzumab with<br />
normofractionated RT for non-metastatic BC. Left ventricular ejection<br />
fraction (LVEF) was assessed by echocardiography or myocardial<br />
scintigraphy at baseline, before and after RT, every three months<br />
for one year, then annually. A LVEF strictly lower than 55%, was<br />
considered as altered. Trastuzumab was delivered every three weeks<br />
(8 mg/kg in the first infusion then 6 mg/kg) during a median time of<br />
12 months (3-62). All toxicities were evaluated using the Common<br />
Terminology Criteria for Adverse Effects version 3.0. Survival data<br />
were defined as the time from the histological diagnosis of BC until<br />
occurrence of the event. Loco-regional recurrence free- and alive pts<br />
were censored at the date of their last known contact. Survival and<br />
interval rates as well as their confidence interval (CI) were calculated<br />
using the Kaplan–Meier method.<br />
Results: Median age was 52 years (25-83). Median follow-up was<br />
50 months (13-126). The clinical tumour staging was: T0 or T1 in<br />
131 pts (43.4%), T2 in 122 pts (40.4%), T3 or T4 in 49 pts (16.2%).<br />
The regional lymph nodes were histologically involved in 132 pts<br />
(43.0%). The left breast was treated in 155 pts (50.3%). The IMC<br />
was irradiated in 227 pts (73.7%), among them 114 (37.0%) in the<br />
left side. Before trastuzumab, anthracycline-based regimens were<br />
administered in 280 pts (90.9%). The median dose of trastuzumab<br />
was 6145 mg (1845-29180). Acute skin toxicity was acceptable with<br />
226 (74.1%) grade 1, 67 (22.0%) grade 2 and 12 (3.9%) grade 3 skin<br />
reactions. Esophagitis was observed in 31 pts (10.0%): 26 (8.4%)<br />
grade 1; 4 (1.3%) grade 2, and 1 (0.3%) grade 3. Out of 286 pts with<br />
assessments at the median time of 23 months, late telangiectasia grade<br />
1 occurred in 14 pts (4.9%) and grade 2 in 10 pts (3.5%), local pain<br />
grade 1 in 39 pts (13.7%) and grade 2 in 8 pts (2.8%), fibrosis grade<br />
1 in 53 pts (18.6%) and grade 2 in 20 pts (7.0%). At the completion<br />
of RT, 11 pts (3.6%), whose cardiologic assessment at baseline was<br />
normal, presented a clinically silent LVEF alteration. During followup,<br />
44 patients experienced cardio-vascular morbidity revealed by:<br />
asymptomatic LVEF alteration (50.0%), thrombo-embolic event<br />
(18.2%), tachycardia (15.9%), ischemic cardiomyopathy (6.8%),<br />
pericarditis (4.5%), hypertrophic cardiomyopathy (2.3%) or arterial<br />
hypertension (2.3%). The cumulative incidence of these events at 48<br />
months was 13.3% CI95% [9.4; 17.2]. A symptomatic congestive<br />
heart failure was reported for 3 pts (1.0%). No death of cardiac origin<br />
was observed. At 48 months, loco-regional control was 95% CI95%<br />
[92; 98] and overall survival was 98% CI95% [96; 100].<br />
Conclusions: In this prospective study of BC pts treated with<br />
trastuzumab and RT, both the rates of skin and esophageal toxicities<br />
were acceptable with excellent local control. Further follow-up is<br />
warranted to assess late cardiac toxicity.<br />
P5-21-04<br />
Real-world use and effectiveness of adjuvant trastuzumab in 2665<br />
consecutive breast cancer patients<br />
Tjan-Heijnen VCG, Seferina SC, Lobbezoo DJA, Voogd AC,<br />
Dercksen MW, van den Berkmortel F, van Kampen RJW, van de<br />
Wouw AJ, Joore MA, Borm GF. Maastricht University Medical<br />
Centre, Maastricht, Limburg, Netherlands; GROW-School for<br />
Oncology and Developmental Biology, Maastricht University<br />
Medical Centre, Maastricht, Limburg, Netherlands; Máxima Medical<br />
Centre, Veldhoven, Brabant, Netherlands; Atrium Medical Centre<br />
Parkstad, Heerlen, Limburg, Netherlands; Orbis Medical Center,<br />
Sittard-Geleen, Limburg, Netherlands; VieCuri Medical Centre,<br />
Venlo, Limburg, Netherlands; Radboud University Medical Center,<br />
Nijmegen, Gelderland, Netherlands<br />
Background The impact of drug prescriptions in the real world as<br />
opposed to strict trial prescription is only rarely assessed even though<br />
it is well recognized that incorrect use may harm a patient and may<br />
have a huge impact on health care resources. We aimed to assess<br />
how and to whom trastuzumab was given since its introduction in<br />
September 2005 as adjuvant treatment, and to assess its efficacy in<br />
daily practice.<br />
Patient and methods We set up a registry of all patients diagnosed<br />
with stage I-III invasive breast cancer in 5 Dutch hospitals during the<br />
years 2005-2007. Patients were included irrespective of HER2 status<br />
and of treatment received. We present the main patient and tumor<br />
characteristics, treatment delivered and 5-year treatment outcomes.<br />
Results Of 2665 patients included, n=479 (18%) had a HER2 positive<br />
tumor. As of September 2005, adjuvant trastuzumab was given to<br />
96% of patients with a HER2 positive tumor receiving adjuvant<br />
chemotherapy. The median age of these patients was 51 (27 - 72)<br />
years. Their median tumor size was 23 (5 - 65) mm, 55% had nodepositive,<br />
57% ER-positive and 47% PR-positive disease. In 83% of<br />
patients, trastuzumab was delivered in sequence after (taxane-based)<br />
chemotherapy, mainly in the first years after introduction, and in 91%<br />
in a 3-weekly regimen. Trastuzumab was delivered for a median of<br />
49 (IQR 45 - 52) weeks. For patients with a HER2 positive tumor<br />
www.aacrjournals.org 485s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
treated with adjuvant trastuzumab (n=232), the five-year disease-free<br />
survival was 81%. For patients with a HER2 positive tumor who<br />
were not treated with trastuzumab (n=247) the five-year disease-free<br />
survival was 75% (p=0.13). Corresponding 5-year overall survival<br />
rates were 91% and 78%, respectively (p=0.0002).<br />
Conclusion In the Netherlands, trastuzumab was rapidly implemented<br />
since its introduction in September 2005. Characteristics of patients<br />
treated with trastuzumab resembled those included in the HERA study.<br />
Similarly, outcomes were in agreement with reported phase III studies.<br />
More detailed and multivariate analyses will be shown at the meeting.<br />
Funding Netherlands Organization for Health Research and<br />
Development (ZonMw: 80-82500-98-9056) and Roche Netherlands.<br />
P6-01-01<br />
Metastatic and non-metastatic isogenic breast cancer cells lines<br />
show different metabolic signatures in response to intermittent<br />
hypoxia and transient glutamine/glucose deprivation<br />
Simoes RV, Ackerstaff E, Serganova I, Kruchevsky N, Sukenick G,<br />
Blasberg R, Koutcher JA. Memorial Sloan-Kettering <strong>Cancer</strong> Center,<br />
New York, NY; Cornell University, New York, NY<br />
INTRODUCTION. <strong>Cancer</strong> cells quickly adapt to their<br />
microenvironment by reprogramming their metabolism. Specific<br />
metabolic responses to defined stress conditions, mimicking tumor<br />
microenvironmental changes, may therefore unveil signatures of<br />
cancer phenotype, not detected in standard tissue culture.<br />
PURPOSE. To identify distinct metabolic signatures associated with<br />
metastatic ability, we investigated in the two isogenic breast cancer<br />
cell lines, 4T1 (highly metastatic) and 67NR (non-metastatic), how<br />
glutamine supply/deprivation affects cellular glucose metabolism,<br />
and vice-versa, in aerobic or hypoxic conditions, and the effects on<br />
cell growth.<br />
METHODS. 4T1 and 67NR cells were cultured in medium A, i.e.<br />
DME containing 1% P/S, 10% FBS, 25 mM glucose (Glc), and 6 mM<br />
glutamine (Gln). Cell growth was determined in tissue culture from<br />
cells cultured for 48 h in various media A-D: A, all nutrients available;<br />
B: A but no Gln; C: A but 2 mM Gln; D: A but no Glc. Cellular<br />
mitochondrial function was also assessed in both 4T1 and 67NR cells<br />
using an XF96 Analyzer (Sea Horse Bioscience, Billerica, MA) and<br />
the specific inhibitors: oligomycin, FCCP, antimycin and rotenone.<br />
Metabolism was studied in cells grown on microcarriers in the various<br />
media A-D under aerobic (∼21% O2) and hypoxic conditions (∼1%<br />
O2), using our magnetic resonance (MR)-compatible cell perfusion<br />
system on a 500 MHz spectrometer. For the cell perfusion studies,<br />
Glc or Gln were exchanged for 1-13C-Glc or 3-13C-Gln respectively.<br />
The metabolic fate of 13C-labeled nutrients was followed under the<br />
various environmental conditions by 13C MR spectroscopy (MRS),<br />
while energy metabolism was observed by 31P MRS.<br />
RESULTS. Deprivation of either Glc or Gln for 48 h reduced<br />
significantly the cell growth of 4T1 and 67NR cells, resulting in a<br />
similar growth rate for the nutrient-deprived 4T1 and 67NR cells.<br />
As determined from the MR experiments, each cell line adopted<br />
different metabolic strategies to cope when exposed to specific<br />
metabolite stress conditions, including on the level of oxygen<br />
availability. Unlike in 67NR cells, glycolysis is glutamine-dependent<br />
in the more aggressive 4T1 cell line (∼2-fold higher glucose-derived<br />
lactate synthesis rate was observed in the presence of glutamine),<br />
which decreases when oxygen becomes available to fuel TCA cycle<br />
activity, as monitored by glucose-derived glutamate synthesis. The<br />
studies further indicate an impaired TCA cycle activity in 67NR<br />
cells, reflected in a high accumulation rate of glucose- or glutaminederived<br />
succinate (significantly higher compared to 4T1 cells). This is<br />
consistent with the mitochondrial functional analysis, showing higher<br />
mitochondrial TCA activity in 4T1 cells than in 67NR, most likely<br />
due to impairment of succinate dehydrogenase (SDH, respiratory<br />
Complex II) in the latter.<br />
CONCLUSIONS. Our results support the association between<br />
increased mitochondrial metabolism and metastatic potential,<br />
observed recently. We are investigating the SDH status in these cells<br />
lines and in additional metastatic and non-metastatic breast cancer<br />
cell lines, to establish whether SDH, and glutamine metabolism, could<br />
be potential targets for therapy.<br />
P6-01-02<br />
Adipose tissue from breast cancer patients with the metabolic<br />
syndrome promotes proliferation and invasion of tumor cells<br />
and influences expression of genes involved in carcinogenesis.<br />
McGarrigle SA, Carroll PA, Healy LA, Boyle T, Pidgeon GP, Kennedy<br />
MJ, Connolly EM. Trinity College Dublin and St. James’s Hospital,<br />
Dublin, Ireland<br />
Background<br />
Obesity is a public health issue of global proportions and is recognised<br />
as a risk factor for post-menopausal breast cancer. Similarly, the<br />
metabolic syndrome (MetS) is recognised as a high risk state for<br />
cancer in general. Previously we have shown that the MetS is common<br />
in postmenopausal breast cancer patients and is associated with a more<br />
aggressive tumor biology. However, the molecular mechanisms by<br />
which obesity and/or the MetS promote breast cancer remain unclear.<br />
Adipose tissue, including mammary fat, is a functionally active<br />
endocrine organ. The aims of this study were to determine whether<br />
factors secreted by mammary adipose tissue could affect tumor cell<br />
biology and to assess the effect of the MetS on this adipose depot<br />
and its subsequent effect on tumor cells.<br />
Methods<br />
Adipose tissue from fresh mastectomy specimens was cultured in<br />
serum free media for 72 h to produce adipose conditioned media<br />
(ACM). MCF-7 and MDA-MB 231 cell lines were treated with ACM<br />
for 24-48 h. Tumor cell function was then assessed by measuring cell<br />
proliferation (BrDU assay) and cell invasion. In addition, expression<br />
of 84 genes implicated in pathways involved in carcinogenesis<br />
was examined in these cell lines following ACM treatment, using<br />
quantitative PCR arrays.<br />
Results<br />
In the estrogen receptor (ER) positive MCF-7 cell line, ACM<br />
from MetS breast cancer patients promoted significantly greater<br />
proliferation compared to ACM from normal weight patients (203.6<br />
± 34.23 vs 136.8 ± 11.58%, p =0.022). Similarly, ACM from MetS<br />
patients significantly increased invasion of MCF-7 cells compared to<br />
ACM from normal weight patients (153.4 ± 6.027 vs 126.3 ± 6.03%<br />
RFU, p =0.006). No differences in cell proliferation or invasion<br />
between cells treated with ACM from MetS patients compared to<br />
ACM from normal weight patients were found in the ER negative<br />
MDA-MB-231 cell line. Treatment of MCF-7 cells with ACM from<br />
MetS patients resulted in significant alterations (>2 fold up/down<br />
regulation) in expression of 11 genes involved in carcinogenesis.<br />
Primarily, genes implicated in invasion/metastasis and adhesion<br />
were differentially expressed between ACM-treated cells and cells<br />
treated with control media. On the other hand, when MDA-MB-231<br />
cells were treated with ACM from the same patients only one gene,<br />
SERPIN B5 was significantly up-regulated > 2 fold.<br />
Conclusions<br />
These data demonstrate that factors secreted from mammary adipose<br />
tissue from metabolically unhealthy patients promote proliferation<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
486s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
and invasion of ER positive tumor cells and influence expression of<br />
genes involved in carcinogenesis in these cells. These effects were<br />
not observed in ER negative tumor cells suggesting that they may<br />
be mediated, at least in part by the estrogen receptor. These results<br />
have provided insight into how mammary adipose tissue may act via<br />
a paracrine mechanism to influence aspects of carcinogenesis and into<br />
how the metabolic syndrome may modulate this.<br />
P6-01-03<br />
Decreasing the metastatic potential in Triple Negative <strong>Breast</strong><br />
<strong>Cancer</strong> through the miR-17 cluster<br />
Jin L, Simone B, <strong>San</strong>o Y, Lim M, Zhao S, Savage JE, Baserga<br />
R, Camphausen K, Simone NL. Thomas Jefferson University,<br />
Philadelphia, PA; National <strong>Cancer</strong> Institute, Bethesda, MD<br />
Background: In animal models of breast cancer, caloric restriction<br />
(CR), or a 25-30% reduction of calories, has decreased tumor initiation<br />
and progression. We sought to determine if CR could be used as a<br />
novel therapeutic intervention to enhance cytotoxic therapies such as<br />
radiation (RT) and alter the molecular profile of triple negative breast<br />
cancer (TNBC), which displays a poor prognosis.<br />
Methods/Results: In two murine models of TNBC (4T1 which is<br />
highly metastatic and 67NR which is locally aggressive), mice with<br />
palpable tumors were treated with radiation, caloric restriction (30%<br />
intake reduction) or both. 3 times per week measurements revealed<br />
significant tumor regression with RT or diet modification, and an even<br />
greater regression is observed combining diet modification with RT.<br />
Concurrently, many reports have shown that TNBC is most distinct<br />
from other breast tumor subtypes due to up-regulation of the miR-<br />
17-92 cluster which we have shown by RT-PCR is downregulated<br />
with both CR and radiation (RT) and even further decreased with<br />
the combination. cDNA arrays done on all conditions revealed that<br />
the top 5 statistically significant GO terms with high fold changes<br />
were all associated with extracellular matrix and metastases. In silico<br />
analysis demonstrated 5 ECM related genes that were targets of the<br />
miR-17 cluster: collagen 4 alpha 1 (COL4A1), collagen 4 alpha 3<br />
(COL4A3), laminin alpha 3 (LAMA3), metallopeptidase inhibitor<br />
2 and 3 (TIMP2 and TIMP3) and these were inversely correlated<br />
with the miRs.<br />
Conclusions: CR, or altering the metabolism of breast cancer, can<br />
be combined with RT to decrease progression of TNBC tumors and<br />
that the miR-17-92 cluster is also decreased with these conditions.<br />
cDNA arrays suggest that extracellular matrix (ECM) proteins play<br />
a large role in the mechanism of action of CR and RT combined.<br />
Combination therapy with CR and RT can decrease the metastatic<br />
potential in TNBC and in part does this through the miR-17-92 cluster<br />
by way of controlling ECM.<br />
P6-01-04<br />
DDB2 a new regulator of metabolism and cell death in human<br />
breast tumor cells<br />
Klotz R, Besancenot V, Brunner E, Becuwe P, Grandemange S.<br />
Université de Lorraine, Vandoeuvre les Nancy, France<br />
The protein Damaged DNA Binding-2 (DDB2) is well known for<br />
its role in DNA repair by nucleotide excision repair. Interestingly,<br />
DDB2 is differentially expressed in breast cancer expressing the<br />
estrogen receptor alpha or not. Recent works performed in our<br />
laboratory showed a new role of DDB2 in the control of proliferation<br />
and invasive abilities in different breast tumor cells through its<br />
involvement in the transcriptional regulation of target genes. Two<br />
genes involved in tumorigenic processes, MnSOD (manganese<br />
superoxide dismutase) and IκBα (inhibitor alpha of Nuclear Factorkappa<br />
B), have been found to be regulated by DDB2. In addition,<br />
transcriptomic analyses on cells that differentially express DDB2<br />
showed that several genes involved in the regulation of cellular<br />
metabolism are modulated. Our aim is now to focus on the effects of<br />
DDB2 expression on cellular metabolism and glycolysis. The results<br />
indicated that the overexpression of DDB2 leads to a respiratory chain<br />
dysfunction and an increase of the glycolytic pathway. Moreover,<br />
we observed an increased production of reactive oxygen species in<br />
these cells, compared to parental cells. As mitochondria are involved<br />
in cell death, we performed different experiments to evaluate the<br />
impact of DDB2 in the response to anticancer agents (Doxorubicin,<br />
and 5-fluorouracile (5-FU)) commonly used in the treatment of breast<br />
cancer. Interestingly, the cells exhibit a greater sensitivity to anticancer<br />
drugs when DDB2 is overexpressed. As these two agents are related<br />
to DNA damaged, we have also used other molecules, the apoptotic<br />
inducer, TNFα (Tumor Necrosis Factor alpha), and the Paclitaxel<br />
(an antimicrotubule agent) to precise the role of DDB2 on cell death.<br />
Similar results were obtained, thus demonstrating the influence of<br />
DDB2 overexpression in the response to cell death. The identification<br />
of molecular mechanisms responsible for these cellular modifications<br />
could place DDB2 and these target genes as predictive markers of<br />
sensitivity to anticancer drugs in breast cancer.<br />
P6-01-05<br />
Enhancement of 18 F-FDG uptake and glycolysis by epidermal<br />
growth factor via PI3K activation in T47D breast cancer cells<br />
Lee EJ, Park JW, Cung Q, Jung K-H, Lee JH, Paik J-Y, Lee K-H.<br />
Samsung Medical Center, Sungkyunkwan University School of<br />
Medicine, Seoul, Korea<br />
It is well known that the binding of epidermal growth factor (EGF)<br />
to EGF receptors (EGFR) stimulates proliferation of breast cancer<br />
cells via activation of mitogen-activated protein kinase (MAPK) and<br />
phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling<br />
pathways. There was a report that glucose consumption and lactate<br />
production were increased in MDA-MB-468 breast cancer cells<br />
following EGF exposure. However, the effect of EGF in enhancing<br />
glucose uptake and signaling pathways that are involved have not been<br />
clearly revealed. We thus investigated the role of EGF in stimulation<br />
of 18 F-FDG uptake in T47D breast cancer cells, and further elucidated<br />
the molecular mechanisms that are involved.<br />
Exposure of T47D cells to 100 ng/mL EGF for 24 h caused a<br />
substantial augmentation of 18 F-FDG uptake to even greater extents<br />
to 310.8% ± 30.1% of control cells (P < 0.001), and this effect<br />
of EGF showed dose- and time-dependency. Increased glucose<br />
uptake by EGF occurred through enhanced membrane GLUT-1<br />
expression as well as hexokinase activity. Inhibition experiments with<br />
cycloheximide showed that the metabolic effect by EGF required<br />
new protein biosynthesis. Stimulation of glucose uptake by EGF<br />
was dependent on sufficient EGFR expression because 18 F-FDG<br />
uptake in MCF-7 cells weakly expressing EGFR was not affected<br />
by EGF treatment. Although EGF was also a stimulator of T47D<br />
cell proliferation (137.3 ± 7.3% of basal levels at 24 h, P < 0.001),<br />
the metabolic effect occurred in a manner that clearly preceded and<br />
surpassed the proliferative effect. EGF-stimulated proliferation was<br />
significantly inhibited by the EGFR inhibitor BIBX1382, the PI3K<br />
inhibitor LY294002 and the specific MAPK inhibitor PD98059.<br />
Unlike proliferation, the ability of EGF to augment 18 F-FDG uptake<br />
was found to be dependent on PI3K but not on MAPK activity.<br />
These findings yield the insight into our understanding of the role of<br />
EGF and the molecular basis that are involved in glucose metabolism<br />
of breast cancer cells.<br />
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P6-02-01<br />
Apoptotic cell clearance lies at the interface of post-lactational<br />
involution and breast cancer<br />
Cook RS, Stanford JC, Earp S. Vanderbilt University; University of<br />
North Carolina<br />
Background. Cytokines that promote wound healing and immune<br />
tolerance are profoundly upregulated during post-lactational<br />
involution of the breast and promote tumor growth and malignancy.<br />
This observation is supported by increasing evidence that postlactational<br />
involution produces a highly malignant microenvironment<br />
contributing to poor outcome of pregnancy associated breast cancers<br />
(PABCs) which arise within 5 years of a full-term pregnancy. We<br />
have discovered that one mechanism driving cytokine modulation<br />
during post-lactational involution is efferocytosis, or the phagocytic<br />
clearance of apoptotic cells (ACs). Cell death is a prominent feature<br />
of the post-lactational breast, when up to 90% of the entire epithelial<br />
content dies and must be removed, making this an ideal model to study<br />
both apoptosis and AC clearance. Without efferocytosis, residual ACs<br />
undergo secondary necrosis, which stimulates acute inflammation<br />
and expression of Th1 cytokines. Thus, efferocytosis prevents<br />
secondary necrosis of dying cells, enhances immune tolerance and<br />
wound healing through production of Th2 cytokines. In healthy postlactational<br />
breast tissue this is an optimal physiological response that<br />
promotes breast remodeling. However, in the context of breast cancer,<br />
efferocytosis may be pro-tumorigenic.<br />
Results. We have shown that post-lactational efferocytosis is<br />
necessary to re-establish breast tissue homeostasis after lactation, and<br />
for re-initiating successful lactation after future pregnancies. We have<br />
also demonstrated that during the earliest phases of post-lactational<br />
involution, the breast epithelium is the primary phagocytic resource<br />
in the breast, although it is clear that macrophages engulf dying cells<br />
during later stages of involution. We have identified the receptor<br />
tyrosine kinase MerTK as a necessary mediator of efferocytosis and<br />
subsequent cytokine modulation during post-lactational involution.<br />
Further, MerTK-mediated cytokine changes in the post-lactational<br />
mammary microenvironment promotes malignant progression of<br />
spontaneously forming PABC in a transgenic mouse model, as<br />
genetic targeting of MerTK decreased tumor growth and metastasis<br />
without altering tumor latency. Post-lactational tumors expressed<br />
abundant Th2 and wound healing cytokines as compared to tumors<br />
in nulliparous mice. However, loss of MerTK in post-lactational<br />
mammary tumors impaired the expression of Th2 and wound healing<br />
cytokines, while inducing the expression of Th1 cytokines.<br />
Conclusion. These results suggest that efferocytosis-mediated<br />
cytokine regulation is a key driver of malignant severity in pregnancy<br />
associated mammary tumors. These data are consistent with our<br />
previous demonstrations that MerTK in the mammary tumor<br />
microenvironment increases tumor malignancy. Targeted inhibition<br />
of MerTK may decrease efferocytosis-mediated cytokine modulation<br />
in breast tumors to limit pro-tumorigenic cytokine production<br />
and stimulate production of cytokines associated with anti-tumor<br />
immunity.<br />
P6-02-02<br />
Altered matrix homeostasis regulates estrogen biosynthesis in<br />
adipose tissue<br />
Ghosh S, Ashcraft K, Li R. UT Health Science Center at <strong>San</strong> <strong>Antonio</strong>,<br />
TX<br />
Several estrogen-dependent pathological conditions including breast<br />
cancer, uterine fibroids, and endometriosis are associated with local<br />
overexpression of aromatase, a key enzyme in estrogen biosynthesis<br />
and important therapeutic target for postmenopausal ER+ breast<br />
cancer. In addition, excessive aromatase expression in adipose tissue<br />
at least partially accounts for obesity-associated breast cancer risk<br />
among postmenopausal women. While altered matrix homeostasis<br />
is associated with these aromatase-overexpressing tissues, little is<br />
known as to whether it can directly impact local steroidogenic gene<br />
expression and estrogen biosynthesis. A paucity of knowledge in<br />
this area is partly due to the lack of proper model systems that can<br />
recapitulate the mechanical properties of a cell’s microenvironment.<br />
Our data indicate that matrix alone can significantly stimulate<br />
aromatase transcription in breast stromal cells (BSCs) via distinct<br />
signaling pathways. With the help of a repertoire of molecular and<br />
biophysical tools, such as micropost, micropattern and polyacrylamide<br />
gel and 3-dimensional matrix culture, we determined that matrix<br />
rigidity and cellular shape play important role in the regulation of<br />
aromatase transcription in the BSCs. We further discovered that<br />
cytoskeleton dynamics can significantly alter the ECM-stimulated<br />
aromatase transcription in BSCs. Following careful and elaborate<br />
studies with the help of siRNA-mediated knockdown and overexpression<br />
of the individual factors, we found that a non-canonical<br />
collagen receptor member of discoidin domain receptor (DDR) family,<br />
DDR1, transduce the external signal inside the cells to facilitate<br />
the aromatase transcription. Further studies with siRNA-mediated<br />
knockdown and specific inhibitors revealed that DDR1 activates a<br />
signaling cascade, which promotes activation of the cJun kinase (JNK-<br />
1) by phosphorylation and subsequently the activation of Activation<br />
Protein-1 family member JunB. Activated JunB physically binds at<br />
the cancer-specific promoters of aromatase and induce transcription<br />
in stromal cells. To determine the consequence of the altered matrix<br />
generated aromatase on the growth of estrogen receptor (ER)-<br />
positive breast cancer cell lines we set up in vitro co-culture system.<br />
Proliferation of ZR75-1 and its ability to produce estrogen-stimulated<br />
genes were enhanced in multiple fold, when the cells were co-cultured<br />
physically with BSCs inside collagen or fed with BSC conditioned<br />
media in the presence of testosterone.<br />
The link between matrix homeostasis and hormone metabolism is<br />
a vastly under-explored topic. Results from our work has bridged a<br />
major gap of knowledge in this field. Findings from the study also<br />
identified new factors that are key for the tissue-specific activation<br />
of estrogen biosynthesis and provide novel prognostic tools and<br />
markers, as well as new therapeutic targets for reducing local estrogen<br />
production, thus overcoming the side effects often associated with<br />
systemic inhibition of aromatase. The proposed work promises to<br />
establish a novel paradigm for regulation of steroidogenic gene<br />
expression and estrogen production and may have a far-reaching<br />
impact on the etiology and treatment of endocrine diseases that are<br />
associated with altered matrix homeostasis.<br />
P6-02-03<br />
Mouse Models Of <strong>Breast</strong> <strong>Cancer</strong> Identify Oncogene-Specific<br />
Stroma Associated With Human <strong>Breast</strong> <strong>Cancer</strong> Molecular<br />
Subtypes<br />
Saleh SM, Laferriere J, Cory S, Souleimanova M, Zacksenhaus E,<br />
Muller W, Hallett M, Park M. McGill University, Montreal, QC,<br />
Canada; Toronto General Hospital, Toronto, ON, Canada<br />
<strong>Breast</strong> <strong>Cancer</strong> is a highly heterogeneous disease that involves a<br />
complex cross talk between the tumor cells and their surrounding<br />
microenvironment. Previous work in our lab has utilized laser capture<br />
microdissection (LCM) to isolate breast tumor epithelium as well as<br />
tumor associated stroma cells. These isolated cell populations were<br />
subjected to gene expression analysis, which separated the stroma<br />
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samples into distinct subtypes. Pairing these stroma subtypes with<br />
genomic subtypes resulted in pairs having different outcomes hinting<br />
at the importance of these interactions (Finak et al, In preparation).<br />
Although this and other data now support a role for stroma in tumor<br />
progression, it is still unclear how these distinct differences in the<br />
stroma are induced.<br />
We hypothesized that specific changes within stroma are related to<br />
the oncogenic event occurring in the tumor epithelium. The use of<br />
human data for analysis generates correlative conclusions due to<br />
compounding factors such as genetic variance and living conditions.<br />
In an attempt to get more causative results, we used transgenic mouse<br />
models of breast cancer within the same strain (FVB) and where<br />
the gene is driven by the same promoter (MMTV), changing only<br />
the oncogene: Wnt1, NeuNDL2-5, PyVMT and activated Met. This<br />
allowed us to link differences observed in the stroma back to the<br />
epithelial oncogenic change.<br />
Through the use of LCM, linear amplification of the RNA and<br />
hybridization to Agilent microarrays, we generated a combined dataset<br />
of 33 samples including adjacent tumor epithelial, tumor stroma,<br />
in addition to pooled whole tumour samples and a pooled normal<br />
mammary fat pad sample, as control tissue. Unsupervised clustering<br />
of the most variable genes confirmed that the LCM isolated epithelial<br />
and stroma compartments specifically.<br />
Hierarchal clustering of the most variable genes was also used to<br />
determine the number of stroma groups. This approach revealed that<br />
there were 4 oncogene associated stroma groups, confirming that each<br />
of the oncogenes generated distinct stroma subtypes.<br />
Using the Rank Product package to compare each stroma group<br />
against the others identified over 1000 differentially expressed<br />
genes defining the stroma subtypes. Pathway analysis of these genes<br />
identified differences in both cell recruitment and pathway activation.<br />
To understand if these stroma classes were relevant to the human<br />
disease, the mouse stromal genes were used to order a large human<br />
whole tumour dataset using the BreSAT ordering (Lesurf et al, In<br />
preparation). This showed that the mouse models shared similarities<br />
with human samples from different molecular subtypes.<br />
P6-02-04<br />
TMEM (Tumor MicroEnvironment of Metastasis) in human<br />
breast cancer is a blood vessel associated intravasation<br />
microenvironment unrelated to lymphatics<br />
Ginter PS, Robinson BD, D’Alfonso TM, Oktay MH, Gertler FB,<br />
Rohan TE, Condeelis JS, Jones JG. Weill Cornell Medical College,<br />
New York, NY; Albert Einstein College of Medicine, Bronx, NY;<br />
Massachusetts Institute of Technology, Cambridge, MA<br />
In breast cancer, both lymph node and distant metastasis represent<br />
dissemination of tumor cells from a primary site, but the mechanism<br />
of spread and the subsequent risk of mortality may not be the<br />
same. Historically, lymphatic spread has been documented both<br />
descriptively, as presence or absence of lymphovascular invasion<br />
(LVI), and as a formal part of TNM staging. Until recently, however,<br />
there has been no way to directly assess the risk of hematogenous<br />
dissemination by the primary tumor.<br />
Observations from multiphoton-based intravital imaging of rodent<br />
models of breast cancer and the analysis of Mena function in tumor<br />
cells in vivo have characterized an intravasation microenvironment<br />
(ME) involved in the systemic dissemination of tumor cells from<br />
primary breast tumors. We have identified the corresponding structure<br />
in FFPE tissue and called it TMEM (Tumor MicroEnvironment of<br />
Metastasis). This microanatomic landmark is defined as the direct<br />
apposition of a Mena-overexpressing intravasation competent<br />
carcinoma cell, a perivascular macrophage, and an endothelial cell.<br />
In a case control study of 30 case-control pairs, where each matched<br />
pair differed only in their metastatic status – non-metastatic vs.<br />
metastatic – we found that the density of TMEM was significantly<br />
associated with development of systemic metastasis (p = 0.00006).<br />
The relationship of hematogenous- and lymphatic-mediated tumor<br />
cell spread is not understood. Using the previously described cohort<br />
in which we showed that TMEM was associated with metastasis,<br />
the purpose of this study was to 1) assess intratumoral lymphatic<br />
density, 2) determine if TMEM- lymphatic structures associated with<br />
lymphatics exist, and 3) determine if TMEM- lymphatic structures<br />
correlate with systemic metastatic risk. Cases were stained with a<br />
triple immunostain identical to that used in our earlier study except<br />
that D2-40 (a lymphatic marker) was used, rather than CD31 (a blood<br />
vessel marker). The marker for macrophages (CD68) and invasive<br />
tumor cells (Mena) remained the same. Two pathologists, blinded to<br />
outcome, evaluated the presence or absence of intratumoral lymphatics<br />
and quantitated the number of TMEM-lymphatic structures per 10<br />
high power (400x) fields in areas of highest intratumoral lymphatic<br />
density. A TMEM-lymphatic structure was defined as the direct<br />
apposition of a lymphatic (D2-40) endothelial cell with a macrophage<br />
and invasive tumor cell.<br />
Intratumoral lymphatics were absent in a majority of tumors in each<br />
of the 2 groups (18 of 30 non-metastatic, 16 of 30 metastatic; p=0.6).<br />
TMEM-lymphatic structures were rare and were equally present in<br />
the 2 groups (3 metastatic and 3 non-metastatic cases). Using the<br />
Wilcoxon (paired) signed-rank test, we found no significant difference<br />
in the density of these structures between the two groups (p = 0.4).<br />
Furthermore, TMEM-lymphatic structures did not correlate with<br />
the presence of lymph node metastases (p=0.8). We conclude that<br />
lymphatic vessels do not participate in the TMEM assembly that<br />
has been associated with hematogenous metastasis. TMEM density<br />
assessment reflects a hematogenous intravasation ME and offers a<br />
novel approach to the assessment of metastatic risk.<br />
P6-02-05<br />
A novel culturing 3-D model to evaluate the role of tumor<br />
microenvironment in IBC.<br />
Dong X, Franco-Barraza J, Mu Z, Alpaugh RK, Cristofanilli M,<br />
Cukierman E. Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA<br />
Introduction: Inflammatory breast cancer (IBC) is a highly aggressive<br />
form of breast cancer associated with extremely poor outcomes.<br />
The clinical and pathological characteristics of the disease are the<br />
peculiar invasion of the dermal lymphatics as tumor emboli and the<br />
development of early recurrences. We aimed to establish a 3D model<br />
to evaluate the role of tumor microenvironment.<br />
Methods: We used human tumor-associated fibroblasts (or fibroblasts<br />
derived from metastatic skin) from IBC patients to build a multilayer<br />
extracellular matrix structure which effectively mimics aspects of<br />
the mesenchymal microenvironment of IBCs. Using this in vivo-like<br />
microenvironment we proceeded to test both matrix effects upon<br />
IBC’s phenotypes and IBC modifications upon the cell-derived 3D<br />
matrices.<br />
We seeded the IBC cells into the matrix and cultured for 3 days,<br />
then tested the characterization markers cancer cells and ECM<br />
e.g.Phalloidin, E-cadherin, Ki67, α5β1 integrin and fibronectin by<br />
immunofluorescence and the expression of E-cadherin and vimentin as<br />
marker of epithelial-mesenchymal transition (EMT) by western blot.<br />
Results: We divided six IBC cell lines into 2 groups depending<br />
on the phenotypes acquired when cultured in the IBC fibroblastderived<br />
ECM. SUM149 (EGF receptor positive and aggressive<br />
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phenotype), BR016 and LG018 (harvested from patient’s pleural<br />
effusions) presented a single cell organization with a spindle-like or<br />
mesenchymal type (as opposed to cluster) morphology. In comparison,<br />
SUM190 (HER2 positive and non aggressive tumorigenesis),<br />
MDA-IBC-3 and FC-IBC-02 (abstracted from patient’s pleural<br />
effusion) presented a phenotype resembling mammospheres or in<br />
vivo emboli. Moreover, this last group of cells showed a peculiar<br />
capability for ECM modifications which greatly differed from the<br />
ECM modifications that were apparent following 3 day culturing of<br />
the above mentioned group represented by SUM149. In addition,<br />
proliferation measurements by Ki67 expression demonstrated a<br />
significant increased in 3D culture for SUM149, BR016 and LG018<br />
compared with that in 2D culture, while no differences in proliferation<br />
were observed in the other three cell lines. Moreover, the expression<br />
of E-cadherin known to be upregulated in IBC tumors was increased<br />
in all cancer cells when seeded into the human fibroblast-derived<br />
3D matrix indicating a potential role of the microenvironment in<br />
promoting proliferation, growth and invasion.<br />
Conclusion: The present study demonstrated the establishment of<br />
a novel IBC stromal 3D model using extracellular matrix produced<br />
from human fibroblasts of patients with advanced IBC. We showed a<br />
dynamic interaction between cancer cells and the microenvironment<br />
and potential sorting of IBC cells into two discrete groups which also<br />
correlate with their aggressive behaviors in vivo. We believe that these<br />
system may serve to predict levels of IBC tumorigenesis. We will<br />
proceed to further study the two identified responsive phenotypes with<br />
the goal of uncovering mechanisms of IBC tumor-stromal interactions<br />
and better understand ECM influences upon IBC development and<br />
progression. The ultimate goal will be to use the system to study IBC<br />
biology and better design drugs that will specifically affect the newly<br />
identified phenotypes.<br />
P6-02-06<br />
A 3D tri-culture model of normal mammary gland. A tool for<br />
breast cancer initiation studies<br />
Nash CE, Holliday DL, Mavria G, Tomlinson DC, Hanby AM, Speirs<br />
V. Leeds Institute of Molecular Medicine, The University of Leeds,<br />
Leeds, West Yorkshire, United Kingdom<br />
The mechanisms involved in breast cancer initiation are not well<br />
understood. This may in part be due to a lack of an in vitro model<br />
that faithfully recapitulates the morphology, phenotype and in vivo<br />
architecture of the human mammary gland. Most in vitro models<br />
of normal breast have relied on the use of reconstituted basement<br />
membrane gels to induce luminal epithelial cell polarity and have<br />
neglected the role of myoepithelial cells and fibroblasts in this process.<br />
We aimed to develop a 3D in vitro culture system of normal breast<br />
which includes three of the major functional cell types embedded<br />
in a more physiologically relevant collagen 1 matrix. We used this<br />
system to investigate the mechanisms behind breast cancer initiation<br />
via genetic manipulation of some well known oncogenes and tumour<br />
suppressors involved in breast cancer progression.<br />
Myoepithelial cells (Myo1089) and fibroblasts (generated in house)<br />
were isolated and immortalised from breast reduction mammoplasty<br />
samples collected with ethical approval. Following characterisation,<br />
these were virally transfected with Enhanced Green Fluorescent<br />
Protein (EGFP) and dsRed protein respectively to enable tracking.<br />
3D cultures were established in collagen 1 and included the nontumorigenic<br />
luminal epithelial cell line HB2, EGFP Myo1089 cells<br />
and dsRed fibroblasts. Cells were cultured for 3 weeks in Transwell<br />
cell culture inserts. Following fixation these were analysed by H&E,<br />
confocal microscopy and immunohistochemistry. Morphology and<br />
immunostaining profiles were compared to sections of normal breast<br />
tissue.<br />
Immunohistochemical characterisation using the following antibodies:<br />
E-cadherin, epithelial membrane antigen, vimentin, laminin 5,<br />
collagen 4 plus luminal and basal cytokeratins, demonstrated polarised<br />
epithelial structures with lumen formation and basement membrane<br />
production with a similar immunostaining profile to normal breast<br />
tissue. The importance of including myoepithelial cells and fibroblasts<br />
in maintaining these structures was demonstrated. We established this<br />
model is amenable to genetic manipulation by overexpressing Her2 in<br />
HB2 cells, and knocking out ERβ1 in EGFP Myo1089 cells and Rac1<br />
and Dock4 in dsRed fibroblast cell lines using shRNA techniques.<br />
These were included in separate models with morphological and<br />
phenotypic effects determined by confocal microscopy.<br />
In summary we have developed an in vitro model of normal breast<br />
tissue that includes three of the major functional breast cell types<br />
cultured in a physiologically relevant 3D matrix. We have validated<br />
the morphology and protein expression profile against human breast<br />
tissue specimens and confirm that this is a suitable model of normal<br />
breast. The model is suitable for experimental manipulation and<br />
cell behaviour can be easily visualised using standard laboratory<br />
techniques. We conclude this is a robust in vitro model of normal<br />
breast tissue offering an alternative cost-effective method of studying<br />
genes involved in breast cancer initiation.<br />
P6-02-07<br />
In vitro 3D Model of <strong>Breast</strong> Tumor Stroma<br />
Jaganathan H, Mitra S, Dave B, Godin B. The Methodist Hospital<br />
Research Institute, Houston, TX<br />
One in eight women is diagnosed with breast cancer in the United<br />
States every year. Despite advancements for early diagnosis and<br />
initial treatment of breast cancer, the complexity and multiplicity of<br />
biological factors and barriers in tumor microenvironment prevent<br />
potent active agents from reaching their targets in cancer cells.<br />
There has been a growing body of evidence about the importance of<br />
three-dimensional (3D) culture systems in discovery and modeling<br />
of biological processes with in vivo relevance. A few examples that<br />
have been reported in 3D monocultures include different growth<br />
patterns of normal and malignant breast cancer cells in 3D cultures of<br />
laminin-rich gels and effect on cell polarity pathways. These effects<br />
are not observed in conventional two-dimensional (2D) cultures,<br />
showing that cells organized in a 3D matrix can shed light on novel<br />
mechanisms in breast cancer biology. Moreover, neither 2D nor<br />
3D monoculture models available today mimic the complexity of<br />
clinically observed tumor microenvironment (tumor stroma), which<br />
also contains fibroblasts, macrophages and endothelial cells and<br />
represents an important physiological barrier for efficient delivery of<br />
therapeutics to breast tumors. In this work we propose and investigate<br />
an in vitro system mimicking the tumor microenvironment in which<br />
relevant cell populations in tumor microenvironment are co-cultured<br />
with breast cancer cells*. The system uses the Nano3D® platform<br />
based on magnetic levitation. 3D tumor models for breast cancer were<br />
designed and optimized by co-culturing SUM159 and MDA-MB-231,<br />
triple negative breast cancer cells, with 293T fibroblasts. The cells<br />
were co-cultured at different ratios and for a various time periods.<br />
Further, to assess the similarity of the in vitro system to the in vivo<br />
disease, we tested an an orthotopic model of breast cancer in SCID<br />
beige mice. Histological analysis of frozen tissues from in vitro and<br />
in vivo studies confirmed that the in vitro 3D system based on the<br />
mixture of fibroblasts and cancer cells has structural similarities to<br />
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the in vivo observed tumor stroma. Engineering an in vitro 3D tumor<br />
model that accurately represents the in vivo tumor will further benefit<br />
research efforts in breast cancer diagnosis and therapy.<br />
*Patent pending – inventors: B. Godin, G. Souza, and B. Dave<br />
Acknowledgments: The authors acknowledge a financial support<br />
from the Susan G. Komen Postdoctoral Fellowship #<strong>PDF</strong>12229449.<br />
P6-02-08<br />
Molecular drivers of adipogenotoxicosis in breast tumorassociated<br />
adipose<br />
Ellsworth RE, Field LA, van Laar R, Deyarmin B, Hooke JA, Shriver<br />
CD. Windber Research Institute, Windber, PA; Signal Genetics, New<br />
York, NY; Walter Reed National Military Medical Center, Bethesda,<br />
MD; Henry M. Jackson Foundation, Windber, PA<br />
Background: Having long been thought to function only as an inert<br />
energy storage depot, the role of adipose tissue in tumorigenesis has<br />
been largely ignored; however, adipose is an active endocrine organ<br />
that can directly influence tumor growth. Improved understanding of<br />
the role of adipose in tumorigenesis is crucial given the association<br />
between obesity and breast cancer risk in post-menopausal women,<br />
increasing rates of obesity and use of autologous fat transfer in breast<br />
reconstruction.<br />
Methods: Adipose, adjacent to and distant from (>3 cm from<br />
the closest tumor margin) invasive breast tumors, was laser<br />
microdissected from 20 post-menopausal women, and from 22<br />
post-menopausal women with non-malignant breast disease. Gene<br />
expression data were generated using U133A 2.0 microarrays. Data<br />
were analyzed to identify significant patterns of differential expression<br />
between adipose classes at the individual gene and molecular pathway<br />
level. Gene expression differences were validated using qRT-PCR in<br />
an additional set of 29 specimens.<br />
Results: SPP1, RRM2, MMP9 and PLA2G7 were expressed at >3-<br />
fold (P3-fold higher expression<br />
of EGFL6 and ITGB2 and >3-fold lower levels of PIP, which are<br />
involved in growth, proliferation, and cellular adhesion in adjacent<br />
compared to non-malignant adipose. Pathway analysis revealed that<br />
immune response differs between non-malignant, distant and tumoradjacent<br />
adipose with an enhanced B- and T-cell response detected in<br />
adjacent compared to distant or non-malignant adipose. Inflammatory<br />
response as well as DNA transcription and replication pathways were<br />
differentially expressed in distant compared to non-malignant adipose.<br />
Conclusions: Gene expression levels differ in breast adipose<br />
depending on presence of and proximity to tumor cells. Adipose<br />
adjacent to the tumor demonstrated the largest immune response,<br />
supporting the idea of adipogenotoxicosis, which through proinflammatory<br />
and genotoxic responses, promotes tumor development.<br />
In addition, genes involved in cellular proliferation, degradation of the<br />
extracellular matrix and angiogenesis are differentially expressed in<br />
adjacent compared to distant or non-malignant adipose, thus tumoradjacent<br />
adipose may be contributing to the growth and invasion of<br />
the primary tumor. These data thus suggest that adipose is not an<br />
inert component of the breast microenvironment but plays an active<br />
role in tumorigenesis.<br />
P6-02-09<br />
Role of HGF in obesity-associated tumorigenesis: C3(1)-Tag mice<br />
as a model for human basal-like breast cancer<br />
Sundaram S, Freemerman AJ, Hamilton J, McNaughton K, Galanko<br />
JA, Darr DB, Perou CM, Troester MA, Makowski L. University of<br />
North Carolina at Chapel Hill, Chapel Hill, NC<br />
Obesity is associated with basal-like breast cancer (BBC), an<br />
aggressive breast cancer subtype. The objective of this study was to<br />
determine whether high fat diet-induced obesity promotes BBC onset<br />
in adulthood and to evaluate the role of stromal-epithelial interactions<br />
in obesity-associated tumorigenesis. Specifically, we hypothesized<br />
that hepatocyte growth factor (HGF) plays a promoting role in BBC,<br />
which tends to express the HGF receptor, c-Met. In C3(1)-Tag mice,<br />
a murine model of BBC, we demonstrate that obesity leads to a<br />
significant increase in HGF secretion and an associated decrease in<br />
tumor latency. By immunohistochemical analysis, normal mammary<br />
tissue exhibit obesity-induced hepatocyte growth factor (HGF) in<br />
stroma and corresponding epithelial expression of c-Met. HGF<br />
secretion was also increased in primary mammary fibroblasts isolated<br />
from normal mammary and tumors of obese mice compared to lean.<br />
These results show that diet-induced elevation of HGF expression is a<br />
stable phenotype, maintained after several passages and after removal<br />
of dietary stimulation. In cocultures, neutralization of HGF blunted<br />
tumor cell migration; further linking diet-mediated HGF-dependent<br />
effects in tumor aggressiveness. In sum, these results suggest that<br />
HGF plays an important role in obesity-associated carcinogenesis and<br />
raise the hypothesis that diet may affect lasting changes in stroma,<br />
potentially through epigenetic means. Understanding the effects of<br />
obesity on risk and progression is important given epidemiologic<br />
studies that imply half of BBC could be eliminated by reducing<br />
obesity. Our findings suggest the possibility that reducing obesity may<br />
be useful in preventing obesity-associated breast cancer mediated by<br />
the HGF/c-Met pathway.<br />
P6-03-01<br />
Molecular Dissection of <strong>Breast</strong> Luminal Cell Transcription<br />
Factor Networks<br />
Bargiacchi FG, Earp HS, Perou CM. University of North Carolina<br />
Chapel Hill, NC<br />
During mammary development, cellular differentiation and lineage<br />
commitment are driven by distinct growth cycles under the control<br />
of local epithelial and mesenchymal paracrine signaling mechanisms.<br />
Within the mammary gland are multipotent stem cells, which give rise<br />
to luminal and myoepithelial lineages. The mechanisms that govern<br />
differentiation into these distinct cell populations are not completely<br />
understood, yet critically important for a complete understanding of<br />
normal development and breast tumorigenesis. Recent studies have<br />
shown that retroviral transduction of mouse and human fibroblasts<br />
with four transcription factors can initiate the conversion of a somatic<br />
cell into an embryonic stem cell-like state, with capabilities of<br />
differentiating into cell types of all three germ layers. The generation<br />
of induced pluripotent stem cells (iPS) illustrates that transformation<br />
of a mature cell into a more immature state can erase most epigenetic<br />
programming critical for the differentiation of that cell. Our goal is<br />
to determine whether mammary specific transcription factors can<br />
directly transdifferentiate fibroblasts or human mammary epithelial<br />
cells (HMEC) into functionally differentiated ER+/luminal cells.<br />
To address this goal of creating ER+/luminal cells via an iPS<br />
type approach, we have developed a model in which an hTERT –<br />
immortalized human mammary epithelial cell line are transduced<br />
utilizing a multifunctional lentiviral expression vector system,<br />
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which allows the simultaneous expression and/or silencing of<br />
multiple candidate genes. We are investigating the abilities of various<br />
combinations of transcription factors (TFs) to convert somatic<br />
cells to fully functional differentiated mammary epithelial cells.<br />
Nine candidate TFs (including ER , GATA3, FOXA1, XBP1 and<br />
CDKN2C) were chosen based upon their differential expression in<br />
genomic transcriptional data set of primary human breast tumors,<br />
and in fluorescence-activated cell sorting (FACS) of normal breast<br />
cell populations. These TFs are highly expressed in ER+/luminal<br />
cells, and some are known to be important lineage-specific factors.<br />
Ectopic overexpression of these cDNAs in HMECs indicated<br />
that these transcription factors have both unique and overlapping<br />
contributions towards inducing the expression of genes responsible<br />
for luminal differentiation. Examining the expression patterns of<br />
individually transduced cells using a classifier of differentiation<br />
status (Differentiation Score, Prat et al. 2010) identified several genes,<br />
including ESR1 and GATA3, as causing a transition towards the<br />
luminal subtype. These individual gene data will guide the selection<br />
of combinations, since we anticipate that, as was seen for iPS cells,<br />
multiple genes will be required for transdifferentiation into the luminal<br />
cell lineage. Since there are presently no cell lines or mouse models<br />
of Luminal A/ER+ breast cancers, the artificial creation of such of a<br />
cell line would be of great value.<br />
P6-04-01<br />
Global analysis of breast cancer metastasis suggests cellular<br />
reprogramming is central to the endocrine resistant phenotype.<br />
Bolger JC, McCartan D, Walsh CA, Hao Y, Hughes E, Byrne C, Hill<br />
ADK, O’Gaora P, Young LS. Royal College of Surgeons in Ireland,<br />
Dublin 2, Ireland; University College Dublin, Ireland<br />
The development of breast cancer resistance to endocrine therapy<br />
results from altered cellular plasticity leading to the emergence of<br />
a hormone independent tumour. We have previously shown that the<br />
endocrine resistant phenotype is poorly differentiated and has greater<br />
metastatic potential when compared with an endocrine sensitive<br />
phenotype. The underlying mechanism of how an ER positive,<br />
endocrine sensitive tumour can turn on these adaptive mechanisms<br />
remains unresolved. We hypothesise that cellular reprogramming<br />
can occur as a result of long-term exposure to endocrine treatment<br />
which manifests clinically as tumour recurrence. Our aim was to<br />
identify the mechanism of breast cancer cellular reprogramming in<br />
a clinical context.<br />
In this study we adopted a global approach to define transcriptional<br />
networks significantly elevated in the breast cancer metastatic<br />
setting. Using RNAseq we determined the gene expression profile<br />
of three ER positive patients who developed tumour recurrence on<br />
tamoxifen treatment. RNAseq was performed on primary tumours,<br />
axillary node metastases and subsequent distant metastases. Following<br />
bioinformatic analysis, we defined the genes that were significantly<br />
elevated in the metastatic tumours. In the metastases, genes clustered<br />
away from those in the primary and node, with 209 genes uniquely<br />
elevated in the metastatic context, suggesting altered gene expression<br />
in response to endocrine therapy. Pathway analysis of genes<br />
significantly elevated in the metastatic setting included developmental<br />
pathways (WNT signalling and TGFbeta), growth factor signalling<br />
pathways (MAPkinase), cell adhesion molecules, junction adherens<br />
and pathways in cancer. Further analysis provided a list of clinically<br />
relevant transcriptional networks which may facilitate tumour cell<br />
de-differentiation. Transcription factors including Myc, SMAD2,<br />
ESR, TCF3, CUX1 and CLOCK were identified which potentially<br />
drive reprogramming in response to endocrine treatment.<br />
We interrogated this data to identify downstream targets of this ‘dedifferentiation’<br />
network for new predictive markers of response to<br />
endocrine treatment. Bioinformatic analysis identified PAWR, an<br />
inhibitor of progenitor cell expansion as a potential SMAD2 target.<br />
In a xenograft model of endocrine resistance, PAWR expression was<br />
found to be reduced in metastatic tissue from lung, liver and bone<br />
compared with the primary tumour. In human breast cancer patients<br />
PAWR significantly associated with a good response to endocrine<br />
treatment and luminal A status (p=0.0008), establishing PAWR as a<br />
predictor of good response to endocrine therapies.<br />
We have identified a transcriptional network which may drive a<br />
de-differentiated phenotype following endocrine treatment. Data<br />
presented here proposes a mechanism by which apparently less<br />
aggressive Luminal A type tumours may fail endocrine treatment and<br />
develop subsequent recurrence. This represents a fundamental shift in<br />
how we approach the development of resistance to endocrine therapy,<br />
establishing a number of biomarkers which will allow tracking of<br />
response to endocrine therapy or allow accurate early prediction of<br />
those who will respond to treatment.<br />
P6-04-02<br />
Final progression-free survival analysis of BOLERO-2: a phase<br />
III trial of everolimus for postmenopausal women with advanced<br />
breast cancer<br />
Piccart M, Baselga J, Noguchi S, Burris H, Gnant M, Hortobagyi G,<br />
Mukhopadhyay P, Taran T, Sahmoud T, Rugo H. Institut Jules Bordet,<br />
Université Libre de Bruxelles, Brussels, Belgium; Massachusetts<br />
General Hospital <strong>Cancer</strong> Center and Harvard Medical School,<br />
Boston, MA; Osaka University, Osaka, Japan; Sarah Cannon<br />
Research Institute, Nashville, TN; Comprehensive <strong>Cancer</strong> Center,<br />
Medical University of Vienna, Vienna, Austria; The University<br />
of Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX; Novartis<br />
Pharmaceuticals Corporation, East Hanover, NJ; University of<br />
California, <strong>San</strong> Francisco Helen Diller Family Comprehensive<br />
<strong>Cancer</strong> Center, UCSF, <strong>San</strong> Francisco, CA<br />
Introduction: Treatment options for postmenopausal women with<br />
hormone receptor-positive (HR + ) breast cancer (BC) who relapse or<br />
progress on a nonsteroidal aromatase inhibitor (NSAI) are limited.<br />
Interim analyses of the BOLERO-2 trial demonstrated that combining<br />
the oral mammalian target of rapamycin (mTOR) inhibitor, everolimus<br />
(EVE), with the steroidal aromatase inhibitor, exemestane (EXE),<br />
significantly prolonged progression-free survival (PFS) in this patient<br />
population. Protocol-specified final PFS analyses are presented.<br />
Methods: The phase III, double-blind, BOLERO-2 trial randomized<br />
postmenopausal women with HR + BC progressing or recurring after<br />
NSAIs to EVE (10 mg once daily; n = 485) plus EXE (25 mg once<br />
daily) or placebo (PBO; n = 239) plus EXE. The primary endpoint<br />
was PFS. Secondary endpoints included overall survival, safety, bone<br />
turnover, and overall response rate.<br />
Results: At a median follow-up of 18 months, 510 PFS events were<br />
reported. The addition of EVE to EXE significantly prolonged median<br />
PFS versus EXE monotherapy as per local assessment (7.8 vs 3.2 mo,<br />
respectively; HR = 0.45 [95% CI, 0.38-0.54]; log-rank P < .0001).<br />
Furthermore, these data were consistent with results based on central<br />
assessment (11.0 mo for EVE + EXE vs 4.1 mo for EXE alone;<br />
HR = 0.38 [95% CI, 0.31-0.48]; log-rank P < .0001). Fewer deaths<br />
were reported with EVE + EXE (25.4%) vs PBO + EXE (32.2%).<br />
In addition to significantly improving PFS and delaying disease<br />
progression in bone, PFS benefits with EVE + EXE versus PBO +<br />
EXE were consistent in all prospectively defined subgroups, including<br />
subsets of patients with visceral metastases (n = 406), 3 or more sites<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
492s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
of metastasis (n = 271), and Eastern Cooperative Oncology Group<br />
(ECOG) performance status 1 or 2 (n = 274). The safety profile of<br />
EVE + EXE was consistent with that reported at the interim analysis<br />
and with data for EVE from other oncology settings. Updated overall<br />
survival data will be presented.<br />
Conclusions: Adding EVE to EXE markedly prolonged PFS in the<br />
overall population and in all patient subsets, validating the rationale of<br />
targeting the mTOR pathway to improve clinical outcome in patients<br />
with HR + advanced BC progressing during or after NSAI therapy.<br />
P6-04-03<br />
Changes in breast tumor metabolism and estradiol binding<br />
as measured by FES PET in patients treated with the histone<br />
deacetylace inhibitor vorinostat and aromatase inhibitor therapy<br />
Linden HM, Kurland BF, Specht JM, Vijayakrishn GK, Gralow JR,<br />
Peterson LM, Schubert EK, Link JM, David MA, Eary JF, Krohn<br />
KA. University of Washington, Seattle, WA; Fred Hutchinson<br />
<strong>Cancer</strong> Research Center, Seattle, WA; University of Pennsylvania,<br />
Philadelphia, PA<br />
Background: Some estrogen receptor-positive (ER+) metastatic breast<br />
cancers are bone and soft tissue dominant, indolent, and controlled<br />
by endocrine therapy. However, these tumors eventually become<br />
refractory to endocrine therapy and need a mechanism to reset the<br />
“estrogen-dependence” to allow continued benefit upon progression.<br />
Histone deacetylase inhibitors (HDACi) act as modulators of gene<br />
expression that are promising therapeutic agents for this group of<br />
tumors (Huang 2000, Sabnis 2011). Preclinical and clinical data<br />
demonstrate in ER-poor tumors and cell lines ER up-regulation and<br />
consequently enhanced lethality to endocrine agents. The optimal dose<br />
and schedule are not known, but two promising phase II studies show<br />
benefit in a continuous schedule (Yardley 2011, Munster 2011). FES<br />
PET is a promising imaging agent used as a biomarker to determine<br />
which patients will benefit from endocrine therapy, and to monitor<br />
estradiol binding during therapy (Mortimer 2001, Linden 2011).<br />
Methods: Patients with ER+ HER2- metastatic breast cancer with<br />
prior aromatase inhibitor (AI) exposure and clinical benefit of<br />
endocrine therapy were eligible for a phase II study of HDACi therapy<br />
to restore sensitivity to AI therapy. Following baseline FDG PET,<br />
FES PET and standard imaging (CT, MRI, ultrasound and/or bone<br />
scan as indicated by tumor location), patients received 2 weeks of<br />
vorinostat therapy (400 mg po daily). FES PET was performed at 2<br />
weeks while on HDACi therapy. Patients then received 6 weeks of<br />
AI monotherapy. FDG PET, FES PET and response assessment were<br />
performed at 8 weeks. Patients with clinical benefit (stable disease or<br />
response) continued on the regimen, 2 weeks of vorinostat followed<br />
by 6 weeks of AI.<br />
Results: To date, 8 patients have been enrolled of whom 6 have<br />
completed the first 8 weeks of treatment and all correlative imaging<br />
studies. FES biomarker imaging results are mixed, with some patients<br />
showing an increase in tumor estradiol concentrating ability by FES<br />
PET on HDACi therapy, and decline in metabolic activity by FDG.<br />
Two patients continue on treatment with clinical benefit. Results will<br />
be updated as accrual continues.<br />
Conclusions: Changes in estradiol binding are measured by serial<br />
FES PET in patients on HDACi therapy support preclinical concept<br />
of HDACi modulation of ER expression in metastatic breast cancer.<br />
Molecular imaging is a promising tool to monitor Estradiol binding<br />
pharmacodynamics, and Vorinostat HDACi therapy is a promising<br />
novel approach to allow patients to avoid toxicities of traditional<br />
chemotherapy once their tumor has progressed on endocrine therapy.<br />
Funding: P01, MKA, Merck<br />
P6-04-04<br />
Upregulation of the androgen agonist prosaposin in aromatase<br />
inhibitor resistant breast cancer; mediation by the developmental<br />
protein HOXC11<br />
McIlroy M, Hao Y, Bane FT, Young L, O’Gaora P. Royal College<br />
of Surgeons in Ireland, Dublin, Ireland; University College Dublin,<br />
Ireland<br />
Aromatase inhibitors work by abrogating the activity of the enzyme<br />
cyp 19 (Aromatase) which converts adrenal androgens into Estrogen<br />
within mammary adipose tissue. It is the synthesized steroid<br />
estrone that plays a pivotal role in promoting breast cancer growth<br />
in postmenopausal women. The development of resistance to AI<br />
therapy is still being elucidated, however studies have shown that<br />
tumour adaptability is of vital importance in the cancer cells ability<br />
to evade treatment. This may occur via the switch from estrogen<br />
dependent to estrogen-independent growth which manifests as the loss<br />
of positive estrogen receptor and progesterone receptor status. The<br />
levels of androgens generated by the adrenal glands of women decline<br />
gradually with age but are not dramatically impacted by menopause.<br />
As breast cancer cells are treated AI drugs to block the conversion of<br />
androstendione to estrogen these androgenic steroids will continue to<br />
circulate. Elucidation of the adaptive changes in the cancer cells in<br />
response to the altered steroid environment is therefore of interest.<br />
Research from this lab has identified the homeobox protein HOXC11<br />
as an interacting partner of the steroid receptor coactivator SRC1 in<br />
endocrine resistance. HOXC11 target genes are undefined and so<br />
motif-mapping and RNA-seq experiments were undertaken to help<br />
elucidate the role of HOXC11 in the development of resistance and<br />
metastatic spread. From these studies we have identified Prosaposin<br />
(PSAP) as a putative HOXC11 regulated gene. PSAP is a known<br />
androgen agonist associated with metastatic potential in prostate<br />
cancer and endocrine resistance in breast cancer. Studies performed<br />
confirmed the ability of HOXC11 to regulate PSAP in AI resistant<br />
breast cancer. At a translational level PSAP is an extremely attractive<br />
target for clinical investigation due to its secretory nature which<br />
facilitates quantification from blood serum. Studies exploring the<br />
levels of secreted PSAP in resistant cell line models were undertaken<br />
and only the AI (letrozole) resistant cells had detectable levels of<br />
PSAP. Furthermore when we looked at levels of PSAP in breast<br />
cancer patients 18% had detectable amounts of the protein in their<br />
serum and the sample with the most elevated level was discovered<br />
to be from a patient who had suffered disease recurrence whilst<br />
undergoing AI therapy. High levels of serum PSAP also associated<br />
with strongly positive staining for androgen receptor in matched<br />
patient tissue. Survival analysis on a cohort of breast cancer patients<br />
(n=680) suggests that in AI treated patients there is a trend indicting<br />
that positivity for androgen receptor may result in reduced diseasefree<br />
survival. As a secreted protein PSAP will be readily detectable<br />
in breast cancer patients’ serum from a simple blood sample and<br />
may indicate that the tumour cells are adapting to an androgen rich<br />
environment promoting disease progression.<br />
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P6-04-05<br />
Tamoxifen dose escalation based on endoxifen level: a prospective<br />
trial with genotyping, phenotyping and pharmacokinetics over<br />
4 months.<br />
Zaman K, Dahmane E, Perey L, Bodmer A, Anchisi S, Wolfer A,<br />
Galmiche M, Stravodimou A, Buclin T, Eap C, Decosterd L, Csajka<br />
C, Leyvraz S. University Hospital CHUV, Lausanne, Switzerland;<br />
Ensemble Hospitalier de la Côte, Morges, Switzerland; University<br />
Hospital CHUV, University of Geneva, Lausanne, Switzerland;<br />
University Hospital, Geneva, Switzerland; Hôpital Cantonal, Sion,<br />
Switzerland<br />
Background<br />
Retrospective studies assessing the impact of tamoxifen (Tam)<br />
metabolism and its active metabolite, endoxifen, on the efficacy of<br />
the treatment produced conflicting results. The prospective CYPTAM-<br />
BRUT 2 trial is ongoing 1 . In the present study we assessed if the level<br />
of Tam metabolites could be improved by doubling tamoxifen dose in<br />
breast cancer patients (pts) with any CYP2D6 genotype, poor (PM),<br />
intermediate (IM) and also extensive metabolizer (EM).<br />
Patients and methods:<br />
This multicenter, prospective, open-label trial included pts treated<br />
with Tam for ≥ 4 months. CYP2D6 activity was determined centrally<br />
by genotyping and phenotyping (dextromethorphan test). Liquid<br />
chromatography-tandem-mass spectrometry was used to measure<br />
Tam, N-desmethyltamoxifen (N-DMT), 4-hydroxytamoxifen (4-HT)<br />
and endoxifen twice at baseline (Tam 20 mg qd), then at days 30,<br />
90 and 120 after having increased the dose to 20 mg bid. Endoxifen<br />
increase and the differences between genotype/phenotype subgroups<br />
were analyzed by ANOVA.<br />
Results:<br />
76 pts were analyzed. Steady-state concentrations for Tam and its<br />
metabolites were reached in 30 days after doubling the dose. A<br />
range of 1.6 to 1.8 fold increase was observed. Geometric mean<br />
plasma concentrations in ng/ml (CV%) were: at baseline and day 30<br />
respectively 134 (48) and 246 (46) for tamoxifen (p < 0.0001); 246<br />
(53) and 413 (48) for N-DMT (p < 0.0001); 2.3 (44) and 3.7 (51) for<br />
4HT (p < 0.0001); 18.7 (89) and 31.1 (92) for endoxifen (p = 0.005).<br />
The level of endoxifen increased 1.4 to 1.7 folds in all genotype<br />
subgroups with geometric mean plasma concentrations in ng/ml<br />
(CV%): 6.9 (36) to 9.7 (24) in PMs (p = 0.7); 14.2 (69) to 20.7 (76)<br />
in IMs (p < 0.0001); and 22.6 (76) to 38.7 (85) in EMs (p < 0.0001).<br />
Similar results were obtained while considering phenotype subgroups.<br />
Genotypes and phenotypes explained less than 30% of the variability<br />
in endoxifen levels.<br />
The occurrence of hot flashes and night sweating were followed<br />
prospectively. Endoxifen levels did not predict an increase in HF/<br />
NS events’ overall occurrence (OR = 1.01, CI 95% 0.78 – 1.31 for HF<br />
and 1.01, CI 95% 0.79 – 1.29 for NS). Twelve pts received CYP2D6<br />
inhibitors. Nine pts did not complete the planned 4 months with<br />
tamoxifen 20 mg bid. The main reasons were mood disorders, hot<br />
flashes, headache and nausea. Self-reported treatment compliance<br />
assessed by monthly anonymous questionnaire was ≥ 95%, except<br />
80-95% in 4 pts.<br />
Conclusions:<br />
This is the first trial reporting the impact of the increase of tamoxifen<br />
dose in all CYP2D6 genotypes, including EMs. Dose escalation of<br />
tamoxifen increased significantly the plasma level of endoxifen by<br />
similar ratio in all genotype subgroups.<br />
Because of a huge inter-individual variability genotyping and<br />
phenotyping are not adequate surrogate markers of endoxifen level.<br />
Very low endoxifen levels are observed even in pts classified as EM.<br />
Future trials aiming to improve the plasma level of endoxifen<br />
should consider direct measurement of the metabolite in plasma and<br />
adjust tamoxifen dose according to the initial level of the metabolite<br />
independently of the genotype.<br />
Reference 1: A. Dieudonné, Journal of Clinical Oncology, 2011 ; vol<br />
29, No 15, suppl (May 20, 2011) : TPS 140<br />
P6-04-06<br />
Inverse regulation of Neuregulin1 and HER-3 during treatment<br />
with aromatase inhibitors of estrogen receptor-positive breast<br />
cancer<br />
Flågeng MH, Larionov A, Geisler J, Dixon JM, Lønning PE, Mellgren<br />
G. Haukeland University Hospital, Bergen, Norway; University<br />
of Edinburgh, United Kingdom; Akershus University Hospital,<br />
Lørenskog, Norway; University of Bergen, Norway<br />
Background: Resistance to endocrine therapy may be promoted<br />
by deregulation of growth factor signaling pathways in addition to<br />
its intimate bidirectional crosstalk with the estrogen receptor (ER)<br />
signaling pathway. We have previously shown HER-2/neu mRNA<br />
upregulation in HER-2/neu non-amplified tumors responding<br />
to therapy with aromatase inhibitors (AIs) [1]. Targeting HERdownstream<br />
signaling pathways may represent a strategy to overcome<br />
acquired endocrine resistance. Here, we aim at exploring the effect<br />
of treatment with AIs on the HER-receptor family members and<br />
the HER-3/-4 ligand neuregulin1 (NRG1) in ER+ breast cancers.<br />
Methods: Matched tumor biopsies were collected from 85 ER+<br />
breast cancers before and after three months of neo-adjuvant treatment<br />
with the AIs letrozole or anastrozole. For 64 of the patients, tumor<br />
biopsies were also available at two weeks of treatment. The patients<br />
were classified as either responders or non-responders depending<br />
on more or less than 50% reduction in tumor size, respectively.<br />
RNA was extracted from tumors and mRNA expression analyses<br />
of HER-1-4 and NRG1 were performed by real-time PCR using<br />
gene-specific primers. Changes in mRNA levels during treatment<br />
were estimated using the non-parametric Wilcoxon sign-rank test,<br />
while the correlations between mRNA levels were analyzed using<br />
2-tailed Spearman rank test. Results: Among all the ER+ HER-2/<br />
neu non-amplified tumors we observed a significant increase in<br />
mRNA expression of EGFR/HER-1 (51/64 tumors, p
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
1. Flageng, M.H., L.L. Moi, J.M. Dixon, J. Geisler, E.A. Lien, W.R.<br />
Miller, P.E. Lonning, and G. Mellgren, Br J <strong>Cancer</strong>, 2009.101:<br />
1253-60.<br />
2. Makhija, S., L.C. Amler, D. Glenn, F.R. Ueland, M.A. Gold, D.S.<br />
Dizon, V. Paton, C.Y. Lin, T. Januario, K. Ng, A. Strauss, S. Kelsey,<br />
M.X. Sliwkowski, and U. Matulonis, J Clin Oncol, 2010. 28:1215-23.<br />
P6-04-07<br />
Significance and therapeutic potential of PELP1-mTOR axis in<br />
breast cancer progression and therapy resistance<br />
Gonugunta VK, Cortez V, Sareddy GR, Roy SS, Zhang H, Tekmal<br />
RR, Vadlamudi RK. UTHSCSA, <strong>San</strong> <strong>Antonio</strong>, TX; Shantou University<br />
Medical College, Shantou, China<br />
Proline, Glutamic-acid and Leucine-rich Protein 1 (PELP1) is a<br />
proto-oncogene that modulates ER signaling by functioning as an<br />
ER-coregulator. Emerging studies demonstrated that in a subset of<br />
breast tumors, PELP1 is predominantly localized in the cytoplasm<br />
and that PELP1 participates in extranuclear signaling by facilitating<br />
ER interactions with Src, PI3K, and AKT. PELP1 expression is<br />
upregulated in breast cancer, its deregulation contributes to therapy<br />
resistance, and PELP1 is a prognostic marker of poor survival.<br />
However, the mechanism by which PELP1 extranuclear actions<br />
contributes to cancer progression and therapy resistance remains<br />
unknown. We have recently discovered that PELP1 has the potential<br />
to interact with mammalian target of rapamycin (mTOR), a serine/<br />
threonine kinase that forms two distinct complexes called mTORC1<br />
(containing Raptor and PRAS40) and mTORC2 (containing<br />
Rictor and Protor). The objective of this application is to test<br />
whether crosstalk occurs between mTOR and PELP1 signaling<br />
axis and to test whether mTOR targeting drugs can be used to<br />
target PELP1 oncogenic functions. We have used breast cancer<br />
cells with PELP1 overexpression (MCF7-PELP1, ZR75-PELP1,<br />
T47D-PELP1) or PELP1 down regulation (MCF7-PELP1shRNA,<br />
ZR75-PELP1shRNA) along with controls to study the role of PELP1<br />
in the regulation of mTOR axis. PELP1 knockdown significantly<br />
reduced downstream mTOR signaling components as analyzed by<br />
Western analysis using phospho-S6K, -4EBP1, -mTOR and -Akt,<br />
antibodies. Overexpression of PELP1 activated mTOR signaling<br />
components. Using immunoprecipitation, we have demonstrated<br />
that PELP1 interacts with mTOR. Further immunopreciptation<br />
analysis using Rictor and Raptor specific antibodies revealed that<br />
PELP1 associates with both TORC1 and TORC2 complexes. Using<br />
PELP1WT and PELP1cyto (that predominantly localizes in the<br />
cytoplasm), we have demonstrated the differential activation of mTOR<br />
signaling components: PELP1WT activated both TORC1 and TORC2<br />
pathways, while PELP1cyto uniquely activated TORC2. mTOR<br />
targeting drugs (Rapamycin or AZD8055) showed a significant effect<br />
on the in vitro proliferation of PELP1 model cells. AZD8055 is more<br />
potent in reducing PELP1 driven tumor growth in vivo compared<br />
to rapamycin. Immunohistochemical studies on xenografts derived<br />
from MCF7, MCF7-PELP1WT and MCF7-PELP1cyto models<br />
demonstrated that PELP1 signaling modulates mTOR signaling<br />
in vivo and inhibition of mTOR signaling rendered PELP1 driven<br />
tumors to be highly sensitive to therapeutic inhibition. Further,<br />
mTOR inhibitors sensitized tamoxifen therapy resistant PELP1cyto<br />
model cells to hormonal therapy. IHC analysis of mammary glands<br />
and mammary tumors from PELP1Tg mice revealed deregulation<br />
of mTOR signaling components with excessive activation of S6K<br />
and 4EBP1. Using breast tumor tissue arrays (n=100), we found<br />
significant correlation of PELP1 cytosolic localization with mTOR<br />
signaling. Collectively, the experimental results from these studies<br />
identified PELP1-mTOR axis as a novel component of PELP1<br />
oncogenic functions and suggests, mTOR inhibitor(s) will be effective<br />
chemotherapeutic agents for down regulating PELP1 oncogenic<br />
functions and for blocking PELP1-mediated therapy resistance.<br />
P6-04-08<br />
FOXA1 expression: regulated by EZH2 and associated with<br />
favorable outcome to tamoxifen in advanced breast cancer<br />
Reijm EA, Helmijr JCA, Soler CMJ, Beekman R, Gerritse FL, Pragervan<br />
der Smissen WJC, Ruigrok-Ritstier K, van IJcken WFJ, Stevens<br />
MG, Smid M, Look MP, Meijer ME, Sieuwerts AM, Sleijfer S, Foekens<br />
JA, Berns EMJJ, Jansen MPHM. Erasmus MC - Daniel den Hoed,<br />
Rotterdam, Netherlands; Erasmus MC, Rotterdam, Netherlands<br />
Background: Enhancer of Zeste Homolog 2 (EZH2) is a member of<br />
the polycomb complex 2 and serves as a histone methyltransferase.<br />
Through trimethylation of histone 3 of lysine 27, EZH2 regulates<br />
‘genome wide’ gene transcription silencing.<br />
Downregulation of EZH2 is associated with increased expression<br />
of the estrogen receptor (ER) and favorable outcome to tamoxifen<br />
in metastatic breast cancer. The binding of ER to its target genes is<br />
enhanced by Forkhead Box A1 (FOXA1), a pioneer factor that binds<br />
to and opens chromatized DNA. The aim of this study is to investigate<br />
the potential association between EZH2 and FOXA1 and their relation<br />
with treatment outcome in patients with advanced breast cancer.<br />
Experimental design: EZH2 and FOXA1 mRNA levels were<br />
analysed using available gene expression profile-data of 344 primary<br />
breast cancer specimens of lymph-node-negative (LNN) patients and<br />
in 109 ER-positive (ER+) tumors of patients with metastatic disease<br />
treated with first-line tamoxifen. To functionally analyze EZH2, cell<br />
lines were generated with different knockdown-constructs for EZH2,<br />
followed by evaluation of mRNA and protein expression levels and<br />
chromatin immunoprecipitation (ChIP) experiments combined with<br />
qPCR and/or next generation sequencing (NGS; ChIPseq).<br />
Results: In the 344 LNN breast tumors, EZH2 was highly expressed<br />
in breast tumors of the basal subtype. In contrast, FOXA1 was hardly<br />
expressed in this subtype, but highly in the luminal A and B subtypes.<br />
FOXA1 was related to a prolonged time to progression (TTP) after<br />
tamoxifen (HR=0.51 [0.35-0.74], P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P6-04-09<br />
Lack of response to aromatase inhibitors involves distinct<br />
mechanisms<br />
Turnbull AK, Larionov AA, Renshaw L, Kay C, Sims AH, Dixon JM.<br />
University of Edinburgh, United Kingdom<br />
Background: Estrogen is a key hormone involved in cancer cell<br />
development. It forms a complex with estrogen receptor alpha (ER)<br />
which binds to estrogen response elements (EREs) in the promoter<br />
regions of genes under its transcriptional control. Letrozole inhibits<br />
local production of estrogen. Despite the prevalent use of such drugs<br />
little is known about their effect at molecular and transcriptomic level.<br />
A better understanding of the molecular mechanisms underlying why<br />
approximately 75% of ER rich cancers respond might help to elucidate<br />
the mechanisms characterising a lack of response in some patients.<br />
Methods: A new gene expression dataset was generated from<br />
sequential core biopsy/theatre samples (before treatment, 10-14 days<br />
on treatment and at surgery) taken from ER+ patients undergoing<br />
neo-adjuvant letrozole treatment. Clinical response to treatment<br />
was assessed by changes in tumour volume based on 3D ultrasound<br />
(performed by a single operator).<br />
Results: On letrozole the majority of ER+ tumours respond with<br />
dramatic early transcriptomic changes. A significant reduction in<br />
proliferation is seen through down-regulation of key cell cycle control<br />
genes such as CyclinD1, CyclinA, CyclinB1, CyclinB2 and CDK2,<br />
and genes involved with the initiation phase of DNA replication<br />
such as the MCM complex. Several of these (including CyclinD1,<br />
CyclinB2 and MCM2) have been shown to contain candidate ERE<br />
sequences in their promoter region and therefore down-regulation<br />
of these would be concordant with deprivation of estrogen. There<br />
is also a significant up-regulation of genes including collagens,<br />
lamanins, integrins and others involved with intra-cellular adhesion<br />
and extra-cellular matrix (ECM) remodelling. Preliminary analysis<br />
suggests the involvement of a local immune response as a potential<br />
mechanism for tumour cell death, as genes involved with antigen<br />
presentation, leukocyte trans-endothelial mediation, natural killer cell<br />
mediated cytotoxicity and T-cell mediated cell death are significantly<br />
up-regulated within the clinically responding group.<br />
Two distinct subsets were seen in non-responders. The first subgroup<br />
shows a ‘classical non-response profile’ with very little change in<br />
expression of genes involved with cell cycle, ECM remodelling,<br />
cellular adhesion and antigen presentation between baseline and<br />
14-days of treatment. The second subgroup have a gene expression<br />
profile similar to the responding group with a down-regulation of cell<br />
cycle and up-regulation of genes involved with ECM remodelling,<br />
cellular adhesion and antigen presentation. Whether these are true<br />
non-responders is not clear.<br />
Conclusion: Approximately half of clinically non-responding patients<br />
have molecular profiles similar to responding patients whilst the<br />
other half have a distinct pattern of expression with significantly less<br />
change in genes associated with cell cycle control, ECM remodelling,<br />
intra-cellular adhesion and antigen presentation. On-going work will<br />
elucidate long term outcomes in these two groups.<br />
P6-04-10<br />
Comprehensive gene and protein assessment of the role of Her2 in<br />
the response to neoadjuvant Letrozole suggests patients without<br />
amplification may also benefit from anti-Her2 treatment<br />
Webber V, Turnbull AK, Larionov AA, Sims AH, Harrison D, Renshaw<br />
L, Dixon JM. Melville Trust for Care and Cure of <strong>Cancer</strong>, Edinburgh;<br />
Western General Hospital, Edinburgh<br />
Background:<br />
Older postmenopausal patients with large operable or locally<br />
advanced oestrogen receptor positive, invasive breast cancers are<br />
candidates for treatment with neoadjuvant letrozole. HER2 positivity<br />
is a potential marker for early endocrine therapy resistance. In this<br />
study we have evaluated the effects of HER2 amplification, gene<br />
and protein expression at diagnosis and following 14 and 90 days of<br />
treatment with neoadjuvant Letrozole.<br />
Methods:<br />
70 postmenopausal women with large operable and locally advanced<br />
oestrogen receptor (ER) positive invasive breast cancers were treated<br />
with neoadjuvant letrozole. Response was assessed by 3D ultrasound.<br />
Sequential core biopsies were taken at 0, 14 days and 3 months of<br />
treatment. 12 patients were HER2 positive (either 3+ or 2+ FISH<br />
positive), 20 were HER2 2+ FISH negative and 38 were HER2<br />
negative (0 or +).<br />
Results:<br />
43 patients were responders to letrozole and 17 were non-responders.<br />
7 of the 17 non-responders were HER2 positive. Analysing response<br />
in two groups (HER2 2+ and 3+ together versus 0 or +) there was<br />
a greater difference in response rate between these two groups than<br />
when splitting into conventional HER2 positive and negative groups<br />
(P
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
not all patients with ER+ BC respond to hormonal therapy (e.g.<br />
tamoxifen and aromatase-inhibitor) but a large number will eventually<br />
develop resistance to long term therapy.<br />
Purpose: Development of resistance to endocrine therapy is a<br />
clinical issue in ER+ BC. Studies with human cell lines have shown<br />
that upregulation of PI3K-AKT-mTOR and MEK-ERK pathways<br />
contributes to resistance to endocrine therapy (Miller TW et al JCO<br />
2011; <strong>San</strong>chez CG et al <strong>Breast</strong> <strong>Cancer</strong> Res 2011). Using leterozoleresistant<br />
ER+ BC model, we investigated the effects of PI3K-AKTmTOR<br />
pathway inhibitor alone and in combination with MEK1/2<br />
inhibitor.<br />
Methodology: The anti-proliferative, anti-migratory, and intracellular<br />
signaling (pAKT, pS6RP, p4EBP1 and pERK) effects of GDC-0941<br />
(Class I PI3K inhibitor) or GDC-0980 (dual PI3K/mTOR inhibitor)<br />
alone and in combination with GDC-0973 (MEK1/2 inhibitor) were<br />
evaluated in aromatase overexpressed (MCF-7aro), letrozole-resistant<br />
(MCF-7aro/LetR) and long-term-estrogen-deprived (LTEDaro) BC<br />
cell lines by MTT assays, integrin-mediated migration assay and<br />
Western blots.<br />
Results: 1) Both GDC-0980 and GDC-0941 exhibited excellent in<br />
vitro cell killing activity in MTT assay in all cell lines with IC50’s<br />
10-30 nM & 0.2-1.5 µM respectively. PI3K pathway inhibitors<br />
were more potent when combined with GDC-0973; 2) Integrinmediated<br />
migration was significantly higher in both MCF-7aro/LetR<br />
andLTEDaro cells than MCF-7 and MCF-7aro cells; 3) Both MCF-<br />
7aro/LetR and LTEDaro cells movement were significantly abrogated<br />
following the treatment of GDC-0980, and the combination of GDC-<br />
0980 plus GDC-0973 more effectively blocked integrin-mediated<br />
migration; 4) Inhibition of phosphorylation of AKT (S473/T308),<br />
S6RP and 4EBP1 (T37/46) was observed following PI3K pathway<br />
inhibitors; 5) pERK was upregulated following the treatment of<br />
GDC-0941 (PI3K inhibitor); 6) Basal level of pERK was significantly<br />
high in MCF7/LetR and MCF7/LTED cells, and GDC-0980 failed to<br />
change the level of pERK in those cell lines; and 7) Combination of<br />
PI3K pathway inhibitor plus MEK1/2 inhibitor significantly blocked<br />
activation of both pathways.<br />
Conclusion: Our in vitro data suggest that therapeutic targeting of<br />
the PI3K-AKT-mTOR and the MEK-ERK signaling pathways should<br />
be effective in abrogating aromatase-inhibitor-resistance in ER+ BC.<br />
P6-04-12<br />
Novel selective estrogen receptors degraders regress tumors in<br />
pre-clinical models of endocrine-resistant breast cancer<br />
Hager JH, Darimont B, Joseph J, Govek S, Grillot K, Aparicio A,<br />
Bischoff E, Kahraman M, Kaufman J, Lai A, Lee K-J, Lu N, Nagasawa<br />
J, Prudente R, Qian J, Sensintaffar J, Shao G, Heyman R, Rix P, Smith<br />
ND. Aragon Pharmaceuticals, <strong>San</strong> Diego, CA<br />
80% of all breast cancers express the estrogen receptor alpha (ERα)<br />
and thus are treated with anti-hormonal therapies that directly block<br />
ER function (e.g.Tamoxifen) or hormone synthesis (Aromatase<br />
Inhibitors). While these therapies are initially effective, acquired<br />
resistance invariably emerges. Importantly, the majority of these<br />
tumors continue to depend on ERα for growth and survival. The<br />
emerging evidence that ERα can signal in both a ligand-dependent<br />
and ligand-independent manner supports the development of agents<br />
that are not only competitive ERα antagonists but also reduce steady<br />
state levels of the receptor and thus limit both modes of signaling.<br />
We have identified novel, non-steroidal ERα antagonists that<br />
induce degradation of ERα in breast cancer cell lines at picomolar<br />
concentrations resulting in significant reduction in steady state ERα<br />
protein levels. Using peptide-based conformational profiling, we show<br />
that these Selective Estrogen Receptor Degraders (SERDs) induce<br />
estrogen receptor conformations that are distinct from both fulvestrant<br />
and tamoxifen indicating a unique mechanism of action. This unique<br />
biological profile coupled with good oral pharmacokinetics produces<br />
tumor regressions in both tamoxifen-sensitive and -resistant models<br />
of breast cancer in vivo. Recent pre-clinical and clinical data indicate<br />
that PI3K pathway signaling can contribute to the endocrine resistant<br />
state. In a preclinical model of tamoxifen resistant breast cancer in<br />
which SERD monotherapy only produces tumor growth inhibition,<br />
SERD therapy in combination with torc1/2 inhibition results in frank<br />
tumor regressions. These orally bioavailable SERDs hold promise as<br />
a next generation therapy for the treatment of ER+ breast cancer as<br />
monotherapy, as well as in combination with agents that target other<br />
pathways involved in both intrinsic and acquired endocrine resistance.<br />
P6-04-13<br />
HOXB7 functions as a co-activator of estrogen receptor in the<br />
development of tamoxifen resistance<br />
Jin K, Teo WW, Yoshida T, Park S, Sukumar S. Johns Hopkins<br />
University School of Medicine, Baltimore, MD<br />
Background: Multiple factors including long term treatment with<br />
tamoxifen are involved in the development of selective estrogen<br />
receptor modulator (SERM)-resistance in ERα positive breast cancer.<br />
Increased expression of HER family members can also directly alter<br />
cellular responses to tamoxifen, but the mechanism underlying the<br />
increased expression of the HERs is not clear. In this report we show<br />
that HOXB7 is an upstream regulator of HER2 and ER expression.<br />
Results: Overexpression of HOXB7 results in upregulation of HER2<br />
and ERα target genes, while knockdown of HOXB7 with siRNA in<br />
tamoxifen-resistant cell lines causes decrease of HER2 and ERα<br />
target genes expression and loss of tamoxifen resistance. To mediate<br />
upregulation of HER2 and ER-target genes occurring in tamoxifen<br />
resistance, the HOXB7-ERα complex recruits ERα coactivators and<br />
promotes HER2- and ER-target genes transcriptional activity through<br />
direct binding to the HER2 enhancer and regulatory regions of ER<br />
target genes. However, depletion of HOXB7 negatively affects the<br />
binding affinity of its cofactors to the HER2 enhancer element and<br />
ER-binding sites. Also, it is likely that miR196a controls HOXB7<br />
expression; reducing miR196a levels in tamoxifen-resistant cells<br />
causes an increase of HOXB7 expression. Overexpression of miR196a<br />
sensitizes MCF-7 tamoxifen resistant cells to tamoxifen through<br />
downregulation of HER2 and ER-target genes while inhibition of<br />
miR196a by anti-miR196a inhibitors increases tamoxifen resistance<br />
through the upregulation of HER and ER target genes in MCF-7<br />
cells. Further, miRNA 196a is regulated by c-MYC which undergoes<br />
stabilization through the EGFR-HER2 signaling pathway. Depletion<br />
of c-MYC by MYC shRNA enhances tamoxifen sensitivity by<br />
increasing the level of miR196a transcripts. Also, by c-MYC ChIP<br />
assay, we found that c-MYC inhibits miR196a expression through<br />
direct binding to its promoter region.<br />
Conclusions: Overexpression of HOXB7 is a key event in the<br />
initiation and maintenance of tamoxifen resistance. These studies<br />
suggest that HOXB7 acts as a key regulator orchestrating two<br />
major groups of target molecules, ERα and HER2, in the oncogene<br />
hierarchy. Blocking MYC expression or reexpression of miR196a<br />
in TAM-R cells may provide novel strategies for reversing SERMresistance.<br />
Therefore, we have provided additional evidence that<br />
supports the thesis that functional antagonism of HOXB7 has the<br />
potential to circumvent tamoxifen resistance.<br />
www.aacrjournals.org 497s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Reference: Jin K, Kong X, Shah T, Penet MF, Wildes F, Sgroi DC,<br />
Ma XJ, Huang Y, Kallioniemi A, Landberg G, Bieche I, Wu X, Lobie<br />
PE, Davidson NE, Bhujwalla ZM, Zhu T, Sukumar S. The HOXB7<br />
protein renders breast cancer cells resistant to tamoxifen through<br />
activation of the EGFR pathway. Proc Natl Acad Sci U S A. 2012<br />
Feb 21;109(8):2736-41.<br />
P6-04-14<br />
Targeting the PI3K/mTOR pathway in patient-derived xenograft<br />
models of endocrine resistant luminal breast cancer<br />
Cottu PH, Bagarre T, Assayag F, Bièche I, Chateau-Joubert S,<br />
Fontaine J-J, Decaudin D, Slimane K, Vincent-Salomon A, Marangoni<br />
E. Institut Curie, Paris, France; Institut Curie, Saint-Cloud, France;<br />
Ecole Veterinaire d’Alfort, Maisons-Alfort, France; Novartis Pharma,<br />
Rueil Malmaison, France<br />
Background. Most ER+ tumors will eventually escape endocrine<br />
treatments. PI3K/mTOR pathway targeting has improved clinical<br />
results in endocrine treatments resistant (ETR) patients, however with<br />
unsustained responses. Our laboratory has developed several models<br />
of ETR luminal breast cancer (LBC) patient derived xenografts (PDX)<br />
suitable for biological studies (Cottu et al, AACR 2012 & IMPAKT<br />
2012). The aims of the present study were 1) to analyze the biological<br />
factors associated with acquired ETR in relevant models of LBC;<br />
2) to determine the therapeutic interest of combining everolimus<br />
with different ET models resistant to different endocrine treatments<br />
(ET). Methods. Implementation of LBC models has been reported<br />
(Cottu et al, BCRT 2012). ETR models were derived by selecting<br />
tumors growing under continuous ET, subsequently re-engrafted<br />
and rechallenged with endocrine therapies (tamoxifen, letrozole,<br />
fulvestrant), and with everolimus alone and combined with ETs. When<br />
possible, initial sensitive tumors were simultaneously treated with the<br />
same protocols. At progression, or after at least 120 days of continuous<br />
therapies, tumor tissue was retrieved. Tissue microarrays (TMA)<br />
were performed to analyze the biological modifications associated<br />
to ET and mTOR targeting. Triplicate immunohistochemistry of<br />
P-AKT/AKT, P-mTOR/mTOR and P-S6 were performed in addition<br />
to standard markers. Transcriptomic and RTPCR analyses are also<br />
being conducted. Results. Three models resistant to tamoxifen and 2<br />
models resistant to surgical ovariectomy used a surrogate to estrogen<br />
deprivation, were developed from 3 initial PDX, and were maintained<br />
as independent hormone-resistant variants. All these models retained<br />
a luminal phenotype, based on IHC and transcriptomic analyses<br />
and had a wt PI3KCA. ETR models had an expression profile very<br />
similar to the initial PDX, suggesting that minor changes may be<br />
associated with the acquisition of an ETR phenotype. Three of these<br />
models have been tested. One tamoxifen resistant model confirmed<br />
a resistance specific to tamoxifen only and a high level of sensitivity<br />
to a fulvestrant everolimus combination. A second PDX yielded 2<br />
other models resistant to tamoxifen and ovariectomy. These 2 models<br />
developed a resistance to all ET modalities. Therapeutic testing<br />
with combinations of everolimus and ETs were highly efficient, but<br />
everolimus alone was as efficient in these 2 models with complete and<br />
durable responses. Activation of the PI3K pathway was demonstrated<br />
in all cases by IHC analyses (expression of pAKT and pS6), and<br />
complementary ongoing RTPCR analyses. Everolimus based effects<br />
were associated with tumor fibrosis, a strong inhibition of Ki67 and<br />
pS6, but not always pAKT. The expression of ER was not modified<br />
by treatments, except in the fulvestrant-treated mice where it was<br />
strongly inhibited. Conclusion. We have developed and validated a<br />
platform of ETR models derived from our LBC original PDX. These<br />
models retained a luminal phenotype although highly resistant to ET.<br />
Activation of the PI3K pathway has been confirmed in ETR models,<br />
and everolimus alone, or combined with ET confirms high and durable<br />
efficacy. Updated mechanistic analyses performed at different time<br />
points will be presented at the meeting.<br />
P6-04-15<br />
The involvement of LMTK3 in endocrine resistance is mediated<br />
via multiple signaling pathways<br />
Giamas G, Xu Y, Filipovic A, Grothey A, Coombes CR, Stebbing J.<br />
Imperial College, London, United Kingdom<br />
We have previously identified new kinases that are able to<br />
phosphorylate and/or modulate ERα activity via a high-throughput<br />
RNA interference screening. Amongst the most potent novel<br />
regulators was LMTK3, a previously uncharacterized molecule. We<br />
found that LMTK3 confers its anti-tumor effects predominantly via<br />
ERα-regulated signaling. Evolutionary analyses revealed LMTK3<br />
was the only kinase that has adaptively evolved and subjected to<br />
Darwinian positive selection, an intriguing and suggestive result given<br />
the unique susceptibility of humans to ERα + breast cancer compared<br />
to the great apes (especially for chimpanzees [Pan troglodytes], our<br />
closest living relatives). Furthermore, in a large cohort of human<br />
breast cancer patients (n=613), LMTK3 protein levels and intronic<br />
polymorphisms were significantly associated with disease-free and<br />
overall survival and predicted response to endocrine therapy. Finally,<br />
using an established orthotopic mouse model we demonstrated<br />
that inhibition of LMTK3 significantly reduces tumor volume and<br />
bioluminescence.<br />
Now, by performing: i) mass spectrometry (MS), ii) SILAC-based<br />
quantitative proteomics and iii) genome microarray experiments of<br />
ERα + breast cancer cell lines (Tam-sensitive and Tam-resistant) in<br />
the presence or absence of various treatments (Tam, E2, ICI), we<br />
reveal certain genes, including well-defined oncogenes and tumorsuppressors<br />
that are statistically up- or down-regulated.<br />
Interestingly, amongst the newly identified LMTK3-regulated genes/<br />
proteins were targets belonging to already established signalling<br />
pathways implicated in cell survival, cytoskeletal rearrangement,<br />
transformation, and autophagy.<br />
In addition, inhibition of LMTK3 re-sensitised a Tam treatment breast<br />
cancer mouse model, to Tam treatment, leading to decreased tumour<br />
growth. Moreover, in patients’ plasma samples, acquired LMTK3 gene<br />
amplification (copy number variation) was associated with relapse<br />
whilst receiving tamoxifen. In aggregate, these data support a role for<br />
LMTK3 in both innate (intrinsic) and acquired (adaptive) endocrine<br />
resistance in breast cancer.<br />
Further results and mechanistic data concerning LMTK3 actions will<br />
be presented, placing for the first time this new kinase in the maps<br />
of signal transduction.<br />
P6-04-16<br />
The role of RIP140 and FOXA1 in breast cancer endocrine<br />
sensitivity and resistance<br />
Harada-Shoji N, Coombes RC, Lam EW-F. Imperial College London,<br />
United Kingdom<br />
Background<br />
The estrogen receptor-α (ERα) is implicated in the initiation and<br />
progression of breast cancer. Endocrine therapeutics , including<br />
tamoxifen (OHT) and fulvestrant (ICI182780; ICI) improve diseasefree<br />
survival. Despite positive effects, de novo or acquired resistance<br />
to endocrine therapies frequently occurs. It has recently been<br />
published that nuclear receptor–interacting protein 1, NRIP1, also<br />
called RIP140, encodes an ER corepressor RIP140 and has a role in the<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
498s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
regulation of breast cancer cell growth in response to anti-estrogens.<br />
FOXA1 has previously been shown to function as a ‘pioneer factor’<br />
and dictate ER dependent gene expression in both normal and<br />
malignant breast epithelial cells. In this study we investigated the<br />
expression of ERα cofactors RIP140 and FOXA1 and their roles in<br />
hormonal therapy and endocrine resistance.<br />
Methods<br />
Tamoxifen sensitive or resistant breast cancer cell lines were analysed<br />
for protein and mRNA expression by western blotting and quantitative<br />
real-time PCR with or without the inhibition of ERα with tamoxifen or<br />
ICI. To determine the functional role of RIP140 and FOXA1 as well<br />
as their interaction in breast cancer, tamoxifen sensitive breast cancer<br />
cells (eg. MCF-7 and ZR-75-1) were transfected with either RIP140<br />
or FOXA1 expression vector and examined for the expression of ERtarget<br />
genes by Western blot and RT-qPCR analysis. The consequence<br />
of depletion of RIP140 and FOXA1 by RNA interference (RNAi) was<br />
also studied in these breast cancer cells. The expression of RIP140<br />
and FOXA1 and potential target genes were also validated in breast<br />
cancer patient samples by Immunohistochemistry.<br />
Results<br />
We first examined the basal expression levels of RIP140 and FOXA1<br />
in tamoxifen sensitive as well as resistant breast cancer cell lines. The<br />
expression levels of RIP140 were low in the resistance cells compared<br />
with their parental sensitive counterparts, while that of FOXA1 had<br />
no significant difference between the cell lines. The degradation of<br />
ERα by ICI treatment resulted in the down-regulation of RIP140 and<br />
FOXA1 expression in the endocrine sensitive. Our experiments also<br />
demonstrated the functional interaction between RIP140 and FOXA1<br />
and showed that depletion of RIP140 by RNA interference (RNAi) in<br />
sensitive cells resulted in reduction of FOXA1 expression.<br />
We also indentified from this work, a number of ER-regulated genes<br />
which are activated by FOXA1 and repressed by RIP140 expression.<br />
The regulation of these target genes by ERα, FOXA1 and RIP140<br />
were also confirmed in the breast cancer patient samples.<br />
Conclusion<br />
The results from this study demonstrated that RIP140 and FOXA1<br />
play a pivotal role in dictating hormonal sensitivity and resistance<br />
in breast cancer. Moreover, this work also identified a number of<br />
ERα-regulated genes which are downstream targets of FOXA1 and<br />
RIP140, and as such, they may be reliable prognostic markers for<br />
endocrine sensitivity in breast cancer.<br />
P6-04-17<br />
The androgen metabolite-dependent growth in hormone receptor<br />
positive breast cancer as a novel aromatase inhibitor-resistance<br />
mechanism<br />
Hanamura T, Niwa T, Nishikawa S, Konno H, Ghono T, Kobayashi Y,<br />
Kurosumi M, Takei H, Yamaguchi Y, Ito K-I, Hayashi S-I. Graduate<br />
School of Medicine, Tohoku University, Sendai, Japan; Shinshu<br />
University School of Medicine, Matsumoto, Japan; Saitama <strong>Cancer</strong><br />
Center, Saitama, Japan<br />
Introduction: Aromatase inhibitors (AIs) have been reported<br />
to exert their anti-proliferative effects not only by reducing the<br />
production of estrogens but also by unmasking the inhibitory effect<br />
of androgens such as testosterone (TS) or dihydrotestosterone (DHT)<br />
in postmenopausal women with hormone receptor-positive breast<br />
cancer. The behavior of androgens in AI-resistance mechanisms is<br />
not sufficiently understood. 5α-androstane-3β,17β-diol (3β-diol)<br />
generated from DHT by 3β-hydroxysteroid dehydrogenase type 1<br />
(3β-HSD type 1: HSD3B1) has androgenic activity and substantial<br />
estrogenic activity, representing a potential mechanism of AI<br />
resistance.<br />
Methods: To investigate these issues, ERE-GFP-transfected MCF-<br />
7-E10 cells were cultured for 3 months under steroid-depleted, TSsupplemented<br />
conditions which is the similar as the AI treatment.<br />
Among the surviving cells, two stable variants that show ER activity<br />
depending on androgen metabolites were selected as AD-EDR<br />
(androgen metabolite-dependent and estrogen depletion-resistant) by<br />
monitoring GFP expression. Using these cell lines, we investigated<br />
the process of adaptation to androgen-abundant conditions and the<br />
role of androgens in AI-resistance mechanisms.<br />
Results: AD-EDR cell lines showed increased growth and induction<br />
of estrogen-responsive genes rather than androgen-responsive<br />
genes by androgens or 3β-diol. Further analysis revealed increased<br />
expressions of HSD3B1 and reduced expression of androgen receptor<br />
(AR) in these cell lines. In parental MCF-7-E10 cells, ectopic<br />
expression of HSD3B1 or inhibition of AR resulted in adaptation to<br />
estrogen-deprived and androgen-abundant conditions. In coculture<br />
with stromal cells replicating the local estrogen production from<br />
androgen, AD-EDR cell lines showed AI resistance compared with<br />
parental MCF-7-E10 cells. Immunohistochemistry and real-time PCR<br />
analyses on 9 pairs of primary and recurrent tissue samples from AIresistant<br />
breast cancer revealed the decrease of AR protein expression<br />
in all cases and increase of HSD3B1 mRNA expression in 5.<br />
Conclusion: In the present study, we successfully cloned two stable<br />
variants that show ER activity depending on androgen metabolites.<br />
Investigation of these cell lines suggested that the increased function<br />
of 3β-HSD type 1 and reduced function of AR contribute to AI<br />
resistance by enhancing the androgen metabolite-dependent growth<br />
and reducing the inhibitory effect of androgens. Our data of clinical<br />
samples suggest that this mechanism also acts as an AI-resistance in<br />
clinical breast cancer in some cases.<br />
P6-04-18<br />
Evaluation of the molecular mechanisms behind fulvestrant<br />
resistant breast cancer<br />
Kirkegaard T, Hansen SK, Reiter BE, Sorensen BS, Lykkesfeldt AE.<br />
Danish <strong>Cancer</strong> Society Research Center, Copenhagen, Denmark;<br />
Aarhus University Hospital, Aarhus, Denmark<br />
To study the mechanisms behind treatment resistance, we have<br />
previously established a large panel of antiestrogen resistant breast<br />
cancer cell lines based on the estrogen receptor (ER)-positive breast<br />
cancer cell line, MCF-7. It seems to be a general phenomenon that<br />
MCF-7 cells switch from ER driven to human epidermal growth<br />
factor receptor (HER) driven cell growth upon development of<br />
fulvestrant resistance. To obtain a broader knowledge of the resistance<br />
mechanisms, we have established four fulvestrant resistant subclones<br />
from the ER-positive breast cancer cell line, T47D.<br />
The parental T47D cells were confirmed to be estrogen responsive<br />
and short-term treatment of the parental T47D cells with fulvestrant<br />
severely reduced cell growth as well as protein expression of ER<br />
and the estrogen regulated proteins, insulin-like growth factor 1<br />
receptor alpha (IGF-1Rα) and progesterone receptor (PR). All<br />
four fulvestrant resistant cell lines had reduced mRNA and protein<br />
expression of HER1 and HER4 compared to T47D, while HER2 was<br />
highly up regulated in the fulvestrant resistant cell lines and ER was<br />
lost. No difference in response to the HER2 inhibitor trastuzumab<br />
or the specific HER2 kinase inhibitor AG825 was observed between<br />
the fulvestrant resistant cell lines and T47D, indicating that HER2<br />
is not the main driver of fulvestrant resistance in T47D cells. We<br />
found no indication of involvement of the two classical signaling<br />
pathways downstream of the HER receptors (Ras/Raf/Erk and PI3K/<br />
Akt). However, the JNK inhibitor SP600125 preferentially inhibited<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
growth of two tested fulvestrant resistant cell lines. Withdrawal of<br />
fulvestrant for several weeks did not result in regain of ER expression,<br />
or in change of HER receptor expression, supporting a stable resistant<br />
phenotype.<br />
In conclusion, loss of ER expression explains the lack of effect of<br />
fulvestrant in the T47D fulvestrant resistant cell lines. Noteworthy,<br />
the observed over expression of HER2 in the fulvestrant resistant<br />
T47D cells does not seem to be the main driver of cell growth, as<br />
HER2 targeted therapies like trastuzumab and HER2 kinase inhibitor<br />
did not exert a preferential growth inhibition of resistant cells. These<br />
breast cancer cells with high endogenous HER2 expression will be<br />
used as a model mimicking HER2 positive breast cancer which does<br />
not respond to standard HER2 targeted therapies.<br />
P6-04-19<br />
Neutralizing antibody to human GP88 (progranulin) restores<br />
sensitivity to tamoxifen and inhibits breast tumor growth in<br />
mouse xenografts<br />
Serrero G, Dong J, Hayashi J. A&G Pharmaceutical Inc, Columbia,<br />
MD<br />
The 88 kDa glycoprotein GP88 (Progranulin, PCDGF, acrogranin)<br />
is the largest member of the granulin/epithelin family of growth<br />
modulators characterized by 7.5 cysteine-rich granulin/epithelin<br />
repeats. Our laboratory has demonstrated that GP88 represents<br />
an ideal therapeutic and diagnostic target in breast cancer. Our<br />
published studies have demonstrated that: 1) GP88 expression<br />
increases with tumorigenesis; 2) inhibition of GP88 expression<br />
by antisense transfection in MDA-MB-468 cells inhibited by 90%<br />
tumor formation in nude mice; 3) in ER+ breast cancer cells, GP88<br />
stimulates proliferation and its overexpression confers estrogen<br />
independence and resistance to several anti-estrogens and aromatase<br />
inhibitor; 4) In Her-2 overexpressing breast tumors, GP88 stimulated<br />
Her-2 phosphorylation and conferred trastuzumab resistance; 5) GP88<br />
is expressed in 80% invasive ductal carcinoma and 60% of ductal<br />
carcinoma whereas it is negative in lobular carcinoma, benign lesions<br />
and normal mammary epithelial cells; 6) pathological studies with<br />
530 cases of ER+ invasive ductal carcinoma showed that GP88 tumor<br />
expression measured by immunohistochemistry (IHC) is a prognostic<br />
indicator of recurrence in early stage breast cancer patients; High<br />
GP88 tissue expression was associated with a 4-fold increase in risk<br />
of recurrence at 5 years; 7) GP88 is secreted and can be detected<br />
in the serum of breast cancer patients at an increased level when<br />
compared to healthy subjects. Based on these results, we developed<br />
a neutralizing anti-GP88 antibody AG1. AG1 was expressed in a high<br />
yield CHO cell line and formulated. AG1 inhibits GP88 biological<br />
effect (proliferation and migration) in a dose-dependent fashion in<br />
vitro. Here we will report the results of studies investigating the effect<br />
of AG1 on the tumor development of tamoxifen sensitive (MCF-7)<br />
and resistant (TamR) estrogen receptor positive breast cancer cells<br />
lines injected in nude mice. We show that AG1 alone (5mg/kg)<br />
inhibited tumor growth of MCF-7 cells injected into nude mice in<br />
a similar efficacy as tamoxifen. Interestingly, in tamoxifen resistant<br />
cells derived from MCF-7, the anti-GP88 antibody AG1 inhibited by<br />
more than 50% tumor formation of TamR cells in combination with<br />
tamoxifen, whereas tamoxifen only had no effect.<br />
These data suggest that inhibiting GP88 provides a novel and<br />
alternative therapeutic pathway for the restoration of tamoxifen<br />
sensitivity in ER+ breast cancer.<br />
This works is supported by grant 2R44CA124179 from the National<br />
<strong>Cancer</strong> Institute and 02-2010-010 from the Avon Foundation for<br />
Women.<br />
P6-04-20<br />
Endocrine resistance in invasive lobular carcinoma cells parallels<br />
unique estrogen-mediated gene expression<br />
Sikora MJ, Luthra S, Chandran UR, Dabbs DJ, Welm AL, Oesterreich<br />
S. University of Pittsburgh <strong>Cancer</strong> Institute, Pittsburgh, PA;<br />
University of Pittsburgh, PA; Magee-Womens Hospital, Pittsburgh,<br />
PA; University of Utah Huntsman <strong>Cancer</strong> Institute, Salt Lake City, UT<br />
Invasive lobular carcinoma (ILC) represents ∼10% of newly<br />
diagnosed breast tumors, accounting for ∼30,000 cases annually in the<br />
US. However, ILC has been understudied as a breast cancer subtype.<br />
ILC-specific signaling pathways and responses to endocrine therapies<br />
are not well characterized. Recent retrospective analyses of luminaltype<br />
breast cancers suggest that ILC patients treated with endocrine<br />
therapy have poorer disease-free survival and overall survival than<br />
invasive ductal carcinoma (IDC) patients with similar biomarkers. We<br />
hypothesize that unique transcriptional control of estrogen receptoralpha<br />
(ERα) by estrogens and anti-estrogens in ILC cells drive a<br />
differential response of ILC tumors to endocrine therapies.<br />
The ILC cell lines MDA MB 134VI and SUM44PE were used as in<br />
vitro models of ILC tumors to examine responses to estradiol (E2)<br />
and the anti-estrogens tamoxifen (Tam), 4-hydroxytamoxifen (4OHT),<br />
endoxifen (Bx), and fulvestrant (ICI). We examined cell growth and<br />
expression of canonical ERα-regulated genes in response to E2. Cells<br />
were also treated with anti-estrogens +/- E2 to examine their ability<br />
to inhibit E2-induced growth. To establish a genome-wide profile of<br />
ERα-mediated gene regulation in ILC cells, ILC cells were subjected<br />
to gene expression microarray analysis following 0-24hrs treatment<br />
with 1nM E2. In parallel to these in vitro studies, in vivo models of ILC<br />
are being assessed for endocrine responsiveness, including MDA MB<br />
134VI xenografts and the primary human tumor xenograft HCI-013.<br />
We observed that both MDA MB 134VI and SUM44PE are growthinduced<br />
by E2 treatment. However, both cell lines also present de novo<br />
resistance to Tam, 4OHT, and Bx. While ICI treatment completely<br />
blocked E2-induced growth in MDA MB 134VI, Tam, 4OHT, and<br />
Bx acted as partial agonists. Treatment with these compounds alone<br />
induced ∼25% growth relative to E2, and E2-induced growth could<br />
only be inhibited ∼75%. Similarly, SUM44PE cells are strongly<br />
growth-inhibited by ICI treatment, whereas growth is not reduced<br />
by Tam, 4OHT, or Bx treatment. Consistent with these observations,<br />
novel patterns of gene expression are induced by E2 treatment in ILC<br />
cells. E2-treatment induced canonical targets (e.g. GREB1, IGFBP4)<br />
in both ILC cell lines. However, in MDA MB 134VI cells only ∼35%<br />
of genes regulated by E2 at 24hrs overlap with those regulated in the<br />
IDC cell line MCF-7. Further, a subset of the overlapping genes is<br />
differentially regulated between cell types, including ESR1 (1.25-<br />
fold and 0.67-fold versus control in MDA MB 134VI and MCF-7,<br />
respectively), HOXC6, PMP22, and L1CAM. Examination of these<br />
observations in in vivo models is currently ongoing.<br />
These data are consistent with the hypothesis that E2 and antiestrogens<br />
differentially regulate ERα-mediated gene expression<br />
in ILC cells versus IDC cells. The de novo resistance to tamoxifen<br />
observed in ILC cells may correlate with the worse outcomes in<br />
ILC patients observed in retrospective analyses. We hypothesize<br />
that elucidation of the mechanisms responsible for differential ERα<br />
regulation may reveal novel therapeutic targets for treating ILC<br />
patients and overcoming endocrine resistance.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
500s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
P6-04-21<br />
AIB1 expression specifically predicts breast cancer patient<br />
response to aromatase inhibitor therapy<br />
Vareslija D, O’Hara J, Tibbitts P, McBryan J, Hao Y, Hill A, Young<br />
L. Royal College of Surgeons Ireland, Dublin, Ireland<br />
Aromatase inhibitors (AI) have evolved over the last decade into an<br />
effective therapeutic regime for postmenopausal women with primary<br />
or advanced breast cancer. Despite their remarkable success in the<br />
clinic, intrinsic resistance to therapy occurs in a proportion of patients,<br />
while other patients who respond initially to treatment will relapse<br />
with recurrent disease. Previous studies suggest that this may be due,<br />
at least in part to estrogen receptor (ER) hypersensitivity.<br />
We undertook ER ChIPseq analysis on AI resistant cell model and<br />
data for this suggests that ER transcriptional regulation alone may<br />
not be responsible for the development of the resistant phenotype.<br />
We examined the role of the established ER coactivator protein<br />
AIB1. AIB1 has previously been associated with initiation of breast<br />
cancer and resistance to endocrine therapy. In tamoxifen treated<br />
patients, expression of AIB1 in conjunction with an activated HER2<br />
cascade has been associated with treatment resistance and early<br />
disease recurrence. By contrast, we have observed that AIB1 alone<br />
can predict response to AIs. In our TMA the expression of AIB1<br />
associated with disease recurrence (p=0.025) and reduced disease<br />
free survival time (p=0.0471) in patients treated with AIs as firstline<br />
therapy. Reflecting increased growth factor activity reported in<br />
AI resistance, AIB1 expression associated with the growth factor<br />
second messenger signaling proteins, p-Src and pERK1/2, but not the<br />
receptor HER2. These results suggest that AIB1 may utilize additional<br />
transcription factors other than ER to drive endocrine resistance.<br />
Additionally, we show that AIB1 is highly expressed in AI resistant<br />
metastases; therefore, monitoring AIB1 expression may be useful<br />
to screen for disease progression and detect disease advancement<br />
before metastases appear.<br />
Our studies of cell line models of AI resistance suggest that AIB1<br />
may play a functional role in aggressive, migratory, phenotype of<br />
AI resistance. We have generated cell line models of resistance to<br />
letrozole (LetR) and anastrozole (AnaR). Our resistance models<br />
have higher levels of AIB1 and have increased migratory capacity.<br />
Interestingly, knockdown of AIB1 reduces the migratory capacity of<br />
the resistant cells.<br />
Furthermore, we have observed that AIB1 regulation of ER target<br />
genes is selectively enhanced in AI resistant cells in a promoter<br />
specific context. AIB1 recruitment to ER target genes such as pS2 and<br />
Myc becomes insensitive to letrozole. By contrast, AIB1 recruitment<br />
to cyclinD1 retained letrozole sensitivity. Our evidence suggests that<br />
steroidal regulation of transcription factors such as Jun and Fos may<br />
contribute to this promoter-specific regulation of ER target genes.<br />
We establish a role for AIB1 in AI-resistant breast cancer and describe<br />
a new mechanism of ERalpha/AIB1 gene regulation which could<br />
contribute to the development of an aggressive tumour phenotype.<br />
We provide evidence of a central role for AIB1 in regulating selective<br />
ER transcriptional activity and driving tumour recurrence in AI<br />
treated patients. Tackling the emerging problem of AI resistance in a<br />
timely fashion will enable us to tailor existing therapies and improve<br />
outcome in specific patient groups before disease recurrence becomes<br />
a clinical issue.<br />
P6-04-22<br />
Regulation of Notch localization by endocrine therapy in Estrogen<br />
Receptor positive breast cancer cells: Clinical implications for<br />
endocrine resistance<br />
Espinoza I, Caskey M, Baker RC, Miele L. University of Mississippi,<br />
Jackson, MS<br />
Background: Estrogen receptors occur in about two-thirds of breast<br />
tumors and endocrine therapy is probably the most important systemic<br />
therapy for hormone receptor positive breast cancer. However,<br />
after an initial response to hormonal therapy, most tumors develop<br />
resistance leading to disease progression. Central mechanisms<br />
thought to be involved in this process include: 1) alterations in tumor<br />
cell physiology causing insensitivity to drug-induced apoptosis or<br />
induction of drug-detoxifying mechanisms; 2) expression of energydependent<br />
transporters that eject anti-cancer drugs from cells and<br />
3) the emergence of cancer stem-like cell clones that are estrogenindependent<br />
and/or antiestrogen resistant. We and others have shown<br />
that Notch signaling mediates survival signals in ER+ breast cancer<br />
cells; induces expression of drug transporter ABCG2 (BCRP),<br />
activates ERα in the absence of estrogen and mediates survival of<br />
breast cancer stem-like cells. Previously, we demonstrated a crosstalk<br />
between ERα and Notch signaling whereby estrogen inhibits Notch<br />
activation and estrogen withdrawal or tamoxifen re-activate Notch,<br />
a possible mechanism of resistance. The mechanism of these effects<br />
has remained elusive. Methods: we used sub-cellular fractionation and<br />
immunofluorescence staining to investigate the total expression and<br />
cellular distribution of Notch signaling components in MCF-7 cells<br />
treated with 17-β-estradiol, or estrogen-free medium. Results: Our<br />
data shows that in cells treated with estrogen-free medium, Notch1<br />
is located in the Lipid Rafts (LR) in the plasma membrane, along<br />
with Notch signaling components such as presenilin 1 (the catalytic<br />
subunit of γ-secretase), ADAM10 and Notch negative regulator<br />
NUMB. There is published evidence that γ-secretase is most active<br />
in lipid rafts.17-β-Estradiol modifies the membrane lipid composition<br />
and change the localization of Notch and Notch regulators (such as<br />
ADAM10, presenilin-1 and NUMB) at the plasma membrane, thereby<br />
altering the activation of Notch. These observations are consistent<br />
with a model in which the lipid composition of the plasma membrane<br />
is a critical factor in regulating the rate of Notch activation. FDAapproved<br />
cholesterol lowering drugs affect Notch signaling in ways<br />
consistent with this model. Conclusions: Our findings indicate that<br />
endocrine therapy affects Notch signaling at least in part through<br />
alterations in membrane composition and lipid raft localization of<br />
Notch signaling components.<br />
P6-04-23<br />
Targeting of endocrine therapy resistance through combined<br />
mTOR and histone deacetylase inhibition<br />
Ordentlich P, Flechsig S, Hoffmann J. Syndax Pharmaceuticals,<br />
Waltham, MA; EPO-GmbH Berlin, Berlin, Germany<br />
Background: Primary and acquired resistance to endocrine therapy<br />
in advanced breast cancer presents a significant barrier to maximizing<br />
the clinical effectiveness of these agents. Preclinical data has<br />
demonstrated that up-regulation and/or constitutive activation of<br />
estrogen independent growth signaling pathways drive resistance<br />
to aromatase inhibitors and that targeting of these pathways is an<br />
effective strategy to overcoming the resistance. We recently reported<br />
in a randomized, placebo controlled phase 2 study that entinostat<br />
(ENT), an oral class 1 selective HDAC inhibitor, combined with<br />
exemestane extended PFS and OS in postmenopausal women with<br />
ER+ positive breast cancer that had progressed on a prior nonsteroidal<br />
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aromatase inhibitor. Likewise, everolimus (EVE), a mTORi,<br />
combined with exemestane or tamoxifen (TAM) also significantly<br />
extended PFS in a similar patient population. In order to determine the<br />
potential benefit of combining ENT with EVE plus hormone therapy<br />
we have piloted a series of xenograft studies in primary human tumor<br />
models of TAM sensitivity and resistance.<br />
Methods: Athymic nude mice bearing xenografts of tissue derived<br />
directly from patient tumors (MaCa4049 – TAM sensitive; MaCa3366/<br />
TAM – partially resistant to TAM) were treated with A) vehicle B)<br />
2 mg/kg EVE C) 2 mg/kg EVE + 10 mg/kg TAM D) 15 mg/kg ENT<br />
E) 2mg/kg EVE + 10mg/kg TAM + 15 mg/kg ENT. Tumor samples<br />
taken at the end of the study were cryoconserved for analysis of gene<br />
and protein expression and protein phosphorylation.<br />
Results: Growth of MaCa4049 tumors was inhibited in all treatment<br />
groups relative to vehicle in two independent studies conducted<br />
in this tumor model. Groups B, C and D demonstrated a similar<br />
level of activity while maximal inhibition was observed in Group<br />
E (combination of EVE + ENT + TAM). All treatments were<br />
generally well tolerated with weight loss similar in groups C and E.<br />
Treatment of MaCa3366/TAM tumors resulted in similar levels of<br />
tumor growth inhibition in groups B, C and E which were all highly<br />
effective in suppressing tumor growth in this model. As EVE alone<br />
was highly effective as a single agent in the MaCa3366/TAM model<br />
the contribution of ENT will be assessed through molecular analysis<br />
of tumors upon study completion. Efficacy results and analysis of<br />
tumor samples from completed studies will be presented to provide<br />
insight into mechanism of action for the triple combination.<br />
Conclusions: Preclinical data demonstrating enhanced activity of<br />
entinostat combined with everolimus and hormone therapy provides<br />
the rationale for clinical investigation of this novel therapeutic<br />
approach to targeting hormone therapy resistance.<br />
P6-04-24<br />
Overexpression of protein kinase C alpha differentially activates<br />
transcription factors in T47D breast cancer cells in the presence<br />
of 17β-estradiol both in the 2D and 3D environments.<br />
Pham TND, Asztalos S, Weiss MS, Shea LD, Tonetti DA. University<br />
of Illinois at Chicago, IL; Northwestern University, Evanston, IL<br />
Background: Our lab has previously shown that overexpression of<br />
protein kinase C alpha (PKCα) results in a hormone independent,<br />
tamoxifen resistant phenotype in the T47D:A18 breast cancer cell<br />
line. Moreover, 17β-estradiol (E2) inhibits colony formation of<br />
T47D/PKCα in 3D Matrigel and tumor growth in vivo but not in the<br />
2D environment (Zhang et al, Mol. <strong>Cancer</strong> Res, 2009). Differential<br />
transcriptional activation may account for the phenotypic changes<br />
observed in T47D/PKCα cells. In this study, we sought to identify<br />
transcription factors (TF) differentially activated in T47D:A18/neo<br />
versus T47D:A18/PKCα grown in 3D Matrigel in the presence and<br />
absence of E2, and compare these TFs with those activated in the 2D<br />
environment using a high-throughput screening (HTS) technology.<br />
Methods: A system for rapid, non-invasive, large scale, dynamic<br />
quantification of TF activity was developed (Weiss et al, PLoS ONE,<br />
2010). Reporter constructs were created containing a TF binding site<br />
that preceeds a basal promoter to produce firefly luciferase (Fluc)<br />
using a lentiviral backbone. The control construct contained only<br />
the basal promoter and was used for normalization. T47D/PKCα and<br />
T47D/neo cells were infected with lentiviral reporter constructs. Cells<br />
were seeded either on top of Matrigel or without Matrigel in 384 well<br />
plates in E2-free media. After 3 days, cells were treated with either<br />
E2 (10-9M) or vehicle (0.1% ethanol). Fluc activity was assessed by<br />
bioluminescence imaging at 24, 48 and 72 hours following treatment<br />
using Xenogen IVIS Spectrum imaging system.<br />
Results: Initial findings showed differential transcriptional activities<br />
between the parental T47D/neo and T47D/PKCα cell lines at the basal<br />
level (without E2 treatment) in the 3D environment. Specifically,<br />
TFs involved in tumorigenesis (such as ETS1, STAT5) or the EMT<br />
process (such as SNAI1) were more highly activated in T47D/PKCα<br />
cells. Furthermore, E2 has a modulating effect on the activities of<br />
TFs in the two cell lines over time; observed both in the 2D and 3D<br />
environments. In particular, some TFs, such as Oct4, ETS1, and<br />
Stat5; were modulated (either induced or suppressed) by E2 only in<br />
T47D/PKCα cells.<br />
Conclusion: These findings suggest that overexpression of PKCα<br />
alters TF activity in T47D breast cancer cells both basally and in<br />
response to E2. This HTS technology allowed us to reveal the dynamic<br />
regulation of TF activation in PKCα overexpressing T47D breast<br />
cancer cells. We are now beginning to understand the mechanism<br />
whereby PKCα may mediate differential response to E2 dependent<br />
on the microenvironment. This HTS approach is likely to lead to the<br />
identification of new therapeutic targets.<br />
P6-04-25<br />
Genomic Deregulation and Therapeutic Role of Nemo-like Kinase<br />
in Luminal B <strong>Breast</strong> <strong>Cancer</strong><br />
Cao X, Qin L, Kim J-A, Tan Y, Wang X, Schiff R. Lester & Sue Smith<br />
<strong>Breast</strong> Center, Baylor College of Medicine, Houston, TX<br />
Luminal B breast tumors are notoriously known as high grade<br />
breast cancer prone to Tamoxifen resistance and early recurrence.<br />
Chromosomal abnormalities are a crucial class of drug targets<br />
in cancer which can be classified into numerical and structural<br />
rearrangements. Gene amplification is the result of numerical<br />
rearrangement that generates multiple copies of an otherwise normal<br />
human gene, such as Her2 amplification observed in breast cancer.<br />
Gene fusion is the result of structural rearrangement that fuses<br />
together pieces of two different genes, such as BCR-ABL gene fusion<br />
identified in leukemia.<br />
Due to their critical role in causing human cancers and their presence<br />
exclusively in the tumor tissues, gene amplifications and fusions<br />
provide highly specific drug targets with only minimal side effects.<br />
In order to identify these chromosome aberrations that can serve<br />
as new therapeutic targets in breast cancer, we developed a novel<br />
bioinformatics analysis called “copy number signature analysis”.<br />
This is based on the observation that driving gene fusions and their<br />
original (wild-type) genes are often amplified in fusion-positive<br />
tumors, or tumors without the fusions respectively. This suggests that<br />
gene fusions and amplifications may synergize to activate important<br />
oncogenes; if directly druggable, these aberrations will provide<br />
substantial opportunities for new therapies.<br />
Applying this analysis to the newly emerged genomic data from the<br />
<strong>Cancer</strong> Genome Atlas (TCGA) project nominated Nemo-like kinase<br />
(NLK) as a lead therapeutic target for invasive breast cancer. NLK<br />
encodes a serine-threonine mitogen activated protein kinase that<br />
plays a pivotal role in transforming growth factor beta pathway and<br />
embryo development. Genomic amplifications and rearrangements<br />
at NLK locus happen in 7%-9% of breast tumors, which may lead<br />
to deregulated serine-threonine kinase activity. Of note, these<br />
aberrations preferentially present in luminal B or Her2 positive<br />
breast tumors, suggesting their association with these high grade<br />
tumors. Most interestingly, transient inhibition of NLK through<br />
small RNA interference in multiple breast cancer cell lines harboring<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
NLK deregulations, we observed potent inhibition of cell growth<br />
and capability of forming tumor-like colonies, as well as increased<br />
sensitivity to Tamoxifen treatment.<br />
These data suggest that NLK might be deregulated by genetic events<br />
which may promote growth-factor signaling and Tamoxifen resistant<br />
phenotype. Molecular assays detecting NLK chromosomal aberrations<br />
may serve as a predictive biomarker for endocrine resistance in breast<br />
cancer as well as selection of patients for appropriate treatment.<br />
P6-04-26<br />
Tamoxifen may block estrogen induced secretion of certain<br />
cytokines to interrupt tumor associated macrophage infiltration<br />
in breast cancer<br />
Ding J, Chen CM, Jin W, Shao Z, Wu J. <strong>Breast</strong> <strong>Cancer</strong> Institute, Fudan<br />
University Shanghai <strong>Cancer</strong> Center, Shanghai, China; Shanghai<br />
Medical College, Fudan University, Shanghai, China<br />
The role of tumor microenvironment during the initiation and<br />
progression of breast cancer is now realized to be of critical<br />
importance, both for understanding of the fundamental cancer<br />
biology and exploiting relatively new mechanism for breast cancer<br />
metastasis. Macrophage is a one of the most common components<br />
in the breast cancer microenvironment. Normally, the macrophage in<br />
tumor microenvironment is referred to tumor associated macrophage<br />
(TAM), which shares some attributes of alternatively activated<br />
macrophage. Many pre-clinical and clinical studies demonstrate an<br />
inverse correlation between TAM infiltration and patients’ prognosis<br />
indicating a macrophage supporting role for tumor progression. It is<br />
well documented that selective patients with breast cancer can benefit<br />
from anti-estrogen therapy. However, the mechanisms involved are<br />
still not fully elucidated. Our previous study indicates that highly<br />
tumorigenic breast cancer cell line MDA-MB-231 can educate<br />
monocyte differentiation into alternatively activated macrophage,<br />
while weakly tumorigenic cell line MCF-7 (without estrogen<br />
supplementation) can not. In the present study, we explored the effects<br />
of estrogen and tamoxifen on the secreting of certain cytokines, which<br />
are required for monocyte chemotaxis and differentiation. <strong>Breast</strong><br />
cancer cell lines with different estrogen receptor status were applied<br />
to estimate the level of cytokines (IL4, IL6, M-CSF, GM-CSF, and<br />
MCP-1) before and after cultured with 17β-estradiol, tamoxifen or<br />
both. We found that weakly invasive breast cancer cell lines (MCF-<br />
7, T47D, MDA-MB-468, and SKBR3) generally expressed lower<br />
levels of such cytokines compared with highly invasive breast cancer<br />
cell lines (MDA-MB-231, MDA-MB-231-BO, MDA-MB-231<br />
HM, Bcap 37, BT549, and Hs578T) at baseline. However, the<br />
discrepancies could be compensated partially by exposure to 10nM<br />
17β-estradiol in estrogen receptor (ER) positive cell lines (MCF-7<br />
and T47D). Moreover, the compensation was substantially blocked<br />
by 2µM tamoxifen. On the contrary, tamoxifen, alone, didn’t affect<br />
the secretion of such cytokines mentioned above in vitro. Based on<br />
these findings, we tentatively concluded that some patients with<br />
ER positive breast cancers benefiting from anti-estrogen therapy<br />
may partially attributes to blocking monocyte differentiation into<br />
TAM, which destroyed the tumor microenvironment. These findings<br />
suggest the future possibility of using TAM as a novel therapeutic<br />
target in patients with anti-estrogen resistance and primary triplenegative<br />
breast cancers (TNBC) with no effectively therapeutic<br />
measures nowadays, which are defined by lack of estrogen receptor,<br />
progesterone receptor and ERBB2 gene amplification, representing<br />
approximately 16% of all breast cancers.<br />
P6-04-27<br />
EBAG9 immunoreactivity is a potential prognostic factor for<br />
poor outcome of breast cancer patients with adjuvant tamoxifen<br />
therapy<br />
Shigekawa T, Ijichi N, Ikeda K, Miyazaki T, Horie-Inoue K, Shimizu C,<br />
Saji S, Aogi K, Tsuda H, Osaki A, Saeki T, Inoue S. Research Center<br />
for Genomic Medicine, Saitama Medical University; International<br />
Medical Center, Saitama Medical University; Tokyo Metropolitan<br />
<strong>Cancer</strong> and Infectious Disease Center, Komagome Hospital; National<br />
<strong>Cancer</strong> Center Hospital; Graduate School of Medicine, Kyoto<br />
University; National Shikoku <strong>Cancer</strong> Center; Graduate School of<br />
Medicine, The University of Tokyo<br />
Estrogen receptor-binding fragment associated gene 9 (EBAG9) is<br />
a primary estrogen responsive gene originally cloned from MCF-7<br />
human breast carcinoma cells. Upregulation of EBAG9 expression<br />
has been observed in several malignant tumors such as advanced<br />
breast cancers, indicating that EBAG9 may contribute to tumor<br />
progression. In the present study, the immunohistochemical analyses<br />
of EBAG9 were performed using the specimens from breast cancer<br />
patients treated with tamoxifen as adjuvant therapy. To investigate the<br />
association between EBAG9 expression and the therapeutic effect of<br />
tamoxifen in breast cancer, we used adjuvant tamoxifen-treated breast<br />
cancer patient tissues from 3 institutions. The study was approved<br />
by the institutional review board. Patients with distant metastases<br />
within 5 years after surgery followed by tamoxifen treatment were<br />
defined as relapse cases, whereas those without distant metastases<br />
were defined as relapse-free cases. The immunoreactivity of EBAG9<br />
was predominantly detected in the cytoplasm of breast cancer cells.<br />
Notably, EBAG9 immunoreactivity level was substantially elevated<br />
in the breast cancer samples from the relapse patients, and the positive<br />
immunoreactivity of EBAG9 was correlated with poor prognosis<br />
of the patients with adjuvant therapy. These results suggest that<br />
EBAG9 expression in tumor regions is associated with unfavorable<br />
prognosis of patients with adjuvant tamoxifen therapy and EBAG9<br />
immunoreactivity can serve as a biomarker for adjuvant tamoxifen<br />
efficacy.<br />
P6-04-28<br />
Changes in BAG-1 expression level affect the Tamoxifen-induced<br />
apoptosis and Gegitinb-induced apoptosis in breast cancer cells<br />
Lu S, Zhuang X, Liu H. Tianjin Medical University <strong>Cancer</strong> Institute<br />
and Hospital, Tianjin, China; Tianjin Medical University, Minstry of<br />
Education, Tianjin, China<br />
BAG-1 (bcl-2-associated athanogene-1) is a multifunctional<br />
protein which can interact with a number of molecules to regulate<br />
diverse biological processes including apoptosis, proliferation,<br />
signal transduction and transcription. BAG-1 protects cells from<br />
a wide range of apoptotic stimuli including radiation, hypoxia and<br />
chemotherapeutic agents and growth factor withdrawal. Therefore,<br />
BAG-1 may contribute to reduced cell death in cancer development,<br />
as well as to resistance to important therapeutic agents. Our study<br />
showed that the TAM sensitive cell line MCF-7 expressed lower<br />
levels of BAG-1 than the TAM resistant cell line MCF-7/TAMR,<br />
which was induced from MCF-7 cell line by culturing in medium<br />
containing 4-OH TAM (1×10- 7 M) for 6 months. Our study also<br />
found that down-regulation of BAG-1 significantly enhanced the<br />
sensitivity of the TAMR/MCF-7 cells to TAM treatment. Additionally,<br />
we used vectors carrying the individual BAG-1 isoforms to transfect<br />
the MCF-7 cells, and found that BAG-1 p50 was the only isoform<br />
that inhibited the TAM-induced apoptosis in the MCF-7 cells, while<br />
the other isoforms had little effect. Besides, we detected strong<br />
www.aacrjournals.org 503s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
expression of BAG-1 in several breast cancer cell lines including<br />
T47D, MCF-7, MDA-MB231 and SK-BR-3. We even observed a<br />
1.56 fold increase of EGFR in T47D cells transfected with BAG-1<br />
siRNA when compared with the negative control. To further explore<br />
the association between BAG-1 expression and Gefitinb response in<br />
breast cancer cell lines, we used Gefitinb of different concentrations<br />
to treat cells for 24 hours, 48 hours and 72 hours respectively. The<br />
results of cell viability assay indicated that the down-regulation of<br />
BAG-1 in breast cancer cell line T47D significantly enhanced the<br />
T47D cells’ sensitivity to Gefitinb-induced apoptosis.<br />
In summary, our results indicated that BAG-1 may have influence in<br />
the development of TAM resistance and Gefitinb resistance in breast<br />
cancer. However, our study was conducted in breast cancer cells in<br />
vitro; further studies on the relationship between BAG-1 expression<br />
and response to TAM and Gefitinb in a large cohort of breast cancer<br />
patients may be needed to confirm our findings.<br />
P6-04-29<br />
Vitamin D induces expression of estrogen receptor and restores<br />
endocrine therapy response in estrogen receptor-negative breast<br />
cancer<br />
<strong>San</strong>tos N, Diaz L, Ordaz D, Garcia J, Barrera D, Avila E, Halhali<br />
A, Medina H, Camacho J, Larrea F, Garcia R. Instituto Nacional<br />
de Ciencias Médicas y Nutrición Salvador Zubirán, México, DF,<br />
Mexico; Centro de Investigación y de Estudios Avanzados del I.P.N.,<br />
México, DF, Mexico<br />
Background: Approximately 30% of all breast tumors do not express<br />
estrogen receptor (ER) and patients with these tumors present poor<br />
prognosis and respond poorly to hormone therapy. Calcitriol through<br />
its vitamin D receptor (VDR) exerts antiproliferative, apoptotic and<br />
pro-differentiating effects in cancer. Calcitriol´s effects upon ER<br />
expression in breast cancer cells is controversial. Therefore, in order<br />
to clarify this issue, the aim of the present study was to determine if<br />
calcitriol induces ERα expression in ERα-negative breast cancer cells<br />
and could restore antiestrogen responses. The evaluation of calcitriol<br />
effects was performed in terms of proliferation and regulation of the<br />
following genes: Cyclin D1, involved in cell cycle, and Ether-à-go-go<br />
1 (Eag1), related to cell proliferation and tumor progression.<br />
Methods: Cultured cells derived from ERα-negative breast tumors<br />
and an established ERα-negative breast cancer cell line (SUM 229)<br />
were used in this study. These cells were treated with calcitriol<br />
and reverse transcription-PCR or western blotting analyses were<br />
performed to assess ERα expression. Growth assays with XTT were<br />
used to evaluate the antiproliferative response to the antiestrogens<br />
fulvestran and tamoxifen. Gene expression analysis for Cyclin D1 and<br />
Eag1 was evaluated by real time PCR in cells treated simultaneously<br />
with calcitriol plus estradiol or fulvestran.<br />
Results: The treatment with calcitriol in ER-negative breast cancer<br />
cells resulted in the induction of ERα. This effect was specifically<br />
mediated through the vitamin D3 receptor (VDR), since the VDR<br />
antagonist TEI-9647 effectively inhibited the ability of calcitriol to<br />
stimulate ERα gene expression. Consequently, the induction of ERα<br />
by calcitriol restores the response to antiestrogens in breast cancer<br />
cells by inhibiting cell proliferation. Co-treatment of calcitriol and<br />
antiestrogens down-regulated Cyclin D1 and Eag1 gene expression.<br />
Conclusion: Calcitriol induced the expression of ERα and restored<br />
antiestrogenic responses in ERα-negative breast cancer cells.<br />
Moreover, fulvestran down regulated mRNA expression of Cyclin D1<br />
and Eag1 when ERα-negative cells were pre-treated with calcitriol.<br />
These results suggest that the combined treatment with calcitriol and<br />
antiestrogens could be a new therapeutic strategy for ERα-negative<br />
breast cancer patients.<br />
P6-04-30<br />
COUP-TFII suppresses NFκB activation in endocrine-resistant<br />
breast cancer cells<br />
Litchfield LM, Klinge CM. University of Louisville School of<br />
Medicine, Louisville, KY<br />
COUP-TFII is an orphan nuclear receptor that functions as either a<br />
transcriptional activator or repressor. We previously reported that<br />
COUP-TFII expression is reduced in endocrine-resistant LCC9<br />
breast cancer cells and that overexpression of COUP-TFII restored<br />
the ability of the antiestrogen tamoxifen to inhibit cell proliferation.<br />
An increase in NFκB activity and p65/RELA expression has been<br />
reported in endocrine-resistant breast cancer cells. Because NFκB<br />
activation results in increased expression of anti-apoptotic and proproliferative<br />
genes, increased NFκB signaling promotes the survival<br />
of cancer cells. The goal of the current study was to further elucidate<br />
the mechanism by which COUP-TFII enables cells to maintain<br />
endocrine sensitivity and to determine if COUP-TFII can modulate<br />
NFκB activity in tamoxifen-resistant breast cancer cells. To examine<br />
whether COUP-TFII can suppress NFκB activity, MCF-7 (tamoxifensensitive,<br />
TAM-S) and LCC9 (tamoxifen-resistant, TAM-R) breast<br />
cancer cells were transfected with a NFκB luciferase reporter and<br />
treated with TNFα to activate NFκB. NFκB activity was elevated in<br />
LCC9 TAM-R cells and co-transfection with COUP-TFII reduced<br />
NFκB activity. COUP-TFII overexpression led to a statistically<br />
significant reduction in the expression of NFκB subunits RELA,<br />
RELB, NFKB1, and REL in LCC9 cells. Significantly reduced<br />
expression of NFκB target genes IL6, ICAM1, TNFAIP3, and CCL2<br />
was also evident upon COUP-TFII overexpression, reflecting the<br />
suppression of the NFκB pathway by COUP-TFII. Inhibition of NFκB<br />
activation by COUP-TFII also led to a reduction in cell viability in<br />
TAM-R cells in response to tamoxifen treatment. Together these<br />
data indicate a novel role for COUP-TFII in suppression of NFκB<br />
activity which may explain the ability of COUP-TFII to promote<br />
tamoxifen-sensitivity. COUP-TFII may be both a useful biomarker to<br />
predict tamoxifen-sensitivity as well as a target to restore endocrine<br />
sensitivity to resistant cells.<br />
Supported by NIEHS T32 ES011564 predoctoral fellowship to L.M.L.<br />
and Susan G. Komen for the Cure grant KG080365 to C.M.K.<br />
P6-05-01<br />
Evaluation of the prognostic significance of androgen receptor<br />
(AR) expression in relation to ER expression in breast cancer (BC)<br />
Gucalp A, Datko FM, Patil S, Hedvat CV, Kalinsky K, Hudis CA,<br />
Traina TA, Moynahan ME. Memorial Sloan-Kettering <strong>Cancer</strong> Center;<br />
Columbia University Medical Center<br />
Background: AR is expressed in 60-80% of invasive BC. Emerging<br />
data suggest that AR expression may have a prognostic role in BC<br />
irrespective of ER and that the androgen-signaling pathway may<br />
be involved in BC pathogenesis. We previously identified an ARdependent<br />
subset of ER/PR(-) BC and reported clinical benefit<br />
from AR-inhibition (Gucalp, ASCO 2012). We now describe the<br />
prevalence, clinicopathologic characteristics, and survival outcomes<br />
of AR(+) BC in relation to expression of ER in a single-institution<br />
retrospective cohort.<br />
Methods: We identified 590 patients (pts) with resectable BC (tumor<br />
>1cm) who had surgery at MSKCC from 1992-1996. IRB approval<br />
was obtained. Tissue microarray (TMA) construction/scoring has been<br />
described (Kalinsky CCR 2009). TMAs were stained, scanned and<br />
digitally scored (Aperio ScanScope XT) for nuclear steroid receptors<br />
(ER, AR), HER2, p53, and MIB1 (Ki67). Using digital quantification<br />
of tumor cell nuclear staining, pts were categorized into the following<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
7 groups: ER dominant (ERD, both ER and AR >10% with ER>AR<br />
by >5%), ER only (ER>10%, AR 10%, 10%, AR>ER by >5%), AR<br />
only (AR>10%, ER
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
NVP-BEZ235. Interestingly, we observed that all AR-positive TNBC<br />
cell lines examined contain PIK3CA mutations (H1047R) suggesting<br />
selection for deregulation of the PI3K pathways during evolution of<br />
AR expressing breast cancers. Further investigation of a panel of<br />
AR-positive TNBC tumors showed that PIK3CA kinase mutations<br />
are a frequent event in this TNBC subtype (69.2% vs. 26.9%) and<br />
not just an artifact of the LAR cell line models. We show that PI3K<br />
pathway activation plays a role in resistance to AR antagonists,<br />
as there are elevated levels of activated AKT in residual tumors<br />
after bicalutamide treatment of xenograft tumors. Furthermore, we<br />
demonstrate that genetic/pharmacological targeting of AR synergizes<br />
with PI3K/mTOR inhibition in both two- and three-dimensional cell<br />
culture models. Moreover, the combination of bicalutamide with<br />
PI3K/mTOR inhibitors GDC0980 or NVP-BEZ235 decreased tumor<br />
volume in mouse xenograft studies . Our preclinical data provide<br />
the rationale for pre-selecting AR-positive TNBC patients for future<br />
clinical trials evaluating the combination of AR antagonists with<br />
PI3K/mTOR inhibitors.<br />
P6-05-04<br />
Expression of the Androgen Receptor in triple negative tumors<br />
and its modulation by receptor tyrosine kinases and downstream<br />
pathways<br />
Cuenca D, Montero JC, Morales JC, Prat A, Pandiella A, Ocana<br />
A. Albacete University Hospital, Albacete, Spain; <strong>Cancer</strong> Research<br />
Center, CIC-CSIC, Salamanca, Spain; Lineberger <strong>Cancer</strong> Center,<br />
University of North Carolina<br />
Background: Androgen receptor (AR) plays a central role in some<br />
tumor types like prostate cancer. Its expression and function in breast<br />
cancer is relatively unknown. Studies have linked tyrosine kinase (TK)<br />
receptors and their intracellular signaling pathways with AR status. In<br />
the present work we study the presence of AR in breast cancer human<br />
samples and how TKs can control its expression.<br />
Methods: Tumor samples from patients were used to assess the<br />
expression of AR by western-blot. Membrane and intracellular<br />
kinases were evaluated using phosphoprotein arrays. Cell lines<br />
representative of all breast cancer subtypes were used to assess the<br />
expression of the AR and other signaling proteins using western-blot<br />
and phosphoprotein arrays. Proliferation studies with several kinase<br />
inhibitors were measured by MTT assays. We also interrogated<br />
publicly available gene expression microarray data sets with annotated<br />
clinical-pathological data.<br />
Results: Across all the intrinsic subtypes of breast cancer, the<br />
expression of AR gene was found highly expressed in HER2-enriched<br />
and Luminal tumors and lowly expressed in Basal-like and/or triplenegative<br />
(TN) tumors. In TN tumors, PDGFRβ and EGFR were<br />
found highly activated, together with AKT and Erk1/2. A positive<br />
correlation was observed between activation of EGFR and PDGFRβ<br />
and the expression of AR. In vitro, AR protein expression varied<br />
across cell lines and was found more expressed in MCF7 (Luminal)<br />
and HS578T (TN), BT549 (TN), HCC70 (TN) and no expressed<br />
in HBL100 (TN) and MDA-MB231 (TN). Administration of the<br />
antiandrogen bicalutamide produced an anti-proliferative effect that<br />
was increased by association of an Erk1/2 inhibitor. Inhibition of the<br />
PI3K-mTOR pathway in BT549 and HS578T reduced the expression<br />
of AR but did not augment the action of bicalutamide. In TN tumors,<br />
AR gene and protein was found more expressed in older compared<br />
to younger patients.<br />
Conclusions: In breast cancer, AR is expressed and is controlled by<br />
receptor TKs through the PI3K-mTOR pathway. An increased antiproliferative<br />
effect is observed with the combination of bicalutamide<br />
and Erk1/2 inhibitors. AR expression correlates with age at diagnosis.<br />
P6-05-05<br />
Triple receptor comparison between primary breast cancer and<br />
metachronous or synchronous liver metastasis<br />
Tuyls S, Brouckaert O, Vanderstichele A, Vanderhaegen J, Amant<br />
F, Leunen K, Smeets A, Berteloot P, Van Limbergen E, Weltens C,<br />
Peeters S, Vanbeckevoort D, Floris G, Moerman P, Paridaens R,<br />
Wildiers H, Vergote I, Christiaens M-R, Neven P. University Hospitals<br />
Leuven, Belgium<br />
Background: Decisions about systemic treatment in women with<br />
metastatic breast cancer are currently based on the presence of<br />
estrogen receptors (ER), progesterone receptors (PR) or Human<br />
Epidermal growth factor Receptor 2 (HER2 receptors) in the primary<br />
tumor. Recently, several studies have reported significant discordances<br />
in ER, PR and HER2 status between the primary tumor and metastatic<br />
lesions and this may vary by metastatic site. Prognostic implications<br />
remain unclear although alterations in ER, PR and/or HER2 can<br />
influence metastatic management. This study represents one of the<br />
largest studies evaluating how frequent receptor discordances occur<br />
in liver metastasis, whether this alters therapeutic options and impacts<br />
prognosis.<br />
Patients and methods: 246 breast cancer patients with histological<br />
confirmed liver metastasis were analyzed in this retrospective study.<br />
Immunohistochemistry (IHC) and/or FISH were used to determine<br />
ER, PR and HER2 receptor status. We excluded patients when<br />
comparison between receptors of primary tumor and metastasis was<br />
impossible due to missing data (n=85), when liver metastasis did not<br />
originate from breast cancer (n=36) and when pathology was obtained<br />
from autopsy specimens (n=38).<br />
Results: 87 patients had matched tissue samples of primary tumor<br />
and liver metastasis with possible comparison of at least one of the<br />
receptors. Table 1 summarizes changes in ER, PR, HER2 between<br />
primary and metastatic lesion. Discordance in receptor status was<br />
associated with shorter time to death (63.3 months) compared to the<br />
concordant group (75.5 months).<br />
table1<br />
- to + + to - total discordance<br />
ER 2/12 (16.7%) 16/75 (21.3%) 18/87 (20.7% with 95% CI 12.8-30.7)<br />
PR 6/23 (26.1%) 32/63 (50.8%) 38/86 (44.2% with 95% CI 33.5-55.3)<br />
HER2 1/50 (2.0%) 0/13 (0%) 1/63 (1.6% with 95% CI 0.04-8.53)<br />
Conclusions: A significant proportion of ER and PR show discordance<br />
between primary tumor and liver metastasis. However we could not<br />
establish the same level of discordance for the HER2 receptors as<br />
in other studies. In general, only about 1 in 5 patients gained new<br />
(endocrine or targeted) therapeutic options. Tissue confirmation<br />
remains important to evaluate whether metastatic disease has become<br />
endocrine insensitive (in approximately 1 in 5 patients), avoiding<br />
unnecessary delay in chemotherapy. Discordance in receptors may<br />
be associated with inferior prognosis.<br />
P6-05-06<br />
Serum estradiol levels in postmenopausal ER+/PR- breast cancer<br />
are lower than those in postmenopausal ER+/PR+<br />
Yamamoto Y, Ibusuki M, Goto H, Murakami K, Iwase H. Kumamoto<br />
University Hospital, Kumamoto, Japan<br />
(Background) Activation of growth factor receptor (GFR) signaling<br />
is related with ER+/PR- breast cancer (BC). Proportion of ER+/PRphenotype<br />
in ER+ BC in postmenopausal patients is higher than that<br />
in premenopausal. However, this phenomenon cannot be explained<br />
by only GFR signaling activation. We hypothesized that ER+/PRphenotype<br />
in postmenopausal patients has at least two subtypes, one<br />
is related with activation of GFR signaling and the other is related<br />
with suppression of PR expression due to low estrogenic stimulation.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
(Purpose) The aim of this study is to clarify out hypothesis.<br />
(Patients and methods) We measured serum E2 levels with<br />
radioimmuno assay (range of E2 levels : 1.3 to 50 pg/ml) in 154<br />
postmenopausal ER+ BC patients. Cut-off levels of ER and PR<br />
were used 10% or more expression in tumor cells. We analyzed<br />
the correlation between serum levels of E2 and clinicopathological<br />
factors including PR expression. We also examined the relationship<br />
between HER2 expression levels and ki67 labeling index in ER+/<br />
PR- BC. In addition, we analysed the difference in ki67 LI between<br />
in premenopausal patients (n=65) and in postmenopausal patients.<br />
(Results) Median serum levels of E2 in ER+/PR+ phenotype (6.7<br />
pg/ml) were significantly higher than in ER+/PR- phenotype (4.5<br />
pg/ml)(p=0.036). Serum levels of E2 was positively associated<br />
with body mass index (p=0.01). However, there was no significant<br />
difference between serum E2 levels and other clinicopathological<br />
factors including tumor size, nodal status, nuclear grade, levels of<br />
ER expression and ki67 LI. In ER+/PR- phenotype, ki67 LI were<br />
varied (Median: 7.5%, range: 0.5 to 85%). Ki67 LI in Postmenopausal<br />
patients with ER+/PR- phenotype was significantly lower than that<br />
in premenopausal patients with ER+/PR- phenotype (p=0.0022).<br />
Expression levels of HER2 was positively associated with ki67<br />
LI(p=0.002).<br />
(Conclusions) ER+/PR- cancer in postmenopausal patients may<br />
have two types of phenotype. One is highly proliferative phenotype<br />
that is stimulated with GFR signaling. The other is low proliferative<br />
one that PR expression is suppressed by without sufficient estrogen<br />
supply. Serum levels of E2 might affect development of ER+ BC in<br />
postmenopausal women, especially in case of no activation of GFR<br />
signaling.<br />
P6-05-07<br />
Amplified in breast cancer 1 and ankyrin repeat containing<br />
cofactor 1 mediate estrogen induced repression of the ErbB2<br />
oncogene<br />
Garee JP, Riegel AT. Georgetown University, Washington, DC<br />
The oncogene amplified in breast cancer 1 (AIB1/SRC3) is a nuclear<br />
receptor coactivator and plays an important role in the regulation<br />
of gene transcription. Additionally, AIB1 is important in malignant<br />
progression as AIB1 has been shown to be a gene amplified in breast<br />
cancer and is also over-expressed in a variety of cancer types. Previous<br />
work from our laboratory has identified a splice variant of AIB1<br />
termed AIB1-∆4. This splice variant arises from the splicing of exon 4<br />
from the mature mRNA. This leads to the formation of an N terminally<br />
truncated form of the AIB1 protein, which is a more potent coactivator<br />
of steroid dependent transcription compared to the full length AIB1.<br />
This suggests that the N-terminal fragment of AIB1, which is not<br />
present in AIB1-∆4, may act to dampen AIB1 mediated transcriptional<br />
activation. The presence of this N terminal region suggests this region<br />
may be a site of interaction with a repressive protein, which could<br />
interact with AIB1 and not AIB1-∆4. We have identified ANCO1 as<br />
an N terminal AIB1 binding protein that acts to repress AIB1 mediated<br />
transcriptional activity. Co-immunoprecipitation experiments have<br />
indicated interaction between AIB1 and ANCO1 but not between<br />
AIB1-∆4 and ANCO1 indicating ANCO1 binds in the N terminal<br />
region of AIB1. AIB1 has a clinical implications and association<br />
with the oncogene ErbB2, which is an estrogen repressed gene with<br />
hormone effect acting through an estrogen response element (ERE)<br />
in intron 1 of the ErbB2 gene. We wanted to determine if the AIB1/<br />
ANCO1 complex played a role in hormone regulation of ErbB2.<br />
Silencing of AIB1 and ANCO1 by shRNA led to a reversal of<br />
estrogen-induced repression of ErbB2 indicating this protein complex<br />
may play a role in mediating this repression. Examining binding of<br />
these proteins to the intronic ERE of ErbB2 we determined that AIB1<br />
and ANCO1 are recruited in the presence of estrogen. Additionally,<br />
repressive proteins such as HDAC3, HDAC4 and N-CoR are recruited<br />
along with the AIB1/ANCO1 complex. While AIB1-∆4 can still be<br />
recruited to the intronic ERE no additional repressive proteins are<br />
recruited. This suggests a mechanism by which the AIB1/ANCO1<br />
complex can recruit repressive proteins to repress ErbB2 gene<br />
transcription, while AIB1-∆4 can escape this repressive mechanism.<br />
This may potentially have interesting clinical implications, as high<br />
levels of AIB1-∆4 may be responsible for increasing the expression<br />
levels of the ErbB2 oncogene.<br />
P6-05-08<br />
Significant heterogeneity in ERalpha and PR receptor status in<br />
different distant breast cancer metastases of the same patient<br />
Hoefnagel LDC, van der Groep P, Broers JE, van der Wall E, van<br />
Diest PJ. UMC Utrecht, Utrecht, Netherlands<br />
Purpose: Receptor conversion for estrogen receptor alpha (ERα),<br />
progesterone receptor (PR) and human epidermal growth factor<br />
receptor 2 (HER2) in single distant breast cancer metastases has<br />
been described before. However, most patients develop multiple<br />
metastases. Heterogeneity in receptor status between different<br />
metastases of the same patient has not been studied, probably since<br />
such material is very rare. The consequence of such heterogeneity<br />
would mean that as many metastases as possible need to be biopsied<br />
to re-assess receptor status.<br />
We therefore aimed to study heterogeneity of receptor status between<br />
different distant metastases of the same patient in a relatively large<br />
group by re-staining all primary tumors and metastases with current<br />
optimal immunohistochemical methods on full sections.<br />
Material and methods: Formalin fixed paraffin embedded tissue of<br />
primary breast carcinomas and corresponding multiple (≥2) distant<br />
metastases from 38 female patients were collected from several<br />
pathology departments in The Netherlands and stained for ERα, PR<br />
and HER2 by IHC. We evaluated the heterogeneity of receptor status<br />
between the metastases and the correlation with the primary tumor.<br />
Results: In the 4 cases that showed ER conversion, 2 (50%) showed<br />
heterogeneity in receptor expression between different metastases<br />
of the same patient. Of the 17 cases that showed PR conversion, 12<br />
cases (71%) showed heterogeneity in expression between metastases.<br />
There were no changes in the receptor profile of primary breast cancer<br />
to their metastases for HER2 in this group.<br />
Conclusion: In a significant number of metastatic breast cancer<br />
patients, there is heterogeneity in ER and PR receptor status between<br />
different breast cancer metastases of the same patient. This implies<br />
that as many metastases as possible need to be biopsied to re-assess<br />
receptor status and set the optimal indication for hormonal therapy in<br />
these patients. Alternatively, non-invasive assessment of the receptor<br />
status by molecular imaging may be an easier future way to assess<br />
receptor status of all metastatic lesions.<br />
www.aacrjournals.org 507s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P6-05-09<br />
Unravelling the global effect of estrogen on breast cancer cell<br />
proteome using quantitative proteomics.<br />
Pavlou MP, Drabovich AP, Dimitromanolakis A, Diamandis EP.<br />
University of Toronto, ON, Canada; Mount Sinai Hospital, Toronto,<br />
ON, Canada; University Health Network, Toronto, ON, Canada;<br />
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto,<br />
ON, Canada<br />
Estrogens exert their function through genomic and non-genomic<br />
pathways mediated mainly by estrogen receptors. Estrogen signalling<br />
is highly complex and once activated initiates cancer cell proliferation<br />
and survival, playing a pivotal role in breast cancer development and<br />
progression. The identification of estrogen regulated genes is the<br />
first step towards elucidating the mechanisms of estrogen function.<br />
Although numerous studies have investigated the effect of estradiol<br />
at the mRNA level, assessment of global changes at the protein level<br />
has been limited mainly due to technological limitations.<br />
Here, we present the most extensive proteomic study in the quest of<br />
proteins whose expression is regulated or associated with estradiol<br />
action. To facilitate accurate quantification of proteins, we first<br />
developed and optimized a proteomic protocol for cell lysis and<br />
sample preparation, based on a mass spectrometry-compatible<br />
detergent. Following our protocol coupled to stable isotope labelling<br />
with amino acids in cell culture (SILAC) of MCF-7 breast cancer<br />
cells, we quantified approximately 4,000 proteins and identified 153<br />
proteins differentially expressed upon estradiol stimulation. Notably,<br />
known estrogen regulated proteins such as trefoil 1(TFF1) and<br />
progesterone receptor (PGR) showed a four- and three-fold increase<br />
respectively, at 48 hours after estradiol stimulation. Forty eight of<br />
153 differentially expressed proteins have been found to contain<br />
estrogen receptor elements (EREs) indicating direct regulation by<br />
estradiol. Protein-protein network analysis (STRING) revealed an<br />
extensive protein network related to cell proliferation. Differential<br />
expression of proteins was verified in three estrogen receptor positive<br />
breast cancer cell lines (MCF-7, HCC-1428, BT-483) using a targeted<br />
mass spectrometry-based quantitative approach; selected reaction<br />
monitoring (SRM). A multiplex SRM assay was developed for the<br />
simultaneous quantification of 56 proteins. The same assay was<br />
utilized to study the kinetics of these proteins in time and in presence<br />
of inhibitors of estrogen receptor facilitating the distinction between<br />
direct and indirect protein targets.<br />
To our knowledge, such an extensive network of estrogenregulated<br />
genes has never been previously studied at the protein<br />
level. Interestingly, numerous differentially expressed proteins<br />
identified in the present study have not been connected to estrogen<br />
signalling or breast cancer before. The role of these proteins in breast<br />
carcinogenesis and their potential as therapeutic targets warrants<br />
further investigation.<br />
P6-05-10<br />
Progestins exert divergent growth effects and regulate tumorunique<br />
gene cohorts in patient derived breast cancer xenografts<br />
Sartorius CA, Finlay-Schultz J, Li C, Rosen RB, Hendricks P, Wisell<br />
J, Finlayson C, Elias A, Kabos P. University of Colorado Denver<br />
Anschutz Medical Campus, Aurora, CO<br />
Background: Progesterone is an important hormone for development<br />
and normal function of the breast; however, its role in established<br />
breast cancers is less clear. Progestins have been implicated in<br />
regulating tumor cell growth, signaling, differentiation state, and<br />
stem/progenitor properties in breast cancer cells. High dose progestin<br />
treatment can be an effective therapy for some advanced breast tumors,<br />
through an unknown mechanism. Progesterone receptors (PRs) are<br />
considered positive prognostic indicators, although their levels vary<br />
considerably among luminal subtype breast tumors. Progestin/PR<br />
regulated genes in tumor cells have only been determined in cultured<br />
breast cancer cells and mouse mammary tumor models. Here we<br />
define tumor unique progestin-dependent growth effects and gene<br />
regulation profiles in patient-derived luminal breast tumor xenografts.<br />
Methods: For these studies, three luminal estrogen receptor<br />
(ER)+PR+ transplantable xenografts were used that were derived<br />
from one pleural effusion and two previously untreated primary<br />
tumors. All three tumors were estrogen dependent to various degrees<br />
and contained variable levels of ER (5-90%) and PR (5-90%).<br />
Tumors were grown in vivo under continuous placebo, estrogen,<br />
or estrogen plus progestin conditions for 8-10 weeks and growth<br />
parameters monitored. Gene expression profiles were determined<br />
from dissected tumors using Affymetrix® GeneChip human gene 1.1<br />
ST microarrays and results analyzed using Partek Genomics Suite<br />
software. Specific gene regulation was confirmed by q-RT-PCR and<br />
immunohistochemistry.<br />
Results: Progestins had an inhibitory, neutral, and stimulatory effect<br />
on estrogen dependent growth in each of the three tumor lines.<br />
Accordingly, there was relatively little overlap in PR regulated genes<br />
between the three tumors. In the tumor in which progestin treatment<br />
had a potent anti-tumor effect, progestins were strong repressors of<br />
estrogen/ER-regulated genes. Gene expression patterns between<br />
the natural hormone progesterone and the synthetic drug MPA were<br />
compared in one tumor line and found to be mostly similar. The<br />
percent of PR+ tumor cells may have influenced the potency of gene<br />
regulation. Unique progestin regulated genes were discovered in this<br />
human tumor model system that were involved in immune response,<br />
cytokine signaling, and stem/progenitor cell features.<br />
Conclusions: Women with breast cancer are exposed to progestins<br />
naturally or through hormonal therapies and these may have a<br />
profound effect on tumor biology. In some tumors, progestins are<br />
potently anti-proliferative, while in others they elicit the opposite<br />
effect and potentiate estrogen induced tumor growth. The diversity of<br />
progestin-regulated genes in each tumor underscores the hormone’s<br />
context dependent effects. Determining progestin dependent gene<br />
signatures in patient tumors may pinpoint appropriate candidates for<br />
progestin therapy in advanced tumors and/or provide a prognostic<br />
tool for predicting tumor progression.<br />
Funded by: NIH R01 CA140985 (C.A.S.), the Grohne Fund (P.K.),<br />
and the University of Colorado <strong>Cancer</strong> Center (C.A.S., P.K.)<br />
P6-05-11<br />
Leptin and Leptin receptor expression in human breast cancer<br />
Wazir U, Al Sarakbi W, Jiang WG, Mokbel K. The London <strong>Breast</strong><br />
Institute, The Princess Grace Hospital, London, United Kingdom;<br />
Cardiff University-Peking University Oncology Joint Institute,<br />
Cardiff, United Kingdom<br />
INTRODUCTION: Leptin is a protein that plays a key role in<br />
regulating energy intake and energy expenditure, including appetite<br />
and metabolism. It is one of the most important adipose derived<br />
hormones and has been suggested to act as a growth factor in<br />
neoplasms. Obesity has been linked to increased risk of breast<br />
cancer in postmenopausal women. Increased peripheral production<br />
of oestrogen has been regarded as the main cause for this association,<br />
but other factors affecting fat metabolism may be implicated. There<br />
is recent evidence that Leptin stimulates cancer cell proliferation in<br />
MCF-7 cancer cells. Both Cox2 and hTERT have been proposed as<br />
mediators of Leptin’s carcinogenic role.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
508s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
Our objective was to determine, using quantitative PCR, whether<br />
the mRNA expression levels of Leptin and Leptin receptor were<br />
consistent with a tumour proliferative function and whether levels<br />
from these genes were positively correlated with clinical outcome<br />
in breast cancer.<br />
METHODS: A total of 153 samples were analysed. The levels<br />
of transcription of Leptin and its receptor were determined using<br />
quantitative PCR and normalised against (CK19). Transcript levels<br />
within breast cancer specimens were compared to normal background<br />
tissues and analysed against conventional pathological parameters<br />
and clinical outcome over a 10 year follow-up period.<br />
RESULTS: The levels of Leptin and Leptin receptor mRNA were<br />
significantly higher in malignant samples (p = 0.0011 and 0.0014<br />
respectively). This difference remained statistically significant<br />
when comparing levels between normal samples and all malignant<br />
subgroups according to their NPI, grade, stage, local recurrence, and<br />
distant metastasis in both ER receptor positive and negative samples.<br />
It was also present across all histological types for both Leptin and<br />
its receptor.<br />
There was no significant change in mRNA transcription levels<br />
correlating with tumour grade, stage, disease free survival, or<br />
development of loco regional recurrence.<br />
There was also no statistically significant difference in levels of<br />
expression of both Leptin and its receptor when comparing ER<br />
positive to negative patients (p= 0.74 and 0.27 respectively).<br />
Leptin levels showed a significantly positive correlation with Leptin<br />
receptors (r=0.504, 0.0000000222). We have observed no significant<br />
correlations between Leptin and hTERT or Cox2.<br />
CONCLUSION: This study demonstrates compelling evidence that<br />
both Leptin and Leptin receptor mRNA transcription levels are more<br />
readily expressed in cancerous tissues providing further evidence<br />
that it plays a significant role in the process of breast carcinogenesis.<br />
However, Leptin levels did nor correlate with tumor’s stage, clinical<br />
outcome, hTERT or Cox-2 levels.<br />
P6-05-12<br />
Lack of Frequent Estrogen Receptor Mutation in Primary <strong>Breast</strong><br />
Tumors<br />
Oesterreich S, Kitchens C, Gavin P, Wu C-C, Riehle K, Coarfa C,<br />
Edwards D, Schiff R, Milosavljevic A, Lee A. University of Pittsburgh<br />
<strong>Cancer</strong> Institure, Pittsburgh, PA; Baylor College of Medicine,<br />
Houston, TX; NSABP, Pittsburgh, PA<br />
The estrogen receptor alpha (ESR1) is a critical driver of breast<br />
tumorigenesis, and as such has been a target for therapy for many<br />
years. Early reports using <strong>San</strong>ger sequencing and conformational<br />
assays reported that there were little if any mutations in ER-positive<br />
tumors, although a few somatic mutations have recently been described<br />
in tumors and cell lines. We set out to validate the authenticity of<br />
these reported somatic mutations by performing analysis of ER<br />
DNA sequence variants (DSVs) in 66 ER+ breast tumors, and 39<br />
breast cancer cell lines. We utilized a combined approach of target<br />
capture sequencing of ESR1, and subsequent testing for novel and<br />
previously identified DSVs using an orthogonal mass spectrometry<br />
based sequencing approach. A DNA capture approach was designed<br />
to capture all exons, flanking splice sites, and the 3’UTR of ESR1.<br />
DNA was captured and sequenced using SOLiD.<br />
Using stringency with a cut-off with at least 2 variant reads, variants<br />
in at least 20% of the reads, and requiring evidence for the variants in<br />
both strands, we identified 4 previously reported SNPs (rs2077647;<br />
rs46432; rs1801132; rs2228480), and two previously reported somatic<br />
mutations H6Y and N532Y. We developed mass-spectrometry assays,<br />
including controls, for these DSVs, and in addition, we included 10<br />
DSVs which had previously been reported as somatic mutations in<br />
breast (and other) cancer. Applying mass-spec based analysis to breast<br />
tumors and cell lines, we were able to confirm previously reported<br />
SNPs, and one previously reported mutations (H6Y). This mutation<br />
was found in one breast tumor and one cell line. None of the other<br />
reported somatic mutations could be confirmed in tumors or cell<br />
lines. Functional assays on the ESR1H6Y DSV failed to identify<br />
differences to wildtype receptor. The lack of a phenotype, and the<br />
infrequent occurrence of this DSV do not support a major driver role<br />
for ESR1H6Y.<br />
This analysis suggests that ESR1 mutations are a rare event in ER+<br />
primary breast cancer.<br />
P6-05-13<br />
ESR1 gene amplification in breast cancer: influence of RNAse<br />
treatment on FISH results<br />
Moelans CB, Holst F, Hellwinkel O, Simon R, van Diest PJ. University<br />
Medical Center Utrecht, Netherlands; University Medical Center<br />
Hamburg Eppendorf, Hamburg, Germany<br />
Introduction The frequency of estrogen receptor 1 (ESR1)<br />
amplification in breast cancer has long been controversial. High<br />
frequencies of amplification were more likely to be reported when<br />
measured by FISH compared to other methods such as qPCR, CGH<br />
and multiplex-ligation dependent probe amplification (MLPA). It was<br />
recently reported that HSR-like FISH clusters were RNAse sensitive<br />
which could lead to overestimation of ESR1 amplification frequency<br />
by FISH. We therefore compared copy numbers by FISH without<br />
and with RNAse treatment with MLPA in 53 tumor samples from 24<br />
tumors with ESR1 copy number increase by FISH.<br />
Methods Seventy five tumour areas (for each tumor with increased<br />
ESR1 copy number at least one area with the highest amplified copy<br />
number and cell density by FISH (Zytovysion)) from 38 breast cancers<br />
were laser microdissected and subjected to MLPA (kit P078-B1).<br />
Twenty four of these tumors (15 amplified and 9 gained; 53 areas)<br />
were also treated with RNAse A to compare copy numbers without<br />
and with RNAse treatment (blinded).<br />
Results RNAse treatment removed cloudy clusters but did not<br />
significantly change ESR1 gene copy numbers (p=0.47; average copy<br />
number was 4.60 pre- and 4.44 post-RNAse). However, CEP6 copy<br />
numbers were slightly higher after RNAse treatment (p=0.09; average<br />
copy number 2.17 pre- and 2.23 post-RNAse) leading to a significant<br />
decrease in ESR1/CEP6 ratios (p=0.006; average ratio 2.16 pre- and<br />
1.98 post-RNAse). 12/15 FISH-amplified cases were still amplified<br />
after RNAse treatment, whereas three cases were re-classified as<br />
gains (cut-off ratio 1.3). 7/9 FISH-gained cases remained gained<br />
after RNAse treatment, one case was reclassified as amplified and<br />
the other case as non-amplified. Spearman rho correlation between<br />
MLPA and FISH prior and after RNAse treatment was 0.57 and 0.56,<br />
respectively (both p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Also, mosaic heterogeneity (cell-to-cell variation) was frequently<br />
observed by FISH (present in 60% of the samples in this study).<br />
Conclusion Cloudy clusters by FISH are RNAse sensitive and could<br />
lead to overestimation of copy numbers. However, after RNAse<br />
treatment, ESR1 copy numbers remain increased. These copy number<br />
increases could at least in some cases be confirmed by MLPA,<br />
suggesting that they are DNA-based. ESR1 copy number increases<br />
seem to occur quite frequently in breast cancer, but the levels are in<br />
most cases not high enough to designate the sample as “amplified”<br />
by all techniques. PCR-based methods could be influenced by<br />
heterogeneity or contamination with normal cells and reported results<br />
depend on the cut-offs used and on the definition of amplification.<br />
P6-05-14<br />
Estrogen-induced genes in ductal carcinoma in situ(DCIS): their<br />
comparison with invasive ductal carcinoma.<br />
Ebata A, Suzuki T, Takagi K, Miki Y, Onodera Y, Nakamura Y,<br />
Fujishima F, Ishida K, Watanabe M, Tamaki K, Ishida T, Ohuchi N,<br />
Sasano H. Tohoku University Graduate School of Medicine, Sendai,<br />
Miyagi, Japan; Tohoku University Hospital, Sendai, Miyagi, Japan<br />
It is well known that estrogens play important roles in both the<br />
pathogenesis and development of invasive ductal carcinoma (IDC) of<br />
human breast. However, molecular features of estrogen actions have<br />
remained largely unclear in pure ductal carcinoma in situ (pDCIS),<br />
regarded as a precursor lesion of many IDCs. This is partly due to<br />
the fact that gene expression profiles of estrogen-responsive genes<br />
have not been examined in pDCIS. Therefore, we first examined the<br />
profiles of estrogen-induced genes in estrogen receptor (ER)-positive<br />
pDCIS and DCIS (DCIS-c) and IDC (IDC-c) components of IDC<br />
cases (n = 4, respectively) by microarray analysis. Estrogen-induced<br />
genes identified in this study were tentatively classified into three<br />
different groups in the hierarchical clustering analysis, and 33%<br />
of the genes were predominantly expressed in pDCIS rather than<br />
DCIS-c or IDC-c cases. Among these genes, the status of MYB<br />
(c-MYB), RBBP7 (RbAp46) and BIRC5 (survivin) expression in<br />
carcinoma cells was significantly higher in ER-positive pDCIS(n =<br />
53) than that in ER-positive DCIS-c (n = 27) or IDC-c (n = 27) by<br />
subsequent immunohistochemical analysis of the corresponding genes<br />
(P < 0.0001, P = 0.03 and P = 0.0003, respectively). In particular,<br />
the status of c-MYB immunoreactivity was inversely (P = 0.006)<br />
correlated with Ki-67 in the pDCIS cases. These results suggest<br />
that expression profiles of estrogen-induced genes in pDCIS may be<br />
different from those in IDC, and c-MYB, RbAp46 and survivin may<br />
play particularly important roles among estrogen induced genes in<br />
ER-positive pDCIS.<br />
P6-05-15<br />
Glucocorticoids has diverse effect on the tumorigenicity in<br />
estrogen receptor positive and estrogen recptor negative cancer<br />
cells<br />
Gao M, Yeh L-C, Chang C-P, Cheng A-L, Lu Y-S. National Taiwan<br />
University Hospital, Taipei, Taiwan<br />
Background: Glucocorticoids (GCs) exerts its biologic effects via<br />
GC receptor (GR), which has been linked to signal transduction<br />
pathways inducing apoptosis in many hematological malignancies.<br />
Generally, GCs are considered not affecting the growth of gross<br />
tumor of most non-hematological solid tumor. However, a recent<br />
study using meta-analysis of primary breast tumor gene expression<br />
from 1378 early breast cancer patients with long-term follow-up,<br />
showing that high levels of GR expression significantly correlated<br />
with shorter relapse-free survival in estrogen receptor (ER) negative<br />
patients. On the contrary, in ER+ breast cancer patients, high levels<br />
of GR expression in tumors were significantly associated with better<br />
outcome relative to low levels of GR expression. (<strong>Cancer</strong> Res. 2011,<br />
15;71: 6360-70). We hypothesized that GC has differential effect on<br />
the tumorigenicity in ER+ and ER- breast cancer cells.<br />
Methods: Twelve ER- breast cancer cell lines and 5 ER+ breast<br />
cancer cell lines were tested. MTT assay, clonogenic assay and soft<br />
agar assay was performed with cancer cells treated with or without<br />
dexamethasone (DEX). Flow cytometry were applied to detect the<br />
effect of DEX on the expression of cancer stem cell markers after<br />
treatment with DEX. Nude mice tail vein injection assay of cancer<br />
metastasis was performed to evaluate the in vivo tumorigenicity.<br />
Transfection with ER expression vector to MDA-MB231, a triple<br />
negative cancer cell, by lipofectamine was carried to determine the<br />
role of ER in this scenario.<br />
Results. DEX significantly enhanced colony forming ability and/or<br />
tumorigenicity in 12 ER- breast cancer cell lines. However, DEX<br />
did not affect the proliferation rate of these cancer cells according<br />
to MTT assay. We further explored whether DEX could affect the<br />
population of cancer stem-like cell, and thereby resulted in increase<br />
of tumorigenicity. By flow cytometry study, we found treatment of<br />
DEX significantly increased the number stem cell marker + (for<br />
examples, ALDH+) cells in ER- cancer cell lines, but not in ER+<br />
cell lines. Sorting and collection of these stem cell marker + cells<br />
demonstrated that they had much higher colony forming efficiency<br />
and tumorigenicity. Further, in nude mice model by tail vein<br />
injection with MDA-MB-231-Lu2 (derived from lung metastasis of<br />
MDA-MB-231 cells after two in vivo passages in nude mice using<br />
intracardiac injection), treatment of DEX significantly increased the<br />
lung metastatic foci number and size. In contrast, DEX significantly<br />
decreased the colony forming ability and tumorigenicity in 5 ER+<br />
cancer cell lines. Short term exposure (72hr) of DEX resulted in<br />
increased p21 expression and cell cycle G1 arrest in MCF7, an ER+<br />
cancer cell. Prolong incubation of MCF7 cells with DEX (more than<br />
10 days) induced cell apoptosis. When MDA-MB231 cells were<br />
stably transfected with ER, MDA-MB231/ER cells showed similar<br />
phenotype as those of ER+ cancer cell lines, i.e., DEX decreased<br />
the clonogenic and tumorigenicity ability. Studies on underlying<br />
mechanisms are ongoing, and preliminary result showed that there<br />
is cross talk between ER and GR.<br />
Conclusions: GC increased tumorigenicity in ER- breast cancer cells,<br />
but decrease tumorigenicity in ER+ cancer cells.<br />
P6-06-01<br />
Lobular involution reduces breast cancer risk through<br />
downregulation of invasive and proliferative cellular processes<br />
Radisky DC, Visscher DW, Stallings-Mann ML, Frost MH, Allers TM,<br />
Degnim AC, Hartmann LC. Mayo Clinic, Jacksonville, FL; Mayo<br />
Clinic, Rochester, MN<br />
Background: Age-related lobular involution (LI) is a physiological<br />
process, usually accelerated with menopause, in which the epithelial<br />
tissue of the breast gradually regresses. Our previous analysis of a<br />
cohort of more than 14,000 women who had a benign breast biopsy<br />
at the Mayo Clinic revealed that women who had undergone LI were<br />
at significantly reduced risk of subsequent breast cancer development.<br />
In our studies of postmenopausal women specifically, we found<br />
that more than 40% had not completed the process of LI, and that<br />
the increased breast cancer incidence in older women was strongly<br />
associated with incomplete LI. We sought to determine the potential<br />
protective mechanistic effects of lobular involution.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
510s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
Methods: We generated primary human mammary epithelial cell lines<br />
(HMECs) from breast biopsies of women who showed no LI (N=6),<br />
partial LI (N=7), or complete LI (N=6). These cell lines were analyzed<br />
for proliferation in culture and profiled for genomic signatures using<br />
Affymetrix gene arrays. We also analyzed RNA isolated from a<br />
cohort of archived formalin-fixed, paraffin-embedded (FFPE) benign<br />
breast biopsy samples from postmenopausal women who had either<br />
completed the process of LI (N=4) or who had not initiated LI (N=8)<br />
for genomic signatures using Whole-Genome DASL Assays.<br />
Results: We found that LI was associated with decreased cellular<br />
proliferation and inhibition of processes associated with tumor<br />
development and progression. Specifically, we found that HMECs<br />
derived from benign breast biopsies in which LI was not evident<br />
showed increased proliferation and elevated expression of Twist<br />
(P=0.002), a transcription factor associated with epithelialmesenchymal<br />
transition (EMT) and breast cancer development. We<br />
are assessing differentially expressed genes for association with breast<br />
cancer risk using a nested case:control group of benign breast biopsies<br />
from women in our cohort who subsequently developed breast cancer<br />
(N=85) vs those who did not (N=142) and for whom LI status at the<br />
time of initial biopsy was known.<br />
Conclusions: LI may decrease cancer risk through inhibition of key<br />
tumorigenic processes. Identification of processes associated with<br />
the physiologic risk reduction seen with LI may provide insight into<br />
novel avenues for risk reduction.<br />
P6-06-02<br />
Characterization of an exosome-associated apoptosis-inducing<br />
activity produced by triple negative breast cancer cells.<br />
Georgoulia NE, Iliopoulos D, Mitchison TJ. Harvard Medical School,<br />
Boston, MA; Dana Farber <strong>Cancer</strong> Institute, Boston, MA<br />
Purpose: We sought to investigate whether breast cancer cells can<br />
suppress the proliferation of other breast cancer cells in order to<br />
understand the biological significance of cell heterogeneity in breast<br />
cancer.<br />
Materials and Methods: 20 breast cancer cell lines, corresponding<br />
to all molecular profiles of breast cancer, were cultured in a 20x20<br />
conditioned medium protocol. Cell proliferation and apoptosis were<br />
evaluated by EdU (5-ethynyl-2’-deoxyuridine)<br />
and PARP (Poly ADP ribose) cleaved labeling respectively, and<br />
documented by fluorescence microscopy. Serum free conditioned<br />
media (CM) were prepared from all the cell lines, 24hrs of incubation,<br />
and screened for their anti-proliferative effect against the different<br />
breast cancer tumor cells. Active media were ultra-centrifuged and<br />
both the supernatants as well as the pellets were assessed for the<br />
anti-proliferative activity.<br />
Results: Using this 20Χ20 matrix, CM obtained from two out of<br />
six triple negative breast cancer cells displayed anti-proliferative<br />
activity against the majority of cell lines, irrespectively of their<br />
molecular phenotype including triple negative cells. No significant<br />
anti-proliferative activity was observed in CMs from luminal or<br />
HER2(+) cell lines. However the two triple negative CMs induced a<br />
significant decrease in the cell lines’ proliferation index, which was<br />
associated with a concomitant increase in cells’ apoptotic index.<br />
Ultracentrifugation revealed that the apoptosis-inducing activity was<br />
retained in the pellet but not the supernatant of the CM. Negative<br />
staining electron microscopy (EM) revealed the presence of exosomes<br />
in the CM’s ultra-centrifuged pellet, which stained positive for cd63<br />
surface protein marker using an immunogold assay.<br />
Conclusions: These data strongly suggest that some triple negative<br />
breast cancer cell lines posses exosome-mediated apoptosis-inducing<br />
activity. This activity may have biological and clinical relevance<br />
since it could be a factor participating in the selection of tumor<br />
cell subpopulations of different degrees of aggressiveness. Further<br />
proteomic and microRNA profiling of the exosomes is ongoing in<br />
order to characterize this exosome-mediated apoptosis-inducing<br />
activity.<br />
P6-06-03<br />
Caveolin-1: A potential mediator of RhoC GTPase driven<br />
Inflammatory breast cancer cell invasion.<br />
Joglekar M, van Golen K. University of Delaware, Newark, Delaware<br />
The proposed study focuses on Inflammatory <strong>Breast</strong> <strong>Cancer</strong> (IBC),<br />
which is one of the most aggressive forms of locally advanced<br />
breast cancer. IBC is an understudied disease in terms of identifying<br />
various molecular entities that could potentially be responsible for<br />
the aggressiveness of this disease. Recent advancements reveal that<br />
IBC has a unique molecular profile when compared with non-IBC.<br />
Caveolin-1 is found to have opposite expression pattern in IBC<br />
versus non-IBC. Our lab has shown that Caveolin-1 is found to be<br />
over-expressed in IBC whereas in non-IBC its expression is much<br />
reduced compared to normal mammary epithelial cells.<br />
Caveolin-1 is known to be associated with specialized lipid rafts<br />
in the plasma membrane called ‘caveolae’. ‘Caveolin scaffolding<br />
domain (CSD)’ from amino acids 82-101 concentrates variety of<br />
signaling molecules such as growth factor receptors, protein kinases,<br />
heterotrimeric G proteins and Rho GTPases. Thus it is known as a<br />
potential regulator of many signaling pathways. Rho GTPases are<br />
members of the Ras superfamily of small GTP binding proteins<br />
involved in cytoskeletal rearrangements during cell motility and<br />
invasion. Our lab has previously shown that RhoC GTPase is over<br />
expressed in IBC and that exogenous expression of RhoC GTPase<br />
produces motile and invasive phenotype in human mammary<br />
epithelial cells (HMECs) similar to SUM149 IBC cells. Thus the<br />
overall objective of this study is to determine if caveolin-1 over<br />
expression mediates the RhoC GTPase driven invasive phenotype<br />
of IBC via its scaffolding action.<br />
The first objective of this study is to elucidate the effect of caveolin-1<br />
over expression on SUM149 IBC cell invasion. This was done by<br />
down regulating caveolin-1 to a level that is comparable to human<br />
mammary epithelial cells (HMECs) by using si caveolin-1. With<br />
the same si caveolin-1 or exogenous CSD synthetic peptide, we<br />
performed Matrigel invasion assays followed by cell viability and<br />
proliferation assay. Si caveolin-1 did not produce significant changes<br />
in cell viability over the period of four days as well as in Ki-67<br />
staining which was used as a proliferation marker. Caveolin-1 down<br />
regulation reduced cell invasion by 90% compared to untreated<br />
cells. Similarly, exogenous CSD synthetic peptide treatment reduced<br />
SUM149 cell invasion significantly. In order to understand caveolin-1<br />
localization in SUM149 cells, we performed immuno gold labeling<br />
of caveolin-1 by transmission electron microscopy as well as sucrose<br />
gradient centrifugation. Both these methods showed distinct pool of<br />
cytoplasmic caveolin-1 in addition to plasma membrane associated<br />
caveolin-1. Co-localization of caveolin-1 and RhoC GTPase was<br />
studied by co-transfecting cells with GFP-caveolin-1 and RFP-RhoC<br />
GTPase.<br />
Thus, this data suggests potential role of caveolin-1 over expression<br />
in regulating IBC cell invasion. Due to its ability to concentrate<br />
variety of signaling molecules, caveolin-1 could act as a principle<br />
regulator of several downstream events that make cells motile and<br />
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<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
invasive through RhoC GTPase activation. Thus studying caveolin-1<br />
localization and effect of its regulation on the signaling pathways<br />
could help understand the important molecular mechanisms in IBC.<br />
P6-06-04<br />
Withdrawn by Author<br />
P6-06-05<br />
Down-regulation of the circadian factor Period 2 by the oncogenic<br />
E3 ligase Mdm2: Relevance of circadian components for cell<br />
cycle progression<br />
Liu J, Gotoh T, Vila-Caballer M, <strong>San</strong>tos CS, Yang J, Finkielstein CV.<br />
Virginia Tech, Blacksburg, VA<br />
Circadian rhythms are mechanisms that measure time on a scale<br />
of about 24 h and that adjusts our body to external environmental<br />
signals. Core circadian clock genes are defined as genes whose protein<br />
products are necessary components for the generation and regulation<br />
of circadian rhythms. Circadian proteins also regulate genes involved<br />
in either cell division or death; and a perturbation of the balance<br />
among these processes leads to cancer development and progression.<br />
A key aspect of cancer research is identifying new regulatory<br />
pathways involved in proliferation and differentiation of cell.<br />
Disruption of circadian rhythm has recently emerged as a new<br />
potential risk factor in the development of cancer, pointing to the<br />
core gene period 2 (per2) as a tumor suppressor. However, it remains<br />
unclear how the circadian network regulates tumor suppression, nor<br />
which, if any, of its components is either the ultimate effector that<br />
influences the fate of the cell.<br />
Initial experiments were devoted to identifying new interacting<br />
partners for Per2 using a two-hybrid system. Interestingly, among the<br />
positive clones analyzed was the oncogenic protein Mdm2. This result<br />
was validated by immunoprecipitation of recombinant and endogenous<br />
Per2/Mdm2 complexes from unstressed cells. Pull-down assays using<br />
tagged-expressed proteins fragments and labeled proteins were later<br />
used to map the interacting regions between Per2 and Mdm2. Our<br />
results show Mdm2 binds to the central flexible region of Per2 known<br />
to interact with various protein partners. Thus, we hypothesized that<br />
binding of Mdm2 to Per2 might act by mediating its ubiquitination<br />
and therefore altering Per2 stability. We next examined the formation<br />
of the Mdm2/p53/Per2 complex by immunoprecipitation. Our data<br />
show anti-p53 antibody is able to co-immunoprecipitate Per2 and<br />
Mdm2. Moreover, in vitro and in vivo ubiquitination assays show<br />
that binding of Per2 to p53 prevented ubiquitination of p53 by Mdm2<br />
without altering their binding. Immunofluorescence studies using<br />
H1299 cells (p53-) confirmed Per2 role in p53 stabilization and for<br />
localization. Overall our results suggest that Mdm2 modulates the<br />
stability of Per2 and p53 in unstressed cells, and might be responsible<br />
for the oscillatory levels of these proteins observed in a 24 h cycle.<br />
P6-06-06<br />
The therapeutic potential and hazard of exposure to Cerbera<br />
odollam leaf extracts<br />
Chung F, Chan K, Lim YY, Li B. Monash University Sunway Campus,<br />
Subang Jaya, Selangor, Malaysia; Taylor’s University, Subang Jaya,<br />
Selangor, Malaysia<br />
Background: Despite its significance in leading to the reduction of<br />
breast cancer mortality rates, therapeutic regiments for breast cancer<br />
still face two major problems: (1) the heterogeneity of the tumours and<br />
(2) the prevalence of drug resistance towards anti-estrogen therapy.<br />
The leaf extracts from Cerbera odollam were screened for active<br />
compounds with the potential to overcome these problems.<br />
Methods: Hormone responsive (MCF7) and hormone-independent<br />
cell lines (MDA-MB-231) were treated with the fractionated<br />
methanolic extracts of C. odollam followed by analyses on cell<br />
cycle perturbations and gene expression changes resulting from the<br />
treatment. The stated analyses were performed by flow cytometry,<br />
semi-quantitative RT-PCR, western blotting and immunofluorescence.<br />
The active fraction was identified, upon which HPLC separation was<br />
performed to identify the putative active compound.<br />
Results: Initial experiments revealed that a fractionated extract<br />
contains a potent cytostatic agent which is active towards hormoneresponsive<br />
but not hormone-independent breast cell lines [the<br />
Estrogen Receptor-alpha (ERα) positive MCF7 cells remained<br />
static in growth for 10 days]. Comparison of the effects of the active<br />
and inactive fractions on MCF7 cells revealed key differences in<br />
cell growth and expression of ERα and its downstream regulated<br />
genes. The active compound was identified to be neriifolin (a cardiac<br />
glycoside) which also exhibited prolonged cytostatic effects (for 10<br />
days upon treatment of 18.7 nM) similar to the active fraction. Gene<br />
expression analyses suggested that the ERα/Estrogen (E2) regulatory<br />
pathway and p53-dependent p21 WAF1 transactivaton could be the<br />
cellular targets.<br />
Conclusion: Although neriifolin could be a potential drug for breast<br />
cancer treatment, its severity in down regulation of the ERα/E2<br />
regulatory pathway which is critical during female development<br />
indicates the potential health hazard from our exposure to C. odollam.<br />
We are now focusing on establishing assay to evaluate whether<br />
neriifolin could cause drug resistance (similar to tamoxifen) by<br />
silencing ERα expression through hypermethylation of the ERα<br />
promoter.<br />
P6-07-01<br />
Withdrawn by Author<br />
P6-07-02<br />
Prediction of oncotype DX ® recurrence score using pathology<br />
generated equations<br />
Bhargava R, Klein ME, Shuai Y, Brufsky AM, Puhalla SL, Jankowitz<br />
R, Dabbs DJ. Magee-Womens Hospital of UPMC, Pittsburgh, PA;<br />
University of Wisconsin-Madison School of Medicine and Public<br />
Health, Madison, WI; University of Pittsburgh <strong>Cancer</strong> Institute,<br />
Pittsburgh, PA<br />
BACKGROUND: Oncotype DX ® is a quantitative reverse<br />
transcription polymerase chain reaction based assay that has been<br />
shown to have prognostic and predictive value in estrogen receptor<br />
(ER) positive breast cancers. The result is reported as a recurrence<br />
score (RS) ranging from 0-100, divided into low risk (
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
New Magee Equation 1 (nME1): RS = 15.31385 + Nottingham<br />
score*1.4055+ ER H-score*(-0.01924) + PR H-score*(-0.02925) +<br />
(0 for HER2 negative, 0.77681 for equivocal, 11.58134 for HER2<br />
positive) + Tumor size*0.78677 + KI67 index*0.13269.<br />
New Magee Equation 2 (nME2): RS = 18.8042+ Nottingham<br />
score*2.34123 + ER H-score*(-0.03749) + PR H-score*(-0.03065)<br />
+ (0 for HER2 negative, 1.82921 for equivocal, 11.51378 for HER2<br />
positive) + Tumor size*0.04267.<br />
New Magee Equation 3 (nME3): RS = 24.30812+ ER<br />
H-score*(-0.02177) + PR H-score*(-0.02884) + (0 for HER2<br />
negative, 1.46495 for equivocal, 12.75525 for HER2 positive) +<br />
KI-67*0.18649.<br />
RESULTS: The concordance between the risk category of oncotype<br />
DX ® and our equations was 55.8%, 59.4%, and 54.4% for nME1,<br />
nME2, and nME3 respectively. With exclusion of the intermediate risk<br />
categories for both the actual RS and estimated RS, the concordance<br />
for each equation increased to more than 95%, reflecting the very<br />
low two step discordance (100% {76/76}, 98.6% {75/76}, and<br />
98.7% {79/80} for nME1, nME2, and nME3 respectively). Even<br />
when the estimated RS fell in the intermediate category with any of<br />
the equations, the actual RS was either intermediate or low in more<br />
than 85% of the cases. The Pearson correlation coefficient between<br />
estimated and actual RS was similar for each of the equations<br />
(0.61661, 0.60386 and 0.59407 for nME1, nME2 and nME3,<br />
respectively).<br />
CONCLUSIONS: Any of the 3 equations can be used to estimate the<br />
RS depending on available data. If the estimated RS is clearly high or<br />
low, the oncologists should not expect a dramatically different result<br />
from oncotype DX®, and the oncotype DX® test may not be needed.<br />
Conversely, an oncotype DX® result that is dramatically different<br />
from what is expected based on standard morpho-immunohistologic<br />
variables should be thoroughly investigated.<br />
P6-07-03<br />
Risk classification of Early Stage <strong>Breast</strong> <strong>Cancer</strong> as Assessed by<br />
MammaPrint and Oncotype DX Genomic Assays<br />
Clough KB, Poulet B, Jamshidian F, Butler S, Svedman C, Levy E.<br />
L’Institut du Sein-Paris <strong>Breast</strong> Centre, Paris, Ile de France, France;<br />
Genomic Health, Inc., Redwood City, CA<br />
Background: The 21-gene Oncotype DX® Recurrence Score® assay<br />
has been validated for prediction of 10-year risk of distant recurrence<br />
and likelihood of benefit from chemotherapy (CT) in patients (Pts)<br />
with estrogen receptor-positive (ER+) early stage breast cancer<br />
(ESBC). MammaPrint ® is a multi-gene assay that has been validated<br />
as a prognosticator in a heterogenous Pt population that includes ER+,<br />
ER-, triple negative and HER2+ Pts. While the development and<br />
validation cohorts for these genomic assays are significantly different,<br />
the tests are frequently believed to provide equivalent information.<br />
The aim of the present study was to assess how these tests classify<br />
patients when compared side by side in the same Pt specimen.<br />
Materials and methods: Pts with ER+, HER2- , ESBC in which the<br />
MammaPrint assay had been sent were identified at the Institut du<br />
Sein, Paris, France. Clinical and pathological characteristics and<br />
the MammaPrint results (failure, low or high risk) were collected.<br />
Oncotype DX quantitative RT-PCR analysis was performed at<br />
Genomic Health and was blinded to the clinical and MammaPrint<br />
data. Descriptive statistics were calculated for failure rates, cross<br />
classification, and tumor characteristics.<br />
Results: Informed consent and sufficient tumor material for analysis<br />
was available from 67 Pts who were predominantly low and<br />
intermediate risk by clinicopathologic features: Tumor grade- 24<br />
low, 36 intermediate and 7 high; Histology- 49 ductal, 14 lobular<br />
and 4 other. MammaPrint analysis had failed to deliver result for 10<br />
of the 67 Pts. Recurrence Score results were generated in all 67 Pts.<br />
The risk classification of the MammaPrint and Oncotype DX tests in<br />
the 57 patients where both results were available is presented in the<br />
Table below. Of note, there were only 2 high Recurrence Score results<br />
compared with 22 high risk MammaPrint results. Furthermore, 45%<br />
of the Pts with high risk MammaPrint result had a low Recurrence<br />
Score result; they also had high quantitative ER expression of more<br />
than 9.5 expression units by RT-PCR, which is associated with likely<br />
hormonal therapy benefit. There was no clear association between<br />
tumor characteristics and MammaPrint failure or differences in risk<br />
classification.Conclusions: This direct comparison demonstrates that<br />
the MammaPrint and Oncotype DX tests classify a large proportion<br />
of Pts differently. Of note, nearly half of the Pts with high risk<br />
MammaPrint result had a low Recurrence Score indicating minimal,<br />
if any, benefit from chemotherapy.<br />
Table 1. Mammaprint and Recurrence Score classification<br />
Mammaprint<br />
Low Risk High Risk Total<br />
Low Recurrence Score 23 (65%) 10 (45%) 33 (58%)<br />
Intermediate Recurrence Score 11 (31%) 11 (50%) 22 (39%)<br />
High Recurrence Score 1 (3%) 1 (5%) 2 (4%)<br />
Total 35 (100%) 22 (100%) 57 (100%)<br />
P6-07-04<br />
Evaluation of Adjuvant! Online for primary operable grade 2<br />
breast cancers with 10-year follow-up<br />
Van Calster B, Brouckaert O, Wildiers H, Christiaens M-R,<br />
Weltens C, Paridaens R, Van Limbergen E, Neven P. On behalf of<br />
Multidisciplinary <strong>Breast</strong> Centre, UZ Leuven<br />
Background: In primary operable breast cancers, Adjuvant!Online<br />
(AOL) uses demographics and clinic-pathological markers to<br />
predict the 10-year breast cancer specific survival (BCSS) with and<br />
without adjuvant systemic therapy. Grade 2 BC is a difficult group<br />
for adjuvant treatment decisions. We compared the observed with<br />
the AOL-estimated BCSS rate in our centre in consecutive women<br />
primary operated for a grade 2 BC.<br />
Patients and Methods: All patients with grade 2 primary operable<br />
breast cancer from UZL diagnosed between 1/1/2000 and 31/3/2002.<br />
After 10 years of follow-up, patients were evaluated for BCSS<br />
and dead from other cause. For each patient, the adjuvant! Online<br />
algorithm (version 8) was applied to predict BCSS taking the patients’<br />
adjuvant therapy into account. Adjuvant! Online was validated by<br />
assessing the calibration and discrimination. Discrimination was<br />
assessed by the area under the ROC curve. The expected BCSS rate<br />
was obtained by averaging the predicted probabilities of BCSS. Next,<br />
logistic calibration was performed by predicting observed BCSS<br />
within 10 years of follow-up with the odds of the predicted probability<br />
of BCSS (odds BCSS). In this analysis, the intercept should be 0 and<br />
the coefficient for odds BCSS 1 for perfect calibration of the predicted<br />
probabilities. A likelihood ratio test is used to test the null hypothesis<br />
of perfect calibration.<br />
Outcome after 10 years follow-up N (%)<br />
Alive 358 (80.5%)<br />
Death due to BC 29 (6.5%)<br />
Death due to other cause 58 (13.0%)<br />
Lost to follow-up 6<br />
Percentages exclude the cases that were lost to follow-up.<br />
Results: Six patients were lost to follow-up. The median age at<br />
diagnosis of the remaining 445 patients was 56 years (IQR 48 to 67<br />
years, range 26 to 89 years). In 433/445 cases (97%), the prediction<br />
from AOL was available. The median AOL predicted probability for<br />
BCSS was 89.1% (IQR 83.2 to 94.6%, range 20.3 to 98.9%). The<br />
observed BCSS rate was 93.3% whereas the AOL-expected rate was<br />
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<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
86.7%. The likelihood ratio test for perfect calibration was statistically<br />
significant (p
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
Methods: 162 pts were enrolled in IBCSG 27-02, BIG 1-02, NSABP<br />
B-37. RT was recommended but not required if a completion/<br />
salvage mastectomy was performed after an ipsilateral breast tumor<br />
recurrence. Hormonal therapy was required for ER+ and/or PR+<br />
tumors and anti-HER2 therapy was given at investigator discretion.<br />
Stratification criteria were hormone receptor status of recurrence, site<br />
of recurrence (breast, mastectomy scar/chest, regional lymph nodes),<br />
and use of prior C.<br />
Results: Primary surgery was breast conserving: 98 (60%) and<br />
mastectomy: 64 (40%). Nodal surgery for primary cancer was sentinel<br />
node resection: 19 (12%), axillary node (AN) sampling: 37 (23%), AN<br />
dissection: 88 (56%), more extensive nodal surgery: 6 (4%), and no<br />
nodal surgery: 8 (5%). The sites of first ILRR were breast 87 (54%),<br />
mastectomy scar/chest wall 55 (34%), and regional lymph nodes 20<br />
(12%), and were similarly distributed by treatment arms. Of the 98<br />
pts who originally had a lumpectomy, 92 (94%) received RT. Among<br />
these 92, ILRR were in-breast: 82 (89%), chest wall: 3 (3%), and<br />
regional node: 7 (8%). Salvage mastectomy was performed in 76/98<br />
(78%) with prior lumpectomy. Of the other 22 pts, 16 had repeat<br />
lumpectomies, 5 had AN resection, and 1 had chest wall resection. Of<br />
the 64 who originally had mastectomy, 52 (81%) recurred in the scar/<br />
chest wall and 12 (19%) in the regional nodes. 15 pts (23%) received<br />
post-mastectomy RT, 4 of whom had regional nodal recurrences. Of<br />
the 139 pts who had ER status reported for the primary tumor, 18<br />
(13%) had a different ER status reported for the ILRR (table). PR<br />
expression was discordant in 29 (25%).<br />
Estrogen Receptor Status<br />
ILLR<br />
Primary Negative Positive Total<br />
Negative 42(89%) 5(11%) 47<br />
Positive 13(14%) 79(86%) 92<br />
Tot. known 55 84 139<br />
Missing 3 20 23<br />
Average time from surgery for ILRR to surgery for second LRR was<br />
1.6 yrs (range: 0.08 -5.8). The average pt age for second LRR was<br />
60.4 yrs versus 54.5 yrs for those who developed distant failures. At<br />
median follow up of 4.5 yrs, 15 pts developed a second LRR (9 local,<br />
6 regional), 7 (47%) of whom have died. Of the 32 (20%) pts who<br />
developed a distant failure, 17 (53%) have died. C following ILRR<br />
appears to reduce second LRR (5 v 10).<br />
Conclusions Similar to the effect observed in distant failure rates,<br />
C reduced the rate of second LRR by half. A second LRR following<br />
multimodality therapy for an ILRR is a strong prognostic indicator of<br />
subsequent death in this population, comparable to pts experiencing<br />
distant metastasis.<br />
Funding: NCI PHS grants U10-CA-37377, -69974, -12027, -69651,<br />
and CA-75362.<br />
P6-07-07<br />
Withdrawn by Author<br />
P6-07-08<br />
Associations between lifestyle parameters and prognostic factors<br />
used for stratifying for adjuvant treatment in breast cancer<br />
Guldberg TL, Christensen S, Ravnsbaek A, Zachariae B, Jensen AB.<br />
Aarhus University Hospital, Aarhus, Denmark<br />
Background: At present, tumour related factors and age at time of<br />
diagnosis are used to determine type of adjuvant treatment for women<br />
diagnosed with early stage breast cancer (ESBC).<br />
Aim: To investigate associations between lifestyle parameters and<br />
prognostic factors used for stratifying for adjuvant treatment, by<br />
correlating known clinical prognostic factors to comorbidity, body<br />
mass index (BMI), and physical activity.<br />
Method: 4917 women who had been treated for ESBC in Denmark in<br />
2001-2004 were identified. Disease-and treatment data were obtained<br />
from The Danish <strong>Breast</strong> <strong>Cancer</strong> Cooperative Group. Data concerning<br />
comorbidity was collected at the surgical departments. Health related<br />
behaviours were assessed by questionnaires three months after<br />
surgery, using the Physical Activity Scale for the Elderly to assess<br />
level of physical activity.<br />
Results: All lifestyle parameters were significantly associated with<br />
one or more tumour related prognostic factors at time of surgery:<br />
Increasing BMI was associated with unfavourable nodal status (OR:<br />
1.026; 95%CI:1.009-1.043), with not having grade I malignancy<br />
(OR:1.028; 95%CI:1.008-1.048) and with tumour size >20mm<br />
(OR:1.083; 95%CI: 1.065-1.102) but not with oestrogen receptor (ER)<br />
status (OR:1.002; 95%CI:0.981-1.023). Similarly, decreasing levels of<br />
physical activity was associated with nodal status (OR: 1.001; 95%CI:<br />
1.001-1.003), with tumour size (OR: 1.002; 95%CI: 1.001-1.003) and<br />
with higher grade of malignancy (OR: 1.001; 95%CI: 1.000-1.003;<br />
p=0.014), but not with ER status (OR: 1.000; 95%CI:0.999-1.002).<br />
Comorbidity was significantly associated with tumour size>20mm<br />
(OR: 1.137; 95%CI: 1.002-1.275), but not with nodal status (OR:<br />
0.989; 95%CI: 0.878-1.115), higher grade of malignancy (OR: 0.918;<br />
95%CI: 0.803-1.050) or ER status (OR: 1.176; 95%CI: 0.992-1.393).<br />
Some of the significant associations between lifestyle parameters and<br />
tumour related prognostic factors only pertained to premenopausal<br />
women. This pattern was observed in the associations between<br />
BMI and nodal status (Premenopausal: χ2: 14.55; p=0.002.<br />
Postmenopausal: χ2:2.39; p=0.495), and physical activity and tumour<br />
size (Premenopausal: χ2:13.72; p=0.008. Postmenopausal: χ2: 7.10;<br />
p=0.130). No such differences were found for comorbidity.<br />
Conclusion: Higher levels of BMI and comorbidity were found to<br />
be associated with poorer prognostic factors at time of surgery in<br />
women suffering from ESBC. Furthermore, inactivity and higher<br />
BMI was associated with significantly poorer prognostic factors in<br />
the premenopausal population than it was in the postmenopausal<br />
population. Physically inactive women had poorer prognostic factors<br />
at time of surgery; however, caution is needed due to possible<br />
confounding by treatment parameters. Future data on the relapsepattern<br />
in this cohort will shed further light on whether specific<br />
lifestyle patterns can predict disease outcome and the potential<br />
relevance of stratifying women suffering from ESBC to relevant<br />
adjuvant treatment according to lifestyle parameters at time of<br />
diagnosis, especially in the younger premenopausal population.<br />
P6-07-09<br />
Identification of Trophinin associated protein (TROAP) as a<br />
novel biological marker in breast cancer (BC): Co-expression of<br />
TROAP and TOPO2A predicts response of anthracycline based<br />
chemotherapy (ATC-CT)<br />
Abdel-Fatah TMA, Balls G, Miles AK, Moseley P, Green A, Rees<br />
R, Ellis IO, Chan SYT. Nottinigah City Hospital NHS Trust; The<br />
Van Geest <strong>Cancer</strong> Research Center, Nottingham Trent University;<br />
University of Nottingham<br />
Introduction<br />
Recently, TOPO2A alteration was found to be a predictor for ATC-CT<br />
and by using neural network and pathways analysis of gene expression<br />
array data , TROAP gene was revealed as a major hub in TOPO2A<br />
pathway and strongly related to genes that are involved in mitotic<br />
cell cycle regulation. In addition, we found that TROAP gene was<br />
among top 10 ranked genes out of 48,000 of transcripts, that accurately<br />
predicted worse clinical outcome, and differentiated between low and<br />
high grade based on a 10-fold external cross-validation analysis with<br />
www.aacrjournals.org 515s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
an average classification accuracy of >99.999%. TROAP protein is<br />
essential for centrosome integrity and proper bipolar organisation<br />
of spindle assembly during mitosis and plays essential role in cell<br />
proliferation.<br />
In the current study the molecular and clinicopathological functions<br />
of TROAP expression and its effect on management of breast cancer<br />
have been investigated.<br />
Methods<br />
The co-expression of TROAP and TOPO2A protein was evaluated by<br />
using dual immunoflurescent in BC cell lines. In addition both TROAP<br />
and TOP2A protein expressions were immunohistochemically (IHC)<br />
assessed in 40 normal breast tissues and a well characterised series<br />
of 1650 primary BC and were correlated to clinicopathological and<br />
other biomarkers. IHC staining was performed using Anti-TROAP<br />
rabbit polyclonal (HPA044102; Sigma).<br />
The association between TROAP and response to chemotherapy was<br />
investigated in 350 ER negative BC treated with adjuvant ATC-CT<br />
and 260 locally advanced BC treated with neoadjuvant ATC-CT. In<br />
addition the clinical outcome of TROAP expression was evaluated in a<br />
series of 180 ER- high risk BC patients who did not received any CT.<br />
Results<br />
No expression of TROAP protein was observed in normal breast tissue<br />
while, 25% of BC showed TROAP protein overexpression. By using<br />
dual immunoflurescent in BC cell lines, The MCF7 cells showed<br />
strong cytoplasmic TROAP staining with no TOPO2A expression,<br />
while The T47D cells did not express TROAP but expressed<br />
TOPO2A. SKBr3, MDA468 and MDA231 cell lines showed coexpression<br />
of TROAP and TOPO2A. TROAP overexpression was<br />
significantly associated with aggressive clinico-pathological features<br />
including; high grade, high mitotic rate, absence of hormonal<br />
receptors, overexpression of HER2, TOP2A and EGFR (p
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
invasive ductal carcinoma (IDC). The prognostic factors for IMPC<br />
are not well characterized due to the relative scarcity of cases reported<br />
in the literature.<br />
Methods: We analyzed the National <strong>Cancer</strong> Institute’s Surveillance,<br />
Epidemiology, and End Results (SEER) database to evaluate<br />
prognostic factors of a population of 645 breast IMPC patients<br />
and 300,060 breast IDC patients reported between 2001 and 2008.<br />
Using univariate and multivariate analyses, hazard ratios (HR) were<br />
calculated for disease-specific (DSS) and overall survival (OS) for<br />
these patients using parameters such as patient age at diagnosis,<br />
histological grade, ER status, PR status, tumor size, and degree of<br />
lymph node positivity. Subset analysis of high grade, lymph nodepositive<br />
patients was performed to compare DSS and OS between<br />
IMPC and IDC.<br />
Results: The 5-year DSS and OS for IMPC patients were 92.1% and<br />
84.6% compared to 5-year DSS and OS of 88.5% and 80.2% for IDC<br />
patients. At presentation, TNM staging of IMPC cases was similar<br />
to IDC except for a higher percentage of LN metastases (52.4% in<br />
IMPC vs. 34.7% in IDC). Of those with known estrogen receptor<br />
(ER) status, 84.2% of IMPC cases were ER-positive, which was<br />
associated with better DSS (Hazard Ratio (HR) 0.36, p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
series with local recurrence, Grade 3 , >3 nodes involved, tumour<br />
diameter >40mm, coded dichotomously, and age coded as above as<br />
independent variables.<br />
Results<br />
The results of the analyses are given in the table below.<br />
Regression analyses (case matched subset and whole series)<br />
Variable Hazard ratio 95% CI P value<br />
Matched cases (n = 340)<br />
Local recurrence 1.63 1.17 - 2.28 0.0041<br />
Age deviation 1.03 per year 1.01 - 1.05 0.015<br />
Whole series (n = 2945)<br />
Local recurrence 1.33 1.01 - 1.75 0.0410<br />
Age deviation 1.05 per year 1.04 - 1.06 40mm 1.66 1.31 - 2.13 3 +ve nodes 2.99 2.46 - 3.66
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
by analysing the differences in the published taxane effect in the<br />
EBCTCG Chemotherapy overview (4) according to tumour grade.<br />
Methods : Annual event rate ratios and 95% CIs were calculated<br />
from data on over 20,000 early breast cancer patients treated with<br />
chemotherapy (4). P-values for trend in taxane effect were calculated<br />
across 3 tumour grade categories or for heterogeneity between 2<br />
categories.<br />
Results : The table shows annual event rate ratios (CIs) for grade<br />
categories, for taxane-plus-anthracycline-based regimen versus<br />
the same, or more (< doubled or ∼doubled) non-taxane cytotoxic<br />
chemotherapy. Significantly different taxane effects were observed<br />
across categories of tumour grade. For both endpoints taxane benefit<br />
increased with lower tumour grade, there was a smaller effect in high<br />
grade tumours and no evidence the treatment benefit decreased with<br />
follow up time.<br />
Taxane Effect by Differentiation status<br />
Event rate ratio<br />
Grade<br />
(95%CI)<br />
N Grade 3 Grade 2 Grade 1/2 Grade 1 P-value<br />
BRCa Mortality 20,770 1.08(.94-1.25) 0.77(.65-0.90) 0.68(.47-0.98)
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
predictive biomarkers to detect these non-responsive breast cancers at<br />
time of diagnosis may allow for improved clinical outcome for these<br />
patients. FKBP4 (FKBP52) is a co-chaperone protein that has been<br />
shown to regulate progesterone but not estrogen receptor activity, and<br />
was recently found to be highly expressed in early stage breast cancer<br />
compared to benign breast tissue.This evidence suggests that FKBP4<br />
may play an important role in endocrine-responsive breast cancers.<br />
Methods: Global proteomic screening for biomarkers of aggressive<br />
breast cancer was performed on tissue samples from 24 patients with<br />
lymph node negative (LN-) disease and 24 patients with lymph node<br />
positive (LN+) disease randomly selected from the Calgary Tamoxifen<br />
Cohort, a retrospective cohort of breast cancer patients treated with<br />
adjuvant tamoxifen [n=511] from 1985-2000 at the Tom Baker <strong>Cancer</strong><br />
Centre (Calgary, Canada). Liquid tissue lysates from FFPE tissue were<br />
analyzed by mass spectrometry and differentially expressed proteins<br />
were identified by the semi-quantitative spectral count method.<br />
FKBP4 was identified as an upregulated target in LN+ patients. The<br />
mRNA expression database of Kao et al. (BMC <strong>Cancer</strong>, 2011) was<br />
used to assess the prognostic potential of targets identified in the<br />
proteomic screen. FKBP4 protein expression was evaluated in tissue<br />
microarrays built from FFPE samples from the Calgary Tamoxifen<br />
Cohort using quantitative fluorescence immunohistochemistry and<br />
HistoRx AQUA analysis. Ten-year overall survival (OS) or five-year<br />
disease free survival (DFS) were the primary outcomes. Continuous<br />
variable FKBP4 data was dichotomized at the top quartile for both<br />
mRNA and protein expression analysis.<br />
Results: Univariate analysis demonstrated a significant association<br />
between high levels of FKBP4 mRNA and worse OS in ER+Her2-<br />
patients [n=182, HR=2.118 (1.070-4.192), p=0.031] within the Kao<br />
et al database. Similarly, univariate analysis demonstrated that high<br />
levels of FKBP4 protein expression was associated with significantly<br />
worse DFS in ER+ Her2- patients [n=358, HR=1.632 (1.001-2.659),<br />
p=0.049] in the Calgary Tamoxifen Cohort. FKBP4 was found to be an<br />
independent prognostic factor in both mRNA and protein expression<br />
cohorts using multivariate analysis adjusted for age, T stage, and<br />
lymph node status [OS: HR=2.786 (1.394-5.570), p=0.004], or age,<br />
tumor size, tumor grade, and lymph node status [DFS: HR=1.875<br />
(1.021-3.442), p=0.043], respectively.<br />
Conclusions: Proteomic screening from FFPE tissue can identify new<br />
breast cancer biomarker candidates. Using this technique we have<br />
identified FKBP4 as an independent prognostic factor in ER+Her2-<br />
breast cancers, measured either by mRNA expression analysis or by<br />
quantitative protein expression analysis. Further studies are required<br />
to determine if FKBP4 may also be a predictive biomarker for<br />
tamoxifen response in ER+HER2- patients.<br />
P6-07-18<br />
Identification of Sperm Associated Antigen 5 (SPAG5) as a novel<br />
biological and predictive biomarker in <strong>Breast</strong> cancer<br />
Abdel-Fatah TMA, Ball G, Miles AK, Moseley P, Green A, Rees B,<br />
Ellis IO, Chan SYT. Nottingham City Hospital NHS Trust, Nottingham;<br />
The John van Geest <strong>Cancer</strong> Research Centre, Nottingham Trent<br />
University; University of Nottingham<br />
Introduction<br />
SPAG5 has been found to be involved in the functional and dynamic<br />
regulation of mitotic spindles, and to be essential for chromosome<br />
segregation fidelity. Recently we found by using neural network<br />
and pathways analysis of a gene expression array data that SPAG5<br />
was among top 10 ranked genes out of 48,000 of transcripts, that<br />
accurately predicted worse clinical outcome based on a 10-fold<br />
external cross-validation analysis with an average classification<br />
accuracy of >99.999%. Moreover we found that 5% of BC showed<br />
amplification of SPAG5 locus at chromosome 17q11.2 and SPAG5<br />
mRNA expression levels displayed a statistically significant<br />
correlation with its copy number.<br />
Methods<br />
In the current study the molecular and clinicopathological features<br />
of SPAG5 expression and its effect on management of BC have been<br />
investigated in 2800 BC patients with primary operable invasive BCs<br />
constituted four cohorts:<br />
1) A series of 1650 BC patients received adjuvant endocrine and/or<br />
CMF chemotherapy according to NPI.<br />
2) A series of 256 BC received adjuvant anthracycline-based<br />
chemotherapy (ATC-CT)<br />
3) A series of 140 primary BC HER2+ patients treated with ATC-CT+<br />
Herceptin 4) To validate SPAG5 as a predictor factor for ATC-CT,<br />
260 patients with locally advanced primary breast cancer treated with<br />
neoadjuvant ATC-CT were included and the pathological complete<br />
response (pCR) was used to evaluate the response to chemotherapy.<br />
Immunohistochemical staining was performed using Anti--SPAG5<br />
rabbit polyclonal (HPA022479; Sigma).<br />
Results: i) By using dual immunoflurescent in BC cell lines, coexpression<br />
of SPAG5 and proliferating cell nuclear antigen (PCNA)<br />
was detected in 4 out of 5 of the breast cancer cell lines screened<br />
(MCF7, T47D, MDA468 and MDA231) providing evidence for the<br />
importance of SPAG5 in cell proliferation. ii) 20% of breast cancer<br />
showed SPAG5 protein overexpression. SPAG5 overexpression<br />
showed a statistically significant association with ER-, PR-, triple<br />
negative phenotype, high grade tumour, high ki67, basal like<br />
phenotype and epithelial mesenchymal transition phenotype, p53<br />
mutation and absence of DNA repair genes (BRCA1, ATM and<br />
XRCC1); p values
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
Patients and methods<br />
Primary operable breast cancer patients diagnosed between 1/1/2000<br />
and 31/12/2009 treated in UZ Leuven were retrieved from the<br />
prospectively managed database (n=4318). Her-2 status was missing<br />
in 93 and ER/PR in 2 patients. Of the remaining patients, 3330 were<br />
luminal (ER and/or PR positive) HER2 negative (full cohort details:<br />
Brouckaert O., et al. Ann Oncol. 2012 Apr 6). Missing values were<br />
observed in 137 patients (4.1%), and these were imputed using<br />
‘multivariate imputation by chained equations’. A competing risks<br />
proportional hazards model was used for multivariable analysis<br />
(includes age, size, grade, screening, palpability, nodal status,<br />
histology, type of surgery, radiotherapy, endocrine and chemotherapy)<br />
of distant metastasis free interval (DMFI) and breast cancer specific<br />
survival (BCSS). We used a predefined set of predictors, investigated<br />
non-linearity of the predictor effects, checked the proportional hazards<br />
assumption, and tested for interactions with grade.<br />
Results<br />
Median follow-up was 76 months and 5-year survival probability<br />
93%. PR is an independent prognostic variable but this is grade<br />
dependent for DMFI, but not for BCSS (interaction p=0.15), although<br />
PR positivity was mainly protective for grade 3 breast cancers again<br />
(table 1). Palpability is a strong prognostic variable for DMFI and<br />
BCSS and was strongly correlated with screen detection (yes/no) and<br />
here, we found no evidence of grade dependency.<br />
Table 1: descriptive statistics and multivariable adjusted hazard ratios (within a competing risk<br />
framework) for distant metastatic free interval (DMFI) and breast cancer specific survival (BCSS)<br />
N (%) DMFI BCSS<br />
Age (+10y) 58 (median) 0.87 (0.77-0.98) 0.85 (0.73-0.99)<br />
Tumor size (+1cm) 20mm (median) 1.06 (1.01-1.12) 1.01 (0.94-1.09)<br />
Palpable 2603 (78.2%) 2.07 (1.13-3.79) 2.69 (1.16-6.22)<br />
pN0 2041 (61.3%) Reference Reference<br />
pN1 944 (28.3%) 1.59 (1.11-2.27) 1.96 (1.25-3.06)<br />
pN2 228 (6.8%) 3.16 (1.97-5.05) 4.12 (2.26-7.50)<br />
pN3 117 (3.5%) 8.12 (4.94-13.4) 10.79 (5.88-19.8)<br />
Grade (+1 unit) - 5.78 (2.74-12.2) 3.22 (2.39-4.36)<br />
PR (in grade 1) - 4.03 (1.01-16.12)* -<br />
PR (in grade 2) - 1.49 (0.76-2.91) -<br />
PR (in grade 3) - 0.55 (0.35-0.85) -<br />
PR (overall) - - 0.57 (0.38-0.87)<br />
Chemotherapy 985 (29.6%) 0.60 (0.41-0.89) 0.48 (0.29-0.80)<br />
* Although marginally significant, this result is clinically unreliable due to low numbers (10<br />
metastatic events in 568 PR+ grade 1 breast cancers, but 0 events in only 56 PR- grade 1 breast<br />
cancers.<br />
Conclusion<br />
PR status and palpability may further refine prognosis of patients with<br />
luminal HER2 negative breast cancers. For PR, prognostic value is<br />
grade dependent, but for palpability, this is grade independent.<br />
P6-07-20<br />
Variables measured at Central Nervous System (CNS) relapse, but<br />
not Immunophenotype, identify groups of breast cancer patients<br />
with shorter post CNS-relapse survival<br />
Gómez HL, Pinto JA, Schwarz JL, Vigil CE, Vallejos CS. Instituto<br />
Nacional de Enfermedades Neoplásicas, Lima, Peru; Oncosalud,<br />
Lima, Peru<br />
Objective: We evaluated breast cancer immunophenotype and<br />
variables measured at CNS-relapse as prognostic factors in a cohort<br />
of Hispanic patients.<br />
Methods: We reviewed data from 2602 breast cancer women in<br />
stages I-III diagnosed between 2000 and 2005 at the Instituto<br />
Nacional de Enfermedades Neoplásicas, Lima, Perú. According to<br />
immunophenotype, tumors were categorized in luminal A (RE+ and/or<br />
RP+, HER2-), luminal B (RE+ and/or RP+, HER2+), HER2 (RE-, RP-,<br />
HER2+) and triple negative (RE-, RP-, HER2-). Clinicopathological<br />
data at diagnosis and at CNS relapse were evaluated and used to<br />
calculate prognostic scores according to Recursive Partitioning<br />
Analysis (RPA) score, Graded Prognostic Assessment (GPA) Score,<br />
and Basic Score for Brain Metastases. Endpoints were time to CNS<br />
metastasis and Post CNS-relapse survival.<br />
Results: With a median follow-up of 7.5 years, 818 (31.4%) patients<br />
had locoregional or distant recurrence. In total, 159 (6.1%) patients<br />
developed CNS metastases, of whom 92 (3.5%) as the first site of<br />
recurrence and 22 meningeal metastases were detected. In triple<br />
negative, 51 (32.1%) developed SNC metastases, 46 (28.9%) in<br />
luminal A, 37 (23.3%) in HER2 and 25 (15.7%) in luminal B patients.<br />
Median time since breast cancer diagnosis to SNC metastases was<br />
28.1 months (mo) and the variables influencing it were Clinical T<br />
(P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Results: A total of 157 cases had CNS relapse from which 124 had<br />
only brain metastases, 19 only leptomeningeal carcinomatosis (LMC),<br />
and 14 both. Forty three cases were [HR+, HER2-] (5 LMC), 68<br />
were TN (13 LMC) and 51 were [HR+/-, HER2 +] (15 LMC). 152<br />
cases were in clinical stages I-III at diagnosis (96.8% of all SNC<br />
relapses). There was no association between IHC phenotypes and age<br />
at CNS relapse, ECOG Performance Status (P=0.837), extracraneal<br />
metastases (P=0.304), control of primary tumor (P=0.164), number<br />
or volume of brain metastases (P=0.706). Significant association was<br />
found between phenotype and time from diagnosis to development of<br />
CNS metastases (≤8 months: 16.3% in TN, 7.3% in Her-2 and 0% for<br />
[HR+, HER2-]; P=0.017 ) and histological grade (grade III: 74.4% in<br />
TN, 55.% in Her-2 and 30% for [HR+, HER2-]; P=0.006). Symptoms/<br />
signs commonest in LMC patients were cephalea (7 cases, 72%),<br />
meningism (6, 24%), nausea (6, 24%), vomiting (5, 20%), ataxia (5,<br />
20%), facial palsy (4, 16%), somnolence (4, 16%), paraparesia (3,<br />
12%), hiporeflexia (3, 12%), apraxia (3, 12%), arreflexia (3, 12%),<br />
poor sphincter control (3, 12%), hemiparesia (2, 8%), seizures (2,<br />
8%), bradypsichia (2, 8%), neuropathic pain (1, 4%). Meningism<br />
was most frequent in TN cases (50%). Post recurrence survival was<br />
shorter in LMC TN patients (3.61mo vs 4.89mo to [HR+, HER2-]<br />
vs 5.95mo to [HR+/-, HER2 +; P=0.044] and in LMC patients with<br />
meningism (1.38mo vs 5.26mo; P=0.02). Multivariate analysis<br />
identify meningism as the worse risk factor for survival in patients<br />
relapsed with LMC (HR: 4.33 compared with patients without LMC;<br />
P=0.066). Conclusions: In LMC patients, meningism was identified<br />
as a sign related to shorter survival after the SNC relapse.<br />
P6-07-22<br />
Association between SPARC mRNA expression, prognosis and<br />
response to neoadjuvant chemotherapy in early breast cancer<br />
(BC): a pooled in-silico analysis<br />
Azim Jr HA, Singhal S, Michiels S, Ignatiadis M, Djazouli K,<br />
Fumagalli D, Desmedt C, Piccart M, Sotiriou C. Universite Libre de<br />
Bruxelles, Brussels, Belgium; Institut Jules Bordet, Brussels, Belgium;<br />
Celgene International<br />
Background: SPARC (Secreted Protein Acidic and Rich in Cysteine)<br />
is known to regulate cell growth and to inhibit cell-cycle progression.<br />
It has high affinity in binding albumin and hence has been suggested<br />
to predict benefit of albumin-bound cytotoxic agents. We conducted<br />
a pooled analysis to elucidate SPARC expression according to BC<br />
molecular subtypes and its association with clinical outcome in<br />
early BC.<br />
Methods: We used publically available datasets and normalized<br />
microarray data as published by the original studies. Eligible patients<br />
were those who received no adjuvant systemic therapy (untreated<br />
series), were treated with tamoxifen (tam-treated series) or were<br />
treated with neoadjuvant anthracyclines ± paclitaxel or docetaxel<br />
(neoadjuvant series). We computed 2 SPARC modules, SPARC7 and<br />
SPARC8 that were composed of genes with an absolute correlation<br />
above 0.7 and 0.8 with SPARC, respectively. In the untreated series,<br />
we examined the expression of SPARC according to BC subtype<br />
defined by PAM50. We investigated the correlation with other gene<br />
modules representing diverse biological processes; proliferation<br />
(AURKA, GGI), immune (STAT1, IRM), and stroma (DCN, PLAU).<br />
We investigated the association with relapse-free survival (RFS) in<br />
univariate and multivariate models, both in the untreated and tamtreated<br />
series. This was performed in all patients and according to BC<br />
subtype. In the neoadjuvant series, we investigated the association<br />
with pathological complete response (pCR) in all patients and<br />
according to BC subtype. All multivariate models were adjusted for<br />
tumor size, nodal status, age and histological grade.<br />
Results: 1008, 393 and 996 patients were included in the untreated,<br />
tam-treated and neoadjuvant series, respectively. SPARC expression<br />
was highest in luminal-A, small (< 2 cm) and low histological grade<br />
tumors (all p
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
For all cut off points, there was no significant difference in survival<br />
rate and recurrence rate. We observed high-rates of lymphatic invasion<br />
and lymph node metastasis even in patients with a low proportion<br />
of IMPC lesion.<br />
Conclusion<br />
Our results provide no evidence to support a relationship between<br />
proportion of IMPC lesion and breast cancer prognosis. However,<br />
lymphatic invasion and lymph node metastasis was a high frequency<br />
with low proportion of the IMPC.<br />
The number of cases, lymphatic invasion, LN positive, recurrence rate and overall survival<br />
# of cases
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Conclusion<br />
In this large dataset with long follow up our results indicate that<br />
high annexin A1 expression among women with breast cancer was<br />
associated with favorable patient and tumor characteristics and an<br />
improved RFS. Annexin A1 should be explored further as a potential<br />
prognostic biomarker.<br />
P6-07-26<br />
Prognostic significance of the maximal value of the baseline<br />
standardized uptake value on fluorine 18 fluorodeoxyglucose<br />
positron emission tomography /computed tomography for<br />
predicting pathologic malignancy of operable breast cancer with<br />
neoadjuvant chemotherapy<br />
Kadoya T, Akimoto E, Emi A, Shigematsu H, Masumoto N, Okada<br />
M. Hiroshima University, Hiroshima, Japan<br />
PURPOSE: [18F]-fluorodeoxyglucose (FDG) positron emission<br />
tomography (PET)/computed tomography (CT) is potentially useful<br />
in predicting pathological complete response (pCR), disease free<br />
survival (DFS) and overall survival (OS) of breast cancer patients<br />
with neoadjuvant chemotherapy.<br />
MATERIALS AND METHODS: 77 breast cancer patients (mean<br />
age ± SD: 52.6 ± 11.2 years) with clinical Stage I∼III between<br />
January 2006 and December 2011, were prospectively evaluated<br />
(median follow up period:26.5 months). Neoadjuvant chemotherapy<br />
of an anthracycline-based regimen and taxane was performed, and<br />
patients underwent a whole-body FDG PET/CT before and after<br />
chemotherapy. The maximal value of the baseline standardized<br />
uptake values (SUVmax) were assessed for predicting pCR, DFS and<br />
OS. For the evaluation of relationship between SUVmax values and<br />
prognosticators such as hormone receptors, human epidermal growth<br />
factor receptor 2 (HER2), nuclear grade, lymph node metastasis and<br />
tumor size, statistical analyses were performed using Student t test<br />
and log-rank test, and p values of less than 0.05 were considered to<br />
indicate statistically significant differences.<br />
RESULTS: Clinical Stage included were I (n = 2, 2.6%), II (n=62,<br />
80.5%) and III (n=12, 15.6%). Tumors with estrogen receptor positive<br />
were 52 (67.5%) and negative were 24 (31.2%). Therapeutic response<br />
by neoadjuvant chemotherapy was obtained in 15 patients (19.5%)<br />
with pCR and 60 (77.9%) without pCR. Patients were divided into<br />
two groups according to cut-off SUVmax established on the basis<br />
of receiver operating characteristic (ROC) analysis (6.0 Odds ratio(95%Cl) P<br />
(n=46) (n=31) (Student t test)<br />
ER negative 9 15 3.75 0.02<br />
ER positive 36 16 (1.36-10.35)<br />
PgR negative 13 15 2.31 0.083<br />
PgR positive 32 16 (0.89-6.00)<br />
HER2 negative 31 18 1.51 0.70<br />
HER2 positive 8 7 (0.47-4.85)<br />
There was a significant difference in OS between two groups (p=0.05),<br />
but, pCR (OR:1.07, 95%Cl:0.34-3.40, P=0.86) and DFS (P=0.07) did<br />
not show strong relationship with SUVmax values.<br />
Comparison of prognosis<br />
SUV max≤6.0 SUV max>6.0 Odds ratio P<br />
(n=46) (n=31) (95%Cl)<br />
pCR 9 6 1.07 0.86<br />
Non pCR 35 25 (0.34-3.40) (Student t test)<br />
Disease free 44 27 0.07<br />
Recurrence 1 4 (log-rank test)<br />
Alive 45 28 0.02<br />
Dead 0 3 (log-rank test)<br />
CONCLUSION: SUVmax on FDG PET/CT before neoadjuvant<br />
chemotherapy have a predictive value for high-grade malignancy<br />
and prognosis in clinical Stage I∼III breast cancer.<br />
P6-07-27<br />
Body mass index and survival after breast cancer diagnosis in<br />
Japanese women<br />
Kawai M, Minami Y, Nishino Y, Ohuchi N, Kakugawa Y. Tohoku<br />
University Graduate School of Medicine, Sendai, Miyagi, Japan;<br />
Miyagi <strong>Cancer</strong> Center Research Institute, Natori, Miyagi, Japan;<br />
Miyagi <strong>Cancer</strong> Center Hospital, Natori, Miyagi, Japan<br />
Background: Body mass index (BMI) may be an important factor<br />
affecting breast cancer outcome. Studies conducted mainly in Western<br />
countries have reported a relationship between higher BMI and a<br />
higher risk of all-cause death or breast cancer-specific death among<br />
women with breast cancer, but only a few studies have been reported<br />
in Japan so far. In the present prospective study, we investigated<br />
the associations between BMI and the risk of all-cause and breast<br />
cancer-specific death among breast cancer patients overall and by<br />
menopausal status and hormone receptor status. Methods: The study<br />
included 653 breast cancer patients admitted to a single hospital<br />
in Japan, between 1997 and 2005. BMI was assessed using a selfadministered<br />
questionnaire. The patients were completely followed<br />
up until December, 2008. Hazard ratios (HRs) and 95% confidence<br />
intervals (CIs) were estimated according to quartile points of BMI<br />
categories, respectively:
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
P6-07-28<br />
Assessment of T stage in the multiple breast carcinomas<br />
Gong G, Jo J-H, Lee HJ, Kang J. University of Ulsan College of<br />
Medicine, Asan Medical Center, Republic of Korea; University of<br />
Ulsan College of Medicine, Gangneung Asan Hospital, Republic of<br />
Korea; Seoul National University Bundang Hospital, Republic of<br />
Korea; Haeundae Paik Hospital, Inje University College of Medicine,<br />
Republic of Korea<br />
Background: Tumor size is an important predictor of nodal metastasis,<br />
recurrence, distant metastasis in invasive breast carcinomas. T stage<br />
assignment of the multiple simultaneous ipsilateral breast carcinomas<br />
is based on the largest tumor with the suffix “(m)” to indicate<br />
multiplicity in the AJCC staging, and sum of the sizes should not<br />
be used. The aim of this study is to compare current AJCC staging<br />
and two test models using the aggregate of all tumor foci and the<br />
aggregate of all tumor volume in the single and multiple breast<br />
carcinomas. Methods: We reviewed original pathologic reports of<br />
1145 consecutive patients with invasive ductal carcinoma, 2003-2004.<br />
131 (11.4%) patients had multiple masses. Three factors were used to<br />
compare T stages; (1) the greatest dimension of the largest invasive<br />
component (T), (2) the aggregate of all tumor foci (TA), and (3) the<br />
aggregate of all tumor volume (TV). T stage follows AJCC (7th ed,<br />
2010) system. TA and TV were categorized as followings: TA1 < 2cm,<br />
2cm ≤ TA2 < 5cm and TA3 ≥ 5cm; TV1 < 8cm³ (average diameter <<br />
2cm), 8 cm³ ≤ TV2 < 125cm³ and TV3 ≥ 125cm³ (average diameter<br />
≥ 5cm). Clinicopathologic parameters were analyzed according to T<br />
stage. Results: Axillary lymph node metastasis was more common<br />
in the cases with multiple masses (64/131, 48.9%) than single mass<br />
(397/1014, 39.2%) and the number of the metastatic lymph node was<br />
also higher in multiple cases. Multiple breast carcinomas tended to<br />
show frequent recurrence, and disease specific death compared with<br />
the single cases in the same stage. (p < 0.05) Among 606 cases of<br />
T1, 34 cases were reclassified to TA2 and in 487 cases of the T2, 23<br />
cases were reclassified to TA3. TV also showed reclassification of the<br />
cases. Multiplicity, T stage, TA stage, and TV stage were significant<br />
factors for nodal positivity in the univariate analysis (p < 0.05). Nodal<br />
positivity was remained in the multivariate analysis for recurrence and<br />
disease specific death, but the other factors were not significant for<br />
nodal involvement, recurrence and disease specific death. Conclusion:<br />
Multiple breast carcinomas has adverse patients’ outcome than single<br />
carcinoma with same T stage of AJCC system and a better staging<br />
method is required to cover multiple carcinomas.<br />
P6-07-29<br />
Independent prognostic value of age depends on breast cancer<br />
subtype<br />
Brouckaert O, Salihi R, Laenen A, Vanderhaegen J, Amant F, Leunen<br />
K, Smeets A, Berteloot P, Van Limbergen E, Weltens C, Moerman P,<br />
Peeters S, Paridaens R, Floris G, Wildiers H, Vergote I, Christiaens<br />
M-R, Neven P. UZ Leuven; Interuniversity Centre for Biostatistics<br />
and Statistical Bioinformatics<br />
Background: Whether age is an independent prognostic factor in<br />
early breast cancer remains controversial. Different cut-off values<br />
have been suggested in different studies and few studies assessed its<br />
value in triple negative breast cancer and other phenotypes.<br />
Methods: We included all primary operable breast cancer patients<br />
from our prospectively managed database in UZ Leuven, Belgium.<br />
We excluded male patients, patients treated elsewhere first, patients<br />
treated with primary systemic treatment first. We assessed the effect<br />
of age as a continuous and categorical variable for distant metastasis<br />
free interval (DMFI), locoregional free interval (LRRFI) and breast<br />
cancer specific survival (BCSS) in multivariable analysis (correcting<br />
for phenotype, tumor size, nodal status, chemo-, endocrine-,<br />
radiotherapy, type of breast and axillary surgery). We assessed the<br />
effect of age for DMFI, LRRFI and BCSS in basal-like breast cancer<br />
and other phenotypes.<br />
Results: We included 4318 patients with a mean/median age of 58/ 57<br />
years (1170 patients were younger than 50 years) and with a median<br />
follow-up of 6,0 years. Multivariate analysis confirmed age as an<br />
independent prognostic variable for LLRFI (HR1.91; 95% CL:1.33-<br />
2.74; P=0.0005), DMFI (HR:1.77; 95% CL:1.33-2.36; P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
In logistic regression analysis, significantly fewer HER2+HR+ pts<br />
achieved pCR compared to HER2+HR- pts regardless of the pCR<br />
definitions.<br />
Logistic regression analysis of pCR rate using diffrent definitions according to HR status<br />
HER2+HR- HER2+HR+ Odds ratio P<br />
N=74 % N=89 %<br />
ypT0 ypN0 20 27 12 14 0.42 0.033<br />
ypT0/is ypN0 27 36 17 19 0.37 0.005<br />
ypT0/is ypN0/+ 31 42 19 21 0.38 0.005<br />
(Conclusions) HER2+HR+ breast cancer pts had lower achievement<br />
rate of pCR, which was less prognostic compared to that in<br />
HER2+HR- pts regardless of pCR definitions. pCR is a suitable<br />
surrogate end point for HER2+HR- pts but not for HER2+HR+ pts<br />
in clinical trial settings.<br />
P6-07-31<br />
Assessing germline Homologous Recombination pathway<br />
deficiency in BRCA1 mutation carriers using Single Cell Network<br />
Profiling.<br />
Rosen DB, Leung LY, Louie B, Evensen E, Fields SZ, Cesano A,<br />
Shapira I, Hawtin RE. Nodality Inc, South <strong>San</strong> Francisco, CA;<br />
Monter <strong>Cancer</strong> Center, North Shore Long Island Jewish Medical<br />
School, Lake Success, NY<br />
Background: Inherited alterations in BRCA1/2 genes increase<br />
genomic instability and cancer susceptibility. DNA sequencing detects<br />
BRCA1/2 mutations, but has the following limitations; 1) mutations<br />
may have unknown functional significance, 2) epigenetic alterations<br />
and mutations in other Homologous Recombination (HR) pathway<br />
components are not detected, and 3) the combined effects of pathway<br />
mutations are not understood. Thus a functional assessment of HR<br />
competence at the single cell level remains an unmet need as BRCA1/2<br />
sequencing does not holistically inform on functionality of the HR<br />
pathway. Single Cell Network Profiling (SCNP) is a multiparametric<br />
flow cytometry-based assay that simultaneously measures, at the<br />
single cell level, extracellular surface markers and functional changes<br />
in intracellular signaling in response to extracellular modulators<br />
(Kornblau et al. Clin <strong>Cancer</strong> Res 2010). In this study, we tested the<br />
ability of SCNP to detect and quantify functional changes in HR<br />
signaling using peripheral blood mononuclear cell (PBMC) samples<br />
from BRCA1 mutation carriers (MUT) and wild type (WT) subjects.<br />
Methods: HR pathway activity was examined in PBMCs from<br />
BRCA1 MUT (n=21) or WT (n=20) subjects. Cell lines carrying<br />
BRCA1 MUTor WT genes were used as controls. PBMCs were<br />
stimulated with anti-CD3 and anti-CD28 for 24 hours to induce T<br />
cell proliferation then treated with PARP inhibitor (PARPi) AZD2281<br />
+/- Temozolomide (TMZ) for 48h or 72h to induce DNA damage.<br />
DNA damage response (DDR) readouts were measured in both<br />
CyclinA2- and CyclinA2+ T cell subsets. Measurements included<br />
induced levels of p21, p53 and phosphorylation (p-) of p-H2AX,<br />
p-DNA-PKcs, p-RPA2/32, and p-BRCA1.<br />
Results: As expected based on the mechanism of action of PARPi,<br />
higher levels of induced p-H2AX and p53 were observed in<br />
CyclinA2+ cells of BRCA1 MUT versus WT cell line controls. In<br />
PBMCs, T cell proliferation (%CyclinA2+) was positively associated<br />
with PARPi induced DDR readouts. After controlling for proliferation,<br />
statistically significant differences in PARPi induced DDR signaling<br />
were observed between BRCA1 MUT and WT samples in many<br />
simultaneously assessed readouts including p-H2AX, p53 and p21<br />
(increased in MUT), particularly in CyclinA2+ cells. Additionally,<br />
BRCA1 MUT samples displayed lower basal p-BRCA1 but higher<br />
induced p-BRCA1 levels compared to BRCA1 WT samples.<br />
Conclusions: SCNP was able to detect and quantify functional<br />
differences between PBMC samples from BRCA1 MUT<br />
(haploinsufficient) and WT donors by quantitatively assessing DDR<br />
signaling in CyclinA2+ T cells. Once verified on a larger data set, the<br />
assay could form the basis for the development of screening tests to<br />
identify subjects at higher risk of developing cancer or stratification<br />
tests to inform on cancer patient selection for treatment with PARP<br />
inhibitors.<br />
P6-07-32<br />
Prognosis of metastatic breast cancer subtypes: the hormone<br />
receptor/HER2 positive subtype is associated with the most<br />
favorable outcome<br />
Tjan-Heijnen VCG, Lobbezoo DJA, van Kampen RJW, Voogd AC,<br />
Dercksen MW, van den Berkmortel F, Smilde TJ, van de Wouw AJ,<br />
Peters FPJ, van Riel JMGH, Peters NAJB, Borm GF. Maastricht<br />
University Medical Center, Maastricht, Netherlands; Maxima<br />
Medical Center, Eindhoven, Netherlands; Atrium Medical Center<br />
Parkstad, Heerlen, Netherlands; Jeroen Bosch Hospital, Den<br />
Bosch, Netherlands; Viecuri Medical Center, Venlo, Netherlands;<br />
Orbis Medical Center, Sittard, Netherlands; St Elisabeth Hospital,<br />
Tilburg, Netherlands; St Jans Hospital, Weert, Netherlands; Radboud<br />
University Medical Center, Nijmegen, Netherlands<br />
Background<br />
In early breast cancer the different subtypes and their prognostic<br />
relevance are well known, contrary to the knowledge on prognostic<br />
relevance of subtypes in metastatic breast cancer. This study<br />
presents survival estimates after diagnosis of distant metastases of<br />
breast cancer subtypes in a recent cohort in which the treatment is<br />
representative of current clinical practice.<br />
Patients and methods<br />
All patients diagnosed with metastatic breast cancer in one of eight<br />
participating hospitals in the South-East part of the Netherlands<br />
between 2007-2009 were included and all medical charts were<br />
reviewed. Patients were categorized in 4 subtypes based on the<br />
hormone receptor (HR) and human epidermal growth factor receptor<br />
2 (HER2) status of the primary tumor; HR positive/HER2 negative,<br />
HR positive/HER2 positive, HR negative/HER2 positive and triple<br />
negative (TN). Metastatic survival was estimated using the Kaplan-<br />
Meier product-limit method. Cox proportional hazards model was<br />
used to determine the prognostic impact of breast cancer subtype,<br />
adjusted for possible confounders.<br />
Results<br />
A total of 815 patients were included; the HR+/HER2- subtype<br />
comprising 66%, the HR-/HER2+ subtype 8%, the TN subtype 15%<br />
and the HR+/HER2+ subtype 11% of patients. The four subtypes were<br />
associated with different metastatic survival times; the HR+/HER2+<br />
subtype was associated with the best metastatic survival (median,<br />
32.9 months), compared to 22.1 months for the HR+/HER2- subtype,<br />
19.5 months for the HR-/HER2+ subtype and 7.7 months for the TN<br />
subtype. Aside from subtype, other prognostic factors of metastatic<br />
survival were site of metastases and metastatic-free interval.<br />
Conclusion<br />
Of the four subtypes, the HR+/HER2+ subtype was associated with<br />
the most favorable outcome, in terms of metastatic survival.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
526s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
P6-07-33<br />
A clinicopathologic analysis of 45 patients with metaplastic<br />
breast cancer<br />
Verma S, Cimino-Mathews A, Figueroa Magalhaes MC, Zhang Z,<br />
Stearns V, Connolly RM. Sidney Kimmel Comprehensive <strong>Cancer</strong><br />
Center at Johns Hopkins, Baltimore, MD; St. Agnes Hospital,<br />
Baltimore, MD; Johns Hopkins Hospital, Baltimore, MD<br />
Background:<br />
Metaplastic breast carcinoma (MBC) is a rare tumor, accounting for<br />
< 1% of all breast cancers. The 5-year survival rate is approximately<br />
65% vs. 89% for conventional invasive ductal cancer (IDC), therefore<br />
improved treatment options are required. Evidence as to how to<br />
manage patients with MBC is derived from a number of single<br />
institution case series, and usually follows the treatment paradigm for<br />
conventional IDC. We aimed to review the clinicopathologic features<br />
of women with MBC treated at our institution to add to the current<br />
literature, and to identify potential prognostic biomarkers of outcome.<br />
Patients and Methods: The study was approved by the Institutional<br />
Review Board of John Hopkins University. We retrospectively<br />
identified patients > 18 yrs of age with histologic confirmed diagnosis<br />
of MBC through the Johns Hopkins Pathology archives from March<br />
1999-February 2012. We collected and reviewed data relating to<br />
clinicopathological features, local and systemic treatments, and<br />
patient outcomes. Survival probabilities at specific time points were<br />
estimated using the Kaplan-Meier method and confidence intervals<br />
(CI) obtained using the Greenwood formula.<br />
Results: Of 45 cases identified, median age was 59 (range 38-93),<br />
62% of patients were white and 36% were black. Histologic subtypes<br />
identified were chondroid (24%), spindle (20%), sarcomatoid<br />
(16%), squamous (11%) and mixed (29%). Median tumor size<br />
3cm (range 1-14.8cm); lymph node status was positive (24.4%) /<br />
negative (51.2%) /unknown (24.4%); 60% had grade 3 tumors;<br />
69% were estrogen receptor (ER)/progesterone receptor (PR)/<br />
HER2-negative (triple-negative), 20% ER/PR-positive, with 4<br />
HER2 positive tumors and 3 HER2-unknown. Two patients had<br />
metastatic disease at diagnosis. Neoadjuvant therapy (anthracyclinetaxane<br />
based in 83%) was administered in 6 patients, with one<br />
patient achieving complete pathological response to dose dense<br />
adriamycin and cyclophosphamide followed by weekly paclitaxel.<br />
All patients underwent surgery (82% negative margins) and 60%<br />
received adjuvant radiation. Adjuvant chemotherapy, predominantly<br />
anthracycline +/- taxane-based was administered in 58% cases<br />
(excluding neoadjuvant). 5 year recurrence-free survival (n=43)<br />
was 63.3% (95% CI, 0.382-0.884) with median follow up of 26.2<br />
months (range 1.7-137.2 months). 5 year overall survival (n=45)<br />
was 68.7% (95% CI, 0.448-0.926) at median follow up 28 months<br />
(range 2.4-137.9 months).<br />
Conclusion: We report one of the largest single institution case series<br />
of clinicopathologic features associated with MBC in the literature.<br />
MBC is associated with a worse prognosis than conventional IDC,<br />
despite a relatively low rate of positive nodal involvement. The<br />
majority of patients in this series had high grade, triple-negative<br />
tumors and were treated with optimal local and systemic therapy. We<br />
will report results of subgroup analyses at the time of presentation. We<br />
also aim in the future to analyze available archival tumors to identify<br />
potential prognostic and predictive biomarkers, and anticipate that<br />
these results will provide the rationale for clinical trials with novel<br />
investigational agents in this area of unmet need.<br />
P6-07-34<br />
Disease-related outcomes with adjuvant chemotherapy in HER2<br />
positive or triple negative T1a/bN0 breast cancers<br />
Shao T, Olszewski AJ, Boolbol SK, Migdady Y, Boachie-Adjei K, Sakr<br />
BJ, Klein P, Sikov W. Beth Israel Medical Center, Continuum <strong>Cancer</strong><br />
Centers of New York, New York, NY; The Warren Alpert Medical<br />
School of Brown University, Providence, RI<br />
Background: Previous studies reported higher relapse rates in<br />
T1a/bN0 breast cancers characterized by high-risk biology (HER2<br />
positive or triple negative). The benefits of adjuvant chemotherapy<br />
in this group have not been evaluated. The purpose of our study<br />
was to determine potential impact of chemotherapy on incidence of<br />
relapses and to define the population appropriate for treatment based<br />
on observational data.<br />
Methods: We pooled data from two multi-institutional databases<br />
spanning the period of 1996-2008 (Beth Israel Medical Center) and<br />
2000-2010 (Brown University). We fitted a propensity score model<br />
to adjust for unbalanced confounders between the groups treated or<br />
untreated with adjuvant chemotherapy and, in case of HER2+ disease,<br />
with trastuzumab. Competing risk analysis was employed to study the<br />
effect of chemotherapy on cancer relapses in the matched population.<br />
Results: The study included 321 patients (160 from Beth Israel and<br />
161 from Brown) with a median age of 57 years (range 28-88). 111<br />
(35%) cases were triple negative (TN) and 210 (65%) were HER2+ (of<br />
which 64% were ER+). 41% patients received adjuvant chemotherapy<br />
and 22% of HER2+ cases received trastuzumab. The treated<br />
group differed from untreated with regards to distribution of age,<br />
menopausal status, year of diagnosis, histological subtype and grade,<br />
tumor size, rates of mastectomy, and adjuvant endocrine therapy. All<br />
confounders were successfully balanced with the propensity score<br />
analysis. With a median follow-up of 56 months, 20 relapses (12<br />
locoregional and 8 distant) and 10 unrelated deaths occurred. The<br />
cumulative incidence of relapse at 5 years was 7.3% (95% CI, 4.3-<br />
11.4) and relapse-free survival was 90.2% (95% CI, 85.2-93.6). Age<br />
less then 35 years (46.4% vs. 6.1%, p=0.0004) and TN status (12.9%<br />
for TN versus 4.8% for HER2+, p=0.03) were associated with higher<br />
risk of relapse. No significant differences with regards to tumor size<br />
(T1a or T1b), surgery type and other variables were observed. There<br />
was no significant effect of chemotherapy on incidence of relapse<br />
(Hazard ratio 1.2, 95% CI 0.34-4.23, p=0.78), relapse-free survival<br />
or distant recurrence-free interval after propensity score adjustment.<br />
Additionally in the HER2+ patients, no benefit of trastuzumab was<br />
detected (hazard ratio 0.78, 95% CI 0.06-9.85, p=0.85). Adjuvant<br />
endocrine therapy was associated with lower risk of relapse in the<br />
ER+ subgroup (p=0.04).<br />
Conclusion: Survival outcomes in very early stage breast cancer<br />
are excellent with current therapy even in biologically aggressive<br />
subtypes. Triple negative status and very young age correlate with<br />
higher incidence of relapse. While adjuvant endocrine therapy may be<br />
effective in ER positive subset, the risk/benefit ratio of chemotherapy<br />
with or without trastuzumab remains uncertain.<br />
P6-07-35<br />
Dragonfly Effect or Ironic Paradox: Prognostic Implication of<br />
Postsurgical Drain in <strong>Breast</strong> <strong>Cancer</strong> Patients<br />
Yin W, Lin Y, Shen Z, Shao Z-M, Lu J. Fudan University Shanghai<br />
<strong>Cancer</strong> Center, Shanghai, China<br />
Background: Surgical removal of primary breast cancer may result<br />
in subsequent alterations of host milieu. Massive clinical data have<br />
indicated that surgical extirpation favorably modifies the natural<br />
history for some patients, but it may also precipitate the metastatic<br />
www.aacrjournals.org 527s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
outgrowth for others. Drainage fluid, harvested from a post-surgical<br />
wound, appears to be a physiological response to surgical trauma.<br />
However, few clinicians have recognized that the volume of wound<br />
drain might mirror the postoperative recurrence kinetics.<br />
Methods: A total of 1439 patients were selected retrospectively<br />
from a large database of patients who underwent surgery between<br />
Jan 1, 2000 and Dec 31, 2002 in Fudan University Shanghai <strong>Cancer</strong><br />
Center, Shanghai, China. The Spearman rank correlation analysis<br />
was conducted to evaluate the association between drainage volume<br />
of postoperative day 1 (POD1) and clinicopathological parameters,<br />
which included age at diagnosis, body weight at diagnosis, total<br />
number of excised axillary lymph nodes (ALNs), time to drainage<br />
volume less than 30ml (TTV30), total protein and albumin<br />
concentrations in serum. Survival curves were performed with<br />
Kaplan–Meier method and annual recurrence hazard was estimated<br />
by hazard function.<br />
Results: Drainage volume of POD1 was positively correlated with age<br />
at diagnosis (Spearman’s P < 0.001), weight at diagnosis (P
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
P6-07-38<br />
The Value of Progesterone Receptor in Predicting the Recurrence<br />
Score for Hormone-Receptor–Positive Invasive <strong>Breast</strong> <strong>Cancer</strong><br />
Patients<br />
Onoda T, Yamauchi H, Yagata H, Hayashi N, Yoshida A, Nakamura<br />
S. St Luke’s International Hospital, Tokyo, Japan; Showa University,<br />
Tokyo, Japan; Yokohama Asahi Central General Hospital, Kanagawa,<br />
Japan<br />
Background: Molecular genomic profiling currently plays a<br />
major role in treatment decisions for breast cancer patients. The<br />
21-gene signature (Oncotype DX ® [ODX]) is one of the most wellvalidated<br />
assays. Herein we evaluated the associations between high<br />
Recurrence Score (RS) measured by the ODX and pathological<br />
factors. Methods: From October 2007 to October 2010, the ODX<br />
assay was performed for 139 hormone-receptor–positive invasive<br />
breast cancer patients at single institution. Correlations between the<br />
RS and the following pathological factors were analyzed: tumor size<br />
(T), lymph node metastasis (N), nuclear atypia (NA), mitotic counts<br />
(MC), nuclear grade (NG), lymphatic and vascular invasion (LI and<br />
VI), estrogen receptor (ER), progesterone receptor (PgR), HER2, and<br />
Ki-67. Expression of ER, PgR, HER2, and Ki-67 was examined by<br />
immunohistochemistry. The Ki-67 labeling index was automatically<br />
counted with an Ariol-SL50 instrument (APPLIED IMAGING). The<br />
other pathological factors were estimated under the supervision of<br />
one experienced pathologist. Spearman rank correlation coefficients<br />
were calculated for the analyses. When the r was >0.4 or
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
and PgR-negative status might indicate poor prognosis. However,<br />
this study was a retrospective analysis of a limited, heterogeneous<br />
patient group. A large-scale cohort study in the Japanese population<br />
is, therefore, recommended.<br />
P6-07-40<br />
Initial Neutrophil-to-Lymphocyte ratio in primary breast cancer<br />
patients: a simple and useful biomarker as prognostic factor<br />
Han A, Noh H, Lee J. Yonsei Univeristy Wonju Medical School, Wonju,<br />
Gangwon, Republic of Korea<br />
Background: Increasing neutrophil/lymphocyte ratios (NLR) on<br />
preoperative blood tests have been associated with worse survival<br />
of patients with colorectal, gastric, hepatocellular, pancreatic and<br />
lung cancer. However the utility of NLR to predict mortality in<br />
breast cancer patients has not been studied. The aim of our study<br />
was to determine whether the NLR is predictive of disease specific<br />
mortality in breast cancer and subtype-adjusted prognostic effect in<br />
breast cancer patients.<br />
Methods: We retrospectively identified all the patients with primary<br />
breast cancer diagnosed at Yonsei University Wonju Medical School<br />
between January 2000 and June 2011 who underwent primary<br />
surgery and completed all phase of their treatment. <strong>Breast</strong> cancer<br />
with infiltrating ductal histology was included and divided into 4<br />
subtypes: Luminal A, Luminal B, Her2-enriched, and basal type. Each<br />
immunohistochemical characteristics are as followings: Luminal A:<br />
ER and/or PgR positive and negative Her2, Luminal B: ER and/or<br />
PgR positive with positive HER2, Her2-enriched: negative ER and<br />
PR with positive Her2, and triple negative as basal.<br />
Results: Patients with NLR≥2.5 showed significantly lower 5-year,<br />
10-year breast cancer specific survival than patients with NLR
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
Patients diagnosed as invasive breast cancer without Paget’s disease<br />
were recruited in control group for clinical and pathologic features<br />
comparison.<br />
Since tumors in PD group expressed more high risk factors (see<br />
results), a matched study was done to investigate whether the poor<br />
survival of PD group was by nature or due to the overexpression of<br />
high risk factors. The matched group was derived from all the patients<br />
who received mastectomy for invasive breast cancer (with no Paget’s<br />
disease) during 2001 to 2005 in FUSCC. The match was conducted<br />
according to four variables: dimension of tumor, lymph node status,<br />
hormone receptor status and Her2 status. After matching, patients<br />
were randomly selected in a 3:1 ratio to patients in PD group.<br />
[Results]<br />
52 patients were recruited in PD group. 22 (42.3%) patients’ primary<br />
symptom were nipple change, 25 (48.1%) patients’ primary symptom<br />
were mass in breast. Physical examination found no nipple-areola<br />
change in 24 patients at diagnosis, their Paget’s disease were found<br />
unexpectedly by routine nipple-areola section examination after<br />
mastectomy.<br />
More than 8000 invasive breast cancers were diagnosed during 2001<br />
to 2005. 700 patients (140 consecutive patients per year, average<br />
monthly patient amount) were recruited in control group. Compared<br />
with control group, tumors in PD group had larger size, more axillary<br />
lymph node involvement, lower hormone receptor expression, higher<br />
HER2 expression and worse survival.<br />
Comparison of Pathologic Features (Control Group) and Survival (Matched Group) with PD Group<br />
PD group (n=52) Control Group (n=700) Matched Group (n=156)<br />
Dimension ≤2cm 24 (46.2%) 423 (60.4%)∗ 72 (46.2%)<br />
>2cm 28 (53.8%) 277 (39.6%) 84 (53.8%)<br />
Lymph Node + 28 (53.8%) 250 (35.7%)∗ 84 (53.8%)<br />
- 24 (46.2%) 450 (64.3%) 72 (46.2%)<br />
Hormone receptor + 18 (34.6%) 488 (69.7%)∗ 54 (34.6%)<br />
- 34 (65.4%) 212 (30.3%) 102 (65.4%)<br />
Her2 + 40 (76.9%) 149 (21.3%)∗ 120 (76.9%)<br />
- 12 (23.1%) 551 (78.7%) 36 (23.1%)<br />
5y Relapse-Free Survival 52.2% 86.7%∗ 81.4%∗<br />
5y Overall Survival 62.1% 91.8%∗ 85.9%∗<br />
∗compared with PD group, P
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
of the breast, diagnosed between 2000 to 2009 that had undergone<br />
treatment in the National <strong>Cancer</strong> Institute of Brazil.<br />
OBJECTIVES<br />
Analyze overall survival and the main prognostic factors among<br />
women with infiltrating lobular carcinoma of the breast, diagnosed<br />
from 2000 to 2009 that had undergone treatment in the National<br />
<strong>Cancer</strong> Institute of Brazil.<br />
MATERIALS AND METHODS<br />
The survival curves were obtained in a hospital cohort of 843 patients<br />
with infiltrating lobular carcinoma of the breast diagnosed and treated<br />
between 2000 to 2009. The study variables were: age, race, tobacco,<br />
alcohol consumption , tumor-related variables, and treatment-related<br />
variables. Survival functions were calculated by the Kaplan-Meier<br />
method.<br />
RESULTS<br />
The mean follow up time was 64,27 months (sd 33,76), with 30,2% of<br />
deaths occurred in the period where the mean patients age was 58,58<br />
years (sd 13,22). The overall survival (OS) was 105,61 months (95%<br />
CI, 101,68 to 109,54). The OS for patients with 4 or more positives<br />
axillary lymph nodes was 91,66 months (95% CI, 83,19 to 100,13;<br />
p
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
RESULTS: 47 PR and 89 HR girls have completed surveys. Age did<br />
not differ between groups (Mage=15.6; SD=2.4). 30% of HR girls<br />
have a mother with BC. 67% of HR girls vs. 30% of PR girls reported<br />
self-perceived risk for adult BC to be “higher than other girls my<br />
age,” (p=
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P6-08-03<br />
Informational needs and psychosocial assessment of patients in<br />
their first year after metastatic breast cancer diagnosis<br />
Seah DS, Lin NU, Curley C, Winer E, Partridge A. Dana-Farber<br />
<strong>Cancer</strong> Institution, Boston, MA<br />
Background:<br />
Psychosocial distress is common after a diagnosis of breast cancer.<br />
Little is known about the informational needs and the psychosocial<br />
adjustment of patients diagnosed with metastatic breast cancer (MBC)<br />
within the first year of their diagnosis.<br />
Methods:<br />
Patients with MBC from a single academic institution completed a<br />
cross-sectional self-administered paper survey. The survey included<br />
demographics, the Medical Outcomes Study Short Form-36 (SF-36),<br />
the Hospital Anxiety and Depression Scale (HADS), and Toronto<br />
Informational Needs Questionnaire-<strong>Breast</strong> <strong>Cancer</strong> (TINQ). Medical<br />
history was obtained by chart review. The Spearman correlation<br />
coefficient assessed the relationship between TINQ and the following:<br />
age at MBC diagnosis, disease free interval (DFI), time between<br />
survey completion and MBC diagnosis, number of lines of therapy,<br />
and HADS.<br />
Results:<br />
Fifty-two (90%, 50F 2M) patients completed the survey. Median<br />
age at MBC diagnosis was 52 yrs (range 22-81). Thirty-nine (75%)<br />
patients had completed college, 92% were Caucasian. Median time<br />
between MBC diagnosis and survey completion was 6 months (range<br />
1-12). Sixteen (31%) patients had de novo stage 4 disease. At time of<br />
survey completion, 36 (69%) patients were on 1st line therapy with<br />
some patients were receiving their 4th line of therapy. SF-36 scores<br />
were lower in all 8 subscales compared to the general population.<br />
In particular, role limitations due to physical health (Norm-based<br />
transformation mean score 39.3, SD=12.1), social functioning (Mean<br />
41.8, SD=12.7), role limitations due to emotional problems (Mean<br />
43.3, SD=13.3), vitality (Mean 44.1, SD=10.8) and general health<br />
(Mean 44.3, SD=12.1) were diminished. The Physical and Mental<br />
Component Summary norm-based transformation scores were 43.2<br />
(SD=11.7) and 45.4 (SD=11.3) respectively.9/48 (19%) patients<br />
met criteria for anxiety, and 4/48 (8%) patients met criteria for<br />
depression by HADS criteria (scores > 11). TINQ scores range from<br />
51 to 255, with 35/52 (69%) having a total score > 200, suggesting<br />
high informational need. Of the 5 subscales, treatment information<br />
was most important, followed by information about disease, physical<br />
care, psychosocial needs and investigative tests. The most important<br />
informational issues for patients were: if there was cancer anywhere<br />
else in their body (Mean score 4.78), how to deal with side effects<br />
(Score 4.78), and if there were ways to prevent treatment side effects<br />
(Score 4.77), with a score of 5=extremely important, and 1= not<br />
important.<br />
Only DFI correlated with TINQ (Spearman coefficient -0.413,<br />
P=0.011), with patients who had a shorter DFI having greater<br />
informational needs. Age at MBC diagnosis, time of completion of<br />
survey, number of lines and HADS were not significant.<br />
Conclusion:<br />
Based on this study, patients with recently diagnosed MBC have<br />
high informational needs and poor psychosocial adjustment. The<br />
overall quality of life appears to be worse in this population of<br />
patients compared to the general population. There is also a subset<br />
of patients who are dealing with significant anxiety and depression.<br />
Additional research, education, and supportive care services aimed at<br />
meeting the informational and psychosocial needs of women living<br />
with MBC are warranted.<br />
P6-08-04<br />
The Impact of a <strong>Breast</strong> <strong>Cancer</strong> Diagnosis in Young Women on<br />
their Relationship with their Mothers<br />
Ali A, Fergus K, Wright F, Pritchard K, Kiss A, Warner E. Sunnybrook<br />
Health Sciences Centre, Odette <strong>Cancer</strong> Centre, University of Toronto,<br />
Toronto<br />
Background: <strong>Breast</strong> cancer in younger women (≤ 40) is associated<br />
with greater physical and psychological morbidity than in older<br />
women. No study to our knowledge has examined the effect of a<br />
breast cancer diagnosis in young women on their relationship with<br />
their mothers, or the support needs of these mothers. Methods: We<br />
developed and pre-tested a self-administered questionnaire on 10<br />
survivors of breast cancer diagnosed ≤ age 40 for clarity, content<br />
and sensitivity (<strong>San</strong> <strong>Antonio</strong>, 2011). Then, consecutive recurrencefree<br />
women age ≤ 40 at diagnosis, within 4 years of a breast cancer<br />
diagnosis, whose mothers were alive at diagnosis, were asked to<br />
complete the modified questionnaire in a medical oncology follow-up<br />
clinic. Results: Of 110 eligible daughters approached from 07/2011<br />
– 05/2012, 90 with a mean age 36 (range 21-43) participated in the<br />
study. Stage at diagnosis: 1- 23 (26%), 2- 46 (51%) 3- 21 (23%).<br />
Ethnicity: Asian: 29 (32%), Caucasian 43 (48%), Black 2 (2%), Mix/<br />
Other 16 (18%). At diagnosis, 15 were living with their mothers, 44<br />
were not living in the same city including 23 who were in different<br />
countries, 7 of whom were not informed of the diagnosis as the<br />
daughters did not want to worry them. Mean age of the 88 mothers<br />
alive at time of study was 64 (range 48-84) and 16 had previously<br />
had breast cancer. Illness attributions: Eight blamed their mothers<br />
for their developing breast cancer, and 22 believed their mothers<br />
felt responsible to some extent (overlap in 4). Supports: Of the 43<br />
daughters who had turned to their mothers for emotional support<br />
over the year prior to diagnosis, all but one did so after diagnosis,<br />
as did 20% of those who had not turned to mothers over the year<br />
prior to diagnosis. In 11 cases, the daughters turned to their mothers<br />
before approaching anyone else for support. Of the 83 daughters<br />
who informed mothers of their diagnosis, 76 (92%) reported their<br />
mothers were emotionally and/or practically supportive. The 4 most<br />
difficult issues faced by daughters were fatigue, anxiety, breast loss<br />
and menopausal symptoms, with 70 daughters discussing at least<br />
some issues with their mothers. Of the 35 working mothers, 27 took<br />
time off to support their daughters. Nineteen mothers slept over or<br />
moved in with the daughters during their treatment, 8 of whom had<br />
been living in a different country. Forty-four (44/83=53%) daughters<br />
reported that the breast cancer diagnosis had a favorable impact on<br />
their relationship with their mothers. Formal supports for mothers:<br />
Thirty-two (32/83=39%) reported their mothers did not have adequate<br />
psychosocial support, and 59 (59/90=66%) indicated health care<br />
professionals could help mothers by providing brochures on caring<br />
for a daughter with breast cancer, having professionally led education<br />
sessions, as well as support groups. Conclusion: Mothers are an<br />
important source of support for young breast cancer daughters, and<br />
most daughters perceived that the diagnosis resulted in the motherdaughter<br />
relationship becoming closer. However, the physical and<br />
emotional toll on mothers appears to be high. Future studies should<br />
address the effects of a breast cancer diagnosis in a young daughter<br />
from the mothers’ perspective, and the benefit of formal, culturally<br />
sensitive supports for these mothers.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
534s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
P6-08-05<br />
Changes in Cognitive Function in Older Women With <strong>Breast</strong><br />
<strong>Cancer</strong> Treated with Standard Chemotherapy and Capecitabine<br />
within CALGB 49907<br />
Freedman RA, Pitcher B, Keating NL, Barry WT, Ballman KV,<br />
Kornblith A, Mandelblatt J, Kimmick GG, Hurria A, Winer EP, Hudis<br />
CA, Cohen HJ, Muss HB. Dana-Farber <strong>Cancer</strong> Institute, Boston, MA;<br />
Duke University Medical Center, Durham, NC; Harvard Medical<br />
School, Boston, MA; Mayo Clinic, Rochester, MN; Georgetown<br />
University, Washington, DC; City of Hope, Duarte, CA; Memorial<br />
Sloan-Kettering, New York, NY; University of North Carolina, Chapel<br />
Hill, NC<br />
Background<br />
Cognitive changes for older women who receive chemotherapy are<br />
poorly understood.<br />
Methods<br />
<strong>Cancer</strong> and Leukemia Group B (CALGB) 49907 enrolled 633 women<br />
≥65 years with early stage breast cancer and randomized them to<br />
standard adjuvant chemotherapy (AC or CMF) or capecitabine (N<br />
Eng J Med 360:2055, 2009). Patients enrolled on the Quality of Life<br />
companion study (N = 350) included women who had cognitive<br />
and psychological functioning sufficient for providing informed<br />
consent and participation in the trial (J Clin Oncol 29:1022, 2011).<br />
Participants completed an 18 item questionnaire focusing on their<br />
subjective report of cognitive function (attention, problem-solving,<br />
speed, new learning, and remote memory) at 6 time points (baseline,<br />
mid-treatment, within 1 month post treatment, and at 12, 18, and 24<br />
months post treatment). Possible scores for each item ranged from 1-7<br />
(‘above average’ - ‘severe problem’). Cognitive function score (CFS)<br />
was defined as the mean score of items 1-18. Cognitive impairment<br />
was defined as CFS 1.5 standard deviations above the overall average<br />
baseline. Univariate associations were tested between baseline CFS<br />
and patient characteristics (treatment, race, education, number of<br />
positive nodes, hormone receptor status, HER2 status, performance<br />
status, number of comorbidities, fatigue and depression) using<br />
Kruskal-Wallis testing. Frequency distributions were used to describe<br />
cognitive impairment. Multivariate analyses were not completed<br />
because few women reported subjective cognitive impairment during<br />
the study period.<br />
Results<br />
297 assessments were received at baseline, 280 at both mid-treatment<br />
and within 1 month post-treatment, 259 at 12 months, 245 at 18<br />
months and 240 at 24 months post-treatment. The median age was 72<br />
(65-85); 32% received AC, 21% CMF, and 47% capecitabine. Most<br />
women were white (87%) and had a performance status of 0 (73%).<br />
Approximately half of women had a high school degree or less and<br />
the majority had stage I-II (78%), hormone-receptor positive (68%)<br />
cancers and most did not experience depression or fatigue at baseline.<br />
At baseline, the overall mean CFS was 2.1 (‘normal ability’) and 19<br />
women (6%) had mild to severe impairment. Baseline scores did not<br />
differ by treatment (p=0.35). Worse cognitive function at baseline<br />
was associated with less education (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P6-08-07<br />
Quality of life of women with breast cancer: A Middle East<br />
perspective<br />
Jassim GA, Whitford DL. Royal College of Surgeons in Ireland-<br />
Medical University of Bahrain, Busaiteen, Bahrain<br />
Background: <strong>Breast</strong> cancer is the most common cancer among<br />
women worldwide. Scarce information is currently available on the<br />
quality of life (QoL) of breast cancer survivors in the Middle East<br />
region. The objective of this study is to describe QoL of Bahraini<br />
women with breast cancer and investigate the association between<br />
their QoL and their sociodemographic and clinical data.<br />
Methods: This is a cross sectional study in which the Arabic version<br />
of the European Organization for Research and Treatment of <strong>Cancer</strong><br />
general quality of life questionnaire (QLQ-C30) and the disease<br />
specific questionnaire (QLQ-BR23) were administered to a random<br />
sample of 337 Bahraini women with breast cancer.<br />
Statistical analysis: The collected data were coded, entered and<br />
analyzed using the statistical package SPSS. Relevant descriptive<br />
statistics were computed for all items. A higher score represents a<br />
“better” level of functioning, or a “worse” level of symptoms. The<br />
“Score” served as the dependent (Outcome) variable in the study<br />
for the purpose of data analysis. Sociodemographics and clinical<br />
information represented the independent variables. The equality of<br />
means across categories of each categorical independent variable<br />
was tested using ANOVA and independent t-test. Non-parametric<br />
tests (Kruskal Wallis and Mann Whitney tests) were used instead if<br />
the statistical assumptions of using the parametric tests were violated.<br />
Results: Of the total sample only 239 consented to participation. The<br />
mean age of participants was 54.4 (SD±10.7). Participants had a mean<br />
score for global health of 63.9 (SD±21.3). Among functional scales,<br />
social functioning scored the highest mean (77.5) whereas emotional<br />
functioning scored the lowest (63.4). The most distressing symptom<br />
on the symptom scales of QLQ-C30 was fatigability (Mean 35.2).<br />
Using the disease specific tool (QLQ-BR23) it was found that sexual<br />
functioning scored the lowest mean (25.9) whereas “upset due to hair<br />
loss” symptom scored the highest mean (46.3). Significant mean<br />
differences for various functional and symptom scales were observed<br />
among categories of age, marital status, type of surgery, stage of<br />
disease, monthly income, educational status and time since diagnosis.<br />
Discussion: Comparable global QoL mean was reported by<br />
participants in this study despite the limited structured psychological<br />
support available for breast cancer Bahraini women compared to<br />
advanced services in the western community. Women showed poor<br />
performance on sexual functioning and enjoyment. One of the reasons<br />
might be that single women were under less pressure to worry about<br />
their partner’s opinion because traditionally and religiously the local<br />
society is restricting dating and premarital sex. On the other hand,<br />
married women were constantly intimidated by the second wife’s<br />
option.<br />
Conclusion: Bahraini women showed good functioning on most<br />
functional and symptom scales. Poorest functioning was reported for<br />
emotional and sexual domains. On the symptom scales, fatigue and<br />
arm morbidities were the most bothersome symptoms. Differences<br />
in several QoL domains are discussed in view of sociocultural and<br />
religious aspects. Health professionals need to develop a culturally<br />
sensitive clinical approach to enhance QoL of women with breast<br />
cancer in the Middle East region.<br />
P6-08-08<br />
Three months of adjuvant hormone therapy does not increase<br />
fatigue or cognitive failure: results of a prospective early stage<br />
breast cancer trial.<br />
Kennedy D, Lower EE. Oncology Hematology Consultants,<br />
Cincinnati, OH<br />
INTRODUCTION: The diagnosis and treatment of breast cancer<br />
may alter a patient’s mental and physical quality of life. Fatigue<br />
and impaired cognition have been reported after chemotherapy and<br />
hormone therapy. The purpose of this study was to prospectively<br />
determine the incidence of fatigue and cognitive changes in early<br />
stage breast cancer patients during adjuvant hormone therapy and<br />
to evaluate the relationship of dysfunction with other risk factors.<br />
METHODS: Fifty-four consecutive patients of a single medical<br />
oncologist with newly diagnosed hormone dependent breast cancer<br />
prescribed adjuvant hormone therapy enrolled in this prospective<br />
study. Data collected included age, race, menopausal status, breast<br />
cancer stage, body mass index, Functional Assessment of Chronic<br />
Illness Therapy-Fatigue (FACIT)-F, Fatigue Assessment Scale (FAS),<br />
short form 36 (SF-36), cognitive failure questionnaire (CFQ), Beck<br />
depression inventory (BDI-2) , Epworth sleepiness scale, and facial<br />
recognition (FR) and sheep dash time (SDT) to assess executive<br />
functioning. All tests were administered by one nurse prior to hormone<br />
initiation (0 mo) and after 3 months (3 mo) of therapy. Statistical<br />
analysis was performed using Student t test for paired data with a p<br />
value of
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
P6-08-09<br />
Overcoming <strong>Breast</strong> <strong>Cancer</strong>: The Importance of Connecting with<br />
Fellow Survivors<br />
Geoghegan C, Whitman B. Y-ME National <strong>Breast</strong> <strong>Cancer</strong><br />
Organization, Chicago, IL; Whitman Insight Strategies, New York, NY<br />
Y-ME National <strong>Breast</strong> <strong>Cancer</strong>’s Organization, founded in 1978,<br />
is not-for-profit organization with a mission to “To assure through<br />
information, empowerment, and peer support, that no one faces breast<br />
cancer alone.” Each year, Y-ME’s 24x7x365 <strong>Breast</strong> <strong>Cancer</strong> Hotline<br />
receives approximately 40,000 contacts. Callers to Y-ME’s toll-free<br />
Hotline are referred by clinicians, community groups and global<br />
cancer organizations that recognize the importance of providing<br />
emotional relief to patients and their loved ones. Trained and certified<br />
peer counselors, all breast cancer survivors, staff the hotline. Callers<br />
can speak to a Spanish or English speaking peer counselor or have an<br />
interpreter in any of over 150 languages added to the line.<br />
An online survey conducted by Whitman Insight Strategies on behalf<br />
of the Y-ME National <strong>Breast</strong> <strong>Cancer</strong> Organization was conducted to<br />
better understand the psychosocial needs of breast cancer patients and<br />
survivors. Surveys were conducted on April 3-5, 2012, among 400<br />
breast cancer patients and survivors 18 years of age and older across<br />
the United States. The margin of error for total sample is ±4.9% at<br />
the 95% confidence interval. Respondents received an email invite<br />
to participate in a short online survey; their emails were selected at<br />
random among online market research panelists who had previously<br />
indicated that they have or had breast cancer.<br />
The results indicate that talking to a breast cancer survivor can be<br />
instrumental in overcoming breast cancer: 84% of breast cancer<br />
patients and survivors say this is one of the most important ways<br />
of coping with breast cancer and 68% wish that they could have<br />
been connected to other survivors. Access to a 24x7x365 hotline,<br />
where breast cancer survivors provide emotional support and<br />
practical advice, is considered important by virtually all women<br />
surveyed (95%)--73% think this is “extremely” or “very” important.<br />
Unfortunately, although Y-ME provides such a hotline; however,<br />
awareness of it is extremely low (14%). We encourage all healthcare<br />
providers to encourage patients to reach our to Y-ME by calling 800-<br />
221-2141 and time of the day or night.<br />
Those who had another survivor to talk were asked to select among<br />
a number of relevant responses to the question: What did talking<br />
to another breast cancer patient/survivor provide you with? The<br />
following table provides the proportion that selected each response.<br />
Proportion Selecting Each Response<br />
Response<br />
% of Responders<br />
A feeling that I was not alone 70%<br />
A better idea of what to expect 61%<br />
Emotional support 60%<br />
Hope 53%<br />
Optimism 44%<br />
Better understanding of what diagnosis means 41%<br />
Peace of mind 38%<br />
Questions to ask doctor/healthcare provider 37%<br />
Someone I could count on 34%<br />
Needed information about how to cope 32%<br />
Help for my family 17%<br />
P6-08-10<br />
<strong>Cancer</strong> as self: a novel assessment of patient identity as it relates<br />
to a cancer diagnosis<br />
Horst KC, Fero KE, Haimovitz K, Dweck CS. Stanford University,<br />
Stanford, CA<br />
Introduction:<br />
Previous studies have demonstrated that an individual’s attitude<br />
towards self may impact how one faces challenges. Those who view<br />
themselves as malleable (growth mindset) approach challenges and<br />
problems as a learning opportunity and an opportunity to improve<br />
and change. In contrast, those who are more fixed in their approach<br />
(fixed mindset) have difficulty with challenges or setbacks. In the<br />
present study, we applied this conceptual framework to a cohort of<br />
breast cancer patients to evaluate their attitudes towards the cancer<br />
diagnosis. The goal of this study is to test the internal validity of<br />
this questionnaire and to correlate its findings with patient-reported<br />
measures of depression, anxiety and insomnia.<br />
Methods:<br />
Twenty consecutive breast cancer patients undergoing radiation<br />
therapy completed an electronic survey consisting of 4 scales: the<br />
Hospital Anxiety and Depression Scale (HADS; 14 items), the<br />
Insomnia Severity Index (ISI; 7 items), a validated psychological<br />
questionnaire assessing fixed versus growth mindset (8 items), and<br />
an experimental questionnaire evaluating whether the patient views<br />
their disease as self-defining. Demographic and clinical variables<br />
were also collected. A principal components factor (PCF) analysis<br />
was used to examine the internal structure of the new questionnaire.<br />
Hierarchical linear regression analyses were performed to assess its<br />
relationship to other variables.<br />
Results:<br />
Twenty patients completed the survey during the first week of<br />
radiotherapy. Median age was 57 (range, 31-81). Five patients (25%)<br />
had Stage 0 disease, 9 (45%) Stage I, 0 (0%) Stage II, 5 (25%) Stage<br />
III, and 1 (5%) Stage IV. Seven patients (35%) received chemotherapy<br />
while 13 (65%) did not. Eleven patients (55%) had significant others<br />
while undergoing treatment and 9 (45%) were single. The PCF<br />
analysis confirmed that the items of the experimental questionnaire<br />
were internally consistent (α = .88), such that all were retained in<br />
the final scale for subsequent analyses. The extent to which patients<br />
saw cancer as self defining was statistically significantly associated<br />
with their reported levels of depression (r = .60, p < .005) and<br />
anxiety (r = .60, p < .005). There was a similar trend with reported<br />
levels of insomnia which was not statistically significant (p=0.2).<br />
Of the demographic and clinical variables, only stage of cancer was<br />
associated with depression and anxiety.<br />
Conclusions:<br />
Patients undergoing treatment for breast cancer who view the cancer<br />
diagnosis as self-defining are more likely to self-report depression,<br />
anxiety, and insomnia. In this cohort, the experimental questionnaire<br />
demonstrated strong internal validity. An intervention that alters<br />
patients’ perception of identity as it relates to the cancer diagnosis<br />
could be a promising compliment to the standard treatment of<br />
depression, anxiety, and insomnia.<br />
P6-09-01<br />
Investigating the effectiveness of a psycho-educational behavioral<br />
intervention for cancer-related cognitive dysfunction in women<br />
with breast and gynecological cancer: Knowledge, self-efficacy,<br />
and behavioral change.<br />
Bernstein LJ, Dissanayake D, Tirona KM, Nyhof-Young JM, Catton<br />
PA. Princess Margaret Hospital, Toronto, ON, Canada; University<br />
of Toronto, ON, Canada<br />
Background: Approximately one third of individuals receiving<br />
chemotherapy for breast cancer experience cancer-related cognitive<br />
dysfunction (CRCD). CRCD significantly impacts quality of life,<br />
employment, and social relationships, and can hinder ability to<br />
return to pre-cancer activities. The cause is likely multi-factorial,<br />
and currently no medical treatment exists. The <strong>Cancer</strong> Survivorship<br />
Program at Princess Margaret Hospital provides a behavioralintervention<br />
for patients with CRCD. The single, one-on-one, hour<br />
www.aacrjournals.org 537s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
long session provides information and compensatory strategies to<br />
improve knowledge, self-management skills, and decrease the impact<br />
of cognitive dysfunction on daily life.<br />
Methods: A mixed-method study assessed patient perceptions.<br />
Eligible women had been or were currently being treated for a<br />
diagnosis of breast or gynecological cancer and were English<br />
speakers. Likert-scale based questionnaires were administered<br />
immediately before, immediately after, and 6 weeks post-intervention.<br />
Six parameters were evaluated quantitatively: i) program delivery, ii)<br />
perception of knowledge, iii) distress, iv) self-efficacy, v) behavior<br />
change, and vi) behavioral change effectiveness. Ten individuals also<br />
participated in qualitative, semi-structured audio-recorded interviews<br />
1-6 weeks post questionnaire completion. Responses were analyzed<br />
using the constant comparative method.<br />
Results: 72 female cancer survivors (61 breast; 11 gynecological;<br />
mean age 51.3) completed questionnaires. Immediately postintervention,<br />
patients reported significant increases in perception of<br />
knowledge, self-efficacy, and decreases in CRCD-related distress, and<br />
these improvements were maintained at 6 week follow up (p < .01 in<br />
all cases). Participants reported numerous benefits associated with<br />
increased knowledge, including a sense of validation and reassurance,<br />
and increased confidence and success in managing their symptoms.<br />
No statistically significant differences in intervention effectiveness<br />
were observed as a function of patient age (older or younger than<br />
50), education (greater or less than grade 12), or employment status<br />
(skilled worker or higher vs lower). However, individuals of low<br />
employment status were less satisfied with the volume of information<br />
in the intervention. Interviews indicated their preference for an<br />
additional session to reinforce the techniques discussed. Thematic<br />
analysis also indicated that adoption of new compensatory strategies<br />
was associated with a sense of control, confidence and pride for all<br />
patients; although barriers were identified for some that prevented<br />
long-term use (e.g. techniques take time and effort). Employment<br />
distress was mainly tied to difficulties with work tasks.<br />
Conclusions: A one-hour, psycho-educational behavioral intervention<br />
can be effective for breast and gynecological cancer patients suffering<br />
from CRCD. Benefits can last at least 6 weeks. Results suggest a need<br />
for better intervention integration with oncology appointments, a<br />
follow-up session to help individuals assimilate CRCD information,<br />
and increased session personalization to address individual difficulties<br />
and job concerns.<br />
P6-09-02<br />
Pre-treatment cognitive function (CF) in women with locally<br />
advanced breast cancer (LABC) and in healthy controls.<br />
Bernstein LJ, Seruga B, Pond G, Tirona KM, Dodd A, Tannock<br />
IF. Princess Margaret Hospital, Toronto, ON, Canada; University<br />
of Toronto; Institute of Oncology Ljubljana, Slovenia; McMaster<br />
University, Hamilton, ON, Canada<br />
Background: Several studies have reported that women with breast<br />
cancer may have cognitive dysfunction prior to chemotherapy<br />
(ChT), and that cognitive dysfunction may be related to the cancer<br />
itself or to the psychological impact of a cancer diagnosis. Previous<br />
studies assessing CF in breast cancer patients pre-ChT have done<br />
so after surgery. Women with LABC receive ChT prior to surgery,<br />
and therefore provide a unique opportunity to assess CF without the<br />
confounding factor of surgery. This study reports CF in women with<br />
newly diagnosed LABC compared to healthy controls.<br />
Methods: Baseline information including participant demographics,<br />
smoking/alcohol history, co-morbidities, and medications were<br />
collected. Women with LABC underwent a 2-hour battery of CF tests<br />
prior to neoadjuvant ChT. Six cognitive domains using standardized,<br />
validated, and reliable neuropsychological tests were assessed: verbal,<br />
visual-spatial, memory, attention, processing speed, and executive<br />
function. Performance on each test was transformed to z-scores<br />
using normative data (average range z-score = -1 to 1). Participants<br />
also completed self-report questionnaires for CF (FACT-COG3<br />
and PAOFI), fatigue (FACIT-F subscale) and affect (HADS). Data<br />
obtained were compared to those for age-matched healthy women<br />
who were administered the same battery of tests and measures.<br />
Results: Forty-seven women with LABC and 22 controls were<br />
assessed. All women completed the CF tests and questionnaires<br />
within 2 hours. There were no significant differences between patients<br />
and controls in age (pts median age=49; controls=48), education<br />
(median years in school=16 for both), smoking or alcohol history,<br />
co-morbidities, mood disorders (anxiety, depression), previous history<br />
of concussion, or current medication for mood or sleep problems.<br />
Objective CF testing demonstrated no significant difference in the<br />
mean performance of women with LABC vs that of controls in any<br />
objective domain, nor were there statistically significant differences<br />
in the frequency of deficits (e.g., 96% of pts had < 2 deficits; 86%<br />
of controls had < 2 deficits). Women with LABC did not report<br />
worse CF, fatigue, or depressive symptoms compared to controls.<br />
Anxiety was the only self-reported measure where patients had more<br />
symptoms (mean HADS 7.6 vs 5.4, p < .036). Consistent with the<br />
literature, only weak to no association was observed between any<br />
of the objective measures of CF and the self-reported measures.<br />
Multivariate regression analyses found for both patients and controls,<br />
low education level (≤12 years), smoking history (≥10 pack year),<br />
alcohol intake (≥10 drinks/week), and currently taking medication<br />
for anxiety, depression, or sleep to be associated with poorer CF as<br />
measured on at least one objective domain.<br />
Conclusion: When assessed prior to ChT and surgery, no significant<br />
difference in objectively assessed or self-reported CF was observed<br />
between women with LABC and healthy controls. The effects of<br />
cancer treatment will be evaluated as part of a longitudinal study.<br />
P6-09-03<br />
Fatigue after breast cancer may be related to conditions other<br />
than the cancer. The impact of comorbidity is essential.<br />
Reidunsdatter RJ, Hjermstad M, Oldervoll L, Lundgren S. HiST/<br />
NTNU, Trondheim, Norway; HIST, Trondheim, Norway; NTNU,<br />
Trondheim, Norway; Oslo University Hospital, Oslo, Norway;<br />
Røros Rehabilitation, Røros, Norway; St. Olav University Hospital,<br />
Trondheim, Norway<br />
Purpose: Fatigue after treatment for breast cancer is common, but is<br />
also prevalent in people with chronic diseases such as heart failure,<br />
diabetes, and depression etc. The primary objective was to compare<br />
the level of fatigue between BC patients one year after end of<br />
treatment with data from a representative survey of the Norwegian<br />
population (GenPop). Secondary aim was to explore the association<br />
between chronic conditions and fatigue and in both samples.<br />
Design and Method: 245 patients treated with chemo –and/or<br />
radiotherapy after surgery, were assessed one year after treatment.<br />
Comorbidity was recorded by clinical examinations in patients and<br />
by self-report in the GenPop (N=652). Fatigue was measured by the<br />
3-item subscale of the EORTC QLQ-C30, with higher scores on the<br />
0-100 scale implying more fatigue. Analysis of covariance was applied<br />
to compare age-adjusted mean scores between groups.<br />
Results: Mean age was 58 (9) years in patients and 52 (14) years<br />
in GenPop. 23% of patients and 32% of GenPop had one or more<br />
of the following conditions; cardiovascular- or pulmonary disease,<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
538s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
diabetes or depression. No significant differences were found in<br />
fatigue between BC patients and GenPop (mean score 26.7 vs.<br />
29.7). Comorbidity was the greatest determinant of increased<br />
fatigue, regardless of BC treatment. Patients with comorbidity were<br />
significantly more fatigued than those without comorbidity (mean<br />
difference 10.4), as found in the GenPop (mean difference 13.3).<br />
Conclusion: Similar fatigue levels in BC patients and GenPop one<br />
year after treatment is promising, but longer follow-up is needed.<br />
Comorbidity conditions should always be assessed when evaluating<br />
fatigue and other patient related outcomes. Prevention or treatment<br />
of common chronic conditions might be considered in rehabilitation<br />
programs to reduce fatigue in cancer survivors.<br />
P6-09-04<br />
The Association of Low Level Arm Volume Increases with<br />
Lymphedema Symptoms Following Treatment for <strong>Breast</strong> <strong>Cancer</strong><br />
Skolny MN, Miller CL, Shenouda M, Jammallo LS, O’Toole J,<br />
Niemierko A, Taghian AG. Massachusetts General Hospital, Boston,<br />
MA<br />
Purpose/Objective: The symptoms associated with breast cancerrelated<br />
lymphedema are well-documented, and include sensations<br />
of heaviness, swelling, and tightness in the upper extremity and<br />
trunk. However, the clinical significance of low-level arm volume<br />
changes frequently experienced by breast cancer patients is not well<br />
understood. We sought to determine the association of low level arm<br />
volume changes with patient-reported lymphedema symptoms in<br />
women treated for breast cancer.<br />
Methods: 267 patients who underwent surgical treatment for breast<br />
cancer from 2010- 2012 were identified from a cohort of patients<br />
prospectively screened for lymphedema at our institution. Patients<br />
were assessed with perometer arm volume measurements and a<br />
survey of lymphedema symptoms pre and post operatively, and at<br />
3-7 month intervals thereafter. Inclusion in this analysis was limited<br />
to unilaterally affected women with ≥ 3 assessments and ≥ 6 months<br />
of post-surgical follow-up. Arm volume changes were quantified as<br />
Relative Volume Change (RVC): RVC= (A2*U1)/ (U2*A1) - 1, where<br />
A1 is pre-operative arm volume and A2 is post-operative arm volume<br />
on the affected side, and U1 and U2 are arm volumes on the unaffected<br />
side at these time points. Low level arm volume change was defined as<br />
a measurement with RVC ≥ 5% -
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P6-09-06<br />
Family Members’ Burden in Patients with Metastatic and Early<br />
Stage <strong>Breast</strong> <strong>Cancer</strong><br />
Wan Y, Gao X, Mehta S, Zhang Z, Faria C, Schwartzberg L. Pharmerit<br />
North America; Eisai, Inc.; The West Clinic<br />
BACKROUND: No previous studies have assessed the indirect<br />
costs attributable to family members of patients with metastatic<br />
breast cancer (MBC). This retrospective database study compared<br />
productivity loss and cost associated with family members of patients<br />
with MBC vs. early-stage breast cancer (EBC).<br />
METHODS: The Thomson Reuters MarketScan Health and<br />
Productivity Management (HPM) data (2005-2009) were used. MBC<br />
and EBC patients with no other tumors and 12-month continuous<br />
enrollment in medical insurance after the index diagnosis date were<br />
identified. Adult working family members of these MBC/EBC patients<br />
were identified based on their enrollee ID numbers since the enrollees<br />
from the same family were assigned the same ID except for the last<br />
two digits. The patients’ working family members who were eligible<br />
for absenteeism and did not have any cancer diagnosis were included<br />
and used as a proxy for “caregivers”. The reasons for absenteeism<br />
included sickness, personal leave, disability, recreation, Family and<br />
Medical Leave Act (FMLA) and others. The productivity loss was<br />
measured as the leave days taken under FMLA or personal leave by<br />
the family members during a 12-month follow-up period. Associated<br />
indirect costs were estimated by multiplying leave days with daily<br />
wages obtained from the 2011 Bureau of Labor Statistics. Descriptive<br />
analyses and a generalized linear model with log link and gamma<br />
distribution were conducted.<br />
RESULTS: A total of 209 MBC/1,166 EBC patients’ family members<br />
were eligible for absenteeism, with a mean age of 50/51 years. 1,373<br />
out of the 1,375 family members were male. Majority of the family<br />
members (52%) worked in manufacturing industry, followed by<br />
transportation/communication/utilities (28%) and oil gas extraction/<br />
mining industry (15%). 52% of the family members had PPO health<br />
insurance. Family members of MBC and EBC patients had similar<br />
clinical and demographic characteristics. Similar proportions of<br />
MBC and EBC patients’ family members had overall and individual<br />
type of absenteeism. However, MBC patients’ family members had<br />
more FMLA/personal leave days and higher costs vs. EBC patients<br />
(overall mean: 2.8±6.1 vs. 2.1±4.8; $2,366±5,095 vs. $1,741±3,995,<br />
both p=.047). Among those who had non-zero FMLA/personal<br />
leave days (MBC vs. BC: N=92/44% vs. 502/43%), mean FMLA/<br />
personal leave days and costs were 6.4±7.8 vs. 4.8±6.3; $5,375±6,556<br />
vs. $4,043±5,272 respectively, both p=.033. After adjusting for<br />
covariates, MBC patients’ family members incurred 40% (p=.06)<br />
more absenteeism-related costs due to FMLA/personal leave vs.<br />
EBC patients’ family members. Additionally, occupation in oil/gas<br />
extraction/mining (vs. manufacturing non-durable goods industry,<br />
p
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
P6-09-08<br />
COMPliance and Arthralgia in Clinical Therapy: The COMPACT<br />
trial, assessing the incidence of arthralgia, therapy costs and<br />
compliance within the first year of adjuvant anastrozole therapy<br />
Harbeck N, Blettner M, Bolten WW, Hindenburg H-J, Jackisch<br />
C, Klein P, König K, Kreienberg R, Rief W, Wallwiener D, Zaun<br />
S, Hadji P. University of Munich, Germany; University of Mainz,<br />
Germany; Klaus-Miehlke-Hospital for Rheumatology, Wiesbaden,<br />
Germany; Head of BNGO e.V., Germany; Hospital for Gynecology<br />
and Obstetrics, Offenbach, Germany; d.s.h. Statistical Services,<br />
Rohrbach, Germany; Gynecological Society Germany e.V., Germany;<br />
University Women’s Hospital, Ulm, Germany; Outpatient Clinic for<br />
Psychotherapy, Philipps-University, Marburg, Germany; University<br />
Women’s Hospital, Tübingen, Germany; AstraZeneca GmbH, Wedel,<br />
Germany; Women’s Hospital Phillips-University, Marburg, Germany<br />
Background: Aromatase Inhibitors (AI) are well established as<br />
adjuvant treatment for postmenopausal (PMP) women with hormone<br />
receptor positive (HR+) early breast cancer (EBC). However, phase<br />
III clinical trials have reported higher rates of arthralgia associated<br />
with AI than tamoxifen. This study aims to collect real world data on<br />
the effects of AI-associated arthralgia on patient compliance, patient<br />
outcomes and on treatment of arthralgia.<br />
Methods: COMPACT is an open, prospective, non-interventional,<br />
non-randomized study (NCT00857012) run in Germany. PMP women<br />
with HR+ EBC who had been on adjuvant anastrozole (ANA) for<br />
3-6 months were enrolled and stratified by initial adjuvant ANA or<br />
switch from tamoxifen. All patients received regular standardized<br />
information about breast cancer from baseline to week 20 to support<br />
treatment compliance. Data on demographics, arthralgia, related<br />
therapies, other side effects and QoL were collected at baseline,<br />
3, 6 and 9 months. Primary endpoints are scaled data on arthralgia<br />
and compliance within the first year of ANA therapy. Secondary<br />
endpoints include incidence of arthralgia, therapy costs, reasons for<br />
non-compliance, and influence of arthralgia on clinical outcome.<br />
Results: Between Apr 2009 and Mar 2011, 2313 patients were<br />
enrolled, 2007 on upfront ANA and 306 on switch from tamoxifen.<br />
The mean age at baseline was 64.5 years, mean BMI 27.7. Only<br />
17.0% of patients had received HRT prior to their EBC. At baseline,<br />
41.9% reported symptoms relating to skeleton or musculature. 12.0%<br />
reported arthralgia existing prior to ANA treatment and 13.2% stated<br />
a worsening of pre-existing arthralgia or new arthralgia after starting<br />
ANA. Predictors for non-adherence to AI therapy were former nonadherence,<br />
general symptom load on the side effect scale GASE,<br />
and low benefit expectation at treatment start. Risk of arthralgia was<br />
related to BMI (lowest for patients with BMI ≤24.1 kg/m², highest<br />
with BMI >30.5 kg/m² at all time points; OR>1) and upfront therapy<br />
(switch patients had a reduced risk of 68% at 6 and 61% at 9 months<br />
compared to patients with ANA upfront, p=0.002). Patients with<br />
prior chemotherapy had lower rates of arthralgia before start of ANA<br />
(10.4% vs 13.3%, p=0.036) but higher rates after the start of ANA and<br />
before study start (27.0% vs 22.5%, p=0.013). Patients with arthralgia<br />
showed higher compliance rates at all time points (p
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P6-09-10<br />
Informational needs among women considering breast<br />
reconstruction post-mastectomy.<br />
Ahmed I, Harvey A, Amsellem M. <strong>Cancer</strong> Support Community,<br />
Washington, DC<br />
For many women, the complexity of processing and learning about<br />
their breast cancer diagnosis is further complicated by decisions to<br />
be made about breast reconstruction post-mastectomy. For women<br />
considering reconstruction post-mastectomy, obtaining information<br />
about reconstruction procedures and outcomes is a process, and<br />
multiple factors may influence the decision-making process. Little is<br />
known about the extent to which patient’s knowledge and expectations<br />
related to breast reconstruction procedures weigh on their decisionmaking<br />
process.<br />
To better understand and meet the needs of women facing<br />
reconstruction, the <strong>Cancer</strong> Support Community surveyed 1,185<br />
women diagnosed with breast cancer. Women answered questions<br />
either: online (n=840) in August, 2010; or via paper and pencil (n=<br />
345) after attending a breast reconstruction workshop held at multiple<br />
sites nationwide in 2011. In addition to demographics, and diagnostic<br />
and treatment history, women reported their decision regarding<br />
reconstruction, experience searching for and receiving information,<br />
and expectations about reconstruction.<br />
Respondents were primarily Caucasian (81.9%), and the mean age at<br />
diagnosis was 48.9. 21.2% of respondents were first diagnosed with<br />
breast cancer in the past year, and 30.0% were diagnosed at least five<br />
years ago. Online respondents were more likely to be Caucasian, less<br />
likely to have been recently (less than one year) diagnosed with breast<br />
cancer, and more likely to have already made a decision regarding<br />
reconstruction, as compared to workshop attendees, but were similar<br />
in all other respects for these analyses.<br />
Most respondents (57.3%) had either undergone or had decided to<br />
undergo breast reconstruction. 18.4% of respondents reported they<br />
decided not to undergo reconstruction, and 8.9% reported they were<br />
not eligible. Additionally, 15.5% of respondents were currently<br />
considering or planning to consider their options for reconstruction<br />
at a later time.<br />
Of the women who were currently considering or planning to consider<br />
breast reconstruction, information-seeking patterns and informational<br />
needs were reported. Aside from their health care team, most women<br />
sought additional information about reconstruction from other women<br />
with breast cancer (40.9%), medical literature (46.0%), patient support<br />
groups (35.6%), friends and family (41.3%), and the Internet (57.2%).<br />
Over one-third of respondents considering reconstruction (34.5%)<br />
would have liked to have had more information about the risks and<br />
benefits of reconstruction at the time of mastectomy versus at a later<br />
time. These women also reported a number of factors influencing their<br />
current point in the decision-making process, including: concerns<br />
about implant safety (83.3%); concerns about additional treatment<br />
and recovery (85.5%); concerns about failed procedures (91.5%); and<br />
confusion about the reconstruction decision-making process (72.2%).<br />
Survey responses suggest women considering breast reconstruction<br />
have a variety of informational needs, some of which are not being<br />
met. Results suggest there is still work to be done with regard to<br />
establishing realistic expectations about the procedures and outcomes,<br />
providing comprehensive information at various stages throughout<br />
the process, and across the various choices.<br />
P6-09-11<br />
Examining patient treatment choices involving efficacy, toxicity,<br />
and cost tradeoffs in the metastatic breast cancer setting<br />
White CB, Smith ML, Abidoye O, Lalla D. Carol B. White &<br />
Associates; Research Advocacy Network; Genentech, Inc.<br />
Background: Most patients with metastatic breast cancer are treated<br />
with chemotherapies and/or targeted therapies. These therapies have<br />
toxicity profiles that vary with agent(s) used. Patient attitudes towards<br />
different adverse events (AE’s) may vary and factor into treatment<br />
decisions. Different patients may have specific feelings about tolerable<br />
and unacceptable AE’s, especially when balanced against possible<br />
treatment benefit. As more agents/combinations become available, it<br />
becomes increasingly important to understand which adverse events<br />
impact treatment decisions. Previous research has shown that conjoint<br />
analysis (CA) is a valid methodology that allows patients to express<br />
preferences and is particularly useful when designed based on specific<br />
treatment profiles (Smith, ASCO 2011; Smith, ASCO 2012).<br />
Methods: The objective of this study was to assess patient<br />
preferences using CA based on profiles of two MBC regimens<br />
(trastuzumab+docetaxel and T-DM1). Patients were presented pairs<br />
of hypothetical treatments (describing benefit, AE’s, and cost) and<br />
asked what their preferred alternative was; a follow-up question asked<br />
if they would take the treatment if it were the only option available.<br />
Five AE’s (alopecia, peripheral neuropathy, diarrhea, fatigue, and<br />
neutropenia) with differing likelihood, severity, and/or duration were<br />
included. There were 3 stages in preparing the CA survey: the first<br />
comprised two online focus groups conducted with patients with<br />
metastatic disease. Stage 2 included the development of the CA<br />
survey using patient language to describe the AE’s and their impact,<br />
as well as images to represent likelihoods, progression-free survival<br />
(PFS), and costs. Stage 3 is initiating and will recruit patients with<br />
the assistance of several breast cancer organizations (target n= 600).<br />
Analysis of response patterns allows study of the influence of each<br />
variable and provides a basis for prediction of treatment choice for<br />
any combination of benefit, AE’s, and cost. Final analysis will be<br />
complete in September 2012.<br />
Results: Findings from the focus groups facilitated an understanding<br />
of PFS, of experience with and impact of the AE’s on decisionmaking,<br />
and of attitudes. In Stage 2, the survey was pretested with<br />
seven patients and took approximately 20 minutes to complete.<br />
Feedback suggested the questions were relevant and realistic.<br />
Suggestions allowed for improvement of the CA explanatory<br />
material, as well as refinement of a few answer choices to questions<br />
outside the CA section of the survey. Final study results will present<br />
the proportion of patients who are predicted to prefer each of two<br />
treatment profiles, the impact of each attribute level on treatment<br />
preference and differing preferences seen in patient subgroups. This<br />
information will provide valuable insight into patient preferences and<br />
inform future development of new therapies. In addition, these results<br />
may generate discussion and consideration of patient preferences in<br />
conversations about patient care and treatment selection.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
542s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
P6-10-01<br />
A randomized phase 2 study of the antibody-drug conjugate<br />
CDX-011 in advanced GPNMB-overexpressing breast cancer:<br />
The EMERGE study<br />
Yardley DA, Weaver R, Melisko ME, Saleh MN, Arena FP, Forero<br />
A, Cigler T, Stopeck A, Citron D, Oliff I, Bechhold R, Loutfi R,<br />
Garcia A, Crowley E, Green J, Yellin MJ, Davis TA, Vahdat LT.<br />
Florida <strong>Cancer</strong> Specialists, Tampa, FL; University of California,<br />
<strong>San</strong> Francisco Helen Diller Family Comprehensive <strong>Cancer</strong> Center,<br />
<strong>San</strong> Francisco, CA; Sarah Cannon Research Institute/Tennessee<br />
Oncology, PLLC, Nashville, TN; Georgia <strong>Cancer</strong> Specialists PC,<br />
<strong>San</strong>dy Springs, GA; Arena Onc Assoc PC, Lake Success, NY; Bium<br />
Inc, Birmingham, AL; Weill Cornell Medical College, New York, NY;<br />
Celldex Therapeutics, Inc., Needham, MA; Arizona <strong>Cancer</strong> Center<br />
at the University of Arizona, Tucson, AZ; <strong>Cancer</strong> Treatment Centers<br />
of America/Midwestern Regional Medical Center, Zion, IL; Orchard<br />
Healthcare Research Inc., Skokie, IL; Oncology Hematology Care,<br />
Cincinnati, OH; Henry Ford Health System, Detroit, MI; USC/Norris<br />
Comprehensive <strong>Cancer</strong> Center, Los Angeles, CA<br />
Background: GPNMB is an internalizable transmembrane<br />
glycoprotein overexpressed in multiple tumor types, including breast<br />
cancer (BC). GPNMB promotes BC metastases in a murine model<br />
and is a poor prognostic marker in patients (pts) (Rose 2010). CDX-<br />
011 (glembatumumab vedotin) is a fully human GPNMB-specific<br />
monoclonal antibody conjugated to the potent cellular toxin MMAE<br />
via a protease-sensitive peptide linker, designed to cleave upon<br />
cellular internalization. In Phase I/II studies of CDX-011 in BC<br />
(n=42), an objective response rate (ORR) (including confirmed and<br />
unconfirmed response) of 12% overall and 20% for “triple-negative”<br />
(ER/PR/HER2-; TN) pts was observed (Saleh, ASCO 2010).<br />
Methods: The Phase II EMERGE study examined the efficacy of<br />
CDX-011 by level of GPNMB expression. Refractory BC (2-7 prior<br />
cytotoxic regimens in metastatic setting), GPNMB expression in ≥ 5%<br />
of tumor or stroma cells (as centrally determined on archival tumor),<br />
and no persistent treatment-related toxicity (including neuropathy) of<br />
≥ Grade 2 severity were required for enrollment. Pts were stratified<br />
by GPNMB expression pattern (any tumor, low stromal or high<br />
stromal) and randomized 2:1 to CDX-011 (1.88 mg/kg IV q 21 days)<br />
or “investigator’s choice” (IC) single-agent chemotherapy, and treated<br />
until progression (PD) or intolerance with IC pt crossover permitted to<br />
CDX-011 at PD. Endpoints: ORR (primary), progression-free survival<br />
(PFS), safety, pharmacokinetics, pharmacodynamics.<br />
Results: 99% of screened tumor samples expressed GPNMB. 122<br />
treated pts (81 CDX-011 vs. 41 IC) had median age = 56 vs. 56 years;<br />
median # prior anticancer regimens = 6 vs. 5; visceral disease (liver/<br />
lung) = 83% vs. 80%; TN = 33% vs 27%, respectively. To date, 15<br />
IC pts have crossed over to CDX-011, and 14 pts (8 CDX-011, 6<br />
IC) continue on treatment. CDX-011 was well tolerated with less<br />
hematologic toxicity than IC; CDX-011-related toxicity included<br />
rash (overall = 38%; Grade 1 = 20%; Grade 2 = 15%; Grade 3 =<br />
3%) and neuropathy (overall = 18%; Grade 1 = 8%; Grade 2 = 7%;<br />
Grade 3 = 2%).<br />
ORR<br />
Median PFS (months)<br />
CDX-011 IC CDX-011 IC p-value<br />
All pts 19% (15/81) 14% (5/36) 2.1 1.7 0.6763<br />
TN 21% (5/24) 0% (0/9) 2.3 1.6 0.4071<br />
hGPNMB 32% (8/25) 13% (1/8) 2.5 1.4 0.0996<br />
TN & hGPNMB 36% (4/11) 0% (0/3) 3.0 1.3 0.0032<br />
hGPNMB = high tumor GPNMB expression (in ≥25% of tumor cells). CDX-011 includes 15 pts<br />
who crossed over after PD on IC. ORR analysis includes confirmed and unconfirmed response and<br />
excludes pts who discontinued study without evaluable post-baseline imaging (n=15 for CDX-011;<br />
n=5 for IC).<br />
Conclusions: CDX-011 was a well-tolerated and active agent in this<br />
heavily pre-treated BC pt population. Preliminary analysis of the<br />
EMERGE study demonstrates enhanced activity of CDX-011 in TN<br />
as well as high GPNMB expressing BC tumors, confirming that CDX-<br />
011 is a targeted agent. This noted promising activity in advanced TN<br />
and hGPNMB enriched pt populations warrants further evaluation.<br />
P6-10-02<br />
MLN8237 (alisertib), an investigational Aurora A Kinase<br />
inhibitor, in patients with breast cancer: Emerging phase 2 results<br />
Alvarez RH, DeMichele A, Mailliez A, Benaim E, Fingert H,<br />
Schusterbauer C, Zhang B, Melichar B. The University of Texas<br />
MD Anderson <strong>Cancer</strong> Center, Houston, TX; Abramson <strong>Cancer</strong><br />
Center, Philadelphia, PA; Centre Oscar Lambret, Lille, Cedex 59,<br />
France; Millennium Pharmaceuticals, Inc., Cambridge, MA; Fakultní<br />
nemocnice Olomouc - Onkologická klinika, Olomouc, Czech Republic<br />
Background: Aurora A Kinase (AAK) is a key mitotic regulator<br />
amplified or overexpressed in a variety of tumor types including preinvasive<br />
and invasive breast cancer. In mouse mammary epithelium,<br />
AAK overexpression induces genetic instability and tumor formation.<br />
In breast cancer patients (pts), AAK overexpression is often associated<br />
with poor prognosis. Therefore, AAK is an attractive target in cancer<br />
treatment. MLN8237 is an oral, selective AAK inhibitor under<br />
evaluation in pts with different advanced tumors. An ongoing multiindication<br />
phase 2 (NCT01045421) trial evaluates MLN8237 in pts<br />
with solid tumors; here we present preliminary phase 2 data on the<br />
breast cancer cohort.<br />
Methods: Eligible pts were female ≥18 years of age with stage IV<br />
breast cancer, ECOG PS 0–1, measurable disease by RECIST, and<br />
≤4 prior cytotoxic chemotherapy regimens. Stratification on receptor<br />
subtype was performed to ensure 8–10 pts with triple negative disease<br />
and 8–10 patients with HER2 positive disease. Oral MLN8237 50 mg<br />
was administered twice-daily for 7 days, followed by 14 days’ rest<br />
in 21-day cycles. The primary objective was overall response rate;<br />
response was determined by RECIST v1.1. Secondary objectives<br />
included assessment of safety. A Simon’s optimal 2-stage design was<br />
used; 20 pts were initially enrolled, and this cohort was expanded if<br />
≥2 partial responses (PR) were observed in response-evaluable pts.<br />
Results: In the first 20 pts, 2 had PR and the cohort was expanded<br />
to a total of 53 (data cut-off: March 29, 2012). Median age was 60<br />
years (range 33–81). Pts received a median of 3 cycles (range 1-14)<br />
and 20 pts (38%) received ≥6 treatment cycles. Of 45 responseevaluable<br />
pts, 6 pts (13%) had a best response of PR and 26 (58%)<br />
had stable disease (SD). Median duration of SD was 68 days, of which<br />
2 pts (4%) had SD for ≥6 months (clinical benefit rate [PR+SD ≥6<br />
months] =18%). One HER2+ patient with 2 prior lines of therapy<br />
(carboplatin/docetaxel/trastuzumab + trastuzumab maintenance;<br />
gemcitabine/lapatinib/ trastuzumab) had PR 6 months. Fifty-three pts<br />
were evaluable for toxicity. Drug-related adverse events (AEs) were<br />
reported in 49 pts (92%) and were commonly grade 1–2 in severity.<br />
The most frequent drug-related AEs included alopecia (n=26, 49%),<br />
neutropenia (n=25, 47%), diarrhea (n=23, 43%), fatigue (n=21, 40%),<br />
and stomatitis (n=19, 36%). A total of 34 pts (64%) reported grade ≥3<br />
drug-related AEs, including neutropenia (n=23, 43%) and leukopenia<br />
(n=8, 15%). Two pts (4%) discontinued due to AEs; there were no<br />
on-study deaths. Treatment is ongoing in 21 pts.<br />
Conclusions: Emerging phase 2 data reported here provide<br />
preliminary evidence of antitumor activity of oral MLN8237 in<br />
pts with relapsed/refractory breast cancer. AEs were frequent but<br />
generally reversible and manageable by dose reduction and supportive<br />
care.<br />
www.aacrjournals.org 543s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
P6-10-03<br />
The PKC inhibitor PKC412 antagonizes breast cancer cell growth<br />
and enhances tamoxifen sensitivity<br />
Shou J, Chew SA, Mitsiades N, Kumar V, Fu X, Chamness G, Osborne<br />
K, Schiff R. Lester & Sue Smith <strong>Breast</strong> Center, Baylor College of<br />
Medicine, Houston, TX; Baylor College of Medicine, Houston,<br />
TX; Dan L Duncan <strong>Cancer</strong> Center, Baylor College of Medicine,<br />
Houston, TX<br />
Background: AIB1 (SRC-3, NCoA3), a member of the p160/steroid<br />
receptor coactivators family, plays a critical role in cell growth and<br />
proliferation. In estrogen receptor-alpha positive (ER+) breast cancer<br />
(BC) cells, it coactivates estrogen- and additional transcription<br />
factors-dependent gene transcription, reducing the antagonistic<br />
activity of tamoxifen and resulting in tamoxifen resistance (TR). We<br />
have previously shown that BC patients whose tumors expressed high<br />
levels of both AIB1 and HER-2 had worse outcomes with tamoxifen<br />
therapy, suggesting that AIB1 may be an important diagnostic and<br />
therapeutic target. Our findings that knocking down AIB1 attenuates<br />
ER signaling and inhibits breast cancer cell growth further indicate<br />
that the manipulation of AIB1 level could be an approach to treating<br />
BC and overcoming TR. Recently, it has been shown that protein<br />
kinase C (PKC) isoforms phosphorylate AIB1 and prevent its<br />
proteasome-mediated degradation. The present study was carried<br />
out to test if the multi-targeted kinase and PKC inhibitor PKC412<br />
(midostaurin) is capable of promoting degradation of AIB1, inhibiting<br />
BC cell growth, and promoting tamoxifen antagonistic activity.<br />
Methods: The ER+ MCF7, T47D, and ZR75-B BC cells and their<br />
tamoxifen-resistant derivatives (TR) were used. The Methylene<br />
Blue assay was employed to measure cell viability of BC cell lines<br />
after treatment with PKC412 or the combination of PKC412 with<br />
tamoxifen. To determine the impact of PKC412 on AIB1 and ER<br />
proteins and mRNA levels, we used immunoblotting and RT-qPCR,<br />
respectively.<br />
Results: PKC412 successfully inhibited the growth of MCF7,<br />
T47D, and ZR75-B cells, and their tamoxifen-resistant derivatives.<br />
Treatment with PKC412 depleted AIB1 protein and reduced the<br />
level of ER protein without significant alteration in AIB1 mRNA<br />
level. Consequently, ER signaling was disrupted, as reflected by<br />
decreased expression of ER target genes such as GREB1. PKC412<br />
also enhanced tamoxifen’s antagonistic activity in the parental cell<br />
lines and sensitized tamoxifen-resistant MCF7 and ZR75-B cells to<br />
tamoxifen.<br />
Conclusions: The results of this study suggest that the multi-targeted<br />
kinase and PKC inhibitor PKC412 can post-translationally destabilize<br />
AIB1 protein and ER, inhibiting BC cell growth and viability.<br />
PKC412 enhances tamoxifen’s antagonistic activity on BC growth;<br />
furthermore, it sensitizes tamoxifen-resistant cells to tamoxifen. Thus,<br />
PKC412 is a promising agent to treat BC and, in combination with<br />
tamoxifen, to delay or overcome TR.<br />
P6-10-04<br />
The Presence of Anaplastic Lymphoma Kinase Recapitulates<br />
Formation of <strong>Breast</strong> Tumor Emboli with Encircling<br />
Lymphovasculogenesis<br />
Liu H, Chu K, Ochoa AE, Ye Z, Zhang X, Jin J, Wright MC, Barsky<br />
SH, Cristofanilli M, Robertson FM. The University of Texas MD<br />
Anderson <strong>Cancer</strong> Center, Houston, TX; University of Nevada School<br />
of Medicine, Reno, NV; Fox Chase <strong>Cancer</strong> Center, Philadelphia, PA<br />
Background: Genetic abnormalities in the anaplastic lymphoma<br />
kinase (ALK) gene result in activation of signaling pathways<br />
including Akt, mTor, and JAK/Stat3. ALK has been shown to be a<br />
primary oncogenic driver in a variety of human tumors, including both<br />
hematologic malignancies such as anaplastic large cell lymphoma,<br />
as well as solid tumors including neuroblastoma, non-small cell lung<br />
cancer, myofibroblastic tumors and most recently, high grade serous<br />
ovarian carcinoma. While only ∼3% of all breast cancers have been<br />
reported to have ALK genetic abnormalities, our studies revealed that<br />
inflammatory breast cancer (IBC), the most lethal variant of breast<br />
cancer, is characterized by prevalent ALK gene amplification with<br />
activated ALK signaling. The present studies investigated the role<br />
of ALK in breast cancer by expressing full-length wild type ALK<br />
in MCF-7 cells.<br />
Materials and Methods: Clones of MCF-7 breast cancer cells<br />
expressing wild type ALK or non-target vector were produced by<br />
lentivirus infection and selection of single cell clones. MCF-7 ALK<br />
clones were evaluated using live cell and phase contrast imaging,<br />
immunofluorescent staining with confocal imaging, gene profiling,<br />
phospho-protein array analysis, western blot and ELISA validation.<br />
In vivo studies were performed by injection of MCF-7 ALK clones<br />
into using NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice using IACUC<br />
approved animal protocols.<br />
Results: When cultured on plastic substrates, MCF-7 ALK clones<br />
formed tumor cell aggregates instead of monolayer cultures, and when<br />
cultured as tumor spheroids under non-adherent 3D conditions had<br />
a distinct cellular phenotype with significantly greater clonogenicity<br />
than either non-target vector MCF-7 clones or the parental cell line.<br />
Whole transcriptome analysis, with validation using protein arrays,<br />
western blots and ELISA analysis revealed that the presence of<br />
ALK up-regulated phospho-src. In vivo studies revealed that ALK<br />
expressing MCF-7 clones formed tumor emboli that were enwrapped<br />
by dermal lymphatic vessels, essentially recapitulating the phenotype<br />
of IBC tumor emboli that exhibit encircling lymphovasculogenesis.<br />
Enforced expression of wild type ALK in another breast cancer cell<br />
line resulted in similar formation of tumor emboli.<br />
Discussion: These studies provide first time evidence for the<br />
association between full length ALK and formation of highly invasive<br />
tumor emboli enwrapped by lymphatic vessels, which is a primary<br />
characteristic of IBC. These studies, taken together with discovery of<br />
the prevalence of ALK gene amplification in IBC patients, indicate<br />
that ALK represents an important therapeutic target for IBC, with<br />
the availability of new ALK targeted therapies to evaluate as single<br />
agents and in combinations with other agents that may effectively<br />
target IBC tumor emboli that we have now linked to ALK and which<br />
represent the metastatic lesion of this lethal variant of breast cancer.<br />
Funding by Susan G. Komen Organization Promise Grant KG081287<br />
(FMR and MC).<br />
P6-10-05<br />
SU2C Phase 1b Trial of Dual PI3K/ mTOR Inhibitor BEZ235<br />
with Letrozole in ER+/HER2- Metastatic <strong>Breast</strong> <strong>Cancer</strong> (MBC)<br />
Mayer IA, Abramson VG, Balko JM, Isakoff SJ, Forero A, Kuba MG,<br />
<strong>San</strong>ders ME, Li Y, Winer E, Arteaga CL. Vanderbilt-Ingram <strong>Cancer</strong><br />
Center, Nashville, TN; Massachussets General Hospital, Boston, MD;<br />
University of Alabama at Birmingham, AL; MD Anderson <strong>Cancer</strong><br />
Center, Houston, TX; Dana-Farber <strong>Cancer</strong> Institute, Boston, MD<br />
Background: Mutations in PIK3CA, the gene encoding the p110alpha<br />
subunit of PI3K, have been associated with antiestrogen resistance<br />
in ER+ BC. In general, antiestrogen-resistant cancers retain ER and<br />
responsiveness to estradiol, suggesting that treatment of ER+/PI3K<br />
mutant BC should include PI3K inhibitors plus endocrine therapy.<br />
Methods: We are conducting a phase Ib open-label trial of letrozole<br />
(2.5 mg/d) with the dual PI3K/ mTOR inhibitor BEZ235 (400 mg<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
544s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
BID, sachet formulation) in post-menopausal patients with ER+/<br />
HER2 negative MBC. Upon toxicity, BEZ235 was reduced to 400 mg<br />
in AM/ 200 mg in PM (dose level -1), and 200 mg BID (dose level<br />
-2), in a standard 3+3 de-escalation design. Treatment continues until<br />
unacceptable toxicity or disease progression. Tumor assessments are<br />
performed every 2 months. All tumor biopsies are being analyzed for<br />
PI3K pathway alterations.<br />
Results: To date, 9 patients have been accrued; 6 on dose level 1 (400<br />
mg BID) and 3 on dose level -1 (400 mg in AM/ 200 mg in PM).<br />
Of note, the latter 3 patients have been on treatment for less than 2<br />
weeks at the time of abstract submission. Median age was 55 years<br />
(range 40 - 65); all patients had disease progression on previous<br />
endocrine therapy, and 100% had bone metastases and 30% had<br />
visceral metastases. Preliminary toxicities for dose level 1 cohort (400<br />
mg BID) are summarized in the table below. The DLT was grade 3<br />
mucositis, which happened less than 3 weeks of study initiation, in<br />
a total of 3 out of 6 patients. All grade 3 mucositis cases improved<br />
after BEZ235 interruption for 7 days and subsequent dose reduction.<br />
These 3 events triggered activation of the dose level -1 cohort (400<br />
mg AM/ 200 mg PM). The first 3 patients on dose level 1 cohort (2<br />
of which have PIK3CA mutated tumors) had their tumor assessment<br />
scans at 8 weeks post treatment initiation; all patients were found to<br />
have stable disease.<br />
Toxicity: Percentage (%) of Patients by Grade<br />
Toxicity Grade 1 (%) Grade 2 (%) Grade 3 (%) Total<br />
Mucositis 0 22 22* 44<br />
Nausea 44 0 0 44<br />
Diarrhea 44 11 0 55<br />
Dyspepsia 0 11 0 11<br />
Fatigue 11 11 0 22<br />
* DLT<br />
Discussion: The combination of letrozole/BEZ235 is still being<br />
evaluated in patients with ER+/HER2MBC. Safety, tolerability and<br />
preliminary antitumor activity data will be updated at the meeting.<br />
P6-10-06<br />
Rational combination therapy against triple-negative breast<br />
cancer<br />
Al-Ejeh F, Miranda M, Simpson PT, Chenevix-Trench G, Lakhani SR,<br />
Khanna KK. Queensland Institute of Medical Research, Brisbane,<br />
QLD, Australia; The University of Queensland, Brisbane, QLD,<br />
Australia<br />
Background: Triple negative breast cancer (TNBC) is an aggressive<br />
subtype of breast cancer with higher incidence of recurrence,<br />
more distant metastasis, and poorer survival. This subtype is also<br />
characterized by complex genomes where little of their genomes<br />
remain at normal copy number but without high, focal copy number<br />
amplifications. At the transciptome level, the majority of TNBC<br />
(∼75%) are classified as basal-like breast cancer (BLBC) according<br />
to the five intrinsic subtypes. Despite considerable genomic and<br />
gene expression characterization of TNBC, proteomic and phosphoproteomic<br />
investigations of this disease are limited with no available<br />
targeted therapies in clinical use.<br />
Methods & Results: We used the Kinex TM antibody array (http://<br />
www.kinexus.ca/) to interrogate protein/phosphoproteins levels in<br />
43 primary breast cancer biopsies (16 TNBC, 16 ER/PR positive<br />
and 11 HER2-positive) and 16 breast cancer cell lines. Unsupervised<br />
hierarchical clustering of protein/phosphoprotein levels revealed<br />
two subgroups of TNBC in comparison to other subtypes. Western<br />
blotting and Proteome Profiler TM Arrays (R&D Systems) were used<br />
to validate deregulated proteins/phosphoproteins in TNBC. Pathway<br />
analysis revealed that one subgroup of TNBC exploits overlapping<br />
and cross-talking networks for survival. These signaling networks<br />
are downstream from elevated activation of EGFR, integrins and<br />
Insulin-like growth factor 1 receptor (IGF1R).<br />
Targeted molecular inhibitors of activated kinases in these pathways<br />
showed specificity against basal-like/TNBC cell lines compared to<br />
other subtypes in vitro. These activated kinases/networks represent<br />
druggable targets for the treatment of TNBC but may be limited by<br />
compensatory effect of the complex cross-talking signaling networks.<br />
To overcome compensatory downstream signaling that would limit<br />
the inhibition of a given pathway; we developed EGFR-targeted<br />
radioimmunotherapy (RIT) strategy to systemically deliver cytotoxic<br />
loads of beta particles ( 177 Lu) that would kill targeted cells and<br />
surrounding cells by crossfire effect. The combination of EGFRdirected<br />
RIT with chemotherapy and PARP inhibition successfully<br />
treated orthotopic and metastatic TNBC models established from<br />
cell lines and patient-derived xenografts. The superior efficacy of<br />
this triple-agent combination therapy is explained by enhanced DNA<br />
damage and reduced DNA repair response, higher apoptotic cell death<br />
and the elimination of putative breast cancer stem cells.<br />
Conclusion: Proteomic analysis of TNBC provides a powerful tool<br />
to elucidate druggable signaling networks with therapeutic potential.<br />
TNBC utilizes complex interacting signaling networks and rational<br />
combination therapies are required for effective therapy.<br />
P6-10-07<br />
Phase I study of BYL719, an alpha-specific PI3K inhibitor, in<br />
patients with PIK3CA mutant advanced solid tumors: preliminary<br />
efficacy and safety in patients with PIK3CA mutant ER-positive<br />
(ER+) metastatic breast cancer (MBC)<br />
Juric D, Argiles G, Burris HA, Gonzalez-Angulo AM, Saura C, Quadt<br />
C, Douglas M, Demanse D, De Buck S, Baselga J. Massachussetts<br />
General Hospital <strong>Cancer</strong> Center, Boston, MA; Vall d’Hebron<br />
University Hospital, Barcelona, Spain; Sarah Cannon Research<br />
Institute, Nashville, TN; M.D. Anderson <strong>Cancer</strong> Center, Houston, TX;<br />
Novartis Pharma Corporation, East Hanover, NJ; Novartis Pharma<br />
AG, Basel, Switzerland<br />
Background:<br />
Deregulation of the PI3K pathway occurs in >50% of breast cancers.<br />
Mutations in PIK3CA, the gene encoding the p110alpha subunit of<br />
PI3K contributes to resistance to endocrine and anti-HER2 therapies.<br />
BYL719 is a potent, specific oral inhibitor of the alpha subunit of<br />
PI3K, which inhibits wild-type p110alpha and its most common<br />
somatic mutations (IC 50 =5 nM) much more potently than other PI3K<br />
isoforms.<br />
Methodology:<br />
BYL719 has been investigated in a phase I study in patients with<br />
PIK3CA mutant advanced solid tumors. BYL719 has a favorable<br />
safety and PK profile; the MTD was established at 400 mg once<br />
daily (Juric et al., AACR 2012). As of 5 September 2012, 79 patients<br />
have been enrolled in this phase I study, among them 20 patients<br />
with PIK3CA mutant ER+ MBC. 5 of these patients had ER+/<br />
HER2 positive (HER2+) MBC. Presence of PIK3CA mutations was<br />
determined by either local or central assessment.<br />
Results:<br />
20 patients with ER+ PIK3CA mutant MBC were treated once daily<br />
with BYL719 at doses of 30 mg (n=1), 180 mg (n=1), 270 mg (n=1),<br />
400 mg (n=14) and 450 mg (n=3). Median age was 55 years (range<br />
40-78). 15/20 patients with ER+ PIK3CA mutant MBC had HER2<br />
negative and 5/20 had HER2+ MBC. Patients had received a median<br />
of 5 previous treatment regimens (range 1-11). Most patients had<br />
received multiple prior lines of endocrine therapy including tamoxifen<br />
www.aacrjournals.org 545s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
and aromatase inhibitors; 9 patients also received fulvestrant and 16<br />
patients received prior chemotherapy. HER2+ patients have been<br />
previously treated with trastuzumab and/or lapatinib.<br />
Based on a recent analysis of 19 patients (data cut-off 5 July 2012), the<br />
safety of BYL719 in patients with ER+ MBC was comparable to the<br />
overall study population. Most frequent adverse events (AEs; ≥10%)<br />
suspected to be related to BYL719 were hyperglycemia, diarrhea,<br />
nausea, fatigue, decreased appetite, vomiting, rash and erythematous<br />
rash, dysgeusia, dry mouth, and stomatitis. The majority of AEs were<br />
CTCAE grade 1/2 and were clinically well manageable. Most frequent<br />
CTCAE grade 3/4 events were hyperglycemia and erythematous rash.<br />
18/20 PIK3CA mutant ER+ MBC patients were treated at potentially<br />
effective doses of ≥270 mg/day. 6/18 patients (33%) achieved tumor<br />
shrinkage > 20%, among them 2 patients achieved partial responses<br />
(PR) by RECIST. Median progression free survival (PFS) analyzed<br />
in 17 patients treated at ≥270 mg/day in the ER+ BC patients was<br />
7.3 months (CI [4.6,9.5]), compared to 3.7 months (CI [1.8,5.5]) in<br />
38 patients with other PIK3CA mutant solid tumors (data cut-off 5<br />
July 2012)<br />
Conclusion: BYL719 has a favorable safety profile with manageable<br />
side effects, which were mainly related to its mechanism of action.<br />
BYL719 shows promising preliminary clinical activity as single agent<br />
in patients with PIK3CA mutant ER+ MBC, warranting further clinical<br />
development. The investigation of BYL719 continues in patients with<br />
ER+ MBC as single agent, and in combination with endocrine therapy.<br />
P6-11-01<br />
Intermittent High Dose Proton Pump Inhibitor Improves<br />
Progression Free Survival as Compared to Standard<br />
Chemotherapy in the First Line Treatment of Patients with<br />
Metastatic <strong>Breast</strong> <strong>Cancer</strong><br />
Hu X, Wang B, Sun S, Chiesi A, Wang J, Zhang J, Fais S. Fudan<br />
University Shanghai <strong>Cancer</strong> Center, Shanghai, China; National<br />
Institute of Health, Roma, Italy<br />
Purpose<br />
High dose proton pump inhibitor (PPI) has proved to be potentially<br />
effective when combined with chemotherapy in preclinical data.<br />
This study (NCT01069081) was designed to investigate whether the<br />
efficacy of chemotherapy could be improved with the addition of<br />
proton pump inhibitor (PPI) in patients with metastatic breast cancer.<br />
Patients and Methods<br />
Females elder than 18 years old with histologically confirmed<br />
metastatic breast cancer were eligible for participation. Patients<br />
enrolled were randomly assigned to three arms: Arm A, docetaxol 75<br />
mg/m 2 on d4, followed by cisplatin 75 mg/m 2 on d4, repeated every<br />
21 days until maxinum 6 cycles or presence of disease progression<br />
or intolerable toxicity; Arm B, the same chemotherapy plus<br />
esomeprazole 80 mg p.o. bid three days on and the subsequent four<br />
days off, beginning on d1 repeated weekly up to disease progression,<br />
intolerable toxicity, patient’s withdrawal, or a maximum of 66<br />
weeks; Arm C, the same as Arm B with the only difference being<br />
dose of esomeprazole at 100 mg p.o. bid. The primary endpoint was<br />
progression free survival (PFS), and the secondary endpoints were<br />
time to progression (TTP), objective response rate (ORR), safety<br />
profile, and overall survival (OS).<br />
Results<br />
From Aug. 2009 to Dec. 2011, 100 women signed informed consent<br />
form (ICF) and 94 patients have undergone at least one injection of<br />
chemotherapy. Three patients had severe hypersensitivity reactions,<br />
two occurring after the first injection of docetaxol and one in the<br />
second cycle. After a median follow up of 17 months, 68 (72.3%)<br />
patients got disease progression and 23 (24.5%) patients died. Median<br />
PFS for the whole group (n=94), arm A (n=33), arm B (n=30), arm C<br />
(n=31) were 8.9, 7.5, 10.9, and 9.5 months, respectively (p=0.082).<br />
A significant difference was observed between patients who had<br />
taken PPI and who not with median PFS of 9.5 and 7.5 months,<br />
respectively (p=0.030). Among 17 patients with triple negative<br />
breast cancer, this difference was bigger with median PFS of 9.5 and<br />
3.3 months, respectively (p=0.014). The overall response rates for<br />
the whole group, arm A, arm B, arm C were 58.5%, 51.5%, 63.3%,<br />
61.3%, respectively.<br />
Conclusion<br />
This trial is the first randomized study to demonstrate antitumor effects<br />
of intermittent high dose PPI in patients with metastatic breast cancer.<br />
Docetaxel and cisplatin doublet is comparable to the other first-line<br />
chemotherapeutical regimens and the addition of proton pump<br />
inhibitor to the doublet improves efficacy with no adding toxicity,<br />
especially in patients with triple negative breast cancer.<br />
Key Words Proton Pump Inhibitor (PPI), Triple Negative <strong>Breast</strong><br />
<strong>Cancer</strong> (TNBC), Phase II Study, Metastatic <strong>Breast</strong> <strong>Cancer</strong>,<br />
Chemotherapy<br />
P6-11-02<br />
Inhibition of mTOR and Fatty Acid Synthase (FASN) overcome<br />
acquired resistance to Trastuzumab, Lapatinib and both in<br />
HER2+ breast cancer<br />
Puig T, Blancafort A, Giro A, Viqueira A, Viñas G, Massaguer A,<br />
Carrion-Salip D, Bolos MV, Urruticoechea A, Oliveras G. University<br />
of Girona and Girona Biomedical Research Institute (IDIBGi),<br />
Girona, Spain; Catalan Institute of Oncology (ICO) and Girona<br />
Biomedical Research Institute (IDIBGi), Girona, Spain; Pfizer,<br />
Madrid, Spain; University of Girona, Spain; Catalan Institute of<br />
Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain<br />
Introduction:<br />
Resistance to dual biological blockade of HER2 positive breast cancer<br />
arises as a novel therapeutic challenge with high clinical relevance.<br />
We have shown that inhibition of fatty acid synthase (FASN) has<br />
anticancer activity and enhances the effect of chemotherapy and<br />
anti-HER2 drugs in pre-clinical breast cancer models. Furthermore,<br />
our group has recently observed that inhibition of FASN can reverse<br />
resistance to anti-HER2 therapies.<br />
The development of FASN inhibitors has consequently appeared as a<br />
novel anti-target modality for treating cancer. However, the clinical<br />
use of FASN inhibitors, such as Cerulenin, C75 and Epigallocatechin<br />
3-gallate (EGCG) is limited by anorexia and induced body weight<br />
loss or by its low in vivo potency and stability. We synthesized novel<br />
EGCG-related inhibitors to improve their use as anti-tumor agents.<br />
Within these, G28UCM was selected for its inhibitory effect of FASN<br />
activity and selective cytotoxicity in tumor cells.<br />
Recently, it has been reported that mTOR blockade acts synergistically<br />
with HER2 inhibition to induce cell death and tumor regression in<br />
resistant breast cancer models.<br />
Materials and Methods:<br />
We have developed long term HER2+/ FASN+ breast cancer cell lines<br />
(SKBr3) resistant to the HER2-monoclonal antibody Trastuzumab<br />
(SKTR), the EGFR/HER2-tyrosine kinase inhibitor Lapatinib<br />
(SKLR) or both (SKLTR). Once established, we have characterized<br />
these cells by studying a panel of EGF receptors signaling proteins<br />
with western blot analysis, changes in adherence to extracellular<br />
matrix proteins and invasion capacity with colorimetric assays. Using<br />
MTT assay, we have assessed the effect of the mTOR-inhibitor,<br />
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December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
Temsirolimus, and G28UCM on viability of parental and resistant<br />
cells. The isobologram method has been used to estimate the possible<br />
synergistic effect between both treatments.<br />
Results:<br />
Resistant cells maintained downstream HER2 pathway activation<br />
by stimulating the expression/activation of alternative EGF family<br />
receptors and/or those specific ligands. Moreover, these cells increased<br />
adherence to extracellular matrix proteins and invasion capacity.<br />
Different combination regiment of Temsirolimus with G28UCM<br />
displayed a strong synergistic effect in inducing cell death of both,<br />
parental and resistant HER2+ breast cancer cells.<br />
SKBr3 SKTR SKLR SKLTR<br />
Trastuzumab 30,5 +/- 0,7 n.s. n.s. n.s.<br />
Lapatinib 1,3 +/- 1,1 9,5 +/- 2,1 n.s. n.s.<br />
Temsirolimus 4,8 +/- 0,9 6,0 +/- 0,8 5,3 +/- 0,7 5,7 +/- 1,2<br />
G28UCM 11,6 +/- 1,9 10,3 +/- 1,5 11,2 +/- 1,4 5,5 +/- 1,1<br />
Temsirolimus + Ix=0,02 +/- 0,02** Ix=0,71 +/- 0,02** Ix=0,03 +/- 0,09** Ix=0,55 +/- 0,11**<br />
G28UCM (synergism) (synergism) (synergism) (synergism)<br />
Table 1. IC30 value (µM). ns, no significant cell proliferation inhibition. Interaction index (Ix): Ix ><br />
1 is antagonism, Ix = 1 is additivism and Ix < 1 is sinergism. Data are means ± SE. * (p < 0.05) and<br />
** (p < 0.01) indicate the level of statistical significance of the Ix compared with an Ix of 1.<br />
Conclusions:<br />
The inhibition of mTOR and FASN is a potential novel therapeutic<br />
strategy in dual resistant HER2 positive breast cancer.<br />
P6-11-03<br />
Site-Specific, Concomitant Delivery of Rapamycin and Paclitaxel<br />
in <strong>Breast</strong> <strong>Cancer</strong>: Consequent Synergistic Efficacy Enhancement<br />
Blanco E, <strong>San</strong>gai T, Hsiao A, Ruiz-Esparza GU, Ferrari M, Meric-<br />
Bernstam F. The Methodist Hospital Research Institute, Houston, TX;<br />
The University of Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX<br />
Background: The phosphatidylinositol 3-kinase (PI3K)/Akt/<br />
mammalian target of rapamycin (mTOR) (PI3k/Akt/mTOR) pathway<br />
is dysregulated in certain breast cancers. Ongoing clinical trials aim<br />
to therapeutically exploit this pathway through administration of<br />
rapamycin (RAP), an mTOR inhibitor, in combination with paclitaxel<br />
(PTX). However, actual drug synergy in clinical settings may not<br />
be fully realized due to disparate pharmacokinetic parameters of<br />
individual drug formulations, wherein drugs or their effects may never<br />
be present in the tumor at the same time. Our objective was to generate<br />
a nanoparticle platform capable of site-specifically delivering precise<br />
amounts of rapamycin and paclitaxel to breast tumors with hopes<br />
of increasing synergistic targeting of the PI3k/Akt/mTOR pathway.<br />
Materials and Methods: Drug-containing nanoparticles composed<br />
of amphiphilic block copolymers of pegylated poly(ε-caprolactone)<br />
(PEG-PCL, MW = 5k-5k) were fabricated and nanoparticle size and<br />
drug loading efficiency was determined. In vitro growth inhibition<br />
of nanoparticle formulations of varying ratios was evaluated in<br />
MCF-7 and MDA-MB-468 breast cancer cells via sulforhodamine<br />
B assays, after which median-effect plot analyses and combination<br />
index calculations were conducted. Antitumor efficacy studies were<br />
performed in female nude mice bearing MDA-MB-468 tumors, in<br />
which nanoparticles were administered intravenously twice a week<br />
for the duration of three weeks. Biodistribution of drug-containing<br />
nanoparticles in extracted tumors were examined, as well as reverse<br />
phase protein array (RPPA) analysis to gain insights into site-specific<br />
synergy.<br />
Results: Nanoparticles were spherical, with an average diameter of<br />
9 nm. Both rapamycin and paclitaxel loaded favorably, allowing for<br />
customization of different ratios within nanoparticles. Combination<br />
indices demonstrated that a 3:1 ratio of RAP:PTX had the most<br />
synergy in MDA-MB-468 breast cancer cells in vitro, a synergy<br />
found to be preserved in vivo. Significant tumor regression (> 1.5<br />
fold reduction from initial tumor volume) was observed in vivo upon<br />
administration of 3:1 RAP:PTX (15:5 mg/kg) nanoparticles. The<br />
precise ratio of rapamycin and paclitaxel (3:1) was found maintained<br />
in tumors 24 h after administration, an effect not achievable with free<br />
drug formulations. RPPA analysis demonstrated effective blocking<br />
of mTOR and Akt 24 h after administration of nanoparticles, key<br />
events in drug synergy.<br />
Discussion: Site-specific delivery of synergistic agents in preciselycontrolled<br />
drug ratios, possible through their incorporation into<br />
nanoparticles, was shown to be highly efficacious against breast<br />
tumors. Findings demonstrate the ability to deliver specific drug ratios<br />
to tumors, potentially precluding the need to administer maximal<br />
doses of both agents in order to achieve synergy, lessening patient<br />
side-effects. This study demonstrates the potential for prediction<br />
of in vivo therapeutic outcomes from in vitro synergistic findings.<br />
Nanoparticle delivery of drugs may also yield enhanced understanding<br />
of mechanisms of synergy between molecular-targeted drugs and<br />
traditional chemotherapeutics in vivo, resulting in novel and more<br />
efficacious treatment regimens.<br />
P6-11-04<br />
Targeting the tumor microenvironment: tetrathiomolybdate<br />
decreases circulating endothelial progenitor cells in women with<br />
breast cancer at high risk of relapse.<br />
Jain S, Kornhauser N, Lam C, Ward MM, Chuang E, Cigler T, Moore<br />
A, Donovan D, Cobham MV, Schneider S, Hurtado Rua SM, Lane<br />
ME, Mittal V, Vahdat LT. Weill Cornell Medical College<br />
Background: Bone marrow-derived endothelial progenitor cells<br />
(EPCs) constitute an important part of the tumor microenvironment<br />
and are critical for metastatic progression in preclinical models and<br />
breast cancer patients (Jain et al, <strong>Breast</strong> <strong>Cancer</strong> Res Treat, 2012).<br />
Tetrathiomolybdate (TM), a copper-depleting compound inhibits<br />
angiogenesis, tumor growth, and metastasis. This study explores<br />
the effect of TM on EPCs in patients at high risk for breast cancer<br />
recurrence.<br />
Methods: This phase II study enrolled stage 3, 4 without evidence of<br />
disease (NED), and any node-positive triple negative breast cancer<br />
patient. Only concomitant hormone therapy was allowed. Patients<br />
received induction TM 180 mg daily at baseline followed by an<br />
equal or lower daily dose (median 100 mg, range 0-140) to maintain<br />
ceruloplasmin (Cp) level < 17 mg/dl (target for copper depletion).<br />
We monitored EPCs (CD45dim/CD133+/VEGFR2+), Cp, CEA, and<br />
CA15-3 at baseline and monthly. Wilcoxon signed-rank was used to<br />
compare Cp and EPC levels between baseline and subsequent time<br />
points. All p-values were two-sided with statistical significance<br />
evaluated at the 0.05 alpha level.<br />
Results: 50 patients (33 adjuvant, 17 Stage 4 NED, and 22 triple<br />
negative) were enrolled. In the first 40 patients enrolled who had<br />
received at least 24 months of TM, EPC and Cp data were available<br />
for analysis. Of these 40 patients, 1 patient did not take TM due to<br />
patient preference, and 736 cycles of TM (average 18.9 per patient)<br />
were administered. Median age was 50 years (range 29-66). Median<br />
number of tumor size and positive lymph nodes among adjuvant<br />
patients were 3.5 cm (range 1.2-7) and 9 (range 0-42), respectively. Of<br />
the patients receiving hormone therapy, 11 patients were on tamoxifen<br />
and 16 patients were on an aromatase inhibitor. Median baseline Cp<br />
level was 30 mg/dL (range 20-47). 71% patients adequately copper<br />
depleted at month 1 to a mean Cp of 14.8 mg/dL. A larger proportion of<br />
triple negative patients copper depleted (82%) compared to hormone<br />
receptor positive subtypes (47%) and HER2/neu positive subtypes<br />
(67%). Median EPCs/ml decreased from baseline to last dose by<br />
16 in patients that achieved the copper depletion target, p=0.014.<br />
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Conversely, in patients that did not copper deplete, median EPCs/ml<br />
increased by 136, p=0.005. Of the 50 patients on study, 7 patients<br />
relapsed in which a significant increase in EPCs preceded an objective<br />
clinical relapse and a tumor marker rise by a median of 1 month. Only<br />
grade 3/4 toxicity was hematologic, occurred in 49 cycles (6.7%),<br />
and resolved in 5-13 days with TM held and resumed at a lower dose.<br />
Conclusions: TM is a well-tolerated oral copper chelator that may<br />
contribute to maintaining EPCs below baseline in copper-depleted<br />
patients. Molecular subtype may impact on the ability to copper<br />
deplete. EPCs may have potential as a surrogate marker for early<br />
relapse and as a therapeutic target for interrupting the metastatic<br />
progression.<br />
P6-11-05<br />
Novel sorafenib-derivatives induce apoptosis in breast cancer<br />
cells through STAT3 inhibition<br />
Liu C-Y, Tseng L-M, Chang K-C, Chu P-Y, Su J-C, Shiau C-W, Chen<br />
K-F. Taipei Veterans General Hospital, Taipei, Taiwan; National<br />
Yang-Ming University, Taipei, Taiwan; St. Martin De Porres Hospital,<br />
Chia-Yi, Taiwan; National Taiwan University Hospital, Taipei, Taiwan<br />
Background: STAT3 has emerged as a novel potential anti-cancer<br />
target and its signaling is constitutively activated in various cancers<br />
including breast cancer. Our previous study has shown that STAT3 is<br />
a major kinase-independent target of sorafenib in HCC. (J Hepatol.<br />
2011). Moreover, recent evidence has shown that p-STAT3 can be<br />
down-regulated by phosphatases, such as SHP-1 tyrosine phosphatase.<br />
We have designed and synthesized a series of sorafenib analogues<br />
devoid of sorafenib’s kinase inhibition activity, some of which showed<br />
stronger p-STAT3 inhibition and apoptosis-inducing effects than<br />
sorafenib in HCC cells (Eur J Med Chem. 2011). Here, we tested<br />
the efficacy of novel sorafenib derivatives, SC-1 and SC-43, in breast<br />
cancer cells and examined the drug mechanism.<br />
Methods: Six <strong>Breast</strong> cancer cell lines were used for in vitro studies.<br />
Cell viability was examined by MTT-assay. Apoptosis was examined<br />
by both flow cytometry and Western blot. Signal transduction<br />
pathways in cells were assessed by Western Blot. SHP-1 activity<br />
was measured by a phosphatase activity assay kit. In vivo efficacy<br />
of Sorafenib, and sorafenib derivatives were tested in xenografted<br />
nude mice.<br />
Results: Sorafenib, SC-1 and SC-43 induced apoptosis in association<br />
with down-regulation of P-STAT3 and its downstream proteins Cyclin<br />
D1 and survivin in a dose-dependent manner in breast cancer cell<br />
lines (HCC-1937, MDA MB-468, MDA MB-231, MDA MB-453,<br />
SKBR-3, MCF-7) and the apoptotic effects induced by SC-1 and<br />
SC-43 were more potent than Sorafenib. Over-expression of STAT3<br />
in MDA MB-468 cells protected cells from apoptosis induced by<br />
sorafenib, SC-1 and SC-43. Moreover, SC-1 and SC-43 up-regulated<br />
higher SHP-1 activity than sorafenib by in vitro phosphatase assays.<br />
Knockdown of SHP-1 by siRNA reduced apoptosis induced by SC-1<br />
and SC-43. Importantly, SC-1 and SC-43 showed in vivo efficacy in<br />
MDA-468 xenografted tumor.<br />
Conclusions: Our data indicated that inhibiton of p-STAT3 by upregulating<br />
SHP-1 activity mediated apoptotic effects of sorafenib,<br />
SC-1 and SC-43 in breast cancer cells.<br />
P6-11-06<br />
A phase Ib study of LCL161, an oral inhibitor of apoptosis (IAP)<br />
antagonist, in combination with weekly paclitaxel in patients with<br />
advanced solid tumors<br />
Dienstmann R, Vidal L, Dees EC, Chia S, Mayer EL, Porter D,<br />
Baney T, Dhuria S, Sen SK, Firestone B, Papoutsakis D, Cameron<br />
S, Infante JR. Vall d’Hebron University Hospital, Barcelona, Spain;<br />
Hospital Clinic i Provincial, Barcelona, Spain; University of North<br />
Carolina Lineberger Comprehensive <strong>Cancer</strong> Center, Chapel Hill, NC;<br />
British Columbia <strong>Cancer</strong> Agency, University of British Columbia,<br />
Vancouver, BC, Canada; Dana-Farber <strong>Cancer</strong> Institute, Boston, MA;<br />
Novartis Pharmaceuticals Corporation, Cambridge, MA; Novartis<br />
Pharmaceuticals Corporation, Florham Park, NJ; Sarah Canon<br />
Research Institute, Nashville, TN<br />
Background: Impaired apoptosis is a common feature of cancer<br />
cells and may contribute to chemoresistance. LCL161 is an oral<br />
small molecule antagonist of Inhibitor of Apoptosis Proteins<br />
(IAPs) that sensitizes a subset of tumors from diverse lineages to<br />
treatment with cytotoxic therapies, including paclitaxel. Multiple<br />
breast cancer models are sensitive to LCL161 as a single agent and<br />
LCL161 acts synergistically with paclitaxel in these models. A phase<br />
I study established an LCL161 dose of 1800 mg once weekly as<br />
well tolerated, with strong evidence of pharmacodynamic activity<br />
at doses ≥320 mg. This ongoing phase Ib study defines the dose<br />
limiting toxicities (DLTs), maximum tolerated dose (MTD), safety,<br />
and pharmacokinetics (PK) of LCL161 in combination with weekly<br />
paclitaxel.<br />
Methods: Patients with advanced/metastatic solid tumors were treated<br />
with paclitaxel 80 mg/m 2 each week followed by escalating doses of<br />
LCL161 administered once weekly immediately following paclitaxel.<br />
PK and biomarker sampling was performed.<br />
Results: Thirty-two patients have received LCL161 doses of 600 mg<br />
(n=3), 1200 mg (n=5), 1500 mg (n=4), and 1800 mg (n=20). The most<br />
frequent adverse events considered LCL161-related included diarrhea<br />
(n=11; 1 Grade 3), nausea (n=8), fatigue (n=7; 2 Grade 3), peripheral<br />
neuropathy (n=6; 1 Grade 3), vomiting (n=6), decreased appetite<br />
(n=5), alopecia (n=4), and anemia (n=4). The principal DLTs were<br />
neutropenia, fatigue, and neuropathy. Significant cytokine release<br />
syndrome, the DLT of single-agent LCL161, has not been observed<br />
likely due to the use of dexamethasone as a premedication. No PK<br />
interaction between LCL161 and paclitaxel was observed. RECIST<br />
partial responses have been observed in 4 patients with diverse tumor<br />
types, including breast cancer. Preliminary antitumor activity in the<br />
expansion cohort with breast cancer patients will be presented.<br />
Discussion: LCL161 and paclitaxel combination therapy is well<br />
tolerated, with manageable toxicities and no evidence of a PK<br />
interaction that might interfere with the activity of either agent.<br />
Enrollment of additional patients with breast and ovarian cancer into<br />
an expansion cohort is ongoing, utilizing an approach to identify those<br />
more likely to respond to treatment with IAP antagonists.<br />
P6-11-07<br />
The <strong>Cancer</strong> Stem Cell-Targeting Wnt Inhibitor VS-507 Reduces<br />
<strong>Breast</strong> <strong>Cancer</strong> Growth and Metastasis<br />
Ring JE, Kolev VN, Padval MV, Keegan M, Vidal CM, Neill AA,<br />
Shapiro IM, Pachter JA, Xu Q. Verastem, Inc., Cambridge, MA<br />
<strong>Cancer</strong> stem cells (CSCs) support tumor viability and growth through<br />
their ability to self-renew and differentiate into heterogeneous tumor<br />
tissue. CSCs are typically resistant to standard cytotoxic agents,<br />
leading to their enrichment and the consequent regrowth of refractory<br />
tumors. While this population has been challenging to directly target<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
therapeutically, we are actively developing novel agents, such as VS-<br />
507, that selectively target the cancer stem cell subpopulation in vivo.<br />
Previously, we and others have shown that VS-507, a cancer stem-cell<br />
specific agent, inhibits Wnt signaling with corresponding reduction<br />
of the LRP6 protein, a Frizzled co-receptor upregulated in breast<br />
cancer cell lines. In the current study, we have continued to examine<br />
the effect of VS-507 on the Wnt/Beta-catenin signaling pathway to<br />
further elucidate its mechanism of action. We determined that VS-<br />
507 also decreases expression of the second Frizzled co-receptor<br />
LRP5 in MDA-MB-231 breast cancer cells stimulated by Wnt3A.<br />
The combined inhibition of the co-receptors LRP5 and LRP6 may<br />
contribute to the observed inhibition of Beta-catenin-mediated<br />
transcription by VS-507 in a TOP-Flash assay. Accordingly, VS-507<br />
reduced expression of Axin2, a transcriptional target of Beta-catenin.<br />
Because human breast cancer cell lines represent a mixed population<br />
of CSC and non-CSC cells, we evaluated VS-507 across a panel of cell<br />
lines by monitoring changes in viability and in the percentage of cancer<br />
stem cells. In SUM159 triple negative breast cancer cells, VS-507<br />
had micromolar potency against the bulk population with preferential<br />
nanomolar potency against the ALDEFLUOR+ CSC population with<br />
similar effects observed in the Hoechst side population (SP) CSC<br />
assay. In contrast, cytotoxic anticancer drugs such as paclitaxel and<br />
cisplatin increased the percentage of ALDEFLUOR+ cancer stem<br />
cells under similar conditions. In vivo, oral administration of VS-507<br />
(15 mg/kg, QD daily) as a single agent partially inhibited MDA-<br />
MB-231 tumor growth, consistent with its observed inhibition of the<br />
cancer stem cell subpopulation. Furthermore, VS-507 inhibited lung<br />
metastasis in a 4T1.2 murine breast cancer model. In summary, these<br />
results further elucidate the mechanism by which VS-507 inhibits<br />
Wnt/Beta-catenin signaling. VS-507 reduces tumor cell proliferation<br />
in vitro with preferential effects on cancer stem cells which translate<br />
to inhibition of tumor growth, enhancement of efficacy of cytotoxic<br />
agents such as docetaxel, and inhibition of metastasis in mouse<br />
models. These data provide additional support for the development<br />
of VS-507 as a novel anti-cancer stem cell agent.<br />
P6-11-08<br />
A multicenter, open-label Ph IB/II study of BEZ235, an oral dual<br />
PI3K/mTOR inhibitor, in combination with paclitaxel in patients<br />
with HER2-negative, locally advanced or metastatic breast cancer<br />
Campone M, Fumoleau P, Gil-Martin M, Isambert N, Beck JT,<br />
Becerra C, Shtivelband M, Duval V, di Tomaso E, Roussou P, Urban<br />
P, Urruticoechea A. Centre René Gauducheau, Nantes, France;<br />
Centre Georges François Leclerc, Dijon, France; Institut Català<br />
d’Oncologia, Barcelona, Spain; Highlands Oncology Group,<br />
Fayetteville, AR; Baylor University Medical Center, Dallas, TX;<br />
Ironwood <strong>Cancer</strong> and Research Centers, Chandler, AZ; Novartis<br />
Pharma AG, Basel, Switzerland; Novartis Institutes for BioMedical<br />
Research, Inc., Cambridge, MA<br />
Background: The PI3K/AKT/mTOR pathway is frequently altered<br />
in breast cancer (BC). Alterations in PIK3CA or inactivation of<br />
PTEN are observed in 10–40% and in up to 50% of breast tumors,<br />
respectively. The PI3K/AKT/mTOR pathway can be further activated<br />
through various receptor classes or cross-talk with other pathways,<br />
making it a rational target for therapeutic intervention in BC. BEZ235<br />
is an oral dual inhibitor of mTOR and PI3K. It has demonstrated antiproliferative<br />
activity, substantial growth inhibition, and induction of<br />
apoptosis in preclinical studies. In a Ph I study, single-agent BEZ235<br />
(600 mg BID) was shown to have less toxicity than the equivalent<br />
once-daily dosing, and have preliminary evidence of activity in<br />
advanced solid tumors (Arkenau, et al. ASCO 2012:#3097).<br />
Methods: This is a multicenter, open-label Ph IB/II study of<br />
continuous, oral BEZ235 twice daily (BID) in combination with<br />
paclitaxel (80 mg/m 2 ; IV weekly [QW]) in women with HER2-<br />
negative (HER2–), metastatic or inoperable locally advanced BC<br />
(NCT01495247).<br />
For the Ph IB part, women with HER2–, metastatic or inoperable<br />
locally advanced BC, who are suitable for treatment with paclitaxel,<br />
are eligible for enrollment. The primary objective is to determine the<br />
maximum tolerated dose (MTD)/recommended Ph II dose (RP2D)<br />
of BEZ235 in combination with paclitaxel based on dose-limiting<br />
toxicities (DLTs) using an adaptive 5-parameter Bayesian logistic<br />
regression model with overdose control. The MTD is defined as the<br />
highest drug dosage not causing medically unacceptable DLTs in<br />
more than 35% of the treated patients during Cycle 1 (1 cycle = 28<br />
days). Secondary objectives include safety (CTCAE), preliminary<br />
activity (RECIST), and pharmacokinetics (PK). Estimated enrollment<br />
is 15–30 patients into the Ph IB part.<br />
Results: As of June 2012, 13 pts have been enrolled into the Ph IB<br />
part of the trial. The first cohort (n=7 pts) received BEZ235 200 mg<br />
BID + 80 mg/m 2 QW paclitaxel. Of these 7 pts, 3 are ongoing, with 2<br />
pts having received treatment for more than 12 weeks so far, and 4 pts<br />
have discontinued (2 due to an adverse event [AE]; 1 due to an AE/<br />
pt’s decision; and 1 due to disease progression). Of the 6 evaluable<br />
pts in the first cohort, 2 experienced DLTs: Grade 3 stomatitis (1<br />
pt) and Grade 2/3 neutropenia (1 pt). Most common AEs included<br />
stomatitis and GI toxicity (e.g. diarrhea, nausea/vomiting). To date,<br />
reported Grade 3 AEs related to study drug were stomatitis (2 pts),<br />
neutropenia (1 pt), and skin rash (1 pt). Among the 3 pts with at least<br />
one tumor evaluation, 1 pt with a triple-negative metastatic BC, who<br />
had previously been treated with paclitaxel, experienced a RECIST<br />
partial response which was confirmed on second tumor evaluation.<br />
PK analysis is ongoing.<br />
Conclusions: Additional patients have been enrolled at BEZ235 200<br />
mg BID/paclitaxel 80 mg/m 2 QW to provide further information on<br />
the safety and activity profile of this combination. Updated safety<br />
and efficacy results will be presented. Upon determination of the<br />
MTD/RP2D, the randomized Ph II part will begin to compare<br />
weekly paclitaxel given with or without BEZ235 BID as the first-line<br />
treatment of HER2– metastatic BC.<br />
P6-11-09<br />
FAK Inhibitor VS-4718 Attenuates <strong>Breast</strong> <strong>Cancer</strong> Stem Cell<br />
Function In Vitro and In Vivo<br />
Kolev VN, Vidal CM, Shapiro IM, Pavdal M, Keegan M, Xu Q, Pachter<br />
JA. Verastem, Cambridge, MA<br />
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that<br />
mediates signal transduction by integrins as well as growth factor<br />
receptors. FAK has been implicated in multiple steps of carcinogenesis<br />
including tumor initiation, growth and metastasis. Amplification and<br />
overexpression of FAK have been observed in aggressive human<br />
cancers including breast cancer. We have now observed that VS-4718,<br />
a selective FAK kinase inhibitor, exhibits preferential inhibitory<br />
effects on breast cancer stem cells.<br />
VS-4718 is a potent and selective FAK kinase inhibitor that blocks<br />
fibronectin-stimulated FAK autophosphorylation at Tyr397 at low<br />
nanomolar concentrations. To determine if FAK plays a role in the<br />
biology of breast cancer stem cells, VS-4718 was evaluated in a<br />
multitude of cancer stem cell assays both in vitro and in vivo. In<br />
parallel, treatment of SUM159 triple negative breast cancer cells<br />
in vitro with FAK shRNA inhibits tumorsphere formation. These<br />
data taken together indicate a role of FAK in breast cancer stem cell<br />
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renewal. Similarly, pre-treatment of SUM159 cells with VS-4718 in<br />
matrigel attenuated secondary tumorsphere formation. Furthermore,<br />
VS-4718 reduced the side population (SP) and the percentage of<br />
ALDEFLUOR+ cancer stem cells in SUM159 breast cancer cells in<br />
vitro. In direct contrast, standard-of-care agent paclitaxel increased<br />
the percentage of ALDEFLUOR+ cancer stem cells in all three assays.<br />
The in vivo effect of VS-4718 on cancer stem cells was evaluated<br />
in SUM159 and MDA-MB-231 human triple negative breast cancer<br />
xenograft models. Following systemic administration, VS-4718<br />
induced significant reduction of cancer stem cells in tumors as<br />
assessed by a decrease in ALDEFLUOR+ cells and tumorsphereforming<br />
efficiency relative to vehicle-treated tumors.<br />
In summary, our results indicate the importance of FAK in the selfrenewal<br />
of breast cancer stem cells in vitro and in vivo, and support the<br />
clinical development of the selective FAK inhibitor VS-4718 to target<br />
cancer stem cells for the treatment of triple negative breast cancer.<br />
P6-11-10<br />
IBL2001: Phase I/II study of a novel dose-dense schedule of oral<br />
indibulin for the treatment of metastastic breast cancer.<br />
Traina TA, Hudis C, Seidman A, Gajria D, Gonzalez J, Anthony SP,<br />
Smith DA, Chandler JC, Jac J, Youssoufian H, Korth CC, Barrett<br />
JA, Sun L, Norton L. Memorial Sloan-Kettering <strong>Cancer</strong> Center,<br />
New York, NY; Evergreen Hematology and Oncology, Spokane, WA;<br />
Compass Oncology, Vancouver, WA; The West Clinic, Memphis, TN;<br />
US Oncology Research, Woodlands, TX; ZIOPHARM Oncology, Inc.,<br />
Boston, MA; Harmon Hill Consulting, New York, NY<br />
Background: Indibulin (ZI0-301) is a novel, oral, synthetic small<br />
molecule microtubule inhibitor which binds tubulin at a different<br />
site than taxanes and vinca alkaloids. Preclinical data demonstrate<br />
indibulin does not interact with acetylated (neuronal) tubulins and in<br />
clinical studies has not exhibited the neurotoxicity associated with<br />
other tubulin binders. Indibulin has potent antitumor activity in human<br />
cancer cell lines, including multidrug-, taxane-, and vinblastineresistant.<br />
Norton-Simon modeling based on cell line data suggested<br />
that dose dense (dd) administration could optimize efficacy while<br />
limiting toxicity.<br />
Methods: Eligible patients (pts) have metastatic or unresectable<br />
locally advanced breast cancer, ECOG performance status ≤ 2,<br />
adequate organ function, measurable or nonmeasurable disease<br />
and any number of prior therapies. Uncontrolled gastrointestinal<br />
malabsorption syndrome and grade 2 or higher peripheral neuropathy<br />
are the principal exclusions. Adverse events (AEs) are graded by<br />
CTCAE v. 4.0. Objective disease status is evaluated according to<br />
RECIST 1.1. The primary objective of the phase (Ph) I portion of the<br />
study is to determine the maximum tolerated dose (MTD) of indibulin<br />
when given in dd fashion 5 days treatment, 9 days rest using standard<br />
3+3 dose escalation schema.<br />
Phase I Dose Cohorts<br />
Cohort Dose (mg) Q1D x 5<br />
1 25<br />
2 50<br />
3 100<br />
4 150<br />
5 200<br />
6 275<br />
7 350<br />
8 450<br />
The secondary objectives are to evaluate safety profile at various<br />
dosing levels, pharmacokinetics (PK) and preliminary activity of<br />
indibulin. Once the MTD is defined, a food effect cross- over group<br />
(N=12) will be enrolled. Two groups of 6 pts each will be treated<br />
in either the fed or fasted state during the first cycle. A subgroup of<br />
13 pts consisting of 12 pts from the food effect group plus the last<br />
pt from the MTD cohort will be evaluated for PFS at 4 months and<br />
will serve as the population for the first stage of a Simon two-stage<br />
design. If 4 or more out of 13 pts do not progress at 4 months, the Ph<br />
II portion of the study will be opened.<br />
Results: Twenty one pts (20 F, 1 M) have been enrolled to cohorts<br />
1 through 6 and the dose escalation is ongoing. Preliminary safety<br />
and efficacy data have been analyzed for 18 pts treated in cohorts 1<br />
through 5 and are presented henceforth. No DLT has been observed<br />
and no MTD has been reached. Median age 58 years (32-81). PS<br />
0=4, 1=12, 2=2. Median number of prior therapies 5 (1-12). Most<br />
frequent treatment-emergent AEs were: anorexia, constipation, cough,<br />
nausea (each in 39% pts); dyspnea (33%); fatigue, vomiting (each<br />
28%). There were no related grade 3-4 AEs. PK analysis revealed<br />
that indibulin plasma exposures increased approximately dose<br />
proportionally from 25 to 200 mg with C max of 165 ± 89 ng/mL and<br />
AUC 0-24 of 1411 ± 111 ng•h/mL at 200 mg. There were no objective<br />
responses. Stable disease was seen in 1 pt in the 150 mg cohort.<br />
Longest duration on-study was 4 months.<br />
Conclusions: Oral indibulin was well tolerated in the doses up to 200<br />
mg and the dose-proportional PK with lack of DLTs allows for further<br />
dose-escalation. Stable disease observed at sub-MTD dose may be a<br />
sign of activity in this heavily pre-treated population.<br />
P6-11-11<br />
Multistage Delivery of Paclitaxel: Increased Drug Stability and<br />
Sustained Release Results in Enhanced Efficacy in <strong>Breast</strong> <strong>Cancer</strong><br />
Blanco E, <strong>San</strong>gai T, Hsiao A, Ferrati S, Bai L, Liu X, Meric-Bernstam<br />
F, Ferrari M. The Methodist Hospital Research Institute, Houston, TX;<br />
The University of Texas MD Anderson <strong>Cancer</strong> Center, Houston, TX<br />
Background: A significant challenge for effectively treating cancer<br />
is overcoming biological barriers that reduce circulation times<br />
and increase degradation of possible treatments. We established<br />
an innovative approach to address this issue by embedding drugcontaining<br />
nanoparticles within the pores of a larger mesoporous<br />
silicon particle (MSP) in order to optimize site-specific localization<br />
and release of therapeutic agents. The objective is to develop<br />
a nanotherapeutic-based multistage platform for breast cancer<br />
treatment, wherein paclitaxel, a mitotic inhibitor used in the treatment<br />
of breast tumors, will be loaded into polymeric micelles, which in<br />
turn will be loaded within MSPs. We hypothesize that this nested<br />
incorporation of drugs within MSPs, combined with enhanced tumor<br />
transport, will result in a more pronounced and sustained antitumor<br />
effect.<br />
Materials and Methods: Micelles were assembled from amphiphilic<br />
block copolymers consisting of poly(ethylene glycol)-poly(εcaprolactone)<br />
(PEG-PCL, MW = 5k-5k). Nanoparticle size, zeta<br />
potential, and morphology was determined, and PTX loading and<br />
release kinetics from micelles analyzed. Drug-containing micelles<br />
were incorporated into MSPs by a previously established dry-loading<br />
method, wherein nanoparticles were incorporated into pores via<br />
capillary action. Loading of fluorescent micelles was used to verify<br />
loading within MSPs via fluorescence microscopy and flow cytometry<br />
analysis. Sulforhodamine B assays were used to evaluate the in vitro<br />
antitumor efficacy of the platform in MCF-7 and MDA-MB-468<br />
breast cancer cells. In vivo efficacy was evaluated in MDA-MB-468<br />
breast tumors in female nu/nu mice.<br />
Results: Resulting micelles had an average size of 20 nm, as confirmed<br />
through TEM, with paclitaxel loaded into micelles very effectively.<br />
Release kinetics showed that 50% of the drug was released within<br />
4 hours and 80% released within 24 hours. Loading of micelles into<br />
MSPs depended largely on electrostatic interactions, with micelles<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
550s<br />
<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
loading better within pores of MSPs displaying increased positive<br />
charge. Micelle loading into MSPs was successful as demonstrated<br />
by flow cytometry, and release was significantly retarded (< 30% of<br />
drug released over 4 d). Incubation of micelle-containing MSPs with<br />
breast cancer cells in vitro showed that MSPs could be internalized<br />
by cells, after which a sustained and delayed release of the payload<br />
was observed in cells. <strong>Breast</strong> tumors treated with MSPs demonstrated<br />
sustained tumor suppression (169 mm 3 compared to initial starting<br />
volume of 200 mm 3 ) at day 35 following a single injection. It is<br />
important to note that sustained tumor efficacy was achieved with<br />
nanoparticle and free drug formulations, however, with the caveat of<br />
repeated administrations.<br />
Discussion: A novel multistage approach to chemotherapy effectively<br />
allows a secondary payload to be loaded and preserved within the<br />
MSPs until reaching the tumor site. This prevents premature release<br />
of the drug and allows for a sustained release which may potentially<br />
result in fewer patient side effects. Future studies will involve loading<br />
of multiple nanoparticle types into MSPs and addition of targeting<br />
and diagnostic components.<br />
P6-11-12<br />
Nanoparticle-enhanced chemotherapeutics delivery in drugresistant<br />
triple-negative breast cancer<br />
van de Ven AL, Landis MD, Paskett LA, Meyn A, Frieboes HB, Chang<br />
JC, Ferrari M. The Methodist Hospital Research Institute, Houston,<br />
TX; University of Louisville, KY<br />
Chemotherapeutics delivery is generally poor in tumors characterized<br />
by rapid perfusion and low blood volume fraction. Systemically<br />
administered nanoparticles can be engineered to overcome abnormal<br />
flow conditions to act as intravascular drug depots for the localized<br />
delivery of high concentrations of chemotherapeutics. The feasibility<br />
of this approach was first demonstrated using melanoma, and is<br />
now being further investigated using well-characterized human<br />
triple-negative breast cancer biopsies implanted into mice. Intravital<br />
microscopy studies of human cancer-in-mice selected for differing<br />
vascular morphologies have yielded intriguing preliminary data<br />
regarding the role of tumor vascularity in drug and particle delivery.<br />
The first-pass perfusion of a 40kDa dextran tracer revealed that<br />
BCM-2665 tumors are perfused ∼6x more rapidly than BCM-4195<br />
tumors (11.3 ± 2.3s vs. 67.6 ± 11.0) and contain ∼30% lower volume<br />
fraction of blood (0.046 ± 0.011 vs. 0.062 ± 0.015). Interestingly, flow<br />
parameters that adversely impact drug accumulation appear to favor<br />
plateloid particle accumulation. BCM-2665 xenografts receiving<br />
an i.v. injection of 1000x400nm particles show ∼10x more particle<br />
accumulation than BCM-4195 tumors (24.8 ± 3.2 x103/mm3 vs. 3.5<br />
± 0.4 x103/mm3). The ability of these therapeutic particles to reach<br />
tumors appears to be primarily driven by flow-related parameters,<br />
which we characterize using a combination of intravital microscopy,<br />
computed tomography, and mathematical modeling. The total number<br />
of particles accumulated within a given tumor appears to be largely<br />
driven by the number of particles entering the tumor, since ∼65-70% of<br />
entering plateloid particles are retained by the tumor vasculature. This<br />
suggests that cytotoxic intravascular drug depots may be a promising<br />
strategy for increasing the efficiency of chemotherapeutics delivery<br />
to drug-resistant tumors and is the premise of ongoing therapeutic<br />
response studies. Clearly if more drugs can be delivered to the tumors,<br />
better outcomes can be expected for the patients.<br />
P6-11-13<br />
In vitro antineoplastic evaluation of rationally designed<br />
naphtoquinone-derived drugs in triple-negative breast cancer<br />
cell line<br />
Madeira KP, Daltoé RD, Herlinger AL, Guimarães IS, Allochio Filho<br />
JF, Teixeira SF, Valadão IC, Greco S, Rangel LBA. Federal University<br />
of Espirito <strong>San</strong>to, Brazil<br />
Background: <strong>Breast</strong> cancer (BC) comprises multiple diseases<br />
harboring different genetic alterations, which subtypes respond<br />
differently to treatment, and are associated to distinct clinical<br />
outcomes. Likewise, triple negative breast cancer (TNBCs) are a<br />
heterogeneous subgroup of BC, immunophenotypically negative<br />
for estrogen and progesterone receptor, and HER2, that account for<br />
10-15% of all invasive BC, affecting mostly African-American and<br />
Hispanic pre-menopausal women. Considering that TNBC have poor<br />
prognosis, and cannot be effectively treated with current targeted<br />
therapies, the discovery of new treatment options is imperative.<br />
Methods: Novel naphtoquinone-derived drugs were rationally<br />
designed to act through multiple pathways aiming the avoidance<br />
of drug-resistant phenotype acquisition by tumor cells, and were<br />
synthesized following high efficiency and low cost method. Drugs<br />
antineoplastic efficacy (AE) was accessed in claudin-low TNBC cell<br />
line, MDA-MB-231, through the evaluation of cellular metabolic<br />
viability (CMV) (MTT method). Drugs structures are protected by<br />
patent. Cells were cultured in RPMI media supplemented with 10%<br />
(v/v) FBS and antibiotics until subconfluence; then, 1.5x10 5 cells/<br />
well were subcultured for 72h prior to treatment with drugs (10 -4 , 10 -5 ,<br />
10 -6 , 10 -7 , and 10 -8 M). After 24h, CMV was assessed. Experiments<br />
in which the lineage was treated with cisplatin, doxorubicin or<br />
paclitaxel were run in parallel. The mean and standard-deviation<br />
of the absorbancies were used to calculate CMV and drugs IC 50<br />
(PrismaGraphPad version 5.1).<br />
Findings: We screened the AE of 43 novel naftoquinones-derived<br />
drugs in MDA-MB-231 lineage; seven have decreased its CMV by, at<br />
least, 50%, as: PIC1 (IC 50 1.15x10 -4 M; CMV decrease of 50%); PIC6<br />
(IC 50 4.24x10 -5 M; CMV decrease of 70%); PIC10 (IC 50 5.07x10 -5 M;<br />
CMV decrease of 70%); PIC 20 (IC 50 1.38x10 -5 M; CMV decrease<br />
of 90%); PIC21 (IC 50 5.00x10 -5 M; CMV decrease of 70%); S5 (IC 50<br />
7.26x10 -5 M; CMV decrease of 60%); M20 (IC 50 7.94x10 -5 M; CMV<br />
decrease of 60%). Their AE was significantly higher than that of<br />
cisplatin (IC 50 1.56x10 -4 M; CMV decrease < 10%), doxorubicin (IC 50<br />
1.76x10 -4 M; CMV decrease of 38%), and paclitaxel (IC 50 5.05x10 -7 M;<br />
CMV decrease of 20%).<br />
Interpretation: Altogether, our results present potential novel<br />
antineoplastic drugs to treat TNBC from a panel of in house<br />
rationally designed naftoquinones-derived compounds, developing<br />
an innovative and economically viable project.<br />
P6-11-14<br />
Post-hoc safety and tolerability assessment in patients receiving<br />
palliative radiation during treatment with eribulin mesylate for<br />
metastatic breast cancer<br />
Yardley DA, Vahdat L, Rege J, Cortés J, Wanders J, Twelves C. Sarah<br />
Cannon Research Institute, Nashville, TN; Weill Cornell Medical<br />
College, New York, NY; Eisai Inc, Woodcliff Lake, NJ; Vall d’Hebron<br />
University Hospital, Barcelona, Spain; European Knowledge Center,<br />
Eisai Ltd., Hatfield, Hertfordshire, United Kingdom; St James<br />
University Hospital, Leeds, United Kingdom<br />
Background: Management of advanced breast cancer frequently<br />
includes palliative radiation therapy (RT) and many chemotherapy<br />
agents are radiation-sensitizers. We assessed whether the safety profile<br />
www.aacrjournals.org 551s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
of eribulin differed between metastatic breast cancer (MBC) patients<br />
receiving eribulin alone and those who also received palliative RT.<br />
Methods: Two previous phase 2 and 3 eribulin trials (Studies 211<br />
and 305, respectively) enrolled a total of 794 patients with locally<br />
recurrent or MBC who had received 2-5 prior chemotherapy<br />
regimens. In both trials eribulin mesylate (1.4 mg/m 2 ) was given on<br />
Days 1 and 8 of a 21-day cycle and intercurrent palliative RT was<br />
permitted. In this post-hoc analysis, patient-level data were pooled<br />
for a descriptive comparison of adverse events (AEs) between the<br />
patients who received RT during their study treatment and those<br />
who did not. RT delivered within 3 weeks of initiation of eribulin or<br />
RT encompassing >30% of marrow was excluded. If palliative RT<br />
was utilized on study, the protocol requirements were as follows:<br />
indications included bone pain, bronchial obstruction, ulcerating skin<br />
lesions; the total field for palliative RT was not to involve >10% of<br />
total bone marrow; and the irradiated lesion was not to be used for<br />
tumor response assessment. During palliative RT, eribulin treatment<br />
was to be delayed and then resumed when the patient had recovered<br />
from any RT-associated toxicities.<br />
Results: Of the 794 patients (291 patients in Study 211 and 503 in<br />
Study 305) who received eribulin, 44 (5.5%) received palliative RT.<br />
Site of radiation therapy<br />
Frequency*<br />
Arm/shoulder 3<br />
Back/spine 19<br />
Brain (whole) 7<br />
Chest 3<br />
Head/neck 2<br />
Leg/hip 17<br />
Undisclosed 9<br />
7 patients received RT at multiple sites.<br />
The majority (26/44, 60%) received ≥10 cGys. Baseline demographics<br />
were similar between the RT (n=44) and no RT (n=750) subgroups,<br />
as was the use of concomitant medications. Six of 44 patients (14%)<br />
continued eribulin treatment during the palliative RT, contrary to<br />
protocol recommendation. The AE profiles over the course of the<br />
study were similar between subgroups. The most common events<br />
reported in both subgroups (RT vs no RT) were neutropenia (50% vs<br />
55%), alopecia (48% vs 51%), nausea (43% vs 40%), fatigue (39%<br />
vs 32%), and asthenia (27% vs 32%). There were no significant<br />
differences in Grade 3/4 treatment-emergent AEs, or other AEs (total<br />
AEs: 56.8% vs 58.9%). Potential localized events that were more<br />
frequent in the RT subgroup were bone pain (27% vs 15%), back<br />
pain (27% vs 10%), and musculoskeletal pain (14% vs 8%); many<br />
represent potential indications for RT. Half (22/44) of patients started<br />
RT 30 days after the start of eribulin treatment. Palliative RT was<br />
short in duration; 33 (75%) patients received ≤7 days, and 11 (25%)<br />
patients received 8-20 days. Six of the 44 irradiated patients (14%)<br />
had a skin-related toxicity, but most were alopecia (7/8 events) and<br />
all were associated with eribulin.<br />
Conclusions: This post-hoc subgroup analysis suggests palliative RT<br />
while receiving eribulin treatment does not appear to have an effect<br />
on the AE profile of eribulin. Further studies to define the optimal<br />
use of radiotherapy with eribulin are warranted.<br />
P6-12-01<br />
Adjuvant treatment in breast cancer patients aged 70 years or<br />
older during three years. A systematic review of patients charts.<br />
Nätterdal T, Klint L, Holmberg E, Gunnarsdottír KA, Linderholm BK.<br />
Institution of Medical Sciences, Sahlgrenska Univeristy Hospital,<br />
Gothenburg, Sweden; Sahlgrenska University Hospital, Gothenburg,<br />
Sweden; Karolinska Institute Science Park, Stockholm, Sweden<br />
Background and aims: In general, previous studies on adjuvant<br />
chemotherapy have not included the elderly breast cancer (BC)<br />
population. Our aim was to investigate the actual recommended<br />
adjuvant therapy for patients’ age ≥70 years in clinical routine. We<br />
also determined the proportion of patients that terminated therapy<br />
in correlation to documented BC relapses. Material and Methods:<br />
Charts from consecutive patients diagnosed with a primary stage I-III<br />
BC from 1 st January 2005 through 31 st December 2007, age ≥70 years<br />
were studied (n=358). Data regarding standard BC parameters at<br />
diagnosis, adherence to recommended adjuvant therapy, reasons for<br />
suspension of treatment and outcome were documented. Comparisons<br />
were performed with patients divided into three age groups (70-74;<br />
75-79; and ≥80 years) and between different treatment modalities<br />
(i.e. endocrine therapy; chemotherapy; trastuzumab). Results: Higher<br />
age was statistically significantly correlated with axillary metastases<br />
(70-74y n=30, [30%]; 75-79 n=41, [49%]; and ≥80y n=120 [42%],<br />
(p=0.011), while tumor size were equal (p=0.103). No difference was<br />
found regarding routine BC parameters as histological type (p=0.636)<br />
or grade (p=0.662); vascular invasion (p=0.681); ER (p=0.892);<br />
PgR (p=0.718) or HER2 status (p=0.542). A total of 286 patients<br />
were advised adjuvant systemic therapy; only two patients received<br />
trastuzumab. A higher proportion of the oldest patients ≥80 (n=32<br />
[22%]) were left without any treatment compared with 75-79y (n=17<br />
[17%] and 70-74y (n=13 [13%], (p=0.0002), this was explained by<br />
differences regarding chemotherapy. Data on compliance was lacking<br />
for five patients, however there was a trend not reaching statistically<br />
significance revealing a correlation between higher age and a more<br />
frequent treatment termination (p=0.061). Treatment suspension was<br />
for chemotherapy (70-74y n=21, [52%]; 75-79 n=17, [71%]; and<br />
≥80y n=3 [100%] and for ET (70-74y n=69, [25%]; 75-79 n=66,<br />
[32%]; and ≥80y n=104 [46%]. There was a statistically significant<br />
correlation between higher age and more breast cancer relapses<br />
(BCR) (p=0.015) and RFS (p=0.038). We found a higher proportion<br />
of BCR among patients terminating planned treatment (n=112; 27%<br />
BCR) compared with patients adherent to therapy (n=168; 8% BCR)<br />
(p=0.015). Patients not recommended any treatment (n=62) had an<br />
intermediate outcome with 16% BCR. This observation was found<br />
in all age groups; patients terminating therapy; 70-74y 21% BCR,<br />
75-79y 42% BCR and ≥80y 20% BCR respectively compared with<br />
patients’ adherent to therapy 70-74y 6% BCR, 75-79y 10% BCR and<br />
≥80y 7% respectively. Conclusions: Elderly patients are diagnosed<br />
with BC at a later stage and adjuvant chemotherapy, as well as,<br />
endocrine therapy prematurely terminated. Insufficient treatment<br />
was significantly associated with increased risk of relapse. Less toxic<br />
regimens should be carefully investigated.<br />
P6-12-02<br />
Use of cytochrome P450 interacting medications in the setting of<br />
adjuvant therapy for breast cancer.<br />
Njiaju UO, Kolesar JM, Johnston SA, Eickhoff JC, Osterby KR,<br />
Poggi LE, Tevaarwerk AJ, Millholland RJ, Oliver KA, Heideman<br />
JL, Wisinski KB. University of Wisconsin-Madison, WI; University of<br />
Wisconsin-Madison; University of Wisconsin Hospitals and Clinics<br />
Background: In the current era of personalized medicine, oral<br />
targeted therapies are increasingly used in cancer treatment. In<br />
breast cancer, oral anti-estrogen agents have historically been part<br />
of standard treatment for hormone receptor positive disease. More<br />
recently, other targeted agents have been introduced in the metastatic<br />
setting, and are being evaluated as adjuvant therapies. Many oral<br />
medications, including anticancer therapies, are metabolized by<br />
cytochrome P450 (CYP450) enzymes raising possibility of drug-drug<br />
interactions that may affect toxicities or breast cancer outcomes.<br />
We sought to evaluate concomitant CYP450 medication use among<br />
women seeing a medical oncologist to discuss adjuvant systemic<br />
therapy for breast cancer.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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<strong>Cancer</strong> Research
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
Methods: We performed an electronic medical record database<br />
extraction. Adult women diagnosed with breast cancer from 1/2008-<br />
7/2011 were identified from the University of Wisconsin Hospital and<br />
Clinics <strong>Cancer</strong> Registry. Medication lists were extracted from the first<br />
encounter with a medical oncologist after the initial breast cancer<br />
diagnosis. Non-systemic medications were excluded. Cytochrome<br />
P450 (CYP450) enzyme-interacting medications were categorized as<br />
inhibitors, inducers, and/or substrates of specific enzymes including<br />
CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9,<br />
CYP2D6, CYP2E1, and CYP3A4. CYP450 inhibitors and inducers<br />
were further characterized as strong, moderate or weak acting.<br />
Results: A total of 455 women with non-metastatic breast cancer<br />
were identified. Mean age was 56.6 years (range of 23-90) and<br />
413 (91%) were Caucasian. Polypharmacy, defined as use of 3-5<br />
medications, was seen in 123 (27.0%) women. A total of 236 (51.9%)<br />
women were on 0-4; 109 (24.0%) on 5-10; and 13 (2.9%) on > 10<br />
medications at the time of first encounter with a medical oncologist<br />
after a breast cancer diagnosis. 23 (5.05%) women were on strong<br />
CYP450 enzyme inhibitors while 72 (15.8%) were on strong inducers.<br />
CYP450 enzymes most commonly affected were CYP3A4, CYP2C9,<br />
and CYP2D6. Among medications taken on a fixed schedule,<br />
levothyroxine and simvastatin were the most commonly used, while<br />
simvastatin and ranitidine were the most common CYP450 interacting<br />
medications. Further classification of potential CYP450 interactions<br />
is ongoing.<br />
Conclusions: A significant proportion of patients were on one or more<br />
CYP450 interacting medications in the setting of adjuvant therapy for<br />
breast cancer. Given the number of new oral cancer agents that are<br />
also CYP450 interacting, the potential for drug interactions should<br />
be recognized and appropriate management strategies implemented.<br />
P6-12-03<br />
Effects of high dose of bisphosphonate therapy on bone<br />
microarchitecture of the peripheral skeleton in women with early<br />
stage breast cancer<br />
Shao T, Shane ES, McMahon D, Crew KD, Kalinsky K, Maurer M,<br />
Brown M, Gralow JR, Hershman DL. Beth Israel Medical Center,<br />
Continuum <strong>Cancer</strong> Centers of New York, New York, NY; Columbia<br />
University Medical Center, New York, NY; University of Washington/<br />
Seattle <strong>Cancer</strong> Care Alliance, Seattle, WA<br />
Background: Randomized studies investigating adjuvant<br />
bisphosphonates in women with breast cancer are ongoing. While<br />
bisphosphonates would be expected to prevent the deterioration of<br />
bone microarchitecture that accompanies hormone or chemotherapy,<br />
complete suppression of osteoclast activity for prolonged periods<br />
of time can decrease repair of micro-cracks, and possibly lead to<br />
decreased bone strength. While bone strength is governed by the<br />
amount of bone present, trabecular and cortical components of bone<br />
microarchitecture also contribute independently to bone strength.<br />
We aimed to characterize the effects of long-term bisphosphonates<br />
on bone microarchitecture in women with breast cancer using highresolution<br />
peripheral quantitative computed tomography (HR-pQCT)<br />
of the distal radius and tibia.<br />
Methods: We conducted a cross-sectional study involving early stage<br />
breast cancer patients treated with bisphosphonates on the S0307<br />
clinical trial. Women were randomized to receive zoledronic acid,<br />
oral clodronate or oral ibandronate in doses far higher than those<br />
used in osteoporosis treatment as per protocol. After 18-36 months of<br />
bisphosphonate therapy, participates underwent a one-time evaluation<br />
of areal bone mineral density (aBMD) of the 1/3 radius, lumbar spine,<br />
and hip by dual energy x-ray absorptiometry (DXA), and cortical and<br />
trabecular volumetric BMD (vBMD) and trabecular microarchitecture<br />
of the radius and tibia by HR-pQCT. HR-pQCT measurements were<br />
compared to healthy young premenopausal women and age-matched<br />
Caucasian women.<br />
Results: Baseline characteristics of the 12 enrolled patients: median<br />
age of 53 (range 40-67); white/Hispanics 7/5; pre/postmenopausal<br />
4/8; mean body mass index 28.7 kg/m2 (20.9-34.8); average time<br />
on bisphosphonates 20 months (18-30); zoledronic acid/clodronate/<br />
ibandronate 5/6/1. The median aBMD DXA T-score of the 1/3<br />
radius, lumbar spine and total hip were normal at +0.3, +0.1, and<br />
+0.2, respectively. Mean total, cortical, and trabecular vBMD of the<br />
radius as measured by HR-pQCT were 330±71, 905±55, and 146±35<br />
mg hydroxyapatite/cm3, respectively. Mean cortical thickness was<br />
0.803±0.170 mm, and mean trabecular number was 1.9±0.2. Mean<br />
total, cortical, and trabecular vBMD of the tibia were 285±54, 880±54,<br />
and 150±38 mg hydroxyapatite/cm3, respectively. Mean cortical<br />
thickness was 1.135±0.264 mm, and mean trabecular number was<br />
1.7±0.3. There were no statistically significant differences between<br />
study group and each control. However, results were more similar to<br />
healthy young premenopausal control than the age-matched control.<br />
Conclusion: Women on long-term bisphosphonate therapy for breast<br />
cancer had normal aBMD by DXA and normal cortical and trabecular<br />
vBMD, cortical thickness and trabecular number at the peripheral<br />
skeleton compared to healthy young women and age-matched women.<br />
This preliminary data is reassuring for cancer survivors if benefits<br />
from this therapy are established in the adjuvant setting.<br />
Radius Study Group Mean (SD) Premenopausal Control Mean (SD)<br />
vBMD (mg HA/cm3)<br />
Total 330 (71) 330 (57)<br />
Cortical 905 (55) 904 (44)<br />
Trabecular 146 (35) 160 (33)<br />
Cortical thickness (mm) 0.803 (0.170) 0.804 (0.149)<br />
Trabecular number 1.9 (0.2) 1.7 (0.2)<br />
P6-13-01<br />
Lyso-thermosensitive liposomal doxorubicin + local hyperthermia<br />
for radiation-pretreated chest wall recurrence<br />
Formenti S, Rugo H, Myerson R, Diederich C, Straube W, O’Conner<br />
B, Matzkowitz AJ, Goodman RL, Muggia F. New York University<br />
<strong>Cancer</strong> Institute, New York, NY; UC <strong>San</strong> Francisco, <strong>San</strong> Francisco,<br />
CA; Siteman <strong>Cancer</strong> Center, Saint Louis, MO; Rhode Island Hospital,<br />
Providence, RI; New Hope <strong>Cancer</strong> Center, Hudson, FL; Saint<br />
Barnabas Medical Center, Livingston, NJ<br />
Background: Chest wall recurrence (CWR) causes much morbidity<br />
when not controlled by local measures. Lyso-thermosensitive<br />
liposomal doxorubicin (LTLD) provides accelerated release of<br />
doxorubicin (Dox) at ≥ 39° C, and is being studied for CWR based<br />
on the pioneering thermochemotherapy work of Dewhirst and<br />
colleagues at Duke. We now report on its tolerance, pharmacology,<br />
and preliminary antitumor effects in a dose-escalation study<br />
combined with local hyperthermia (LH) for radiation-refractory<br />
CWR. LH selectively increases liposomal permeability in tumor<br />
microvasculature, and promotes release of Dox from LTLD, and Dox<br />
tumor uptake, in addition to LH anti-tumor effects.<br />
Methods: This phase I study entered patients (pts) with CWRs <<br />
3 cm deep failing all standard Tx including surgery, radiation, and<br />
chemotherapy: pts received up to 6 LTLD/LH treatments every 21<br />
days at a starting dose of 40 mg/m 2 (cohort 1) and escalated to 50 mg/<br />
m 2 (cohort 2). LTLD was infused IV over 30 minutes (min); followed<br />
within 30 min by microwave or ultrasound LH. The thermal dose<br />
goal was 40°C-42°C for 60 min. Pharmacokinetic samples for total<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
plasma Dox and doxorubicinol (Doxol) were taken at 0.5, 5, 10 and<br />
24 hours after starting infusion. Left ventricular ejection fraction was<br />
monitored every other cycle.<br />
Results: Eleven pts with a median of 4 prior chemotherapy regimens<br />
(range 2 — 12) were enrolled; all but one had prior anthracycline<br />
(AC). All pts received ≥ 2 cycles. The within subject variability in<br />
Dox and Doxol exposure was small with mean Cycle 2 vs Cycle 1<br />
ratios ranging from 0.99 to 1.06.<br />
Cmax/dose (ng/ml)/(mg/m 2 ) Cycle 1 Cycle 2<br />
Dox 499.82 512.00<br />
Doxol 0.46 0.45<br />
AUClast/dose ((ng*hr/ml)/(mg/m 2 )<br />
Dox 1338.12 1381.82<br />
Doxol 7.96 8.04<br />
Grade 3 and 4 toxicities included reversible neutropenia in 17 (40.5%)<br />
and one case (each) of mucositis (grade 1), chest wall thermal burn,<br />
and chest wall cellulitis (both grade 4); these occurred in only ≥ 5%<br />
of 42 cycles given. No cardiomyopathy or hand-foot toxicity occurred.<br />
The rate of clinically-significant (≥ 6 point) QoL improvement on<br />
the FACT-B after 2 cycles was 54.5% (95% CI: 25.1% - 83.9%),<br />
including 1 lasting > 3 months. The local objective response rate was<br />
encouraging: 45.5% (95% CI: 16.1% - 74.9%), with 1 complete and<br />
4 partial local responses.<br />
Conclusion: LTLD + LH is safe in CWR after prior radiation<br />
and doxorubicin. A phase II study is planned for pharmacologic<br />
evaluations and to add pts with less or no anthracycline treatment.<br />
P6-13-02<br />
Overcoming therapy resistance of metastatic breast cancer by<br />
enhanced tumor delivery of polymeric doxorubicin<br />
Shen H, Xu R, Mai J, Huang Y, Ferrari M. The Methodist Hospital<br />
Research Institute, Houston, TX<br />
Metastatic breast cancers are treated with chemotherapy drugs in<br />
clinic. However, patients usually develop therapy resistance quickly<br />
due to intrinsic and acquired mechanisms. Poor drug delivery to<br />
tumor cells may also contribute to therapy resistance. To address<br />
both biological and mass transport barriers to effective therapy,<br />
we developed a new doxorubicin-based formulation, polymeric<br />
doxorubicin (pDox), to be delivered using a porous silicon drug<br />
carrier, the multistage vector (MSV). We show the novel, rationally<br />
designed MSV/pDox drug enriches in tumor tissues and has<br />
considerable therapeutic efficacy in two animal models of triple<br />
negative breast cancer lung metastasis, conferring a significant<br />
survival advantage to animals treated with MSV/pDox over all other<br />
control groups (80% survival for the MSV/pDox group at 24 weeks<br />
post treatment vs. 0% survival for all others, log-rank test, p
December 4-8, 2012 <strong>Abstract</strong>s: General Session 6<br />
P6-14-01<br />
Estrogen/progestogen use after <strong>Breast</strong> <strong>Cancer</strong> – a long-term<br />
follow-up of the Stockholm randomized trial.<br />
Fahlén MC, Fornander T, Johansson H, Rutqvist L-E, Wilking N,<br />
von Schoultz E. Capio St Görans Hospital, Stockholm, Sweden;<br />
Karolinska Institutet, Stockholm, Sweden<br />
Background. The management of hormonal deficiency symptoms in<br />
breast cancer survivors is still an unsolved problem. While several<br />
studies have shown that menopausal hormone therapy (MHT) may<br />
increase the risk of breast cancer in healthy women, its effects on<br />
recurrence for women already affected by breast cancer is unclear.<br />
Observational studies have even suggested that there may be a<br />
decreased recurrence rate for women using MHT. The few clinical<br />
trials in this field have all been closed preterm.<br />
Methods. The Stockholm trial was started in 1997 as a randomized<br />
open study with two parallel groups. Postmenopausal women who had<br />
undergone primary surgery for breast cancer were asked to participate.<br />
After inclusion they were randomized to either treatment with MHT<br />
(n=188) or not (n=190). The study was designed to minimize the<br />
dose of progestogen in the MHT arm. The trial was stopped in 2003<br />
when another Swedish study (HABITS), with a similar arrangement,<br />
reported increased recurrence. However the Stockholm material<br />
showed no excess risk after 4 years of follow-up. A long-term followup<br />
has now been performed.<br />
The aim. We wanted to determine if it was possible to treat the<br />
menopausal symptoms experienced by women with breast cancer<br />
and on breast cancer medication, without compromising their safety.<br />
Statistical method. The median follow-up time was calculated<br />
using the reversed Kaplan-Meyer technique. Proportional hazards<br />
regression was used to model event specific hazards. Results from the<br />
regression models were presented as hazard ratios together with 95%<br />
confidence intervals. Differences in time to specific event distributions<br />
were tested using the log-rank test. All analyses were based on the<br />
intention-to-treat principle.<br />
Findings. The mean duration of hormone use in the MHT group was<br />
2.6±1.2 years. After a median of 10.8 years of follow-up, there was no<br />
difference in new breast cancer events: 60 in the MHT group versus 48<br />
among controls (HR=1.3;95%CI=0.9-1.9). Among women on MHT,<br />
11 had local recurrence and 12 distant metastases versus 15 and 12 for<br />
the controls. There were 14 contra-lateral breast cancers in the MHT<br />
group and 4 in the control group (HR=3.6;95%CI=1.2-10.9;p=0.013).<br />
There was no difference in overall mortality between the groups. The<br />
total number of deaths in the menopausal hormone therapy group<br />
was 19 (10 from breast cancer) and in the control group 18 (11 from<br />
breast cancer). Also there was no difference in the occurrence of new<br />
primary malignancies other than contra-lateral breast cancer – 21 in<br />
the MHT group and 16 in the non MHT group.<br />
Interpretation. The number of new events did not differ between the<br />
groups, in contrast to previous reports. The increased recurrence<br />
in HABITS has been attributed to this trials higher progestogen<br />
exposure. As both trials were prematurely closed, data do not allow<br />
firm conclusions. In neither of the studies there were any increased<br />
mortality from breast cancer or other causes in the MHT-group.<br />
Current guidelines typically consider MHT contraindicated in breast<br />
cancer survivors. Our findings suggest that, in some women symptom<br />
relief may outweigh the potential risks of MHT.<br />
P6-14-02<br />
Withdrawn by Author<br />
P6-14-03<br />
Statin and aspirin use is not associated with a reduced risk of<br />
VTE’s in breast cancer patients<br />
Shai A, Rennert HS, Ballan Haj M, Lavie O, Steiner M, Rennert<br />
G. Lin Medical Center, Haifa, Israel; Carmel Lady Davis Medical<br />
Center, Haifa, Israel<br />
Introduction: Statins and aspirin have been shown to reduce the risk<br />
of venous thromboembolic events (VTE’s) in the general population<br />
in randomized trials.<br />
Aim: To assess whether statins and aspirin reduce the incidence of<br />
deep vein thrombosis and pulmonary embolism in patients diagnosed<br />
with breast cancer.<br />
Methods: The <strong>Breast</strong> <strong>Cancer</strong> in Northern Israel Study (BCINIS) is an<br />
on-going population-based case-control study of consecutive breast<br />
cancer cases and matched controls diagnosed in the northern part of<br />
Israel since 2000.<br />
Only cases insured by the Clalit Health Services (64%) were included<br />
in this analysis. Data on medication use and VTE were extracted<br />
from the computerized database. Patients taking Warfarin or LMWH<br />
were excluded.<br />
Statistical analysis was performed using SPSS (v 18). Use of<br />
medications was analyzed as a time dependent covariate in a Cox<br />
Regression model.<br />
Results: Of 3552 patients 261 (7.3%) had a VTE during a median<br />
follow up of 4.7 years.<br />
In a multivariate analysis age (HR 1.03, 95% CI 1.02-1.04), BMI (HR<br />
2.12, 95% CI 1.43-3.14 for BMI >30), chemotherapy (HR 3.87, 95%<br />
CI 2.50-5.98) and metastatic disease (HR 2.27, 95% CI 1.10-6.53)<br />
were associated with an increased risk for VTE’s.<br />
Statins, mainly simvastatin and pravastatin, were used by 55.7%<br />
of the patients, and 45.7% used aspirin. Neither statins nor aspirin<br />
were associated with a significantly reduced risk for a VTE. After<br />
controlling for age, BMI, stage, chemotherapy and tamoxifen use the<br />
HR for statins was 0.80, CI 0.56-1.13, p=0.2, and the HR for aspirin<br />
was 1.004, CI 0.74-1.76, p=0.98.<br />
Conclusion: In contrast to the findings in the general population, statin<br />
and aspirin use were not associated with a reduced risk for VTE’s in<br />
our cohort of breast cancer patients. Our results might be explained<br />
by an alternate mechanism of VTE formation in breast cancer and the<br />
use of low potency statins (simvastatin and pravastatin) in this cohort.<br />
P6-14-04<br />
Rosehip extracts prevent triple negative breast cancer cell<br />
proliferation by regulation the phosphorylation of p70S6 Kinase.<br />
Coburn TL, Cagle PD, Shofoluwe AI, Martin PM. North Carolina<br />
Agricultural and Technical State University, Greensboro, NC<br />
Triple Negative <strong>Breast</strong> <strong>Cancer</strong> (TNBC) is an aggressive form of<br />
breast cancer, characterized by its lack of the human epidermal<br />
growth factor receptor-2 (HER-2), the estrogen receptor (ER), and<br />
the progesterone receptor (PR). Due to the lack of these hormone<br />
receptors, TNBC has abnormal therapeutic results; leading to the<br />
need for unique treatment methods. TNBC has a partial response<br />
to chemotherapy, which is associated with the lack of clinically<br />
established targeted therapies. Plant extracts have shown to be useful<br />
as chemopreventive agents due to their disruption of pro-survival<br />
and proliferative mechanisms on cancer cells. Rosehip extracts have<br />
shown potential anti-proliferative activity against cancer cells in vitro.<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
This study investigated the effect of rosehip extracts in TNBC cell<br />
lines (HCC1806 and MB157) and basal-like breast cancer cell lines<br />
(HCC70 and HCC1500). To determine the inhibitory role of rosehip<br />
extracts in cell proliferation, MTT assays were conducted, following<br />
treatment with varying concentrations of rosehip extracts (1mg/ml,<br />
250ug/ml, 25ug/ml, and 25ng/ml) for 48 hours. The data suggests<br />
that rosehip extracts, can significantly decrease cell proliferation in<br />
all the breast cancer cell lines assayed. Preliminary studies suggest<br />
that this is accomplished without toxic effects. Western blot analysis<br />
was used to investigate which signaling pathway rosehip extracts<br />
were affecting. Western Blot analysis suggests that rosehip extracts<br />
are inhibiting p70 S6 kinase phosphorylation and its ability to act as<br />
a kinase for S6 ribosomal protein. Based on these findings, rosehip<br />
extracts prevent cell proliferation by interfering with the p70 S6<br />
kinase signaling.<br />
P6-14-05<br />
Impact of breast cancer CME: Physician practice pattern,<br />
knowledge, and competence assessments<br />
Haas M, Heintz A, Stacy T. Educational Concepts Group, LLC,<br />
Atlanta, GA<br />
Background<br />
Several scientific advances for women with breast cancer have taken<br />
place in the last decade. The National <strong>Cancer</strong> Institute reports that<br />
approximately 2.5 million women with a history of breast cancer are<br />
alive today due to advances in screening, detection, treatment, and<br />
supportive care.<br />
Due to the volume and pace of scientific advances within the<br />
specialty of oncology, the timely dissemination of clinical trial<br />
results and discussions regarding the appropriate incorporation of<br />
advances into therapeutic strategy is necessary to provide the highest<br />
quality patient care. Furthermore, increasing awareness in the breast<br />
cancer community on similarities and differences amongst practice<br />
management strategies helps to identify individual practice patterns<br />
and benchmark individual knowledge and competence against one’s<br />
professional peers.<br />
Methods<br />
Between November 2011 and November 2012, educational outcomes<br />
assessments were gathered during 95 independent continuing medical<br />
education (CME) activities held within community and academic<br />
institutions and practices across the United States. The activities<br />
educated oncology healthcare providers on recent updates to the<br />
development and integration of new therapies in the management of<br />
ER+, HER2+ and/or HER2- breast cancer.<br />
Participants were asked a series of case-based questions via an<br />
audience response system to assess baseline knowledge, competence,<br />
and identify practice patterns. Assessments were repeated post a<br />
1-hour independent CME certified activity, with an additional 6-week<br />
electronic follow-up. Barriers to implementing the information<br />
learned were captured at 6-week follow-up. Educational gaps were<br />
identified through documentation and comparison of current best<br />
practices versus actual participant responses.<br />
Results<br />
To date, a total of 568 healthcare providers have participated in the<br />
initiative of which 326 (57%) were physicians. Number of years in<br />
practice included < 10 years (22%), 10-20 years (50%), 21-30 years<br />
(13%), > 30 years (15%). The number of breast cancer patients seen<br />
per month included ≤ 10 (45%), 11-20 (17%), 21-30 (15%), 31-40<br />
(8%), and > 40 (15%). This represents a potential impact of 3,706<br />
patient lives.<br />
Provider competency in applying recent literature to the patient care<br />
setting was both assessed and measured. Results of patient therapy<br />
selection in the first-line and relapsed MBC setting will be reported.<br />
Knowledge and awareness regarding recent clinical trials as well as<br />
self-reported competence in discussing the mechanism of action,<br />
efficacy, and safety data from recent clinical trials will be presented.<br />
Participants reported a number of barriers to applying data learned<br />
at the activities into clinical practice. Responses included lack of<br />
reimbursement (24%), treatment side effects (24%), newness of<br />
treatment data (40%), perceived efficacy (8%) and treatment not<br />
commercially available (4%).<br />
Conclusion<br />
The results suggest the education of providers on the most currently<br />
available clinical trial results and peer discussion of how to optimize<br />
translation of this information into patient care increases breast<br />
cancer provider knowledge and competence. <strong>Breast</strong> cancer CME<br />
plays an important role in improving the care of patients and practice<br />
of medicine.<br />
OT1-1-01<br />
A phase II study of neoadjuvant epirubicin/cyclophosphamide<br />
(EC) followed by weekly nanoparticle albumin-bound paclitaxel<br />
with or without trastuzumab for node-positive breast cancer<br />
Hirano A, Hattori A, Kamimura M, Ogura K, Kim N, Setoguchi<br />
Y, Okubo F, Inoue H, Jibiki N, Miyamoto R, Kinoshita J, Kimura<br />
K, Fujibayashi M, Shimizu T. Tokyo Women’s Medical University,<br />
Medical Center East, Tokyo, Japan; Tokyo Women’s Medical<br />
University, Yachiyo Medical Center, Yachiyo, Japan<br />
Background<br />
Paclitaxel is considered standard treatment for metastatic breast cancer<br />
(MBC) and is often used as adjuvant and neoadjuvant chemotherapy<br />
for patients with early-stage disease. Conventional paclitaxel requires<br />
solvents such as polyoxyethylated castor oil; however, such solvents<br />
are associated with toxicity including peripheral neuropathy and<br />
hypersensitivity reaction. Moreover, the use of the drug requires<br />
special tubing and in-line filters. Therefore, nanoparticle albuminbound<br />
paclitaxel (nab-PTX) requiring no solvent has been developed.<br />
Nab-PTX was effective in patients with MBC and as a neoadjuvant<br />
therapy. A comparison between weekly and triweekly nab-PTX<br />
suggested that weekly nab-PTX was superior in progression-free<br />
survival.<br />
Trial design<br />
This is a phase II trial to evaluate the efficacy and toxicity of<br />
neoadjuvant epirubicin/cyclophosphamide (EC) (epirubicin/<br />
cyclophosphamide) followed by weekly nab-PTX with or without<br />
trastuzumab for node-positive breast cancer. Patients receive four<br />
cycles of epirubicin (90 mg/m 2 ) and cyclophosphamide (600 mg/<br />
m 2 ) every 3 weeks, followed by four cycles of nab-PTX (125 mg/m 2 )<br />
on days 1, 8 and 15 in a 28-day cycle. Fifteen cycles of trastuzumab<br />
(2 mg/kg, loading 4 mg/kg) are added to the nab-PTX regimen in<br />
HER2-positive patients every week.<br />
Eligibility criteria<br />
Patients with histologically diagnosed invasive breast cancer based<br />
on a core needle biopsy of the T1-4 N1-3 without previous operation<br />
or chemotherapy are included in this trial. Eligible patients are aged<br />
between 20 years and 70 years with a performance status of 0 to 2<br />
and adequate organ functions.<br />
Specific aims<br />
The primary endpoint is the pathologic complete response (pCR) rate<br />
in the breast and axilla, and the secondary endpoints are the breast<br />
conserving rate, toxicities, feasibility and overall survival.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
556s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT1<br />
Statistical methods<br />
The sample size was calculated using the Simon method, with a type<br />
I error of 10% and a study power of 80%.<br />
1. HER2-negative patients<br />
The expected rate of pCR was 25% and the required number of<br />
patients was estimated to be 33.<br />
2. HER2-positive patients<br />
The expected rate of pCR was 50%, and the required number of<br />
patients was estimated to be 21.<br />
Present and target accrual<br />
Patient accrual within two medical centers started in April 2011<br />
with 20 patients being on study to date (2012, June 12). A total of<br />
56 patients (22 are HER2-positive and 34 are HER2-negative) are<br />
planned to be enrolled in the trial.<br />
OT1-1-02<br />
A single-arm phase IIIb study of pertuzumab and trastuzumab<br />
with a taxane as first-line therapy for patients with HER2-positive<br />
advanced breast cancer (PERUSE)<br />
Bachelot T, Ciruelos E, Peretz-Yablonski T, Schneeweiss A, Puglisi<br />
F, Mitchell L, Dünne A, Miles D. Centre Leon Bérard, Lyon, France;<br />
Hospital Universitario 12 Octubre, Madrid, Spain; Hadassah-<br />
Hebrew University Medical Center, Jerusalem, Israel; National<br />
Center for Tumor Diseases, University-Hospital Heidelberg,<br />
Germany; University Hospital of Udine, Italy; F. Hoffmann-La Roche,<br />
Basel, Switzerland; Mount Vernon <strong>Cancer</strong> Centre, Mount Vernon<br />
Hospital, Middlesex, United Kingdom<br />
Background: Pertuzumab (P), a humanized monoclonal antibody,<br />
inhibits signaling downstream of HER2 by binding to the dimerization<br />
domain of the receptor and preventing heterodimerization with<br />
other HER family members. The epitope recognized by P is distinct<br />
from that bound by trastuzumab (H) and so their complementary<br />
mechanisms of action result in a more comprehensive HER2 blockade.<br />
Data from the phase III trial CLEOPATRA showed significantly<br />
improved PFS in patients (pts) receiving P + H + docetaxel compared<br />
with H + docetaxel + placebo as first-line treatment for HER2-positive<br />
metastatic breast cancer (BC).<br />
Trial design: PERUSE is a phase IIIb, multicenter, open-label,<br />
single-arm study in pts with HER2-positive metastatic or locally<br />
recurrent BC who have not been treated with systemic nonhormonal<br />
anticancer therapy for metastatic cancer. Pts will receive, P: 840 mg<br />
initial dose, 420 mg q3w IV; H: 8 mg/kg initial dose, 6 mg/kg q3w<br />
IV; taxane: docetaxel, paclitaxel, or nab-paclitaxel according to local<br />
guidelines. Treatment will be administered until disease progression<br />
or unacceptable toxicity. A planned protocol amendment will allow<br />
hormone receptor-positive pts to receive endocrine therapy alongside<br />
P+H after completion of taxane therapy, in line with clinical practice.<br />
Eligibility criteria: At baseline, pts must have an LVEF of ≥50%,<br />
an ECOG PS of 0, 1, or 2, a disease-free interval of ≥6 months, and<br />
must not have received prior anti-HER2 agents for the treatment of<br />
metastatic BC. Prior H and/or lapatinib in the (neo)adjuvant setting<br />
is permitted, providing there was no disease progression during<br />
treatment. Pts must not have experienced other malignancies within<br />
the last 5 yrs other than carcinoma in situ of the cervix or basal cell<br />
carcinoma. There must be no clinical or radiographic evidence of CNS<br />
metastases or clinically significant cardiovascular disease.<br />
Specific aims: As H was not widely available in the (neo)adjuvant<br />
setting prior to CLEOPATRA recruitment, a relatively low proportion<br />
of pts in CLEOPATRA had previously received H. PERUSE will<br />
assess the safety and tolerability of P+H + choice of taxane as first-line<br />
therapy for pts with HER2-positive metastatic or locally advanced<br />
BC in a pt population likely to have experienced wider exposure to<br />
prior H therapy.<br />
Statistical methods: The primary endpoints of the PERUSE study<br />
are safety and tolerability. Secondary endpoints include PFS, OS,<br />
ORR, CBR, duration of response, time to response and QoL. The final<br />
analysis will be performed when 1500 pts have been followed up for<br />
at least 12 months after the last pt receives last study treatment unless<br />
they have been lost to follow-up, withdrawn consent, or died, or if the<br />
study is prematurely terminated by the sponsor. Safety analyses are<br />
planned after enrollment of ∼350, 700, and 1000 pts. Additionally,<br />
a data and safety monitoring board will review safety data after ∼50<br />
pts have been enrolled and then every 6 months.<br />
Current and target accrual: Enrollment of the first pt is expected in<br />
June 2012 with a total of 1500 pts planned to be recruited.<br />
OT1-1-03<br />
PERSEPHONE: Duration of Trastuzumab with Chemotherapy<br />
in women with HER2 positive early breast cancer.<br />
Earl HM, Cameron DA, Miles D, Wardley AM, Ogburn ERM, Vallier<br />
A-L, Loi S, Higgins HB, Hiller L, Dunn JA. University of Cambridge,<br />
Cambridge, United Kingdom; NIHR Cambridge Biomedical Research<br />
Centre, Cambridge, United Kingdom; Edinburgh University,<br />
Edinburgh, United Kingdom; Mount Vernon <strong>Cancer</strong> Centre,<br />
Middlesex, United Kingdom; The Christie Hospital, Manchester,<br />
United Kingdom; Warwick Clinical Trials Unit, University of<br />
Warwick, Coventry, United Kingdom; Cambridge <strong>Cancer</strong> Trials<br />
Centre, Cambridge<br />
Background: Persephone is a phase III randomised controlled trial<br />
comparing six months of trastuzumab to the standard 12 month<br />
duration in patients with HER2 positive early breast cancer in respect<br />
of disease free survival, safety and cost-effectiveness. A Persephone<br />
sister study, the PHARE trial run by the National Institute for <strong>Cancer</strong>,<br />
successfully closed to recruitment in 2010. A prospective metaanalysis<br />
is planned once each trial has reported individually.<br />
Methods: A total of 4000 patients will be randomised into each of the<br />
two treatment groups. Eligible participants must be Her2 positive with<br />
a histological diagnosis of invasive breast cancer and no evidence<br />
of metastatic disease. Patients will receive neo-adjuvant or adjuvant<br />
chemotherapy and have no previous diagnosis of malignancy unless<br />
managed by surgical treatment only and disease-free for 10 years.<br />
Patients can be randomised at any time prior to receiving their 10th<br />
cycle of trastuzumab.<br />
The power calculations assume that the disease-free survival (DFS)<br />
of the standard treatment of 12 months trastuzumab will be 80% at<br />
4 years. On this basis, with 5% 1-sided significance and 85% power,<br />
a trial randomising 2000 in each arm will have the ability to prove<br />
non-inferiority of the experimental arm defining non-inferiority as<br />
‘no worse than 3%’ below the control arm 4 year DFS. Primary<br />
outcome is disease-free survival non-inferiority (equivalence) of 6<br />
months trastuzumab compared with 12 months in women with early<br />
breast cancer. Secondary outcomes are overall survival non-inferiority<br />
(equivalence); expected incremental cost effectiveness; cardiology<br />
function and analysis of predictive factors for development of cardiac<br />
damage. Two mandatory sub-studies are: Tumour block collection to<br />
discover molecular predictors of survival with respect to duration of<br />
trastuzumab treatment and blood sample collection, used to discover<br />
single nucleotide polymorphisms (SNPs) as genetic/pharmaco-genetic<br />
determinants of prognosis, toxicity and treatment outcome. A third<br />
optional sub-study is the quality of life questionnaires.<br />
www.aacrjournals.org 557s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Results: Persephone opened to recruitment in October 2007. To date,<br />
2152 patients (54%) of its total have been randomised from 147 UK<br />
sites. Recruitment is due to complete by December 2013 and the first<br />
planned interim analysis of the primary outcome will be mid-2016.<br />
Conclusion: The IDSMC last reviewed the trial in December 2011 and<br />
congratulated the Trial Management Group on the conduct of the trial<br />
and the quality of the data. No safety concerns were identified, and<br />
the IDSMC proposed that the trial continue to planned recruitment.<br />
OT1-1-04<br />
ALTERNATIVE: safety and efficacy of lapatinib (L), trastuzumab<br />
(T), or both in combination with an aromatase inhibitor (AI)<br />
for the treatment of hormone receptor-positive (HR+), human<br />
epidermal growth factor receptor 2 positive (HER2+) metastatic<br />
breast cancer<br />
Johnston S, Wroblewski S, Huang Y, Harvey C, Nagi F, Franklin N,<br />
Gradishar W. Royal Marsden NHS Foundation Trust and Institute<br />
of <strong>Cancer</strong> Research, London, United Kingdom; GlaxoSmithKline,<br />
Collegeville, PA; GlaxoSmithKline, Stockley Park, United Kingdom;<br />
Northwestern University, Chicago, IL<br />
Background: Overexpression of the human epidermal growth<br />
factor receptor 2 (HER2) gene in breast cancer is associated with an<br />
aggressive phenotype, poor prognosis, and resistance to endocrine<br />
therapies. Of HER2+ patients, ∼50% are also hormone receptorpositive<br />
(HR+). For patients who are both HER2+ and HR+,<br />
combining the AI letrozole with the dual tyrosine kinase inhibitor L<br />
has been shown to improve outcomes compared with letrozole alone.<br />
The combination of L and T, a humanized monoclonal antibodytargeting<br />
HER2, has been shown to improve outcomes compared<br />
with L alone.<br />
Trial design: The ALTERNATIVE study is a Phase III, randomized,<br />
open-label, multicenter trial, which will examine the efficacy of L/T/<br />
AI in combination versus T/AI alone. Patients will be randomized<br />
to 1 of 3 treatment arms: L 1000 mg po QD plus T (loading dose of<br />
8 mg/kg followed by maintenance with 6 mg/kg IV q3w plus an AI<br />
po QD); T plus an AI; or L 1500 mg po QD plus an AI. Choices of<br />
AI include letrozole, anastrozole, or exemestane.<br />
Eligibility criteria: Postmenopausal female patients with HER2+/<br />
HR+ metastatic breast cancer (MBC) who have received neo/adjuvant<br />
T and endocrine therapy, are treatment naïve for MBC, and are not<br />
candidates for chemotherapy.<br />
Specific aims: The primary efficacy endpoint is overall survival<br />
(OS), defined as the time from randomization until death due to any<br />
cause, for L/T/AI compared with T/AI alone. Secondary efficacy<br />
objectives include comparisons of OS between T/AI and L/AI as<br />
well as between T/L/AI and L/AI in addition to comparisons of<br />
progression-free survival, overall response rate, time to response, and<br />
duration of response. The safety objective is to evaluate the safety<br />
and tolerability for all 3 treatment groups.<br />
A 4-year recruitment is anticipated. More than 200 centers across<br />
37 countries are planned; approximately 110 centers are currently<br />
open for enrollment.<br />
Statistical methods: The study is powered to detect a 42% reduction<br />
in risk of death (hazard ratio=0.70) in patients who receive L/T/AI<br />
(median 28.5 months) versus T/AI (median 20 months) using a 1-sided<br />
test for superiority with α=0.025. The required number of total events<br />
to achieve a power of 80% is 249. Secondary comparisons are not<br />
powered and will be based on the intent-to-treat population.<br />
Present and target accrual: Twenty-six (26) of 525 patients have<br />
been randomized. Patients who have participated in previous neo-/<br />
adjuvant trials including a T regimen are eligible, provided they meet<br />
all other inclusion criteria.<br />
The study is currently recruiting patients, with an anticipated target<br />
accrual of 525 patients by March 2016.<br />
Clinical trial registry number: NCT01160211<br />
OT1-1-05<br />
A Phase I pharmacokinetics trial comparing PF-05280014 and<br />
trastuzumab in healthy volunteers (REFLECTIONS B327-01)<br />
Ricart AD, Zacharchuk C, Reich SD, Meng X, Barker KB, Taylor CT,<br />
Hansson AG. Pfizer Inc., <strong>San</strong> Diego, CA; Pfizer Inc., Cambridge, MA;<br />
Pfizer Inc., New Haven, CT<br />
Background: Trastuzumab is a humanized recombinant monoclonal<br />
antibody that selectively binds the extracellular domain of human<br />
epidermal growth factor receptor 2 (HER2) and is approved for<br />
treatment of breast and gastric cancers. PF05280014 is being<br />
developed as a potential biosimilar to trastuzumab. In nonclinical<br />
evaluations, PF-05280014 has an identical amino acid sequence to<br />
trastuzumab and similar physicochemical and in vitro functional<br />
properties. The goal of this phase I trial is to demonstrate the<br />
pharmacokinetic similarity of PF-05280014 to trastuzumab sourced<br />
from both the United States (trastuzumab-US) and European Union<br />
(trastuzumab-EU).<br />
Trial design: In this double-blind, parallel group, single dose<br />
trial, subjects will be randomized 1:1:1 into 3 arms: PF-05280014;<br />
trastuzumab-US, and trastuzumab-EU (NCT01603264).<br />
Eligibility: Healthy male volunteers, 18-55 years of age with normal<br />
left ventricular ejection fraction are eligible. Multiple exclusion<br />
criteria common to Phase 1 trials are in effect. All subjects must<br />
provide informed consent.<br />
Aims: The primary objectives are to demonstrate the pharmacokinetic<br />
similarity of PF-05280014 to trastuzumab-US and trastuzumab-EU.<br />
Secondary objectives include evaluating the safety, tolerability, and<br />
immunogenicity of PF-05280014 compared with US-licensed and<br />
EU-approved trastuzumab products.<br />
Statistical methods: Pharmacokinetic similarity will be demonstrated<br />
if the 90% confidence interval of the ratio of the area under the<br />
concentration-versus-time curve from time 0 to the last time point<br />
with quantifiable concentration (AUC T ) and maximum concentration<br />
(C max ) of PF-05280014 to both trastuzumab-US and trastuzumab-EU<br />
are within 80% – 125%. At least 93 subjects, 31/arm, will be needed<br />
to provide >81% power to demonstrate pharmacokinetic similarity<br />
for all comparisons. The planned enrolment is 105 subjects to account<br />
for subjects who may not complete the full follow-up period. The<br />
intent-to-treat (ITT) population is defined as all subjects who are<br />
randomized to receive treatment. The modified ITT population is<br />
defined as all subjects who are randomized and receive at least one<br />
dose of treatment and will be used to assess safety, tolerability, and<br />
immunogenicity. The per-protocol population is defined as all subjects<br />
who are randomized to and receive treatment and do not have any<br />
major protocol violations and will be used for the primary evaluation<br />
of pharmacokinetic parameters.<br />
Accrual: The target accrual is 105 subjects; present accrual is<br />
17subjects.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
558s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT1<br />
OT1-1-06<br />
A phase III randomized study of Paclitaxel and Trastuzumab<br />
versus Paclitaxel, Trastuzumab and Lapatinib in first line<br />
treatment of HER2 positive metastatic breast cancer.<br />
Crown JP, Moulton B, O’Donovan N. St Vincent’s University<br />
Hospital, Elm Park, Dublin, Ireland; ICORG (All Ireland Cooperative<br />
Oncology Research Group), Dublin 4, Ireland; National Institute for<br />
Cellular Biotechnology, Dublin City University, Dublin 9, Ireland<br />
Background: Preclinical studies have shown that dual targeting<br />
of the extracellular domain and the kinase domain of HER2 using<br />
trastuzumab (H) and lapatinib (L) produces greater growth inhibition<br />
than single agent treatment. The combination of trastuzumab<br />
and lapatinib has shown improved clinical outcome compared to<br />
lapatinib alone in the pre-treated metastatic setting (EGF104900),<br />
and compared to trastuzumab in the neo-adjuvant setting (Neo-Altto).<br />
This international phase III randomised trial will compare the efficacy<br />
of trastuzumab and paclitaxel (T) with trastuzumab, paclitaxel and<br />
lapatinib in first line treatment of HER2 positive metastatic breast<br />
cancer, and will examine potential predictive biomarkers of response<br />
to trastuzumab and/or lapatinib.<br />
Study Design and Eligibility: Six hundred patients with invasive<br />
HER2 positive (3+ or FISH positive) metastatic breast cancer<br />
(measurable disease per RECIST 1.1), who have not received prior<br />
systemic therapy for metastatic disease, will be randomised to receive<br />
(A) weekly paclitaxel (80 mg/m², for 3 weeks of a 4 week cycle) plus<br />
trastuzumab (8 mg/kg loading dose day 1 and 4mg/kg every 2 weeks)<br />
or (B) weekly paclitaxel (80 mg/m², for 3 weeks of a 4 week cycle)<br />
plus trastuzumab (8 mg/kg loading dose day 1 and 4 mg/kg every<br />
2 weeks) plus lapatinib (1,000 mg daily), until disease progression,<br />
unacceptable toxicity or consent withdrawal.<br />
Objectives: The primary objective of the study is to compare the<br />
efficacy of THL versus TH in first line treatment of metastatic HER2<br />
positive breast cancer. Secondary objectives include: (i) examining<br />
the objective tumour response rate and overall survival; (ii) assessing<br />
the safety and tolerability of lapatinib when administrated with both<br />
paclitaxel and trastuzumab; (iii) examining the effects of the TH<br />
regimen versus the THL regimen on health-related quality of life<br />
(FACT-B); (iv) examining potential biomarkers in tumour tissue<br />
and serum samples; (v) determining if prophylactic loperamide<br />
significantly reduces the number of diarrhoea-related adverse events.<br />
Statistical Methods: The expected median progression free survival<br />
time for the control arm is 6.9 months based on the trastuzumab plus<br />
paclitaxel arm of the phase III trastuzumab plus chemotherapy trial.<br />
A total of 600 evaluable patients (and 485 observed events) would be<br />
sufficient to detect an increase to 8.9 months in median PFS time for<br />
the THL combination, with 80% power and a two sided significance<br />
level of 0.05. Progression-free survival will be analysed at nine<br />
months after enrolment ends and overall survival will be analysed<br />
at 30 months after the end of enrolment. Objective response will be<br />
defined as the proportion of patients who receive a complete or partial<br />
response as defined by RECIST 1.1.<br />
Accrual: This study will accrue six hundred patients across forty<br />
International centres. Countries signed up to participate include<br />
Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy,<br />
Netherlands, Norway, Poland, Portugal, Switzerland and Spain. The<br />
study opened to accrual in Ireland Feb 12 and six patients have been<br />
accrued to date.<br />
Funding: Trial supported by GlaxoSmithKline. Lapatinib kindly<br />
supplied by GlaxoSmithKline.<br />
OT1-1-07<br />
Human epidermal growth factor receptor 2 (HER2) suppression<br />
with the addition of lapatinib to trastuzumab in HER2-positive<br />
metastatic breast cancer (LTP112515)<br />
Lin N, Danso MA, David AK, Muscato J, Rayson D, Houck, III WA,<br />
Ellis C, DeSilvio M, Garofalo A, Nagarwala Y, Winer E. Dana-<br />
Farber <strong>Cancer</strong> Institute, Boston, MA; Virginia Oncology Associates,<br />
Norfolk, VA; Augusta Oncology Associates, Augusta, GA; Missouri<br />
<strong>Cancer</strong> Associates, Columbia, MO; QEII Health Sciences Centre,<br />
Halifax, NS, Canada; Virginia <strong>Cancer</strong> Specialists, PC, Winchester,<br />
VA; GlaxoSmithKline Oncology, Collegeville, PA<br />
Background: The combination of lapatinib (L) with trastuzumab (T)<br />
results in enhanced antitumor activity in preclinical models of HER2-<br />
positive breast cancer (BC), due to the complementary mechanisms<br />
of action of the two agents. In patients with prior T-treated HER2-<br />
positive metastatic BC (MBC), treatment with T plus L was<br />
associated with longer progression-free survival (PFS) and overall<br />
survival (OS) compared with L alone. The combination also had an<br />
acceptable safety and tolerability profile. In patients with stage II/III<br />
BC, preoperative treatment with the combination plus paclitaxel (P)<br />
resulted in significantly higher pathologic complete response rates<br />
compared with P combined with either agent alone. This evidence<br />
supports the concept of dual HER2 blockade as a treatment strategy<br />
for HER2-positive MBC. Current common clinical practice for most<br />
patients experiencing clinical benefit from first-line treatment with<br />
T plus chemotherapy is to continue T as maintenance therapy after<br />
completion of the recommended number of chemotherapy cycles.<br />
The present study is designed to evaluate whether the addition of L<br />
improves PFS among women with HER2-positive MBC receiving<br />
T as maintenance therapy.<br />
Methods: In this open-label, Phase III study, 280 patients will be<br />
stratified by line of treatment (first/second) and hormone receptor<br />
status (positive/negative), then randomized 1:1 to receive maintenance<br />
treatment with either L (1000 mg qd, continuously) in combination<br />
with T (6 mg/kg once every 3 weeks [q3w]), or T (6 mg/kg q3w)<br />
alone. Patients will receive study treatment until disease progression,<br />
death, discontinuation due to adverse events, or patient withdrawal.<br />
The primary endpoint is PFS; secondary endpoints are; OS, clinical<br />
benefit rate, and safety.<br />
Key eligibility criteria include females, age ≥18 years with HER2-<br />
positive MBC who have completed 12 to 24 weeks of first- or<br />
second-line treatment with T plus chemotherapy with an objective<br />
response or stable disease at time of chemotherapy discontinuation.<br />
Patients with stable brain metastases are eligible if entering the study<br />
on second-line treatment.<br />
Efficacy endpoints will be analyzed in the intent-to-treat population. A<br />
total of 193 PFS events is required to detect a 50% increase in median<br />
PFS (hazard ratio=0.667) from 18 weeks (T alone) to 27 weeks ( L<br />
plus T). The hypothesis will be tested using a 1-sided test with 80%<br />
power and a type I error of 0.025. One interim analysis is planned<br />
for futility when approximately 97 PFS events (50% of the required<br />
events) have been observed. Safety endpoints will be analyzed in<br />
all randomized patients who receive ≥1 dose of study medication.<br />
The trial is currently open for accrual in the United States and Canada.<br />
clinicaltrials.gov - NCT00968968<br />
www.aacrjournals.org 559s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
OT1-1-08<br />
Clinical outcomes among ErbB2+ MBC patients treated with<br />
lapatinib-capecitabine after trastuzumab progression: Role of<br />
early switch to lapatinib (TYCO study).<br />
Abulkhair O, Uslu R, Sezgin C, Büyükberber S, Darwish T, Isikdogan<br />
A, Gumus M, Dane F, Sevinc A, Halawani H, Uncu D, Marrero N,<br />
Tobler J, Soares C, Landis S, Moraes E, Gidekel R, <strong>San</strong>tillana S,<br />
Nunez P, Cagnolati S, Rodriguez JG. Ege University Medical Faculty,<br />
Izmir, Turkey; Gazi University Medical Faculty, Ankara, Turkey;<br />
King Abdulaziz Medical City National Guard Health Affairs, Riyadh,<br />
Saudi Arabia; King Abdullah Medical City - Oncology Centre,<br />
Jeddah, Saudi Arabia; Dicle University Medical Faculty, Diyarbakir,<br />
Turkey; Kartal Training and Research Hospital, Istanbul, Turkey;<br />
Marmara University Training and Research Hospital, Istanbul,<br />
Turkey; Gaziantep University Medical Faculty, Gaziantep, Turkey;<br />
King Fahad Specialist Hospital, Dammam, Saudi Arabia; Numune<br />
Training and Research Hosptial, Ankara, Turkey; Instituto Docente<br />
de Urología, Valencia, Venezuela; GlaxoSmithKline, Rio de Janeiro,<br />
Brazil; GlaxoSmithKline, Buenos Aires, Argentina; GlaxoSmithKline,<br />
Stockley Park, United Kingdom; Hospital Oncológico Padre<br />
Machado, Caracas, Venezuela; Centro Oncologico-FIDES-La Plata,<br />
Buenos Aires, Argentina<br />
Background: Lapatinib in combination with capecitabine is a standard<br />
of care treatment for ErbB2+ metastatic breast cancer (MBC) patients<br />
who have progressed after anthracyclines, taxanes and trastuzumab<br />
treatment. Results from the lapatinib pivotal trial showed that the<br />
addition of lapatinib to capecitabine increased median time to<br />
progression (TTP) even among heavily pre-treated patients (median of<br />
4 prior lines of therapy). A post-hoc exploratory sub-group analysis of<br />
this trial suggested that earlier administration of lapatinib-capecitabine<br />
in MBC patients who progress after trastuzumab may produce better<br />
clinical outcomes. The TYCO study was designed to evaluate if early<br />
initiation of lapatinib-capecitabine in patients with ErbB2+ MBC who<br />
have progressed on trastuzumab-containing regimen improves TTP<br />
in comparison with a delayed start of the therapy.<br />
Trial design: TYCO is an international, multicenter, prospective,<br />
observational study in 269 ErbB2+ MBC patients whose disease has<br />
progressed after treatment with trastuzumab in the metastatic setting.<br />
Two cohorts will be compared; Group 1: patients receiving lapatinibcapecitabine<br />
just after the first trastuzumab progression, and Group<br />
2: patients receiving lapatinib-capecitabine after two or more lines<br />
of treatment after first trastuzumab progression. The study duration<br />
is of 12 months with data collection at baseline and approximately<br />
every 3 months thereafter.<br />
Major Eligibility Criteria:<br />
1. Females ≥18y with confirmed ErbB2+ MBC who have progressed<br />
after a previous trastuzumab-containing regimen,<br />
2. Pts eligible for standard therapy with lapatinib-capecitabine at<br />
approved conventional doses, as per local approved label.<br />
3. Pts eligible to start standard treatment with Lapatinib-capecitabine<br />
at conventional doses, or receiving standard treatment with Lapatinibcapecitabine<br />
at conventional doses, for no longer than 10 weeks from<br />
the start of the treatment to the date of inclusion in the study;<br />
Aims: Primary objective of this study is to determine if early switch<br />
to lapatinib-capecitabine in patients with ErbB2+ metastatic breast<br />
cancer who have progressed on trastuzumab containing regimen<br />
improves time to disease progression as determined by treating<br />
physician either clinically or radiologically. Secondary objectives<br />
include overall response rate and overall survival.<br />
Statistical Methods: Kaplan-Meier plots will be used to describe the<br />
median TTP after start of lapatinib-capecetabine. Cox proportional<br />
hazard model will be developed to estimate the adjusted hazard ratio<br />
(and 95% confidence intervals) comparing TTP for the two treatment<br />
group using propensity score methods (trimmed sample, adjustment<br />
for the continuous propensity score measure, and doubly robust<br />
adjustment) to adjust for potential confounding by indication that<br />
may arise due to the non-randomised design.<br />
Present and Target Accrual: Enrollment began in February 2010,<br />
and as per May 2012, 266 patients have been included from Turkey,<br />
Venezuela, Argentina, Saudi Arabia and Colombia.<br />
Country<br />
Enrollment<br />
Turkey 134<br />
Venezuela 44<br />
Argentina 29<br />
Saudi Arabia 38<br />
Colombia 21<br />
Total 266<br />
OT1-1-09<br />
Opti-HER HEART: A prospective, multicenter, single-arm,<br />
phase II study to evaluate the safety of neoadjuvant liposomal<br />
doxorubicin plus paclitaxel, trastuzumab, and pertuzumab in<br />
patients with operable HER2-positive breast cancer.<br />
Gavilá J, Llombart A, Guerrero A, Ruiz A, Guillem V. Fundación<br />
Instituto Valenciano de Oncología, Valencia, Spain; Hospital Arnau<br />
de Vilanova, Valencia, Spain; SOLTI <strong>Breast</strong> <strong>Cancer</strong> Research Group,<br />
Barcelona, Spain<br />
Background:<br />
In recent years, the concomitant use of two anti-HER2 therapies<br />
has been generating great expectations. Of note, despite the high<br />
activity reported by several studies, none has ever included a<br />
chemotherapeutic regimen with anthracyclines. The therapeutic value<br />
of anthracyclines in HER2-positive breast cancer (BC) has been<br />
well established. However, the feasibility of their combination with<br />
trastuzumab is still controversial. Liposomal anthracyclines, on the<br />
other hand, may offer a safer alternative. Of note, in our institutional<br />
experience using a regimen of liposomal doxorubicin plus weekly<br />
paclitaxel and trastuzumab as standard neoadjuvant therapy for stage<br />
II-III breast cancer (BC) patients reach a pathological complete<br />
response (pCR) rate of 65%, without any grade 3/4 cardiac toxicity.<br />
Trial Design: This study seeks to optimize the treatment of patients<br />
with operable HER2-positive BC, while minimizing cardiac risk, by<br />
combining dual anti-HER2 blockade plus a taxane and a liposomal<br />
anthracycline. In this single-arm, phase II clinical trial, patients will<br />
receive neoadjuvant therapy for six 21-day cycles. Regimen consists<br />
of: trastuzumab 4 mg/kg loading dose on Day 1 of Cycle 1, then 2<br />
mg/kg on Days 8 and 15 and on Days 1, 8, and 15 of subsequent<br />
cycles; pertuzumab 840 mg loading dose on Day 1 of Cycle 1, then<br />
420 mg on Day 1 of the following cycles; liposome-encapsulated<br />
doxorubicin 50 mg/m2 on Day 1 of each cycle; and, paclitaxel 80<br />
mg/m2 on Days 1, 8, and 15 of each cycle. ECG will be performed<br />
at baseline and every planned visit. Left ventricular ejection fraction<br />
(LVEF) decline will be assessed at baseline, weeks 6 and 12, before<br />
surgery, and every 3 months thereafter during the adjuvant period,<br />
for a total of 12 months. In order to assess biomarkers of cardiac<br />
injury, blood samples will be collected at the same time points. An<br />
initial safety run-in phase is included, in which the first ten enrolled<br />
patients undergo an intensified safety monitoring for cardiac and<br />
hematological adverse events.<br />
Eligibility: Female patients 18-74 years old with primary HER2-<br />
positive invasive breast cancer eligible for definitive surgery, with<br />
adequate cardiac function.<br />
Specific aims: The primary objective is to assess cardiac safety,<br />
measured by the incidence of symptomatic cardiac events and by<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
560s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT1<br />
asymptomatic LVEF decline. Secondary objectives include efficacy,<br />
breast conservation rate, additional safety and tolerability, and<br />
predictive biomarkers of cardiotoxicity.<br />
Statistical methods: Assuming that the incidences of cardiac events<br />
with regimens containing anti-HER2 agents are 3% for symptomatic<br />
and 15% for asymptomatic, 83 patients will be required to reject the<br />
null hypothesis with 80% confidence. Additionally, efficacy will be<br />
evaluated by pCR rates.<br />
Target accrual: Recruitment started in September 2012 and will<br />
include 83 patients across 20 sites in Spain. Trastuzumab and<br />
pertuzumab are kindly provided by Roche. The trial is supported by<br />
a grant from TEVA.<br />
OT1-1-10<br />
DETECT III - A multicenter, randomized, phase III study to<br />
compare standard therapy alone versus standard therapy plus<br />
lapatinib in patients with initially HER2-negative metastatic<br />
breast cancer but with HER2-positive circulating tumorcells<br />
Melcher CA, Janni JW, Schneeweiss A, Fasching PA, Hagenbeck CD,<br />
Aktas B, Pantel K, Solomayer EF, Ortmann U, Jaeger BAS, Mueller<br />
V, Rack BK, Fehm TN. University Hospital Duesseldorf, Germany;<br />
National Center for Tumor Diseases, Heidelberg, Germany;<br />
University Hospital Erlangen; University Hospital Essen, Germany;<br />
University Medical Center Hamburg-Eppendorf, Hamburg, Germany;<br />
University Hospital Homburg, Germany; Ludwig-Maximilians-<br />
University Munich, Munich, Germany; University Hospital Hamburg-<br />
Eppendorf, Germany; University Hospital Tuebingen, Germany<br />
Background: Despite a HER2-negative primary tumor approximately<br />
20-30% of patients develop HER2-positive metastases (Zidan et al.<br />
2005; Tewes et al. 2009). As previously described in the DETECT I<br />
trial (Fehm et al. 2010) determination of HER2 status on circulating<br />
tumor cells (CTCs) is one option for re-evaluating HER2-status<br />
in the metastatic setting. Currently it is unclear if HER2-targeted<br />
therapy based on the assessment of HER2-status of CTCs reveals a<br />
clinical benefit.<br />
Trial design: DETECT III is a randomized, open-label, two arm phase<br />
III study comparing standard treatment alone vs. standard treatment<br />
plus HER2-targeted therapy with lapatinib in HER2-negative<br />
metastatic breast cancer patients with HER2-positive CTCs. Choices<br />
of chemotherapy and endocrine therapy include: docetaxel, paclitaxel,<br />
capecitabine, vinorelbine, non pegylated liposomal doxorubicin,<br />
letrozole, exemestane and anastrozole.<br />
Main eligibility criteria:<br />
1. metastatic breast cancer with HER2-negative primary tumor tissue<br />
and/or biopsies from metastatic sites or locoregional recurrences<br />
2. evidence of ≥ 1 HER2-positive CTC<br />
3. ≥ 1 evaluable metastatic lesion according to RECIST<br />
4. Tumor evaluation within 6 weeks before randomization<br />
Specific aims:<br />
Objective<br />
The objective of the trial is to prove the clinical efficacy of lapatinib in<br />
patients with metastasizing breast cancer who exhibit HER2-positive<br />
circulating tumor cells (CTC) although the primary tumor tissue and/<br />
or biopsies from metastatic sites were investigated for HER2 status<br />
and showed HER2-negativity.<br />
Primary endpoint:<br />
· Progression free survival<br />
Secondary endpoints:<br />
· Overall response rate<br />
· Clinical benefit rate<br />
· Overall survival<br />
· Dynamic of CTC<br />
· Quality of life<br />
· Safety and tolerability of lapatinib<br />
Statistical methods: The primary endpoint will be analyzed by<br />
Kaplan-Meier method using the logrank test in order to compare<br />
the PFS distributions of the two arms. Efficacy, toxicity and other<br />
event rates are calculated, providing confidence intervals. In case<br />
of comparison between patient groups, these rates will be analyzed<br />
by Fisher’s exact test or test. The Kaplan Meier analysis for all<br />
event related data will be carried out overall for the whole patient<br />
population. Furthermore a Cox regression analysis will be done using<br />
the following covariates<br />
· Hormone receptor status (positive/negative)<br />
· Number of prior chemotherapy lines for metastatic disease<br />
· Prior endocrine therapy for metastatic disease<br />
· Endocrine treatment vs. cytotoxic treatment<br />
· One metastatic site vs. multiple metastatic sites<br />
· Bone metastases vs. no bone involvement<br />
· Performance status ECOG Score (0 / > 0)<br />
Present accrual and target accrual: As only half of the patients<br />
with HER2-negative metastatic breast cancer show CTC-positivity<br />
and of those approximately 32% will exhibit HER2-positive CTC<br />
(Fehm et al. 2010), screening of about 1420 patients is required to<br />
enroll 228 patients. First patient was screened in February 2012. As<br />
of July 27 th 2012 117 patients were screened and 21 were found to<br />
have HER2-positive CTCs<br />
OT1-1-11<br />
TBCRC 022: Phase II Trial of Neratinib for Patients with Human<br />
Epidermal Growth Factor Receptor 2 (HER2)-Positive <strong>Breast</strong><br />
cancer and Brain Metastases<br />
Freedman RA, Gelman RS, Wefel JS, Krop IE, Melisko ME, Ly A, Agar<br />
NYR, Connolly RM, Blackwell KL, Nabell LM, Ingle JN, Van Poznak<br />
CH, Puhalla SL, Niravath PA, Ryabin N, Wolff AC, Winer EP, Lin N.<br />
Dana-Farber <strong>Cancer</strong> Institute, Boston, MA; The University of Texas<br />
MD Anderson <strong>Cancer</strong> Center, Houston, TX; University of California,<br />
<strong>San</strong> Francisco, CA; Brigham and Women’s Hospital, Boston, MA;<br />
Johns Hopkins University, Baltimore, MD; Duke University, Durham,<br />
NC; University of Alabama, Birmingham, AL; Mayo Clinic, Rochester,<br />
MN; University of Michigan, Ann Arbor, MI; Univerity of Pittsburgh,<br />
Pittsburgh, PA; Baylor, Houston, TX<br />
Background: 1/3 of women with metastatic HER2+ breast cancer<br />
will develop central nervous system (CNS) metastases yet evidencebased<br />
treatments for women with progressive CNS disease are limited.<br />
Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4<br />
which has promising activity in HER2+ breast cancer. Preclinical<br />
evidence suggests it may cross the blood brain barrier.<br />
Trial Design: This is a multicenter, phase II, open-label study of<br />
neratinib for patients with HER2+ breast cancer and brain metastases.<br />
Neratinib is administered at 240 mg orally daily during a 28 day<br />
cycle. Two cohorts will be enrolled: Cohort 1 will enroll 40 patients<br />
with progressive CNS disease; cohort 2 will enroll ≤5 patients who<br />
are candidates for surgical excision of intracranial disease. Surgical<br />
candidates receive neratinib 7-21 days preoperatively and resume<br />
postoperatively. All patients are re-staged every 2 cycles. Those who<br />
develop non-CNS progression have an option to extend therapy with<br />
trastuzumab+neratinib. Circulating tumor cells (CTC) are collected at<br />
baseline and progression; neurocognitive testing, HADS and EORTC<br />
QLQ30/BN20 measures are administered at baseline, cycle 2, cycle<br />
3, and progression (cohort 1). Intracranial tumor, cerebrospinal fluid<br />
(CSF), and plasma are collected at surgery (cohort 2).<br />
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Specific Aims: The primary endpoint is CNS objective response<br />
rate (ORR) by composite criteria. Additional endpoints include:<br />
non-CNS ORR, progression-free survival, overall survival (OS),<br />
site of 1st progression, and toxicity. Correlative and exploratory<br />
endpoints include association of CTC count and OS and longitudinal<br />
neurocognitive function and quality of life. In an exploratory<br />
analysis (cohort 2), we will quantify neratinib concentrations in<br />
CSF, intracranial tissue, and plasma and examine associations with<br />
response.<br />
Eligibility: Patients must have confirmed HER2+ metastatic disease<br />
with ≥1 parenchymal brain lesion measuring ≥10 mm that is new<br />
or progressed after completing ≥1 line of standard CNS-directed<br />
treatment (cohort 1) or CNS disease that is amenable for surgery,<br />
including those without prior CNS treatments (cohort 2). Additional<br />
eligibility criteria (cohorts 1,2) include: adequate performance status<br />
and end organ/marrow function, and ejection fraction ≥50%. Any<br />
number of prior lines of therapy is allowed, including prior lapatinib.<br />
Statistical Methods: Cohort 1 has a 2-stage design with up to 40<br />
patients. CNS ORR is defined as ≥50% reduction in sum volume of<br />
CNS target lesions, without evidence of new lesions, progression of<br />
non-target CNS lesions, non-CNS disease progression, worsening<br />
neurological symptoms, or increase in corticosteroids. CNS lesion<br />
measurements are performed centrally by the Harvard Tumor Imaging<br />
Metrics Core. If 1/18 patients have a CNS response in the 1st stage,<br />
another 22 patients will enroll. With this design, if ≥5 of 40 patients<br />
achieve a CNS response, the drug will be deemed worthy of future<br />
study. This 2-stage design has 92% power to distinguish between<br />
a true CNS ORR of 20% and a null of 6% (one-sided type I error<br />
rate=9%).<br />
Accrual: Accrual has begun. Target=45 (cohort 1=40, cohort 2=5)<br />
OT1-1-12<br />
NSABP FB-7 Trial: A Phase II Randomized Clinical Trial<br />
Evaluating Neoadjuvant Therapy Regimens with Weekly<br />
Paclitaxel and Neratinib or Trastuzumab or Neratinib and<br />
Trastuzumab Followed by Doxorubicin and Cyclophosphamide<br />
with Postoperative Trastuzumab in Women with Locally<br />
Advanced HER2-Positive <strong>Breast</strong> <strong>Cancer</strong><br />
Lu J, Jacobs SA, Buyse ME, Paik S, Wolmark N. State University<br />
of New York at Stony Brook, Stony Brook, NY; National Surgical<br />
Adjuvant <strong>Breast</strong> and Bowel Project, Pittsburgh, PA<br />
Neratinib is an oral, small molecule which acts as an irreversible<br />
inhibitor of the pan ErbB receptor tyrosine kinase. Dual ErbB<br />
blockade combined with chemotherapy improves efficacy in Her-<br />
2 positive breast cancer. Both NeoALTTO (Lancet 2012) and<br />
Neosphere (Lancet Oncol 2012) trials demonstrated higher pCR for<br />
Her-2 positive breast cancer receiving dual anti-Her-2 neoadjuvant<br />
blockade therapy. The purpose of this trial is to determine the activity<br />
and safety profile of Neratinib as mono-blockade or in combination<br />
with Trastuzumab as dual blockade in neoadjuvant therapy of locally<br />
advanced breast cancer (stage IIB, III A, B and C).<br />
Methods: This NSABP Foundation Research Program study (FB-<br />
7) is designed as a Phase II, multi-center, three arm clinical trial for<br />
patients with Her-2 positive locally advanced breast cancer. 126<br />
patients will be enrolled. The initial two- arm study of Neratinib<br />
or Trastuzumab in combination with Paclitaxel began in December<br />
2010. 30 patients were enrolled by December of 2011 at which time<br />
the study was placed on hold awaiting the recommended phase II<br />
dose of the three drug combination, Neratinib, Trastuzamab and<br />
Paclitaxel ( NSABP FB-8 trial), which is a Phase I dose-escalation<br />
study in women with metastatic Her-2 positive breast cancer. The<br />
amended FB -7 trial is now a three arm trial of weekly Paclitaxel<br />
and Neratinib or Trastuzumab or Neratinib and Trastuzumab for 4<br />
cycles followed by Doxorubicin and Cyclophosphamide for 4 cycles<br />
prior to surgical resection. Patients will then receive postoperative<br />
Trastuzumb to complete one total year of Her-2 blockade therapy. The<br />
primary goal of this study is to determine the pathologic complete<br />
response in breast and axillary lymph nodes following completion<br />
of neoadjuvant therapy.<br />
OT1-1-13<br />
Dual blockade with Afatinib and Trastuzumab as neooadjuvant<br />
treatment for patients with locally advanced or operable breast<br />
cancer receiving taxane-anthracycline containing chemotherapy<br />
(DAFNE)-GBG70<br />
Hanusch C, Schneeweiss A, Untch M, Paepke S, Kuemmel S,<br />
Jackisch C, Huober J, Hilfrich J, Gerber B, Eidtmann H, Denkert C,<br />
Costa S-D, Blohmer J-U, Loibl S, Nekljudova V, von Minckwitz G.<br />
Rotkreuzklinikum Muenchen; University Heidelberg; Helios Klinik<br />
Berlin; Frauenklinik Muenchen; Kliniken Essen Mitte; Klinikum<br />
offenbach; University Duesseldorf; Eilenriedeklinik Düsseldorf;<br />
University Rostock; University Kiel; Charite Berlin; University<br />
Magdeburg; <strong>San</strong>kt Gertrauden Berlin; German <strong>Breast</strong> Group, Neu-<br />
Isenburg<br />
Background: Anthracycline/taxane based combination chemotherapy<br />
of at least 18 weeks represents the standard of care in the neoadjuvant<br />
setting. In HER2 positive disease trastuzumab is given concurrently<br />
to chemotherapy and achieves a pCR rate (no invasive residuals in<br />
breast and nodes) of approx. 40% which can be increased by double<br />
anti HER2 blockade by approximately 20%. There are no data on the<br />
combination of afatinib (BIBW 2992), an irreversible HER family<br />
inhibitor with trastuzumab.<br />
Methods: This is a multi-centre, prospective, open-label phase II<br />
study evaluating the efficacy and safety of afatinib in combination<br />
with weekly paclitaxel + trastuzumab followed by epirubicin/<br />
cyclophosphamide/trastuzumab as neoadjuvant therapy in<br />
patients with untreated HER2-positive early breast cancer. Pts<br />
with histologically confirmed, centrally reviewed HER2 positive,<br />
unilateral, primary operable or locally advanced breast cancer can be<br />
included. Tumor size has to be at least 2cm by sonography.<br />
All patients will be treated for a total duration of 30 weeks (6 weeks<br />
with afatinib (20mg) and trastuzumab (8/6mg/kg) alone, 12 weeks<br />
with weekly paclitaxel (80mg/m²), afatinib and trastuzumab and 12<br />
weeks with epirubicin/cyclophosphamide/trastuzumab according to<br />
standard). During the first 2 weeks afatinib 20 mg will be given only<br />
every other day to reduce the risk of diarrhea and skin toxicities.<br />
Primary prophylaxis with loperamide 2x 2 mg daily is obligatory<br />
during the first 4 weeks of afatinib/trastuzumab and the first 2 weeks<br />
of afatinib/trastuzumab/paclitaxel. Thereafter prophylaxis with<br />
loperamide can be stopped if no diarrhea grade > 1 occurred.<br />
Primary objective is pathological complete response (pCR = ypT0/<br />
is ypN0). Secondary objectives are pCR by other definitions, clinical<br />
response rates, rate and type of surgery, toxicity and compliance, pCR<br />
related to skin toxicity and diarrhoea and pre-specified molecular<br />
markers. An extensive biomaterial collection is integreated, including<br />
obligatory biomaterial (e.g. skin biopsies) collection at baseline, prior<br />
to start of paclitaxel at the end of paclitaxel and prior to surgery.<br />
Neoadjuvant anthracycline-taxane-based chemotherapy given<br />
simultaneously with trastuzumab after central HER 2-testing results in<br />
a pCR rate of approx. 50%. The addition of a dual anti HER2 blockade<br />
to chemotherapy increased the pCR by absolute 20%. A pCR rate of<br />
70% is expectedand and a pCR rate of 55% or lower excluded; with<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
562s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT1<br />
α=0.1 and 1-ß=80%, this requires 65 evaluable patients for two-sided<br />
one group χ2-test. An integrated safety phase is planned for the first<br />
15 patients entering the study.<br />
The trial is registered under NCT015591477. It is financially<br />
supported by Boehringer Ingelheim.<br />
Results: Centres have been initiated after approval by ethics<br />
committee and authorities. Three patients have been recruited. It is<br />
planned to recruit 12 months in 15 sites in Germany.<br />
OT1-1-14<br />
Open-label, Phase II trial of afatinib, with or without vinorelbine,<br />
for the treatment of HER2-overexpressing inflammatory breast<br />
cancer (IBC)*<br />
Swanton C, Cromer J, On Behalf of the 1200.89 Trial Group. CR-UK<br />
London Research Institute, London, United Kingdom; Boehringer<br />
Ingelheim, North Ryde, Australia<br />
Background: IBC is a rare but aggressive form of BC accounting<br />
for 1–5% of all BC. Despite recent treatment advances, prognosis<br />
remains poor, with 3-year survival rate of 40% vs. 85% in non-IBC.<br />
IBC commonly lack ER/PR and more frequently harbor HER2 gene<br />
amplification (∼40%), and EGFR overexpression (∼30%) that are<br />
associated with poor prognosis. Recent data reported clinical efficacy<br />
of lapatinib, a reversible EGFR/HER2 inhibitor, in trastuzumab<br />
naïve/resistant HER2-positive IBC. Afatinib is an oral irreversible<br />
ErbB Family Blocker that blocks signaling through activated EGFR<br />
(ErbB1), HER2 (ErbB2), ErbB4 receptors, and transphosphorylation<br />
of ErbB3. Afatinib demonstrated preclinical activity in trastuzumabresistant<br />
cell lines, HER2-positive tumor xenografts and HER2-<br />
negative SUM149 xenograft model derived from an IBC cell line.<br />
Its clinical efficacy was shown in heavily pretreated, HER2-positive<br />
metastatic BC patients (pts) who progressed after trastuzumab, with<br />
a partial response in 10% and a clinical benefit in 46% of pts. The<br />
combination of afatinib and vinorelbine has been shown to be more<br />
effective than either compound alone in reducing tumor volume in<br />
the SUM190 xenograft model. The purpose of this biomarker-driven<br />
trial is to investigate the efficacy and safety of afatinib alone and<br />
in combination with vinorelbine following progression on afatinib<br />
monotherapy and the genomic changes that occur during treatment in<br />
pts with trastuzumab pretreated or naïve HER2-positive IBC.<br />
Methods: Pts are recruited in two parallel cohorts of 20 pts<br />
each – trastuzumab-naïve and trastuzumab failure cohorts. Key<br />
eligibility criteria: Histologically-confirmed HER2-positive BC;<br />
investigator-confirmed IBC characterized by diffuse erythema and<br />
edema (peau d’orange) – dermal lymphatic emboli or palpable mass<br />
are not necessary for diagnosis; no prior anti-HER2 therapy except<br />
trastuzumab in the trastuzumab failure cohort; no prior vinorelbine;<br />
ECOG performance status 0–2; disease must be biopsiable. All pts<br />
start afatinib monotherapy (40 mg/day oral) in 4-week cycles (Part<br />
A). Following disease progression, pts may receive afatinib (40 mg/<br />
day) + vinorelbine (i.v. 25 mg/m 2 /week) (Part B). Primary endpoint:<br />
Clinical benefit defined as stable disease (for ≥6 months), partial<br />
response or complete response (RECIST 1.1). Secondary endpoints:<br />
Objective response, duration of objective response and progressionfree<br />
survival. Other endpoints include overall survival and safety.<br />
Endpoints are assessed separately for Part A and Part B. In Part A<br />
(afatinib monotherapy) fresh tumor biopsies are taken pretreatment<br />
and following progressive disease, and blood samples are taken<br />
pretreatment to explore predictive markers of response/resistance to<br />
afatinib, to describe the IBC population that may benefit most and<br />
for tumor DNA next-generation sequencing and proteomic analysis.<br />
This is one of the first prospective clinical trials to integrate deep<br />
exome sequencing into trial design to assess proof of principle of a<br />
personalized cancer medicine approach to improve individualized<br />
pt treatment. The trial is planned to accrue 40 pts worldwide and<br />
recruitment is ongoing since August 2011.<br />
*Updated abstract from ASCO 2012.<br />
OT1-1-15<br />
LUX-<strong>Breast</strong> 3: Randomized Phase II trial of afatinib (BIBW<br />
2992) alone or with vinorelbine versus investigator’s choice of<br />
treatment in patients (pts) with HER2-positive breast cancer<br />
(BC) with progressive brain metastases after trastuzumab and/<br />
or lapatinib-based therapy*<br />
Joensuu H, Ould-Kaci M, On Behalf of the 1200.67 Trial Group.<br />
Helsinki University Central Hospital, Helsinki, Finland; Boehringer<br />
Ingelheim, Paris, France<br />
Background: BC is one of the most common causes of central<br />
nervous system (CNS) metastases and approximately a third of pts<br />
with HER2-positive, advanced BC will develop brain metastases<br />
with a poor prognosis. Efficacy of systemic therapies is limited<br />
since few drugs can readily cross the blood-brain barrier. BC brain<br />
metastases represent a high unmet medical need for which novel<br />
therapies are needed. Afatinib is an oral irreversible ErbB Family<br />
Blocker that blocks signaling through activated EGFR (ErbB1), HER2<br />
(ErbB2) and ErbB4 receptors and transphosphorlyation of ErbB3.<br />
Afatinib has shown preclinical activity in trastuzumab-resistant cell<br />
lines and HER2-positive tumor xenografts. Its clinical efficacy has<br />
been demonstrated in pts with heavily pretreated, HER2-positive<br />
metastatic BC (MBC), who progressed after trastuzumab therapy,<br />
with partial responses (PRs) in 10% and clinical benefit in 46%<br />
of pts. In a Phase I afatinib trial, a sustained PR was observed in a<br />
non-small cell lung cancer (NSCLC) pt with brain metastasis and<br />
in a Phase II trial in NSCLC, pts with or without brain metastases<br />
achieved comparable objective response on afatinib. The purpose of<br />
this trial (NCT01441596) is to investigate whether afatinib alone or<br />
in combination with vinorelbine has any effect on HER2-positive BC<br />
with brain metastases after prior trastuzumab and/or lapatinib therapy.<br />
Methods: Key eligibility criteria: Histologically confirmed HER2-<br />
positive BC; recurrent/progressive brain metastases during/after prior<br />
trastuzumab and/or lapatinib therapy; at least one measurable and<br />
progressive lesion in the CNS (≥10 mm on T1-weighted, gadoliniumenhanced<br />
MRI) after prior systemic and/or radiation therapy; extra-<br />
CNS lesions allowed; prior surgery, whole brain radiotherapy or<br />
stereotactic radiosurgery allowed; ECOG performance status (PS)<br />
0–2; no prior treatment with HER2-tyrosine kinase inhibitor other<br />
than lapatinib. Eligible pts are stratified by: ECOG PS score 0–1<br />
vs. 2; number of brain metastases ≤3 vs. >3; prior lapatinib therapy.<br />
Pts are randomized to (n=40/arm): Arm A: Afatinib (40 mg/day<br />
oral); Arm B: Afatinib (40 mg/day oral) + vinorelbine (25 mg/m 2 /<br />
week); Arm C: Investigator’s choice of medical treatment approved<br />
for MBC. All treatments are administered in a 3-weekly course.<br />
Primary endpoint: Pt benefit at 12 weeks (i.e. absence of CNS/extra<br />
CNS disease progression as per RECIST 1.1 and no tumor-related<br />
worsening of neurological signs/symptoms or increase in steroid<br />
dosage). Secondary and other endpoints: Progression-free survival,<br />
overall survival, safety and afatinib concentration in plasma and<br />
cerebrospinal fluid in ≥12 pts who consent to participate in the PK<br />
study. The trial is planned to accrue 120 pts worldwide. When 20<br />
pts in each treatment arm have been treated for at least 12 weeks<br />
(or progressed before Week 12), a Data Monitoring Committee will<br />
www.aacrjournals.org 563s<br />
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CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
evaluate the benefit–risk ratio to decide whether to proceed with the<br />
trial or stop one of the treatment arms for futility. The study began<br />
in October 2011 and enrollment is ongoing.<br />
*Updated abstract from ASCO 2012.<br />
OT1-1-16<br />
LUX-<strong>Breast</strong> 1: Randomized, Phase III trial of afatinib (BIBW<br />
2992) and vinorelbine vs. trastuzumab and vinorelbine in patients<br />
with HER2-overexpressing metastatic breast cancer (MBC)<br />
failing one prior trastuzumab treatment*<br />
Xu B, Im S-A, Huang C-S, Im Y-H, Ro J, Zhang Q, Arora R, Mehta<br />
A, Jung K, Yeh D-C, Lee S, Jassem J, Wojtukiewicz M, Chen S-C,<br />
Lahogue A, Uttenreuther-Fischer M, Hurvitz S-A, Harbeck N,<br />
Piccart-Gebhart M, On Behalf of the LUX-<strong>Breast</strong> 1 Study Group.<br />
Chinese Academy of Medical Sciences, Beijing, China; Seoul National<br />
University Hospital, Seoul, Korea; National Taiwan University<br />
Hospital, Taipei, Taiwan; Samsung Medical Center, Seoul, Korea;<br />
National <strong>Cancer</strong> Center, Goyang, Korea; Third Affiliated Hospital<br />
of Harbin Medical University, Heilongjiang Province, China; Sujan<br />
Surgical <strong>Cancer</strong> Hospital & Amravati <strong>Cancer</strong> Foundation, Amravati,<br />
India; Central India <strong>Cancer</strong> Research Institute, Nagpur, India; Asan<br />
Medical Center, Seoul, Korea; Taichung Veterans General Hospital,<br />
Taichung, Taiwan; Severance Hospital, Seoul, Korea; Medical<br />
University, Gdansk, Poland; Medical University, Bialystok, Poland;<br />
Chang Gung Memorial Hospital - Linkou Branch, Taoyuan County,<br />
Taiwan; SCS Boehringer-Ingelheim Comm.V, Brussels, Belgium;<br />
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany;<br />
UCLA, Los Angeles, CA; University of Munich, Munich, Germany;<br />
Institut Jules Bordet, Brussels, Belgium<br />
Background: Afatinib is a ErbB Family Blocker that irreversibly<br />
blocks signaling from all relevant ErbB Family dimers. Afatinib<br />
is being developed in EGFR (ErbB1)-driven (non-small cell lung<br />
cancer [NSCLC]/head and neck squamous cell carcinoma) and<br />
HER2 (ErbB2)-driven (breast) malignancies, and has shown clinical<br />
efficacy in NSCLC patients with EGFR activating mutations. 1,2<br />
In trastuzumab-resistant, HER2-positive (SUM190) xenografts,<br />
afatinib showed antitumor activity which was superior to lapatinib.<br />
Afatinib monotherapy activity in this SUM190 model was increased<br />
by the addition of intravenous (i.v.) vinorelbine. Clinically, afatinib<br />
monotherapy demonstrated activity in an open-label, single-arm,<br />
Phase II trial in patients with HER2-positive MBC after progression<br />
on trastuzumab, with a progression-free survival (PFS) of 15.1<br />
weeks, an overall survival (OS) of 61.0 weeks and 10% objective<br />
response (OR). 3 HER-reprogramming appears to play an important<br />
role in resistance 4 and recent clinical trial results have indicated that<br />
targeting more than one ErbB Family member increases efficacy. 5<br />
Thus afatinib, as an ErbB Family Blocker, should add to the portfolio<br />
of drugs available to treat trastuzumab resistance in HER2-positive<br />
BC patients. This is currently being tested in the LUX-<strong>Breast</strong> 1 trial.<br />
Methods: LUX-<strong>Breast</strong> 1 (NCT01125566) is a Phase III, openlabel,<br />
multicenter trial evaluating the efficacy and safety of afatinib<br />
+ vinorelbine vs. trastuzumab + vinorelbine in patients with<br />
HER2-overexpressing MBC who progressed on, or after one prior<br />
trastuzumab-based treatment regimen. Patients are randomized 2:1<br />
to afatinib (40 mg/day oral) + vinorelbine (i.v. 25 mg/m 2 /week)<br />
or trastuzumab (i.v. 2 mg/kg/week after 4 mg/kg loading dose)<br />
+ vinorelbine (i.v. 25 mg/m 2 /week). Patients receive continuous<br />
treatment in the absence of disease progression or unacceptable<br />
toxicity. Key eligibility criteria include histologically-confirmed<br />
HER2-positive MBC; no prior treatment with vinorelbine or HER2-<br />
targeted treatment other than trastuzumab; progression on one prior<br />
trastuzumab based regimen in either the adjuvant (or
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT1<br />
retreatment with paclitaxel (i.e. should not have been pretreated with<br />
paclitaxel within the past 12 months), or are eligible for treatment with<br />
vinorelbine (i.e. should not have been pretreated with vinorelbine).<br />
Exclusion criteria include inadequate cardiac, renal, hepatic and<br />
hematological function, pre-existing gastrointestinal dysfunction,<br />
rapidly progressing visceral MBC, interstitial lung disease, and active<br />
brain metastases. The primary endpoint is objective response (OR)<br />
and secondary endpoints include best overall response, duration of<br />
OR, progression-free survival (PFS) and safety. PFS and safety will<br />
be assessed separately for afatinib mono- and combination therapy.<br />
An early stopping rule was deployed to minimize the number of<br />
pts treated should afatinib be ineffective; once 20 evaluable pts<br />
(according to RECIST 1.1) completed at least two courses of afatinib<br />
(or progressed during the first course), a meeting was held to evaluate<br />
the objective tumor response rate and to decide whether to proceed<br />
with the trial or stop due to futility. If at least one unconfirmed OR<br />
had been witnessed from all available information at the time, then<br />
the trial was to continue to full accrual. This early stopping rule for<br />
futility has been passed and the trial will continue to full accrual. Pt<br />
enrollment began in May 2011 in ∼40 sites and five countries.<br />
1. Lin NU, et al. <strong>Breast</strong> <strong>Cancer</strong> Res Treat 2012. DOI: 10.1007/<br />
s10549-012-2003-y.<br />
*Updated abstract from ASCO 2012.<br />
OT1-2-01<br />
NSABP B-43: A phase III clinical trial to compare trastuzumab<br />
(T) given concurrently with radiation therapy (RT) to RT alone<br />
for women with HER2+ DCIS resected by lumpectomy (Lx)<br />
Cobleigh MA, Anderson SJ, Julian TB, Siziopikou KP, Arthur DW,<br />
Rabinovitch R, Zheng P, Mamounas EP, Wolmark N. National<br />
Surgical Adjuvant <strong>Breast</strong> and Bowel Project, Pittsburgh, PA; Rush<br />
University Medical Center, Chicago, IL; University of Pittsburgh<br />
Graduate School of Public Health, Pittsburgh, PA; Allegheny General<br />
Hospital, Pittsburgh, PA; Northwestern University Feinberg School<br />
of Medicine, Chicago, IL; Virginia Commonwealth University,<br />
Richmond, VA; University of Colorado, Aurora, CO; Aultman<br />
Hospital, Canton, OH<br />
Background: A significant amount of DCIS is ER negative and/or<br />
overexpresses HER2. This provides an opportunity to test molecular<br />
therapy in DCIS.<br />
In xenograft models and cell lines, T boosts RT effectiveness. In<br />
T-treated HER2+ patients, apoptosis occurs within 1 wk of single<br />
agent T use, with T found in ductal aspirates. Ample safety evidence<br />
for T exists. T given during whole breast irradiation (WBI) may<br />
improve results for lumpectomy (Lx) resected HER2+ DCIS. A trial<br />
to examine this question will enhance the understanding of breast<br />
tumor biology and the prevention of such tumors and could possibly<br />
extend breast-conserving surgery benefits for women with DCIS.<br />
Method: After Lx for pure DCIS, each patient’s DCIS lesion is<br />
centrally tested for HER2 by IHC analysis. HER2 2+ tumors undergo<br />
FISH analysis. HER2 3+ or FISH+ patients can be randomly assigned<br />
to 2 doses of T, 3 weeks apart during WBI or to WBI alone.<br />
Women ≥18 yrs. with a margin-clear Lx for pure DCIS, with ECOG<br />
status 0/1 who are clinically or pathologically node negative are<br />
eligible. Centrally tested DCIS must be HER2 +. ER and/or PR status<br />
must be known before randomization.<br />
Primary aims are to determine if T decreases ipsilateral breast cancer<br />
recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS.<br />
Secondary aims are to determine the benefit of T in preventing<br />
regional or distant recurrence and contralateral invasive breast cancer<br />
or DCIS. B-43 will determine if DFS, recurrence-free interval, and<br />
OS can be improved with the use of T. 2000 patients will be accrued<br />
over 7.9 yrs, with a definitive analysis of primary endpoints performed<br />
at163 ipsilateral breast cancer events (7.5 - 8 yrs. after protocol<br />
initiation) with an 80% power to detect a hazard reduction of 36%,<br />
from 1.73 ipsilateral breast cancer events per 100 pt-yrs to 1.11 events<br />
per 100 pt-yrs. The 36% observed reduction in the hazard of IIBCR-<br />
SCR-DCIS on the T arm is based on a projection of 40% hazard<br />
reduction if the compliance were perfect, with a 10% noncompliance<br />
rate. As of 5-31-12, 939 patients have been randomized.<br />
NCT00769379Grant support: PHS NCI-U10-CA-69651, -12027, and<br />
NCI P30-CA-14599 from the US NCI and Genentech, Inc.<br />
OT1-2-02<br />
SHARE. A French multiceter phase III trial comparing<br />
accelerated partial irradiation (APBI) versus standard or<br />
hypofractionated whole breast irradiation in low risk of local<br />
recurrence breast cancer<br />
Belkacemi Y, Bourgier C, Kramar A, Lemonier J, Auzac G, Dumas I,<br />
Lacornerie T, Mijonnet S, Mege J-P, Lartigau E. APHP; GH Henry<br />
Mondor and UPEC, Paris, Créteil, France; Institut Gustave Roussy,<br />
Villejuif, France; Oscar Lambret Center, Lille, France; UNICANCER,<br />
Paris, France<br />
Introuction<br />
The six worldwilde ongoing APBI phase III trials are characterized<br />
by a significant heterogeneity regarding inclusion criteria and<br />
stratifications. One non-inferiority trial (SHARE) is currently ongoing<br />
in France.<br />
SHARE Trial design<br />
SHARE will randomize 2800 patients in 3 arms: standard (Arm A;<br />
6.5 weeks) versus hypofractionated (Arm B; 3 weeks) versus APBI<br />
(Arm C; 1 week) using only 3D conformal radiotherapy (3D CRT). In<br />
this trial high quality and homogeneous criteria in surgery, pathology<br />
and RT for the 3 arms is planed.<br />
Primary objective<br />
To estimate and compare the rates of local recurrences between the<br />
experimental and control arms.<br />
Inclusion criteria<br />
Post menopausal women aged ≥ 50y (stratification: < 70 yrs vs ≥<br />
70 yrs)<br />
Menopausal status confirmed since ≥ 12 months (Clinically and/or<br />
biologically)<br />
No previous ipsilateral breast and/or mediastinal irradiation<br />
Pathologic confirmation of invasive carcinoma (all types of invasive<br />
carcinomas)<br />
Unifocal tumor confirmed on the pathologic specimen<br />
Pathologic tumor size of the carcinoma ≤ 2cm (including the in situ<br />
component)<br />
All pathologic grades (stratification: HER2/triple negative vs others)<br />
Clear lateral margins confirmed on the final pathology report. The<br />
minimal size from the invasive and in situ disease should be 2 mm<br />
(≥ 2mm)<br />
pN0 (i+/-) (stratification: pN0 vs pN(i+))<br />
Chemotherapy and trastuzumab are not allowed - RT should be started<br />
≥ 4weeks and ≤ 12 weeks after surgery (including the date of second<br />
excision for close or involved margins)<br />
Clips in the tumor bed placed during surgery (4 to 5 clips)<br />
www.aacrjournals.org 565s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Treatment<br />
Arm A<br />
3D CRT should be started within 12 weeks after the last surgery. A<br />
total of 50 Gy is delivered in 25 fractions, one fraction of 2 Gy per<br />
day, 5 days a week. In this arm, the boost of 10 to 16 Gy is delivered<br />
in 5 to 8 fractions.<br />
Dose prescription (arm B)<br />
The main point is that in both schedules the total dose is delivered<br />
in 3 weeks:<br />
- The Canadian schedule described by Whelan et al. delivers 42.5 Gy<br />
in 16 fractions (2.65Gy/fraction, 5 fractions / week).<br />
- The UK schedule, reported in START B trial delivers 40 Gy in 15<br />
fractions (2.66 Gy/ fraction, 5 fractions / week). Nodal and boost<br />
RT is not allowed.<br />
Arm C<br />
3D CRT should be started within 12 weeks after the last surgery.<br />
Intensity modulated RT (IMRT) and brachytherpayare not allowed.<br />
A total dose of 40 Gy in 10 fractions over 1 week (4Gy per fraction<br />
twice a day with minimal delay of 6h).<br />
Conclusion<br />
In summary, the French trial will allow:<br />
- Selected patients according to age and low risk of local recurrence<br />
parameters.<br />
- To evaluate in a subgroup of patients (4 to 5 centers), the impact of<br />
magnetic resonance imaging (MRI) for patient selection and the rate<br />
of occult disease (multifocality) not detected by standard imaging<br />
evaluation which is considered as an exclusion criteria.<br />
- To determine APBI parameters adapted to the surgical procedure in<br />
the tumor bed remodeling setting.<br />
- To determine homogeneous criteria for the surgical procedure,<br />
minimal requirements and optimal criteria that have to be mentioned<br />
in the final pathology report in all 3 arms of the study.<br />
- To test hypofractionation using 3 weeks-schedules as compared<br />
to APBI<br />
OT2-1-01<br />
Feasibility of sentinel node detection after neoadjuvant<br />
chemotherapy for patient with proved axillary lymph node<br />
involvement: the French prospective multiinstitutional GANEA<br />
2 ongoing trial<br />
Classe J-M, Bordes V, Gimbergues P, Tunon de Lara C, Faure C,<br />
Belichard C, Houpeau J-L, Raro P, Dupré P-F, Houvenaeghel G,<br />
Barranger E, Marchal F, Deblay P, Rouanet P, Lefebvre C, Bourcier<br />
C, Alran S. Institut de <strong>Cancer</strong>ologie de l’Ouest, Nantes Saint Herblain,<br />
France; Centre Jean Perrin, Clermont-Ferrand, France; Institut<br />
Bergonié, Bordeaux, France; Centre Leon Berard, Lyon, France;<br />
Centre Huguenin, Saint Cloud, France; Centre Oscar Lambret, Lille,<br />
France; Centre Hospitalier Universitaire Morvan, Brest, France;<br />
Paoli Calmettes, Marseille, France; CHU Lariboisière, Paris,<br />
France; Centre Alexis Vautrin, Nancy, France; Centre
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT2<br />
OT2-1-02<br />
Clinical node negative breast cancer patients undergoing breast<br />
conserving therapy: follow-up versus sentinel lymph node biopsy<br />
van Roozendaal LM, Smidt ML, de Wilt HHW, van Dalen T, Strobbe<br />
LJA, van der Hage J, Tjan-Heijnen VCG, Linn SC, Serroyen JL.<br />
Maastricht University Medical Center, Maastricht, Netherlands;<br />
Radboud University Nijmegen Medical Center, Nijmegen,<br />
Netherlands; Diakonessen Hospital Utrecht, Utrecht, Netherlands;<br />
Canisius-Wilhelmina Hospital, Nijmegen, Netherlands; Netherlands<br />
<strong>Cancer</strong> Institute - Antoni van Leeuwenhoek Hospital, Amsterdam,<br />
Netherlands; Maastricht University, Maastricht, Netherlands<br />
Background<br />
The ACOSOG-Z0011 study demonstrated no additional value of<br />
complementary axillary lymph node dissection in case of limited<br />
axillary sentinel lymph node (SLN) metastases in breast cancer<br />
patients undergoing breast conserving therapy 1 . Since axillary<br />
ultrasound can exclude advanced axillary metastatic disease preoperative<br />
2 , there is ample opportunity to evaluate whether SLN<br />
biopsies are still indicated in a selected group of breast cancer patients.<br />
Trial design<br />
A prospective non-inferiority randomized multicenter trial was<br />
designed.<br />
<strong>Breast</strong> cancer patients with cT1-2N0 disease, with no evidence for<br />
axillary metastases on ultrasound, treated with breast conserving<br />
therapy (lumpectomy + whole breast radiotherapy), will be<br />
randomized between follow-up and SLN biopsy. If adjuvant systemic<br />
therapy is not indicated by tumor or patient characteristics, gene<br />
expression profiling may be used for evaluation. To assess Quality<br />
of Life, 3 validated questionnaires will be used: QLQ-C30, QLQ-BR<br />
23 and Lymph-ICF 3-5 .<br />
Eligibility criteria:<br />
- Women with histological confirmed cT1-2 invasive unilateral breast<br />
carcinoma<br />
- Clinical node negative: no palpable nodes at physical examination<br />
and an axillary ultrasound without signs of lymph node metastases<br />
(cyto-/histology if indicated)<br />
- Neoadjuvant systemic therapy is allowed.<br />
Specific aims<br />
Primary endpoint is the axillary recurrence rate. The number of<br />
delayed axillary dissections will be registered. Secondary endpoints<br />
are distant-disease free survival, overall survival, local recurrence,<br />
morbidity and Quality of Life.<br />
Statistical methods<br />
Based on a 5-year axillary recurrence free survival rate: failure rate<br />
of 0.99 for controls and a true failure rate of 0.96 (as considered<br />
acceptable) for study subjects. Overall, 2086 patients will be<br />
included to be able to reject the null hypothesis that the failure rate<br />
for experimental and control subjects is inferior by at least 5% (D =<br />
-5%) with probability of 0.8 and alpha of 5%.<br />
Present accrual and target accrual<br />
This study is expected to start in late 2012 after approval by the<br />
Ethical Medical Committee.<br />
References<br />
1. Giuliano, A.E., et al., Axillary dissection vs no axillary dissection<br />
in women with invasive breast cancer and sentinel node metastasis:<br />
a randomized clinical trial. JAMA, 2011. 305(6): p. 569-75.<br />
2. Neal, C.H., et al., Can preoperative axillary US help exclude N2<br />
and N3 metastatic breast cancer? Radiology, 2010. 257(2): p. 335-41.<br />
3. Aaronson, N.K., et al., The European Organization for Research<br />
and Treatment of <strong>Cancer</strong> QLQ-C30: a quality-of-life instrument for<br />
use in international clinical trials in oncology. J Natl <strong>Cancer</strong> Inst,<br />
1993. 85(5): p. 365-76.<br />
4. Sprangers, M.A., et al., The European Organization for Research<br />
and Treatment of <strong>Cancer</strong> breast cancer-specific quality-of-life<br />
questionnaire module: first results from a three-country field study.<br />
J Clin Oncol, 1996. 14(10): p. 2756-68.<br />
5. Devoogdt, N., et al., Lymphoedema Functioning, Disability and<br />
Health questionnaire (Lymph-ICF): reliability and validity. Phys<br />
Ther, 2011. 91(6): p. 944-57.<br />
OT2-1-03<br />
The Z11 design for breast cancer patients undergoing a<br />
mastectomy<br />
van Roozendaal LM, Smidt ML, de Wilt HHW, van Dalen T, Strobbe<br />
LJA, van der Hage J, Tjan-Heijnen VCG, Linn SC, Serroyen JL.<br />
Maastricht University Medical Center, Maastricht, Netherlands;<br />
Radboud University Nijmegen Medical Center, Nijmegen,<br />
Netherlands; Diakonessen Hospital Utrecht, Utrecht, Netherlands;<br />
Canisius-Wilhelmina Hospital, Nijmegen, Netherlands; Netherlands<br />
<strong>Cancer</strong> Institute - Antoni van Leeuwenhoek Hospital, Amsterdam,<br />
Netherlands; Maastricht University, Maastricht, Netherlands<br />
Background<br />
The diagnostic work-up and treatment of axillary lymph nodes in breast<br />
cancer patients is an ongoing topic of research. The ACOSOG-Z0011<br />
study demonstrated no additional value of complementary axillary<br />
lymph node dissection (cALND) in case of limited axillary sentinel<br />
lymph node (SLN) metastases in breast cancer patients undergoing<br />
breast conserving therapy 1 . It is questionable whether these results<br />
can be applied to patients undergoing a mastectomy 2 .<br />
Trial design<br />
A prospective non-inferiority randomized multicenter trial was<br />
designed.<br />
<strong>Breast</strong> cancer patients with cT1-2N0 disease treated with mastectomy<br />
and limited axillary SLN metastases will be randomized for followup<br />
versus complementary axillary treatment. To assess the Quality<br />
of Life and morbidity benefits of this experimental treatment, 3<br />
validated questionnaires will be used: QLQ-C30, QLQ-BR 23 and<br />
Lymph-ICF 3-5 .<br />
Eligibility criteria<br />
- Women with histological confirmed cT1-2 invasive unilateral breast<br />
carcinoma<br />
- Clinical node negative: no palpable nodes in physical examination<br />
and the axillary ultrasound without signs of lymph node metastases<br />
(cyto-/histology if indicated)<br />
- Sentinel lymph node biopsy must contain at least one and a<br />
maximum of 3 (micro)metastases<br />
- Neoadjuvant systemic therapy is allowed<br />
Specific aims<br />
Primary endpoint is the axillary recurrence rate. The number of<br />
delayed axillary dissections will be registered. Secondary endpoints<br />
are distant-disease free survival, overall survival, local recurrence,<br />
morbidity and Quality of Life.<br />
www.aacrjournals.org 567s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Statistical methods<br />
Based on 5-year axillary recurrence free survival rate, a failure<br />
rate of 0.98 among controls and a true failure rate of 0.96 for study<br />
subjects are considered acceptable. Overall, 1114 patients will be<br />
included to be able to reject the null hypothesis that the failure rate<br />
for experimental and control subjects is inferior by at least 5% (D =<br />
-5%) with probability of 0.8 and alpha of 5%.<br />
Present accrual and target accrual<br />
This study is expected to start in late 2012 after approval by the<br />
Ethical Medical Committee.<br />
References<br />
1. Giuliano, A.E., et al., Axillary dissection vs no axillary dissection<br />
in women with invasive breast cancer and sentinel node metastasis:<br />
a randomized clinical trial. JAMA, 2011. 305(6): p. 569-75.<br />
2. Morrow, M. and A.E. Giuliano, To cut is to cure: can we really<br />
apply Z11 in practice? Ann Surg Oncol, 2011. 18(9): p. 2413-5.<br />
3. Aaronson, N.K., et al., The European Organization for Research<br />
and Treatment of <strong>Cancer</strong> QLQ-C30: a quality-of-life instrument for<br />
use in international clinical trials in oncology. J Natl <strong>Cancer</strong> Inst,<br />
1993. 85(5): p. 365-76.<br />
4. Sprangers, M.A., et al., The European Organization for Research<br />
and Treatment of <strong>Cancer</strong> breast cancer-specific quality-of-life<br />
questionnaire module: first results from a three-country field study.<br />
J Clin Oncol, 1996. 14(10): p. 2756-68.<br />
5. Devoogdt, N., et al., Lymphoedema Functioning, Disability and<br />
Health questionnaire (Lymph-ICF): reliability and validity. Phys<br />
Ther, 2011. 91(6): p. 944-57.<br />
OT2-1-04<br />
Intraoperative assessment of tumor margins with a new optical<br />
imaging technology: A multi-center, randomized, blinded clinical<br />
trial<br />
Jacobs LK, Carney PS, Cittadine AJ, McCormick DT, Somera<br />
AL, Darga DA, Putney JL, Adie SG, Ray P, Cradock KA, Tafra L,<br />
Gabrielson EW, Boppart SA. The Johns Hopkins University School<br />
of Medicine, Baltimore, MD; University of Illinois, Urbana, IL;<br />
Diagnostic Photonics, Inc, Chicago, IL; Carle Foundation Hospital,<br />
Urbana, IL; AdvancedMEMS, <strong>San</strong> Francisco, CA; Anne Arundel<br />
Medical Center, Annapolis, MD<br />
Background<br />
Partial mastectomy is the most commonly performed procedure<br />
for invasive breast cancer and is associated with a reexcision rate<br />
commonly ranging from 20% to 40% in the literature. This high rate<br />
of reexcision is associated with significant additional cost (estimated<br />
over $4,000 per reexcision) and lower quality outcomes.<br />
Optical coherence tomography (OCT) is a high-resolution imaging<br />
technology that images tissue structure with micron-scale resolution<br />
– on the same scale as histopathology. It is similar to ultrasound<br />
except it uses near infra-red light waves instead of sound waves to<br />
create detailed images several millimeters deep into tissue. Although<br />
widely used in ophthalmology with growing use in cardiovascular<br />
imaging, high-resolution OCT imaging has a narrow depth of focus<br />
and requires instrumentation that is not well suited for intraoperative<br />
use. Drawing from OCT technology, interferometric synthetic aperture<br />
microscopy (ISAM) is a computational imaging technique that creates<br />
high-resolution, always in-focus images in software with basic optical<br />
instrumentation. A high-resolution ISAM probe and imaging system<br />
has been developed for intraoperative imaging of tissue structure and<br />
has the potential to broadly impact intraoperative assessment of tumor<br />
margins. Intraoperative ISAM imaging of the excised breast cancer<br />
specimen margins and in vivo imaging within the surgical cavity may<br />
reduce the high rate of reexcision associated with partial mastectomy.<br />
Trial Design<br />
The trial design is a prospective, multi-center, randomized, double<br />
arm study comparing the reexcision rate of standard of care partial<br />
mastectomy versus the reexcision rate of standard of care partial<br />
mastectomy plus intraoperative ISAM imaging.<br />
Inclusion Criteria<br />
• Women histologically diagnosed with invasive carcinoma of the<br />
breast (invasive ductal or lobular)<br />
• Undergoing partial mastectomy (lumpectomy) procedure<br />
• Age 18 years or more<br />
Exclusion Criteria<br />
• Multicentric disease<br />
• Bilateral disease<br />
• Neoadjuvant systemic therapy<br />
• All T4 tumors<br />
• Previous radiation in the operated breast<br />
• Prior surgical procedure in the same quadrant<br />
• Implants in the operated breast<br />
• Pregnancy<br />
• Lactation<br />
• Participating in any other investigational study which can influence<br />
collection of valid data<br />
Primary Endpoints<br />
• Measure of surgical reexcision rate<br />
• Rate of tumor at final surgical margins<br />
Secondary Endpoints<br />
• Volume of tissue excised<br />
• Clinical and economic measures of addressing asymmetry<br />
Statistical Methods<br />
The trial is designed to show superiority of the ISAM imaging arm<br />
to the standard of care. Statistical design is two group, continuity<br />
corrected chi-squared test of equal proportions with 90% power and<br />
alpha=0.05. The trial design assumes a baseline reoperation rate in<br />
the standard of care arm of 24% with at least a 50% reduction in the<br />
ISAM imaging arm.<br />
Present Accrual and Target Accrual<br />
Not yet recruiting. Target accrual is 230 patients in the partial<br />
mastectomy + imaging arm and 230 patients in the standard of care<br />
partial mastectomy arm.<br />
OT2-2-01<br />
SOFT and TEXT: Trials of tamoxifen and exemestane with and<br />
without ovarian function suppression for premenopausal women<br />
with hormone receptor-positive early breast cancer<br />
Zickl L, Francis P, Fleming G, Pagani O, Walley B, Price KN, Gelber<br />
RD, Regan MM. International <strong>Breast</strong> <strong>Cancer</strong> Study Group, North<br />
American <strong>Breast</strong> <strong>Cancer</strong> Group<br />
Background<br />
The SOFT and TEXT randomized phase 3 trials address two primary<br />
questions for endocrine treatment of premenopausal women with<br />
hormone receptor-positive breast cancer. 1) In combination with<br />
ovarian function suppression (OFS), does an aromatase inhibitor<br />
(exemestane, E) improve outcome compared with tamoxifen (T)? 2)<br />
Does addition of OFS to T improve outcome compared with T alone?<br />
Trial Designs<br />
SOFT compares 5y of T to OFS+T or OFS+E. OFS can be GnRH<br />
analog (triptorelin) x 5y, oophorectomy or ovarian irradiation. Median<br />
age was 43y (11%
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT2<br />
TEXT compares 5y of OFS+T to OFS+E. Patients were enrolled<br />
prior to CT (if planned). Median age was 43y (9% 5y. The estimated power to<br />
detect a 20%, 25%, or 30% reduction in the hazard with OFS+E vs<br />
OFS+T is 63%, 84%, and 95%, respectively.<br />
The comparison of OFS+T to T alone is planned at 5y MFU (SOFT,<br />
n=2045). The estimated power to detect a 20%, 25%, 30%, or 33.5%<br />
reduction in the hazard is 34%, 52%, 69%, and 80%, respectively.<br />
Accruals<br />
SOFT Target: 3000; Final: 3066<br />
TEXT Target: 2639; Final: 2672<br />
Enrollment 2003-2011; primary analyses expected late 2013/early<br />
2014.<br />
Related Research<br />
Quality of Life (QL) component evaluates QL, menopausal symptoms<br />
and sexual impairment.<br />
TEXT Translational Research investigates patient and tumor features<br />
that may contribute to treatment effectiveness and side effects.<br />
TEXT-Bone investigates changes in bone mineral density and the<br />
role of serial serum markers of bone remodeling as predictors of<br />
bone side effects.<br />
Co-SOFT evaluates changes in cognitive function during the first year.<br />
SOFT-EST evaluates estrogen levels during the first 4y of GnRH<br />
analogue and whether there is a suboptimally estrogen-suppressed<br />
subgroup.<br />
North American Pharmacogenetics study investigates whether genetic<br />
variations that affect T and E metabolism influence efficacy.<br />
OT2-2-02<br />
Prospective multicentre study evaluating the effect of impaired<br />
tamoxifen metabolization on efficacy in breast cancer patients<br />
receiving tamoxifen in the neo-adjuvant or metastatic setting -<br />
The CYPTAM-BRUT 2 trial.<br />
Lintermans A, Dieudonné A-S, Blomme C, Lambrechts D, Wildiers H,<br />
Christiaens M-R, Timmerman D, Van Calster B, Decloedt J, Berteloot<br />
P, Joerger M, Zaman K, Dezentjé V, Neven P. University Hospitals<br />
Leuven, Belgium; Vesalius Research Center and VIB, Catholic<br />
University Leuven, Leuven, Belgium; AZ Sint-Blasius, Dendermonde,<br />
Belgium; AZ Sint-Maarten, Duffel, Belgium; Cantonal Hospital,<br />
Sint-Gallen, Switzerland; University Hospital CHUV, Lausanne,<br />
Switzerland; Leiden University Medical Center, Leiden, Netherlands<br />
Background<br />
Tamoxifen is often used for the prevention and treatment of hormone<br />
receptor positive breast cancer. It is metabolized in the liver through<br />
cytochrome P450 (CYP) enzymes to more active metabolites, of<br />
which endoxifen is considered the most important. It is known<br />
that certain genetic variants in CYP enzymes result in lower serum<br />
endoxifen levels, but their effect on tamoxifen efficacy is not yet clear<br />
as results remain contradictory.<br />
Trial design<br />
CYPTAM-BRUT 2 is a prospective multicentre open label single<br />
arm non randomized observational trial approved by the UZ Leuven<br />
Ethics Committee. Eligibility criteria are postmenopausal women with<br />
estrogen receptor positive invasive breast cancer receiving tamoxifen<br />
as first line therapy in the metastatic or neo-adjuvant setting. Prior<br />
adjuvant endocrine therapy is allowed if there is more than 12 months<br />
after completion of the adjuvant therapy.<br />
Primary endpoint is the relation between endoxifen levels and<br />
objective response rate. Secondary endpoints are the relation between<br />
endoxifen levels and the proportion of patients who are failure-free at<br />
6 months, clinical benefit, tolerability of tamoxifen and the predictive<br />
value of the tamoxifen activity score, based on the presence of genetic<br />
variants and CYP inhibiting drugs. Patients with bone-only lesions<br />
will only be included in the analysis of the secondary endpoints.<br />
The trial is designed to show an improvement of the objective tumor<br />
response rate from 5% in patients with an unfavorable endoxifen<br />
profile (steady-state concentrations < 90nM) to 20% in patients with<br />
a favorable endoxifen profile (steady-state concentrations ≥ 90nM).<br />
With a type I error of 5% and a power of 90%, 231 patients have<br />
to be included into the study. The main secondary study endpoint is<br />
progression-free survival (PFS) at 6 months. With a total number<br />
260 patients eligible for PFS, the study has a power of 80% to detect<br />
a 20% improvement of PFS at 6 months (i.e. from 50% to 70%) in<br />
patients with a favorable endoxifen as compared to patients with an<br />
unfavorable endoxifen profile, and a type-I error of 5%.<br />
Patient accrual<br />
Total sample size is 260 and currently 202 patients from 22<br />
participating centres in Belgium and Switzerland are included (May<br />
2012).<br />
www.aacrjournals.org 569s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
OT2-2-03<br />
Dovitinib (TKI258) or placebo in combination with fulvestrant in<br />
postmenopausal, endocrine-resistant HER2–/HR+ breast cancer:<br />
a phase II study<br />
Andre F, Greil R, Denduluri N, Barrios C, Campone M, Cortes<br />
J, Neven P, Reddick C, Squires M, Zhang Y, Yovine A, Blackwell<br />
K. Institut Gustave Roussy, Villejuif, France; Medizinische<br />
Universitätsklinik Salzburg mit Hämatologie, Salzburg, Austria;<br />
Virginia <strong>Cancer</strong> Specialists, US Oncology, Arlington, VA; Pontifícia<br />
Universidade Católica do Rio Grande do Sul School of Medicine,<br />
Porto Alegre, Brazil; Institut de Cancérologie de l’Ouest-René<br />
Gauducheau, Saint-Herblain, France; Vall d’Hebron Institute<br />
of Oncology, Barcelona, Spain; Hospital Gasthuisberg, Leuven,<br />
Belgium; Novartis Pharmaceuticals Corporation, East Hanover, NJ;<br />
Novartis Pharma AG, Basel, Switzerland; Duke University Medical<br />
Center, Durham, NC<br />
Background: Overcoming endocrine resistance is a critical goal<br />
in the treatment of hormone receptor-positive (HR+) breast cancer.<br />
Molecular mechanisms associated with endocrine resistance include<br />
adaptive cross-talk between the estrogen receptor and the fibroblast<br />
growth factor receptor (FGFR). Up to 8% of HR+/ human epidermal<br />
growth factor receptor 2 negative (HER2–) breast cancer patients<br />
have amplification of the FGFR1 gene, which is associated with<br />
resistance to endocrine therapy. In preclinical models, resistance to<br />
endocrine therapy can be overcome via FGFR1 inhibition. Dovitinib<br />
is a potent oral inhibitor of receptor tyrosine kinases, including FGFR,<br />
vascular endothelial growth factor receptor (VEGFR), and platelet<br />
derived growth factor receptor (PDGFR), that demonstrated antitumor<br />
activity in heavily pretreated breast cancer patients with FGF-pathway<br />
amplification (FGFR1, FGFR2, or ligand FGF3; Andre et al, ASCO<br />
2011). Dovitinib may reverse resistance to endocrine therapy related<br />
to FGF-pathway amplification and may also inhibit angiogenesis,<br />
which plays an essential role in breast cancer development. Dovitinib<br />
is studied here in combination with fulvestrant to determine if it<br />
can improve outcomes in postmenopausal patients with endocrine<br />
resistant HER2-/HR+ breast cancer.<br />
Methods: This is a multicenter, randomized, double-blind, placebocontrolled,<br />
phase II trial that will enroll postmenopausal HER2–/<br />
HR+ locally advanced or metastatic breast cancer patients (N ≈ 150)<br />
progressing within 12 months of completion of adjuvant endocrine<br />
therapy or after ≤ 1 prior endocrine therapy in the advanced setting.<br />
Patients prospectively undergo molecular screening to enrich for<br />
FGF amplification (FGFR1, FGFR2, or FGF3 amplification by<br />
qualitative polymerase chain reaction (qPCR); 45 amplified and 30<br />
nonamplified patients per arm). Patients are randomized 1:1 (stratified<br />
by FGF-amplification and presence of visceral disease) to receive<br />
fulvestrant intramuscularly (500 mg q4w [with an additional dose<br />
2 weeks after the initial dose]) in combination with oral dovitinib<br />
(500 mg, 5 days on/2 days off) or placebo until disease progression,<br />
unacceptable toxicity, death or discontinuation due to any reason<br />
(eg, withdrawal). Crossover is not permitted. The primary endpoint<br />
is progression-free survival, with tumor assessments performed<br />
q8w. Secondary endpoints include overall response rate per RECIST<br />
v1.1, duration of response, overall survival, Eastern Cooperative<br />
Oncology Group performance status and patient-reported outcome<br />
scores over time, and safety. Additionally, the pharmacodynamic<br />
effect of dovitinib on FGFR-associated angiogenic pathways in<br />
tumor specimens and potential predictive biomarkers of response to<br />
dovitinib will be explored.<br />
OT2-2-04<br />
A phase III randomized, placebo-controlled clinical trial<br />
evaluating the use of adjuvant endocrine therapy +/- one year of<br />
everolimus in patients with high-risk, hormone receptor- (HR)<br />
positive and HER2-negative breast cancer: SWOG/NSABP S1207.<br />
Chavez-Mac Gregor M, Barlow WE, Gonzalez-Angulo AM, Rastogi<br />
P, Mamounas EP, Ganz PA, Schott AF, Paik S, Lew DL, Bandos H,<br />
Hortobagyi GN. The University of Texas MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX; SWOG Statistical Center, Seattle, WA; NSABP/Four<br />
Allegheny Center, Pittsburgh, PA; Aultman <strong>Cancer</strong> Center, Canton,<br />
OH; UCLA Jonsson Comprehensive <strong>Cancer</strong> Center, Los Angeles,<br />
CA; University of Michigan, Ann Arbor, MI; NSABP Division of<br />
Pathology, Pittsburgh, PA; NSABP Biostatistical Center, Graduate<br />
School of Public Health, University of Pittsburgh, PA<br />
BACKGROUND: Abnormalities of the PI3kinase/AKT/mTOR<br />
signaling network are some of the most common molecular anomalies<br />
in breast cancer. This pathway has been associated with resistance to<br />
endocrine therapies among HR-positive breast tumors. Everolimus,<br />
an mTOR-inhibitor, has been shown to increase the biological activity<br />
of aromatase inhibitors. In the metastatic setting, everolimus in<br />
combination with tamoxifen or exemestane increased the progressionfree<br />
survival in patients previously treated with endocrine therapy.<br />
S1207 proposes to evaluate the role of everolimus used in combination<br />
with endocrine therapy in the adjuvant setting.<br />
SPECIFIC AIMS/TRIAL DESIGN: S1207 is a SWOG/NSABP<br />
randomized phase III double-blind, placebo-controlled clinical trial.<br />
The primary objective of the study is to assess whether the addition<br />
of one year of everolimus to standard adjuvant endocrine therapy<br />
improves invasive disease-free survival (DFS) among patients with<br />
high risk HR-positive breast cancer. Secondary objectives include<br />
overall survival, distant recurrence-free survival, safety, adherence<br />
and quality of life. Submission of tissue specimens/blood samples<br />
is required for translational studies. Patients will be randomized to<br />
receive standard adjuvant endocrine therapy (selected by treating<br />
physician) in combination with one year of everolimus (10 mg PO<br />
daily) or standard adjuvant endocrine therapy in combination with<br />
one year of matched placebo.<br />
ELIGIBILITY CRITERIA: Patients with histologically confirmed<br />
invasive breast cancer HER2-negative and HR-positive with high risk<br />
features including: 1) node-negative disease with tumors ≥2cm and<br />
a recurrence score (RS) >25; 2) 1-3 positive nodes and RS >25; 3)<br />
patients with ≥4 positive lymph nodes regardless of RS. Patients with<br />
≥4 positive lymph nodes after completing neoadjuvant chemotherapy<br />
are also eligible. All patients must have completed surgery, adjuvant/<br />
neoadjuvant chemotherapy, and radiation therapy (if indicated) before<br />
registration. Prior exposure to mTOR inhibitors is not allowed.<br />
STATISTICAL METHODS/TARGET ACCRUAL: This is a<br />
parallel randomization design with equal allocation to the two<br />
treatment groups (everolimus and placebo). Randomization is<br />
stratified by 4 risk groups. All analyses are intent-to-treat by<br />
randomized assignment of eligible patients. The study plans to<br />
randomize 3,500 patients over a 3.5-year accrual period with the<br />
primary analysis conducted 3 years after the last patient is randomized.<br />
The study has 90% power (with 2-sided α=0.05) to detect an effective<br />
hazard ratio of 0.75 for everolimus versus placebo, corresponding<br />
to a gain in DFS of approximately 4.3% at 5 years. All patients will<br />
be followed for 10 years to assess overall survival and late adverse<br />
events. The expected trial duration from activation to reporting of<br />
DFS is about 7 years.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT2<br />
OT2-2-05<br />
A prospective, randomised multi-centre phase II study evaluating<br />
the adjuvant, neoadjuvant or palliative treatment with tamoxifen<br />
+/- GnRH analogue versus aromatase inhibitor + GnRH analogue<br />
in male breast cancer patients (GBG-54 MALE)<br />
Linder M, von Minckwitz G, Kamischke A, Rudlowski C, Eggemann<br />
H, Nekljudova V, Loibl S. German <strong>Breast</strong> Group, Neu-Isenburg;<br />
Kinderwunschzentrum Münster, Germany; Universitätsfrauenklinik<br />
Bonn; Universitätsfrauenklinik Magdeburg<br />
Background<br />
<strong>Breast</strong> cancer (BC) in men is a rare disease accounting for 0.5-1%<br />
of all BC. The only available information on endocrine therapies<br />
derives from few retrospective case series and studies with small<br />
numbers of patients (pts). Treatment strategies are not based on<br />
data from prospective, randomised clinical studies and optimal<br />
therapy is unknown. Current clinical management is extrapolated<br />
from principles established for female BC. As 90% of male pts have<br />
hormone receptor positive BC, they receive tamoxifen 20mg as<br />
standard adjuvant therapy.<br />
Although women benefit from treatment with aromatase inhibitors<br />
(AI), only case reports exist of men treated with AI. Data from other<br />
entities show, that AI only suppresses oestradiol of 40-50% with<br />
an increase of testosterone. Among men on AIs, the hypothalamicpituitary<br />
feedback loop results in an increase substrate for<br />
aromatisation. By adding a gonadotropin-releasing hormone analogue<br />
(GnRH), the feedback loop would be interrupted and complete<br />
oestrogen suppression may be achieved.<br />
Patients and Methods<br />
The MALE study is a prospective, randomized, phase II study in<br />
which 48 male pts will be included in the adjuvant, neoadjuvant<br />
and metastatic setting. In a 3-arm design, endocrine therapies are<br />
compared consisting of tamoxifen 20mg daily versus tamoxifen<br />
daily+GnRH on day 1 and after 3 months versus exemestane<br />
25mg daily+GnRH on day 1 and after 3 months. The treatment<br />
duration is 6 months. The primary aim is to determine the oestradiol<br />
suppression after 3 months. Secondary endpoints are to compare the<br />
oestradiol suppression after 6 months and to assess the compliance<br />
(with standardized questionnaires as Aging Male Symptom Score,<br />
International Index of Erectile function and International Prostate<br />
Symptom Score), safety and toxicity profile. The determination of<br />
the predefined hormones at baseline and after 3 and 6 months will be<br />
measured centrally. After the antihormonal treatment, all pts should<br />
be treated according to local recommendations. Included can be men<br />
with primary or metastatic endocrine sensitive BC with an indication<br />
of an endocrine therapy who did not receive prior antihormonal<br />
therapy; prior chemotherapy is allowed.<br />
16 evaluable pts per group are needed for the Kruskal-Wallis-Test to<br />
have 80% power to detect at the 5% significance level a difference.<br />
The translational research programme includes the determination of<br />
cytochrome P450 polymorphisms, the hormone receptor activity and<br />
aromatase expression of the tumour tissue.<br />
Results<br />
The time of recruitment should not exceed 2 years with 36 recruiting<br />
sites in Germany. As no study specific treatment or investigation is<br />
planned after the end of treatment, surgery and follow up are not<br />
part of this study, however information on the health status of the<br />
pts will be collected. The trial has been opened in May 2012 and is<br />
currently recruiting.<br />
Conclusion<br />
This is the first study randomizing men with BC to investigate the<br />
ability to suppress estradiol of different endocrine regimen.<br />
OT2-3-01<br />
Phase Ib pilot study to evaluate reparixin in combination with<br />
chemotherapy with weekly paclitaxel in patients with HER-2<br />
negative metastatic breast cancer (MBC)<br />
Schott AF, Wicha M, Cristofanilli M, Ruffini P, McCanna S, Reuben<br />
JM, Goldstein LJ. University of Michigan, Ann Arbor, MI; Fox Chase<br />
<strong>Cancer</strong> Center, Philadelphia, PA; Dompé s.p.a., Milano, Italy; MD<br />
Anderson <strong>Cancer</strong> Center, Houston, TX<br />
Background: <strong>Breast</strong> cancer stem cells (BCSCs) have the ability<br />
to self renew and generate the full range of cells that make up a<br />
bulk tumor. Chemokine receptor 1 (CXCR1) is almost exclusively<br />
expressed in the aldehyde dehydrogenase positive (ALDH+) BCSC<br />
population compared with its expression in bulk tumor cells. CXCR1<br />
is a receptor for CXCL8 (previously IL8), a proinflammatory<br />
chemokine implicated in the metastasis and progression of multiple<br />
malignancies, including breast cancers. CXCL8 has also been shown<br />
to stimulate self-renewal of BCSCs in vitro. Tissue damage induced<br />
by chemotherapeutic agents may induce CXCL8 as part of the injury<br />
response. This suggests that strategies aimed at interfering with the<br />
CXCL8/CXCR1 axis, activated by conventional chemotherapy (CT),<br />
may be able to target BCSCs and increase the efficacy of current<br />
therapies. Reparixin, a low molecular weight blocker of CXCL8<br />
biological activity, reduced ALDH-1+ cells in a human breast cancer<br />
xenograft when administered alone or in combination with taxane<br />
chemotherapy, and reduced metastases. Based on these findings, a<br />
Phase Ib study to determine the safety of paclitaxel plus reparixin<br />
therapy, and to explore the effects of reparixin on BCSCs and the<br />
tumor microenvironment, was initiated. Design and Treatment:<br />
Patients will receive a three-day run-in with reparixin oral tablets<br />
3 times/day (tid) followed by paclitaxel 80 mg/m2/week (Days 1,<br />
8, and 15 for 28-day cycle) + reparixin oral tablets tid.for 21 days.<br />
Three dose levels of 3-6 subjects will be explored in total: Dose level<br />
1 = 400 mg oral reparixin tid; Dose level 2 = 800 mg reparixin tid;<br />
and Dose level 3 = 1200 mg reparixin tid. An additional 6 subjects<br />
will be enrolled at the highest tolerated dose. Safety will be assessed<br />
following one cycle. Treatment continues as long as clinical benefit<br />
is observed. Main Eligibility Criteria: Patients must be female aged<br />
> 18 years with HER-2 negative MBC, eligible for treatment with<br />
paclitaxel (not taxane-refractory), have had up to 3 prior CT lines for<br />
advanced breast cancer (not including neo/adjuvant chemotherapy),<br />
must have measurable disease according to RECIST criteria version<br />
1.1, have ECOG PS of 0-1, have adequate organ function, and have<br />
no brain metastases. Objectives: Primary: To evaluate the safety<br />
and pharmacokinetic (PK) profile of the combination treatment.<br />
Secondary: 1) To evaluate tumor biopsies for the effects of reparixin<br />
on BCSC markers and tumoral microenvironment; 2) To evaluate<br />
blood samples for a) enumeration and molecular characterization<br />
of circulating tumor cells (CTCs), biomarker profiling for BCSC<br />
and epithelial-mesenchymal transition (EMT), and b) inflammatory<br />
cytokines; 3) To assess disease response for indication of efficacy.<br />
Statistical Methods: All tumor data collected will be reviewed and<br />
listed. No formal statistical analysis of this data is planned. Safety<br />
and tolerability analysis will be applied on the safety population with<br />
descriptive statistics for the safety variables.Summary statistics will<br />
be performed for each PK parameter and correlative study parameter.<br />
Accrual status: To date, four subjects have been enrolled at the first<br />
dose level. Target accrual is 15-24 subjects.<br />
www.aacrjournals.org 571s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
OT2-3-02<br />
Phase Ib/II study of an oral PI3K/mTOR inhibitor plus letrozole<br />
compared with letrozole (L) in pre-operative setting in patients<br />
with Estrogen Receptor-positive, HER2-negative early breast<br />
cancer (BC): Phase Ib preliminary data.<br />
Canon JL, Bergh J, Saura C, Oliveira M, Houk B, Millham R, Barton<br />
J, Dowsett M, Giorgetti C. Grand Hopital de Charleroi, Charleroi,<br />
Belgium; Karolinska Institutet and University Hospital, Stockholm,<br />
Sweden; Vall d’Hebron University Hospital, Vall d’Hebron Institute<br />
of Oncology (VHIO), Barcelona, Spain; Pfizer Oncology, La Jolla;<br />
Pfizer Oncology, Groton; Pfizer Biotechnology Unit & Oncology<br />
Clinical Research, <strong>San</strong> Diego; Royal Marsden Hospital, London,<br />
United Kingdom; Pfizer Oncology, Milan, Italy<br />
Background: Acquired hormone independent BC cell growth is<br />
associated with upregulation of the PI3K/mTOR pathway in vitro<br />
and in neo-adjuvant studies of aromatase inhibition (Ghazoui AACR<br />
<strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong>, 2011). Preclinical and clinical studies<br />
suggest that the combination of hormone therapy and a PI3K/mTOR<br />
inhibitor can restore sensitivity to hormone resistant tumours. Luminal<br />
B BCs are more frequently associated with endocrine resistance,<br />
hyperactivation of the PI3K signaling pathway, and increased<br />
expression of the Ki-67 proliferation marker than Luminal A BCs.<br />
This particular population may be a suitable target for PI3K directed<br />
therapy. A reduction in Ki-67 in the neo-adjuvant setting by endocrine<br />
therapy has been shown to correlate with efficacy of that same<br />
therapeutic in the adjuvant setting. Thus, a pre-operative study in high<br />
Ki-67-expressing BCs with short term reduction in Ki-67 as a primary<br />
endpoint could be used to support a study in the adjuvant setting with<br />
a conventional disease free endpoint. Study Design: The study is<br />
conducted in 2 phases, a Phase Ib followed by a randomized Phase<br />
II. The Phase Ib is designed to assess the tolerability of PF-04691502,<br />
an oral PI3K/mTOR antagonist, combined with L in postmenopausal<br />
women with ER positive, HER-2 negative advanced BC. A total of 10<br />
patients will be enrolled in this portion of the study. PF-04691502+L<br />
will be administered until progression of disease. After up to 2 months<br />
of treatment, the safety profile of PF-04691502+L will be evaluated<br />
prior to the initiation of the Phase II portion in a pre-operative setting.<br />
A total of 204 postmenopausal women with ER positive, HER-2<br />
negative early BC selected based on a high level of Ki-67 (>10%)<br />
will be enrolled in the Phase II portion. Patients will be randomized<br />
to receive PF-04691502+L or L alone for 6 weeks. The Phase II is<br />
designed to test the hypothesis that the addition of PF-04691502 to L<br />
can reduce Ki-67 levels after 6 weeks of administration to a greater<br />
degree than L alone, thus supporting the concept that the compound<br />
might mitigate the intrinsic or acquired resistance to hormonal<br />
therapy in a high risk patient population in the adjuvant setting.<br />
Patients will undergo 3 sequential core-biopsies (baseline, weeks 2<br />
and 6) to compare the changes in Ki-67 value from baseline to the<br />
end of the treatments and to test pharmacodynamic effects associated<br />
with PI3K/mTOR pathway modulation. Results: As of May 2012,<br />
8 postmenopausal women with advanced BC were enrolled in the<br />
phase Ib. All patients received PF-04691502 8 mg/day and L 2.5<br />
mg/day. Treatment is ongoing in all patients. The combination has a<br />
manageable safety profile although the median time of observation<br />
is short (47 days). A full set of safety data of patients enrolled in the<br />
Phase Ib will be presented. Also pharmacokinetic profile of L alone<br />
and in combination with PF-04691502 will be shown.<br />
OT2-3-03<br />
Denosumab versus placebo as adjuvant treatment for women<br />
with early-stage breast cancer at high risk of disease recurrence<br />
(D-CARE): An international, randomized, double-blind, placebocontrolled<br />
phase 3 clinical trial<br />
Goss PE, Barrios CH, Chan A, Finkelstein DM, Iwata H, Martin<br />
M, Braun A, Ke C, Maniar T, Coleman RE. Massachusetts General<br />
Hospital, Boston, MA; PUCRS School of Medicine, Porto Alegre,<br />
Brazil; <strong>Breast</strong> <strong>Cancer</strong> Research Centre, Perth, WA, Australia; Aichi<br />
<strong>Cancer</strong> Center, Nagoya, Chikusa-ku, Japan; Hospital Gregorio<br />
Maranon, Madrid, Spain; Amgen Inc., Thousand Oaks, CA; CR-UK/<br />
YCR Sheffield <strong>Cancer</strong> Research Centre, Sheffield, United Kingdom<br />
Bone represents approximately 40% of all first recurrences in women<br />
with early-stage breast cancer and is a common site of distant<br />
recurrence. In preclinical studies, RANKL inhibition significantly<br />
delays skeletal tumor formation, reduces skeletal tumor burden, and<br />
prolongs survival of tumor-bearing mice. Denosumab is approved<br />
for the prevention of skeletal-related events (SREs) in patients with<br />
established bone metastases from solid tumors.<br />
Purpose: The D-CARE trial is designed to assess if denosumab<br />
treatment prolongs bone metastasis-free survival (BMFS) and diseasefree<br />
survival (DFS) in the adjuvant breast cancer setting. The primary<br />
endpoint of this event-driven trial is BMFS. Secondary endpoints<br />
include DFS and overall survival. Additional endpoints are safety,<br />
breast density, incidence of SREs (following the development of bone<br />
metastasis) patient reported outcomes, and biomarkers.<br />
Methods: In this international, randomized, double-blind, and placebo<br />
controlled phase 3 trial, approximately 4,500 women with stage II or<br />
III breast cancer, at high risk for recurrence and with known hormone<br />
and HER-2 receptor status, are eligible. High risk is defined as biopsy<br />
evidence of breast cancer in regional lymph nodes, tumor size > 5<br />
cm, (T3), or locally advanced disease (T4). Standard-of-care adjuvant<br />
or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone<br />
or in combination, must be planned. Patients with a prior history of<br />
breast cancer (except ductal carcinoma in situ or lobular carcinoma<br />
in situ) or distant metastasis, oral bisphosphonate (BP) use within 1<br />
year of randomization, or any intravenous BP use, are not eligible.<br />
Patients are randomized 1:1 to receive denosumab 120 mg or placebo<br />
subcutaneously monthly for 6 months, then every 3 months for a<br />
total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU)<br />
and calcium (≥ 500 mg) will be administered. The trial, sponsored<br />
by Amgen Inc. and registered with the ClinicalTrials.gov identifier<br />
NCT01077154, began enrolling patients in June 2010 and is expected<br />
to complete enrollment in late 2012.<br />
OT2-3-04<br />
A PILOT PHASE II STUDY TO EVALUATE THE IMPACT OF<br />
DENOSUMAB ON DISSEMINATED TUMOR CELLS (DTC) IN<br />
PATIENTS WITH EARLY STAGE BREAST CANCER (ESBC)<br />
Li J, Rugo HS. University of California, <strong>San</strong> Francisco, CA<br />
Background: Bone is the most common site of metastases in breast<br />
cancer (BC). The detection of keratin + cells (DTC) in bone marrow<br />
(BM) has been shown to correlate with an increased risk of disease<br />
recurrence. Receptor activator of nuclear factor kappa b (RANK)<br />
is critical to bone turnover. Pre-clinical studies have shown that<br />
the ligand to RANK (RANKL) can induce metastases of RANKexpressed<br />
tumor cells, and that treatment with a RANKL inhibitor can<br />
reduce BC metastases. Our previous study suggests that higher RANK<br />
expression in tumor at the time of diagnosis correlates with worse<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
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<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT2<br />
recurrent free survival (RFS). Denosumab, a humanized RANKL<br />
inhibitor, has been approved in patients (pts) with osteoporosis and<br />
metastatic BC to bone.<br />
Trial design: We designed a nonrandomized, open label phase II<br />
pilot study evaluating the impact of denosumab on DTCs in pts with<br />
ESBC and DTCs following (neo) adjuvant chemotherapy. A total<br />
of 45 pts will be enrolled; treatment (Rx) consists of denosumab by<br />
subcutaneous injection monthly for 6 months, then every 12 weeks for<br />
6 months for a total of one year. BMA will be repeated at 6 and 12 mo;<br />
samples will be evaluated for DTC and for specific gene expression.<br />
Eligibility criteria: Eligible pts have completed adjuvant<br />
chemotherapy and at least 3 months (mo) of hormonal Rx as<br />
indicated, and have >10 DTC on screening bone marrow aspiration<br />
by immunomagnetic enrichment + flow cytometry (IE/FC).<br />
Specific aims: The primary efficacy endpoint is the reduction of<br />
DTC/ml from >10DTC/ml to ≤ 10DTC/ml at 6 mo and one year,<br />
and the feasibility of denosumab use in this setting. Secondary and<br />
exploratory endpoints are to evaluate the correlation of DTC at each<br />
time point with BC recurrence, and to analyze gene expression of<br />
markers related to bone destruction and inflammation in sorted DTC.<br />
Statistical methods: A total of 45 pts will be enrolled. Based on<br />
results from a previous trial testing zoledronic acid in a group of pts<br />
with similar eligibility, we expect to have evaluable BMA on 37 (82%)<br />
at 1 year. With standard Rx we expect 5% or fewer will have counts<br />
≤10 DTC/ml at 1 year. Using STATA routine sample size (SAMPSI:<br />
sample size and power for means and proportions), as long as 20% of<br />
pts in treated group become DTC-negative, we will have 89% power<br />
to detect this degree of efficacy. These calculations are based on an<br />
“exact” test of the proportion of successes; those with reductions to<br />
≤10DTC/ml in sample sizes of 37 based on one-sided testing at a 5%<br />
level of significance. We will compare the DTC/ml at 6 and 12 mo<br />
to baseline to evaluate reduction in counts.<br />
Present accrual and target accrual: trial will be open in July, 2012<br />
with target accrual of 45 pts.<br />
OT2-3-05<br />
AVASTEM: a phase II randomized trial evaluating anti-cancer<br />
stem cell activity of pre-operative bevacizumab and chemotherapy<br />
in breast cancer<br />
Gonçalves A, Pierga J-Y, Brain E, Tarpin C, Cure H, Esterni B,<br />
Boyer-Chammard A, Bertucci F, Jalaguier A, Houvenaeghel G, Viens<br />
P, Charaffe-Jauffret E, Extra J-M. Institut Paoli Calmettes, Marseille,<br />
France; Institut Curie-Centre René Huguenin, Paris, France; Institut<br />
Jean Godinot, Reims, France<br />
Background:<br />
Bevacizumab (BEV) in combination with chemotherapy (CT)<br />
improved response rate and progression-free survival without<br />
detectable impact on overall survival (OS) in metastatic breast cancer<br />
(BC). BC contains population of cells that display stem-cell properties.<br />
These cancer stem cells (CSC) are known to be relatively insensitive<br />
to cytotoxic chemotherapies and might play a major role in treatment<br />
resistance and relapse. Complex interactions exist between CSC and<br />
angiogenesis: whereas CSC may secrete VEGF and pro-angiogenic<br />
factors and may stay in VEGF-dependant vascular niche, recent<br />
preclinical data indicate that antiangiogenics may increase breast CSC<br />
population via hypoxia. CSC proportion may be monitored in human<br />
BC using IHC staining of ALDH1. AVASTEM trial was designed to<br />
evaluate whether the addition of BEV to conventional CT alters the<br />
proportion of CSC in BC patients receiving neo-adjuvant (NA) CT.<br />
Trial design:<br />
In this open-label phase II randomized study, patients are stratified<br />
by HER2 status and randomized 1:2 to receive NACT:<br />
- arm A (experimental): FEC100 (5FU 500 mg/m², Epirubicin 100<br />
mg/m², Cyclophosphamide 500 mg/m²) + BEV (15 mg/kg, 3-weekly)<br />
x 4 followed by Docetaxel (100 mg/m²) + BEV +/- trastuzumab (T, 8<br />
mg/kg and then 6 mg/kg, 3-weekly) if HER2-positive, x 4<br />
- arm B (control): FEC100 x 4 followed by Docetaxel 100 +/- T if<br />
HER2-positive, x 4.<br />
Tumor biopsies are required at baseline and after the first 4 cycles<br />
of FEC. After NACT, appropriate surgery and radiation therapy are<br />
performed, followed by adjuvant T and hormonal therapy, if indicated.<br />
Eligibility criteria:<br />
- Primary HER2-positive or -negative BC candidate to NACT<br />
(inflammatory breast cancer and synchronous metastatic disease<br />
are eligible)<br />
- Primary BC accessible to initial biopsy<br />
- Left ventricular ejection fraction ≥ 55%<br />
- Appropriate haematological, liver, renal and coagulation functions<br />
Specific aims:<br />
-Primary endpoint: to measure the variations of CSC proportion<br />
(by measuring the amount of IHC ALDH1-positive cells) in tumor<br />
biopsies obtained before C1 and after C4 in patients treated with<br />
BEV-based NACT or with NACT alone.<br />
- Secondary endpoints: tolerance, pCR, disease-free survival,<br />
recurrence-free survival and OS; ancillary studies (CSC<br />
characterization by CD44/CD24 IHC staining and evaluation of<br />
tumor-initiating properties of fresh tumor cells; CTC counts; contrastbased<br />
breast ultra-sonography; transcriptomics and proteomics)<br />
Statistical design:<br />
The difference between percentage of ALDH1-positive cells after 4<br />
cycles of BEV-based NACT and before treatment will be calculated.<br />
In the experimental arm, an equivalence test will be used to validate<br />
the hypothesis that the cell percentage does not increase more than<br />
5% during treatment (under the following hypothesis: no difference<br />
of expression, difference variability σ = 13, significance level of 0.05,<br />
power of 0.8). With the assumption of approximately 20% of missing<br />
data, 50 patients will be included in the tested arm. The control arm<br />
(n=25) is needed to confirm CSC increase during conventional CT.<br />
Present and target accrual:<br />
By May June 2012, 69 patients have been included. A total of 75<br />
patients are to be enrolled. Funded by INCA-PHRC 2009.<br />
OT2-3-06<br />
A phase II, non-randomized, multicenter, exploratory trial of<br />
single agent BKM120 in patients with triple-negative metastatic<br />
breast cancer.<br />
Saura C, Lin N, Ciruelos E, Maurer M, Lluch A, Gavilá J, Winer E,<br />
Baselga J, Rodón J. Vall d’Hebron University Hospital, Barcelona,<br />
Spain; Dana-Farber <strong>Cancer</strong> Institute, Boston, MA; Hospital 12<br />
de Octubre, Madrid, Spain; Columbia University Medical Center,<br />
New York; Hospital Clínico de Valencia, Valencia, Spain; Instituto<br />
Valenciano de Oncología, Valencia, Spain; Massachusetts General<br />
Hospital, Boston; SOLTI <strong>Breast</strong> <strong>Cancer</strong> Research Group, Barcelona,<br />
Spain<br />
Despite best available therapy, triple-negative breast cancer (TNBC)<br />
continues to be associated with poorer outcomes when compared to<br />
other breast cancer subtypes and poses a serious therapeutic challenge.<br />
Therefore, novel and more efficacious therapies are in great need. It<br />
is widely accepted nowadays, that TNBC is not homogeneous, but<br />
comprised of a number of subpopulations very different in genetic<br />
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make-up, oncogene dependence, and response to treatment. Among<br />
these, multiple core phosphatidylinositol-3-kinase (PI3K) pathway<br />
components are known to be altered in TNBC. The relevance of<br />
activating mutations in the PI3KCA gene or PTEN/INPP4B loss of<br />
protein expression on the virulence of breast cancer and response to<br />
PI3K inhibitors is yet to be elucidated. PI3K hyperactivity due to<br />
these alterations suggests that inhibitors of the PI3K pathway may<br />
be used to reverse resistance.<br />
BKM120 is a potent and highly specific oral pan-class I PI3K inhibitor<br />
currently in clinical development. This non-randomized, two-stage,<br />
open-label, single-arm exploratory trial is designed to elucidate the<br />
preliminary therapeutic value of BKM120 in patients with metastatic<br />
TNBC and to identify subpopulations that may mostly benefit.<br />
Women 18 years and above with confirmed mTNBC who have<br />
received at least two prior chemotherapy regimens in the adjuvant or<br />
metastatic setting are eligible to participate. Availability of a tumor<br />
block from the primary tumor or accessible metastasis for biopsy is<br />
mandatory. The primary objective is to determine the clinical activity<br />
of BKM120 defined as the clinical benefit rate (CR, PR or SD for<br />
more than 4 months per RECIST 1.1). Secondary objectives are to<br />
determine progression-free survival, overall survival, safety profile,<br />
pharmacodynamic effects, and to identify biomarkers predictive of<br />
response. BKM120 will be administered orally at a 100-mg dose, once<br />
daily, in a continuous schedule. Treatment will continue until disease<br />
progression, unacceptable toxicity, or decision of the physician or the<br />
patient to terminate participation.<br />
Stage 1 will include up to 50 patients with an intermediate analysis<br />
after the enrollment of the first 29 subjects. If no sufficient activity<br />
is observed, the clinical trial will be terminated. If drug activity is<br />
observed, enrollment will continue up Stage 1 completion. After<br />
50 patients are enrolled, a comprehensive analysis of molecular<br />
markers using technology and knowledge gathered in the Stand Up<br />
to <strong>Cancer</strong> Dream Team will take place. This analysis will be focused<br />
in identifying molecular markers predictive of response that would<br />
guide patient selection for Stage 2. Two clone investigator-initiated<br />
protocols (one for the US, one for Spain) are enrolling in parallel. A<br />
total of 110 patients will take part in this study in four sites in Spain<br />
and in 2 in the US: 50 patients in Stage 1 and 60 in Stage 2, exploring<br />
a maximum of 3 subgroups of 20 patients each. The trial is funded by<br />
a Stand Up to <strong>Cancer</strong> Dream Team Translational Research Grant, a<br />
Program of the Entertainment Industry Foundation (SU2C-AACR-<br />
DT0209) and supported by Novartis. Patient enrollment started in<br />
June 2012.<br />
OT2-3-07<br />
A randomized, phase 2 study of the poly (ADP-ribose) polymerase<br />
(PARP) inhibitor veliparib (ABT-888) in combination with<br />
temozolomide (TMZ) or in combination with carboplatin (C) and<br />
paclitaxel (P) versus placebo plus C/P in subjects with BRCA1 or<br />
BRACA2 mutation and metastatic breast cancer<br />
Isakoff SJ, Pulhalla S, Shepherd SP, Falotico N, Kaufman B,<br />
Friedlander M, Robson M, Domchek S, Garber J, McKeegan E, Chyla<br />
B, Qian J, Giranda VL. Massachusetts General Hospital, Boston, MA;<br />
University of Pittsburgh, PA; Abbott, Abbott Park, IL, Virgin Islands,<br />
British; Sheba Medical Center, Israel; Prince of Wales Hospital,<br />
Sydney, Australia; Memorial Sloan-Kettering <strong>Cancer</strong> Center, New<br />
York, NY; University of Pennsylvania, Philadelphia, PA; Dana Farber<br />
<strong>Cancer</strong> Institute, Boston, MA<br />
Background: Veliparib is a potent, oral PARP inhibitor that inhibits<br />
DNA repair, primarily through single strand break repair. BRCA1/2<br />
mutated tumors are defective in homologous recombination, leading<br />
to more error prone mechanisms of DNA repair and increased<br />
sensitivity to PARP inhibition. Veliparib and TMZ recently<br />
demonstrated promising activity in BRCA1/2 mutation carriers, and<br />
veliparib and C/P is being evaluated in a CTEP Phase 1 study. This<br />
Phase 2 multinational study will evaluate veliparib in combination<br />
with TMZ and in combination with C/P compared to an active,<br />
placebo-controlled arm of C/P in subjects with BRCA1 or BRCA2<br />
mutation and metastatic breast cancer.<br />
Methods: Approximately 240 subjects will be randomized in a 1:1:1<br />
ratio to: 1) Veliparib 40 mg BID D1-7 + TMZ (150 - 200 mg/m 2 QD<br />
D1-5) of every 28 day cycle; or 2) Veliparib 120 mg BID D1-7 +<br />
C (AUC 6, D3) and P (175 mg/m 2 , D3) of every 21 day cycle or 3)<br />
placebo BID D1-7 + C/P. Key eligibility includes known deleterious<br />
BRCA1/2 mutation, ≤1 prior chemotherapy for metastatic disease, and<br />
no prior platinum agent. Randomization will be stratified by hormone<br />
receptor positive versus negative, prior vs. no prior cytotoxic therapy,<br />
and ECOG 0-1 vs 2.<br />
The primary objective is progression-free survival (PFS) using<br />
RECIST 1.1. Secondary objectives include overall survival, objective<br />
response rate, duration of response and safety/tolerability. Optional<br />
paired tissue biopsies will be obtained at baseline and at progression<br />
to evaluate markers of response and resistance. Additional correlatives<br />
for response include assessment of peripheral blood, CTCs, and<br />
archived tissue for markers of disease status, gene methylation and<br />
mutational status, and tumor-specific alteration of cellular proteins/<br />
peptides and/or nucleic acids. Using the log-rank test for PFS, with<br />
150 PFS events the study will have ≥ 80% power at 2-sided α level<br />
of 0.05 to detect a statistically significant treatment effect assuming<br />
a true hazard ratio of 0.58 favoring the 2 treatment groups containing<br />
veliparib. As of June 11, 2012, 5 subjects have been enrolled.<br />
OT2-3-08<br />
Phase III randomized study of the oral pan-PI3K inhibitor<br />
BKM120 with fulvestrant in postmenopausal women with HR+/<br />
HER2– locally advanced or metastatic breast cancer, treated with<br />
aromatase inhibitor, and progressed on or after mTOR inhibitorbased<br />
treatment – BELLE-3<br />
Di Leo A, Germa C, Weber D, Di Tomaso E, Dharan B, Massacesi<br />
C, Hirawat S. <strong>San</strong>dro Pitigliani Hospital of Prato, Prato, Italy;<br />
Novartis Oncology, Paris, France; Novartis Institutes for BioMedical<br />
Research, Inc., Cambridge, MA; Novartis Pharmaceuticals<br />
Corporation, East Hanover, NJ<br />
Background: The PI3K/AKT/mTOR pathway is frequently activated<br />
in breast cancer (BC), and has been implicated in resistance to<br />
endocrine therapies and mTOR inhibitors (mTORi). BKM120 is<br />
an oral inhibitor of all 4 isoforms of class I PI3K (α, β, γ, δ). In<br />
combination with fulvestrant, BKM120 has demonstrated proapoptotic<br />
effects in vitro and anti-tumor activity in vivo. Preliminary<br />
clinical activity was observed with BKM120 in pts with BC, both as<br />
a single agent and in combination with letrozole (Mayer, et al. ASCO<br />
2012:#510), or trastuzumab (Saura, et al. SABCS 2011:#PD09-03).<br />
Use of the pan-PI3K inhibitor BKM120 may overcome resistance to<br />
mTORi in BC by targeting the PI3K pathway upstream; this will be<br />
explored in the current study. Stratification of pts according to PI3K<br />
activation status will definitively conclude whether this biomarker<br />
is predictive of response.<br />
Study design: This is a Phase III randomized, double-blind, placebocontrolled<br />
trial of BKM120 or placebo in combination with fulvestrant<br />
(BELLE-3; CBKM120F2303). Postmenopausal women with HR+/<br />
HER2– locally advanced or metastatic BC whose disease has been<br />
treated with aromatase inhibitor (AI), and is refractory to endocrine<br />
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<strong>Abstract</strong>s: Poster Session OT2<br />
and mTORi combination therapy (progression while on mTORi and<br />
endocrine therapy or within 30 days of end of treatment) are eligible<br />
for enrollment. Other eligibility criteria include: ≤1 previous line of<br />
chemotherapy for advanced disease; and available archival tumor<br />
tissue for analysis of PI3K-related biomarkers. Pts are randomized<br />
(2:1) to receive continuous BKM120 (100 mg) or placebo daily, and<br />
fulvestrant (500 mg). Randomization is stratified according to PI3K<br />
pathway activation (PIK3CA mut and/or PTEN mut and/or loss of<br />
PTEN protein expression by immunohistochemistry), and visceral<br />
disease status. Study treatment is given until disease progression or<br />
until study discontinuation for any reason.<br />
Co-primary endpoints are progression-free survival (PFS) in both full<br />
and PI3K pathway-activated populations based on local investigator<br />
assessment (RECIST 1.1). Key secondary endpoints are overall<br />
survival (OS) in both full and PI3K pathway-activated populations.<br />
Other secondary endpoints are PFS and OS (PI3K non-activated/<br />
unknown population), overall response rate and clinical benefit rate,<br />
safety (CTCAE 4.03), pharmacokinetics of BKM120, and patientreported<br />
quality of life (EORTC QLQ-C30 and QLQ-BR23).<br />
Statistical methods: PFS and OS will be estimated using the Kaplan–<br />
Meier method for full and PI3K pathway-activated populations. Both<br />
primary and key secondary endpoints will be tested using a stratified<br />
log-rank test at levels α governed by a graphical gate-keeping<br />
procedure. A stratified Cox regression will be used to estimate the<br />
hazard ratio, along with two-sided 95% CI.<br />
Target accrual: Estimated enrollment for BELLE-3 is 615 pts.<br />
Recruitment in this Global study is ongoing with planned enrollment<br />
of patients in North America, South America, Europe and Asia.<br />
OT2-3-09<br />
Phase III randomized study of the oral pan-PI3K inhibitor<br />
BKM120 with fulvestrant in postmenopausal women with HR+/<br />
HER2– locally advanced or metastatic breast cancer resistant to<br />
aromatase inhibitor – BELLE-2<br />
Baselga J, Campone M, Cortes J, Iwata H, de Laurentiis M, Jonat W,<br />
Di Tomaso E, Hachemi S, Goteti S, Germa C, Massacesi C, Arteaga<br />
C. Massachusetts General Hospital, Boston, MA; Centre René<br />
Gauducheau, Nantes, France; Vall d’Hebron Institute Oncology,<br />
Barcelona, Spain; Aichi <strong>Cancer</strong> Center Hospital, Nagoya, Aichi,<br />
Japan; Università degli Studi di Napoli Federico II, Naples, Italy;<br />
Christian-Albrechts-Universität zu Kiel, Kiel, Germany; Novartis<br />
Institutes for BioMedical Research, Inc., Cambridge, MA; Novartis<br />
Oncology, Paris, France; Novartis Pharmaceuticals Corporation,<br />
East Hanover, NJ; Vanderbilt-Ingram <strong>Cancer</strong> Center, Nashville, TN<br />
Background: The PI3K/AKT/mTOR pathway has been reported<br />
altered in up to 40% of hormone receptor-positive (HR+) breast<br />
cancers (BC). Furthermore, pathway activation has been implicated in<br />
resistance to endocrine therapy, including aromatase inhibitors (AI).<br />
BKM120 is an oral inhibitor of all 4 isoforms of class I PI3K (α, β,<br />
γ, δ). In combination with fulvestrant, BKM120 has demonstrated<br />
pro-apoptotic effects in vitro, and achieved near-complete tumor<br />
regression in HR+ PIK3CA-mutated estrogen-independent xenografts.<br />
Preliminary clinical activity was observed with BKM120 in patients<br />
with BC, both as a single agent and in combination with letrozole<br />
(Mayer, et al. ASCO 2012:#510) or trastuzumab (Saura, et al. SABCS<br />
2011:#PD09-03).<br />
Study design: This is a Phase III randomized, double-blind, placebocontrolled<br />
trial of BKM120 or placebo in combination with fulvestrant<br />
in postmenopausal women with HR+/HER2– locally advanced or<br />
metastatic BC that progressed on or after AI treatment (BELLE-2;<br />
CBKM120F2302; NCT01610284). After a 14-day fulvestrant runin<br />
phase to allow determination of tumor PI3K pathway activation<br />
status, patients are randomized (1:1) to receive continuous BKM120<br />
(100 mg/d) or placebo, and fulvestrant 500 mg at C1D15, and D1<br />
of all cycles thereafter; 1 cycle=28 days. Randomization is stratified<br />
according to PI3K pathway activation (PIK3CA mut and/or PTEN<br />
mut and/or loss of PTEN protein expression by IHC), and visceral<br />
disease status. Study treatment is given until disease progression or<br />
until study discontinuation for any reason.<br />
Eligibility criteria include: postmenopausal women with HR+/HER2–<br />
locally advanced or metastatic BC refractory to AI (progression while<br />
on AI, or within 4 wks [metastatic] or 12 mos [adjuvant] of last AI<br />
dose); no more than 1 previous line of chemotherapy for advanced<br />
disease; and available archival tumor tissue for analysis of PI3Krelated<br />
biomarkers.<br />
Co-primary endpoints: PFS in the full and PI3K pathway-activated<br />
populations based on local investigator assessment (RECIST 1.1).<br />
Key secondary endpoints: overall survival (OS) in both full and<br />
PI3K pathway-activated populations. Other secondary endpoints:<br />
PFS and OS (PI3K non-activated/unknown population), overall<br />
response rate and clinical benefit rate (both in full, PI3K-activated,<br />
PI3K non-activated/unknown populations), safety (CTCAE 4.03),<br />
pharmacokinetics of BKM120 and fulvestrant, and patient-reported<br />
quality of life (EORTC QLQ-C30 and QLQ-BR23).<br />
Statistical methods: PFS and OS will be estimated using the Kaplan–<br />
Meier method for both full and PI3K pathway activated populations.<br />
Both primary and key secondary endpoints will be tested using a<br />
stratified log-rank test at levels α governed by a graphical gatekeeping<br />
procedure. A stratified Cox regression will be used to estimate<br />
the hazard ratio, along with two-sided 95% confidence interval.<br />
Target accrual: Estimated enrollment for BELLE-2 is 842 patients.<br />
Recruitment in this Global study is ongoing with planned enrollment<br />
of patients in North America, South America, Europe, Asia and Africa.<br />
OT2-3-10<br />
Phase II study of panitumumab, nab-paclitaxel, and carboplatin<br />
for patients with primary inflammatory breast cancer (IBC)<br />
without HER2 overexpression<br />
Willey JS, Alvarez RH, Valero V, Lara JM, Parker CA, Hortobagyi<br />
GN, Ueno NT. Morgan Welch Inflammatory <strong>Breast</strong> <strong>Cancer</strong> Research<br />
Program and Clinic, The University of Texas MD Anderson <strong>Cancer</strong><br />
Center, Houston, TX; University of TX, MD Anderson <strong>Cancer</strong> Center,<br />
Houston, TX<br />
Background: Inflammatory breast cancer (IBC) is the most<br />
aggressive form of primary breast cancer. The outcome for patients<br />
with IBC is bleak despite multimodality treatment approaches.<br />
10-year disease-free survival rates after combined anthracycline<br />
and taxane-containing chemotherapy, surgery, and radiation are<br />
only 20%-25%. Our recent study found EGFR overexpression, a<br />
predictive factor of poor outcome, in 12 of 40 (30%) patients with<br />
IBC. Panitumumab has shown activity against EGFR overexpressing<br />
breast cancer xenograft model.<br />
Trial design: This is a single center, open-label, phase II study to<br />
evaluate the safety and efficacy of panitumumab in combination<br />
with preoperative chemotherapy. The treatment regimen consists<br />
panitumumab 2.5 mg/Kg given intravenously alone for the first week,<br />
followed by weekly panitumumab, nab-paclitaxel (100mg/m 2 ) and<br />
carboplatin (2 AUC) (PNC) for 12 weeks. Patients then will receive<br />
5-FU, epirubicin, and cyclophosphamide (FEC) every 3 weeks for 4<br />
cycles prior to surgery.<br />
Eligibility criteria: 1) Histological confirmation of breast carcinoma<br />
with pathologic evidence of dermal lymphatic invasion and clinical<br />
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diagnosis of IBC, including diffuse erythema, heat, ridging, and peau<br />
d’orange; 2) Normal HER2 expression; 3) No prior therapies for<br />
IBC; 4) Adequate hematologic, cardiac, renal and hepatic functions.<br />
Specific aims: 1) Primary objective is to determine the pathologic<br />
complete response (pCR) rate in patients with primary IBC without<br />
HER2 overexpression; 2) Secondary objectives are to determine the<br />
disease-free survival (DFS), overall survival (OS), the safety and<br />
tolerability of PNC regimens and the correlates of pathologic response<br />
rate and EGFR expression level.<br />
Statistical methods: 1) Previous studies have shown that this IBC<br />
patient population achieved a 13% pCR rate on the standard of care.<br />
We assume a beta (0.26, 1.74) prior distribution for the pCR rate.<br />
This prior distribution has a mean of 13% and a standard deviation<br />
of 19%. 2) We will stop the trial early if P (pCR rate >/= 13%) is<br />
< 0.01. If we determine that there is less than a 1% chance that the<br />
pCR rate is 13% or more we will consider stopping the trial. 3) Once<br />
we have completed the study we will estimate the pCR rate with a<br />
90% credible interval. If we have pCR in 4 of the 40 patients (10%),<br />
then our 90% credible interval for the pCR rate will be 4.0-19.6%.<br />
If we have pCR in 8 of the 40 patients (20%), then our 90% credible<br />
interval for the pCR rate will be 10.6-30.4%. We will also report the<br />
posterior probability that the pCR rate is 13% or more. For example,<br />
if we have pCR in 8 of the 40 patients (20%), then the probability<br />
that the pCR rate is 13% or more is 0.869.<br />
Present accrual and target accrual: To date, 13 patients have been<br />
enrolled. Target accrual is 40 patients.<br />
OT2-3-11<br />
Tivozanib in combination with paclitaxel vs placebo with<br />
paclitaxel in patients with locally advanced or metastatic triplenegative<br />
breast cancer<br />
Mayer EL, Miller K, O’Shaughnessy J, Dickler M, Vogel C,<br />
Leyland-Jones B, Steelman L, Robinson M, Kuriyama N, Agarwal<br />
S. <strong>Breast</strong> Oncology Center, Dana-Farber <strong>Cancer</strong> Institute, Boston,<br />
MA; Indiana University Melvin and Bren Simon <strong>Cancer</strong> Center,<br />
Indianapolis, IN; Baylor-Charles A. Sammons <strong>Cancer</strong> Center, Texas<br />
Oncology and US Oncology, Dallas, TX; Memorial Sloan-Kettering<br />
<strong>Cancer</strong> Center, New York, NY; Sylvester Comprehensive <strong>Cancer</strong><br />
Center, Miami, FL; <strong>San</strong>ford Research/USD, Sioux Falls, SD; AVEO<br />
Oncology, Cambridge, MA<br />
Background: Triple-negative breast cancer (TNBC) is an aggressive<br />
cancer with inferior survival outcomes. Although weekly paclitaxel<br />
(WP) is effective in the treatment (tx) of metastatic breast cancer<br />
(MBC), optimization of therapies for patients (pts) with TNBC is<br />
essential. Angiogenesis is a hallmark of advanced cancer, with subset<br />
analyses suggesting activity of angiogenesis inhibitors in TNBC.<br />
Tivozanib (TIVO) is a potent and selective inhibitor of vascular<br />
endothelial growth factor receptors (VEGFR) 1, 2, and 3 with a<br />
promising role in metastatic renal cell carcinoma, and established<br />
safety in Phase I combination with WP in MBC.<br />
Purpose: This Phase II trial will assess the efficacy and safety of<br />
TIVO + WP in the first-line setting for pts with advanced or metastatic<br />
TNBC and evaluate the performance of candidate angiogenesis<br />
biomarkers.<br />
Objectives: The primary objective of this study is to compare<br />
progression-free survival (PFS) of pts treated with TIVO + WP vs<br />
pts treated with placebo (PB) + WP. Secondary objectives include<br />
objective response rate (ORR), overall survival (OS), safety and<br />
tolerability, quality of life, and correlative candidate biomarker<br />
endpoints. The pharmacokinetics of TIVO + WP also will be<br />
characterized.<br />
Study Design and Methods: This multicenter, randomized,<br />
PB-controlled, two-arm study will enroll pts with metastatic or<br />
unresectable TNBC (evaluable per RECIST) and no prior systemic<br />
therapy. Pts must have confirmed available archival tumor tissue.<br />
Pts will be stratified by ECOG performance score and number of<br />
metastatic sites, then randomized to receive either oral TIVO 1.5 mg<br />
once daily for 3 weeks (wks) on/1 wk off and intravenous WP 90<br />
mg/m 2 for 3 wks on/1 wk off, or PB + WP. One cycle will be 4 wks;<br />
tx will continue until disease progression or unacceptable toxicity.<br />
Archival tumor tissue and blood samples will be evaluated for<br />
response biomarkers, including a hypoxia sensitivity gene signature,<br />
a myeloid resistance gene signature, and angiogenic ligands. All pts<br />
will be followed for survival until death. Adverse events will be<br />
monitored throughout the study. Pharmacokinetic samples will be<br />
collected during cycles 1 and 2. PAM-50–defined intrinsic molecular<br />
subtype populations also will be evaluated retrospectively.<br />
Recruitment of 130 patients is planned, with an interim analysis after<br />
80 pts to measure ORR (130 pts with a total of 82 investigator-assessed<br />
PFS events provides 80% power to detect statistically significant<br />
PFS differences between tx arms). Endpoint analyses will use the<br />
intent-to-treat population. The primary efficacy analysis will use<br />
investigator assessments of response and a two-sided 95% confidence<br />
interval for the hazard ratio produced using Cox proportional hazards<br />
regression models. OS will be compared using the log-rank test.<br />
Analyses of candidate biomarkers and determination of an optimal<br />
predictive cutoff for response also are planned. Trial enrollment will<br />
commence in fall 2012.<br />
Conclusion: This study will determine whether TIVO, a selective<br />
and potent VEGFR inhibitor, combined with WP improves clinical<br />
outcomes in pts with TNBC, and whether clinical activity is associated<br />
with candidate angiogenesis biomarkers.<br />
OT3-1-01<br />
A pilot study of single-dose ipilimumab and/or cryoablation in<br />
women with early-stage breast cancer scheduled for mastectomy<br />
Diab A, McArthur HL, Solomon S, Comstock C, Maybody M, Sacchini<br />
V, Durack J, Gucalp A, Yuan J, Patil S, Thorne A, Sung J, Kotin A,<br />
Morris E, Brogi E, Morrow M, Wolchok J, Allison J, Hudis C, Norton<br />
L. Memorial Sloan-Kettering <strong>Cancer</strong> Center, New York, NY<br />
Background: With cryoablation, probes are inserted into tumors to<br />
induce crystallization, osmotic changes, vascular stasis, and ultimately<br />
tumor necrosis. The resultant release of tumor antigens could activate<br />
a tumor-specific immune response through antigen presentation by<br />
dendritic cells (DC) to T-cells. Cryoablation is an effective treatment<br />
modality in many cancers (Habash 2007), and feasibility studies have<br />
shown that thermal ablation can be performed safely and effectively<br />
in small breast cancers (Noguchi 2007).<br />
To amplify immune response, we use ipilimumab, a fully human<br />
monoclonal antibody that blocks cytotoxic T lymphocyte antigen-4<br />
(CTLA4), a co-inhibitory molecule present on the surface of<br />
activated T cells. Durable and clinically significant responses to<br />
ipilimumab have been reported in prostate, bladder, and renal cell<br />
cancers. Ipilimumab has been most extensively studied in malignant<br />
melanoma, with 10-20% response rates and significant survival<br />
benefits reported (Wolchok 2010, Hodi 2010).<br />
Cryoablation-mediated tumor destruction exposes DCs to sufficient<br />
quantities of tumor antigens and inflammatory cytokines to induce<br />
DC maturation and activation. Furthermore, in preclinical murine<br />
models, the combination of cryoablation with CTLA4 blockade<br />
successfully mediates rejection of metastatic prostate cancer lesions<br />
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and prevents growth of secondary tumors (Waitz 2012). Combined<br />
ablative therapy with CTLA4 blockade is appealing due to the relative<br />
safety of percutaneous ablation in early stage breast cancer and the<br />
efficacy and tolerability of ipilimumab administration in numerous<br />
settings. We therefore hypothesize that this strategy could confer<br />
long-term immunity, and ultimately cure, for women with early<br />
stage breast cancer.<br />
In this pilot study, the safety and tolerability of pre-operative<br />
cryoablation alone, single dose ipilimumab (10mg/kg) alone, or the<br />
combination is being evaluated in women with early stage breast<br />
cancer.<br />
Design: Three sequential test groups of 6 patients are being enrolled<br />
(total N=18). The study groups are: pre-operative cryoablation alone<br />
(A), pre-operative single dose ipilimumab alone (B), and pre-operative<br />
single-dose ipilimumab followed by cryoablation (C). Groups A and<br />
B must meet the safety primary endpoint before enrollment to study<br />
arm C is begun. The timing of all study interventions is defined by<br />
the pre-determined, non-study surgery date.<br />
Primary aim: To determine the safety and tolerability of preoperative<br />
ipilimumab and/or cryoablation in patients with resectable<br />
breast cancer.<br />
Secondary aims: To explore and characterize pre- and postintervention<br />
radiographic and immunological (peripheral blood and<br />
tumor tissue) correlates.<br />
Statistics: If at least 5 of the 6 patients in each group proceed with<br />
surgery without delay, the regimen will be considered safe/tolerable<br />
for further study. Secondary aims are exploratory.<br />
Eligibility: Eligible women are age ≥18y with early-stage, operable,<br />
≥1.5 cm invasive breast cancer, no history of autoimmune disease<br />
and planning mastectomy.<br />
Study Status: As of June 12, 2012, Study Arm A is filled: 4 women<br />
have undergone cryoablation and mastectomy and 2 have undergone<br />
cryoablation and are awaiting surgery.<br />
OT3-1-02<br />
Phase II randomized study of combination immunotherapy with<br />
or without Polysaccharide Krestin (PSK®) concurrently with a<br />
HER2 ICD peptide-based vaccine and trastuzumab in patients<br />
with stage IV breast cancer<br />
Childs JS, Higgins DM, Parker S, Reichow J, Lu H, Standish L,<br />
Disis ML, Salazar LG. University of Washington, Seattle, WA; Bastyr<br />
University, Kenmore, WA<br />
Background: Endogenous immunity in patients with HER2+<br />
metastatic breast cancer (MBC) is likely dampened by an immunesuppressive<br />
tumor microenvironment and not sufficient to control<br />
tumor growth. Thus, most patients have disease relapse after achieving<br />
complete remission with standard therapies. Immunomodulation<br />
directed at enhanced stimulation of tumor specific immunity could<br />
result in immunologic eradication of residual HER2+ tumor cells and<br />
prevent BC relapse. We have shown PSK to be a potent TLR-2 agonist<br />
that stimulates both innate and adaptive immunity in a BC mouse<br />
model. Additionally, we have shown combination immunotherapy<br />
with HER2 peptide vaccines and trastuzumab (TRAZ) to be safe and<br />
able to elicit HER2 specific Th1 immunity and epitope spreading (ES)<br />
which has been associated with survival in vaccinated patients. Lastly,<br />
decreased serum TGF-β elicited by HER2 vaccination correlates<br />
with Th1 ES and may serve as a biomarker to predict cancer vaccine<br />
efficacy. We hypothesize that PSK, when given with TRAZ can<br />
augment vaccine induced HER2 specific TH1 immunity and prevent<br />
disease relapse in patients with optimally treated HER2+ MBC.<br />
Trial design: Phase II randomized two-arm clinical trial. Patients will<br />
be enrolled and randomly assigned in equal numbers to 1 of 2 arms<br />
(15 patients/arm) as follows: Arm 1:HER2 ICD vaccine, TRAZ and<br />
placebo or Arm 2:HER2 ICD vaccine, TRAZ and PSK. All patients<br />
will receive 3 monthly HER2 ICD vaccines plus TRAZ and 4 months<br />
of concomitant PSK or placebo. Serial blood draws for immunologic<br />
monitoring will be done.<br />
Eligibility criteria: Patients with Stage IV HER2+ BC who have been<br />
treated with definitive therapy and are: (1) without evidence of disease<br />
or have stable-bone only disease, (2) receiving TRAZ monotherapy,<br />
and (3) without clinically significant autoimmune disease. Patients<br />
must have normal LVEF per MUGA scan or echocardiogram.<br />
Aims: (1) Evaluate safety of PSK when given with a HER2 vaccine<br />
and TRAZ (2) Evaluate the effect of PSK on serum TGF-β levels when<br />
given with a HER2 vaccine and TRAZ and (3) Evaluate the effect<br />
of PSK on intermolecular ES when given with a HER2 vaccine and<br />
TRAZ. A secondary objective is to evaluate progression free survival<br />
(PFS) and overall survival (OS).<br />
Statistical methods: (1) Toxicity will be determined by clinical and<br />
chemical parameters and grading will be done per CTEP CTCAE<br />
4.0.; (2) Evaluation of TGF-β levels, pre and post-PSK treatment will<br />
be assessed with linear regression models; and analysis of multiple<br />
post-baseline measurements will be performed using generalized<br />
estimating equations; (3) A positive antigen-specific immune response<br />
will be defined as a precursor frequency >1:20,000 antigen-specific<br />
peripheral blood mononuclear cells. Differences in the levels of HER2<br />
immunity will be evaluated between arms using a two-tailed T test.<br />
The degree of ES in each arm will be evaluated with generalized linear<br />
modeling; (4) Large differences in PFS and OS observed between<br />
groups will be noted and described.<br />
Target accrual: 30 patients.<br />
OT3-2-01<br />
Influence of strength and endurance training on selected physical<br />
and psychological parameters and on immune system, metabolism<br />
and circulating tumor cells during adjuvant chemotherapy<br />
Mundhenke C, Weisser B, Keller L, <strong>San</strong>ders L, Summa B, Duerkop<br />
J, Schmidt T, Jonat W. University of Kiel, SH, Germany; Institute<br />
of Sport Science, University of Kiel, SH, Germany; Comprehensive<br />
<strong>Cancer</strong> Center North, Kiel, SH, Germany<br />
Background: Reduced quality of life, limited performance and<br />
fatigue are commonly observed side effects of breast cancer systemic<br />
treatment. In previous studies sport therapy could improve these<br />
symptoms. Sport has also been reported to positively impact the<br />
clinical course of the disease. So far it has remained unclear if these<br />
influences on clinical outcome are caused by alterations in the immune<br />
system or in tumor biology or in glucose or fat metabolism.<br />
The aim of this study is to analyse the implications of individual<br />
interventions in exercise therapy on endurance, muscle strength,<br />
fatigue and quality of life, alterations in the immune system or in<br />
tumor biology or in glucose or fat metabolism for breast cancer<br />
patients during chemo therapy.<br />
Method: The trial is prospectively randomised and controlled and will<br />
involve 60 breast cancer patients receiving adjuvant chemotherapy.<br />
20 patients each are randomized into a strength training group, an<br />
endurance training group or a control group (with standard care). At<br />
the beginning and after 12 weeks the following tests are undertaken:<br />
isometric maximum strength test, a PWC 150 test to determine<br />
the endurance of patients. The standardised questionnaire EORTC<br />
QLQ C30 including module BR23 to measure quality of life and the<br />
questionnaire MFI-20 to determine symptoms of fatigue are filled<br />
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in. Questionnair D2 measures ability to concentrate. Immunologic<br />
parameters as CD4, CD8 and T-REG-cells (FACS-Analysis), the<br />
number of the circulating tumour cells (measured by density gradient<br />
centrifugation) and also the concentration of glucose, insulin, leptin<br />
and adiponectin are being measured at study entry and after 12 weeks.<br />
Momentarily patients are being screened, recruited and randomised<br />
into the trial. The final evaluation of the results is planned II/ 2013.<br />
Discussion: The purpose of this study is to show if additional value<br />
can be added by individualized strength- or endurance training.<br />
Stabilisation or improvement of maximum strength and endurance<br />
during chemotherapy, as well as increase of quality of life and<br />
reduction of symptoms of fatigue would be a major improvement.<br />
Knowledge about effects of physical activity on circulating tumour<br />
cells as well as on immunologic alterations and on glucose and<br />
fat metabolism under chemotherapy could lead to a more specific<br />
counseling of patients and an individualized training program during<br />
chemotherapy.<br />
OT3-2-02<br />
The PREDICT Study ( Prospective, Randomized Early Detection<br />
and Intervention after <strong>Breast</strong> <strong>Cancer</strong>-Treatment, for women at<br />
risk of lymphedema)<br />
Taghian AG, Skolny MN, O’Toole J, Miller CL, Jammallo LS, Specht<br />
MC. Massachusetts General Hospital, Boston, MA<br />
Introduction: It is well-documented that lymphedema is one of the<br />
most feared long-term side effects of breast cancer (BC) treatment.<br />
However, to date, a standardized approach for the quantification and<br />
treatment of breast cancer-related lymphedema (BCRL) has yet to<br />
be established.<br />
Aims: We propose a screening and intervention trial that will assess<br />
the efficacy of early detection and intervention for BCRL. Intervention<br />
comprises the use of compression garments for mild lymphedema<br />
and compression garments +/- nighttime bandaging for moderate<br />
lymphedema. Other factors to be evaluated include: symptom clusters,<br />
treatment adherence, fear avoidance behavior, quality of life (QOL),<br />
upper extremity function, and risk factors for BCRL.<br />
Eligibility Criteria: Women 18 years + with a confirmed BC diagnosis,<br />
no history of BC, no known metastatic or locally advanced disease,<br />
no history of primary lymphedema, sentinel lymph node biopsy or<br />
axillary lymph node dissection as part of definitive breast surgery.<br />
Study Design: A two-stage study which includes a Screening and<br />
an Intervention trial. The screening arm will evaluate arm volume<br />
change during and after BC treatment with target accrual of 8000.<br />
Patients will undergo measurements via perometry and complete<br />
the MGH Lymphedema Evaluation Following Treatment for<br />
<strong>Breast</strong> <strong>Cancer</strong> (LEFT-BC) Survey at each screening appointment<br />
to evaluate changes in functionality, upper extremity utilization<br />
(fear associated avoidance), and QOL. Screening visits will occur<br />
pre- and post - operatively, at the conclusion of chemotherapy and<br />
radiation therapy and every 3-7 months thereafter. Patients will<br />
become eligible for enrollment into the intervention trial if, during<br />
the course of screening, they develop a relative arm volume change<br />
(RVC) of ≥ 5% which persists at a verification measurement within<br />
4-8 weeks. Eligible subjects are enrolled into one of two groups based<br />
on verification RVC: Group I – Mild Lymphedema (5-10% RVC) or<br />
Group II – Moderate Lymphedema (11-20% RVC). Subjects are then<br />
randomized within each group. Group I subjects are randomized to<br />
one of two arms: I-A – Observation, I-B – Compression, and Group<br />
II subjects are randomized to one of two arms: II-A – Compression,<br />
II-B – Compression + Night Compression Bandaging. Target accrual<br />
for the intervention trial is 336 subjects (Group I: 208, Group II: 128).<br />
Clinical Relevance: The results of this study will yield level I evidence<br />
on the effectiveness of early detection and intervention for BCRL.<br />
Findings may shape clinical practice in diagnosis and treatment, as<br />
well as provide insight regarding the risk factors, symptoms, upper<br />
extremity function, and quality of life (QOL) associated with BCRL.<br />
*Funding by award #s R01CA139118 &3P5OCA089393, AGT<br />
OT3-3-01<br />
Eniluracil + 5-fluorouracil + leucovorin (EFL) vs. capecitabine<br />
phase 2 trial for metastatic breast cancer<br />
Rivera E, Chang JC, Semiglazov V, Gorbunova V, Manikhas A,<br />
Krasnozhon D, Kirby G, Spector T. Banner MD Anderson <strong>Cancer</strong><br />
Center, Gilbert, AZ; The Methodist Hospital Research Institute,<br />
Houston, TX; Road Clinical Hospital of the Russian Railways, St.<br />
Petersburg, Russian Federation; Russian Oncological Research<br />
Center n.s.Blokhin RAMS, Moscow, Russian Federation; City Clinical<br />
Oncology Center, St. Petersburg, Russian Federation; Institution<br />
Leningrad Regional Oncology Center, Leningrad Region, Russian<br />
Federation; Adherex Technologies, Inc., Research Triangle Park, NC<br />
Based on a modified dosing protocol designed to optimize efficacy,<br />
an open-label EFL vs. capecitabine (4:3 randomization) Phase 2<br />
trial for metastatic breast cancer is in progress. Eniluracil inactivates<br />
dihydropyrimidine dehydrogenase, thereby preventing the formation<br />
of α-fluoro-β-alanine, and conferring 100% oral bioavailability<br />
and a 5 hr half-life on 5-fluorouracil (5-FU). Study drugs are<br />
administered orally for 1 st - or 2 nd -line treatment for metastatic disease<br />
in patients previously treated with an anthracycline and a taxane.<br />
Arm 1: eniluracil (40 mg) taken 11-16 hr before 5-FU (30 mg/m 2 );<br />
leucovorin (30 mg) taken with 5-FU and the next day. The regimen<br />
is administered once/week for 3 weeks/4 weeks. Arm 2: capecitabine<br />
(1000 mg/m 2 ) taken bid for 14 days/21days. Arm 2 patients with<br />
disease progression could crossover to take EFL in Arm X. Two sites<br />
in the USA and 19 in Russia are enrolling. Currently, 115 patients<br />
(21% are 1 st -line, 70% had previous 5-FU treatment) are enrolled<br />
and 83 have had tumor assessments. EFL was well tolerated with no<br />
unexpected toxicities. As of May 2012, there were 11, 7, & 1 partial<br />
responses in Arms 1, 2, & X, respectively. The primary endpoint,<br />
progression-free survival, will be determined approximately 7.5<br />
months after the trial is enrolled with 140 evaluable patients.<br />
OT3-3-02<br />
ADAPT - Adjuvant Dynamic marker-Adjusted Personalized<br />
Therapy trial optimizing risk assessment and therapy response<br />
prediction in early breast cancer<br />
Gluz O, Hofmann D, Kates RE, Harbeck N, Nitz U. West German<br />
Study Group, Moenchengladbach, NRW, Germany; Ev. Bethesda<br />
Hospital, Moenchengladbach, NRW, Germany; University Clinic<br />
Großhadern, Munich, Bavaria, Germany<br />
Background: Appropriate indication for chemotherapy (CTx) in<br />
patients with hormone receptor (HR) positive breast cancer (BC),<br />
prediction of CTx response, and addition of novel targeted therapies<br />
are the most important questions in adjuvant therapy of early BC. Few<br />
well evaluated prognostic tests identify patients (pts) with a low-risk<br />
profile resulting in a low enough CTx benefit to justify omission of<br />
CTx. Several clinical trials with results still pending have already<br />
addressed this question such as TAILORx, MINDACT, NNBC-3,<br />
WSG-planB.<br />
However, proliferation seems to be a key part of all prognostic<br />
genomic signatures. Moreover, dynamic changes of proliferation<br />
(as a result of endocrine, cytotoxic and targeted therapy) during<br />
therapy have been shown to be most important for outcome prediction<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
578s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT3<br />
in patients with pathological complete response to neoadjuvant<br />
chemotherapy in distinct BC subtypes (luminal B, TNBC, HER2+).<br />
Trial design: ADAPT is one of the first new generation adjuvant<br />
trials dealing with individualization of adjuvant decision-making<br />
in early BC. The WSG-ADAPT trial combines static assessment of<br />
prognosis of patients by a genomic signature (Recurrence Score in<br />
HR+ disease) and conventional prognostic markers (nodal status)<br />
with dynamic measurement of proliferation/apoptosis changes during<br />
a short course of preoperative therapy. ADAPT will establish early<br />
predictive molecular surrogate markers for outcome by assessing<br />
response to a short 3-week induction treatment, using a baseline<br />
diagnostic core biopsy and a second biopsy after induction treatment.<br />
ADAPT consists of an umbrella trial and four different sub-protocols<br />
(HR+/HER2-, HR+/HER2+, HR-/HER2+ HR-/HER2-) and is set up<br />
as a prospective, multi-center, controlled, non-blinded, randomized<br />
phase II/III trial.<br />
Eligibility criteria: Pre-/postmenopausal women with histologically<br />
confirmed unilateral primary invasive early BC. Women identified<br />
to require chemo- or targeted (anti-HER2) therapy must have<br />
adequate laboratory values and organ function. Pts must have no<br />
contraindications for the planned treatment.<br />
Specific aims: Primary endpoints will include evaluation of the<br />
dynamic test for outcome prediction and prospective comparison<br />
of 5yr EFS in responders (intermediate risk (RS 12-25) and good<br />
response to short-term endocrine therapy in HR+/HER2- as well as<br />
pts with pCR in HER2+/triple negative (TN) disease) compared to<br />
low risk HR+/HER2- (RS≤11, N0-1) pts (control group). Secondary<br />
endpoints will include overall survival.<br />
Statistical methods: Assumption across sub-protocols is that adjuvant<br />
CTx can be spared in HR+/HER2- BC or pCR be achieved in<br />
HER2+/TN in expected 1120 (HR+/HER2-) or 170 (HER2+/TN) pts<br />
respectively within the main phase. Their outcome will be compared<br />
to the control group (expected n=640 HR+/HER2- pts: low risk (by<br />
RS) and thus no CTx). Assuming 94% 5yr survival in control group,<br />
one-sided test of non-inferiority at 95% CI will have 80% power for<br />
a survival non-inferiority margin corresponding to 3.2% (i.e. 90.8%<br />
survival).<br />
Present and target accrual: By June 2012, 11 of 12 initial sites have<br />
been initiated, and 7 pts recruited. Target accrual for run-in phase is<br />
400 pts (4000 for run-in and main phase).<br />
OT3-3-03<br />
Withdrawn by Author<br />
alopecia more than 24 months after their last chemotherapy infusion.<br />
Optimal information of patients about alopecia and persisting alopecia<br />
appears to be mandatory before treatment : 47% of patients undergo<br />
a psychological shock during hair loss. Morevover, BCIRG 001<br />
study (TAC versus FAC) led to the conclusion that docetaxel 75 mg/<br />
msq is responsible for persisting alopecia for 3% of patients. So, by<br />
extrapolating, in France, each year, docetaxel could induce a persisting<br />
alopecia in 300 patients. To confirm this figure, “ERALOP” study is<br />
in progress to evaluate precisely the incidence of persisting alopecia<br />
after docetaxel in early breast cancer patients and then theses data will<br />
be communicated to ANSM. It must be noticed that 8% of patients<br />
refused to be treated because of the risk of persistant alopecia (Trueb<br />
et al, 2010). That’s why it is a worldwide public health problem, with<br />
personal and societal implications.<br />
As alopecia is universal after FEC100 regimen, the cooling scalp has<br />
been supposed to be very effective during docetaxel 1 hour infusion<br />
and to allow a better hair regrowth but with a high risk in term of<br />
tolerance. Since 2012, a prospective clinical trial “ALOPREV” has<br />
begun in Western France to evaluate tolerance of cooling scalp,<br />
after 3-4 courses of FEC100 regimen and during 3-4 courses of<br />
docetaxel 100 mg/msq, for patients treated for early breast cancer.<br />
So, ALOPREV is designed as a safety trial. First, cooling scalp<br />
major toxicities (headache, neck pain, discomfort associated with<br />
cold, sinusitis) are evaluated during each docetaxel course by the<br />
patient. Then, auto-questionnary about hair loss and regrowth, nails<br />
disorders and others toxicities due to docetaxel and questionnary about<br />
quality of life (EORTC QLQ-C30 and BR-23 scales) is completed<br />
by the patients before, during and after treatment. Patients will<br />
be followed-up 12 months and final toxicities will be reported by<br />
physicians. According to our daily practice, it will demonstrate that<br />
60% of patients could tolerate two consecutive cooling scalps during<br />
docetaxel infusion, and with statistical considerations (alpha-beta<br />
risks and 10% of ineligibility). So 160 patients must be included<br />
during inclusion period (18 months). 10 public or private care centers<br />
have been opened (45 investigators). This trial implicates particularly<br />
nurses teams and all patients will sign an informed consent before<br />
FEC100 courses. ALOPREV started two months ago and 25 patients<br />
are already enrolled.<br />
In conclusion, cooling scalp is known to be safe, manageable and<br />
partially effective before hair loss. ALOPREV will evaluate safety<br />
and efficacy to avoid persisting alopecia after hair loss.<br />
OT3-3-04<br />
ALOPREV : first cooling scalp trial for prevention of persisting<br />
alopecia after docetaxel for early breast cancer patients.<br />
Bourgeois H, Soulié P, Lucas B, Mercier Blas A, Zannetti A, Delecroix<br />
V, L’haridon T, Blot E, Delaloge S, Grudé F. Clinique Victor Hugo,<br />
Le Mans, France; Observatoire dédié au <strong>Cancer</strong> Bretagne Pays de<br />
Loire, Angers, France; Institut de Cancérologie de l’Ouest, Angers<br />
Nantes, France; CHRU Morvan, Brest, France; CHP, Saint Grégoire,<br />
France; CHD, Cholet, France; Pôle Hospitalier Mutualiste, Saint<br />
Nazaire, France; CHD, La Roche sur Yon, France; Centre Hospitalier<br />
Bretagne Atlantique, Vannes, France; Clinique Océane, Centre Saint<br />
Yves, Vannes, France; Institut Gustave Roussy, Villejuif, France<br />
During SABCS 2009, Western France Observatory of <strong>Cancer</strong><br />
has presented “ALOPERS” results from more than one hundred<br />
patients with persisting alopecia or suboptimal hair regrowth after<br />
chemotherapy for early breast cancer. Docetaxel 75-100 mg/msq<br />
was concerned for majority of patients. 43% of patients experienced<br />
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OT3-3-05<br />
Neurotoxicity characterization phase II randomized study of nabpaclitaxel<br />
versus conventional paclitaxel as first-line therapy of<br />
metastatic HER2-negative breast cancer. An ONSOCUR Study<br />
Group.<br />
Ciruelos E, Bueno C, Cantos B, Carrión R, Echarri M, Enrech S,<br />
García Saenz JA, Guerra JA, Lara MA, Martínez N, Rodríguez-<br />
Antona C, Domínguez-González C, <strong>San</strong>z JL, Baquero J, Cortés-Funes<br />
H, Sepúlveda JM. Hospital 12 de Octubre, Madrid, Spain; Hospital<br />
Universitario Ramón y Cajal, Madrid, Spain; Hospital Universitario<br />
del Sureste, Arganda del Rey (Madrid), Spain; Hospital Universitario<br />
Clínico <strong>San</strong> Carlos, Madrid, Spain; Hospital Universitario Severo<br />
Ochoa, Leganés (Madrid), Spain; Hospital Universitario Puerta<br />
de Hierro Majadahonda, Majadahonda (Madrid), Spain; Hospital<br />
Universitario Infanta Cristina, Parla (Madrid), Spain; Hospital<br />
Universitario Infanta Leonor, Madrid, Spain; Hospital Universitario<br />
de Getafe, Getafe (Madrid), Spain; Hospital Universitario de<br />
Fuenlabrada, Fuenlabrada (Madrid), Spain; APICES, Madrid,<br />
Spain; Celgene, Madrid, Spain; Centro Nacional de Investigaciones<br />
Oncologicas, Madrid, Spain<br />
Background: Nab-paclitaxel (Nab-P) is a nanoparticle albumin-bound<br />
form of paclitaxel that is thought to exploit natural albumin pathways<br />
to enhance the selective uptake and accumulation of paclitaxel at<br />
the site of the tumour, thus reducing its diffusion to normal tissues.<br />
Nab-P has been approved for the treatment of metastatic breast cancer<br />
patients who have failed first-line treatment for metastatic disease and<br />
for whom standard, anthracycline-containing therapy is not indicated.<br />
Toxicity profile of Nab-P is well characterized with significantly less<br />
haematological toxicities compared with conventional paclitaxel<br />
(P). Nab-P derived grade III neuropathy is short-lasting and more<br />
reversible than conventional P-derived neuropathy, probably due to<br />
absence of Cremophor solvent, or due to P itself. However there is<br />
still a lack of clinical and physiological characterisation of Nab-P<br />
induced neuropathy. The Current used tools for early detection<br />
and continuous evaluation of neurotoxicity are not optimal. Most<br />
used toxicity scales are limited, as they do not provide a detailed<br />
information of the severity of the neuropathy, its impact on quality of<br />
life, or physiopathology mechanisms. In addition, an inter-individual<br />
variability exists in terms of neurotoxicity predisposition when<br />
taxanes are used; it seems to be related to polymorphic differences in<br />
genes implicated in transport and metabolism of these drugs.<br />
Specific aims: Primary objective is to characterize neurotoxicity<br />
according to Total Neuropathy Score (TNS) and electromyographic<br />
changes. Secondary endpoints are determine the rate of neuropathy<br />
chemo-induced, the predictive value of some genetic variants (SNPs)<br />
for the development of neuropathy, clinical activity, toxicity profile<br />
and safety of treatments and quality of life (EORTC QLQ-C30 and<br />
CIPN20).<br />
Trial design: Phase II open-label randomised clinical trial with four<br />
parallel arms: a) conventional paclitaxel 80 mg/m 2 on days 1, 8 and<br />
15; b) Nab-P 100 mg/m 2 on days 1, 8 and 15; c) Nab-P 150 mg/m 2<br />
on days 1, 8 and 15; d) Nab-P 150 mg/m 2 on days 1 and 15. Study<br />
treatments will be administered in a 28-day cycle until progression<br />
disease, intolerable toxicity or investigator’s decision.<br />
Eligibility criteria: Women >18 years, with cytological or<br />
histological confirmation of HER2-negative breast cancer, metastatic<br />
disease, not prior chemotherapy for advanced disease, no prior grade<br />
> 1 neuropathy from any cause, measurable or evaluable disease,<br />
ECOG >2 and adequate bone marrow, renal and hepatic functions.<br />
No Relevant comorbidities.<br />
Statistical methods: This is an exploratory safety study to better<br />
characterize neurotoxicity in patients treated with Nab-P compared<br />
toP. Therefore no formal sample size or power calculations will be<br />
performed. We expect to recruit 60 patients, 15 in each treatment arm,<br />
in 18 months. Recruitment will start on October 2012.<br />
OT3-3-06<br />
NeoEribulin: A Phase II, non-randomized, open-label, single-arm,<br />
multicenter, exploratory pharmacogenomic study of single agent<br />
eribulin as neoadjuvant treatment for operable Stage I-II HER2<br />
non-overexpressing breast cancer.<br />
Prat A, Llombart A, de la Peña L, Di Cosimo S, Ortega V, Rubio I,<br />
Muñoz E, Harbeck N, Cortés J. Vall d’Hebron University Hospital,<br />
Barcelona, Spain; Hospital Arnau de Vilanova, Valencia, Spain;<br />
SOLTI <strong>Breast</strong> <strong>Cancer</strong> Research Group, Barcelona, Spain; Istituto<br />
Nazionale dei Tumori, Milan, Italy; Brustzentrum am Klinikum der<br />
Universität München, Munich, Germany<br />
Background: The neoadjuvant setting provides a unique opportunity<br />
to identify predictive biomarkers for novel therapeutic molecules.<br />
Eribulin, a novel anti-microtubule agent, has recently been approved<br />
for the treatment of metastatic breast cancer and is currently under<br />
investigation in earlier stages of the disease.<br />
Trial design: This is a Phase II, non-randomized, open-label, singlearm<br />
exploratory pharmacogenomic study of eribulin as monotherapy<br />
that seeks to identify predictive biomarkers of response to this agent.<br />
Eribulin will be administered at 1.23 mg/m 2 (equivalent to 1.4 mg/m 2<br />
of eribulin mesylate) intravenously on Days 1 and 8 of every 21-day<br />
cycle, for 4 cycles. <strong>Breast</strong> surgery will be carried out 3-5 weeks after<br />
completion of study treatment.<br />
Eligibility criteria: Female adults with operable primary Stage I-II<br />
HER2 non-overexpressing breast cancer.<br />
Specific aims: The primary objective is to evaluate the correlation<br />
between pre-treatment mRNA expression from breast tumors and<br />
pathological complete response in the breast (pCR B ) at the time of<br />
surgery. Secondary objectives aim to assess the rate of pCR B and pCR<br />
in the breast and axilla, the clinical and radiological overall response<br />
rates, and the biological activity of the treatment; also, to estimate<br />
the sensitivity and specificity of gene expression to predict clinical<br />
response, to determine the correlation of pCR B with intrinsic breast<br />
cancer subtypes, and to evaluate the safety and tolerability of the<br />
regimen. Additional molecular characterizations by gene expression<br />
and exome or genome sequencing will be performed in order to further<br />
identify biomarkers of response and/or safety.<br />
Statistical methods: This is an exploratory study and sample size is<br />
not based on statistical power. Assuming a pCR in the breast of 15%,<br />
a sample size of 200 patients is estimated to provide a 90% probability<br />
of detecting a gene signature whose expression is associated with a<br />
two-fold increase in odds of achieving a pCR in the breast, assuming<br />
5% of patients would be lost to follow-up and 5% would have<br />
insufficient quality or quantity of mRNA. The rate of pCR in breast<br />
is calculated assuming a pCR in luminal A tumors of 0-2%, in luminal<br />
B tumors of 6-10% and in triple-negative of approximately 20-30%.<br />
Biomarker analyses: Baseline, 21-day treated, and post-treatment<br />
(surgical) primary breast tumor tissue samples will be obtained from<br />
each patient. The expression of 542 genes involved in breast cancer<br />
will be explored with the NanoString technology using formalin–<br />
fixed, paraffin–embedded tissue. The expression of single genes and<br />
the score of each signature in the pre-treatment and 21-day treated<br />
samples will be correlated with the clinical/pathologic outcome using<br />
a variety of statistical approaches.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
580s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT3<br />
Target accrual: 200 patients, including a minimum of 100 subjects<br />
with triple-negative breast cancer, in 32 sites across Spain, Portugal,<br />
France, and Germany. The trial is funded by Eisai and registered with<br />
ClinicalTrials.gov. Patient enrollment began in July 2012.<br />
OT3-3-07<br />
Neoadjuvant bevacizumab with weekly nanoparticle albumin<br />
bound (nab)-paclitaxel plus carboplatin followed by doxorubicin<br />
plus cyclophosphamide (AC) for triple negative breast cancer.<br />
Snider JN, Allen JW, Young R, Schwartzberg L, Javed Y, Jahanzeb<br />
M, Sachdev JC. University of Tennessee, Memphis, TN; The West<br />
Clinic, Memphis, TN; The Center for <strong>Cancer</strong> and Blood Disorders,<br />
Fort Worth, TX<br />
Background:<br />
Triple negative breast cancer (TNBC) predominantly clusters with<br />
“basal like” subtype on genomic profiling. Over-expression of<br />
Secreted Protein Acidic and Rich in Cysteine (SPARC) has been<br />
observed in basal like breast cancer (Charaffe-Jaufrett et al. Oncogene<br />
2006; 2273-84). Endothelial transcytosis of nab- paclitaxel occurs<br />
via albumin- gp60 receptor-caveolin 1 interaction. SPARC entraps<br />
the albumin resulting in higher intratumoral accumulation, which<br />
may explain the increased efficacy of nab-paclitaxel (Desai et al.<br />
Translational Oncology 2009; 59-63). Exploiting this mechanism &<br />
the dysfunctional BRCA mediated DNA repair in basal tumors, we<br />
hypothesize that nab-paclitaxel + the DNA damaging drug carboplatin<br />
would produce high response rates in TNBC. Adding bevacizumab<br />
may enhance efficacy by blocking angiogenesis. In TNBC, pathologic<br />
complete remission (pCR) to neo-adjuvant therapy correlates with<br />
better disease-free survival (DFS). We hypothesize that high pCR<br />
rates can be achieved for patients with TNBC with this combination<br />
translating to an improved DFS than seen historically.<br />
Methods: Patients with palpable & operable TNBC ≥ 2 cm are eligible<br />
for this single stage phase II trial. pCR (defined as the absence of<br />
invasive tumor cells) in the breast is the primary end point, while<br />
pCR in the breast + axillary nodes & pCR + near pCR (residual<br />
tumor < 5mm) in the breast are secondary end points. 57 evaluable<br />
patients are needed, assuming a pCR rate of 25% vs. 40% for the null<br />
& alternate hypotheses respectively. 35 patients have been accrued<br />
to date. Patients receive carboplatin AUC 6 day 1 & nab-paclitaxel<br />
100mg/m 2 days 1, 8 & 15 of a 28 day cycle for 4 cycles and then dose<br />
dense AC for 4 cycles. Bevacizumab is given at 10mg/kg Q 2 weeks<br />
with chemotherapy for the first 6 cycles. Surgery & radiation are per<br />
institutional standards. Bevacizumab is continued postoperatively to<br />
complete 1 year of treatment. A core biopsy for collection of fresh<br />
tumor tissue is required prior to the start of study treatment. Blood is<br />
collected at baseline, and after 4 & 8 cycles for biomarker analysis.<br />
Genomic and expression profiling will be undertaken for correlation<br />
with response.<br />
This study was approved and funded by the National Comprehensive<br />
<strong>Cancer</strong> Network (NCCN) from general research support from Celgene<br />
Corporation.<br />
OT3-3-08<br />
Eribulin/Cyclophosphamide versus Docetaxel/Cyclophosphamide<br />
as Neoadjuvant Therapy in Locally Advanced HER2-Negative<br />
<strong>Breast</strong> <strong>Cancer</strong>: A Randomized Phase II Trial of the Sarah Cannon<br />
Research Institute<br />
Yardley DA, Hainsworth JD, Shastry M, Finney L, Burris HA.<br />
Tennessee Oncology, PLLC, Nashville, TN; Sarah Cannon Research<br />
Institute, Nashville, TN<br />
Background: Neoadjuvant chemotherapy for locally advanced breast<br />
cancer improves survival and rates of breast-conserving surgery.<br />
Pathologic complete response (pCR) after neoadjuvant therapy<br />
strongly correlates with improved disease free survival (DFS) and<br />
provides an early indicator of treatment efficacy. The expected pCR<br />
rate with a standard taxane-containing combination is approximately<br />
18%. Eribulin is a non-taxane synthetic analogue of halichondrin B<br />
that inhibits microtubule dynamics by a novel mechanism of action<br />
distinct from other tubulin-targeting agents. Eribulin is active against<br />
taxane and anthracycline pretreated metastatic breast cancer (MBC)<br />
and is well tolerated with a predictable toxicity profile. Substitution<br />
of eribulin for docetaxel in a neoadjuvant combination regimen<br />
may therefore improve efficacy. This study will evaluate the nonanthracycline<br />
eribulin/cyclophosphamide (ErC) and docetaxel/<br />
cyclophosphamide (TC) combinations as neoadjuvant therapy. The<br />
first ten patients (pts) will be evaluated for tolerability and feasibility<br />
of standard prescribed eribulin monotherapy dosing in combination<br />
with standard dose cyclophosphamide.<br />
Study Objectives: This randomized phase II trial is designed to<br />
determine the pCR rate of locally advanced, HER2-negative breast<br />
cancer treated with 6 cycles of ErC or TC. The secondary objectives<br />
are to evaluate the clinical response rate of ErC as neoadjuvant therapy<br />
and to determine the 2 year DFS of pts treated with ErC and TC.<br />
Eligibility: Females ≥ 18 years with untreated, locally advanced,<br />
HER2-negative breast cancer appropriate for neoadjuvant<br />
chemotherapy are eligible. Eligibility criteria include: adenocarcinoma<br />
histology; clinical T1-3, N0-2, M0 breast tumors; ECOG PS 0- 2;<br />
known hormone receptor status at study entry; adequate bone marrow<br />
and organ function; willingness to provide archived biopsy specimen<br />
for correlative testing. Clinical N3, T1N0M0, and T4 tumors are<br />
excluded. Upfront axillary lymph node sampling and/or definitive<br />
nodal surgery is permitted, and demonstrated pN3a disease is allowed.<br />
Trial Design: A lead-in phase of the trial will enroll 10 pts to be treated<br />
with ErC to determine safety and feasibility of the combination. If<br />
the safety is confirmed, subsequent pts will be stratified by hormone<br />
receptor status (positive vs. triple- negative) and will be randomized<br />
in a 2:1 ratio to Arm 1: ErC or Arm 2: TC. Pts on Arm 1 will receive<br />
eribulin 1.4 mg/m 2 IV (Days 1 & 8) and cyclophosphamide 600<br />
mg/m 2 IV (Day 1). Pts on Arm 2 will receive docetaxel 75 mg/m 2<br />
IV (Day 1) and cyclophosphamide 600 mg/m 2 IV (Day 1). Both<br />
regimens are repeated every 21 days for a total of 6 cycles. After<br />
completion of neoadjuvant chemotherapy, pts will undergo definitive<br />
local surgery, as determined by the treating surgeon. Archival tumor<br />
samples and residual tumor tissue at surgery will be collected for<br />
biomarker evaluations. A total of 66 pts (Arm 1: 44; Arm 2: 22) will<br />
be enrolled to this study. A pCR rate ≥ 18% in patients treated with<br />
ErC is considered a study result that merits further evaluation. This<br />
trial is pending activation and has a total accrual goal of 76 pts.<br />
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<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
OT3-3-09<br />
ARTemis trial - randomised trial with neo-adjuvant chemotherapy<br />
for patients with early breast cancer<br />
Earl HM, Blenkinsop C, Grybowicz L, Vallier A-L, Cameron DA,<br />
Bartlett JMS, Murray N, Caldas C, Thomas J, Dunn JA, Higgins HB,<br />
Hiller L, Hayward L. University of Cambridge, United Kingdom;<br />
NIHR Cambridge Biomedical Research Centre, Cambridge, United<br />
Kingdom; University of Warwick, Coventry, United Kingdom;<br />
Cambridge University Hospitals NHS Foundation Trust, Cambridge,<br />
United Kingdom; Edinburgh University, Edinburgh, United Kingdom;<br />
University of Edinburgh, United Kingdom; Royal Adelaide Hospital,<br />
Adelaide, SA, Australia; <strong>Cancer</strong> Research UK Cambridge Research<br />
Institute, Cambridge, United Kingdom; Western General Hospital,<br />
Edinburgh, United Kingdom<br />
Background: Bevacizumab, a humanised monoclonal antibody<br />
which targets vascular endothelial growth factor (VEGF), has<br />
shown promising anti-tumour effect when given concurrently<br />
with taxane-based chemotherapy in breast cancer. However two<br />
neoadjuvant breast cancer trials have produced conflicting results. The<br />
GEPARQUINTO trial reported significant benefit only in the triple<br />
negative patients (pCR 27.8% vs 36.4% p=0.021). The NSABP-B40<br />
study showed significant benefit for bevacizumab only in the ER+ve<br />
patients (pathological complete response (pCR) in ER+ve population<br />
15.2% vs 23.3%, p=0.008).<br />
Trial design: ARTemis is a phase III randomised trial to determine<br />
whether the addition to neo-adjuvant chemotherapy of bevacizumab<br />
is more effective than standard chemotherapy alone in patients with<br />
HER2-negative early breast cancer. A total of 400 patients will be<br />
randomised into each of the two treatment arms which will allow an<br />
absolute difference in the pCR rates in excess of 10% to be detected<br />
at the 5% (2-sided) level of significance with an 85% power. Primary<br />
outcome is pathological complete response rates after neo-adjuvant<br />
chemotherapy, i.e. no residual invasive carcinoma in the breast, and<br />
no evidence of metastatic disease within the lymph nodes. Secondary<br />
outcomes are disease free survival, overall survival, complete<br />
pathological response rates in breast alone, radiological response<br />
after 3 and 6 cycles of chemotherapy and rate of breast conservation<br />
and toxicities. Translational work (ARTemis-Science): collection of<br />
blood samples, and paraffin-embedded formalin-fixed and fresh tissue<br />
samples to investigate whether markers for chemotherapy response/<br />
resistance, and pharmacogenetic and pharmacogenomic markers can<br />
be correlated with outcomes (pathCR and RFS) in patients randomised<br />
to receive bevacizumab versus those that do not.<br />
Eligibility criteria: Histologically confirmed HER2-negative<br />
invasive breast cancer; T2 to T4 tumour and/or large/fixed axillary<br />
nodes (>20mm / clinical N2 or N3), or inflammatory disease;<br />
suitable for, and fit to receive neo-adjuvant chemotherapy and an<br />
anti-angiogenic.<br />
Results: Recruitment into ARTemis began in April 2009 and as of<br />
June 2012 had recruited 600 (75%) patients and 65 sites are open for<br />
recruitment. ARTemis is due to complete recruitment by first quarter<br />
of 2013 and the first planned interim analysis of the primary outcome<br />
will be December 2013.<br />
Conclusion: The IDSMC reviewed the trial in June 2012 and<br />
recommended continuation of recruitment to this important trial given<br />
there were no safety concerns.<br />
OT3-3-10<br />
ASTER 70s: Benefit of adjuvant chemotherapy for oestrogen<br />
receptor-positive HER2-negative breast carcinoma in women<br />
over 70 according to Genomic Grade. A French UNICANCER<br />
Geriatric Oncology Group (GERICO) and <strong>Breast</strong> Group (UCBG)<br />
multicentre phase III trial.<br />
Brain E, Baffert S, Bonnefoi HR, Cottu P, Girre V, Lacroix-Triki<br />
M, Latouche A, Leger-Falandry C, Peyro Saint Paul HP, Rollot F,<br />
Romieux G, Servent V, Orsini C, Bonnetain F. Institut Curie, Saint-<br />
Cloud, France; Institut Curie, Paris, France; Institut Bergonié,<br />
Bordeaux, France; Centre Hospitalier La Roche sur Yon, La Roche<br />
sur Yon, France; Institut Claudius Regaud, Toulouse, France; CNAM,<br />
Paris, France; Centre Hospitalier Lyon Sud, Lyon, France; Ipsogen<br />
SA, Marseille, France; Centre Val d’Aurelle, Montpellier, France;<br />
Centre Oscar Lambret, Lille, France; R&D Unicancer, Paris, France;<br />
Centre Georges François Leclerc, Dijon, France<br />
Background<br />
Despite a high incidence of oestrogen receptor-positive (ER+)<br />
HER2-negative (HER2-) breast carcinoma (BC) in elderly women,<br />
rationale and modalities of adjuvant chemotherapy (CT) vary greatly<br />
and remain heterogeneous after 70 years, precluding evaluation<br />
of its benefit and impact on functional status and outcome. As for<br />
trials investigating innovative treatments, elderly patients are often<br />
excluded from programs evaluating new modern prognosis classifiers.<br />
Trial design<br />
ASTER 70s is a prospective multicentre trial that investigates the<br />
impact on overall survival (OS) of adjuvant CT in elderly ER+<br />
HER2- BC patients selected with a modern prognosis classifier while<br />
taking into account competing risks for mortality (EudraCT 2011-<br />
004744-22). After surgery, 2,000 patients over 70 years will have<br />
genomic grade (GG) assessed centrally by qRT-PCR on formalin-fixed<br />
paraffin-embedded samples (Ipsogen). Only those with a high GG<br />
or Equivocal (estimation∼700, group I) will be randomized between<br />
endocrine treatment alone and CT followed by endocrine treatment.<br />
CT regimen is left to the choice of investigators amongst 3 regimen<br />
of same duration [4 q3w cycles, docetaxel+cyclophosphamide<br />
(TC), doxorubicin or non pegylated liposomal doxorubicin<br />
(Myocet®)+cyclophosphamide (AC or MC), all with G-CSF],<br />
as well as endocrine treatment (aromatase inhibitor±tamoxifen).<br />
Radiotherapy will follow standard guidelines. Patients with low GG<br />
or not randomized for any reason (estimation∼1,300, group II) will be<br />
followed up as an observational cohort, with endocrine treatment only.<br />
Eligibility criteria<br />
Any ER+ HER2- BC after complete surgery, M0, any pT or pN.<br />
Normal organ functions. No specific BC treatment before surgery. No<br />
exclusion for underlying medical condition unless potential contraindication<br />
to study drugs.<br />
Specific aims<br />
OS is the primary endpoint. Secondary endpoints address competing<br />
risks for mortality, include cost-effectiveness and QTWiST analysis,<br />
geriatric questions, acceptability and quality of life (QLQ C30 and<br />
specific elderly scale ELD15). The Lee’s 4-year mortality score<br />
is calculated. The G8 screening tool is also assessed and used<br />
for stratification. Translational research will focus on ageing and<br />
prognostic biomarkers, and pharmacogenetic.<br />
Statistical methods<br />
Sample size based on 4-year OS (87.5 vs 80%), bilateral test, α=0.05,<br />
β=0.20 and HR= 0.60.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
582s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT3<br />
Present accrual and target accrual<br />
The trial has been opened to inclusion in April 2012. 14 centres have<br />
been activated with 14 patients included: 7 randomized in group I,<br />
2 included in the cohort (group II) and 4 with GG determination<br />
ongoing.<br />
OT3-3-11<br />
A RANDOMIZED PHASE III TRIAL COMPARING<br />
NANOPARTICLE-BASED PACLITAXEL WITH SOLVENT-<br />
BASED PACLITAXEL AS PART OF NEOADJUVANT<br />
CHEMOTHERAPY FOR PATIENTS WITH EARLY BREAST<br />
CANCER (GeparSepto) GBG 69<br />
Untch M, Jackisch C, Blohmer J-U, Costa S-D, Denkert C,<br />
Eidtmann H, Gerber B, Hanusch C, Hilfrich J, Huober J, Kuemmel<br />
S, Schneeweiss A, Paepke S, Loibl S, Nekljudova V, von Minckwitz<br />
G. Helios Kliniken Berlin; Klinikum Offenbach; <strong>San</strong>kt-Gertrauden<br />
Berlin; University Magdeburg; Charite Berlin; University Kiel;<br />
University Rostock; Rotkreuzklinikum Muenchen; Eilenriedeklinik<br />
Dueseldorf; University Duesseldorf; Kliniken Essen Mitte;<br />
Frauenklinik Muenchen; German <strong>Breast</strong> Group, Neu-Isenburg<br />
Background: Anthracycline/taxane based regimen are standard of<br />
care for neoadjuvant therapy in breast cancer. Recent data from the<br />
neo-Tango study suggest that a reverse sequence of taxane followed<br />
by the anthracycline can achieve higher pCR rates. Solvent-based<br />
taxanes (paclitaxel, docetaxel) cause severe toxicities most likely<br />
by the solvents such as cremophor. Nab-paclitaxel is a solvent-free<br />
formulation of paclitaxel encapsulated in albumin. It is believed that<br />
nab-Paclitaxel compared to solvent based paclitaxel followed by<br />
conventional dosed EC might further improve the pCR rate in breast<br />
cancer patients receiving neoadjuvant treatment. Previous studies<br />
have shown that dual anti-HER blockade is superior to trastuzumab<br />
alone resulting in an increase of pCR rate by 20%.<br />
Patients and Methods: The GeparSepto trial, a neoadjuvant,<br />
randomized phase III study, planned to include 1200 pts, randomized<br />
to nab-paclitaxel versus conventional, solvent based paclitaxel given<br />
weekly for 12 weeks followed in both arms by 4 cylces conventionally<br />
dosed EC. The primary objective is to compare the rate of pCR (ypT0<br />
+ ypN0). Further objectives are to compare the pCR rate in predefined<br />
subgroups, pCR by other definition, the clinical response rate and<br />
the rate of breast conserving surgery after chemotherapy in the two<br />
different treatment arms.<br />
Women with untreated, histologically confirmed uni- or bilateral, cT2-<br />
cT4d carcinoma, and no clinically relevant cardiovascular and other<br />
co-morbidities are randomized to receive either paclitaxel (80mg/<br />
m²) or nab-paclitaxel (150 mg/ m²) day 1, 8, 15, q d 22 for 4 cycles<br />
followed by conventional EC (E (90mg/m²)+C (600 mg/m²)) on day 1<br />
q day 22 for 4 cycles. HER2 positive pts receive trastuzumab (loading<br />
dose 8mg/kg followed by 6 mg/kg) and pertuzumab (loading dose 840<br />
mg followed by 420 mg) q3w concomitantly to the chemotherapy.<br />
Biomaterial including FFPE form core biopsy, serum, plasma, full<br />
blood is collected before randomization, after the 12 cycles for (nab-)<br />
paclitaxel therapy and after the 4 cycles of EC before surgery. The<br />
HER2,estrogen receptor, progesterone receptor, Ki67 and SPARC<br />
status will be centrally tested by immunohistochemistry prior to<br />
randomization for stratification. A broad translational program is<br />
planned. It has been assumed that solvent based taxane will achieve an<br />
overall pCR rate of 33% to be increased using nab-paclitaxel to 41%,<br />
corresponding to an odds ratio of 1.41. If 596 patients are enrolled into<br />
each arm, a χ2-test will have an 80% power with a 2-sided significance<br />
level α=0.05 to show the superiority of nab-paclitaxel. Closed test<br />
procedure will be used to test for non-inferiority of nab-paclitaxel first.<br />
The trial is registered under NCT01583426. It is financially supported<br />
by Roche and Celgene.<br />
Results: The centres have been initiated after approval by ethics<br />
committee and authorities.<br />
First patient in will be this months. It is planned to recruit 18 months<br />
in 100 sites in Germany.<br />
Conclusion: Geparsepto will investigate the efficacy of neoadjuvant<br />
nab-paclitaxel compared to solvent based paclitaxel given weekly<br />
and the dual blockade with Trastuzumab and Pertuzumab in HER<br />
2 positive BC.<br />
OT3-4-01<br />
PROMIS: Prospective Registry Of MammaPrint in breast cancer<br />
patients with an Intermediate recurrence Score<br />
Soliman H, Untch S, Stork-Sloots L. Moffitt <strong>Cancer</strong> Center; Agendia<br />
Inc; Agendia NV<br />
Background: Gene expression profiling in breast cancer offers the<br />
potential to improve prognostic accuracy, treatment choice, and<br />
health outcomes in women diagnosed with early-stage breast cancer.<br />
Numerous gene-profiling assays are now available, which can be<br />
applied to a single tumor specimen to provide physicians with a more<br />
complete basis for treatment decisions.<br />
• MammaPrint is a DNA microarray-based in vitro diagnostic that<br />
measures the activity of 70 genes to estimate whether patients are<br />
at high risk or low risk of developing metastases within the first 10<br />
years after curative surgery.<br />
• BluePrint is an 80-gene molecular subtyping profile that<br />
discriminates between three breast cancer subtypes: Luminal, HER2,<br />
and Basal.<br />
• TargetPrint provides a quantitative measurement of estrogen receptor<br />
(ER), progesterone receptor (PR), and HER2, and can serve as a<br />
reliable second pathology assessment for locally-assessed parameters.<br />
• Oncotype DX measures expression of five reference genes and 16<br />
cancer-related genes, quantifying the risk of distant recurrence in<br />
patients with ER+ early breast cancer who are treated with adjuvant<br />
hormonal therapy, and predicting clinical benefit with additional<br />
adjuvant chemotherapy.<br />
Trial design: PROMIS is a prospective, observational, case-only<br />
study that will investigate the additional value of MammaPrint,<br />
BluePrint and TargetPrint in women with an intermediate Oncotype<br />
DX score. An initial CRF – capturing baseline patient characteristics,<br />
pathology information, Oncotype DX score and the recommended<br />
treatment plan – will be completed before receiving the MammaPrint<br />
result. A second CRF – capturing the recommended treatment – will<br />
be completed within 4 weeks after receiving the MammaPrint result.<br />
Eligibility: The study will include women aged ≥18 years with<br />
histologically proven invasive stage I-II, node-negative, hormone<br />
receptor-positive, HER2-negative breast cancer and Oncotype DX<br />
score of 18–30 who signed informed consent.<br />
Objectives: The objectives of the study are to:<br />
1. Describe the frequency of chemotherapy + endocrine versus<br />
endocrine-alone decisions in Oncotype DX intermediate score<br />
patients.<br />
2. Assess the impact of MammaPrint on chemotherapy + endocrine<br />
versus endocrine-alone treatment decisions.<br />
3. Assess the distribution of MammaPrint Low and High Risk in<br />
patients with an intermediate recurrence score.<br />
4. Assess concordance of TargetPrint ER, PR and HER2 results with<br />
Oncotype DX ER, PR and HER2 and with locally assessed IHC/<br />
FISH ER, PR and HER2.<br />
www.aacrjournals.org 583s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
5. Compare clinical subtype based on IHC/FISH ER, PR, HER2 and<br />
Ki-67 (if available) with BluePrint molecular subtype.<br />
Statistical methods: As the project is exploratory, sample size<br />
calculations do not apply as only descriptive statistics will be used.<br />
The frequency of chemotherapy + endocrine versus endocrinealone<br />
decisions in Oncotype DX intermediate score patients will<br />
be calculated before and after receiving the MammaPrint result.<br />
A Chi-square test will be performed for the comparison of the two<br />
proportions.<br />
Accrual: A total of ∼300 eligible patients will be enrolled from<br />
multiple institutions.<br />
Clinical trial registry number: NCT01617954<br />
OT3-4-02<br />
MINT I: Multi-Institutional Neo-adjuvant Therapy, MammaPrint<br />
Project I<br />
Cox C, Blumencranz P, Reintgen D, Saez R, Howard N, Gibson J,<br />
Stork-Sloots L, Glück S. University of South Florida; Morton Plant<br />
Hospital; Florida Hospital North Pinellas; Plano <strong>Cancer</strong> Institute;<br />
Agendia Inc; Agendia NV; Miller School of Medicine, University<br />
of Miami<br />
Background: Women with locally advanced breast cancer (LABC)<br />
are often treated with neo-adjuvant chemotherapy to reduce the size<br />
of the tumor prior to surgery, to enable breast conserving surgery<br />
and to observe the clinical effect of therapy in real time. Studies<br />
have shown that the 25–27% of individuals who have a pathologic<br />
complete response (pCR) to neoadjuvant therapy have a survival<br />
advantage of 80% in 5 years, which is double the expected survival<br />
of the remaining patients without pCR. If patients who are likely<br />
to show a pCR could be identified prior to initiation of therapy, it<br />
would enable more informed treatment decisions – patients likely to<br />
respond would be served well by current neoadjuvant chemotherapy<br />
protocols, while those unlikely to respond may be better suited to<br />
innovative new strategies for drug discovery [von Minckwitz et al.<br />
JCO 2006]. Genomics assays, which are widely used to provide<br />
prognostic and predictive information in early breast cancer, have the<br />
potential to provide information on the likelihood of a patient with<br />
LABC responding to neo-adjuvant therapy [Glück et al. ASCO 2012].<br />
Trial design: MINT I is a prospective study designed to test the<br />
ability of molecular profiling, as well as traditional pathologic and<br />
clinical prognostic factors, to predict responsiveness to neo-adjuvant<br />
chemotherapy in patients with LABC. MammaPrint risk profile,<br />
BluePrint molecular subtyping profile, TargetPrint estrogen receptor<br />
(ER), progesterone receptor (PR) and HER2 single gene readout, and<br />
the 56-gene TheraPrint Research Gene Panel will be analyzed on a<br />
fresh tumor specimen using the whole genome array. Patients will<br />
receive neo-adjuvant chemotherapy pre-specified in the protocol.<br />
Response will be measured centrally. pCR is defined as the absence<br />
of invasive carcinoma in both the breast and axilla at microscopic<br />
examination of the resection specimen, regardless of the presence of<br />
carcinoma in situ.<br />
Eligibility: The study will include women ≥18 years with<br />
histologically-proven invasive breast cancer T2 (≥3.5cm)-T4, N0M0<br />
or T2-T4N1M0, adequate bone marrow reserves and normal renal<br />
and hepatic function who signed an IRB approved informed consent.<br />
Objectives: The objectives of the study are to:<br />
1. Determine the predictive power of MammaPrint and BluePrint<br />
for sensitivity to neo-adjuvant chemotherapy as measured by pCR.<br />
2. Compare TargetPrint ER, PR and HER2 with local and centralized<br />
IHC and/or CISH/FISH assessment.<br />
3. Identify correlations between TheraPrint and response to neoadjuvant<br />
chemotherapy.<br />
4. Identify and/or validate predictive gene expression profiles of<br />
clinical response or resistance to neo-adjuvant chemotherapy.<br />
5. Compare BluePrint with IHC-based subtype classification.<br />
Statistical methods: Standard statistical tests such as the Pearson Chisquare<br />
test will be used to characterize and evaluate the relationship<br />
between chemoresponsiveness and gene expression patterns.<br />
Accrual: A total of 226 eligible patients will be enrolled from multiple<br />
institutions. To date (June 06, 2012), 31 patients have been enrolled.<br />
Clinical trial registry number: NCT01501487.<br />
OT3-4-03<br />
Prospective neo-adjuvant registry trial linking MammaPrint,<br />
subtyping and treatment response: Neo-adjuvant <strong>Breast</strong> Registry<br />
– Symphony Trial (NBRST)<br />
Whitworth P, Gittleman M, Akbari S, Nguyen B, Baron P, Rotkiss M,<br />
Beatty J, Gibson J, Stork-Sloots L, de Snoo F, Beitsch P. Nashville<br />
<strong>Breast</strong> Center; <strong>Breast</strong> Care Specialists; Virginia Hospital Center;<br />
Todd <strong>Cancer</strong> Institute, Long Beach Memorial Medical Center;<br />
<strong>Cancer</strong> Specialists of Charleston; Northern Indiana <strong>Cancer</strong> Research<br />
Consortium; The <strong>Breast</strong> Place Charleston; Agendia Inc; Agendia NV;<br />
Dallas Surgical Group<br />
Background: The FDA-approved MammaPrint 70 gene profile is<br />
performed on a diagnostic multi-gene array. This platform enables<br />
additional gene expression profiles to be analyzed simultaneously on<br />
one tumor specimen. One such gene expression profile is BluePrint,<br />
an 80 gene molecular subtyping profile that discriminates between<br />
three distinctive subtypes; Basal-type, Luminal-type, and HER2-type.<br />
By combining MammaPrint and BluePrint, patients can be stratified<br />
into the following subgroups: Luminal-type/MammaPrint Low<br />
Risk; Luminal-type/MammaPrint High Risk; HER2-type and Basaltype.<br />
Marked differences are observed in response to neo-adjuvant<br />
treatment in groups stratified by MammaPrint and BluePrint [Glück<br />
et al. ASCO 2012].<br />
Trial design: NBRST is a prospective observational, case-only<br />
study linking MammaPrint and BluePrint to neo-adjuvant treatment<br />
response and Distant Metastases-Free Survival (DMFS) and Relapse-<br />
Free Survival (RFS). MammaPrint and BluePrint are assessed on fresh<br />
or formalin-fixed, paraffin-embedded core needle biopsy samples.<br />
Treatment is at the discretion of the physician, adhering to NCCN<br />
approved regimens or a recognized alternative.<br />
Eligibility: The study will include women aged 18–90 with<br />
histologically proven breast cancer, who have started or are scheduled<br />
to start neo-adjuvant chemotherapy or neo-adjuvant hormonal therapy,<br />
after successful MammaPrint and BluePrint assessment, and who<br />
provide written informed consent. Additional inclusion criteria are<br />
that women must have had no excisional biopsy or axillary dissection,<br />
no confirmed distant metastatic disease, and no prior therapy for the<br />
treatment of breast cancer.<br />
Objectives: The main objectives of this registry study are to:<br />
1. Measure chemosensitivity (as defined by pathological complete<br />
response [pCR]) or endocrine sensitivity (as defined by decrease<br />
in longest tumor diameter or RCB1) in the molecular subgroups as<br />
determined by combining MammaPrint and BluePrint results.<br />
2. Compare local IHC and FISH results with TargetPrint results and<br />
BluePrint results.<br />
3. Document impact of MammaPrint, TargetPrint and BluePrint<br />
results on treatment decisions.<br />
4. Assess the 2–3 and 5-year DMFS and RFS for the different<br />
molecular subgroups.<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
584s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
<strong>Abstract</strong>s: Poster Session OT3<br />
Statistical methods: Comparison of response rates between different<br />
molecular subgroups will be conducted using the Pearson Chi-square<br />
test.<br />
Accrual: The trial started in August 2011 and there are currently<br />
36 participating sites in the US. To date (June 06, 2012), 158 of<br />
the planned 400 patients have been enrolled.Clinical trial registry<br />
number: NCT01479101.<br />
OT3-4-04<br />
InVite: an observational pilot study evaluating the feasibility of<br />
genome-wide association studies using self-reported data from<br />
patients with metastatic breast cancer treated with bevacizumab<br />
Leyland-Jones B, Faoro L, Barnholt K, Kiefer A, Yager S, Yi J, Turner<br />
B, Keane A, Wang L, Eriksson N, Milián ML, O’Neill V. Genentech,<br />
Inc.; 23andMe; <strong>San</strong>ford Research/USD<br />
Background: Personalized healthcare tailors treatments to patients<br />
and their disease characteristics through the use of genetics and other<br />
biomarkers. Genetic differences among individuals may explain<br />
variations in drug treatment response, including side effects. With such<br />
information physicians could make more informed decisions about<br />
drugs and dosing for a given individual, thereby improving patient<br />
care. Although there has been some success, to a large extent genetic<br />
variation related to drug response remains unexplained.<br />
Bevacizumab, a humanized monoclonal antibody against the<br />
angiogenic factor VEGF, has demonstrated activity in patients with<br />
metastatic breast cancer (MBC). The InVite study will evaluate the<br />
feasibility of performing genomewide association studies using selfreported<br />
information collected via an online platform from patients<br />
with MBC who have been treated with bevacizumab. Using novel<br />
methodology in a convenient, user-friendly, and scientifically rigorous<br />
format, InVite ultimately aims to identify potential pharmacogenetic<br />
associations in this patient population.<br />
Trial design: InVite is a pilot, non-interventional, observational, webbased,<br />
prospective cohort study designed to collect patient-reported<br />
safety, efficacy, and genetic data from patients with MBC treated with<br />
bevacizumab. Data on demographics, breast cancer disease status,<br />
cancer treatment history, bevacizumab-related outcomes, and certain<br />
safety events will be collected directly from patients entirely via<br />
online surveys. Patients will be asked to complete surveys at the time<br />
of enrollment and then every 3 months for 1 year after enrollment. A<br />
saliva sample for DNA collection will be gathered using an at-home<br />
kit. Evaluations of data quality and collection feasibility will be<br />
conducted intermittently. There will be an optional substudy to allow<br />
for blood sample collection for DNA analysis.<br />
Eligibility criteria: ≥18 years of age, residing in the US, locally<br />
recurrent breast cancer or MBC, currently being or having been<br />
treated with bevacizumab starting on or before Dec 31, 2011, fluent<br />
in English, and access to a computer with an internet connection.<br />
Specific aims: The primary objective is to assess the feasibility of<br />
recruiting subjects and collecting biospecimens and self-reported<br />
data online. The secondary objective is to characterize the patient<br />
population. Exploratory objectives include analyzing potential<br />
associations between genetic polymorphisms and 1) bevacizumabinduced<br />
hypertension, the most common bevacizumab-related adverse<br />
event, and 2) patient-reported time-to-progression.<br />
Statistical methods: Baseline demographics, clinical and treatment<br />
characteristics of enrolled patients will be summarized. Each<br />
polymorphism genotyped will be tested for association with the<br />
defined endpoint using appropriate statistical modeling.<br />
Present and target accrual: Accrual as of May 23, 2012 is 82 patients.<br />
Target accrual is 1000 patients.<br />
OT3-4-05<br />
Use of early CIRculating tumor CElls count changes to guide<br />
the use of chemotherapy in advanced metastatic breast cancer<br />
patients: the CirCe01 randomized trial<br />
Bidard F-C, Asselain B, Baffert S, Brain E, Campone M, Delaloge<br />
S, Bachelot T, Tubiana-Mathieu N, Pelissier S, Pierga J-Y. Institut<br />
Curie; Institut de Cancérologie de l’Ouest; Institut Gustave Roussy,<br />
Villejuif; Centre Léon Bérard, Lyon; CHU Limoges<br />
Background<br />
After the SWOG0500 trial, the CirCe01 trial (NCT01349842) is the<br />
second randomized attempt to demonstrate that patients who received<br />
a first cycle of chemotherapy and whose CTC count did not drop<br />
should be switched off this chemotherapy.<br />
The clinical setting used here is a population with high chemoresistance<br />
prevalence, i.e. patients starting a third line chemotherapy; the CTC<br />
test will be also repeated at the beginning of every new chemotherapy<br />
line in patients randomized in the CTC arm (i.e. to evaluate the 3 rd ,<br />
4 th , 5 th … lines).<br />
In the CTC arm, it has been hypothesized that many patients with<br />
chemoresistant tumor will experience repeated early chemotherapy<br />
changes (e.g. 3 chemotherapy regimens tested in 9 weeks), giving<br />
support to the discontinuation of inefficient, toxic and costly<br />
chemotherapies and the start of palliative care. It is believed, for this<br />
subgroup of patients, that such de-escalating management will benefit<br />
both patients and healthcare systems. For some other patients, it is<br />
also expected that they will benefit from the early chemotherapy turnaround<br />
and find earlier an efficient therapy among all those tested.<br />
Methods<br />
The main inclusion criteria are metastatic breast cancer patients<br />
starting a third line of chemotherapy and an elevated CTC count at<br />
baseline.<br />
304 metastatic breast cancer patients will be randomized between the<br />
standard arm, in which the treatment management is made following<br />
the current standard of care, and the CTC-driven arm, in which the<br />
“response” after every first cycle of any new chemotherapy line is<br />
assessed by CTC count made before the second cycle. Chemotherapies<br />
which did not lead to a significant reduction of CTC count are<br />
discontinued, and the patient might be offered another chemotherapy<br />
regimen (which will be also evaluated by CTC).<br />
The medical primary endpoint of the trial is the overall survival,<br />
whereas a medico-economic study as a co-primary endpoint. Several<br />
secondary endpoints are pre-planned, including progression-free<br />
survival, quality of life, anxiety/depression and comparison with<br />
serum markers.<br />
OT3-4-06<br />
Circulating tumor cells to guide the choice between chemotherapy<br />
and hormone therapy as first line treatment for hormone<br />
receptors positive metastatic breast cancer patients: the STIC<br />
CTC METABREAST trial<br />
Bidard F-C, Baffert S, Hajage D, Brain E, Armanet S, Simondi C,<br />
Mignot L, Asselain B, Tresca P, Pierga J-Y. Institut Curie, France<br />
Background<br />
Baseline CTC count already demonstrated its accuracy as an<br />
independent prognostic marker in metastatic breast cancer (MBC),<br />
before the start of any treatment (Cristofanilli, NEJM 2004; Pierga<br />
Ann Oncol 2011) for progression free survival and overall survival.<br />
Multivariate analyses performed in both a pooled analysis (Liu, ASCO<br />
2011) and in the IC 2006-04 study showed that the other independent<br />
prognostic factors were the performance status and hormone-receptor<br />
(HR) status. Oppositely, the other criteria that are frequently used to<br />
www.aacrjournals.org 585s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
choose between hormone therapy and chemotherapy for the treatment<br />
of first line hormone receptor-positive MBC patients (e.g. number of<br />
metastatic sites, visceral disease, metastasis-free interval…) were not<br />
independent prognostic factors. As CTC count is highly correlated to<br />
PFS, we designed a large pivotal phase III trial to evaluate the use of<br />
CTC to determine the disease aggressiveness and the choice of first<br />
line treatment in potentially hormonosensitive MBC.<br />
Trial design<br />
First line metastatic breast cancer patients will be randomized between<br />
the clinician choice and CTC count-driven choice. In the CTC arm,<br />
patients with ≥5 CTC/7.5ml will receive chemotherapy whereas<br />
patients with
December 4-8, 2012<br />
Author Index<br />
1200.67 Trial Group OT1‐1‐15<br />
1200.89 Trial Group OT1‐1‐14<br />
A. Molinolo, A P1‐05‐23<br />
Aaronson, NK<br />
P4‐11‐01<br />
Abadie‐Lacourtoisie, S P1‐14‐21<br />
Abbruzzese, BC<br />
P1‐01‐04<br />
ABCSG<br />
P2‐10‐02<br />
Abdel‐Fatah, TMA P2‐10‐22, P3‐06‐13,<br />
P6‐07‐09, P6‐07‐18<br />
AbdElmageed, Z P4‐06‐14, P4‐06‐16<br />
Abdel‐Rasoul, M<br />
P5‐18‐17<br />
Abd‐El‐Tawab, R<br />
P1‐05‐11<br />
Abdraboh, M<br />
P4‐06‐16<br />
Abdul‐Hussein, M<br />
PD03‐09<br />
Abdulsater, F<br />
P3‐04‐04<br />
Abe, H<br />
PD06‐02, P1‐15‐11<br />
Abe, K<br />
P1‐01‐27<br />
Abernethy, A<br />
P3‐06‐07<br />
Abidoye, O<br />
P6‐09‐11<br />
Abkevich, V<br />
PD09‐04<br />
Abraham, J PD07‐09, PD09‐06<br />
Abraham, JE<br />
P3‐08‐05<br />
Abramson, RG<br />
P4‐01‐03<br />
Abramson, VG P2‐14‐04, P4‐01‐03,<br />
P6‐10‐05<br />
Abranches, MV<br />
P3‐07‐12<br />
Abrial, C<br />
P3‐06‐20<br />
Abu‐Khalaf, M PD05‐05, P4‐01‐02<br />
Abulkhair, O<br />
OT1‐1‐08<br />
Aburto, L<br />
P3‐10‐03<br />
Ackerstaff, E<br />
P6‐01‐01<br />
Adamowicz, K P3‐12‐09, P3‐13‐03<br />
Adams, J<br />
P1‐09‐05<br />
Adams, JE<br />
P4‐13‐09<br />
Adams, JW<br />
P2‐05‐06<br />
Adams, RF P1‐06‐01, P4‐01‐01<br />
Adams, S<br />
P5‐20‐05<br />
Adane, E<br />
P5‐14‐05<br />
Addison, C<br />
P3‐13‐05<br />
Addison, CL P2‐05‐12, P2‐05‐13<br />
Adelaide, J<br />
P5‐03‐01<br />
Ademar, BJ<br />
P3‐01‐03<br />
Ademuyiwa, FO<br />
P3‐07‐02<br />
Adie, SG<br />
OT2‐1‐04<br />
Adnet, P‐Y<br />
S6‐2, P3‐05‐03<br />
Adrada, B<br />
P1‐07‐06<br />
Aebi, S<br />
S3‐2, P6‐07‐06<br />
Affan, AM<br />
P4‐17‐06<br />
Affen, J<br />
P1‐09‐05<br />
Aft, R<br />
P2‐04‐02<br />
Agabiti, E P1‐01‐10, P1‐01‐11<br />
Agalliu, I<br />
PD03‐09<br />
Agar, NYR<br />
OT1‐1‐11<br />
Agarwal, J<br />
P4‐14‐02<br />
Agarwal, P<br />
P2‐10‐03<br />
Agarwal, S<br />
P4‐14‐02,<br />
P4‐14‐02, OT2‐3‐11<br />
Agelaki, S P2‐01‐03, P2‐01‐07<br />
Ager, E<br />
P3‐12‐03<br />
Agrawal, R S4‐1<br />
Agresti, R<br />
P4‐06‐09<br />
A’Hern, R<br />
PD07‐07,<br />
P1‐13‐03, P3‐06‐09<br />
A’Hern, RP<br />
P6‐07‐15<br />
Aherne, ST<br />
P3‐04‐12<br />
Ahirwar, D<br />
P1‐05‐17<br />
Ahlers, S<br />
P5‐17‐03<br />
Ahmed, I<br />
P6‐09‐09, P6‐09‐10<br />
Ahmed, KM P1‐05‐08, P4‐06‐05<br />
Ahmed, S<br />
P1‐14‐15<br />
Ahmed, SA<br />
P3‐08‐06<br />
Ahmed, SI<br />
P4‐14‐14<br />
Ahn, E<br />
P1‐12‐03<br />
Ahn, JH<br />
P2‐05‐20<br />
Ahn, J‐H PD09‐05, P2‐02‐02, P3‐12‐05<br />
Ahn, JS PD09‐05, P2‐05‐20, P4‐06‐13<br />
Ahn, SD<br />
P3‐12‐05<br />
Ahn, SG<br />
P2‐05‐14<br />
Ahn, SH<br />
P3‐01‐02, P3‐12‐05<br />
Ahn, SK<br />
PD05‐07, P1‐01‐08<br />
Ahn, S‐K<br />
P1‐14‐16<br />
Ahrends, T<br />
P5‐04‐01<br />
Ahrendt, GM S2‐1<br />
Aiello, P<br />
P4‐06‐09<br />
Aigner, J<br />
P3‐06‐08, P3‐06‐19<br />
Aihara, T<br />
P2‐13‐04, P2‐13‐07<br />
Aird, E S4‐1<br />
Aivazyan, L<br />
PD03‐04<br />
Akazawa, K<br />
PD07‐05<br />
Akbari, S<br />
OT3‐4‐03<br />
Akcakanat, A<br />
P1‐07‐06<br />
Akens, MK<br />
P4‐03‐04<br />
Akhtar, A<br />
P6‐05‐02<br />
Akimoto, E<br />
P6‐07‐26<br />
Akita, H<br />
P4‐04‐08<br />
Akiyama, F P1‐01‐12, P2‐10‐18<br />
Aktas, B<br />
S1‐7, P1‐14‐05,<br />
P2‐10‐08, OT1‐1‐10<br />
Al Riyami, H<br />
P4‐06‐16<br />
Al Sarakbi, W<br />
P6‐05‐11<br />
Alabek, ML<br />
P4‐11‐06<br />
Alarcon, J<br />
P3‐12‐08<br />
Alazawi, D<br />
P1‐01‐15<br />
Alba, E<br />
P2‐10‐11<br />
Albain, K<br />
PD10‐02, P1‐13‐01<br />
Albain, KS<br />
P1‐12‐04<br />
Albanell, J<br />
P5‐18‐05<br />
Albarracin, C<br />
P5‐20‐09<br />
Albarracin, CT<br />
P6‐07‐25<br />
Albino, T<br />
P2‐10‐05<br />
Albiter, M<br />
P4‐13‐03<br />
Al‐Ejeh, F<br />
P6‐10‐06<br />
Alexa, U<br />
P5‐15‐07<br />
Ali, A<br />
P6‐08‐04<br />
Ali, RA<br />
P4‐17‐06<br />
Ali, S<br />
P2‐10‐16, P2‐10‐22<br />
Ali, SM<br />
P2‐10‐31, P3‐06‐33<br />
Ali, ZA<br />
P4‐09‐12<br />
Al‐Janabi, S<br />
PD02‐03<br />
Alkhayyat, SS<br />
P2‐13‐08<br />
Al‐Kofahi, Y P3‐05‐05, P3‐05‐06<br />
Allen, C<br />
P4‐02‐05<br />
Allen, JD<br />
P5‐14‐02<br />
Allen, JW<br />
OT3‐3‐07<br />
Allers, TM<br />
P6‐06‐01<br />
Allevi, G<br />
PD07‐03<br />
Allison, J<br />
OT3‐1‐01<br />
Allison, MAK<br />
P3‐06‐12<br />
Allochio Filho, JF<br />
P6‐11‐13<br />
Allred, C<br />
PD07‐01<br />
Allred, JB<br />
P1‐12‐06<br />
Allum, W P1‐01‐10, P1‐01‐11<br />
Almendro, V P3‐05‐04, P4‐06‐01<br />
Alnæs, GG<br />
P5‐05‐03<br />
Alpaugh, KR<br />
PD05‐01<br />
Alpaugh, RK PD05‐03, P6‐02‐05<br />
Alperovich, M P4‐14‐03, P4‐17‐07<br />
Alran, S<br />
PD07‐04, P1‐01‐07,<br />
P1‐01‐19, OT2‐1‐01<br />
Alsner, J<br />
P3‐04‐03<br />
Alterovitz, G<br />
P1‐15‐12<br />
Altevogt, P P3‐06‐08, P3‐06‐19<br />
Althaus, B<br />
P5‐18‐11<br />
Alvarado, M<br />
S4‐2, P3‐08‐06,<br />
P4‐14‐04, P4‐16‐07<br />
Alvarado, MD<br />
P5‐15‐01<br />
Alvarez, J<br />
P5‐01‐09<br />
Alvarez, RH P2‐10‐32, P3‐10‐05,<br />
P5‐10‐02, P5‐20‐13,<br />
P6‐10‐02, OT2‐3‐10<br />
Alvarez, RMa<br />
PD08‐06<br />
Alvarez de Lacerda, LC P5‐03‐10<br />
Alvarez‐Cid, M<br />
P4‐02‐07<br />
Alvarez‐Garriga, C<br />
P5‐07‐06<br />
Amadori, D<br />
P5‐18‐01<br />
Amant, F P2‐10‐12, P6‐05‐05,<br />
P6‐07‐05, P6‐07‐29<br />
Ambros, T<br />
P1‐12‐03<br />
Ambrosone, CB<br />
P3‐07‐02<br />
Ameer‐Beg, S<br />
P2‐10‐29<br />
Ames, M<br />
PD10‐08<br />
Amir, E P2‐05‐12, P2‐10‐23, P3‐13‐05<br />
Amornphimoltham, P P1‐05‐23<br />
Amsellem, M P6‐09‐09, P6‐09‐10<br />
Anan, K<br />
P3‐02‐06<br />
Anastario, M<br />
P4‐13‐02<br />
Anastasiadis, PZ<br />
P1‐05‐24<br />
Anchisi, S<br />
P6‐04‐05<br />
Andergassen, U<br />
P2‐01‐02,<br />
P2‐01‐11, P4‐13‐11<br />
Anders, CK<br />
P3‐12‐04<br />
Andersen, J<br />
P4‐11‐04<br />
Anderson, D<br />
P2‐06‐04<br />
Anderson, EE<br />
P5‐13‐03<br />
Anderson, L<br />
P2‐08‐02<br />
Anderson, N<br />
PD03‐04<br />
Anderson, RL<br />
P3‐10‐09<br />
Anderson, S<br />
P2‐05‐06<br />
Anderson, SJ S3‐2, P6‐07‐06, OT1‐2‐01<br />
Anderson, SK<br />
PD10‐04<br />
Anderson, SM<br />
P5‐10‐04<br />
Andersson, M<br />
P1‐09‐01<br />
Andorfer, CA<br />
P1‐05‐24<br />
Andrade, VP PD04‐05, PD05‐02<br />
Andrade, W<br />
P4‐02‐03<br />
André, F<br />
P3‐06‐04,<br />
P5‐13‐02, OT2‐2‐03<br />
Andre, R<br />
P1-15-03<br />
Andreis, D<br />
PD07‐03<br />
Andrieux, N<br />
P1‐01‐21<br />
Aneja, S<br />
P3‐14‐06<br />
Anfossi, S<br />
P2‐03‐01,<br />
P5‐04‐06, P5‐10‐02<br />
Ang, D<br />
P2‐08‐03<br />
Ang, P<br />
P3‐08‐09<br />
Ang, X<br />
P2‐11‐06<br />
Anglin, BV<br />
P1‐15‐09<br />
Angulo‐Gonzalez, AM P5‐20‐13<br />
Anh‐Do, K<br />
P1‐07‐06<br />
Anthony, SP<br />
P6‐11‐10<br />
Antón, A S1‐7 , P1‐07‐18, P2‐01‐06<br />
Anton‐Culver, H<br />
P4‐13‐13<br />
Antúnez, JR<br />
P1‐01‐29<br />
Aogi, K<br />
P1‐14‐02, P2‐13‐04,<br />
P2‐13‐07, P3‐06‐18, P6‐04‐27<br />
Aparicio, A<br />
P6‐04‐12<br />
Aparicio, S<br />
P2‐10‐20<br />
Apple, SK<br />
P4‐08‐05<br />
Appleman, LJ<br />
PD09‐06<br />
Aramendia, JM<br />
P5‐16‐03<br />
Arap, W<br />
P3‐10‐09<br />
Araujo Neto, JT<br />
P1‐01‐28<br />
Arcangeli, A<br />
P5‐10‐01<br />
Arce Salinas, C<br />
P4‐16‐14<br />
Ardavanis, A<br />
P5‐16‐05<br />
Areaga, CL S3‐6<br />
Arena, FP<br />
P6‐10‐01<br />
Arevalo, E<br />
P5‐16‐03<br />
Argiles, G<br />
P6‐10‐07<br />
Aridgides, PD<br />
P3‐12‐02<br />
Arizcum, A P1‐07‐18, P2‐01‐06<br />
Arju, R<br />
P5‐03‐02<br />
Arlen, PM<br />
P5‐16‐06<br />
Arlinghaus, LR<br />
P4‐01‐03<br />
Arlukowicz‐Czartoryska, B P2‐10‐31<br />
Armanet, S<br />
OT3‐4‐06<br />
Armstrong, A<br />
P4‐06‐07<br />
Armstrong, AC<br />
P2‐14‐06<br />
Arnadottir, SS<br />
P5‐10‐05<br />
Arnaout, A PD09‐01, P5‐13‐01<br />
Arnedos, M<br />
P5‐13‐02<br />
Arneson, TJ<br />
P1‐15‐01<br />
Arnoud, L<br />
PD05‐08<br />
Arnould, L P3‐08‐07, P3‐14‐03<br />
Arora, R<br />
OT1‐1‐16<br />
Arteaga, C<br />
OT2‐3‐09<br />
Arteaga, CL PD01‐04, P2‐14‐04,<br />
P5‐19‐01, P6‐10‐05<br />
Arthur, D<br />
P1‐15‐09, P4‐16‐03<br />
Arthur, DW P4‐16‐09, OT1‐2‐01<br />
Arun, BK<br />
P2‐10‐32<br />
Arveux, P<br />
P3‐08‐07<br />
Aryandono, T<br />
P3‐01‐08<br />
Asada, Y<br />
P2‐11‐02<br />
Asaga, S<br />
P3‐02‐06<br />
Asano, T<br />
P4‐12‐06<br />
Asanuma, F<br />
P4‐09‐08<br />
Ashby, WJ<br />
P3‐05‐09<br />
Ashcraft, K<br />
P6‐02‐02<br />
Ashcroft, L<br />
P1‐09‐05<br />
Asher, M<br />
P2‐08‐01<br />
Ashfaq, R<br />
P3‐06‐21<br />
Ashikari, AY<br />
P4‐14‐01<br />
Ashworth, A PD05‐08, P3‐08‐04<br />
Askren, MK S6‐3<br />
Asmann, YW<br />
PD10‐04<br />
Assaf, E<br />
P4‐16‐10<br />
Assayag, F<br />
P6‐04‐14<br />
Asselain, B P1‐13‐04, P1‐14‐03,<br />
P1‐14‐18, P2‐01‐13,<br />
OT3‐4‐05, OT3‐4‐06<br />
Astley, SM<br />
P4‐13‐09<br />
Asztalos, S<br />
P6‐04‐24<br />
Atale, R<br />
PD05‐06, P1‐03‐02<br />
Athanasiadis, A<br />
P1‐13‐09<br />
Atkins, N<br />
P1‐13‐03<br />
Atkinson, RL<br />
P3‐10‐01<br />
ATLAS Collaborators<br />
Worldwide S1‐2<br />
Audretsch, W<br />
P1‐14‐04<br />
Auerbach, M<br />
P5‐20‐03<br />
Augereau, P<br />
P1‐14‐21<br />
Augustin, D P1‐13‐13, P2‐10‐08,<br />
P5‐14‐06, P5‐15‐04<br />
Auman, JT S6‐1<br />
Auricchio, N S5‐7<br />
Ausems, MG<br />
P4‐11‐01<br />
Autier, P<br />
P4‐13‐08<br />
Auzac, G<br />
OT1‐2‐02<br />
Avella, A<br />
P3‐12‐08<br />
Avent, JM<br />
P2‐10‐27<br />
Avery, TP<br />
P5‐14‐03<br />
Avery‐Kiejda, KA<br />
P4‐10‐02<br />
Avila, C<br />
P1‐07‐12<br />
Avila, CC<br />
P3‐08‐06<br />
Avila, E<br />
P4‐06‐19, P6‐04‐29<br />
Awad, D<br />
P2‐11‐03, P2‐12‐01<br />
Awada, A S6‐6<br />
Awolala, Y<br />
P5‐13‐03<br />
Axelrod, D P1‐09‐03, P2‐11‐12,<br />
P4‐14‐03, P4‐17‐07<br />
Ayala de la Peña, F<br />
P3‐06‐15<br />
Ayers, DA<br />
P2‐14‐04<br />
Ayers, GD<br />
P4‐01‐03<br />
Azim Jr, HA S4‐4, P6‐07‐14, P6‐07‐22<br />
Aziza, N<br />
P4‐12‐03<br />
Azizi, M<br />
P5‐17‐04<br />
Azizian, N<br />
P5‐04‐08<br />
Azuero, A<br />
P2‐12‐14<br />
Azuero, CB<br />
P2‐12‐14<br />
Baak, J<br />
P2‐10‐19<br />
Babiera, G PD07‐01, P1‐07‐06<br />
Babiera, GV<br />
P4‐15‐02<br />
Bacanu, F<br />
P5‐02‐02<br />
Bachelot, T P1‐13‐04, P2‐01‐13,<br />
P3‐12‐01, OT1‐1‐02, OT3‐4‐05<br />
Bacigalupo, S<br />
P2‐16‐03<br />
Bading, JR<br />
P2‐05‐10<br />
Badovinac Crnjevic, T P2‐13‐02<br />
Badve, S<br />
P1‐03‐02<br />
Badzio, A P3‐12‐09, P3‐13‐03<br />
Bae, SY<br />
P3‐11‐01<br />
Bae, YK<br />
P5‐04‐07<br />
Bae, Y‐K<br />
P1‐01‐05<br />
Baehner, FL S1‐10<br />
Baffert, S<br />
OT3‐3‐10,<br />
OT3‐4‐05, OT3‐4‐06<br />
Bagarre, T<br />
P6‐04‐14<br />
Bahjat, KS<br />
P4‐04‐02<br />
Bahrami, F<br />
P2‐12‐10<br />
Bai, L<br />
P6‐11‐11<br />
Baier, M<br />
PD07‐02<br />
Baildam, A<br />
P4‐14‐11<br />
Bak, M<br />
P2‐10‐28<br />
Baker, EL<br />
P3‐01‐06<br />
Baker, K<br />
P1‐04‐06<br />
Baker, RC<br />
P6‐04‐22<br />
Balchin, K<br />
P3‐11‐03<br />
Baldassarre, G<br />
P5‐10‐17<br />
Balinger, K<br />
P2‐06‐04<br />
Balko, JM S3‐6, PD01‐04, P6‐10‐05<br />
Ball, G<br />
P5‐10‐07, P6‐07‐18<br />
Ballan Haj, M<br />
P6‐14‐03<br />
Ballester, M<br />
P4‐14‐12<br />
Balleyguier, C<br />
P4‐12‐01<br />
www.aacrjournals.org 587s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Ballman, KV<br />
S5‐4, PD10‐04,<br />
P1‐01‐06, P6‐08‐05<br />
Balls, G<br />
P6‐07‐09<br />
Balmain, A<br />
P5‐05‐03<br />
Balmaña, J<br />
P6‐13‐03<br />
Balsari, A<br />
P5‐18‐10<br />
Balslev, E P3‐06‐03, P3‐06‐32<br />
Balzarini, A<br />
P2‐12‐08<br />
Bambina, S<br />
P4‐04‐02<br />
Ban, G<br />
P2‐13‐01<br />
Bando, H<br />
P1‐14‐02, P1‐14‐08<br />
Bandos, H<br />
OT2‐2‐04<br />
Bandyopadhyay, A P5‐03‐04, P5‐03‐06<br />
Bandyopadhyay, AM P5‐04‐04<br />
Bane, FT<br />
P6‐04‐04<br />
Banerjee, N<br />
PD05‐05,<br />
P4‐01‐02, P5‐07‐03<br />
Banerji, J S3‐3<br />
Baney, T<br />
P6‐11‐06<br />
Bang, B<br />
P4‐03‐11<br />
Banis, S<br />
P3‐06‐24<br />
Banzi, M<br />
PD05‐03<br />
Bao, L<br />
P2‐06‐01<br />
Bao, T<br />
P2‐13‐05<br />
Baquero, J<br />
OT3‐3‐05<br />
Bar, I<br />
P3‐04‐04<br />
Barakat, N<br />
PD02‐01<br />
Barakat, R<br />
P2‐12‐05<br />
Baranyai, Z<br />
P3‐05‐08<br />
Baranzelli, MC PD05‐08, P3‐14‐03<br />
Baravalle, S<br />
P2‐16‐03<br />
Barbareschi, M<br />
P5‐01‐10<br />
Barbeau, E<br />
PD08‐03<br />
Barber, P<br />
P2‐10‐29<br />
Barbieri, E<br />
P2‐10‐16<br />
Barbosa, EM<br />
P1‐01‐28<br />
Bardia, A<br />
P2‐01‐14<br />
Barentsz, MW P4‐14‐08, P5‐01‐11<br />
Bargiacchi, FG<br />
P6‐03‐01<br />
Barginear, M<br />
P5‐10‐13<br />
Barhamand, FB<br />
P1‐12‐04<br />
Barinoff, J<br />
S4‐5, PD06‐01<br />
Barker, J<br />
P4‐17‐03<br />
Barker, KB<br />
OT1‐1‐05<br />
Barlow, WE<br />
OT2‐2‐04<br />
Barnadas, A P1‐07‐18, P2‐01‐06<br />
Barnes, NLP<br />
PD04‐06<br />
Barnes, PJ<br />
P2‐10‐09<br />
Barnes, R<br />
P5‐07‐06<br />
Barnett, CM<br />
PD03‐08<br />
Barnholt, K<br />
OT3‐4‐04<br />
Baron, P<br />
OT3‐4‐03<br />
Barranger, E<br />
OT2‐1‐01<br />
Barrera, D P4‐06‐19, P6‐04‐29<br />
Barrett, J<br />
S4‐1, P2‐10‐29<br />
Barrett, JA<br />
P6‐11‐10<br />
Barrett, OC<br />
P5‐17‐07<br />
Barrett, S<br />
P4‐14‐13<br />
Barrett‐Lee, P S3‐3, S4‐1, P1‐13‐03<br />
Barrett‐Lee, PJ<br />
PD07‐09<br />
Barrios, C<br />
OT2‐2‐03<br />
Barrios, CH<br />
OT2‐3‐03<br />
Barron, RL<br />
P1‐15‐01<br />
Barry, P<br />
P1‐01‐10, P1‐01‐11<br />
Barry, W<br />
P3‐06‐07<br />
Barry, WT P2‐10‐01, P2‐10‐03,<br />
P4‐09‐01, P6‐08‐05<br />
Barsky, SH<br />
P6‐10‐04<br />
Bartlett, J<br />
S3‐3, P1‐13‐03<br />
Bartlett, JMS S1‐5, S4‐6, P1‐07‐17,<br />
OT3‐3‐09<br />
Barton, DL<br />
P2‐11‐01<br />
Barton, J<br />
P1‐14‐14, OT2‐3‐02<br />
Barton, Jr., J<br />
P5‐17‐05<br />
Bartsch, R<br />
P5‐20‐11<br />
Baselga, J S1‐11, S5‐1, S5‐2, S5‐7,<br />
P1‐07‐19, P2‐01‐14, P4‐08‐02,<br />
P5‐18‐01, P5‐18‐02, P5‐18‐26,<br />
P6‐04‐02, P6‐10‐07, OT2‐3‐06,<br />
OT2‐3‐09<br />
Baserga, R<br />
P6‐01‐03<br />
Bass, BL<br />
P6‐07‐11<br />
Basso, R<br />
P1‐01‐28<br />
Bastin, J<br />
P6‐09‐07<br />
Bates, N<br />
P5‐16‐04<br />
Batten, K<br />
P4‐06‐06<br />
Battista, M<br />
P2‐10‐13<br />
Batzoglou, S<br />
PD05‐09<br />
Bauer, JA<br />
P6‐05‐03<br />
Bauerfeind, I<br />
P1‐14‐01<br />
Bauerfeind, IGP S2‐2<br />
Baum, M S4‐2<br />
Baumgartner, A<br />
P4‐08‐06<br />
Bautista‐Pina, V<br />
P5‐10‐12<br />
Baxter, RC<br />
P5‐07‐05<br />
Bayer, RA<br />
P1‐12‐04<br />
Bayona, M<br />
P5‐07‐06<br />
Bazan, F<br />
P5‐18‐22<br />
Bazzola, L<br />
PD07‐03<br />
Beadling, C<br />
P2‐08‐03<br />
Bealin, L<br />
P6‐08‐01<br />
Beardslee, B<br />
P5‐20‐05<br />
Beatty, J<br />
OT3‐4‐03<br />
Becerra, C<br />
P6‐11‐08<br />
Becette, V<br />
PD07‐04<br />
Bechhold, R<br />
P6‐10‐01<br />
Beck, AH<br />
P5‐01‐03<br />
Beck, JT<br />
P6‐11‐08<br />
Beck, T<br />
P2‐10‐25<br />
Beckmann, MW<br />
PD07‐02,<br />
P2‐01‐02, P2‐10‐25<br />
Beckwith, H<br />
P4‐07‐03<br />
Becuwe, P<br />
P6‐01‐04<br />
Bedard, M<br />
P2‐11‐10<br />
Bedrosian, I<br />
P1‐07‐06,<br />
P1‐07‐09, P4‐15‐02<br />
Beekman, R<br />
P6‐04‐08<br />
Beelen, KJ PD01‐02, PD01‐03<br />
Beitsch, P P1‐15‐09, OT3‐4‐03<br />
Beitsch, PD<br />
P2‐10‐42,<br />
P4‐14‐01, P4‐16‐03<br />
Bekhash, A<br />
P5‐01‐07<br />
Belani, CP<br />
PD09‐06<br />
Belau, AK<br />
P1‐14‐05<br />
Belichard, C<br />
P1‐01‐07,<br />
P1‐01‐19, OT2‐1‐01<br />
Belin, L<br />
P5‐21‐03<br />
Belkacemi, Y<br />
P4‐16‐10,<br />
P5‐21‐01, OT1‐2‐02<br />
Bell, K<br />
P5‐01‐09<br />
Bell, R<br />
S5‐2, S6‐4,<br />
S6‐5, P3‐06‐34, P5‐18‐02<br />
Bellardini, P<br />
P1‐01‐25<br />
Bellavance, E<br />
P2‐13‐05<br />
Bellen, G<br />
P2‐12‐06<br />
Bellet, M<br />
P6‐13‐03<br />
Belletti, B<br />
P5‐10‐17<br />
Bellin, LS<br />
P1‐01‐17<br />
Bello, MA P3‐11‐04, P6‐07‐44<br />
Bellon, J<br />
P5‐02‐01<br />
Bellon, JR P3‐10‐06, P4‐06‐01<br />
Belmont, LD<br />
P4‐07‐01<br />
Belousov, A S6‐7<br />
Beltjens, F<br />
P3‐08‐07<br />
Belvin, M<br />
P4‐07‐01<br />
Ben Baruch, N<br />
P5‐20‐06<br />
Ben Younès, I<br />
P3‐12‐01<br />
Benaim, E<br />
P6‐10‐02<br />
Benca, J<br />
P2‐01‐12<br />
Bendahl, P‐O<br />
PD03‐07,<br />
P2‐10‐28, P2‐10‐36<br />
Bender, PFM<br />
P3‐11‐04<br />
Bendifallah, S<br />
P1‐01‐14<br />
Bengier, A<br />
P4‐13‐12<br />
Benke, Z<br />
P2‐10‐24<br />
Benko, L<br />
P1‐07‐17<br />
Benson, JR<br />
P1‐01‐01<br />
Benyunes, MC<br />
P5‐18‐26<br />
Benz, CC<br />
P2‐05‐04<br />
Benz, SC<br />
P2‐06‐05,<br />
P2‐06‐06, P4‐09‐05<br />
Berg, PE<br />
P2‐05‐22<br />
Bergan, R<br />
P1‐09‐07<br />
Berger, AC<br />
P5‐14‐03<br />
Berger, MF<br />
PD05‐02<br />
Berger, MJ<br />
P2‐11‐07<br />
Berger, N<br />
P3‐08‐08<br />
Bergh, J<br />
S1‐11,<br />
PD06‐08, OT2‐3‐02<br />
Bergkvist, L<br />
P2‐12‐09<br />
Bergmann, A P3‐11‐04, P6‐07‐44<br />
Bergstrom, K<br />
P2‐11‐16<br />
Berkowitz, A<br />
P2‐12‐05<br />
Berkowitz, AP<br />
P1‐13‐11<br />
Berlanda, G<br />
P5‐01‐10<br />
Berman, MG S6‐3<br />
Bernales, S<br />
P2‐14‐02<br />
Bernard, P P1‐08‐02, P6‐07‐10<br />
Bernards, R<br />
P4‐09‐05<br />
Bernreuter, W<br />
P3‐03‐03<br />
Berns, EMJJ<br />
PD01‐03,<br />
P3‐06‐01, P6‐04‐08<br />
Bernstein, L<br />
PD08‐02<br />
Bernstein, LJ P6‐09‐01, P6‐09‐02<br />
Berruti, A<br />
PD07‐03<br />
Berry, DL<br />
P1‐05‐12<br />
Berry, JS<br />
P5‐16‐05<br />
Bertaut, A<br />
P3‐08‐07<br />
Berteloot, P P2‐10‐12, P6‐05‐05,<br />
P6‐07‐29, OT2‐2‐02<br />
Bertheau, P<br />
P1‐14‐03<br />
Bertheau, P<br />
P3‐06‐04<br />
Bertolini, I<br />
P5‐17‐06<br />
Berton, S<br />
P5‐10‐17<br />
Bertschinger, J<br />
P5‐18‐25<br />
Bertucci, F<br />
P3‐05‐03,<br />
P5‐03‐01, OT2‐3‐05<br />
Beruti, S<br />
PD02‐01, PD06‐03<br />
Besancenot, V<br />
P6‐01‐04<br />
Beslija, S<br />
P5‐17‐03<br />
Beumer, JH<br />
PD09‐06<br />
Beurdeley, A<br />
P3‐06‐24<br />
Beutler, M<br />
P2‐10‐29<br />
Beuzeboc, P P5‐17‐04, P5‐21‐03<br />
Bevan, P<br />
P5‐20‐01<br />
Beveridge, R<br />
P2‐11‐16<br />
Bezu, C<br />
P1‐01‐14, P4‐14‐12<br />
Bhalla, KN S3‐7<br />
Bhanot, G<br />
P1‐05‐19<br />
Bhar, P<br />
P1‐12‐07<br />
Bhargava, R<br />
P6‐07‐02<br />
Bhaskar, P<br />
P4‐17‐09<br />
Bhat, RR<br />
P4‐06‐02<br />
Bhat, S<br />
P4‐06‐14, P4‐06‐16<br />
Bhatta, P<br />
P2‐13‐09<br />
Bi, L<br />
P5‐03‐14<br />
Bianca, R<br />
P5‐20‐03<br />
Bianchi, F<br />
P4‐06‐09<br />
Bianchini, G S6‐7, P2‐10‐10, P5‐10‐01<br />
Bickell, N<br />
PD08‐01<br />
Bidard, F‐C P2‐01‐01, P2‐01‐04,<br />
P2‐01‐13, OT3‐4‐05, OT3‐4‐06<br />
Bièche, I<br />
P6‐04‐14<br />
Biernat, W<br />
P2‐10‐31,<br />
P3‐12‐09, P3‐13‐03<br />
Bigorie, V<br />
P4‐16‐10<br />
Billig, J<br />
P4‐01‐07<br />
Bilusic, M<br />
P5‐16‐06<br />
Bingham, C<br />
PD05‐03<br />
Binghman, C<br />
PD05‐01<br />
Bingman, A<br />
P2‐11‐07<br />
Binkley, P<br />
P2‐11‐07<br />
Binns, SN<br />
P1‐07‐13<br />
Birch, KE<br />
P4‐13‐10<br />
Birnbaum, D<br />
P5‐03‐01<br />
Bischoff, E<br />
P6‐04‐12<br />
Bischoff, FZ<br />
P2‐01‐10<br />
Bischoff, J<br />
P1‐14‐05<br />
Bishop, JM<br />
P1‐04‐01<br />
Bissell, MJ<br />
P1‐05‐20<br />
Biswal, NC<br />
PD01‐01<br />
Biswas, T<br />
P2‐04‐07<br />
Bitting, R<br />
P4‐06‐07<br />
Bjarnadottir, O<br />
PD03‐07<br />
Bjarnason, G<br />
P2‐12‐03<br />
Bjerre, KD<br />
P3‐06‐03<br />
Black, DM S2‐3<br />
Black, EP<br />
P2‐14‐05<br />
Blackford, A S3‐5<br />
Blackwell, K<br />
OT2‐2‐03<br />
Blackwell, KL P6‐05‐02, OT1‐1‐11<br />
Blaes, AH<br />
Blair, SL<br />
Blancafort, A<br />
Blanc‐Fournier, C<br />
Blanco, E<br />
Blanco, EC<br />
Bland, K<br />
Bland, KI<br />
Blasberg, R<br />
Blaszczyk, P<br />
Blazeby, J<br />
Blazer, KR<br />
Blechman, K<br />
Bleicher, RJ<br />
Bleiker, EM<br />
Blenkinsop, C<br />
Blettner, M<br />
Blinder, VS<br />
Bliss, J<br />
Bliss, JM<br />
P1‐15‐01<br />
P4‐01‐13<br />
P4‐09‐10,<br />
P4‐09‐11, P6‐11‐02<br />
P3‐14‐03<br />
P6‐11‐03, P6‐11‐11<br />
P3‐02‐14<br />
P3‐03‐03<br />
P5‐17‐07<br />
P6‐01‐01<br />
P3‐12‐09, P3‐13‐03<br />
P4‐17‐03<br />
PD08‐06<br />
P4‐14‐03, P4‐17‐07<br />
P1‐01‐16<br />
P4‐11‐01<br />
OT3‐3‐09<br />
P6‐09‐08<br />
P2‐11‐05<br />
PD07‐07, P2‐14‐01<br />
S3‐3, S4‐1,<br />
P1‐13‐03, P6‐07‐15<br />
Blohmer, J S1‐11<br />
Blohmer, JU S4‐5<br />
Blohmer, J‐U S3‐1, PD06‐01, P1‐14‐01,<br />
OT1‐1‐13, OT3‐3‐11<br />
Blomme, C<br />
OT2‐2‐02<br />
Bloom, ES<br />
P4‐15‐02<br />
Bloom, K<br />
P3‐05‐05<br />
Bloom, KJ P2‐10‐04, P3‐05‐06<br />
Bloomfield, D<br />
S3‐3, P1‐13‐03<br />
Blosser, RJ<br />
P1‐03‐02<br />
Blot, E<br />
OT3‐3‐04<br />
Blowers, E<br />
P2‐14‐06<br />
Blows, FM<br />
P3‐08‐02<br />
Blue, MS<br />
P1‐01‐04<br />
Bluethmann, SM<br />
P5‐14‐02<br />
Blumencranz, P<br />
OT3‐4‐02<br />
Blumenthal, G S1‐11<br />
Boachie‐Adjei, K<br />
P3‐08‐08,<br />
P4‐15‐03, P6‐07‐34<br />
Boas, DA<br />
P3‐06‐27<br />
Bobos, M<br />
P1‐07‐15<br />
Bock, C<br />
PD03‐09<br />
Bode, H<br />
P6‐09‐07<br />
Bodmer, A<br />
P6‐04‐05<br />
Boe, M<br />
P3‐04‐01, P3‐04‐02<br />
Boehm, D<br />
P2‐10‐13<br />
Boelke, E<br />
P1‐14‐04<br />
Boemo, M<br />
P1‐05‐19<br />
Boer, K S1‐6<br />
Bogaerts, J<br />
S1‐11,<br />
P3‐02‐01, P3‐05‐02<br />
Bogart, JA<br />
P3‐12‐02<br />
Boggis, C<br />
P1‐09‐05<br />
Boggis, CR<br />
P4‐13‐09<br />
Böhme, M<br />
P1‐14‐05<br />
Böhm‐Vélez, M P4‐02‐09, P4‐02‐10<br />
Bohnsteen, B<br />
P5‐21‐02<br />
Bojar, H<br />
P1‐14‐04<br />
Bolan, P<br />
P3‐03‐01<br />
Bolan, PJ<br />
P1‐14‐11<br />
Bolaños, G<br />
P5‐07‐06<br />
Boley, KM P4‐06‐03, P5‐04‐05<br />
Bolger, JC<br />
P6‐04‐01<br />
Bollet, M<br />
P5‐02‐03<br />
Bolli, GB<br />
P4‐13‐07, P4‐13‐08<br />
Bolos, MV<br />
P6‐11‐02<br />
Bolten, WW<br />
P6‐09‐08<br />
Bona, E<br />
P5‐17‐06<br />
Bonanni, B<br />
PD03‐01,<br />
PD04‐07, PD06‐06<br />
Bonardi, S<br />
PD07‐03<br />
Bonat, J<br />
P5‐14‐03<br />
Bondarenko, IM S1‐6<br />
Bondarenko, IN S1‐4<br />
Bongers, V<br />
P4‐14‐08<br />
Boniol, M P4‐13‐07, P4‐13‐08<br />
Bonnefoi, H S1‐1, S1‐11, S5‐3<br />
Bonnefoi, HR<br />
OT3‐3‐10<br />
Bonnet, F<br />
PD05‐04<br />
Bonnetain, F<br />
OT3‐3‐10<br />
Bonneterre, J P1‐07‐11, P2‐13‐10<br />
Bono, P<br />
PD10‐06<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
588s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
Author Index<br />
Bontenbal, M<br />
P6‐07‐05<br />
Boogerd, W<br />
P1‐15‐05<br />
Boolbol, SK P3‐08‐08, P4‐15‐03,<br />
P6‐07‐34<br />
Booser, DJ<br />
P5‐20‐13<br />
Boothe, DL<br />
P4‐03‐09<br />
Boppart, SA<br />
OT2‐1‐04<br />
Bor, C<br />
P3‐05‐07<br />
Boraas, M<br />
P1‐01‐16<br />
Borakove, M<br />
P4‐04‐06<br />
Bordes, V<br />
OT2‐1‐01<br />
Borg, Å<br />
P2‐10‐37<br />
Borg, J‐P<br />
P3‐12‐01<br />
Borges, MM<br />
P3‐02‐14<br />
Borges, S<br />
P1‐05‐24<br />
Borges, V<br />
P4‐04‐03<br />
Borges, VF<br />
P4‐04‐06<br />
Borgquist, S PD03‐07, P2‐10‐28<br />
Borgstein, PJ<br />
P4‐11‐01<br />
Borm, GF<br />
P1‐14‐07,<br />
P5‐21‐04, P6‐07‐32<br />
Borms, M<br />
P5‐18‐19<br />
Borowsky, AD<br />
P1‐05‐20<br />
Børresen‐Dale, A‐L P2‐10‐20, P3‐04‐03,<br />
P3‐05‐04, P5‐05‐03, P5‐10‐03<br />
Bosc, R<br />
P4‐16‐10<br />
Bose, P<br />
P4‐09‐07<br />
Bose, R S5‐6<br />
Bosq, J<br />
P1‐07‐11<br />
Bosserman, L<br />
P2‐05‐06,<br />
P2‐11‐16, P3‐06‐28<br />
Bossuyt, V<br />
PD05‐05,<br />
P3‐14‐01, P4‐01‐02<br />
Bota, M<br />
P4‐13‐07, P4‐13‐08<br />
Bottai, G<br />
P5‐10‐01<br />
Botteri, E<br />
PD04‐07<br />
Bottini, A<br />
PD07‐03<br />
Boudreau, A<br />
P2‐05‐01,<br />
P4‐09‐02, P5‐05‐01<br />
Bouganim, N<br />
P2‐05‐13,<br />
P3‐13‐05, P5‐13‐01<br />
Boughey, JC S2‐1<br />
Boukovinas, I<br />
P1‐13‐09<br />
Bouma, WH<br />
P4‐11‐01<br />
Bourcier, C<br />
OT2‐1‐01<br />
Bourgeois, H P5‐21‐01, OT3‐3‐04<br />
Bourgier, C PD07‐04, OT1‐2‐02<br />
Bourrgier, C<br />
P5‐13‐02<br />
Bouton, M<br />
PD08‐04<br />
Bowden, NA<br />
P4‐10‐02<br />
Bowden, S S3‐3<br />
Boyages, J<br />
P4‐17‐04<br />
Boyer‐Chammard, A OT2‐3‐05<br />
Boyle, P<br />
P4‐13‐07, P4‐13‐08<br />
Boyle, T<br />
P6‐01‐02<br />
Brabencova, E<br />
P3‐14‐03<br />
Brachtel, E<br />
P2‐01‐14<br />
Brack, S<br />
P5‐18‐25<br />
Brackstone, M P1‐14‐13, P4‐16‐14<br />
Bradbury, AR<br />
P6‐08‐01<br />
Bradley, T<br />
P5‐10‐13<br />
Bradlow, HL<br />
P1‐10‐02<br />
Bradshaw, SH<br />
P5‐01‐01<br />
Braem, K<br />
P2‐13‐06<br />
Brafman, L P1‐09‐02, P2‐12‐01<br />
Brain, E P1‐13‐04, P1‐14‐03, P1‐14‐18,<br />
P2‐01‐04, P2‐01‐13, P3‐06‐04,<br />
P5‐18‐21, OT2‐3‐05, OT3‐3‐10,<br />
OT3‐4‐05, OT3‐4‐06<br />
Brammer, MG<br />
P5‐18‐12<br />
Bramwell, V<br />
P1‐13‐01<br />
Brandi, L<br />
P2‐07‐01<br />
Branle, F<br />
P5‐18‐05<br />
Brar, B<br />
P5‐12‐01<br />
Brase, JC<br />
S4‐3, P2‐10‐11<br />
Brauch, H<br />
P2‐13‐09<br />
Braun, A<br />
OT2‐3‐03<br />
Braun, HJ<br />
P1‐12‐05<br />
Breazna, A S1‐6<br />
Breitschwerdt, EB<br />
P3‐10‐03<br />
Brennan, DJ<br />
P4‐09‐06<br />
Brennan, K<br />
PD02‐07<br />
Breslin, T<br />
P1‐01‐13<br />
Breslin, TM<br />
P1‐13‐05<br />
Brewer, T<br />
PD03‐06, P3‐10‐05<br />
Brewer, TM<br />
PD03‐08<br />
Brew‐Graves, C S4‐2<br />
Brewster, AM<br />
P3‐10‐01<br />
Briggs, K<br />
P5‐18‐21<br />
Brigino, M<br />
P2‐05‐06<br />
Briley, LP<br />
PD10‐05<br />
Brindley, JH<br />
P3‐02‐04<br />
Brink, A<br />
PD07‐01<br />
Brinkman, JA<br />
P1‐05‐12<br />
Brinton, LA P3‐07‐04, P3‐08‐02<br />
Brito, M<br />
P1-15-03<br />
Brock, A<br />
P5‐05‐04<br />
Broderick, J<br />
P6‐08‐06<br />
Broderick, P<br />
P3‐08‐04<br />
Brodowicz, T<br />
P5‐17‐03<br />
Broers, JE<br />
P6‐05‐08<br />
Brogi, E<br />
OT3‐1‐01<br />
Bronson, RT<br />
P4‐08‐05<br />
Brookes, S<br />
P4‐17‐03<br />
Brooks, B<br />
P2‐11‐16<br />
Brooks, SE<br />
P4‐11‐06<br />
Brooks‐Brafman, L<br />
P2‐11‐03<br />
Brophy, ML<br />
P1‐05‐21<br />
Brouckaert, O P2‐10‐12, P5‐18‐19,<br />
P6‐05‐05, P6‐07‐04,<br />
P6‐07‐19, P6‐07‐29<br />
Brousseau, MK<br />
P5‐14‐04<br />
Brouste, V<br />
P3‐14‐03<br />
Brouwer, T<br />
P4‐11‐01<br />
Brown, D S4‐2, S6‐2, P3‐05‐03<br />
Brown, DN<br />
P3‐04‐10<br />
Brown, J<br />
S4‐1, S6‐5,<br />
PD01‐07<br />
Brown, JE S6‐4<br />
Brown, M PD01‐08, P1‐07‐07,<br />
P4‐02‐07, P6‐12‐03<br />
Brown, N<br />
P2‐10‐05<br />
Brown, RE<br />
P3‐06‐06<br />
Brown, S<br />
P4‐16‐09<br />
Brucker, C<br />
P5‐21‐02<br />
Brufsky, AM PD09‐06, P6‐07‐02<br />
Brugge, JS<br />
P4‐08‐05<br />
Brunet, J<br />
P4‐09‐11<br />
Brunner, A<br />
PD05‐09<br />
Brunner, E<br />
P6‐01‐04<br />
Brünner, N P3‐06‐32, P3‐06‐35<br />
Brunotte, F<br />
P4‐02‐06<br />
Brunt, M S3‐3<br />
Bubuteishvili‐Pacaud, L S6‐5, P3‐06‐34<br />
Buchan, I<br />
P3‐08‐01<br />
Buchholz, S<br />
P2‐12‐06<br />
Buchholz, TA<br />
S2‐1, S2‐3,<br />
PD03‐06, P5‐03‐05<br />
Buchmann, J<br />
P2‐10‐38<br />
Buclin, T<br />
P6‐04‐05<br />
Budach, W<br />
P1‐14‐04<br />
Budczies, J S4‐5<br />
Budd, GT<br />
PD02‐04,<br />
P2‐13‐02, P5‐18‐06<br />
Budd, T<br />
P6‐07‐45<br />
Budlovsky, J<br />
P4‐13‐04<br />
Budman, D<br />
P5‐10‐13<br />
Budrys, N<br />
PD03‐09<br />
Bueno, C<br />
OT3‐3‐05<br />
Buffa, FM P1‐06‐01, P4‐01‐01<br />
Bui, S<br />
PD02‐04<br />
Buist, DS<br />
P4‐01‐15<br />
Bulloch, KJ<br />
P2‐11‐08<br />
Bulsara, M S4‐2<br />
Bundred, N<br />
PD07‐07<br />
Bundred, NJ PD04‐06, P1‐01‐26,<br />
P3‐01‐04, P3‐14‐04<br />
Bundred, S<br />
P1‐09‐05<br />
Bundred, SM<br />
P3‐01‐04<br />
Buonomo, C<br />
P4‐15‐04<br />
Buonomo, OC<br />
P4‐15‐04<br />
Burgin, C<br />
PD04‐04<br />
Burnell, MJ<br />
P1‐13‐01<br />
Burnett, D<br />
P2‐11‐17<br />
Burris, H<br />
P6‐04‐02<br />
Burris, HA P1‐14‐14, P5‐17‐05,<br />
P6‐10‐07, OT3‐3‐08<br />
Burrows, J<br />
P1‐07‐19<br />
Burstein, H<br />
P5‐18‐03<br />
Busby, L<br />
P2‐11‐16<br />
Busch‐Devereaux, E P4‐14‐01<br />
Butler, S<br />
P6‐07‐03<br />
Butler, SM S1‐10<br />
Buxo, M<br />
P4‐09‐10<br />
Buyse, ME<br />
OT1‐1‐12<br />
Büyükberber, S<br />
OT1‐1‐08<br />
Byrd, DR S2‐1<br />
Byrne, C<br />
P6‐04‐01<br />
Caan, BJ<br />
P2‐11‐09<br />
Caanen, BA<br />
P6‐08‐02<br />
Caballero, R<br />
P2‐10‐11<br />
Cabaud, O<br />
P5‐03‐01<br />
Caggiano, V P3‐09‐01, P3‐09‐02<br />
Cagle, PD<br />
P6‐14‐04<br />
Caglevic, C<br />
P5‐18‐21<br />
Cagnolati, S<br />
OT1‐1‐08<br />
Cai, G<br />
P3‐12‐12<br />
Cai, J‐F<br />
P2‐05‐05<br />
Cai, X<br />
P1‐05‐21<br />
Caillet, P<br />
P4‐16‐10<br />
Cairo, S<br />
P3‐06‐24<br />
Caldara, A<br />
P5‐01‐10<br />
Caldarella, P<br />
PD06‐06<br />
Caldas, C<br />
P2‐10‐20,<br />
P3‐08‐05, OT3‐3‐09<br />
Caleffi, M<br />
P3‐01‐03<br />
Caley, MP<br />
P2‐02‐03<br />
Calhoun, E<br />
P5‐13‐03<br />
Calin, G<br />
P5‐10‐17<br />
Calin, GA<br />
P5‐10‐01<br />
Calitchi, E<br />
P4‐16‐10<br />
Callahan, R<br />
P2‐04‐08<br />
Callari, M<br />
P2‐10‐10<br />
Callihan, E<br />
P4‐04‐03<br />
Cals, L<br />
P5‐18‐22<br />
Calvert, V P3‐04‐01, P3‐04‐02<br />
Calvo, E<br />
P2‐06‐03<br />
Calvo, I<br />
P1‐14‐10, P5‐18‐15<br />
Calvo, L P1‐07‐18, P2‐01‐06, P2‐10‐11<br />
Caly, M<br />
P5‐01‐04<br />
Camacho, J P4‐06‐19, P6‐04‐29<br />
Camara, O<br />
P5‐03‐13<br />
Cameron, D S1‐11, S3‐3, S5‐2, S6‐4,<br />
S6‐5, P1‐13‐03,<br />
P2‐14‐01, P3‐06‐34, P5‐18‐02<br />
Cameron, DA OT1‐1‐03, OT3‐3‐09<br />
Cameron, S<br />
P6‐11‐06<br />
Camoin, L<br />
P3‐12‐01<br />
Campana, F<br />
P5‐21‐03<br />
Campbell, M<br />
P4‐04‐01<br />
Campbell, MM<br />
P1‐15‐06<br />
Campbell, P S6‐2<br />
Campbell, R<br />
P5‐13‐03<br />
Camphausen, K<br />
P6‐01‐03<br />
Campiglio, M<br />
P4‐06‐09<br />
Campone, M P1‐13‐04, P2‐01‐13,<br />
P3‐04‐04, P3‐05‐07, P3‐12‐01,<br />
P5‐18‐26, P6‐11‐08, OT2‐2‐03,<br />
OT2‐3‐09, OT3‐4‐05<br />
Candelaria, PV<br />
P4‐06‐18<br />
Canet, R<br />
P3‐12‐08<br />
Canisius, SV<br />
P4‐09‐05<br />
Cannas, P<br />
P1‐01‐25<br />
Canney, P<br />
S3‐3, P1‐13‐03<br />
Canon, JL<br />
OT2‐3‐02<br />
Canon, J‐L<br />
P3‐04‐04<br />
Cantos, B<br />
OT3‐3‐05<br />
Cao, X<br />
PD09‐08, P6‐04‐25<br />
Cao, Y<br />
P3‐10‐09<br />
Cappelletti, MR<br />
PD07‐03<br />
Capuano, LG<br />
P1‐01‐25<br />
Caraceni, A<br />
P2‐12‐08<br />
Carbaugh, H<br />
P2‐10‐05<br />
Cardoso, F P3‐02‐01, P3‐05‐02<br />
Carey, B<br />
P1‐15‐07<br />
Carey, L<br />
P6‐05‐02<br />
Carey, LA PD09‐03, PD10‐07<br />
Carillo, A<br />
P5‐13‐03<br />
Carkaci, S<br />
P1‐07‐06<br />
Carl, S<br />
P5‐03‐13<br />
Carlo‐Stella, C<br />
P2‐12‐08<br />
Carlson, JW<br />
PD06‐08<br />
Carlson, K<br />
P1‐15‐07<br />
Carmeliet, P<br />
P3‐06‐34<br />
Carmo, PAO<br />
P6‐07‐44<br />
Carneiro, JP<br />
P2‐12‐04<br />
Carney, PS<br />
OT2‐1‐04<br />
Carothers, S<br />
P2‐11‐07<br />
Carp, NZ<br />
P4‐09‐12<br />
Carp, SA<br />
P3‐06‐27<br />
Carpenter, J<br />
P3‐03‐03<br />
Carpenter, JT<br />
P5‐17‐07<br />
Carrasco, E<br />
S1‐7, P2‐10‐11<br />
Carrasco, J<br />
P3‐04‐04<br />
Carrasco, R<br />
P4‐07‐05<br />
Carrillo, JE<br />
PD08‐05<br />
Carrión, R<br />
OT3‐3‐05<br />
Carrion‐Salip, D<br />
P6‐11‐02<br />
Carroll, J<br />
P3‐02‐10<br />
Carroll, M<br />
P2‐05‐10<br />
Carroll, PA<br />
P6‐01‐02<br />
Carstensen, J<br />
P6‐07‐12<br />
Carter, CC<br />
P2‐10‐27<br />
Carter, CRD<br />
P1‐13‐08<br />
Carter, J<br />
P2‐12‐05<br />
Cartun, RW<br />
P1‐07‐10<br />
Cartwright, F<br />
P2‐11‐12<br />
Cartwright, T<br />
P2‐11‐16<br />
Carvalho, AA<br />
P5‐01‐15<br />
Carvalho, RM<br />
P6‐07‐44<br />
Casagrange, G<br />
P2‐04‐08<br />
Casalini, P<br />
P5‐18‐10<br />
Casas, M<br />
P2‐10‐11, P4‐09‐10<br />
Casbard, A<br />
PD07‐09<br />
Caseras, M<br />
P5‐13‐03<br />
Casey, L<br />
P3‐03‐01<br />
Caskey, M<br />
P6‐04‐22<br />
Casoliva, G<br />
P4‐09‐10<br />
Caspard, H<br />
P3‐07‐08<br />
Castañeda, C<br />
P5‐10‐11<br />
Castañon, E<br />
P5‐16‐03<br />
Castellano, DE<br />
P5‐10‐11<br />
Castiel, M<br />
P2‐12‐05<br />
Castillo, A<br />
P5‐16‐03<br />
Castro, C<br />
P3‐02‐08<br />
Catanzaro, J<br />
P5‐04‐09<br />
Catton, PA<br />
P6‐09‐01<br />
Caudle, AS<br />
P4‐15‐02<br />
Caudrelier, J‐M<br />
P4‐16‐06<br />
Cauley, JA<br />
PD03‐09<br />
Cavallin, F<br />
P3‐04‐04<br />
Cavedon, C<br />
P4‐16‐08<br />
Caveriviere, P<br />
P3‐05‐07<br />
Cavicchioli, F<br />
P4‐06‐10<br />
Cawthorn, S<br />
P4‐17‐03<br />
Cayre, A<br />
P2‐08‐04, P3‐06‐20<br />
Cazzaniga, M PD03‐01, PD06‐06<br />
Ceban, T<br />
P1‐14‐21<br />
Cermignani, L<br />
P3‐07‐13<br />
Cerussi, A<br />
P4‐02‐04<br />
Cesano, A<br />
P6‐07‐31<br />
Ceugnart, L<br />
P4‐14‐10<br />
Chacón, JI P1‐07‐18, P2‐01‐06<br />
Chadha, M P3‐08‐08, P4‐15‐03<br />
Chae, BJ<br />
P2‐05‐02, P4‐03‐01<br />
Chaffanet, M<br />
P5‐03‐01<br />
Chagpar, A<br />
P2‐11‐08<br />
Chagpar, AB<br />
PD04‐04,<br />
P3‐14‐05, P3‐14‐06<br />
Chaigneau, L<br />
P5‐18‐22<br />
Chaim, J<br />
P5‐20‐07<br />
Chaker, M<br />
P1‐15‐08<br />
Chakravarthy, AB<br />
P4‐01‐03<br />
Chakravarty, D<br />
P1‐05‐10<br />
Chalabi, N<br />
P3‐06‐20<br />
Chalchal, H<br />
P1‐13‐01<br />
Chaluvally‐Raghavan, P P5‐10‐03<br />
Chambers, A<br />
P1‐14‐13<br />
Chambers, M<br />
P2‐14‐05<br />
Chamness, G<br />
P6‐10‐03<br />
Chamness, GC S5‐8<br />
Champeny, TL<br />
P2‐11‐15<br />
Chan, A<br />
OT2‐3‐03<br />
Chan, E<br />
P5‐06‐02<br />
Chan, EK<br />
PD04‐02, P4‐16‐01<br />
Chan, HY<br />
P5‐11‐01<br />
www.aacrjournals.org 589s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Chan, K<br />
P6‐06‐06<br />
Chan, M<br />
P3‐08‐09<br />
Chan, SYT P6‐07‐09, P6‐07‐18<br />
Chandarlapaty, S PD04‐05, P4‐08‐02,<br />
P5‐18‐04, P5‐18‐20<br />
Chander, J<br />
P4‐02‐02<br />
Chandiramani, N<br />
P2‐04‐06<br />
Chandler, JC<br />
P6‐11‐10<br />
Chandran, UR<br />
P6‐04‐20<br />
Chang, B<br />
P1‐05‐21<br />
Chang, C‐P<br />
P6‐05‐15<br />
Chang, EY<br />
P4‐03‐01<br />
Chang, J<br />
P4‐03‐11<br />
Chang, JC<br />
S5‐8, P2‐10‐06,<br />
P3‐06‐14, P5‐03‐03, P5‐03‐12,<br />
P6‐07‐11, P6‐11‐12, OT3‐3‐01<br />
Chang, K<br />
P2‐12‐05<br />
Chang, K‐C<br />
P6‐11‐05<br />
Chang, K‐J P3‐06‐02, P4‐03‐02<br />
Chang, M<br />
PD10‐03<br />
Chang, MC<br />
PD03‐02,<br />
PD03‐05, P2‐10‐09<br />
Chang, P‐Y<br />
P4‐04‐07<br />
Chang, Y‐F P5‐10‐14, P5‐10‐16<br />
Chanock, SJ<br />
P3‐08‐02<br />
Chao, C<br />
P5‐15‐06<br />
Chao, J<br />
P2‐14‐08<br />
Chao, KC<br />
PD09‐09<br />
Chao, T‐C<br />
P3‐12‐10<br />
Chao, T‐Y<br />
P4‐04‐07<br />
Chaplain, MAJ P1‐05‐14, P5‐05‐02,<br />
P5‐05‐05, P5‐05‐06<br />
Chapman, J<br />
P1‐13‐01<br />
Chapman, J‐AW P1‐07‐13, P2‐13‐02<br />
Charaffe‐Jauffret, E P3‐12‐11,<br />
P5‐03‐01, OT2‐3‐05<br />
Charitansky, H<br />
P1‐01‐21<br />
Charon‐Barra, C<br />
P3‐08‐07<br />
Chateau‐Joubert, S<br />
P6‐04‐14<br />
Chatterjee, N<br />
P3‐10‐02<br />
Chatterton, RT P1‐09‐07, P2‐10‐30,<br />
P3‐04‐08, P4‐12‐04<br />
Chau, WW<br />
P3‐11‐02<br />
Chaudhary, S<br />
P1‐05‐13<br />
Chauhan, L S3‐7<br />
Chauvet, M‐P P4‐14‐10, P5‐21‐01<br />
Chaves Benito, A<br />
P3‐06‐15<br />
Chavez Mac Gregor, M P5‐20‐02<br />
Chavez‐Mac Gregor, M OT2‐2‐04<br />
Chavrier, P<br />
P5‐01‐04<br />
Chayanam, S PD01‐01, P4‐06‐02<br />
Cheang, MCU P4‐16‐02, P6‐07‐10<br />
Chebil, G<br />
P2‐10‐28, P2‐10‐36<br />
Cheema, K<br />
PD04‐06<br />
Chehayeb Makarem, D P2‐12‐01<br />
Che‐Lehman, J<br />
P1‐14‐18<br />
Chemaly, RF<br />
P4‐15‐02<br />
Chen, A<br />
P4‐03‐02, P4‐13‐05<br />
Chen, AC<br />
P6‐07‐11<br />
Chen, AP<br />
PD09‐06<br />
Chen, B S5‐4<br />
Chen, CM P3‐01‐05, P6‐04‐26<br />
Chen, C‐M<br />
P4‐16‐05<br />
Chen, C‐N<br />
P4‐03‐02<br />
Chen, E<br />
P5‐04‐09<br />
Chen, H<br />
P1‐05‐21, P1‐07‐06,<br />
P4‐07‐05, P6‐07‐25<br />
Chen, J P3‐06‐10, P3‐12‐12, P3‐12‐12<br />
Chen, JJ<br />
P4‐16‐12<br />
Chen, K<br />
P1‐01‐09<br />
Chen, KB<br />
P2‐11‐15<br />
Chen, K‐F<br />
P6‐11‐05<br />
Chen, KM<br />
P2‐09‐04<br />
Chen, L<br />
P2‐10‐26<br />
Chen, PY<br />
P4‐16‐03<br />
Chen, S P2‐14‐08, P6‐04‐11, P6‐07‐36<br />
Chen, S‐C<br />
OT1‐1‐16<br />
Chen, Y<br />
P1‐05‐09, P2‐05‐21,<br />
P3‐04‐06, P3‐09‐03, P5‐01‐07<br />
Chen, Z<br />
P5‐05‐01<br />
Chen, Z‐H P2‐05‐05, P4‐09‐09<br />
Chenevix‐Trench, G P6‐10‐06<br />
Cheng, A‐L P3‐06‐02, P6‐05‐15<br />
Cheng, H S5‐4<br />
Cheng, H‐CS<br />
P4‐16‐05<br />
Cherbavaz, DB S1‐10<br />
Chereau, E P1‐01‐14, P4‐14‐12<br />
Chernyukhin, N<br />
P5‐18‐06<br />
Cheung, KJ<br />
P1‐05‐02<br />
Chew, SA<br />
P6‐10‐03<br />
Chi, D<br />
PD01‐08<br />
Chia, S<br />
P2‐14‐01, P4‐16‐02,<br />
P4‐16‐04, P6‐11‐06<br />
Chia, V<br />
P1‐15‐01<br />
Chia, YL<br />
P3‐06‐31<br />
Chiarelli, AM<br />
P3‐02‐10<br />
Chiba, A<br />
P1‐01‐20<br />
Chien, R<br />
P5‐15‐06<br />
Chiesi, A<br />
P6‐11‐01<br />
Chilcott‐Burns, S<br />
P3‐08‐04<br />
Childs, J<br />
P2‐15‐02, P5‐16‐04<br />
Childs, JS<br />
OT3‐1‐02<br />
Chin, S‐F<br />
P3‐08‐05<br />
Chinchar, E<br />
P4‐06‐04<br />
Chirwa, T P1‐14‐14, P5‐20‐10<br />
Chitale, D<br />
P2‐09‐04<br />
Chiu, J‐H<br />
P3‐12‐10<br />
Chlebowski, R<br />
PD03‐09<br />
Cho, EY<br />
P2‐05‐20<br />
Cho, H<br />
P1‐15‐11<br />
Cho, JH<br />
P1‐01‐23, P2‐05‐03<br />
Cho, JY<br />
P3‐01‐02<br />
Cho, S‐H<br />
PD02‐06<br />
Choi, DS<br />
P5‐03‐03<br />
Choi, HH<br />
P1‐01‐24<br />
Choi, JE<br />
P5‐04‐07<br />
Choi, J‐E<br />
P1‐01‐05, P3‐03‐02<br />
Choi, M P1‐03‐02, P4‐14‐03, P4‐17‐07<br />
Choi, MR<br />
P1‐15‐01<br />
Choi, M‐Y<br />
P3‐11‐01<br />
Choi, Y<br />
P5‐04‐03<br />
Choi, Y‐L<br />
P2‐05‐02<br />
Chollet, P<br />
P3‐06‐20<br />
Choo, E<br />
PD04‐03<br />
Choridah, L<br />
P3‐01‐08<br />
Chow, C<br />
P3‐05‐05<br />
Chow, LWC P1‐14‐02, P2‐05‐16<br />
Chow, W<br />
P2‐14‐08<br />
Choy, NS<br />
P4‐09‐12<br />
Christaki, G P1‐01‐10, P1‐01‐11<br />
Christensen, AG<br />
P3‐04‐05<br />
Christensen, I<br />
P3‐06‐32<br />
Christensen, S<br />
P6‐07‐08<br />
Christgen, M<br />
P2‐10‐08<br />
Christiaens, M‐R P2‐10‐12, P6‐05‐05,<br />
P6‐07‐04, P6‐07‐19,<br />
P6‐07‐29, OT2‐2‐02<br />
Christiansen, J PD02‐01, PD06‐03<br />
Christianson, D<br />
P5‐20‐08<br />
Christie, A<br />
P1‐07‐04<br />
Christiny, PI<br />
P4‐06‐02<br />
Christman, LA<br />
P1‐01‐04<br />
Christopherson, C<br />
PD10‐03<br />
Christophylakis, C<br />
P1‐13‐09<br />
Chu, BC<br />
P2‐14‐07, P5‐20‐12<br />
Chu, E<br />
PD09‐06<br />
Chu, K P4‐06‐03, P5‐04‐05, P6‐10‐04<br />
Chu, N‐M<br />
P4‐16‐05<br />
Chu, P‐Y<br />
P6‐11‐05<br />
Chuang, E P1‐15‐07, P6‐11‐04<br />
Chuang, S‐C<br />
P4‐03‐02<br />
Chumsri, S<br />
P2‐13‐05<br />
Chun, J<br />
P1‐09‐03, P4‐01‐07<br />
Chung, C<br />
P2‐14‐08<br />
Chung, E<br />
P3‐12‐03<br />
Chung, F<br />
P6‐06‐06<br />
Chung, J<br />
P3‐07‐05<br />
Chung, JWL<br />
P3‐08‐06<br />
Chung, MS<br />
P2‐10‐39<br />
Church, TD<br />
P4‐01‐11<br />
Chyla, B<br />
OT2‐3‐07<br />
Cianni, R<br />
P1‐01‐25<br />
Ciciliano, JC<br />
P2‐01‐14<br />
Cigler, T<br />
P1‐15‐07,<br />
P6‐10‐01, P6‐11‐04<br />
Cimino‐Mathews, A P6‐07‐33<br />
Cimprich, B S6‐3<br />
Cinar‐Akakin, H<br />
P2‐11‐07<br />
Ciocca, RM<br />
P4‐09‐12<br />
Ciruelos, E P5‐18‐26, OT1‐1‐02,<br />
OT2‐3‐06, OT3‐3‐05<br />
Ciruelos, EM<br />
P5‐10‐11<br />
Citron, D<br />
P6‐10‐01<br />
Citron, ML<br />
P2‐10‐01<br />
Cittadine, AJ<br />
OT2‐1‐04<br />
Clague, J<br />
PD08‐06<br />
Clancy, R<br />
P1‐05‐09<br />
Clare, SE<br />
PD05‐06, P1‐03‐02<br />
Clarissa, A<br />
P3‐01‐03<br />
Clark, AS<br />
P3‐06‐10<br />
Clark, E S5‐1, P5‐18‐01, P5‐18‐26<br />
Clark, J<br />
P3‐04‐04<br />
Clark, L<br />
P4‐11‐04<br />
Clark, LS<br />
PD10‐07<br />
Clarke, C<br />
P3‐04‐12<br />
Classe, J‐M P1‐01‐21, OT2‐1‐01<br />
Clatot, F<br />
P1‐15‐08<br />
Cleator, S<br />
P3‐02‐04<br />
Clemens, M<br />
P2‐10‐08<br />
Clemente, G<br />
P3‐12‐08<br />
Clemons, M P2‐05‐12, P2‐05‐13,<br />
P2‐13‐02, P5‐13‐01<br />
Clemons, MJ<br />
P1‐15‐06,<br />
P3‐13‐05, P4‐16‐06<br />
Clifton, GT P5‐16‐02, P5‐16‐05<br />
Clisant, S<br />
P2‐13‐10<br />
Clough, KB<br />
P6‐07‐03<br />
Clynes, M<br />
P3‐04‐12<br />
Coarfa, C<br />
P6‐05‐12<br />
Coates, AS S1‐1<br />
Cobham, MV P1‐15‐07, P6‐11‐04<br />
Cobleigh, M<br />
P5‐18‐24<br />
Cobleigh, MA<br />
OT1‐2‐01<br />
Coburn, TL<br />
P6‐14‐04<br />
Cochrane, DR<br />
P2‐14‐02,<br />
P5‐10‐04, P5‐10‐06<br />
Codes, M<br />
P1‐07‐18, P2‐01‐06<br />
Cohen, EN P2‐03‐01, P2‐10‐32,<br />
P5‐04‐06, P5‐10‐02<br />
Cohen, HJ<br />
P6‐08‐05<br />
Cohen, J<br />
P6‐08‐06<br />
Cohen, P<br />
P1‐09‐04<br />
Colavito, S<br />
P3‐14‐01<br />
Colcher, D<br />
P2‐05‐10<br />
Coleman, R<br />
S3‐3, PD07‐09<br />
Coleman, RE<br />
S6‐4, P1‐13‐03,<br />
P2‐02‐04, OT2‐3‐03<br />
Collea, R<br />
P3‐06‐12<br />
Colleoni, M S1‐1<br />
Collin, B<br />
P4‐02‐06<br />
Collins, B<br />
P2‐11‐10<br />
Collins, IM<br />
P4‐13‐10<br />
Collins, J<br />
P5‐05‐04<br />
Collins, L<br />
P5‐01‐03<br />
Collins, R<br />
P1‐07‐04<br />
Colom, B<br />
P3‐12‐08<br />
Colon‐Otero, G S5‐5<br />
Come, S<br />
PD09‐03,<br />
P1‐07‐07, P2‐16‐04<br />
Comen, E<br />
P5‐18‐20<br />
Comstock, C<br />
OT3‐1‐01<br />
Conant, E<br />
P4‐01‐08<br />
Concannon, KF<br />
P2‐01‐14<br />
Condeelis, J<br />
P2‐10‐29<br />
Condeelis, JS<br />
P6‐02‐04<br />
Conklin, D<br />
P4‐08‐01<br />
Connolly, EM<br />
P6‐01‐02<br />
Connolly, EP PD09‐09, P5‐03‐02<br />
Connolly, J<br />
PD04‐04<br />
Connolly, RM P6‐07‐33, OT1‐1‐11<br />
Connor, CS<br />
PD09‐02<br />
Conte, P<br />
P2‐10‐16, P5‐18‐24<br />
Conter, D<br />
P5‐15‐02<br />
Conter, HJ<br />
P5‐15‐02<br />
Conti, P<br />
P2‐05‐10<br />
Contreras, A<br />
P2‐16‐02<br />
Cook, J<br />
P2‐10‐16<br />
Cook, RS<br />
P5‐19‐01, P6‐02‐01<br />
Coolen, A<br />
P2‐10‐29<br />
Coombes, CR<br />
P6‐04‐15<br />
Coombes, G PD07‐07, P2‐14‐01<br />
Coombes, RC P1‐04‐04, P2‐10‐22,<br />
P3‐06‐13, P4‐06‐12, P6‐04‐16<br />
Cooney, RV<br />
P4‐12‐02<br />
Cope, FO<br />
P1‐01‐04<br />
Cope, J<br />
P2‐14‐06<br />
Coppé, J‐P<br />
P5‐05‐01<br />
Cordingley, H<br />
P4‐06‐12<br />
Corica, T S4‐2<br />
Corless, CL<br />
P2‐08‐03<br />
Cornelius, C<br />
P4‐06‐06<br />
Cornell, JE<br />
P1‐05‐18<br />
Cornfeld, D<br />
P4‐01‐02<br />
Correa, RS P3‐01‐07, P3‐02‐13<br />
Cortazar, P S1‐11<br />
Cortes S6‐6<br />
Cortes, J S5‐1, P1‐07‐19, P5‐18‐26,<br />
P6‐11‐14, P6‐13‐03,<br />
OT2‐2‐03, OT2‐3‐09, OT3‐3‐06<br />
Cortés‐Funes, H P5‐10‐11, OT3‐3‐05<br />
Cortez, V<br />
P6‐04‐07<br />
Corwin, A P3‐05‐05, P3‐05‐06<br />
Cory, S<br />
P6‐02‐03<br />
Cosquer, M<br />
P4‐13‐14<br />
Costa, CRA<br />
P3‐11‐04<br />
Costa, L<br />
P3‐06‐33<br />
Costa, S‐D<br />
S3‐1, P1‐14‐01,<br />
OT1‐1‐13, OT3‐3‐11<br />
Costantino, J S1‐11<br />
Costantino, JP S1‐10<br />
Costes, S<br />
P1‐05‐08<br />
Cote, M<br />
PD03‐09<br />
Cottam, B<br />
P4‐04‐02<br />
Cottu, P<br />
PD05‐08, OT3‐3‐10<br />
Cottu, PH P2‐01‐13, P6‐04‐14<br />
Cottu, P‐H<br />
P5‐21‐03<br />
Coudert, B P1‐13‐04, P3‐08‐07<br />
Coupe, V<br />
PD04‐01<br />
Coupland, B<br />
P3‐08‐04<br />
Coussy, F<br />
P4‐13‐03<br />
Coutant, C P1‐01‐07, P1‐01‐14<br />
Couturaud, B<br />
P1‐01‐19<br />
Coveler, A<br />
P5‐16‐04<br />
Covington, K<br />
P4‐08‐09<br />
Cowens, JW<br />
P2‐10‐02<br />
Cox, C<br />
OT3‐4‐02<br />
Cox, D P1‐12‐02, P1‐13‐11, P5‐20‐04<br />
Cox, MB<br />
P5‐07‐02<br />
Cradock, KA<br />
OT2‐1‐04<br />
Crain, B<br />
P2‐06‐01<br />
Crawford, B<br />
P4‐13‐13<br />
Crawford, J<br />
P1‐15‐04<br />
Crawley, FL<br />
P1‐15‐06<br />
Creighton, C<br />
P4‐06‐02<br />
Creighton, CJ<br />
PD01‐01<br />
Crespo, C S1‐7, P1‐07‐18, P2‐01‐06,<br />
P2‐10‐11<br />
Crew, K<br />
P4‐02‐07<br />
Crew, KD PD03‐03, P1‐09‐02,<br />
P2‐11‐03, P2‐12‐01, P6‐12‐03<br />
Cristofanilli, M PD05‐01, PD05‐03,<br />
P2‐01‐01, P2‐03‐01, P2‐10‐32,<br />
P3‐05‐01, P3‐10‐03, P4‐06‐03,<br />
P5‐04‐05, P5‐10‐02, P6‐02‐05,<br />
P6‐10‐04, OT2‐3‐01<br />
Crittenden, MR<br />
P4‐04‐02<br />
Crivello, ML<br />
P1‐01‐16<br />
Croce, MV<br />
P3‐07‐13<br />
Crockett, M<br />
P3‐06‐12<br />
Croley, JJ<br />
P2‐14‐05<br />
Cromer, J<br />
OT1‐1‐14<br />
Cronin, M<br />
PD02‐07<br />
Cronin, MT S3‐6<br />
Crook, TR<br />
P4‐06‐10<br />
Cropet, C<br />
P3‐12‐01<br />
Croucher, PI<br />
PD07‐08<br />
Crow, J<br />
P1‐01‐06<br />
Crow, JR<br />
P1‐07‐09<br />
Crowley, E<br />
P6‐10‐01<br />
Crown, J<br />
P3‐04‐12<br />
Crown, JP S1‐6, P4‐09‐06, OT1‐1‐06<br />
Crozier, C S1‐5<br />
Cruz, M<br />
P4‐02‐03<br />
Csajka, C<br />
P6‐04‐05<br />
Cuenca, D P4‐06‐17, P6‐05‐04<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
590s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
Author Index<br />
Cui, H<br />
P3‐10‐07<br />
Cui, M<br />
P2‐05‐19<br />
Cukierman, E<br />
P6‐02‐05<br />
Culakova, E P1‐15‐04, P3‐06‐07<br />
Cung, Q<br />
P6‐01‐05<br />
Cunliffe, HE<br />
P1‐05‐04<br />
Cuorvo, LV<br />
P5‐01‐10<br />
Cupelo, EC<br />
P3‐12‐02<br />
Curcio, L<br />
P1‐15‐09<br />
Cure, H<br />
OT2‐3‐05<br />
Curley, C<br />
P6‐08‐03<br />
Custer, JL<br />
P2‐11‐15<br />
Cuvier, C<br />
P4‐13‐03<br />
Cuzick, J<br />
S1‐9, PD04‐08,<br />
P1‐09‐05, P2‐10‐15<br />
Czaplicki, KL<br />
P1‐12‐04<br />
Czene, K<br />
P2‐11‐06, P3‐07‐03<br />
Daasner, EJ<br />
P3‐10‐08<br />
Dabakuyo, S<br />
P3‐08‐07<br />
Dabbas, B PD02‐01, PD06‐03<br />
Dabbs, DJ P6‐04‐20, P6‐07‐02<br />
Dafni, U<br />
P5‐18‐02<br />
D’Agostino, Jr., R<br />
P2‐12‐11<br />
Dahl, M‐L<br />
PD10‐09<br />
Dahmane, E<br />
P6‐04‐05<br />
Dai, M‐S<br />
P4‐04‐07<br />
Dai, Y<br />
P2‐06‐01<br />
Dakir, DF<br />
P3‐01‐03<br />
Dale, DC<br />
P1‐15‐04<br />
Dale, R<br />
P4‐16‐09<br />
Dalenc, F<br />
P3‐12‐01, P5‐21‐01<br />
Daley, F<br />
P3‐06‐09<br />
D’Alfonso, TM<br />
P6‐02‐04<br />
Dall, B<br />
P4‐01‐14<br />
Dall, P<br />
P5‐21‐02<br />
Dallal, CM<br />
P3‐07‐04<br />
Dall’Oglio, S<br />
P4‐16‐08<br />
Daltoé, RD P5‐01‐15, P6‐11‐13<br />
Dalvi, T<br />
P3‐07‐08<br />
Daly, M<br />
P6‐08‐01<br />
D’Amato, NC P2‐14‐02, P5‐10‐06<br />
Danaei, M<br />
P1‐07‐16<br />
D’Andrea, G<br />
P5‐18‐20<br />
D’Andrea, S<br />
P5‐10‐17<br />
Dane, F<br />
OT1‐1‐08<br />
Danesi, R<br />
P5‐17‐06<br />
Dang, C P5‐17‐01, P5‐18‐20, P5‐20‐07<br />
Dang, Y<br />
P5‐16‐04<br />
Daniel, B<br />
P5‐20‐10<br />
Daniel, BL P4‐01‐06, P4‐01‐12<br />
Daniel, C<br />
P5‐17‐04<br />
Danso, MA<br />
OT1‐1‐07<br />
Dao, TH<br />
P4‐16‐10<br />
Darai, E<br />
P4‐14‐12<br />
Darb‐Esfahani, S<br />
P3‐06‐05<br />
Darer, J<br />
P4‐13‐12<br />
Darga, DA<br />
OT2‐1‐04<br />
Darimont, B<br />
P6‐04‐12<br />
Darnay, BG<br />
P5‐03‐09<br />
Darr, DB<br />
P6‐02‐09<br />
Darwish, T<br />
OT1‐1‐08<br />
Das, H<br />
P2‐11‐07<br />
Das, M<br />
P2‐11‐07<br />
Das Gupta, S S3‐7<br />
Dasgupta, N<br />
P2‐04‐02<br />
Datko, F<br />
P5‐18‐20<br />
Datko, FM P2‐08‐01, P6‐05‐01<br />
Datto, M<br />
P2‐10‐03<br />
Datto, MB<br />
P4‐09‐01<br />
Dauplat, M‐M<br />
P3‐06‐20<br />
Dave, B<br />
P5‐03‐12, P6‐02‐07<br />
David, AK<br />
OT1‐1‐07<br />
David, MA<br />
P6‐04‐03<br />
Davidson, C<br />
P6‐07‐24<br />
Davidson, D<br />
P3‐06‐28<br />
Davidson, N S5‐5<br />
Davidson, NE S5‐4<br />
Davies, C S1‐2<br />
Davies, S<br />
P3‐06‐09, P6‐07‐10<br />
Davies, SR<br />
P2‐10‐01<br />
Davis, EM<br />
P1‐05‐16<br />
Davis, S<br />
P2‐05‐01, P5‐20‐05<br />
Davis, TA<br />
P6‐10‐01<br />
Dawood, S<br />
P6‐07‐25<br />
Dayao, Z<br />
PD07‐01, P3‐03‐01<br />
De, G<br />
P5‐15‐05<br />
De, P<br />
P5‐19‐03, P6‐04‐11<br />
de Azambuja, E S5‐2, P5‐18‐02<br />
De Benedictis, E<br />
P2‐12‐08<br />
De Blaye, P<br />
P1‐01‐21<br />
De Brot, M<br />
PD04‐05,<br />
PD05‐02, P1‐06‐03<br />
De Buck, S<br />
P6‐10‐07<br />
De Carli, NL<br />
P5‐01‐10<br />
De Cecco, L<br />
P4‐06‐09<br />
de Cock, E<br />
P5‐15‐07<br />
de Cremoux, P P1‐14‐03, P2‐01‐04<br />
De Felice, V<br />
P4‐15‐04<br />
de Graaf, H<br />
P1‐12‐05<br />
de Grève, J<br />
P6‐09‐07<br />
de Groot, SM<br />
P1‐12‐05<br />
de Jongh, FE<br />
P1‐12‐05<br />
De Juán, A P1‐07‐18, P2‐01‐06<br />
de Koning, HJ<br />
P3‐02‐09<br />
De la Haba, JR S1‐7<br />
de la Peña, L<br />
OT3‐3‐06<br />
De la Piedra, C P1‐07‐18, P2‐01‐06<br />
De la Torre, R<br />
P1‐12‐04<br />
De Laere, B<br />
P2‐01‐09<br />
de Laurentiis, M<br />
OT2‐3‐09<br />
De Los <strong>San</strong>tos, J<br />
P3‐03‐03<br />
De Los <strong>San</strong>tos, JF P5‐17‐07, P6‐07‐37<br />
De Masi, C<br />
P1‐01‐25<br />
De Mattos, L<br />
P6‐13‐03<br />
De Mattos Aruda, L<br />
P5‐10‐01<br />
De Mukhopadhyay, K P1‐05‐18<br />
De Nicolo, A<br />
P4‐10‐01<br />
de Roos, MA<br />
P4‐11‐01<br />
de Roquancourt, A<br />
P4‐13‐03<br />
De Rycke, Y<br />
P1‐01‐07<br />
de Silvio, M<br />
P5‐18‐21<br />
de Snoo, F P2‐10‐42, P3‐05‐01,<br />
P3‐05‐02, P3‐06‐11, OT3‐4‐03<br />
de Velasco, GA<br />
P5‐10‐11<br />
de Vries, B P1‐14‐07, P5‐01‐13<br />
de Wilt, HHW OT2‐1‐02, OT2‐1‐03<br />
Deakin, NE<br />
P5‐05‐05<br />
Dean, M<br />
P4‐09‐07<br />
Deas, O<br />
P3‐06‐24<br />
Debeb, B<br />
PD03‐06<br />
Debeb, BG P5‐03‐05, P5‐03‐10<br />
Deblay, P<br />
OT2‐1‐01<br />
Debled, M<br />
PD05‐04<br />
Debska, S<br />
P2‐10‐31,<br />
P3‐12‐09, P3‐13‐03<br />
Decaudin, D<br />
P6‐04‐14<br />
DeCensi, A PD03‐01, PD06‐06<br />
Decker, T PD06‐04, PD06‐05,<br />
P2‐01‐02, P5‐01‐12<br />
Decloedt, J<br />
OT2‐2‐02<br />
Decoster, L<br />
P6‐09‐07<br />
Decosterd, L<br />
P6‐04‐05<br />
Dedeurwaerder, S S6‐2<br />
Dees, EC<br />
PD10‐07, P6‐11‐06<br />
Defrance, M S6‐2<br />
DeFreese, DC<br />
P4‐12‐05<br />
Degnim, AC P4‐12‐03, P5‐01‐08,<br />
P6‐06‐01<br />
Del Castillo, A<br />
PD04‐07<br />
Del Re, I<br />
P5‐17‐06<br />
Del Re, M<br />
P5‐17‐06<br />
Delabaye, I<br />
P3‐13‐01<br />
Delaloge, S P1‐14‐03, P1‐14‐18,<br />
P2‐01‐04, P2‐01‐13, P3‐06‐04,<br />
P4‐09‐05, P4‐12‐01, P5‐13‐02,<br />
OT3‐3‐04, OT3‐4‐05<br />
Delamelena, T<br />
P4‐11‐04<br />
Delattre, O<br />
PD05‐08<br />
Delbeuck, X<br />
P2‐13‐10<br />
Delecroix, V<br />
OT3‐3‐04<br />
DeLeo, III, MJ<br />
P4‐01‐08<br />
Delforge, M<br />
P3‐13‐01<br />
Delgado Sánchez, JJ P1‐01‐29<br />
Dell’Orto, P<br />
PD03‐01,<br />
P3‐05‐02, P6‐07‐14<br />
Delrée, P<br />
P3‐04‐04, P3‐05‐07<br />
Delva, R<br />
P1‐13‐04, P1‐14‐21<br />
Demanse, D<br />
P6‐10‐07<br />
DeMichele, A<br />
P3‐06‐10,<br />
P4‐13‐01, P6‐10‐02<br />
Demichelis, SO<br />
P3‐07‐13<br />
Denat, F<br />
P4‐02‐06<br />
Dendale, R<br />
P5‐21‐03<br />
Denduluri, N PD10‐08, P2‐11‐16,<br />
P4‐11‐04, OT2‐2‐03<br />
Deneuve, J<br />
P5‐13‐02<br />
Deng, G<br />
PD03‐04<br />
Denkert, C S3‐1, S4‐5, PD06‐01,<br />
P1‐14‐01, P3‐06‐05,<br />
OT1‐1‐13, OT3‐3‐11<br />
Dennison, JB<br />
P3‐06‐06<br />
Dent, R S6‐5, P2‐12‐03, P3‐06‐34<br />
Dent, S P3‐04‐11, P3‐11‐03, P3‐13‐05<br />
Dent, SF<br />
P1‐15‐06<br />
Deonarain, M<br />
P4‐06‐12<br />
Deray, G<br />
P5‐17‐04<br />
Dercksen, MW P5‐21‐04, P6‐07‐32<br />
Dercksen, W<br />
PD07‐06<br />
Desai, P<br />
PD03‐09<br />
DeSchryver, K P2‐10‐01, P6‐07‐10<br />
Deshpande, VS<br />
P4‐01‐10<br />
DeSilvio, M<br />
OT1‐1‐07<br />
Desmedt, C S4‐4, S6‐2, P3‐04‐10,<br />
P3‐05‐03, P6‐07‐14, P6‐07‐22<br />
Desrichard, A<br />
P3‐06‐20<br />
Dessen, P<br />
P4‐09‐05<br />
Detour, V<br />
P3‐04‐10<br />
Detre, S<br />
PD07‐07<br />
Deurloo, RJ<br />
P3‐06‐34<br />
DeVries, C<br />
P2‐11‐04<br />
Dewar, J<br />
S4‐1, PD03‐02<br />
Dewar, JA<br />
S4‐2, P5‐18‐05<br />
Dey, N<br />
P5‐19‐03, P6‐04‐11<br />
Deyarmin, B P3‐04‐07, P6‐02‐08<br />
Dezentjé, V<br />
OT2‐2‐02<br />
Dhakal, I<br />
P3‐06‐30<br />
Dharan, B<br />
OT2‐3‐08<br />
Dhuria, S<br />
P6‐11‐06<br />
Di, GH<br />
P3‐01‐05<br />
Di Cosimo, S<br />
OT3‐3‐06<br />
Di Legge, P<br />
P1‐01‐25<br />
Di Leo, A S1‐4, P5‐10‐01, OT2‐3‐08<br />
Di Pasquale, MC<br />
P5‐01‐10<br />
Di Tomaso, E<br />
P4‐08‐01<br />
di Tomaso, E<br />
P6‐11‐08<br />
Di Tomaso, E OT2‐3‐08, OT2‐3‐09<br />
Diab, A<br />
OT3‐1‐01<br />
Diamandis, EP P2‐05‐11, P6‐05‐09<br />
Diamond, JR<br />
P4‐04‐06<br />
Diana, C<br />
P4‐16‐10<br />
Diaz, L<br />
P4‐06‐19, P6‐04‐29<br />
Diaz‐Padilla, I<br />
P2‐10‐23<br />
Dickinson, M<br />
P4‐02‐08<br />
Dickler, M<br />
P2‐12‐05,<br />
P5‐18‐20, OT2‐3‐11<br />
Dickson, N<br />
P5‐17‐05<br />
Diederich, C<br />
P6‐13‐01<br />
Diener, M<br />
P5‐15‐05<br />
Dienstmann, R<br />
P6‐11‐06<br />
Diéras, V P2‐01‐13, P3‐12‐01,<br />
P5‐01‐04, P5‐18‐06<br />
Dietze, O S4‐3<br />
Dieudonné, A‐S<br />
OT2‐2‐02<br />
Dignan, M<br />
P5‐14‐05<br />
Dillenburg Pilla, P<br />
P1‐05‐23<br />
Dillon, P<br />
P3‐07‐11<br />
Dimitromanolakis, A P2‐05‐11,<br />
P6‐05‐09<br />
Dimitrova, N PD05‐05, P4‐01‐02<br />
Dimopoulos, N PD04‐06, P3‐14‐04<br />
Dinesh, A<br />
P4‐02‐02<br />
Ding, J<br />
P6‐04‐26<br />
Ding, L S5‐6<br />
Dinh, P<br />
P1‐07‐08<br />
Dinniwell, R<br />
P4‐16‐14<br />
DiPaola, J<br />
P2‐10‐05<br />
DiPiro, P<br />
P5‐02‐01<br />
DiRamio, A<br />
P2‐10‐05<br />
Dirix, L<br />
S1‐5, P5‐18‐19<br />
Dirix, LY P2‐01‐08, P2‐01‐09,<br />
P3‐10‐04, P3‐10‐08<br />
Disalvatore, L<br />
PD04‐07<br />
Disis, ML<br />
P2‐15‐02,<br />
P5‐16‐04, OT3‐1‐02<br />
Dissanayake, D<br />
P6‐09‐01<br />
Ditsch, N S1‐11<br />
Ditzel, H S4‐4<br />
Ditzel, HJ P3‐04‐05, P4‐09‐04<br />
Diver, J<br />
PD06‐03<br />
Divine, G<br />
P2‐09‐04<br />
Dixon, JM P3‐06‐23, P6‐04‐06,<br />
P6‐04‐09, P6‐04‐10<br />
Djazouli, K<br />
P6‐07‐22<br />
Dnistrian, A<br />
P2‐12‐05<br />
Dobbs, J S4‐1<br />
Dobi, E<br />
P5‐18‐22<br />
Dobrolecki, L<br />
P5‐03‐03<br />
Dodd, A<br />
P6‐09‐02<br />
Dodwell, D<br />
P2‐14‐01<br />
Dogan, A<br />
PD02‐05<br />
Doihara, H P3‐07‐10, P5‐18‐16<br />
Doimi, F S3‐6<br />
Domanitskaya, N<br />
P4‐08‐04<br />
Domchek, S P4‐01‐08, OT2‐3‐07<br />
Domínguez‐González, C OT3‐3‐05<br />
Donders, G<br />
P2‐12‐06<br />
Done, S<br />
P2‐10‐34<br />
Done, SJ PD03‐02, PD03‐05, P2‐10‐33<br />
Dong, J<br />
P6‐04‐19<br />
Dong, Q<br />
P5‐03‐04, P5‐03‐06<br />
Dong, X<br />
P6‐02‐05<br />
Dong, Y<br />
P5‐03‐14<br />
Donohue, S<br />
P2‐11‐15<br />
Donovan, D P1‐15‐07, P6‐11‐04<br />
Doppler, H<br />
P1‐05‐24<br />
Dorca, J<br />
P4‐09‐10, P4‐09‐11<br />
Dorchak, J<br />
P3‐04‐06<br />
Dorchak, JA<br />
P1‐05‐09<br />
Doren, EL P4‐14‐09, P4‐17‐01<br />
Dorent, R<br />
P5‐17‐04<br />
Doridot, V<br />
P1‐01‐07<br />
dos <strong>San</strong>tos, I<br />
P3‐08‐04<br />
Doughty, J<br />
P4‐14‐13<br />
Douglas, M<br />
P6‐10‐07<br />
Douglas, Y<br />
P4‐07‐03<br />
Dowling, RJO PD03‐02, PD03‐05<br />
Dowsett, M<br />
S1‐9, S4‐6, S5‐2,<br />
PD01‐05, PD07‐07, P1‐09‐05,<br />
P1‐13‐03, P2‐10‐15, P2‐14‐01,<br />
P3‐08‐04, P5‐18‐02, OT2‐3‐02<br />
Dowton, AA<br />
P4‐01‐09<br />
Doxey, DK<br />
P1‐03‐02<br />
Doyen, C<br />
P3‐13‐01<br />
Dozynkiewicz, M<br />
P1‐05‐13<br />
Drabble, EH<br />
P4‐14‐05<br />
Drabovich, AP<br />
P6‐05‐09<br />
Drake, C S1‐5<br />
Dranitsaris, G<br />
P3‐13‐05<br />
Dreher, C<br />
P4‐11‐06<br />
Drews‐Elger, K<br />
P1‐05‐12<br />
Driessen, WH<br />
P3‐10‐09<br />
Drobish, A<br />
PD10‐07<br />
Drobniene, M<br />
P5‐02‐02<br />
Drosick, DR<br />
P5‐17‐05<br />
Drukker, CA P2‐10‐42, P3‐02‐01<br />
Drullinsky, P P5‐18‐04, P5‐18‐20<br />
Drummond, D<br />
P4‐02‐05<br />
D’Souza, R<br />
P4‐13‐02<br />
Du, Y<br />
P5‐10‐15<br />
du Bois, A S3‐4<br />
Duan, X<br />
PD10‐02<br />
Dubois, T<br />
P5‐02‐03<br />
Dubsky, P S4‐3, P2‐10‐02, P2‐13‐01<br />
Duchamp, O<br />
P4‐02‐06<br />
Duchnowska, R P2‐10‐31, P3‐12‐09,<br />
P3‐13‐03<br />
Duck, L<br />
P3‐13‐01<br />
Dueck, AC<br />
PD10‐04<br />
Duerkop, J<br />
OT3‐2‐01<br />
Dufour, CR<br />
P5‐18‐08<br />
DuHadaway, JB<br />
P4‐09‐12<br />
Dumas, I<br />
OT1‐2‐02<br />
Dunbier, AK<br />
P4‐06‐11<br />
Dunn, B<br />
P1‐09‐07<br />
Dunn, JA OT1‐1‐03, OT3‐3‐09<br />
Dunn, L<br />
P2‐12‐05<br />
www.aacrjournals.org 591s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Dünne, A<br />
OT1‐1‐02<br />
Dunne, M<br />
P4‐02‐05<br />
Dünnebacke, J<br />
P2‐11‐11<br />
Dupiot‐Chiron, J<br />
PD05‐04<br />
Dupont, EL<br />
P4‐14‐01<br />
Dupré, P‐F P1‐01‐21, OT2‐1‐01<br />
Durack, J<br />
OT3‐1‐01<br />
Duran, H<br />
P1‐14‐10, P5‐18‐15<br />
Duran, J<br />
P3‐12‐08<br />
Dutcus, CE S6‐6<br />
Duval, V<br />
P6‐11‐08<br />
Duvall‐Noelle, NL<br />
P1‐05‐01<br />
Dweck, CS<br />
P6‐08‐10<br />
Dwyer, RM<br />
P2‐05‐09<br />
Eap, C<br />
P6‐04‐05<br />
Earashi, M<br />
P4‐15‐05<br />
Earl, H<br />
S3‐3, P1‐13‐03<br />
Earl, HM<br />
P3‐08‐05,<br />
OT1‐1‐03, OT3‐3‐09<br />
Earle, C<br />
P5‐18‐14<br />
Earp, HS<br />
P6‐03‐01<br />
Earp, S<br />
P6‐02‐01<br />
Eary, JF<br />
P6‐04‐03<br />
Eaton, AA<br />
P3‐07‐09<br />
Eaton, CL<br />
PD07‐08<br />
Ebata, A<br />
P6‐05‐14<br />
Eberhardt, S<br />
P3‐03‐01<br />
Eberle, CE<br />
P2‐11‐05<br />
Eberly, LE<br />
P1‐14‐11<br />
Eccher, C<br />
P5‐01‐10<br />
Eccles, D<br />
P1‐09‐05<br />
Echarri, M<br />
OT3‐3‐05<br />
Echenique, M<br />
P5‐07‐06<br />
Eckel‐Passow, JE<br />
PD10‐04<br />
Eckhardt, BL<br />
P3‐10‐09<br />
Edel, M<br />
P1‐13‐04<br />
Edge, S<br />
P1‐01‐13<br />
Edge, SB<br />
P1‐13‐05<br />
Edgerton, SM P5‐10‐04, P5‐10‐05<br />
Edgren, G<br />
P3‐07‐03<br />
Edirimanne, S P1‐11‐01, P4‐12‐07<br />
Edwards, D<br />
P6‐05‐12<br />
Edwards, J<br />
P1‐05‐13<br />
Eeles, R<br />
P1‐09‐05, P4‐11‐05<br />
Egbeare, DM<br />
P5‐11‐01<br />
Eggemann, H<br />
OT2‐2‐05<br />
Egland, KA<br />
P1‐05‐16<br />
Egleston, B P1‐05‐03, P6‐08‐01<br />
Egleston, BL P1‐01‐16, P2‐01‐01<br />
Eglitis, J<br />
P5‐02‐02<br />
Ehmsen, S<br />
P3‐04‐05<br />
Ehsani, S<br />
P3‐02‐11<br />
Eichner, LJ<br />
P5‐18‐08<br />
Eickhoff, JC<br />
P6‐12‐02<br />
Eidt, S PD10‐06, P3‐06‐08, P3‐06‐19<br />
Eidtmann, H S1‐11, S3‐1, S4‐5,<br />
P1‐14‐01, OT1‐1‐13, OT3‐3‐11<br />
Eiermann, W<br />
S1‐11, S4‐2,<br />
S4‐5, PD06‐01,<br />
Einbeigi, Z<br />
P1‐05‐07<br />
Einhorn, H<br />
P2‐05‐06<br />
Eisen, A<br />
P2‐12‐03, P3‐02‐10<br />
Eisenberg, M<br />
P2‐10‐16<br />
Ejlertsen, B<br />
S1‐1, P3‐06‐03<br />
Eklund, M<br />
P3‐02‐12<br />
El Mamlouk, T<br />
P1‐05‐11<br />
El Sharouni, MA<br />
P4‐01‐17<br />
El‐Ashry, D P1‐05‐12, P5‐10‐08<br />
Eldad, Z<br />
P1‐04‐05<br />
Eldon, MA<br />
P3‐06‐31<br />
Eleftheraki, AG<br />
P1‐07‐15<br />
ElGhonaimy, EA<br />
P1‐05‐11<br />
Elias, A<br />
P6‐05‐10<br />
Elias, AD<br />
P2‐14‐02, P4‐04‐06<br />
Elias, SG<br />
P2‐10‐42, P4‐09‐02<br />
Eliasson, E<br />
PD10‐09<br />
Elkahloun, AG<br />
P1‐05‐18<br />
El‐Khayat, Y<br />
P5‐12‐03<br />
Elkhuizen, PHM<br />
P4‐02‐01<br />
Elling, D<br />
P1‐14‐05<br />
Elliott, C<br />
P2‐13‐02<br />
Ellis, C<br />
OT1‐1‐07<br />
Ellis, IO<br />
P2‐10‐22, P3‐06‐13,<br />
P6‐07‐09, P6‐07‐18<br />
Ellis, M<br />
P2‐04‐02, P6‐07‐10<br />
Ellis, MJ S5‐6, PD07‐01, P1‐08‐01,<br />
P2‐10‐01, P2‐13‐02<br />
Ellis, P<br />
S3‐3, P1‐13‐03,<br />
P2‐10‐29, P2‐14‐01<br />
Ellisen, LW<br />
PD09‐03<br />
Ellison, PT<br />
P3‐01‐01<br />
Ellsworth, RE PD02‐02, P3‐04‐07,<br />
P6‐02‐08<br />
El‐Shinawi, M<br />
P1‐05‐11<br />
Elsoueidi, R<br />
P5‐14‐05<br />
El‐Zein, R<br />
P3‐10‐01<br />
Emami, H<br />
P2‐12‐10<br />
Emerson, BM<br />
P2‐06‐05<br />
Emi, A<br />
P6‐07‐26<br />
Endo, Y<br />
P4‐12‐06<br />
Engelen, K<br />
P3‐05‐02<br />
Engelman, JA<br />
P3‐12‐03<br />
Eng‐Wong, J<br />
P1‐09‐04<br />
Ennis, M<br />
PD03‐05<br />
Enomoto, T<br />
P2‐12‐13<br />
Enrech, S<br />
OT3‐3‐05<br />
Epperson, A<br />
P5‐20‐08<br />
Erbstoesser, E<br />
S4‐5, PD06‐01<br />
Erickson, J<br />
P1‐07‐05<br />
Erickson, KD<br />
P2‐11‐09<br />
Eriksson, N<br />
OT3‐4‐04<br />
Erlander, MG S1‐9, P1‐07‐13, P2‐10‐15<br />
Ersahin, C PD10‐02, P2‐05‐15<br />
Escallon, JM<br />
PD03‐05<br />
Eschenburg, H<br />
P1‐15‐02<br />
Escourrou, G<br />
P3‐05‐07<br />
Eslick, GD P1‐11‐01, P4‐12‐07<br />
Esmail, F<br />
P4‐14‐14<br />
Espié, M S5‐3, P1‐14‐03, P4‐13‐03<br />
Espina, V<br />
P3‐04‐01, P3‐04‐02<br />
Espinós, J P5‐03‐07, P5‐16‐03<br />
Espinosa‐Bravo, M<br />
P1‐01‐29<br />
Espinoza, I<br />
P6‐04‐22<br />
Espirito, J<br />
P2‐11‐16<br />
Esser, A<br />
P4‐15‐04<br />
Esserman, L<br />
S4‐2, P2‐05‐01,<br />
P2‐10‐06, P3‐04‐01,<br />
P3‐04‐02, P4‐04‐01, P4‐13‐13<br />
Esserman, LJ P2‐12‐11, P2‐12‐12,<br />
P3‐02‐01, P3‐02‐12, P3‐06‐10,<br />
P4‐14‐04, P4‐16‐07<br />
Estabrook, A<br />
P3‐08‐08<br />
Esterni, B<br />
OT2‐3‐05<br />
Esteva, F<br />
P5‐20‐02<br />
Esteves, S<br />
P1-15-03<br />
Estevez, LG<br />
P5‐18‐15<br />
Ettl, J S1‐6<br />
Ettore, F<br />
P3‐14‐03<br />
Ettyreddy, AR<br />
P4‐06‐07<br />
Euhus, D<br />
P1‐07‐04<br />
Eustermann, H S3‐4, P1‐15‐02<br />
Evans, A<br />
PD07‐07<br />
Evans, AC<br />
P2‐02‐04<br />
Evans, DGR<br />
P3‐08‐01<br />
Evans, G<br />
P1‐09‐05<br />
Evans, GD P4‐11‐05, P4‐13‐09<br />
Evensen, E<br />
P6‐07‐31<br />
Evron, E<br />
P5‐20‐06<br />
Ewald, AJ<br />
P1‐05‐02<br />
Ewing, CA P4‐14‐04, P4‐16‐07<br />
Exner, R<br />
P2‐13‐01<br />
Extra, J‐M<br />
OT2‐3‐05<br />
Fabian, CJ PD09‐02, P2‐11‐17<br />
Fabris, L<br />
P5‐10‐17<br />
Fackler, MJ P2‐02‐01, P4‐12‐04<br />
Fagerland, M<br />
P3‐01‐01<br />
Fahlén, MC<br />
P6‐14‐01<br />
Fais, S<br />
P6‐11‐01<br />
Faisal, A<br />
P3‐01‐08<br />
Fakhrejahani, E<br />
P1‐14‐02<br />
Falchook, G<br />
P5‐20‐09<br />
Falck, A‐K P2‐10‐28, P2‐10‐36<br />
Falcone, A<br />
P5‐17‐06<br />
Falkson, C<br />
P3‐03‐03<br />
Falkson, CI<br />
P5‐17‐07<br />
Fallowfield, L<br />
P1‐09‐05<br />
Falotico, N<br />
OT2‐3‐07<br />
Falzon, M S4‐2<br />
Fan, L<br />
P1‐13‐07<br />
Fan, Z P2‐05‐19, P5‐03‐14, P5‐10‐05<br />
Fanelli, G<br />
P1‐01‐25<br />
Fanelli, M<br />
P4‐02‐03<br />
Fang, L<br />
P5‐18‐11<br />
Faoro, L<br />
OT3‐4‐04<br />
Farajzadegan, Z<br />
P2‐12‐10<br />
Faria, C<br />
P6‐09‐06<br />
Faridi, JS<br />
P3‐12‐07<br />
Farley, J<br />
P4‐01‐03<br />
Farrar, C<br />
P3‐12‐03<br />
Farrar, JT<br />
P4‐13‐01<br />
Farre, I<br />
P4‐14‐10<br />
Fasano, J<br />
P5‐18‐20<br />
Fasching, P<br />
S1‐11, P3‐06‐05<br />
Fasching, PA PD07‐02, P1‐14‐01,<br />
OT1‐1‐10<br />
Fasciani, G<br />
P4‐06‐06<br />
Fasola, CE<br />
P4‐16‐11<br />
Fatayer, H<br />
P4‐01‐14<br />
Fatima, A<br />
P1‐07‐07<br />
Faure, C<br />
P1‐01‐21, OT2‐1‐01<br />
Favret, A<br />
P3‐06‐12<br />
Fazzio, RT<br />
P1‐01‐22<br />
Federico, V<br />
P3‐07‐06,<br />
P3‐07‐07, P3‐07‐14<br />
Fehm, T S2‐2, S4‐5, PD06‐01,<br />
P2‐01‐02, P6‐07‐05<br />
Fehm, TN<br />
OT1‐1‐10<br />
Fei, K<br />
PD08‐01<br />
Feigenberg, S<br />
P2‐13‐05<br />
Feigin, KN<br />
P6‐05‐02<br />
Feiten, S<br />
P2‐11‐11<br />
Feldman, S P1‐09‐02, P4‐02‐07<br />
Feldman, SM PD03‐03, P4‐14‐01<br />
Felzener, MM<br />
P1‐01‐28<br />
Feng, J‐g<br />
P4‐09‐09<br />
Fennessy, PJ<br />
P1‐01‐15<br />
Ferchiou, M<br />
P4‐12‐01<br />
Fergus, K<br />
P6‐08‐04<br />
Fermeaux, V<br />
P3‐14‐03<br />
Fernandes, L<br />
P2‐10‐29<br />
Fernandez, KL<br />
P2‐10‐40<br />
Fernandez, M<br />
P1‐14‐10<br />
Fernandez, ME<br />
PD08‐05<br />
Fernandez, SV<br />
P3‐10‐03<br />
Fernandez Hidalgo, OA P5‐03‐07,<br />
P5‐16‐03<br />
Fernández‐Zapico, M P5‐03‐07<br />
Fernando, A<br />
P4‐06‐14<br />
Fernö, M P1‐05‐07, P2‐10‐07,<br />
P2‐10‐19, P2‐10‐28, P2‐10‐36<br />
Fero, KE<br />
P6‐08‐10<br />
Feron, J‐G<br />
P1‐01‐07,<br />
P1‐01‐19, P5‐01‐04<br />
Ferrari, M P6‐11‐03, P6‐11‐11,<br />
P6‐11‐12, P6‐13‐02<br />
Ferrarini, I<br />
P5‐17‐06<br />
Ferrati, S<br />
P6‐11‐11<br />
Ferree, S<br />
P2‐10‐02<br />
Ferreira, RS<br />
P3‐01‐07<br />
Ferrero, J‐M<br />
P5‐18‐26<br />
Ferreyros, G<br />
P6‐07‐21<br />
Ferro, A<br />
P5‐01‐10<br />
Ferrusi, I<br />
P5‐18‐14<br />
Fersis, N<br />
P1‐14‐05<br />
Festa, A<br />
PD08‐03<br />
Festy, F<br />
P2‐10‐29<br />
Fettig‐Anderson, L<br />
P4‐07‐03<br />
Field, LA<br />
P3‐04‐07, P6‐02‐08<br />
Fields, SZ<br />
P6‐07‐31<br />
Figarella‐Branger, D P3‐12‐11<br />
Figueroa, JD<br />
P3‐08‐02<br />
Figueroa Magalhaes, MC P6‐07‐33<br />
Filho, EC<br />
P1‐01‐28<br />
Filipits, M<br />
S4‐3, P2‐10‐02<br />
Filipovic, A<br />
P1‐04‐04,<br />
P4‐06‐12, P6‐04‐15<br />
Filleron, T<br />
P3‐05‐07<br />
Finas, D<br />
P2‐10‐25<br />
Fineberg, S<br />
PD08‐01<br />
Finetti, p<br />
P5‐03‐01<br />
Fingert, H<br />
P6‐10‐02<br />
Finkelstein, D<br />
PD09‐03<br />
Finkelstein, DM P3‐06‐27, OT2‐3‐03<br />
Finkielstein, CV<br />
P6‐06‐05<br />
Fink‐Retter, A<br />
P1‐15‐10<br />
Finlay‐Schultz, J<br />
P6‐05‐10<br />
Finlayson, C P4‐04‐06, P6‐05‐10<br />
Finn, RS<br />
S1‐6, P4‐08‐01<br />
Finney, L P5‐17‐05, OT3‐3‐08<br />
Finstad, SE<br />
P3‐01‐01<br />
Finsterbusch, K PD06‐04, P5‐01‐12<br />
Firestone, B<br />
P6‐11‐06<br />
Fisch, K<br />
S4‐3, P2‐10‐11<br />
Fisch, M<br />
P2‐12‐14<br />
Fiskus, W S3‐7<br />
Fiteni, F<br />
P5‐18‐22<br />
Fitoussi, A<br />
P1‐01‐19<br />
Fittipaldi, P<br />
PD05‐03<br />
Fitzal, F<br />
P2‐10‐02, P2‐13‐01<br />
Fjällskog, M‐L<br />
P2‐10‐28<br />
Flågeng, MH<br />
P6‐04‐06<br />
Flamaing, J<br />
P6‐09‐07<br />
Flechsig, S<br />
P6‐04‐23<br />
Fleige, B S2‐2<br />
Fleisch, MC<br />
P2‐07‐01<br />
Fleming, G<br />
OT2‐2‐01<br />
Fleming, T<br />
P2‐04‐02<br />
Fletcher, M<br />
S3‐3, P1‐13‐03<br />
Fletcher, O<br />
P3‐08‐04<br />
Fletcher, S<br />
P3‐07‐05<br />
Fletterick, RJ<br />
P5‐07‐02<br />
Flexman, M<br />
P4‐02‐07<br />
Flinchum, R<br />
P2‐10‐05<br />
Flippo‐Morton, TS S2‐1<br />
Flockhart, D<br />
PD10‐08<br />
Flores, ER<br />
P5‐10‐03<br />
Floris, G P2‐10‐12, P6‐05‐05, P6‐07‐29<br />
Flory, K<br />
PD01‐07<br />
Flote, VG<br />
P3‐01‐01<br />
Flyger, H S4‐2<br />
Focke, CM<br />
PD06‐04,<br />
PD06‐05, P5‐01‐12<br />
Foekens, J<br />
P3‐06‐01,<br />
P3‐06‐32, P3‐06‐35<br />
Foekens, JA<br />
P6‐04‐08<br />
Fohlin, H<br />
P6‐07‐12<br />
Folkerd, E<br />
P3‐08‐04<br />
Fonseca, A‐V<br />
P2‐02‐03<br />
Fontaine, C<br />
P6‐09‐07<br />
Fontaine, J‐J<br />
P6‐04‐14<br />
Fontana, A<br />
P5‐17‐06<br />
Ford, JM PD09‐04, P3‐11‐02, P4‐11‐02<br />
Forero, A P3‐03‐03, P5‐17‐07,<br />
P6‐05‐02, P6‐10‐01, P6‐10‐05<br />
Formenti, S P5‐20‐05, P6‐13‐01<br />
Fornander, T P6‐07‐12, P6‐14‐01<br />
Fornier, M P1‐13‐11, P5‐18‐20<br />
Fornier, MN<br />
P5‐20‐07<br />
Foroni, C<br />
PD07‐03<br />
Forstbauer, H<br />
P2‐10‐25<br />
Forte, C<br />
P4‐14‐13<br />
Foster, K<br />
P1‐09‐07, P4‐08‐04<br />
Foszczynska‐Kloda, M P2‐10‐31,<br />
P3‐12‐09, P3‐13‐03<br />
Foucher‐Goudier, M‐J P1‐13‐04<br />
Fountzilas, G<br />
S5‐4, P1‐07‐15<br />
Fourchotte, V P1‐01‐07, P1‐01‐19<br />
Fournier, C<br />
P2‐13‐10<br />
Fourquet, A<br />
P5‐21‐03<br />
Fourrier‐Réglat, A<br />
P5‐21‐01<br />
Fowble, B<br />
P4‐16‐07<br />
Fowble, BL<br />
P4‐01‐13<br />
Fowles, AM<br />
PD07‐08<br />
Fox, EM<br />
PD01‐04<br />
Franchini, Z<br />
P4‐16‐08<br />
Francis, P<br />
OT2‐2‐01<br />
Franco, R<br />
PD08‐01<br />
Franco‐Barraza, J<br />
P6‐02‐05<br />
Frank, E<br />
P2‐16‐04<br />
Frank, RD P4‐12‐03, P5‐01‐08<br />
Franke, AA<br />
P4‐12‐02<br />
Frankel, PH<br />
P2‐14‐08<br />
Franklin, N<br />
OT1‐1‐04<br />
Fraternali, F<br />
P2‐10‐29<br />
Frazer, KA<br />
P2‐06‐01<br />
Frederiksen, K<br />
P1‐09‐01<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
592s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
Author Index<br />
Freedman, RA P6‐08‐05, OT1‐1‐11<br />
Freeman, JV<br />
P2‐02‐04<br />
Freemerman, AJ<br />
P6‐02‐09<br />
Freitas, NMA<br />
P2‐12‐04<br />
Freitas‐Junior, R<br />
P2‐12‐04,<br />
P3‐01‐07, P3‐02‐13<br />
Frenken, B<br />
P1‐07‐16<br />
Fresno, JA<br />
P5‐10‐11<br />
Fresquet, V<br />
P5‐03‐07<br />
Frieboes, HB<br />
P6‐11‐12<br />
Friedlander, M P4‐13‐10, OT2‐3‐07<br />
Friedman, L<br />
P5‐19‐02<br />
Friedman, LS P4‐07‐01, P6‐04‐11<br />
Friedman, PN<br />
P2‐10‐01<br />
Friedrichs, K<br />
P5‐21‐02<br />
Friese, K<br />
P2‐01‐02, P2‐01‐11<br />
Frigessi, A<br />
P3‐04‐03<br />
Frisell, J<br />
P3‐07‐03<br />
Fritel, X<br />
P1‐01‐07<br />
Fritzer, N<br />
P1‐15‐10<br />
Frost, M<br />
P2‐11‐01, P4‐12‐03<br />
Frost, MH P5‐01‐08, P6‐06‐01<br />
Fruhwirth, G<br />
P2‐10‐29<br />
Frydenberg, H<br />
P3‐01‐01<br />
Fryzek, J<br />
P3‐07‐08<br />
Fu, MR<br />
P2‐11‐12<br />
Fu, S<br />
P5‐20‐09<br />
Fu, X<br />
PD01‐01, P6‐10‐03<br />
Fuchs, E‐M P2‐10‐31, P3‐06‐33<br />
Fuentes, D P2‐11‐03, P2‐12‐01<br />
Fujibayashi, M<br />
OT1‐1‐01<br />
Fujii, H<br />
P4‐03‐07, P4‐15‐05<br />
Fujii, K<br />
P4‐03‐08<br />
Fujii, R<br />
P4‐03‐07<br />
Fujii, Y<br />
P4‐12‐06<br />
Fujimura, T<br />
P4‐16‐13<br />
Fujioka, H<br />
P3‐02‐02<br />
Fujisawa, T P1‐14‐08, P3‐02‐06<br />
Fujishima, F<br />
P6‐05‐14<br />
Fujita, T<br />
P1‐02‐02, P3‐12‐06<br />
Fujiwara, T<br />
P4‐07‐04<br />
Fujiwara, Y P2‐11‐02, P5‐18‐16<br />
Fuks, F S6‐2<br />
Fukumura, D<br />
P3‐12‐03<br />
Fukutomi, T<br />
P4‐03‐08<br />
Fulp, W<br />
P4‐14‐09<br />
Fulp, WJ<br />
P4‐17‐01<br />
Fumagalli, D S6‐2, P1‐07‐08, P3‐04‐10,<br />
P3‐05‐03, P6‐07‐22<br />
Fumoleau, P<br />
S5‐3, P3‐08‐07,<br />
P4‐02‐06, P5‐18‐05, P6‐11‐08<br />
Funian, L<br />
P2‐10‐26<br />
Fuqua, S<br />
P4‐08‐09<br />
Furberg, A‐S<br />
P3‐01‐01<br />
Furhmann, L<br />
P5‐01‐04<br />
Furukawa, H<br />
P4‐16‐13<br />
Futch, K<br />
P5‐18‐09<br />
Fyles, A<br />
P2‐10‐33<br />
Gabbani, M<br />
P4‐16‐08<br />
Gabram, S<br />
P1‐01‐06<br />
Gabrielson, EW<br />
OT2‐1‐04<br />
Gacquer, D<br />
P3‐04‐10<br />
Gaddy, D<br />
P4‐02‐05<br />
Gade, S<br />
S3‐1, P3‐06‐05<br />
Gaffney, D<br />
P5‐01‐09<br />
Gajria, D P5‐18‐04, P5‐18‐20, P6‐11‐10<br />
Gal, J<br />
P4‐15‐01<br />
Galanko, JA<br />
P6‐02‐09<br />
Galant, C<br />
P3‐05‐03<br />
Gallagher, A<br />
P1‐09‐04<br />
Gallagher, RI P3‐04‐01, P3‐04‐02<br />
Gallagher, W<br />
P4‐09‐06<br />
Gallagher, WM<br />
P3‐04‐12<br />
Galligioni, E<br />
P5‐01‐10<br />
Gallion, K<br />
PD08‐05<br />
Galmiche, M<br />
P6‐04‐05<br />
Gamez, A<br />
P5‐10‐11<br />
Gampenrieder, SP<br />
P5‐20‐11<br />
Gandhi, S<br />
P4‐16‐14<br />
Gandini, S<br />
PD06‐06<br />
Ganesan, S<br />
P1‐05‐19<br />
Gang, N<br />
P2‐10‐26<br />
Ganju, RK<br />
P1‐05‐17<br />
Gany, F<br />
P2‐11‐05<br />
Ganz, PA<br />
OT2‐2‐04<br />
Gao, H P2‐03‐01, P5‐03‐04, P5‐03‐06,<br />
P5‐04‐06, P5‐10‐02<br />
Gao, J<br />
P5‐10‐10<br />
Gao, M<br />
P6‐05‐15<br />
Gao, S<br />
P4‐03‐12<br />
Gao, X<br />
P6‐09‐06<br />
Gao, Y<br />
P5‐18‐24<br />
Garbay, J‐R<br />
P4‐14‐12<br />
Garber, J<br />
PD01‐08, OT2‐3‐07<br />
Garber, JE<br />
PD09‐03<br />
García García, T<br />
P3‐06‐15<br />
García Garre, E<br />
P3‐06‐15<br />
García, J<br />
P4‐06‐19<br />
García, R<br />
P4‐06‐19<br />
García Saenz, JA<br />
OT3‐3‐05<br />
García‐Martínez, E<br />
P3‐06‐15<br />
García‐Sáenz, JÁ<br />
P5‐18‐05<br />
Garces, Z<br />
P1‐07‐06<br />
Garcia, A<br />
P6‐10‐01<br />
Garcia, E<br />
P5‐18‐15<br />
Garcia, J<br />
P6‐04‐29<br />
Garcia, R<br />
P6‐04‐29<br />
Garcia Blanco, MA<br />
P4‐06‐07<br />
Garcia‐Aranda, M<br />
P1‐14‐10<br />
Garcia‐Closas, M<br />
P3‐08‐02<br />
Garcia‐Estevez, L<br />
P1‐14‐10<br />
Garcias, C<br />
P3‐12‐08<br />
Garcia‐Saenz, JA S1‐7<br />
Garee, JP<br />
P6‐05‐07<br />
Garey, J<br />
P2‐11‐16<br />
Gargi, P<br />
P2‐10‐29<br />
Garnett, S S1‐4<br />
Garofalo, A<br />
OT1‐1‐07<br />
Garrett, M<br />
P2‐16‐04<br />
Garwood, M<br />
P1‐14‐11<br />
Gasperetti, F<br />
P5‐01‐10<br />
Gates‐Ferris, K P3‐02‐07, P4‐13‐02,<br />
P5‐14‐02<br />
Gattelli, A<br />
PD01‐06<br />
Gatti‐Mays, M<br />
P1‐09‐04<br />
Gaule, P<br />
P3‐04‐12<br />
Gaur, R<br />
P4‐06‐14<br />
Gauthier, A<br />
PD05‐08<br />
Gauthier, G<br />
P5‐18‐12<br />
Gavilá, J P1‐07‐18, P2‐01‐06, OT1‐1‐09,<br />
OT2‐3‐06<br />
Gavin, P<br />
P6‐05‐12<br />
Gaynor, E<br />
P1‐12‐04<br />
Gaynor, ER<br />
PD10‐02<br />
GBG (German <strong>Breast</strong> Group) S1‐7<br />
Gebrim, LH<br />
P2‐05‐17<br />
Gehrmann, M<br />
P2‐10‐13<br />
GEICAM (Spanish <strong>Breast</strong> <strong>Cancer</strong><br />
Research Group) S1‐7<br />
Geiger, XJ<br />
P1‐05‐24<br />
Geisler, J<br />
P6‐04‐06<br />
Gelber, RD S1‐1, S3‐2, S5‐2, P5‐18‐02,<br />
P6‐07‐06, OT2‐2‐01<br />
Gelber, S<br />
S3‐2, P6‐07‐06<br />
Gelman, RS<br />
OT1‐1‐11<br />
Gelmon, K<br />
P1‐13‐01,<br />
P2‐13‐02, P4‐16‐02<br />
Generali, D<br />
PD07‐03<br />
Génin, P<br />
P3‐05‐07<br />
Gennari, MB<br />
P3‐02‐14<br />
Gentilini, OD<br />
PD03‐01<br />
Geoghegan, C<br />
P6‐08‐09<br />
Georgoulia, NE<br />
P6‐06‐02<br />
Georgoulias, V<br />
P1‐13‐09,<br />
P2‐01‐03, P2‐01‐07<br />
Geradts, J<br />
P2‐10‐03,<br />
P3‐06‐07, P4‐09‐01<br />
Gerber, B<br />
S1‐11, S3‐1, S4‐5,<br />
PD06‐01, P1‐14‐01,<br />
OT1‐1‐13, OT3‐3‐11<br />
Gerdes, M<br />
P3‐05‐05<br />
Geretti, E<br />
P1‐07‐03<br />
Germa, C OT2‐3‐08, OT2‐3‐09<br />
Gerritse, FL<br />
P6‐04‐08<br />
Gertler, FB<br />
P6‐02‐04<br />
Gevaert, O<br />
P2‐09‐03<br />
Geyer, C S1‐11<br />
Geyer, CE<br />
P6‐07‐06<br />
Geyer, Jr., CE S3‐2, S5‐5<br />
Ghaffarpour, M<br />
P5‐09‐01<br />
Ghazoui, Z<br />
PD01‐05<br />
Ghimbovschi, S<br />
P2‐05‐22<br />
Ghirelli, C<br />
P4‐06‐09<br />
Ghono, T<br />
P6‐04‐17<br />
Ghosh, K P1‐01‐22, P4‐12‐03, P5‐01‐08<br />
Ghosh, S<br />
P6‐02‐02<br />
Ghuijs, PM<br />
P5‐01‐13<br />
Giacchetti, S P1‐14‐03, P1‐14‐18,<br />
P2‐01‐04, P3‐06‐04, P4‐13‐03<br />
Giacomi, N<br />
P3‐07‐13<br />
Giamas, G<br />
P1‐04‐04,<br />
P4‐06‐12, P6‐04‐15<br />
Gianni, AM<br />
P2‐12‐08<br />
Gianni, L<br />
S1‐11, S5‐2, S6‐7,<br />
P2‐10‐10, P2‐12‐08, P5‐18‐02<br />
Giard, S<br />
P4‐14‐10<br />
Gibbs, IC<br />
P4‐16‐11<br />
Gibson, J<br />
P4‐06‐04,<br />
OT3‐4‐02, OT3‐4‐03<br />
Gibson, L<br />
P3‐08‐04<br />
Gidekel, R<br />
OT1‐1‐08<br />
Gielen, M<br />
P6‐08‐02<br />
Gierach, GL<br />
P3‐07‐04<br />
Giermek, J<br />
P6‐07‐05<br />
Giguère, V<br />
P5‐18‐08<br />
Gil, M S1‐7<br />
Gilcrease, M P5‐03‐05, P5‐20‐09<br />
Gilewski, T P5‐18‐20, P5‐20‐07<br />
Gilks, B<br />
P2‐10‐09<br />
Gillego, A<br />
P3‐08‐08<br />
Gilles, E<br />
P1‐07‐11<br />
Gillett, C<br />
P2‐10‐29<br />
Gilman, PB<br />
P4‐09‐12<br />
Gil‐Martin, M<br />
P6‐11‐08<br />
Gilmer, TM<br />
P4‐08‐05<br />
Gimbergues, P<br />
OT2‐1‐01<br />
Ginestier, C<br />
P5‐03‐01<br />
Ginsburg, GS P2‐10‐03, P3‐06‐07<br />
Ginsburg‐Arlen, A<br />
P2‐11‐16<br />
Ginter, PS<br />
P6‐02‐04<br />
Ginty, F<br />
P3‐05‐05<br />
Giobbie‐Hurder, A S1‐1, S4‐4<br />
Giordano, A P2‐01‐01, P2‐03‐01,<br />
P5‐04‐06, P5‐10‐02<br />
Giordano, SH P5‐20‐02, P5‐20‐13<br />
Giorgetti, C<br />
OT2‐3‐02<br />
Giovanni, C<br />
PD04‐05<br />
Giranda, V<br />
PD09‐06<br />
Giranda, VL<br />
OT2‐3‐07<br />
Giri, D<br />
PD04‐05<br />
Giri, DD<br />
PD05‐02, P6‐05‐02<br />
Girish, S<br />
P5‐18‐11, P5‐18‐24<br />
Giro, A<br />
P4‐09‐11, P6‐11‐02<br />
Girre, V<br />
OT3‐3‐10<br />
Gittleman, M<br />
OT3‐4‐03<br />
Giuliano, AE<br />
P1‐01‐06<br />
Giuliano, M S5‐8<br />
Glas, AM<br />
P4‐09‐05<br />
Gläser, D<br />
PD06‐04, P5‐01‐12<br />
Glassey, E<br />
P1‐01‐26<br />
Glazebrook, KN<br />
P1‐01‐22<br />
Glencer, A P2‐12‐11, P2‐12‐12<br />
Gligorov, J<br />
P3‐06‐20,<br />
P5‐17‐04, P5‐21‐01<br />
Glück, S P1‐12‐02, P3‐06‐11, OT3‐4‐02<br />
Gluz, O<br />
P2‐10‐08, OT3‐3‐02<br />
Gnant, M<br />
S4‐3, P2‐10‐02,<br />
P2‐13‐01, P6‐04‐02<br />
Gobardhan, PD<br />
P4‐14‐08<br />
Gobbi, H<br />
P1‐06‐03<br />
Godellas, C PD10‐02, P1‐02‐01<br />
Godin, B<br />
P6‐02‐07<br />
Godwin, J S1‐2<br />
Goehler, T<br />
P1‐15‐02<br />
Goel, S<br />
P3‐12‐03<br />
Goes, JCS<br />
P1‐01‐28<br />
Goetz, MP<br />
PD10‐08<br />
Goga, A S3‐8<br />
Goicochea, L<br />
P2‐10‐40<br />
Gojis, O<br />
P2‐10‐22<br />
Goka, E<br />
P1‐04‐06<br />
Goldberg, JD<br />
P5‐20‐05<br />
Goldberg, JM<br />
P4‐11‐06<br />
Goldfarb, S<br />
P5‐18‐20<br />
Goldfarb, SB<br />
P2‐12‐05<br />
Goldhirsch, A<br />
S1‐1, S5‐2,<br />
P5‐18‐02, P6‐07‐14<br />
Goldstein, LC<br />
P1‐07‐01<br />
Goldstein, LJ S3‐5, P5‐20‐01, OT2‐3‐01<br />
Goldwasser, F<br />
P5‐17‐04<br />
Golemis, EA<br />
P1‐05‐03<br />
Goloubeva, O<br />
P2‐13‐05<br />
Gomes, DO<br />
P6‐07‐44<br />
Gómez, F<br />
P2‐14‐02<br />
Gomez, H S3‐6<br />
Gómez, HL P6‐07‐20, P6‐07‐21<br />
Gómez, P<br />
P1‐07‐18,<br />
P2‐01‐06, P6‐13‐03<br />
GomezGarcia, EB<br />
P6‐08‐02<br />
Gonçalves, A<br />
P3‐12‐01,<br />
P3‐12‐11, OT2‐3‐05<br />
Gondo, N<br />
P1‐02‐02<br />
Gondou, N<br />
P3‐12‐06<br />
Gong, G<br />
P1‐03‐03, P2‐02‐02,<br />
P3‐12‐05, P6‐07‐28<br />
Gong, G‐y<br />
P3‐01‐02<br />
Gonugunta, VK P5‐04‐04, P6‐04‐07<br />
Gonzalez, J<br />
P5‐07‐06,<br />
P6‐05‐02, P6‐11‐10<br />
Gonzalez, ME<br />
P1‐04‐11<br />
Gonzalez‐Angulo, AM P1‐07‐06,<br />
P3‐06‐06, P5‐20‐02,<br />
P6‐07‐25, P6‐10‐07, OT2‐2‐04<br />
Gonzalves, B<br />
P3‐14‐03<br />
Goodall, G<br />
P5‐04‐04<br />
Goodman, D<br />
P4‐13‐13<br />
Goodman, MT<br />
P4‐12‐02<br />
Goodman, RL<br />
P6‐13‐01<br />
Goodrich, ME<br />
P4‐01‐15<br />
Goodwin, PJ PD03‐02, PD03‐05<br />
Gorbunova, V<br />
OT3‐3‐01<br />
Gore, I<br />
P3‐06‐12<br />
Goss, GD<br />
P2‐05‐13<br />
Goss, PE<br />
S1‐9, PD09‐03,<br />
PD10‐05, P1‐07‐13, P2‐10‐15,<br />
P2‐13‐02, OT2‐3‐03<br />
Gossiel, F S6‐4<br />
Goteti, S<br />
OT2‐3‐09<br />
Goto, H<br />
P6‐05‐06<br />
Gotoh, T<br />
P6‐06‐05<br />
Goubar, A<br />
P3‐06‐04<br />
Gouerant, S<br />
P1‐15‐08<br />
Gough, MJ<br />
P4‐04‐02<br />
Goussia, A<br />
P1‐07‐15<br />
Gouy, S<br />
P4‐14‐12<br />
Govek, S<br />
P6‐04‐12<br />
Gown, AM<br />
P1‐07‐01<br />
Gozalbo, F<br />
P1‐01‐29<br />
Grabau, D<br />
PD03‐07,<br />
P2‐10‐07, P2‐10‐28<br />
Grabulovski, D<br />
P5‐18‐25<br />
Gradishar, W<br />
P1‐12‐07,<br />
P5‐17‐01, OT1‐1‐04<br />
Gradishar, WJ<br />
P2‐10‐01,<br />
P2‐14‐01, P5‐03‐11<br />
Graffy, HJ<br />
P4‐13‐09<br />
Graham, L<br />
P5‐14‐04<br />
Graham, N P3‐04‐11, P3‐11‐03<br />
Gralow, J S5‐4, S5‐5, PD10‐04<br />
Gralow, JR P6‐04‐03, P6‐12‐03<br />
Granados, S<br />
P5‐03‐12<br />
Grandemange, S<br />
P6‐01‐04<br />
Granstam Björneklett, H P2‐12‐09<br />
Granville, T<br />
PD04‐04<br />
Grau, AM<br />
P4‐01‐03<br />
Gravel, DH<br />
P5‐01‐01<br />
Gravenor, D<br />
P1‐14‐14<br />
Graves, M<br />
P1‐05‐05<br />
Gravgaard, KH<br />
P4‐09‐04<br />
Graviss, L<br />
P4‐15‐02<br />
Gray, K<br />
PD10‐03<br />
Gray, R S1‐2<br />
Greco, S<br />
P6‐11‐13<br />
Green, A<br />
P2‐10‐22, P3‐06‐13,<br />
P6‐07‐09, P6‐07‐18<br />
Green, J<br />
P6‐10‐01<br />
www.aacrjournals.org 593s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Greenberg, J<br />
P5‐20‐06<br />
Greenhalgh, R<br />
P1‐09‐05<br />
Greenlee, H<br />
P2‐11‐03<br />
Greenson, JK<br />
P5‐18‐06<br />
Gregory, WM S6‐4<br />
Greil, R S4‐3, P2‐10‐02, P5‐17‐03,<br />
P5‐20‐11, OT2‐2‐03<br />
Gremel, G<br />
P4‐09‐06<br />
Gress, J<br />
P4‐11‐04<br />
Grieve, R<br />
PD07‐09<br />
Griffin, RJ<br />
P3‐06‐30<br />
Griffiths, G<br />
PD07‐09<br />
Grillot, K<br />
P6‐04‐12<br />
Grizzle, WE<br />
P2‐05‐22<br />
Grobmyer, SR<br />
P2‐16‐01<br />
Groman, A<br />
P3‐07‐02<br />
Gronesova, P<br />
P2‐01‐12<br />
Grose, VA<br />
P4‐06‐18<br />
Gross, HM<br />
P1‐12‐06<br />
Grosse, R<br />
P2‐10‐38<br />
Grothey, A<br />
P6‐04‐15<br />
Grubbs, C<br />
P1‐08‐02<br />
Grubbs, CJ<br />
P1‐08‐01<br />
Grudé, F<br />
OT3‐3‐04<br />
Grutman, SB<br />
P4‐14‐01<br />
Gruver, AM<br />
PD02‐04<br />
Gryaznov, SM<br />
P5‐08‐01<br />
Grybowicz, L<br />
OT3‐3‐09<br />
Gu, G<br />
P4‐08‐09<br />
Gu, H<br />
P5‐10‐06<br />
Gu, J‐W<br />
P4‐06‐04<br />
Gu, Y<br />
P1‐03‐03<br />
Guan, J<br />
P4‐07‐01, P5‐19‐02<br />
Guardino, E P5‐18‐06, P5‐18‐24<br />
Guariglia, S<br />
P4‐16‐08<br />
Guarneri, V<br />
P2‐10‐16<br />
Guastalla, J‐P S5‐3<br />
Gucalp, A<br />
P6‐05‐01,<br />
P6‐05‐02, OT3‐1‐01<br />
Gudlaugsson, E<br />
P2‐10‐19<br />
Guenther, M<br />
PD07‐01<br />
Guérin, A<br />
P5‐18‐12<br />
Guerra, JA<br />
OT3‐3‐05<br />
Guerrero, A<br />
S1‐7, OT1‐1‐09<br />
Guerrero, J<br />
P2‐14‐02<br />
Guerrieri‐Gonzaga, A PD03‐01,<br />
PD04‐07, PD06‐06<br />
Guggisberg, N<br />
P1‐07‐10<br />
Gui, G<br />
P1‐01‐10, P1‐01‐11<br />
Guidetti, A<br />
P2‐12‐08<br />
Guilhen, N<br />
P1‐01‐07<br />
Guillem, V<br />
OT1‐1‐09<br />
Guimarães, IS<br />
P6‐11‐13<br />
Guinebretière, JM P1‐14‐18, P3‐06‐04<br />
Guiu, S<br />
P3‐06‐20, P3‐08‐07<br />
Guldberg, TL<br />
P6‐07‐08<br />
Gulley, JL<br />
P5‐16‐06<br />
Gumus, M<br />
OT1‐1‐08<br />
Gunnarsdottír, KA<br />
P6‐12‐01<br />
Gunther, JE<br />
P4‐02‐07<br />
Guo, B<br />
P1‐14‐13<br />
Guo, J<br />
P5‐10‐10<br />
Guo, Q<br />
P3‐08‐05<br />
Guo, R<br />
PD10‐02, P1‐12‐04<br />
Guo, X<br />
PD05‐09<br />
Gupta, I<br />
P4‐06‐14, P4‐06‐16<br />
Gurcan, MN<br />
P2‐11‐07<br />
Gusterson, B S1‐1<br />
Gutekunst, K<br />
P2‐10‐04<br />
Guth, A<br />
P1‐09‐03, P2‐11‐12<br />
Guth, AA PD08‐01, P4‐14‐03, P4‐17‐07<br />
Guthrie, K<br />
P5‐16‐04<br />
Gutierrez, C S5‐8, P2‐16‐02, P2‐16‐03<br />
Gutierrez‐Barrera, AM P2‐10‐32<br />
Gutin, A<br />
PD09‐04<br />
Gutkind, JS<br />
P1‐05‐23<br />
Gwin, WR<br />
P4‐08‐03<br />
Györffy, B P1‐07‐14, P2‐10‐24<br />
Ha, T<br />
P3‐05‐05, P3‐05‐06<br />
Haas, M<br />
P6‐14‐05<br />
Habal, N<br />
P4‐14‐01<br />
Habel, L<br />
P3‐07‐05<br />
Haber, D S5‐7<br />
Haber, DA<br />
P2‐01‐14<br />
Haber, J<br />
P2‐11‐12<br />
Habets, L<br />
P1‐07‐16<br />
Hachemi, S<br />
OT2‐3‐09<br />
Hadad, SM<br />
PD03‐02<br />
Haddad, M<br />
P2‐05‐06,<br />
P2‐10‐16, P2‐10‐31<br />
Haddad, TC<br />
P1‐14‐11<br />
Hadj‐Hamou, S<br />
P5‐01‐05<br />
Hadji, P<br />
P2‐13‐01, P6‐09‐08<br />
Hadjiminas, D<br />
P3‐02‐04<br />
Haffty, BG S2‐1, P4‐16‐03, P4‐16‐09<br />
Hagenbeck, C P2‐01‐02, P4‐13‐11<br />
Hagenbeck, CD<br />
OT1‐1‐10<br />
Hager, JH<br />
P6‐04‐12<br />
Hahn, DE<br />
P4‐11‐01<br />
Hahn, S<br />
P1‐05‐21<br />
Hahn, SS<br />
P3‐12‐02<br />
Haibe‐Kains, B<br />
P3‐04‐10<br />
Haibo, W<br />
P2‐10‐26<br />
Haimovitz, K<br />
P6‐08‐10<br />
Hainsworth, JD<br />
OT3‐3‐08<br />
Hajage, D<br />
P2‐01‐01,<br />
P2‐01‐13, OT3‐4‐06<br />
Hakkim, L P4‐06‐14, P4‐06‐16<br />
Halawani, H<br />
OT1‐1‐08<br />
Hale, DF<br />
P5‐16‐02, P5‐16‐05<br />
Haley, B<br />
P1‐07‐04<br />
Haley, V<br />
P4‐06‐10<br />
Halhali, A P4‐06‐19, P6‐04‐29<br />
Hall, J<br />
PD02‐01<br />
Hallett, M<br />
P6‐02‐03<br />
Hallquist, A<br />
P3‐06‐28<br />
Hallum‐Montes, R<br />
P4‐13‐02<br />
Haloua, M<br />
PD04‐01<br />
Hamaker, M<br />
P1‐12‐05<br />
Hamel, F<br />
P5‐01‐05<br />
Hamilton, J<br />
P6‐02‐09<br />
Hamilton, N PD03‐04, P5‐18‐20<br />
Hammond, MEH<br />
P2‐10‐27<br />
Hamy, A‐S<br />
P4‐13‐03<br />
Han, A<br />
P6‐07‐40<br />
Han, C<br />
P1‐06‐01, P4‐01‐01<br />
Han, D<br />
P4‐03‐11<br />
Han, L P1‐07‐13, P2‐09‐01, P2‐13‐02<br />
Han, MX<br />
P2‐05‐05, P4‐09‐09<br />
Han, Q<br />
P4‐07‐04<br />
Han, SN<br />
P6‐07‐05<br />
Han, SW<br />
PD09‐05<br />
Han, W PD05‐07, P1‐01‐08, P1‐14‐16,<br />
P1‐14‐19, P2‐05‐20, P3‐06‐16,<br />
P5‐18‐23<br />
Han, WS<br />
P2‐10‐35<br />
Hanamura, T<br />
P6‐04‐17<br />
Hanby, A<br />
P2‐10‐29<br />
Hanby, AM<br />
P6‐02‐06<br />
Handricks, C<br />
P5‐20‐10<br />
Hanf, V<br />
PD07‐02, P1‐13‐13<br />
Hanker, L<br />
P2‐10‐17<br />
Hanna, GG<br />
P6‐07‐24<br />
Hanna, W P1‐07‐17, P2‐10‐09<br />
Hannah, A<br />
P3‐06‐31<br />
Hannoun‐Levi, J‐M<br />
P4‐15‐01<br />
Hanoch, Y<br />
P4‐11‐03<br />
Hansen, J<br />
P2‐10‐27<br />
Hansen, N<br />
P1‐01‐06<br />
Hansen, SK<br />
P6‐04‐18<br />
Hanson, I<br />
P2‐05‐04<br />
Hansson, AG<br />
OT1‐1‐05<br />
Hanusch, C<br />
S3‐1, P1‐14‐01,<br />
OT1‐1‐13, OT3‐3‐11<br />
Hao, Y P6‐04‐01, P6‐04‐04, P6‐04‐21<br />
Haqq, C<br />
P2‐05‐01<br />
Haque, R P1‐07‐12, P3‐07‐05, P3‐08‐06<br />
Hara, F<br />
P1‐13‐10, P3‐02‐06<br />
Hara, H<br />
P4‐09‐08<br />
Harada, T<br />
P3‐13‐04<br />
Harada‐Shoji, N<br />
P6‐04‐16<br />
Harashima, H<br />
P4‐04‐08<br />
Harbeck, N P1‐13‐13, P2‐10‐08,<br />
P5‐18‐06, P5‐20‐01, P6‐07‐05,<br />
P6‐09‐08, OT1‐1‐16, OT3‐3‐02,<br />
OT3‐3‐06<br />
Harcourt, D P4‐17‐03, P4‐17‐04<br />
Hardefeldt, PJ P1‐11‐01, P4‐12‐07<br />
Harden, E<br />
P5‐14‐02<br />
Harel‐Bellan, A<br />
P5‐03‐01<br />
Hargreaves, BA<br />
P4‐01‐06<br />
Harismendy, O<br />
P2‐06‐01<br />
Harland, R<br />
P6‐07‐13<br />
Harper‐Wynne, C<br />
PD07‐07<br />
Harrigal, CL<br />
P4‐01‐12<br />
Harrington, P<br />
P3‐08‐05<br />
Harris, AL P1‐06‐01, P4‐01‐01<br />
Harris, E S4‐2<br />
Harris, L<br />
P4‐01‐02<br />
Harris, LN PD05‐05, P3‐14‐01<br />
Harrison, BL<br />
P5‐15‐01<br />
Harrison, D P3‐06‐23, P6‐04‐10<br />
Harrison, LB<br />
P4‐15‐03<br />
Harry, A<br />
P4‐17‐06<br />
Hartman, A‐R PD09‐03, PD09‐04<br />
Hartman, L<br />
P2‐10‐07<br />
Hartman, M P2‐11‐06, P3‐07‐03<br />
Hartman, RD<br />
P1‐01‐04<br />
Hartmann, LC<br />
P4‐12‐03,<br />
P5‐01‐08, P6‐06‐01<br />
Harvey, A P6‐09‐09, P6‐09‐10<br />
Harvey, C<br />
OT1‐1‐04<br />
Harvie, MN<br />
P4‐13‐09<br />
Harwin, W<br />
P5‐20‐10<br />
Hasegawa, Y<br />
PD07‐05<br />
Hasenburg, A S1‐5<br />
Hashimoto, T<br />
P3‐13‐04<br />
Hasteh, F<br />
P2‐06‐01<br />
Hatachi, T<br />
P1‐01‐27<br />
Hatschek, T<br />
P1‐05‐07<br />
Hattori, A<br />
OT1‐1‐01<br />
Hattori, M P1‐02‐02, P3‐12‐06<br />
Hatzis, C<br />
P2‐10‐17<br />
Hauranieh, L<br />
P2‐01‐05<br />
Hauschild, M<br />
PD07‐02<br />
Hauser, N<br />
P4‐03‐06<br />
Hauspy, J<br />
P2‐01‐08<br />
Haviland, J<br />
P3‐06‐09<br />
Haviland, JS S4‐1<br />
Hawes, D<br />
P1‐09‐06<br />
Hawtin, RE<br />
P6‐07‐31<br />
Hayashi, J<br />
P6‐04‐19<br />
Hayashi, M<br />
PD07‐05<br />
Hayashi, N<br />
P5‐15‐06,<br />
P6‐07‐23, P6‐07‐38<br />
Hayashi, S‐I<br />
P6‐04‐17<br />
Hayashi, T<br />
P1‐01‐27<br />
Hayashi, Y<br />
P1‐14‐06<br />
Hayashida, T P1‐14‐09, P3‐06‐22,<br />
P4‐03‐03, P4‐09‐08<br />
Hayes, DF S4‐6, S6‐3<br />
Hayes, DN S6‐1<br />
Hayes, MK<br />
P4‐03‐09<br />
Haynes, AB<br />
P4‐15‐02<br />
Haynes, B PD07‐07, P3‐08‐04<br />
Hayward, L<br />
OT3‐3‐09<br />
Hazra, S S5‐7<br />
He, HH<br />
PD01‐08, P1‐07‐07<br />
He, J<br />
PD02‐07<br />
He, Y S6‐6<br />
Healy, LA<br />
P6‐01‐02<br />
Heath, D<br />
P2‐11‐09<br />
Heckman‐Stoddard, B P1‐09‐07<br />
Hedenfalk, I P1‐05‐07, P2‐10‐28<br />
Hedvat, C<br />
P2‐08‐01<br />
Hedvat, CV<br />
P6‐05‐01<br />
Hee‐Dong, H<br />
P5‐10‐03<br />
Heery, CR<br />
P5‐16‐06<br />
Hefti, MM<br />
P5‐01‐03<br />
Heguy, A<br />
PD04‐05<br />
Hei, TK<br />
PD09‐09<br />
Heideman, JL<br />
P6‐12‐02<br />
Heijnsdijk, EA<br />
P3‐02‐09<br />
Heinrich, B<br />
P5‐20‐01<br />
Heinrich, G<br />
P2‐01‐02<br />
Heinrich, T<br />
P2‐10‐17<br />
Heintz, A<br />
P6‐14‐05<br />
Heinz, R<br />
P5‐10‐06<br />
Heinz, RE<br />
P4‐12‐04<br />
Heinzmann, D<br />
P5‐18‐02<br />
Heiss, B<br />
P2‐13‐05<br />
Helderman‐van den Enden, A P6‐08‐02<br />
Helenowski, I<br />
P1‐09‐07<br />
Helgadottir, H<br />
PD09‐10<br />
Helland, Å<br />
P3‐05‐04<br />
Hellwinkel, O<br />
P6‐05‐13<br />
Helmijr, JC<br />
P3‐06‐01<br />
Helmijr, JCA<br />
P6‐04‐08<br />
Helms, G S2‐2<br />
Hembrough, TA<br />
P1‐07‐19<br />
Henderson, B<br />
P4‐12‐02<br />
Henderson, D P3‐05‐05, P3‐05‐06<br />
Henderson, K<br />
PD08‐02<br />
Henderson, LM<br />
P4‐01‐15<br />
Hendricks, C P1‐14‐14, P5‐17‐05<br />
Hendricks, P<br />
P6‐05‐10<br />
Hendriks, B P1‐07‐03, P4‐02‐05<br />
Hengstler, JG<br />
P2‐10‐13<br />
Hennessy, C<br />
P4‐17‐09<br />
Hennessy, S<br />
P4‐13‐01<br />
Hennings, L<br />
P3‐06‐30<br />
Henry, NL<br />
PD10‐08<br />
Henschel, V<br />
S6‐5, P3‐06‐34<br />
Hepp, P<br />
P2‐10‐25, P4‐13‐11<br />
HERA Study Team S5‐2, P5‐18‐02<br />
Heras, L<br />
P1‐07‐18, P2‐01‐06<br />
Herbert, B‐S P5‐08‐01, P5‐18‐13<br />
Hergenroeder, G<br />
PD01‐01<br />
Herlinger, AL<br />
P6‐11‐13<br />
Hermann, R<br />
P5‐20‐08<br />
Hernandez, BY<br />
P4‐12‐02<br />
Hernandez, C<br />
P5‐14‐02<br />
Hernandez, RK<br />
P2‐13‐03<br />
Herrera, LA<br />
PD08‐06<br />
Herrero, M P1‐14‐10, P5‐18‐15<br />
Hershman, DL PD03‐03, P1‐09‐02,<br />
P2‐11‐03, P2‐12‐01,<br />
P4‐02‐07, P6‐12‐03<br />
Hertz, DL<br />
PD10‐07<br />
Hertzog, B<br />
P5‐01‐09<br />
Herzog, J<br />
PD08‐06<br />
Hess, KR<br />
P2‐03‐01<br />
Hesselberth, J<br />
PD01‐07<br />
Heuts, EM<br />
P5‐01‐13<br />
Heyer, DM<br />
P4‐06‐18<br />
Heyman, R<br />
P6‐04‐12<br />
Heymanns, J<br />
P2‐11‐11<br />
Hibbs, S<br />
P4‐06‐03<br />
Hibshoosh, H PD03‐03, P4‐02‐07<br />
Hickish, T<br />
OT1‐1‐17<br />
Hickman, J<br />
P1‐09‐05<br />
Hicks, J<br />
P3‐14‐01<br />
Hidalgo, M P1‐14‐10, P5‐18‐15<br />
Hidalgo‐Miranda, A<br />
P5‐10‐12<br />
Hiddingh, L<br />
P3‐12‐03<br />
Hieken, TJ<br />
P1‐01‐22<br />
Hielscher, A<br />
P4‐02‐07<br />
Higaki, K P1‐14‐08, P1‐14‐12, P4‐01‐05<br />
Higashide, S<br />
P3‐13‐04<br />
Higgens, D<br />
P5‐16‐04<br />
Higgins, D<br />
P2‐15‐02<br />
Higgins, DG<br />
P4‐09‐06<br />
Higgins, DM<br />
OT3‐1‐02<br />
Higgins, HB OT1‐1‐03, OT3‐3‐09<br />
Higgins, MJ<br />
P2‐13‐02<br />
Higgins, SA<br />
P4‐17‐02<br />
Hikichi, M<br />
P3‐02‐05<br />
Hilaire, L<br />
P2‐10‐04<br />
Hilbert, P<br />
P3‐04‐04<br />
Hilfrich, J S3‐1, S4‐5, PD06‐01,<br />
P1‐14‐01, OT1‐1‐13, OT3‐3‐11<br />
Hill, A<br />
P6‐04‐21<br />
Hill, ADK<br />
P6‐04‐01<br />
Hiller, L OT1‐1‐03, OT3‐3‐09<br />
Hiller, Ral<br />
P2‐01‐11<br />
Hillier, S<br />
P3‐08‐04<br />
Hills, M<br />
PD07‐07<br />
Hilsenbeck, SG S5‐8, PD01‐01<br />
Hilton, JF<br />
P3‐13‐05<br />
Hinck, AP<br />
P1‐05‐18<br />
Hindenburg, H‐J<br />
P6‐09‐08<br />
Hinke, A<br />
P5‐21‐02<br />
Hinrichs, JW<br />
PD02‐03<br />
Hinzey, A<br />
P2‐11‐04<br />
Hirakawa, H<br />
P1‐01‐27<br />
Hirano, A<br />
OT1‐1‐01<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
594s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
Author Index<br />
Hirawat, S P4‐08‐01, OT2‐3‐08<br />
Hiroji, I<br />
P1‐02‐02<br />
Hirokaga, K P6‐07‐30, P6‐07‐39<br />
Hiroko, B<br />
P2‐11‐02<br />
Hirose, S<br />
P1‐14‐09, P3‐06‐22<br />
Hirshfield‐Bartek, J<br />
P3‐10‐06,<br />
P4‐06‐01, P5‐02‐01<br />
Hisamatsu, K<br />
P1‐14‐02<br />
Hitora, T<br />
P4‐03‐07<br />
Hjermstad, M<br />
P6‐09‐03<br />
Ho, C‐L<br />
P4‐04‐07<br />
Hoadley, KA S6‐1<br />
Hoch, U<br />
P3‐06‐31<br />
Hodge, JW<br />
P5‐16‐06<br />
Hodge, S<br />
P2‐05‐15, P5‐16‐06<br />
Hoe, N<br />
P4‐06‐08<br />
Hoefnagel, LDC<br />
PD01‐02,<br />
P2‐06‐02, P6‐05‐08<br />
Hoess, C<br />
P5‐14‐06, P5‐15‐04<br />
Hoffman, A<br />
P1‐03‐01<br />
Hoffman, RM<br />
P4‐07‐04<br />
Hoffmann, G<br />
P1‐13‐13<br />
Hoffmann, J<br />
P6‐04‐23<br />
Hofmann, D<br />
OT3‐3‐02<br />
Hogarth, M<br />
P4‐13‐13<br />
Hogben, K<br />
P3‐02‐04<br />
Hogervorst, FB<br />
P4‐11‐01<br />
Hohl, MK<br />
P4‐03‐06<br />
Hojo, T<br />
P3‐02‐06<br />
Holcombe, C<br />
P4‐17‐03<br />
Holden, AE<br />
PD08‐05<br />
Holen, I<br />
PD07‐08, P2‐02‐04<br />
Holko, M<br />
P2‐10‐30<br />
Hollenbeck, AR<br />
P3‐07‐04<br />
Holliday, DL<br />
P6‐02‐06<br />
Hollingsworth, R<br />
P4‐07‐05<br />
Hollman, D P3‐05‐05, P3‐05‐06<br />
Holmberg, E<br />
P6‐12‐01<br />
Holmberg, L<br />
P2‐10‐29<br />
Holmdahl, J<br />
P2‐10‐07<br />
Holmes, FA<br />
P3‐06‐12<br />
Holmes, JP<br />
P5‐16‐02<br />
Holst, F<br />
P6‐05‐13<br />
Holt, S<br />
P1‐01‐18<br />
Holtrich, U<br />
P2‐10‐17<br />
Holtveg, H S4‐2<br />
Holz, MK<br />
P1‐04‐02<br />
Holzhausen, H‐J<br />
P2‐10‐38<br />
Hong, C‐C<br />
P3‐07‐02<br />
Hong, D<br />
P5‐20‐09<br />
Honisch, E<br />
P2‐07‐01<br />
Honma, N<br />
P3‐06‐18<br />
Hood, K<br />
PD07‐09<br />
Hood, N<br />
PD03‐05<br />
Hoog, J<br />
PD07‐01<br />
Hoogerbrugge, N<br />
P3‐02‐09<br />
Hooke, JA<br />
P2‐05‐21,<br />
P5‐01‐07, P6‐02‐08<br />
Hooning, M<br />
P3‐02‐09<br />
Hooning, MJ<br />
P4‐11‐05<br />
Hopkins, S<br />
P3‐13‐05<br />
Hopper, JL<br />
P4‐13‐10<br />
Hopper‐Borge, E<br />
P4‐08‐04<br />
Hopwood, P S4‐1<br />
Horgan, K P1‐13‐08, P4‐01‐14<br />
Horgan, M<br />
P3‐02‐10<br />
Horie‐Inoue, K<br />
P6‐04‐27<br />
Horiguchi, J PD07‐05, P1‐14‐06,<br />
P2‐05‐07, P3‐06‐29, P5‐18‐16<br />
Horii, R<br />
P1‐01‐12, P5‐01‐02<br />
Horio, A<br />
P1‐02‐02, P3‐12‐06<br />
Horiuchi, D S3‐8<br />
Hornberger, J<br />
P5‐15‐06<br />
Horne, HN<br />
P3‐08‐02<br />
Horng, C‐F<br />
P4‐16‐05<br />
Horowitz, NR P3‐14‐05, P3‐14‐06<br />
Horst, KC P4‐16‐11, P6‐08‐10<br />
Horstman, A<br />
PD02‐03<br />
Hortobagyi, G<br />
P6‐04‐02<br />
Hortobagyi, GN PD03‐06, PD03‐08,<br />
P1‐07‐09, P2‐01‐01, P2‐03‐01,<br />
P3‐10‐05, P5‐03‐09, P5‐04‐06,<br />
P5‐10‐02, P5‐20‐02, P5‐20‐13,<br />
OT2‐2‐04, OT2‐3‐10<br />
Horvat, R<br />
P2‐10‐31<br />
Horvath, LE<br />
P1‐12‐04<br />
Hoskin, P S4‐1<br />
Hoskins, KF<br />
P5‐13‐03<br />
Hosokawa, Y<br />
P4‐03‐05<br />
Hostetter, G<br />
P1‐05‐04<br />
Houck, III, WA<br />
OT1‐1‐07<br />
Houdayer, C<br />
P5‐02‐03<br />
Houk, B<br />
OT2‐3‐02<br />
Houlston, R<br />
P3‐08‐04<br />
Houpeau, J‐L<br />
P1‐01‐21,<br />
P4‐14‐10, OT2‐1‐01<br />
Houshmand, M<br />
P5‐09‐01<br />
Houvenaeghel, G P1‐01‐21, P5‐03‐01,<br />
OT2‐1‐01, OT2‐3‐05<br />
Hoverman, R<br />
P2‐11‐16<br />
Howard, N<br />
OT3‐4‐02<br />
Howe, M<br />
P3‐14‐04<br />
Howe, R<br />
P4‐11‐03<br />
Howell, A P1‐09‐05, P2‐14‐01,<br />
P3‐08‐01, P4‐13‐09<br />
Howell, L<br />
P4‐13‐13<br />
Howell, SJ<br />
P2‐14‐06<br />
Howitt, J<br />
P2‐10‐16<br />
Hozumi, Y P2‐13‐04, P2‐13‐07<br />
Hsiao, A<br />
P6‐11‐03, P6‐11‐11<br />
Hsieh, Y‐F<br />
P4‐04‐07<br />
Hsu, C‐H<br />
PD08‐04<br />
Hsu, L<br />
P3‐10‐05<br />
Hu, H P1‐05‐09, P2‐05‐21, P2‐10‐30,<br />
P3‐04‐06, P3‐04‐08, P3‐09‐03,<br />
P4‐06‐02, P5‐01‐07<br />
Hu, J<br />
P6‐07‐17<br />
Hu, P<br />
P4‐05‐01<br />
Hu, R<br />
P5‐01‐03<br />
Hu, X<br />
P6‐11‐01<br />
Hu, X‐C<br />
P6‐07‐43<br />
Huang, AT<br />
P4‐16‐05<br />
Huang, C<br />
P5‐03‐06<br />
Huang, C‐S<br />
P3‐06‐02,<br />
OT1‐1‐16, OT1‐1‐17<br />
Huang, H<br />
P3‐07‐06,<br />
P3‐07‐07, P3‐07‐14<br />
Huang, J<br />
P2‐05‐05<br />
Huang, L<br />
P2‐10‐29, P6‐07‐36<br />
Huang, P<br />
P2‐05‐05<br />
Huang, W<br />
P2‐05‐06,<br />
P2‐10‐16, P2‐10‐31<br />
Huang, Y<br />
P3‐12‐03,<br />
P6‐13‐02, OT1‐1‐04<br />
Hubbard, RA<br />
P4‐01‐15<br />
Hubert, C<br />
PD05‐04<br />
Hucke, J<br />
P2‐10‐25<br />
Hudis, C S5‐4, S5‐5, P1‐13‐11,<br />
P2‐12‐05, P5‐18‐04, P5‐18‐20,<br />
P6‐11‐10, OT3‐1‐01<br />
Hudis, CA P2‐10‐01, P5‐20‐07,<br />
P6‐05‐01, P6‐05‐02, P6‐08‐05<br />
Hudry, D<br />
P1‐01‐07<br />
Hughes, E<br />
P6‐04‐01<br />
Hughes, M<br />
P1‐01‐13<br />
Hughes, ME S3‐5<br />
Hughes, MR<br />
P1‐05‐05<br />
Hughes, NP P1‐06‐01, P4‐01‐01<br />
Hughes, TA<br />
P1‐13‐08<br />
Hui, M<br />
P3‐07‐03<br />
Huisman, JJ<br />
P4‐11‐01<br />
Hung, M‐H<br />
P3‐12‐10<br />
Hunt, K<br />
PD07‐01<br />
Hunt, KK<br />
S2‐1, P1‐01‐06,<br />
P1‐07‐09, P4‐15‐02<br />
Huo, D<br />
P2‐10‐21<br />
Huo, L<br />
P1‐07‐09<br />
Huober, J<br />
S3‐1, S3‐4, S4‐5,<br />
PD06‐01, P1‐14‐01, P3‐06‐05,<br />
OT1‐1‐13, OT3‐3‐11<br />
Hurd, T<br />
P1‐01‐06<br />
Hurlbert, M<br />
P3‐02‐07,<br />
P4‐13‐02, P5‐14‐02<br />
Hurley, E<br />
P3‐01‐04<br />
Hurley, L<br />
P2‐10‐16<br />
Hurria, A<br />
P2‐14‐08, P6‐08‐05<br />
Hurtado Rua, SM<br />
P6‐11‐04<br />
Hurvitz, S<br />
P4‐01‐13<br />
Hurvitz, SA P4‐08‐01, P4‐08‐05<br />
Hurvitz, S‐A<br />
OT1‐1‐16<br />
Hutchens, S<br />
P2‐12‐11<br />
Huws, A<br />
P1‐01‐18<br />
Hwang, B‐M<br />
P5‐07‐04<br />
Hwang, ES P4‐14‐04, P4‐16‐07<br />
Hwang, H<br />
P1‐01‐23<br />
Hwang, HC<br />
P1‐07‐01<br />
Hwang, J<br />
P2‐12‐11<br />
Hwang, RF<br />
P4‐15‐02<br />
Hwang, S P1‐01‐13, P2‐10‐03,<br />
P3‐06‐07, P4‐01‐13, P4‐13‐06<br />
Hwang, SH<br />
P2‐05‐14<br />
Hwang, SO<br />
P1‐01‐24<br />
Hwangbo, SM<br />
P1‐01‐24<br />
Hylton, NM<br />
P4‐01‐04,<br />
P4‐01‐10, P4‐01‐13<br />
Hynes, NE<br />
PD01‐06<br />
Ibarra‐Drendall, C<br />
P1‐03‐01<br />
Ibrahim, NK P5‐16‐01, P5‐16‐06<br />
Ibusuki, M<br />
P6‐05‐06<br />
Ichinose, Y<br />
P3‐13‐04<br />
Ide, Y<br />
P4‐03‐05<br />
Idvall, I<br />
P2‐10‐37<br />
Igawa, A<br />
P3‐06‐26<br />
Iglehart, JD<br />
P1‐07‐07<br />
Iglesias, J<br />
P1‐12‐07<br />
Ignatiadis, M S4‐4, P6‐07‐14, P6‐07‐22<br />
Iiboshi, Y<br />
P4‐03‐07<br />
Iida, J<br />
P1‐05‐09, P3‐04‐06<br />
Ijichi, N<br />
P6‐04‐27<br />
Ikeda, DM<br />
P4‐01‐12<br />
Ikeda, K<br />
P6‐04‐27<br />
Iliopoulos, D<br />
P6‐06‐02<br />
Illi, J<br />
P3‐04‐01, P3‐04‐02<br />
Im, S‐A S5‐1, PD09‐05, P1‐14‐19,<br />
P2‐05‐20, OT1‐1‐16<br />
Im, Y‐H PD09‐05, P2‐05‐20, P2‐14‐01,<br />
P4‐06‐13, OT1‐1‐16<br />
Imai, S<br />
P3‐13‐04<br />
Imawari, Y P4‐03‐10, P5‐04‐02<br />
Imoto, S<br />
P2‐13‐04, P2‐13‐07<br />
In, Y‐H<br />
PD05‐07<br />
Inaba, M<br />
P1‐01‐20<br />
Inaji, H<br />
P2‐10‐18<br />
Inamoto, T<br />
P3‐13‐04<br />
Inbar, MJ<br />
P5‐17‐03<br />
Incio, J<br />
P3‐12‐03<br />
Infante, JR<br />
P6‐11‐06<br />
Infante, KP<br />
P1‐01‐28<br />
Ingber, D<br />
P5‐05‐04<br />
Ingber, DE<br />
P2‐04‐03<br />
Ingham, SL<br />
P3‐08‐01<br />
Ingle, J<br />
P6‐05‐02<br />
Ingle, JN<br />
P2‐13‐02, OT1‐1‐11<br />
Ingledew, P P5‐12‐01, P5‐12‐02<br />
Inhorn, RC<br />
P5‐17‐05<br />
Inoges, S<br />
P5‐16‐03<br />
Inokuchi, M<br />
P4‐16‐13<br />
Inoue, H<br />
OT1‐1‐01<br />
Inoue, K<br />
P1‐14‐06, P3‐02‐06<br />
Inoue, S<br />
P6‐04‐27<br />
International Ki67 in <strong>Breast</strong><br />
<strong>Cancer</strong> Working Group of the<br />
BIG‐NABCG Collaboration S4‐6<br />
Ioffe, OB<br />
P2‐10‐40<br />
Iorns, E<br />
P1‐05‐12<br />
Ip, P S5‐7<br />
Irvin, WJ<br />
PD10‐08<br />
Irwin, M<br />
P2‐11‐08<br />
Isaacs, C<br />
P1‐09‐04<br />
Isakoff, SJ PD09‐03, P2‐01‐14,<br />
P3‐06‐27, P6‐05‐02,<br />
P6‐10‐05, OT2‐3‐07<br />
Isambert, N<br />
P6‐11‐08<br />
Ishibe, Y<br />
P3‐07‐10<br />
Ishida, K<br />
P6‐05‐14<br />
Ishida, M<br />
P3‐06‐26<br />
Ishida, T P1‐06‐02, P2‐10‐43, P6‐05‐14<br />
Isidoro, M<br />
P1-15-03<br />
Ishiguchi, T<br />
P4‐03‐08<br />
Ishiguro, H<br />
P5‐18‐16<br />
Ishihara, S<br />
P3‐07‐10<br />
Ishikawa, T<br />
PD07‐05<br />
Ishioka, C<br />
P2‐10‐43<br />
Isikdogan, A<br />
OT1‐1‐08<br />
Ismail‐Khan, R<br />
P2‐14‐04<br />
Isner, P<br />
P2‐10‐03<br />
Isola, J<br />
PD10‐06<br />
I‐SPY 1 TRIAL Investigators P2‐10‐06<br />
I‐SPY TRIAL‐1 Investigators P2‐05‐01,<br />
P3‐04‐01,<br />
P3‐04‐02, P3‐06‐10<br />
Ito, K‐I<br />
P6‐04‐17<br />
Ito, M<br />
P1‐14‐12, P4‐01‐05<br />
Ito, T<br />
P4‐03‐07<br />
Ito, Y<br />
P1‐14‐02, P5‐18‐16<br />
Itoi, N<br />
P1‐15‐11<br />
Itoyanagi, N<br />
P1‐01‐27<br />
Ivancic, D P2‐10‐30, P3‐04‐08<br />
Iversen, A<br />
P3‐01‐01<br />
Iwamoto, M P3‐02‐02, P3‐09‐04<br />
Iwamoto, T PD03‐08, P2‐05‐08,<br />
P2‐10‐10, P3‐07‐10,<br />
P3‐10‐05, P5‐10‐01<br />
Iwaniuk, KM<br />
P2‐07‐01<br />
Iwasa, M<br />
P4‐12‐06<br />
Iwase, H P1‐12‐01, P2‐14‐03, P6‐05‐06<br />
Iwase, T<br />
P1‐01‐12<br />
Iwata, H P1‐12‐01, P1‐14‐02, P2‐13‐04,<br />
P2‐13‐07, P3‐02‐06, P3‐12‐06,<br />
P5‐18‐16, P6‐07‐16,<br />
OT2‐3‐03, OT2‐3‐09<br />
Iyer, S<br />
P3‐04‐08<br />
Iyeyasu, H<br />
P4‐02‐03<br />
Izukura, M<br />
P4‐03‐07<br />
Izumchenko, E<br />
P1‐05‐03<br />
Jac, J<br />
P6‐11‐10<br />
Jacene, H<br />
P5‐02‐01<br />
Jacene, HA P3‐10‐06, P4‐06‐01<br />
Jackisch, C S3‐1, S3‐1, S3‐4, S4‐5,<br />
S5‐2, S6‐5, PD06‐01,<br />
P1‐14‐01, P5‐18‐02, P6‐09‐08,<br />
OT1‐1‐13, OT3‐3‐11<br />
Jackson, SA<br />
P5‐20‐13<br />
Jacob, J<br />
P5‐21‐03<br />
Jacobs, J<br />
P4‐08‐04<br />
Jacobs, LK<br />
OT2‐1‐04<br />
Jacobs, SA<br />
OT1‐1‐12<br />
Jacobs, VR P5‐14‐06, P5‐15‐04<br />
Jacobsen, BM<br />
P2‐14‐02<br />
Jacquemier, J<br />
P3‐05‐07,<br />
P3‐14‐03, P5‐03‐01<br />
Jaeger, BAS<br />
P2‐01‐02,<br />
P4‐13‐11, OT1‐1‐10<br />
Jaenicke, F<br />
P1‐13‐13<br />
Jafari, N<br />
P2‐12‐10<br />
Jaffray, D<br />
P4‐02‐05<br />
Jaganathan, H<br />
P6‐02‐07<br />
Jahanzeb, M<br />
OT3‐3‐07<br />
Jain, M<br />
OT1‐1‐17<br />
Jain, RK<br />
P3‐12‐03<br />
Jain, S<br />
P1‐15‐07, P6‐11‐04<br />
Jakesz, R<br />
S4‐3, P2‐10‐02<br />
Jalaguier, A P5‐03‐01, OT2‐3‐05<br />
James, CR<br />
P6‐07‐24<br />
Jammallo, LS P6‐09‐04, OT3‐2‐02<br />
Jamshidian, F S1‐10, P6‐07‐03<br />
Janevski, A PD05‐05, P4‐01‐02<br />
Jankowitz, R<br />
P6‐07‐02<br />
Jankowski, T<br />
P2‐10‐31<br />
Janku, F<br />
P5‐20‐09<br />
Janni, JW<br />
P1‐14‐04,<br />
P4‐13‐11, OT1‐1‐10<br />
Janni, W<br />
P2‐01‐02,<br />
P2‐10‐25, P5‐18‐21<br />
Jansen, MPHM P3‐06‐01, P6‐04‐08<br />
Janssen, E<br />
P2‐10‐19<br />
Janus, N<br />
P5‐17‐04<br />
Jarosz, M<br />
PD02‐07<br />
Jarrett, BL<br />
P2‐11‐04<br />
Jasin, M<br />
PD09‐10<br />
Jaslow, RC<br />
P5‐14‐03<br />
Jassem, J P2‐10‐31, P3‐12‐09, P3‐13‐03,<br />
P5‐02‐02, P5‐04‐01, OT1‐1‐16<br />
Jassim, GA<br />
P6‐08‐07<br />
Javadi, GH<br />
P5‐09‐01<br />
Javed, Y<br />
OT3‐3‐07<br />
www.aacrjournals.org 595s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Jaworska‐Jankowska, M P3‐12‐09,<br />
P3‐13‐03<br />
Jay, A<br />
PD03‐09<br />
Jean, A<br />
P5‐10‐06<br />
Jefferys, SR S6‐1<br />
Jen, J<br />
PD10‐04<br />
Jenkins, RB PD02‐05, PD10‐04<br />
Jensen, AB<br />
P6‐07‐08<br />
Jensen, K<br />
P1‐07‐05<br />
Jensen, KC<br />
PD09‐04<br />
Jensen, RA<br />
PD09‐02<br />
Jeong, J<br />
P2‐05‐14<br />
Jeong, J‐H S1‐10, S5‐5<br />
Jerusalem, G S1‐4<br />
Jeschke, U<br />
P2‐01‐11<br />
Jeselsohn, RM<br />
P1‐07‐07<br />
Jesien‐Lewandowicz, E P3‐12‐09,<br />
P3‐13‐03<br />
Jeter, S<br />
P2‐02‐01<br />
Jeuris, K<br />
P2‐01‐08<br />
Ji, L<br />
P4‐01‐11<br />
Jia, Z<br />
P6‐07‐43<br />
Jian, J‐MJ<br />
P4‐16‐05<br />
Jiang, J S2‐3<br />
Jiang, JX<br />
P3‐13‐06<br />
Jiang, W<br />
P1‐04‐08<br />
Jiang, WG P1‐04‐03, P1‐04‐07,<br />
P1‐04‐09, P6‐05‐11<br />
Jiang, Y‐Z<br />
P2‐06‐07<br />
Jibiki, N<br />
OT1‐1‐01<br />
Jimenez, J<br />
P1‐07‐19<br />
Jin, J P5‐18‐11, P5‐18‐24, P6‐10‐04<br />
Jin, K P2‐09‐01, P4‐06‐08, P6‐04‐13<br />
Jin, L<br />
P1‐01‐09, P6‐01‐03<br />
Jin, W<br />
P6‐04‐26<br />
Jindal, S<br />
P4‐04‐03<br />
Jinno, H<br />
P1‐14‐09, P3‐06‐22,<br />
P4‐03‐03, P4‐09‐08<br />
Jirstrom, K<br />
PD03‐07,<br />
P2‐10‐28, P4‐09‐06<br />
Jiwa, M<br />
PD02‐03<br />
Jo, J‐C<br />
P3‐12‐05<br />
Jo, J‐H<br />
P6‐07‐28<br />
Joe, BN<br />
P4‐01‐10<br />
Joensuu, H PD10‐06, OT1‐1‐15<br />
Joerger, M<br />
OT2‐2‐02<br />
Joffres, M<br />
P4‐17‐08<br />
Joglekar, M P1‐04‐10, P6‐06‐03<br />
Johansson, H PD06‐06, P6‐14‐01<br />
Johansson, O<br />
P2‐10‐37<br />
Johnson, N<br />
P3‐08‐04<br />
Johnson, R<br />
P3‐14‐04<br />
Johnston, S<br />
PD07‐07,<br />
P6‐07‐15, OT1‐1‐04<br />
Johnston, SA<br />
P6‐12‐02<br />
Johnston, SRD<br />
P2‐14‐01<br />
Jonat, W OT2‐3‐09, OT3‐2‐01<br />
Jones, EF<br />
P4‐01‐04<br />
Jones, JG<br />
P6‐02‐04<br />
Jones, KN<br />
P1‐01‐22<br />
Jones, LA<br />
P1‐01‐01<br />
Jones, M<br />
P3‐08‐04<br />
Jones, N<br />
PD05‐04<br />
Jones, NR<br />
P2‐11‐15<br />
Jones, RA<br />
P1‐04‐05<br />
Jones, S<br />
P3‐06‐12<br />
Joore, MA<br />
P5‐21‐04<br />
Jordan, K<br />
P4‐04‐06<br />
Jordan, LB<br />
PD03‐02<br />
Jordan, VC<br />
P2‐13‐09<br />
Jørgensen, CLT<br />
P3‐06‐03<br />
Jose, V<br />
P1‐07‐08<br />
Joseph, D S4‐2<br />
Joseph, J<br />
P6‐04‐12<br />
Joshi, A<br />
PD01‐01<br />
Josselin, E<br />
P5‐03‐01<br />
Jouannaud, C P3‐06‐20, P5‐17‐04<br />
Joukov, V<br />
P4‐10‐01<br />
Jovanovic, B P1‐09‐07, P3‐05‐09<br />
Joy, MT<br />
P1‐01‐04<br />
Jud, SM<br />
PD07‐02<br />
Judde, J‐G<br />
P3‐06‐24<br />
Jueckstock, J<br />
P4‐13‐11<br />
Juhasz, E<br />
P3‐05‐08<br />
Julian, TB S1‐10, S2‐1, OT1‐2‐01<br />
Jun, N<br />
P3‐05‐05, P3‐05‐06<br />
Jung, HH<br />
P4‐06‐13<br />
Jung, JH<br />
P1‐01‐24<br />
Jung, K<br />
OT1‐1‐16<br />
Jung, KH<br />
P3‐12‐05<br />
Jung, K‐H<br />
P6‐01‐05<br />
Jung, ME<br />
PD03‐04<br />
Jung, MS S6‐3<br />
Jung, S<br />
P2‐11‐05<br />
Jung, SH<br />
P1‐10‐01, P5‐07‐04<br />
Jung, SP<br />
P3‐11‐01<br />
Jung, SS<br />
P2‐05‐02, P4‐03‐01<br />
Jung, S‐Y<br />
P1‐01‐03<br />
Jungberg, P<br />
P5‐21‐02<br />
Junghaenel, DU<br />
P6‐08‐06<br />
Jupe, ER<br />
P4‐12‐05<br />
Juretic, A<br />
P4‐04‐04<br />
Juric, D<br />
S5‐7, P6‐10‐07<br />
Justice, R S1‐11<br />
Jyrkkiö, S<br />
PD10‐06<br />
Kaanumalle, L<br />
P3‐05‐06<br />
Kaas, R<br />
P4‐11‐05<br />
Kabos, P<br />
PD01‐07, P6‐05‐10<br />
Kadlubar, SA<br />
P3‐06‐30<br />
Kadouri‐Sonenfeld, L P5‐20‐06<br />
Kadoya, T<br />
P6‐07‐26<br />
Kahan, Z<br />
P5‐02‐02, P5‐17‐03<br />
Kahraman, M<br />
P6‐04‐12<br />
Kai, K PD03‐08, P2‐04‐01, P3‐10‐05<br />
Kaklamani, VG<br />
P5‐03‐11<br />
Kakolyris, S<br />
P1‐13‐09<br />
Kakugawa, Y<br />
P6‐07‐27<br />
Kalinsky, K PD03‐03, P1‐09‐02,<br />
P2‐01‐10, P2‐08‐01,<br />
P2‐11‐03, P2‐12‐01,<br />
P4‐02‐07, P6‐05‐01, P6‐12‐03<br />
Kallakury, BVS<br />
P1‐09‐04<br />
Kallergi, G P2‐01‐03, P2‐01‐07<br />
Kalna, G<br />
P1‐05‐13<br />
Kalogeras, KT<br />
P1‐07‐15<br />
Kalous, O<br />
P4‐08‐01<br />
Kamada, Y<br />
P1‐06‐02<br />
Kamalakaran, S PD05‐05, P4‐01‐02<br />
Kamath, V<br />
P3‐05‐06<br />
Kamigaki, S<br />
P1‐14‐02<br />
Kamimura, M<br />
OT1‐1‐01<br />
Kamio, M P4‐03‐10, P5‐04‐02<br />
Kamischke, A<br />
OT2‐2‐05<br />
Kammler, R<br />
PD10‐03<br />
Kamoun, W<br />
P3‐12‐03<br />
Kan, N<br />
P3‐13‐04<br />
Kandalaft, PL<br />
P1‐07‐01<br />
Kaneda, M<br />
P4‐09‐08<br />
Kaneko, K<br />
P1‐14‐08<br />
Kang, E<br />
P5‐04‐03<br />
Kang, J<br />
P6‐07‐28<br />
Kang, MJ<br />
P3‐12‐05<br />
Kang, SH<br />
P5‐04‐07<br />
Kang, S‐H P1‐01‐05, P3‐03‐02<br />
Kanji, S<br />
P2‐11‐07<br />
Kannarkat, G<br />
P5‐20‐10<br />
Kantelhardt, EJ<br />
P1‐13‐13<br />
Kantelhardt, E‐J<br />
P2‐10‐38<br />
Kao, W‐Y<br />
P4‐04‐07<br />
Kapitza, T P5‐14‐06, P5‐15‐04<br />
Kaplan, C<br />
P4‐13‐13<br />
Kaplan, CP<br />
P4‐13‐05<br />
Kapoor, S<br />
P3‐06‐10<br />
Karaba, M<br />
P2‐01‐12<br />
Karaszewska, B<br />
P5‐18‐21<br />
Karimi, M<br />
P3‐06‐28<br />
Karkera, J<br />
P5‐01‐09<br />
Karlin, NJ<br />
P1‐12‐06<br />
Karliner, L<br />
P4‐13‐05<br />
Karlis, D<br />
P5‐18‐02<br />
Karn, T<br />
P2‐10‐17, P3‐06‐05<br />
Karp, JE S3‐5<br />
Karp, N<br />
P4‐14‐03, P4‐17‐07<br />
Kasem, A P1‐04‐08, P1‐04‐09<br />
Kash, JJ<br />
P1‐12‐04<br />
Kashef‐Haghighi, D<br />
PD05‐09<br />
Kashiwaba, M<br />
P1‐14‐02,<br />
P1‐14‐08, P5‐18‐16<br />
Kasiewicz, M<br />
P4‐04‐02<br />
Kass, EM<br />
PD09‐10<br />
Kast, J<br />
P1‐05‐06<br />
Kataja, V<br />
PD10‐06<br />
Katayama, H<br />
P2‐04‐05<br />
Katchman, BA<br />
P1‐05‐04<br />
Katdare, M<br />
P1‐10‐02<br />
Kates, RE P2‐10‐08, OT3‐3‐02<br />
Kato, H<br />
P3‐13‐04<br />
Kato, K<br />
P4‐03‐10, P5‐04‐02<br />
Kato, T<br />
P2‐11‐02<br />
Katzorke, N<br />
P4‐13‐11<br />
Kaufman, B<br />
P5‐17‐03,<br />
P5‐20‐06, OT2‐3‐07<br />
Kaufman, CS<br />
PD04‐04<br />
Kaufman, J<br />
P6‐04‐12<br />
Kaufman, PA<br />
S6‐6, P2‐05‐06<br />
Kaufmann, M P2‐10‐17, P6‐07‐05<br />
Kaul, K<br />
P3‐05‐01<br />
Kaur, K<br />
P1‐06‐01<br />
Kaushik, M<br />
P1‐14‐15<br />
Kavuri, SM S5‐6<br />
Kawabata, H<br />
P1‐14‐08<br />
Kawai, M<br />
P6‐07‐27<br />
Kawai, N<br />
P3‐07‐10<br />
Kawai, Y<br />
P1‐15‐11<br />
Kawasaki, K<br />
P3‐07‐10<br />
Kay, C PD10‐02, P3‐06‐23, P6‐04‐09<br />
Kaye, P<br />
P5‐14‐04<br />
Kazmi, N<br />
PD03‐04<br />
Ke, C<br />
OT2‐3‐03<br />
Keam, B<br />
PD09‐05, P2‐05‐20<br />
Keane, A<br />
OT3‐4‐04<br />
Kearney, T<br />
P4‐16‐09<br />
Keating, NL<br />
P6‐08‐05<br />
Keegan, M P6‐11‐07, P6‐11‐09<br />
Keene, K<br />
P3‐03‐03<br />
Keene, KS P5‐17‐07, P6‐07‐37<br />
Keisch, M<br />
P4‐16‐03<br />
Kelleher, M<br />
P2‐10‐29<br />
Keller, L<br />
OT3‐2‐01<br />
Kelley, MC<br />
P4‐01‐03<br />
Kellokumpu‐Lehtinen, P‐L PD10‐06<br />
Kelly, CM<br />
P2‐10‐10<br />
Kelly, EM<br />
P5‐11‐02<br />
Kenis, C<br />
P6‐09‐07<br />
Kennedy, D<br />
P6‐08‐08<br />
Kennedy, MJ<br />
P6‐01‐02<br />
Kenney, K<br />
P4‐12‐04<br />
Kenny, K<br />
P3‐05‐05<br />
Kenny, PA<br />
P2‐04‐06<br />
Keogh, M<br />
P5‐10‐13<br />
Kerbrat, P<br />
S5‐3, PD07‐04,<br />
P1‐13‐04, P2‐13‐10<br />
Kere, D<br />
P1‐01‐21<br />
Kerin, M<br />
P3‐08‐04<br />
Kerin, MJ<br />
P1‐01‐15,<br />
P2‐05‐09, P5‐10‐07<br />
Kerlikowske, K<br />
P3‐02‐01,<br />
P4‐01‐15, P4‐13‐05<br />
Kern, P<br />
P2‐10‐14<br />
Kesari, S<br />
P3‐12‐04<br />
Kesarwala, AH P2‐11‐13, P2‐11‐14<br />
Keshtgar, M S4‐2<br />
Kesmodel, S<br />
P2‐13‐05<br />
Kessels, LW<br />
PD07‐06<br />
Keymeulen, KB<br />
P6‐08‐02<br />
Keymeulen, KBMI<br />
P5‐01‐13<br />
Khan, AJ<br />
P4‐16‐09<br />
Khan, J<br />
P4‐14‐13<br />
Khan, M<br />
P4‐16‐01<br />
Khan, QJ<br />
PD09‐02<br />
Khan, SA P1‐09‐07, P2‐10‐30,<br />
P3‐04‐08, P4‐12‐04<br />
Khanna, KK<br />
P6‐10‐06<br />
Khasanov, R S1‐4<br />
Khawaja, S<br />
P1‐01‐18<br />
Khayat, D S5‐3<br />
Khodari, W<br />
P4‐16‐10<br />
Khong, H<br />
P5‐18‐14<br />
Kieback, DG S1‐5<br />
Kiechle, M P5‐14‐06, P5‐15‐04<br />
Kiefer, A<br />
OT3‐4‐04<br />
Kieper, DA P4‐02‐09, P4‐02‐10<br />
Kiermaier, A S5‐1<br />
Kikuchi, M P2‐12‐13, P3‐06‐29<br />
Kil, WH<br />
P3‐11‐01<br />
Kilburn, L<br />
P1‐13‐03<br />
Kilburn, LS<br />
P2‐14‐01<br />
Killelea, B P3‐14‐05, P3‐14‐06<br />
Kim, A<br />
P5‐04‐07<br />
Kim, B<br />
P4‐01‐14<br />
Kim, BS<br />
P4‐03‐11<br />
Kim, CA<br />
P1‐05‐10<br />
Kim, D‐C<br />
PD02‐06<br />
Kim, EJ<br />
P4‐03‐01, P5‐04‐03<br />
Kim, E‐K<br />
P1‐01‐23<br />
Kim, H<br />
P5‐07‐03<br />
Kim, HH<br />
P3‐01‐02, P3‐12‐05<br />
Kim, HJ<br />
PD09‐05, P3‐01‐02<br />
Kim, HK<br />
P4‐02‐07<br />
Kim, J<br />
PD05‐07, P3‐11‐01<br />
Kim, J‐A<br />
PD09‐08, P6‐04‐25<br />
Kim, JE<br />
P3‐12‐05<br />
Kim, JH<br />
PD09‐05<br />
Kim, JS P1‐01‐08, P1‐14‐16, P5‐07‐04<br />
Kim, JW<br />
P5‐16‐06<br />
Kim, JY<br />
PD05‐07, P1‐01‐08,<br />
P1‐14‐16, P2‐10‐35<br />
Kim, M<br />
P2‐10‐41, P3‐11‐01<br />
Kim, MJ<br />
P1‐01‐23<br />
Kim, MK PD05‐07, P1‐01‐08, P1‐14‐16<br />
Kim, N<br />
OT1‐1‐01<br />
Kim, P S5‐7<br />
Kim, S<br />
PD05‐07, P2‐05‐20,<br />
P3‐08‐03, P3‐11‐01<br />
Kim, SB<br />
PD09‐05<br />
Kim, S‐B<br />
P3‐12‐05, P5‐18‐26<br />
Kim, SH<br />
P4‐03‐01<br />
Kim, SI<br />
P1‐01‐23<br />
Kim, S‐I<br />
P2‐05‐03<br />
Kim, SJ<br />
PD07‐05, P2‐10‐18<br />
Kim, SK<br />
P1‐10‐01<br />
Kim, S‐K<br />
P1‐01‐03<br />
Kim, S‐R S1‐10<br />
Kim, SS<br />
P3‐12‐05<br />
Kim, ST S1‐6<br />
Kim, SW<br />
P1‐01‐03<br />
Kim, S‐W<br />
P5‐04‐03<br />
Kim, S‐Y<br />
PD09‐05<br />
Kim, T<br />
PD05‐07, P1‐01‐08,<br />
P1‐14‐16, P3‐06‐16<br />
Kim, WW<br />
P1‐01‐24<br />
Kim, Y<br />
P4‐12‐02<br />
Kim, YW<br />
P1‐10‐01<br />
Kimbung, S<br />
P1‐05‐07<br />
Kimler, BF<br />
PD09‐02<br />
Kimmick, GG<br />
P6‐08‐05<br />
Kimura, K<br />
P3‐02‐02,<br />
P3‐09‐04, OT1‐1‐01<br />
King, DW<br />
P1‐01‐04<br />
King, J<br />
P4‐06‐04<br />
King, K‐L<br />
P3‐12‐10<br />
King, KS<br />
PD10‐05<br />
King, T<br />
P5‐18‐04<br />
King, TA<br />
PD04‐05, PD05‐02<br />
Kinneer, K<br />
P4‐07‐05<br />
Kinoshita, J<br />
OT1‐1‐01<br />
Kinoshita, N<br />
P1‐01‐27<br />
Kinoshita, T P1‐01‐12, P3‐02‐06<br />
Kirby, G<br />
OT3‐3‐01<br />
Kirkegaard, T<br />
P6‐04‐18<br />
Kirova, YM P1‐01‐19, P4‐13‐14,<br />
P5‐01‐05, P5‐21‐03<br />
Kirpotin, D<br />
P4‐02‐05<br />
Kirstein, L<br />
P4‐15‐03<br />
Kirwan, CC P1‐01‐26, P3‐14‐04<br />
Kishimoto, M<br />
P6‐07‐39<br />
Kiss, A<br />
P6‐08‐04<br />
Kitagawa, Y P1‐14‐09, P3‐06‐22,<br />
P4‐03‐03, P4‐09‐08<br />
Kitao, A<br />
P6‐07‐30<br />
Kitchens, C<br />
P6‐05‐12<br />
Kiyokawa, I<br />
P2‐10‐32<br />
Klauschen, F<br />
PD06‐01<br />
Kleer, CG<br />
P1‐04‐11<br />
Klein, ME<br />
P6‐07‐02<br />
Klein, P P3‐08‐08, P6‐07‐34, P6‐09‐08<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
596s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
Author Index<br />
Kleine‐Tebbe, A<br />
P2‐10‐25<br />
Kleinman, R<br />
P2‐11‐12<br />
Klein‐Szanto, AA<br />
P1‐05‐03<br />
Klemens, AE<br />
PD08‐04<br />
Klemp, JR PD09‐02, P2‐11‐17<br />
Klepczyk, LC<br />
P6‐07‐37<br />
Klesczewski, K<br />
P5‐20‐03<br />
Klifa, C<br />
P4‐01‐04<br />
Klimowicz, A<br />
P4‐09‐07<br />
Klimowicz, AC P1‐07‐10, P6‐07‐17<br />
Kline, E<br />
PD01‐07<br />
Klinge, CM<br />
P6‐04‐30<br />
Klint, L<br />
P6‐12‐01<br />
Klintman, M P2‐10‐19, P2‐10‐28<br />
Klotz, R<br />
P6‐01‐04<br />
Kluding, P<br />
P2‐11‐17<br />
Knauer, M<br />
S4‐3, P2‐10‐02<br />
Knight, R<br />
P3‐06‐33<br />
Knoblauch, N<br />
P5‐01‐03<br />
Knoop, A<br />
P4‐09‐04, P5‐15‐07<br />
Knott, A<br />
P5‐18‐01, P5‐18‐26<br />
Knowlton, NS<br />
P4‐12‐05<br />
Knutson, KL<br />
P5‐03‐07<br />
Kobayashi, N<br />
P3‐02‐05<br />
Kobayashi, Y<br />
P6‐04‐17<br />
Koboldt, DC S5‐6<br />
Kochi, M<br />
P1‐14‐12, P4‐01‐05<br />
Koczywas, M<br />
P2‐14‐08<br />
Kodack, DP<br />
P3‐12‐03<br />
Koechlin, A P4‐13‐07, P4‐13‐08<br />
Koehn, TM<br />
P2‐11‐15<br />
Koelbl, H<br />
P2‐10‐13<br />
Koenig, KB<br />
P1‐07‐09<br />
Koeppen, H<br />
P4‐07‐01<br />
Koestler, W<br />
P3‐06‐33<br />
Koffijberg, E<br />
P5‐15‐03<br />
Kofi, P<br />
P2‐05‐10<br />
Kogianni, G<br />
P2‐02‐03<br />
Koh, BS<br />
P3‐01‐02<br />
Koh, YW<br />
P2‐02‐02<br />
Kohn, E<br />
P2‐04‐08<br />
Kohno, N<br />
PD07‐05, P5‐18‐16<br />
Kohno, S<br />
P6‐07‐39<br />
Kojima, I<br />
P1‐01‐20<br />
Koka, M<br />
P2‐10‐40<br />
Kokufu, I<br />
P6‐07‐39<br />
Kölbl, AC<br />
P2‐01‐11<br />
Kolesar, JM<br />
P6‐12‐02<br />
Kolev, VN P6‐11‐07, P6‐11‐09<br />
Kolonel, LN<br />
P4‐12‐02<br />
Komenaka, IK<br />
PD08‐04<br />
Komiya, H<br />
P4‐15‐05<br />
Kondo, N P1‐02‐02, P3‐12‐06<br />
Kong, X<br />
P2‐09‐06<br />
Kong, Y<br />
P5‐10‐10<br />
König, K<br />
P6‐09‐08<br />
Königsberg, R<br />
P2‐13‐01<br />
Konishi, M<br />
PD07‐05<br />
Konno, H<br />
P6‐04‐17<br />
Konno, M<br />
P1‐07‐10,<br />
P4‐09‐07, P6‐07‐17<br />
Kontos, D<br />
P4‐01‐08<br />
Koo, JS<br />
P1‐01‐23, P2‐05‐03<br />
Koolen, BB<br />
P4‐02‐01<br />
Koornstra, RHT<br />
PD01‐03<br />
Köppler, H<br />
P2‐11‐11<br />
Korah, V<br />
P5‐13‐03<br />
Körber, W<br />
P1‐07‐16<br />
Kornaga, EN<br />
P1‐07‐10<br />
Kornak, J<br />
P4‐01‐04<br />
Kornblith, A<br />
P6‐08‐05<br />
Kornhauser, N<br />
P6‐11‐04<br />
Korth, CC<br />
P6‐11‐10<br />
Kosaka, Y<br />
P2‐12‐13<br />
Kosel, M<br />
PD10‐08<br />
Koslow, S<br />
PD04‐05<br />
Koslow Mautner, S<br />
PD05‐02<br />
Köstler, WJ<br />
P2‐10‐31<br />
Kotin, A<br />
OT3‐1‐01<br />
Kotoula, V<br />
P1‐07‐15<br />
Koukel, L<br />
PD10‐09<br />
Kounalakis, N<br />
P4‐04‐06<br />
Kourousis, C<br />
P1‐13‐09<br />
Kousaka, J<br />
P4‐03‐08<br />
Koutcher, JA<br />
P6‐01‐01<br />
Kovács, AK<br />
P3‐05‐08<br />
Kovács, G<br />
P4‐15‐01<br />
Kovacs, A<br />
P1‐05‐07<br />
Kovalenko, N<br />
OT1‐1‐17<br />
Kovatich, AJ<br />
P2‐05‐21,<br />
P3‐04‐06, P5‐01‐07<br />
Kowalski, M<br />
P5‐05‐04<br />
Krag, KJ<br />
PD09‐03, P2‐16‐04<br />
Kramar, A<br />
S5‐3, OT1‐2‐02<br />
Kranwinkel, G P2‐11‐03, P2‐12‐01<br />
Kranwinkle, G<br />
P1‐09‐02<br />
Krappmann, K<br />
P2‐10‐11<br />
Krase, P<br />
P5‐14‐06, P5‐15‐04<br />
Krasnozhon, D<br />
OT3‐3‐01<br />
Krause, S<br />
P2‐04‐03, P5‐05‐04<br />
Kreienberg, R<br />
S3‐4, P6‐09‐08<br />
Kreipe, HH<br />
P2‐10‐08<br />
Krekel, N<br />
PD04‐01<br />
Krekow, L<br />
P2‐05‐06<br />
Krenek, K<br />
P5‐07‐03<br />
Krishnamurthy, S P1‐07‐06, P2‐03‐01,<br />
P3‐10‐09, P3‐10‐10,<br />
P5‐03‐05, P5‐04‐06<br />
Krishnamurthy, SA<br />
P3‐10‐01<br />
Krishnan, SR<br />
PD09‐07<br />
Kristensen, VN<br />
P5‐05‐03<br />
Kristoffersson, U<br />
P2‐10‐37<br />
Krizman, D<br />
P6‐07‐17<br />
Krocker, J<br />
P1‐14‐05<br />
Kroemer, G<br />
P2‐08‐04<br />
Kroep, JR<br />
PD07‐06<br />
Krohn, KA<br />
P6‐04‐03<br />
Kroll, T<br />
P1‐07‐16<br />
Kronenwett, R S4‐3, P2‐10‐11<br />
Kronish, L<br />
P1‐12‐03<br />
Krontiras, H P3‐03‐03, P5‐17‐07<br />
Krop, I<br />
P3‐05‐03, P5‐18‐03<br />
Krop, IE<br />
P5‐18‐06, OT1‐1‐11<br />
Kruchevsky, N<br />
P6‐01‐01<br />
Kruitwagen, RF<br />
P6‐08‐02<br />
Krupa, J<br />
P4‐14‐14<br />
Kruper, L<br />
PD08‐02<br />
Kuba, MG<br />
S3‐6, P6‐10‐05<br />
Kuba, S<br />
P3‐06‐26<br />
Kubik‐Huch, RA<br />
P4‐03‐06<br />
Kubo, K<br />
P1‐14‐06<br />
Kubota, Y<br />
P1‐15‐11<br />
Kuchiki, M<br />
P3‐02‐03<br />
Kuchuk, I<br />
P2‐05‐13,<br />
P3‐13‐05, P5‐13‐01<br />
Kuderer, NM<br />
P1‐15‐04,<br />
P2‐10‐03, P3‐06‐07<br />
Kudla, A<br />
P1‐07‐03<br />
Kudo, Y<br />
P3‐13‐04<br />
Kuehn, T S2‐2<br />
Kuemmel, S<br />
S3‐1, P1‐14‐01,<br />
OT1‐1‐13, OT3‐3‐11<br />
Kuenen, MA<br />
P4‐11‐01<br />
Kuerer, HM S2‐3, P1‐07‐09, P4‐15‐02<br />
Kuffel, M<br />
PD10‐08<br />
Kuhn, W S3‐4<br />
Kuijpers, CC<br />
PD02‐03<br />
Kulka, J<br />
P3‐05‐08<br />
Kulma‐Kreft, M P3‐12‐09, P3‐13‐03<br />
Kulyk, SO S1‐6<br />
Kumaki, N<br />
P2‐05‐08<br />
Kumar, R<br />
P4‐08‐08<br />
Kumar, S<br />
P3‐07‐02<br />
Kumar, V<br />
PD01‐01, P6‐10‐03<br />
Kümmel, S PD07‐02, P1‐14‐05<br />
Kuo, S‐H<br />
P3‐06‐02<br />
Kuo, W‐H<br />
P4‐03‐02<br />
Kuranami, M<br />
P2‐12‐13<br />
Kurbacher, C<br />
S3‐4, P1‐15‐02<br />
Kurebayashi, J<br />
P2‐10‐18<br />
Kurian, AW P3‐11‐02, P4‐11‐02<br />
Kuriyama, N<br />
OT2‐3‐11<br />
Kurland, BF<br />
P6‐04‐03<br />
Kuroi, K P1‐12‐01, P1‐14‐02, P3‐02‐06,<br />
P3‐06‐18, P4‐14‐07, P6‐07‐16<br />
Kurokawa, M<br />
P1‐05‐03<br />
Kurosumi, M<br />
P1‐14‐06,<br />
P5‐01‐02, P6‐04‐17<br />
Kurozumi, S<br />
P1‐14‐06<br />
Kurzrock, R<br />
P5‐20‐09<br />
Kusche, M<br />
P1‐07‐16<br />
Kuy, C<br />
P4‐06‐08<br />
Kvale, EA<br />
P2‐12‐14<br />
Kvecher, L P2‐05‐21, P5‐01‐07<br />
Kwak, HY<br />
P4‐03‐01<br />
Kwan, M<br />
P3‐07‐05<br />
Kwan, W<br />
P4‐17‐08<br />
Kwasny, W<br />
P2‐10‐02<br />
Kwei, SL<br />
P4‐17‐02<br />
Kwiatkowski, F<br />
P3‐06‐20<br />
Kwok, S<br />
PD10‐03<br />
Kwon, DH<br />
P1‐05‐20<br />
Kwon, H‐C<br />
PD02‐06<br />
Kwon, Y<br />
P1‐01‐03<br />
Kwong, A<br />
P3‐11‐02,<br />
P3‐11‐03, P4‐11‐02<br />
Kyshtoobayeva, A P2‐10‐04, P3‐05‐05,<br />
P3‐05‐05, P3‐05‐06<br />
Laadem, A P3‐06‐33, P5‐20‐03<br />
Labbe‐Devilliers, C<br />
P3‐12‐01<br />
Laboy, J<br />
P5‐07‐06<br />
Labrie, F<br />
P2‐06‐03<br />
Lacerda, L PD03‐06, P5‐03‐05<br />
Lacevic, M<br />
P4‐14‐09<br />
Lackner, M<br />
P4‐06‐10<br />
Lacornerie, T<br />
OT1‐2‐02<br />
Lacroix‐Triki, M PD05‐08, P3‐04‐04,<br />
P3‐05‐07, P5‐21‐01,<br />
OT3‐3‐10<br />
Laé, M<br />
P5‐01‐05<br />
Laenen, A<br />
P6‐07‐29<br />
Lænkholm, A‐V<br />
P4‐09‐04<br />
Laeufle, R S6‐5<br />
Laferriere, J<br />
P6‐02‐03<br />
Lafon, D<br />
PD05‐04<br />
Lagier, R<br />
PD10‐03<br />
Lagrange, J‐L<br />
P4‐16‐10<br />
Lahogue, A<br />
OT1‐1‐16<br />
Lai, A<br />
P6‐04‐12<br />
Laidley, AL P1‐15‐09, P4‐14‐01<br />
Lake, D<br />
P1‐13‐11,<br />
P5‐18‐20, P5‐20‐07<br />
Lake, DF<br />
P1‐05‐04<br />
Lakhani, A<br />
PD10‐02<br />
Lakhani, SR<br />
P6‐10‐06<br />
Laki, F<br />
P1‐01‐19<br />
Lakomy, J P3‐12‐09, P3‐13‐03<br />
Lakshmaiah, K<br />
P5‐02‐02<br />
Lalami, Y<br />
P5‐18‐19<br />
Lalla, D<br />
P5‐18‐12, P6‐09‐11<br />
Lalloum, M<br />
P4‐13‐03<br />
Lam, C<br />
P1‐15‐07, P6‐11‐04<br />
Lam, EW‐F<br />
P6‐04‐16<br />
Lam, T<br />
P4‐17‐04<br />
Lamb, CA<br />
P4‐06‐15<br />
Lambaudie, E<br />
P5‐03‐01<br />
Lambrechts, D<br />
P3‐05‐03,<br />
P6‐07‐14, OT2‐2‐02<br />
Lambros, MBK<br />
PD05‐08<br />
Lamoureux, J<br />
PD06‐03<br />
Lampe, D<br />
P1‐14‐05<br />
Lanari, C<br />
P4‐06‐15<br />
Lanchbury, J<br />
PD09‐04<br />
Lanczky, A<br />
P1‐07‐14<br />
Landaverde, D<br />
P2‐12‐07<br />
Landberg, G<br />
PD04‐06<br />
Landis, M<br />
P5‐03‐03<br />
Landis, MD P2‐10‐06, P6‐11‐12<br />
Landis, S<br />
OT1‐1‐08<br />
Landsman‐Blumberg, P P2‐14‐07,<br />
P5‐20‐12<br />
Landstorfer, B<br />
P2‐10‐38<br />
Landua, J<br />
P4‐02‐08<br />
Landucci, E<br />
P5‐17‐06<br />
Lane, D<br />
PD03‐09<br />
Lane, J<br />
P6‐07‐41<br />
Lane, M<br />
P1‐15‐07<br />
Lane, ME<br />
P6‐11‐04<br />
Lang, I S1‐6, S3‐2, P5‐17‐03, P6‐07‐06<br />
Lang, JE<br />
P3‐10‐07<br />
Lang, K P3‐07‐06, P3‐07‐07, P3‐07‐14<br />
Langbaum, TS S3‐5<br />
Lange, C<br />
P1‐07‐11<br />
Langer, L<br />
P4‐11‐04<br />
Lanigan, C<br />
P6‐07‐45<br />
Lannin, D P3‐14‐01, P4‐01‐02<br />
Lannin, DR P3‐14‐05, P3‐14‐06<br />
Lansdown, M<br />
P4‐01‐14<br />
Lantzsch, T P1‐14‐05, P2‐10‐38<br />
Lapetino, S<br />
P1‐02‐01<br />
Lara, J<br />
P2‐10‐16<br />
Lara, JM<br />
OT2‐3‐10<br />
Lara, MA<br />
OT3‐3‐05<br />
Laredo, S<br />
P2‐12‐03<br />
Larionov, A P3‐06‐23, P6‐04‐06<br />
Larionov, AA P6‐04‐09, P6‐04‐10<br />
Laronga, C<br />
P1‐01‐13,<br />
P4‐14‐09, P4‐17‐01<br />
Larrea, F<br />
P4‐06‐19, P6‐04‐29<br />
Larriera, A<br />
P3‐05‐05<br />
Larsen, L<br />
P4‐01‐11<br />
Larsen, MR<br />
P3‐04‐05<br />
Larsimont, D S4‐4, S6‐2, P1‐07‐08,<br />
P3‐04‐10, P3‐05‐03<br />
Larson, R<br />
PD03‐06<br />
Larson, RA P5‐03‐05, P5‐03‐10<br />
Lartigau, E<br />
OT1‐2‐02<br />
Lasry, S<br />
P1‐01‐19<br />
Lassalle, M<br />
P3‐06‐24<br />
Latouche, A<br />
OT3‐3‐10<br />
Lau, A<br />
P5‐18‐20<br />
Laub, GA<br />
P4‐01‐10<br />
Launay‐Vacher, V<br />
P5‐17‐04<br />
Laurà, F<br />
P5‐17‐06<br />
Lavie, O<br />
P6‐14‐03<br />
Lavin, PT<br />
P5‐18‐07<br />
Law, FBF<br />
P3‐11‐02, P4‐11‐02<br />
Lawler, K<br />
P2‐10‐29<br />
Lawler, WE<br />
P2‐05‐06<br />
Lawton, P S4‐1<br />
Layman, RM<br />
P2‐11‐07<br />
Lazar, V<br />
P4‐09‐05<br />
Lazare, M<br />
P3‐05‐05<br />
Lazzeroni, M PD04‐07, PD06‐06<br />
Le Marchand, L<br />
P4‐12‐02<br />
Le Rhun, E P2‐13‐10, P3‐12‐01<br />
Le Ven, E<br />
P3‐06‐24<br />
Leach, MO<br />
P4‐11‐05<br />
Leader, JB<br />
P4‐13‐12<br />
Leary, A<br />
PD07‐07, P2‐12‐15<br />
Lebas, N<br />
PD07‐04<br />
Lebeau, A S2‐2<br />
LeBeau‐Grasso, L<br />
P3‐10‐07<br />
Lebrecht, A<br />
P2‐10‐13<br />
Lecuru, F<br />
P1‐01‐21<br />
Lee, A P4‐03‐11, P5‐10‐13, P6‐05‐12<br />
Lee, AS‐G<br />
P3‐08‐09<br />
Lee, B‐N P2‐10‐32, P5‐04‐06, P5‐10‐02<br />
Lee, C<br />
PD04‐03<br />
Lee, E<br />
P1‐01‐03<br />
Lee, EJ<br />
P6‐01‐05<br />
Lee, H<br />
P4‐02‐05<br />
Lee, HE<br />
P5‐04‐03<br />
Lee, H‐E<br />
P2‐05‐14<br />
Lee, HJ P2‐02‐02, P5‐04‐03, P6‐07‐28<br />
Lee, HM<br />
P2‐05‐14<br />
Lee, H‐S<br />
PD05‐07<br />
Lee, H‐W<br />
PD02‐06<br />
Lee, J<br />
P1‐01‐03, P2‐10‐39,<br />
P4‐03‐11, P6‐07‐40<br />
Lee, JE P2‐05‐20, P2‐10‐41, P3‐11‐01<br />
Lee, JH<br />
P1‐05‐19, P6‐01‐05<br />
Lee, J‐H PD02‐06, P1‐01‐05, P3‐03‐02<br />
Lee, JJ<br />
P1‐01‐24<br />
Lee, JW PD05‐07, P1‐01‐08, P1‐14‐16,<br />
P2‐02‐02, P3‐01‐02, P3‐01‐02,<br />
P4‐16‐14, P5‐18‐23<br />
Lee, K‐C<br />
PD02‐06<br />
Lee, KE<br />
PD09‐05<br />
Lee, K‐H<br />
PD09‐05, P6‐01‐05<br />
Lee, K‐J<br />
P6‐04‐12<br />
Lee, KS<br />
PD09‐05<br />
Lee, LB<br />
P4‐07‐01<br />
Lee, M<br />
P5‐10‐06<br />
Lee, MH<br />
PD09‐05<br />
Lee, M‐R<br />
PD02‐06<br />
www.aacrjournals.org 597s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Lee, O<br />
P1‐09‐07, P2‐10‐30,<br />
P3‐04‐08, P4‐12‐04<br />
Lee, S<br />
P1‐01‐03, P3‐09‐05,<br />
P4‐06‐13, OT1‐1‐16<br />
Lee, SA<br />
P2‐05‐14<br />
Lee, S‐E<br />
PD02‐06<br />
Lee, SJ<br />
P5‐04‐07, P5‐07‐04<br />
Lee, S‐J P1‐01‐05, P3‐03‐01, P3‐03‐02<br />
Lee, SK<br />
P2‐10‐41, P3‐11‐01<br />
Lee, SY<br />
P5‐14‐03<br />
Lee, W<br />
P2‐06‐05<br />
Lee, YH<br />
P1‐01‐24<br />
Lee, YR<br />
P5‐07‐04<br />
Lefebvre, C P1‐01‐21, OT2‐1‐01<br />
Lefeuvre‐Plesse, C<br />
P2‐13‐10<br />
Leger‐Falandry, C<br />
OT3‐3‐10<br />
Legrier, M‐E<br />
P3‐06‐24<br />
Leheurteur, M<br />
P1‐15‐08<br />
Lehman, HL P3‐10‐04, P3‐10‐08<br />
Lehman, R<br />
P1‐13‐11<br />
Lehmann, BD<br />
P6‐05‐03<br />
Lei, L<br />
P4‐05‐01, P4‐09‐09<br />
Lei, X<br />
P5‐20‐02<br />
Leighl, N<br />
P5‐18‐14<br />
Leinonen, M<br />
PD10‐06<br />
Leitch, AM S2‐1<br />
Leitch, M<br />
PD07‐01, P1‐07‐04<br />
Leite, AP<br />
P4‐01‐07<br />
Leitzel, K<br />
P2‐10‐16,<br />
P2‐10‐31, P3‐06‐33<br />
Lembersky, BC S1‐10<br />
Lemonier, J<br />
OT1‐2‐02<br />
Lemonnier, J PD07‐04, P3‐05‐07<br />
Lenhard, M<br />
P6‐07‐05<br />
Lentz, RB<br />
P4‐17‐02<br />
Leonardi, MC<br />
PD04‐07<br />
Leong, H<br />
P1‐05‐20<br />
Leong, L<br />
P2‐14‐08<br />
Leong, W<br />
PD03‐05<br />
Leong, WL<br />
P2‐10‐34<br />
Le‐Petross, HT S2‐1<br />
Lerebours, F<br />
PD07‐04<br />
Leroith, D<br />
P4‐13‐08<br />
Leth‐Larsen, R<br />
P3‐04‐05<br />
Letocha, H<br />
P2‐12‐09<br />
Leunen, K<br />
P2‐10‐12,<br />
P6‐05‐05, P6‐07‐29<br />
Leung, LY<br />
P6‐07‐31<br />
Leung, S<br />
P6‐07‐10<br />
Leung, SCY S4‐6<br />
Levine, EG<br />
P3‐07‐02<br />
Levine, M<br />
P1‐13‐01<br />
Levva, S<br />
P1‐07‐15<br />
Levy, C<br />
P1‐13‐04<br />
Levy, E<br />
P6‐07‐03<br />
Levy, R<br />
P4‐04‐01<br />
Lew, DL<br />
OT2‐2‐04<br />
Lewis, AL<br />
P4‐11‐06<br />
Lewis, CR<br />
PD04‐03<br />
Lewis, J<br />
P1‐05‐20<br />
Lewis, M<br />
P4‐02‐08, P5‐03‐08<br />
Leyland‐Jones, B<br />
S4‐4, S5‐2,<br />
PD10‐03, P5‐18‐02, P5‐19‐03,<br />
P6‐04‐11, OT2‐3‐11, OT3‐4‐04<br />
Leyvraz, S<br />
P6‐04‐05<br />
Lezon‐Geyda, K<br />
PD05‐05<br />
L’haridon, T<br />
OT3‐3‐04<br />
Li, B<br />
P6‐06‐06<br />
Li, C<br />
P6‐05‐10<br />
Li, F<br />
P4‐02‐08<br />
Li, G<br />
P1‐10‐02<br />
Li, H<br />
P5‐05‐04<br />
Li, J<br />
P3‐07‐08, P4‐04‐01,<br />
P4‐05‐01, OT2‐3‐04<br />
Li, JJ<br />
P3‐01‐05<br />
Li, JL<br />
P5‐03‐10<br />
Li, K<br />
P3‐06‐25<br />
LI, KK<br />
P2‐09‐06<br />
Li, L P2‐09‐06, P5‐04‐08, P5‐10‐10<br />
Li, R<br />
P6‐02‐02<br />
Li, S<br />
S5‐6, P2‐04‐02,<br />
P4‐07‐04, P4‐10‐02, P5‐03‐14<br />
Li, SP<br />
P1‐06‐01<br />
Li, W<br />
P4‐08‐10, P5‐04‐08<br />
Li, W‐P<br />
P2‐09‐05<br />
Li, X<br />
P1‐04‐11, P4‐01‐03,<br />
P5‐10‐10, P5‐20‐05<br />
Li, Y<br />
P5‐03‐14, P6‐07‐25,<br />
P6‐07‐37, P6‐10‐05<br />
Lian, Z‐Q<br />
P2‐09‐05<br />
Liao, J P1‐12‐02, P1‐13‐11, P5‐20‐04<br />
Liao, W‐L<br />
P1‐07‐19<br />
Lichinitser, MR S1‐4<br />
Lichtenegger, W<br />
P2‐01‐02<br />
Lie, Y P2‐05‐06, P2‐10‐16, P2‐10‐31<br />
Liede, A<br />
P2‐13‐03<br />
Liedtke, B<br />
P2‐10‐08<br />
Liedtke, C S1‐7, S2‐2, P2‐10‐08,<br />
P3‐06‐05<br />
Liefers, G‐J<br />
PD07‐06<br />
Lien, H‐C<br />
P3‐06‐02<br />
Liesche, F<br />
P2‐01‐11<br />
Lillemoe, HA<br />
P1‐03‐02<br />
Lim, E<br />
PD01‐08<br />
Lim, EA<br />
P4‐02‐07<br />
Lim, K<br />
P5‐20‐07<br />
Lim, M<br />
P6‐01‐03<br />
Lim, W<br />
P4‐03‐11<br />
Lim, YY<br />
P6‐06‐06<br />
Lima, DT<br />
P6‐07‐44<br />
Lima, E<br />
P4‐02‐03<br />
Limat, S<br />
P5‐18‐22<br />
Limentani, SA<br />
P5‐18‐05<br />
Lin, C‐H<br />
P3‐06‐02<br />
Lin, J<br />
P5‐12‐01<br />
Lin, MZ<br />
P5‐07‐05<br />
Lin, N OT1‐1‐07, OT1‐1‐11, OT2‐3‐06<br />
Lin, NU<br />
P2‐16‐04, P3‐12‐04,<br />
P5‐18‐03, P6‐08‐03<br />
Lin, Y<br />
P6‐07‐35<br />
Lina, A<br />
P2‐11‐16, P3‐06‐12<br />
Lind, P<br />
P5‐18‐18<br />
Lindemalm, C<br />
P2‐12‐09<br />
Linden, HM<br />
P6‐04‐03<br />
Linder, M<br />
OT2‐2‐05<br />
Linderholm, BK<br />
P6‐12‐01<br />
Lindh, J<br />
PD10‐09<br />
Lindquist, DL<br />
P3‐06‐12<br />
Lindsay, SP<br />
P2‐11‐09<br />
Lindström, LS<br />
PD06‐08<br />
Ling, H<br />
P6‐07‐42<br />
Ling, Z‐Q P2‐05‐05, P4‐09‐09<br />
Lingle, WL<br />
PD10‐04<br />
Lingsma, H<br />
P4‐11‐05<br />
Link, JM<br />
P6‐04‐03<br />
Linn, S<br />
P3‐06‐01<br />
Linn, SC PD01‐02, PD01‐03, P1‐15‐05,<br />
P6‐07‐05, OT2‐1‐02, OT2‐1‐03<br />
Linnartz, R<br />
P4‐08‐01<br />
Lintermans, A P2‐12‐06, P2‐13‐06,<br />
P5‐18‐19, OT2‐2‐02<br />
Lionaki, A<br />
P6‐07‐13<br />
Liotcheva, V<br />
P2‐10‐03<br />
Liotta, LA P3‐04‐01, P3‐04‐02<br />
Lippman, ME P1‐04‐06, P1‐05‐12<br />
Lipson, D<br />
PD02‐07, PD05‐01<br />
Lipson, JA<br />
P4‐01‐12<br />
Lipton, A<br />
P2‐10‐16,<br />
P2‐10‐31, P3‐06‐33<br />
Lissowska, J<br />
P3‐08‐02<br />
Litchfield, LM<br />
P6‐04‐30<br />
Litsas, G<br />
P5‐18‐03<br />
Little, JL<br />
P1‐05‐03<br />
Litwiniuk, M<br />
P2‐10‐31,<br />
P3‐12‐09, P3‐13‐03<br />
Liu, C S1‐8<br />
Liu, C‐Y<br />
P3‐12‐10, P6‐11‐05<br />
Liu, D<br />
PD03‐06<br />
Liu, F‐F<br />
P2‐10‐33<br />
Liu, G<br />
P1‐14‐17<br />
Liu, H<br />
P1‐12‐06, P4‐06‐03,<br />
P6‐04‐28, P6‐10‐04<br />
Liu, J P2‐11‐06, P5‐18‐20, P6‐06‐05<br />
Liu, JC<br />
P1‐04‐05<br />
Liu, L<br />
P4‐08‐03, P4‐08‐07<br />
Liu, MC PD09‐03, P2‐10‐01, P6‐05‐02<br />
Liu, M‐C<br />
P4‐16‐05<br />
Liu, P<br />
PD03‐08, P5‐10‐10<br />
Liu, Q S1‐10<br />
Liu, R<br />
P4‐05‐01<br />
Liu, S P2‐10‐02, P3‐06‐03, P6‐07‐25<br />
Liu, SX<br />
PD01‐08<br />
Liu, X P3‐05‐05, P4‐06‐08, P6‐11‐11<br />
Liu, Y<br />
P6‐07‐36<br />
Liu, Yb<br />
P6‐07‐36<br />
Liu, Z‐B<br />
P6‐07‐42<br />
Livartowski, A<br />
P4‐13‐14<br />
Llombart, A OT1‐1‐09, OT3‐3‐06<br />
Llop, JR<br />
P4‐06‐18<br />
Lluch, A<br />
OT2‐3‐06<br />
Lo, K‐Y<br />
P4‐04‐07<br />
Lo, S‐K<br />
P3‐08‐09<br />
Lo, SS<br />
PD10‐02, P1‐12‐04<br />
Lo Nigro, C<br />
P4‐06‐10<br />
Lobbes, M<br />
P3‐02‐08<br />
Lobbes, MBI<br />
P5‐01‐13<br />
Lobbezoo, DJA P5‐21‐04, P6‐07‐32<br />
Lobelle, J‐P<br />
P6‐09‐07<br />
Loddo, M<br />
PD04‐08<br />
Loessl, K<br />
P4‐15‐01<br />
Logan, LS<br />
P2‐10‐40<br />
Loghmani, A<br />
P2‐12‐10<br />
Logullo, AF<br />
P2‐05‐17<br />
Loh, S‐W<br />
P1‐01‐01<br />
Lohmann, AE<br />
P4‐16‐04<br />
Loi, S P1‐07‐08, P6‐07‐14, OT1‐1‐03<br />
Loibl, S<br />
S1‐7, S1‐11, S3‐1,<br />
S4‐5, PD06‐01,<br />
P1‐14‐01, P3‐06‐05, P6‐07‐05,<br />
OT1‐1‐13, OT2‐2‐05, OT3‐3‐11<br />
Lokeshwar, BL<br />
P5‐07‐01<br />
Loman, N<br />
PD03‐07,<br />
P1‐05‐07, P2‐10‐37<br />
Lombardo, Y P1‐04‐04, P4‐06‐12<br />
Lomo, L<br />
P3‐03‐01<br />
Longy, M<br />
PD05‐04<br />
Lønning, PE<br />
P6‐04‐06<br />
Loo, WTY<br />
P2‐05‐16<br />
Look, M<br />
P3‐06‐01<br />
Look, MP<br />
P6‐04‐08<br />
Lopez, AM<br />
P5‐12‐03<br />
Lopez, JJ<br />
P4‐17‐01<br />
Lopez, M<br />
P4‐13‐05<br />
Lopez, S<br />
P3‐03‐01<br />
Lopez Diaz, F<br />
P2‐06‐05<br />
López Díaz de Cerio, A P5‐16‐03<br />
Lopez‐Bujanda, Z<br />
P2‐02‐01<br />
Lopez‐Rios, F P1‐14‐10, P5‐18‐15<br />
Lord, CJ<br />
PD05‐08<br />
Lorenz, R<br />
P2‐01‐02<br />
Lories, R<br />
P2‐13‐06<br />
Lortholary, A<br />
S5‐3, P1‐13‐04<br />
Los, M<br />
P1‐12‐05<br />
Lou, C‐J<br />
P2‐05‐05<br />
Louie, B<br />
P6‐07‐31<br />
Louis, B<br />
P5‐21‐01<br />
Louis, E<br />
P5‐18‐19<br />
Loutfi, R<br />
P6‐10‐01<br />
Love, SM<br />
P2‐15‐01<br />
Lower, EE<br />
P6‐08‐08<br />
Lu, D<br />
P5‐18‐24<br />
Lu, H<br />
OT3‐1‐02<br />
Lu, J<br />
P2‐11‐07, P5‐10‐15,<br />
P6‐07‐35, OT1‐1‐12<br />
Lu, JS<br />
P3‐01‐05<br />
Lu, ML<br />
P5‐06‐01<br />
Lu, N<br />
P6‐04‐12<br />
Lu, S<br />
P6‐04‐28<br />
Lu, Y<br />
P4‐08‐05, P5‐10‐03<br />
Lu, Y‐S<br />
P3‐06‐02, P6‐05‐15<br />
Lubet, R<br />
P1‐08‐02<br />
Lubet, RA<br />
P1‐08‐01<br />
Lucas, B<br />
OT3‐3‐04<br />
Lucci, A<br />
P1‐01‐06, P2‐03‐01<br />
Lueck, H‐J S3‐4<br />
Luengo Gil, G<br />
P3‐06‐15<br />
Lum, L<br />
P4‐06‐06<br />
Lundgren, S<br />
P6‐09‐03<br />
Luo, AZ<br />
P4‐06‐03<br />
Luo, C<br />
P1‐05‐09, P2‐05‐21,<br />
P2‐09‐06, P3‐04‐06, P3‐09‐03<br />
Luo, J<br />
PD03‐09<br />
Luo, L<br />
P2‐09‐06<br />
Luo, R<br />
PD07‐01<br />
Luo, Y<br />
PD02‐04<br />
Luque, M P1‐07‐18, P2‐01‐06<br />
Lurie, G<br />
P4‐12‐02<br />
Lurkin, I<br />
P3‐06‐01<br />
Lurvey, HL<br />
P2‐04‐03<br />
Lush, RM<br />
P2‐14‐04<br />
Lussiez, A<br />
P3‐12‐03<br />
Lustberg, MB P2‐11‐04, P2‐11‐07<br />
Luthra, R<br />
P5‐04‐06<br />
Luthra, S<br />
P6‐04‐20<br />
Luu, T<br />
P2‐14‐08<br />
Luus, L<br />
P1‐07‐03<br />
Luu‐The, V<br />
P2‐06‐03<br />
Lux, MP<br />
PD07‐02<br />
LUX‐<strong>Breast</strong> 1 Study Group OT1‐1‐16<br />
LUX‐<strong>Breast</strong> 2 Study Group OT1‐1‐17<br />
Ly, A<br />
OT1‐1‐11<br />
Lyden, M<br />
P1‐15‐09, P4‐16‐03<br />
Lyerly, HK<br />
P4‐08‐07<br />
Lykkesfeldt, AE<br />
P6‐04‐18<br />
Lyman, GH P1‐15‐04, P2‐10‐03,<br />
P3‐06‐07<br />
Lyng, M S4‐4<br />
Lyng, MB<br />
P4‐09‐04<br />
Ma, C<br />
PD07‐01<br />
Ma, ESK<br />
P3‐11‐02, P4‐11‐02<br />
Ma, J<br />
P4‐02‐08<br />
Ma, Q<br />
P4‐03‐12<br />
Ma, X‐J<br />
PD02‐04<br />
Ma, Y<br />
P4‐06‐08<br />
Maartense, E PD07‐06, P1‐12‐05<br />
MacBeath, G<br />
P1‐07‐03<br />
MacGrogan, G<br />
P3‐14‐03<br />
Machado, GDP<br />
P2‐12‐04<br />
Machiels, J‐P P3‐04‐04, P5‐18‐19<br />
Maciel, MdS<br />
P4‐02‐03<br />
Mackay, A<br />
PD05‐08<br />
Mackey, J<br />
S6‐5, P3‐06‐34<br />
Mackie, D<br />
P2‐12‐15<br />
MacNeill, F P1‐01‐10, P1‐01‐11<br />
Macpherson, IR<br />
P1‐05‐13<br />
Madan, A<br />
P3‐14‐01<br />
Madan, RA<br />
P5‐16‐06<br />
Madani, S<br />
P4‐06‐16<br />
Madaras, L<br />
P3‐05‐08<br />
Madden, S P3‐04‐12, P4‐09‐06<br />
Madeira, KP P5‐01‐15, P6‐11‐13<br />
Madhukumar, P<br />
P3‐08‐09<br />
Madlensky, L<br />
P4‐13‐13<br />
Maekawa, Y<br />
P6‐07‐30<br />
Maetens, M<br />
S6‐2, P1‐07‐08<br />
Maffuz‐Aziz, A<br />
P5‐10‐12<br />
Magbanua, M<br />
P2‐05‐01<br />
Magbanua, MJM<br />
P2‐01‐05<br />
Magee, B S4‐1<br />
Maggi, R<br />
P3‐10‐03<br />
Magliocco, A P2‐10‐09, P4‐09‐07<br />
Magliocco, AM P1‐07‐10, P6‐07‐17<br />
Mahajan, S<br />
P4‐02‐02<br />
Mahesh, S<br />
P6‐07‐41<br />
Maheswaran, S<br />
P2‐01‐14<br />
Mahier Aït‐Oukhatar, C P3‐12‐01<br />
Mahler, L<br />
P6‐08‐06<br />
Mahmood, N<br />
P6‐07‐13<br />
Mahtani, RL<br />
P1‐12‐03<br />
Mai, H<br />
PD10‐02<br />
Mai, J<br />
P6‐13‐02<br />
Maibach, R<br />
S3‐2, P6‐07‐06<br />
Maillart, P<br />
P1‐14‐21<br />
Mailliez, A P2‐13‐10, P6‐10‐02<br />
Maisongrosse, V<br />
P3‐05‐07<br />
Maity, S<br />
P4‐01‐02<br />
Majewska, H P3‐12‐09, P3‐13‐03<br />
Majjaj, S<br />
S6‐2, P1‐07‐08,<br />
P3‐04‐10, P6‐07‐14<br />
Makariou, E<br />
P1‐09‐04<br />
Makey, KL<br />
P4‐06‐04<br />
Makhoul, I<br />
P3‐06‐30<br />
Makowski, L<br />
P6‐02‐09<br />
Makrantonakis, P<br />
P1‐13‐09<br />
Makris, A P1‐06‐01, P3‐06‐14<br />
Mala, C<br />
P5‐20‐01<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
598s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
Author Index<br />
Malamos, N<br />
P1‐13‐09<br />
Malamud, S<br />
P3‐08‐08<br />
Malfoy, B<br />
P5‐01‐05<br />
Malhotra, S<br />
P6‐08‐01<br />
Malinina, I<br />
P4‐04‐05<br />
Mallick, R<br />
P2‐05‐12,<br />
P2‐05‐13, P3‐13‐05<br />
Mallon, E S1‐1<br />
Mallon, P<br />
P1‐01‐19<br />
Malmberg, M<br />
P1‐05‐07<br />
Malmström, P P2‐10‐07, P2‐10‐19<br />
Malmtröm, P<br />
P2‐10‐28<br />
Maluta, S<br />
P4‐16‐08<br />
Maly, J<br />
P5‐18‐17<br />
Mamet, R<br />
P1‐01‐13<br />
Mammen, JMW<br />
PD09‐02<br />
Mamounas, E S1‐11<br />
Mamounas, EP S1‐10, S3‐2, S5‐5,<br />
P6‐07‐06, OT1‐2‐01, OT2‐2‐04<br />
Manasova, D<br />
P2‐01‐12<br />
Manasseh, DME<br />
P4‐14‐01<br />
Mandelblatt, J<br />
P6‐08‐05<br />
Manders, P<br />
P4‐11‐05<br />
Mangelsdorf, D<br />
P4‐08‐09<br />
Mani, A<br />
P1‐12‐03<br />
Maniar, T<br />
OT2‐3‐03<br />
Manié, E<br />
P5‐02‐03<br />
Manikhas, A<br />
OT3‐3‐01<br />
Mann, M<br />
PD09‐07, P1‐05‐10<br />
Mansfield, AS<br />
PD02‐05<br />
Manso, L<br />
P1‐07‐18, P2‐01‐06<br />
Manson, J<br />
PD03‐09<br />
Manthey, E<br />
P4‐04‐06<br />
Mañu, A<br />
P5‐03‐07<br />
Manuel, D<br />
P4‐01‐14<br />
Mao, JJ<br />
P4‐13‐01<br />
Marangoni, E<br />
P6‐04‐14<br />
Marchal, F P1‐01‐21, OT2‐1‐01<br />
Marciai, N<br />
P4‐16‐08<br />
Marcom, K<br />
P4‐13‐06<br />
Marcom, P<br />
P1‐01‐13<br />
Marcom, PK P1‐13‐05, P2‐10‐03,<br />
P3‐06‐07, P4‐09‐01<br />
Marcos‐Gragera, R<br />
P4‐09‐11<br />
Mardiak, J P2‐01‐12, P5‐02‐02<br />
Mardis, E<br />
P6‐07‐10<br />
Mardis, ER<br />
S5‐6, P2‐10‐01<br />
Margelí, M P1‐07‐18, P2‐01‐06<br />
Marginean, EC<br />
P5‐01‐01<br />
Margolin, S<br />
PD10‐09<br />
Margossian, AL P2‐16‐02, P2‐16‐03<br />
Margossian, J<br />
P2‐16‐03<br />
Margossian, ML<br />
P2‐16‐02<br />
Markiewicz, A<br />
P5‐04‐01<br />
Markmann, S<br />
P2‐10‐08<br />
Markopoulos, C S1‐5<br />
Marks, J<br />
P4‐13‐06<br />
Marme, F P3‐06‐08, P3‐06‐19<br />
Maroske, M<br />
P2‐13‐01<br />
Márquez‐Garbán, DC PD03‐04<br />
Marre, A<br />
P1‐13‐04<br />
Marrero, N<br />
OT1‐1‐08<br />
Marshall, D<br />
P5‐18‐14<br />
Marshall, HC S6‐4<br />
Martel, C<br />
P2‐06‐03<br />
Martens, J P3‐06‐32, P3‐06‐35<br />
Martin, A‐L PD07‐04, P1‐13‐04,<br />
P3‐04‐04, P3‐05‐07<br />
Martin, FM<br />
P4‐09‐06<br />
Martin, JL<br />
P5‐07‐05<br />
Martin, L<br />
PD03‐09<br />
Martin, L‐A<br />
PD01‐05<br />
Martin, M S1‐4, S1‐7, S3‐2, P2‐10‐11,<br />
P5‐18‐05, P6‐07‐06, OT2‐3‐03<br />
Martin, PM<br />
P6‐14‐04<br />
Martin, P‐M<br />
P1‐13‐13<br />
Martinez, G<br />
P5‐01‐09<br />
Martinez, ME<br />
PD08‐04<br />
Martínez, N P1‐14‐10,OT3‐3‐05<br />
Martínez, P P1‐07‐18, P2‐01‐06<br />
Martínez‐Climent, JA P5‐03‐07<br />
Martinez, R<br />
P5‐07‐06<br />
Martino, S<br />
S5‐5, P2‐10‐01<br />
Martinson, H<br />
P4‐04‐03<br />
Marty, M P1‐14‐03, P1‐14‐18,<br />
P2‐01‐04, P3‐06‐04<br />
Marzec, KA<br />
P5‐07‐05<br />
Marzolini, S<br />
P2‐12‐03<br />
Masaquel, A<br />
P5‐18‐12<br />
Masedunskas, A<br />
P1‐05‐23<br />
Maskarinec, G<br />
P4‐12‐02<br />
Mason, C<br />
P5‐10‐13<br />
Massacesi, C OT2‐3‐08, OT2‐3‐09<br />
Massaguer, A<br />
P6‐11‐02<br />
Massarut, S<br />
S4‐2, P5‐10‐17<br />
Massarweh, SA<br />
P2‐14‐05<br />
Mastropasqua, MG S4‐6<br />
Masuda, H PD03‐06, PD03‐08,<br />
P3‐10‐05, P5‐03‐09<br />
Masuda, M<br />
P1‐01‐20<br />
Masuda, N P1‐12‐01, P1‐14‐02,<br />
P1‐14‐08, P2‐10‐18,<br />
P3‐02‐06, P3‐06‐18,<br />
P5‐10‐09, P5‐18‐16, P6‐07‐16<br />
Masuda, S P2‐10‐18, P5‐01‐02<br />
Masudi, T<br />
P3‐01‐06<br />
Masumoto, N<br />
P6‐07‐26<br />
Mathieson, T<br />
P1‐03‐02<br />
Mathieu, MC P3‐06‐04, P3‐14‐03<br />
Mathieu, M‐C<br />
P1‐14‐03,<br />
P1‐14‐18, P4‐12‐01<br />
Matielle, CR<br />
P1‐01‐28<br />
Matsubara, M<br />
P5‐18‐16<br />
Matsui, H<br />
P2‐06‐01<br />
Matsumoto, H<br />
P1‐14‐06<br />
Matsumoto, K<br />
P6‐07‐30<br />
Matsumoto, M<br />
P1‐01‐27<br />
Matsunami, N<br />
P1‐14‐08<br />
Matsunuma, R<br />
P4‐03‐05<br />
Matsutani, Y<br />
P3‐13‐04<br />
Matsuura, H<br />
P1‐01‐20<br />
Matsuzu, K<br />
P1‐01‐20<br />
Matta, J<br />
P5‐07‐06<br />
Mattar, A<br />
P2‐05‐17<br />
Matthew, MK<br />
P4‐17‐02<br />
Matthews, A<br />
S4‐2, PD04‐03<br />
Matuoka, J<br />
P3‐07‐10<br />
Matuschek, C<br />
P1‐14‐04<br />
Matzkowitz, AJ<br />
P6‐13‐01<br />
Maurer, M PD03‐03, P1‐09‐02,<br />
P2‐11‐03, P2‐12‐01,<br />
P4‐02‐07, P6‐12‐03, OT2‐3‐06<br />
Mauriac, L<br />
P1‐13‐04<br />
Mavria, G<br />
P6‐02‐06<br />
Mavroudis, D P1‐13‐09, P2‐01‐03,<br />
P2‐01‐07<br />
Maximov, PY<br />
P2‐13‐09<br />
Maxwell, CA<br />
P2‐07‐01<br />
May, M<br />
P2‐16‐03<br />
Mayadev, JS<br />
P4‐01‐13<br />
Maybody, M<br />
OT3‐1‐01<br />
Mayer, EL<br />
PD09‐03,<br />
P6‐11‐06, OT2‐3‐11<br />
Mayer, IA<br />
P2‐14‐04,<br />
P4‐01‐03, P6‐10‐05<br />
Mayer, JA<br />
P2‐01‐10<br />
Mazanet, R<br />
P5‐18‐07<br />
Mazouni, C<br />
P4‐12‐01,<br />
P4‐14‐12, P5‐13‐02<br />
Mazzarello, S<br />
P2‐05‐12,<br />
P2‐05‐13, P3‐13‐05<br />
McArthur, HL P5‐20‐07, OT3‐1‐01<br />
McBride, ML<br />
PD04‐02<br />
McBryan, J<br />
P6‐04‐21<br />
McCall, L<br />
S2‐1, PD07‐01<br />
McCall, LM<br />
P1‐01‐06<br />
McCanna, S<br />
OT2‐3‐01<br />
McCartan, D<br />
P6‐04‐01<br />
McCarthy, B<br />
P2‐11‐07<br />
McCormick, DT<br />
OT2‐1‐04<br />
McCready, D<br />
P2‐10‐34<br />
McCready, DR PD03‐05, P2‐10‐33<br />
McCulloch, C<br />
P3‐05‐06<br />
McCurtin, RE<br />
P1‐13‐08<br />
McDaniel, RE<br />
P2‐13‐09<br />
McDermott, AM<br />
P5‐10‐07<br />
McDonagh, C<br />
P1‐07‐03<br />
McDonald, K<br />
P4‐08‐01<br />
McDonnell, SK<br />
PD10‐05<br />
McGarrigle, SA<br />
P6‐01‐02<br />
McGee, SF<br />
P4‐09‐06<br />
McGinness, MK<br />
PD09‐02<br />
McIlroy, M<br />
P6‐04‐04<br />
McKeegan, E<br />
OT2‐3‐07<br />
McLachlan, SA<br />
P4‐13‐10<br />
McLaughlin, SA S2‐1<br />
McLeod, HL<br />
PD10‐07<br />
McLinden, M<br />
P1‐13‐03<br />
McMahon, D<br />
P6‐12‐03<br />
McMahon, S<br />
P5‐16‐06<br />
McManus, J<br />
P1‐05‐21<br />
McMurray, HR<br />
P4‐06‐18<br />
McNagny, KM<br />
P1‐05‐05<br />
McNally, S<br />
P4‐09‐06<br />
McNaughton, K<br />
P6‐02‐09<br />
McShane, LM S4‐6<br />
McTiernan, A<br />
P3‐01‐01<br />
Means‐Powell, J<br />
P4‐01‐03<br />
Means‐Powell, JA<br />
P2‐14‐04<br />
Mebis, J<br />
P5‐18‐19<br />
Medina, H<br />
P6‐04‐29<br />
Meerbrey, KL<br />
PD01‐01<br />
Meershoek‐Klein<br />
Kranenbarg, EM<br />
PD07‐06<br />
Mege, J‐P<br />
OT1‐2‐02<br />
Mego, M<br />
P2‐01‐12<br />
Mehta, A OT1‐1‐16, OT1‐1‐17<br />
Mehta, K<br />
S1‐7, S1‐11,<br />
S3‐1, P1‐14‐01<br />
Mehta, S P1‐06‐01, P4‐01‐01, P6‐09‐06<br />
Mei, Q<br />
P2‐07‐01<br />
Meijer, ME<br />
P6‐04‐08<br />
Meijer, S<br />
PD04‐01<br />
Meinerz, W<br />
P1‐13‐13<br />
Meinhold‐Heerlein, I P3‐06‐05<br />
Meisner, C<br />
P1‐13‐13<br />
Melcher, CA<br />
P2‐01‐02,<br />
P4‐13‐11, OT1‐1‐10<br />
Meliadò, G<br />
P4‐16‐08<br />
Melichar, B<br />
P6‐10‐02<br />
Melin, S<br />
P2‐12‐11<br />
Melisko, M<br />
P2‐12‐11<br />
Melisko, ME P2‐12‐12, P4‐16‐07,<br />
P6‐10‐01, OT1‐1‐11<br />
Mellemkjær, L<br />
P1‐09‐01<br />
Mellgren, G<br />
P6‐04‐06<br />
Mena, M<br />
P5‐03‐07<br />
Meng, X<br />
OT1‐1‐05<br />
Menzin, J<br />
P3‐07‐06,<br />
P3‐07‐07, P3‐07‐14<br />
Mercier Blas, A<br />
OT3‐3‐04<br />
Meredith, R<br />
P3‐03‐03<br />
Meredith, RF P5‐17‐07, P6‐07‐37<br />
Meric‐Bernstam, F P1‐07‐06, P1‐07‐09,<br />
P6‐11‐03, P6‐11‐11<br />
Mery, E<br />
P3‐05‐07, P3‐14‐03<br />
Meschino, W<br />
P3‐02‐10<br />
Mesleard, C<br />
P3‐05‐07<br />
Messer, K<br />
P2‐06‐01<br />
Meszoely, IM<br />
P4‐01‐03<br />
Metaxas, M S4‐2<br />
Metellus, P<br />
P3‐12‐11<br />
Metz, WL<br />
P1‐01‐04<br />
Metzger, O S1‐1, P3‐05‐03, P5‐18‐03<br />
Meyer, ME<br />
P4‐01‐09<br />
Meyers, M<br />
P5‐20‐05<br />
Meyn, A<br />
P6‐11‐12<br />
Miao, RY<br />
P3‐10‐09<br />
Michaelson, R<br />
P2‐10‐16<br />
Michiels, S<br />
S4‐4, P1‐07‐08,<br />
P3‐04‐10, P3‐05‐03,<br />
P4‐09‐05, P6‐07‐14, P6‐07‐22<br />
Miele, L P2‐14‐04, P4‐06‐04, P6‐04‐22<br />
Migdady, Y<br />
P6‐07‐34<br />
Mignot, L<br />
OT3‐4‐06<br />
Mijonnet, S PD07‐04, OT1‐2‐02<br />
Mikami, Y P5‐01‐02, P5‐10‐09<br />
Miki, M<br />
P6‐07‐30<br />
Miki, Y<br />
P6‐05‐14<br />
Milani, M<br />
PD07‐03<br />
Milbourn, DE<br />
P1‐01‐17<br />
Miles, AK P6‐07‐09, P6‐07‐18<br />
Miles, D<br />
P2‐12‐07, P5‐16‐01,<br />
P5‐18‐01, OT1‐1‐02, OT1‐1‐03<br />
Miles, J<br />
P2‐05‐10<br />
Milián, ML<br />
OT3‐4‐04<br />
Milisen, K<br />
P6‐09‐07<br />
Millen, EC P2‐05‐17, P3‐11‐04<br />
Miller, A<br />
P3‐07‐02<br />
Miller, CL P6‐09‐04, OT3‐2‐02<br />
Miller, DV<br />
P2‐10‐27<br />
Miller, K<br />
P3‐12‐04, OT2‐3‐11<br />
Miller, KD P5‐17‐01, P5‐18‐13<br />
Miller, N<br />
P5‐10‐07<br />
Miller, NA<br />
P2‐10‐33<br />
Miller, P<br />
P1‐04‐06, P5‐10‐08<br />
Miller, SM<br />
P6‐09‐05<br />
Miller, V<br />
PD02‐07<br />
Miller, VA S3‐6<br />
Millham, R<br />
OT2‐3‐02<br />
Millholland, RJ<br />
P6‐12‐02<br />
Mills, G<br />
P1‐07‐06<br />
Mills, GB PD01‐01, P3‐06‐06,<br />
P4‐08‐05, P5‐10‐03<br />
Mills, J S4‐1<br />
Milne, RL<br />
P4‐13‐10<br />
Milosavljevic, A<br />
P6‐05‐12<br />
Miltenburg, NC<br />
P1‐15‐05<br />
Mimoto, R P4‐03‐10, P5‐04‐02<br />
Min, S<br />
P4‐03‐11<br />
Min, S‐H<br />
P2‐11‐05<br />
Minami, Y<br />
P6‐07‐27<br />
Minarik, G<br />
P2‐01‐12<br />
Minca, E<br />
P6‐07‐45<br />
Minna, J<br />
P4‐08‐09<br />
Minton, SE<br />
P2‐14‐04<br />
Mir, O<br />
P5‐17‐04<br />
Mira, A<br />
P2‐16‐02<br />
Miranda, M<br />
P6‐10‐06<br />
Miro, C<br />
P5‐18‐15<br />
Miron‐Shatz, T<br />
P4‐11‐03<br />
Mirza, FN<br />
P2‐13‐08<br />
Miskimen, K<br />
PD05‐05<br />
Misra, V<br />
P2‐14‐06<br />
Mitchell, EP P5‐01‐07, P5‐14‐03<br />
Mitchell, L<br />
OT1‐1‐02<br />
Mitchell, SD<br />
P4‐14‐01<br />
Mitchell, T<br />
PD01‐01<br />
Mitchison, TJ<br />
P6‐06‐02<br />
Mitra, S P3‐06‐06, P5‐03‐12, P6‐02‐07<br />
Mitsiades, N<br />
P6‐10‐03<br />
Mitsopoulos, C<br />
PD05‐08<br />
Mittal, V<br />
P6‐11‐04<br />
Mittempergher, L<br />
P4‐09‐05<br />
Mittendorf, EA S2‐1, P1‐01‐06,<br />
P1‐07‐06, P1‐07‐09, P5‐16‐01,<br />
P5‐16‐02, P5‐16‐05, P5‐20‐02<br />
Miura, D<br />
PD07‐05<br />
Miura, N<br />
P4‐04‐08<br />
Miura, T<br />
P2‐10‐32<br />
Miyajima, S<br />
P3‐02‐05<br />
Miyamoto, R<br />
OT1‐1‐01<br />
Miyamoto, Y<br />
P4‐03‐10<br />
Miyashita, M PD07‐05, P1‐06‐02,<br />
P6‐07‐39<br />
Miyazaki, T<br />
P6‐04‐27<br />
Miyoshi, Y<br />
P1‐14‐08,<br />
P5‐18‐16, P6‐07‐39<br />
Mizoo, T<br />
P3‐07‐10<br />
Mizota, Y<br />
P2‐11‐02<br />
Mizuno, H<br />
P4‐03‐07<br />
Mizuno, Y<br />
PD06‐02<br />
Mlineritsch, B P2‐10‐02, P5‐20‐11<br />
Modesto, MG<br />
P1‐01‐28<br />
Modi, S<br />
P5‐18‐04, P5‐18‐20<br />
Modzlewski, R<br />
P1‐15‐08<br />
Moebus, V S3‐4<br />
Moelans, CB<br />
PD02‐03,<br />
P2‐06‐02, P6‐05‐13<br />
Moeller, M<br />
P3‐04‐05<br />
Moerman, P<br />
P2‐10‐12,<br />
P6‐05‐05, P6‐07‐29<br />
Mögele, M<br />
P2‐12‐06<br />
Mohamed, MM<br />
P1‐05‐11<br />
Mohammed, H<br />
P3‐04‐03<br />
Mohar, A<br />
PD08‐06<br />
www.aacrjournals.org 599s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Mohebtash, M<br />
P5‐16‐06<br />
Mokbel, K P1‐04‐03, P1‐04‐07,<br />
P1‐04‐08, P1‐04‐09, P6‐05‐11<br />
Molina, JR<br />
P3‐06‐06<br />
Momen, L<br />
P6‐05‐02<br />
Monsey, J S5‐6<br />
Montcuquet, P<br />
P5‐18‐22<br />
Monteiro, SO<br />
P6‐07‐44<br />
Montero, AJ<br />
P1‐12‐03<br />
Montero, JC P4‐06‐17, P6‐05‐04<br />
Monville, F<br />
P5‐03‐01<br />
Moon, B‐I<br />
P4‐03‐11<br />
Moon, HG<br />
P1‐01‐08<br />
Moon, H‐G PD05‐07, P1‐14‐16,<br />
P1‐14‐19, P2‐10‐35,<br />
P3‐06‐16, P5‐18‐23<br />
Moore, A<br />
P1‐15‐07, P6‐11‐04<br />
Moore, C<br />
P6‐08‐01<br />
Moore, D<br />
P2‐10‐22<br />
Moore, DA<br />
P3‐06‐13<br />
Moore, HM<br />
P1‐04‐11<br />
Moraes, E<br />
OT1‐1‐08<br />
Morales, JC<br />
P6‐05‐04<br />
Morales, S S1‐7<br />
Moran, A<br />
P3‐08‐01<br />
Moran, CJ<br />
P4‐01‐06<br />
Moraras, N<br />
P5‐14‐04<br />
Morden, JP S3‐3<br />
Moreau, F<br />
P3‐04‐04<br />
Moreau, M<br />
P4‐02‐06<br />
Moreira, A<br />
P1-15-03<br />
Morelli, D<br />
P4‐06‐09<br />
Moreno, L<br />
P5‐13‐03<br />
Moreno‐Aspitia, A<br />
P1‐12‐06<br />
Morere, J‐F PD08‐03, P5‐17‐04<br />
Morgan, D S4‐1<br />
Morgan, SC<br />
P4‐16‐06<br />
Mori, M<br />
P5‐05‐01<br />
Mori, T<br />
P1‐15‐11<br />
Moriguchi, Y<br />
P3‐13‐04<br />
Morimoto, T<br />
P1‐14‐02<br />
Morioka, T<br />
P3‐13‐02<br />
Moris, F<br />
P4‐06‐17<br />
Morita, S<br />
P1‐14‐08<br />
Moroso, S<br />
P5‐01‐10<br />
Morris, D<br />
P6‐07‐17<br />
Morris, DG<br />
P1‐07‐10<br />
Morris, E<br />
OT3‐1‐01<br />
Morris, J<br />
P3‐01‐04<br />
Morris, PG<br />
P5‐20‐07<br />
Morrison, L<br />
P6‐07‐45<br />
Morrison, MM<br />
P5‐19‐01<br />
Morrogh, M<br />
PD05‐02<br />
Morrow, M PD04‐05, OT3‐1‐01<br />
Mortimer, JE P2‐05‐10, P2‐14‐08<br />
Morton‐Gittens, JA<br />
P4‐17‐06<br />
Mose, LE S6‐1<br />
Moseley, P P6‐07‐09, P6‐07‐18<br />
Moses, HL<br />
P3‐05‐09<br />
Motahari, B<br />
P5‐09‐01<br />
Motion, J<br />
P1‐09‐05<br />
Motoki, T<br />
P3‐07‐10<br />
Motoyoshi, A<br />
P4‐15‐05<br />
Motsinger‐Reif, AA<br />
PD10‐07<br />
Moulder, S<br />
P5‐20‐09<br />
Moulis, S<br />
P1‐07‐03<br />
Moulton, B<br />
OT1‐1‐06<br />
Mouret‐Fourme, E<br />
PD07‐04<br />
Mouret‐Reynier, M‐A PD07‐04,<br />
P1‐13‐04, P3‐06‐20<br />
Mouri, Y<br />
P4‐03‐08<br />
Mourlane, F<br />
P5‐18‐25<br />
Moy, B<br />
S3‐5, P1‐01‐13,<br />
P1‐13‐05, P3‐06‐27<br />
Moy, L<br />
P4‐01‐07<br />
Moynahan, ME<br />
PD09‐10,<br />
P2‐08‐01, P6‐05‐01<br />
Mrklic, I<br />
P4‐04‐04<br />
Mrozek, E<br />
P2‐11‐07<br />
Mu, D‐B<br />
P1‐14‐17<br />
Mu, Z<br />
P6‐02‐05<br />
Mudalagiriyappa, C<br />
P2‐04‐02<br />
Mueller, BM<br />
PD06‐01<br />
Mueller, V<br />
OT1‐1‐10<br />
Muggia, F<br />
P6‐13‐01<br />
Muhsen, S<br />
PD04‐05<br />
Mukai, H<br />
P2‐13‐04, P2‐13‐07<br />
Mukai, M<br />
P4‐09‐08<br />
Mukaibashi, T<br />
P1‐01‐20<br />
Mukhopadhyay, P<br />
P6‐04‐02<br />
Mullarkey, PJ<br />
P4‐01‐12<br />
Müller, BM<br />
S4‐5, P3‐06‐05<br />
Müller, V<br />
P2‐10‐17,<br />
P3‐06‐05, P6‐07‐05<br />
Muller, W<br />
P6‐02‐03<br />
Muller, WJ<br />
P5‐18‐08<br />
Mullins, DN<br />
P5‐18‐17<br />
Mulrane, L<br />
P4‐09‐06<br />
Munarriz, B<br />
P2‐10‐11<br />
Mundhenke, C<br />
OT3‐2‐01<br />
Muñoz, D<br />
P5‐07‐01<br />
Muñoz, E PD08‐05, OT3‐3‐06<br />
Muñoz, M S1‐7<br />
Muñoz‐Cousuelo, E<br />
P6‐13‐03<br />
Murakami, K<br />
P6‐05‐06<br />
Murakami, K‐I<br />
P2‐14‐03<br />
Murakami, S<br />
P1‐14‐02<br />
Mural, RJ P1‐05‐09, P2‐05‐21,<br />
P3‐04‐06, P3‐09‐03, P5‐01‐07<br />
Murias, A P1‐07‐18, P2‐01‐06<br />
Muris, JJ<br />
PD01‐03<br />
Murphy, C<br />
P5‐18‐20<br />
Murphy, D<br />
PD02‐01<br />
Murphy, DA<br />
PD06‐03<br />
Murphy, T<br />
P2‐10‐05<br />
Murray, JL<br />
P5‐16‐01<br />
Murray, N PD07‐09, OT3‐3‐09<br />
Muscato, J<br />
OT1‐1‐07<br />
Muschler, B<br />
P4‐13‐11<br />
Muss, C<br />
P5‐20‐11<br />
Muss, HB<br />
P6‐08‐05<br />
Muth, M<br />
PD07‐02<br />
Muzumdar, S P4‐06‐14, P4‐06‐16<br />
Muzzio, M<br />
P1‐09‐07<br />
Myerson, R<br />
P6‐13‐01<br />
Myhre, S<br />
P3‐04‐03<br />
Myomoto, A<br />
P5‐10‐09<br />
Nabell, L<br />
P6‐05‐02<br />
Nabell, LM<br />
OT1‐1‐11<br />
Nabholtz, J‐M<br />
P3‐06‐20<br />
Nadi, K<br />
P1‐01‐18<br />
Naeim, A<br />
P4‐13‐13<br />
Nagai, S<br />
P1‐14‐06<br />
Nagaoka, R P2‐05‐07, P3‐06‐29<br />
Nagar, H<br />
P4‐03‐09<br />
Nagarwala, Y<br />
OT1‐1‐07<br />
Nagasawa, J<br />
P6‐04‐12<br />
Nagata, Y<br />
P3‐13‐04<br />
Nagayama, A<br />
P1‐14‐09<br />
Nagayasu, T<br />
P1‐01‐27<br />
Nagi, F<br />
OT1‐1‐04<br />
Naing, A<br />
P5‐20‐09<br />
Nair, BC<br />
PD09‐07<br />
Najita, J<br />
P2‐16‐04<br />
Nakagami, K<br />
P3‐02‐06<br />
Nakagawa, C<br />
P5‐15‐06<br />
Nakagawa, T<br />
P4‐03‐07<br />
Nakamura, S P1‐01‐12, P1‐14‐02,<br />
P2‐10‐18, P5‐15‐06,<br />
P6‐07‐23, P6‐07‐38<br />
Nakamura, Y P3‐06‐26, P6‐05‐14<br />
Nakano, S<br />
P4‐03‐08<br />
Nakao, K<br />
P1‐01‐27<br />
Nakashima, M<br />
P1‐01‐27<br />
Nakata, N<br />
P4‐03‐10<br />
Nakatani, E<br />
P3‐13‐04<br />
Nakayama, H<br />
P1‐01‐20<br />
Nakayama, I<br />
P3‐13‐04<br />
Nakayama, K<br />
P6‐07‐23<br />
Nakayama, T<br />
P1‐14‐02<br />
Nakhlis, F<br />
P3‐10‐06,<br />
P4‐06‐01, P5‐02‐01<br />
Nakijima, H<br />
P2‐06‐04<br />
Nalvarte, I<br />
PD01‐06<br />
Nam, J‐M<br />
P1‐05‐08<br />
Nam, SJ P2‐05‐20, P2‐10‐41, P3‐11‐01<br />
Namjoshi, M P2‐14‐07, P3‐07‐06,<br />
P3‐07‐07, P3‐07‐14,<br />
P5‐15‐05, P5‐20‐12<br />
Nanda, S<br />
PD01‐01, P4‐06‐02<br />
Nannini, M<br />
P5‐19‐02<br />
Nascimento, CCP<br />
P3‐02‐14<br />
Nash, CE<br />
P6‐02‐06<br />
Nasias, D<br />
P2‐01‐03<br />
Nassar, A<br />
P5‐01‐08<br />
Nasser, MW<br />
P1‐05‐17<br />
Nasu, H<br />
P4‐03‐05<br />
Natarajan, L<br />
P2‐11‐09<br />
Natori, T<br />
PD06‐02<br />
Natrajan, R<br />
PD05‐08<br />
Nätterdal, T<br />
P6‐12‐01<br />
Naume, B<br />
P3‐05‐04<br />
Nayak, SR<br />
P2‐09‐02<br />
Nazareth, LV<br />
P2‐06‐01<br />
Nearchou, A<br />
P5‐18‐18<br />
Neciosup, SP<br />
P6‐07‐21<br />
Negoro, S<br />
P6‐07‐30<br />
Neill, AA<br />
P6‐11‐07<br />
Nekljudova, V S2‐2, S3‐1, P6‐07‐05,<br />
OT1‐1‐13, OT2‐2‐05, OT3‐3‐11<br />
Nelson, MT<br />
P1‐14‐11<br />
Nemeth, Z<br />
P3‐05‐08<br />
Nemoto, M<br />
P4‐03‐03<br />
Nerenberg, M<br />
PD02‐01<br />
Nerich, V<br />
P5‐18‐22<br />
Nerurkar, A P1‐01‐10, P1‐01‐11<br />
Nestle‐Kraemling, C P1‐14‐04<br />
Neubauer, M<br />
P2‐11‐16<br />
Neugebauer, J<br />
P2‐01‐11<br />
Neugebauer, JK<br />
P2‐01‐02<br />
Neumayer, L S3‐5<br />
Neumayer, LA<br />
P4‐14‐01<br />
Neumeister, V<br />
P2‐10‐06<br />
Neven, P P2‐10‐12, P2‐12‐06, P2‐13‐06,<br />
P5‐18‐19, P6‐05‐05, P6‐07‐04,<br />
P6‐07‐05, P6‐07‐19, P6‐07‐29,<br />
P6‐09‐07, OT2‐2‐02, OT2‐2‐03<br />
Newburger, D<br />
PD05‐09<br />
Newell, P<br />
P4‐04‐02<br />
Newitt, D<br />
P4‐01‐04<br />
Newitt, DN<br />
P4‐01‐10<br />
Ng, CKY<br />
PD05‐08<br />
Ng, D<br />
P5‐18‐14<br />
Ng, EKO<br />
P3‐11‐02, P4‐11‐02<br />
Ng, T<br />
P2‐10‐29<br />
Ng, W‐K<br />
P2‐05‐16<br />
Ngan, E<br />
P1‐05‐22<br />
Ngeow, J<br />
P3‐08‐09<br />
Ngo, C<br />
P1‐01‐07, P1‐01‐19<br />
Nguyen, B<br />
OT3‐4‐03<br />
Nguyen, N P2‐09‐01, P4‐08‐08<br />
Nguyen, S<br />
P5‐12‐01<br />
Nguyen, SKA P4‐17‐08, P5‐12‐02<br />
Nguyen, TH<br />
P2‐05‐22<br />
Nguyen, T‐T<br />
P5‐03‐01<br />
Nichol, A<br />
PD04‐02<br />
Niederacher, D<br />
P2‐07‐01<br />
Niehoff, P<br />
P4‐15‐01<br />
Nielsen, D P3‐06‐32, P3‐06‐35<br />
Nielsen, DL<br />
P3‐06‐03<br />
Nielsen, S P3‐06‐32, P3‐06‐35<br />
Nielsen, T P2‐10‐02, P6‐07‐10<br />
Nielsen, TO S4‐6, P3‐06‐03, P4‐16‐02<br />
Niemierko, A<br />
P6‐09‐04<br />
Nightingale, G<br />
P2‐13‐05<br />
Niikura, N P2‐05‐08, P3‐13‐02<br />
Nijenhuis, MV<br />
P2‐10‐42<br />
Nik‐Zainal, S S6‐2<br />
Niland, JC<br />
P1‐13‐05<br />
Nilsson, MP<br />
P2‐10‐37<br />
Nimeh, N<br />
P1‐14‐14<br />
Niméus‐Malmström, E P2‐10‐07<br />
Nimnual, AS<br />
P5‐06‐02<br />
Ninomiya, J<br />
P1‐14‐06<br />
Niraula, S<br />
PD03‐05<br />
Niravath, PA<br />
OT1‐1‐11<br />
Nisenbaum, B<br />
P5‐20‐06<br />
Nishikawa, S<br />
P6‐04‐17<br />
Nishimiya, H<br />
P2‐12‐13<br />
Nishimur, R<br />
PD06‐07<br />
Nishimura, S<br />
P3‐06‐26<br />
Nishino, Y<br />
P6‐07‐27<br />
Nishiyama, K P3‐06‐26, P3‐07‐10<br />
Nishiyama, S<br />
P1‐01‐20<br />
Nishiyama, T<br />
P4‐12‐06<br />
Nitz, U S3‐4, P2‐10‐08, OT3‐3‐02<br />
Niu, CJ<br />
P4‐03‐04<br />
Niwa, S<br />
P3‐10‐10<br />
Niwa, T<br />
P6‐04‐17<br />
Njiaju, UO<br />
P6‐12‐02<br />
NNBC 3‐Europe Study Group P1‐13‐13<br />
Nodora, J<br />
PD08‐04<br />
Nofech‐Mozes, S P1‐07‐17, P2‐10‐09<br />
Nogami, T<br />
P3‐07‐10<br />
Nogi, H<br />
P4‐03‐10, P5‐04‐02<br />
Noguchi, M<br />
P4‐15‐05<br />
Noguchi, S P2‐10‐18, P6‐04‐02<br />
Noh, DY<br />
P2‐10‐35<br />
Noh, D‐Y PD05‐07, P1‐01‐08,<br />
P1‐14‐16, P1‐14‐19,<br />
P2‐05‐20, P3‐06‐16, P5‐18‐23<br />
Noh, EM<br />
P5‐07‐04<br />
Noh, H<br />
P6‐07‐40<br />
Nolan, T<br />
P5‐14‐04<br />
Noll, DC S6‐3<br />
Nonogaki, S<br />
P2‐05‐17<br />
Noor, L<br />
P4‐17‐09<br />
Nordenskjöld, B<br />
P6‐07‐12<br />
Norman, J<br />
P1‐05‐13<br />
Northey, JJ<br />
P1‐05‐22<br />
Northfelt, D<br />
P5‐17‐01<br />
Nortier, HWR<br />
P1‐12‐05<br />
Nortier, JWR S3‐2, PD07‐06, P6‐07‐06<br />
Norton, L P2‐10‐01, P5‐18‐04,<br />
P5‐20‐07, P6‐11‐10, OT3‐1‐01<br />
Nourieh, M<br />
P5‐01‐04<br />
Novik, Y<br />
P5‐20‐05<br />
Nunez, A<br />
P5‐12‐03<br />
Nuñez, J<br />
P5‐16‐03<br />
Nuñez, LE<br />
P4‐06‐17<br />
Nunez, P<br />
OT1‐1‐08<br />
Nyante, SJ<br />
P3‐07‐04<br />
Nygaard, S<br />
P3‐06‐32<br />
Nyhof‐Young, JM<br />
P6‐09‐01<br />
Oates, C<br />
P4‐17‐03<br />
Oba, H<br />
P1‐14‐06<br />
Obdeijn, I‐M<br />
P3‐02‐09<br />
O’Brien, NA<br />
P4‐08‐01<br />
O’Brien, P<br />
P1‐13‐01<br />
Ocal, T<br />
P1‐05‐04<br />
Ocana, A P2‐10‐23, P4‐06‐17, P6‐05‐04<br />
O’Cathail, S<br />
P3‐02‐04<br />
Ochoa, AE<br />
P6‐10‐04<br />
O’Conner, B<br />
P6‐13‐01<br />
O’Connor, DP<br />
P4‐09‐06<br />
Oda, M<br />
P4‐03‐05<br />
O’Donoghue, JM<br />
P4‐17‐06<br />
O’Donovan, N P3‐04‐12, OT1‐1‐06<br />
Oesterreich, S<br />
P2‐09‐02,<br />
P6‐04‐20, P6‐05‐12<br />
Ofo, E<br />
P2‐10‐29<br />
O’Gaora, P P6‐04‐01, P6‐04‐04<br />
Ogasawara, Y<br />
P3‐07‐10<br />
Ogburn, ERM<br />
OT1‐1‐03<br />
Ogilvie, T<br />
P1‐07‐10<br />
Ogiya, R<br />
P3‐13‐02<br />
Ogura, D<br />
P3‐10‐10<br />
Ogura, H<br />
P4‐03‐05<br />
Ogura, K<br />
OT1‐1‐01<br />
Oh, D‐Y<br />
PD09‐05<br />
Oh, P<br />
P2‐12‐03<br />
Ohanessian, R<br />
P2‐16‐03<br />
O’Hara, C<br />
P3‐08‐01<br />
O’Hara, J<br />
P1‐05‐06, P6‐04‐21<br />
Ohashi, S<br />
P4‐16‐13<br />
Ohashi, T<br />
P4‐03‐07<br />
Ohashi, Y P1‐13‐10, P2‐13‐04, P2‐13‐07<br />
Ohde, S<br />
P6‐07‐23<br />
Ohno, S<br />
P1‐14‐02, P1‐14‐08,<br />
P3‐06‐18, P3‐06‐26<br />
Ohsumi, S P2‐13‐07, P4‐14‐07<br />
Ohta, T<br />
P4‐16‐13<br />
Ohtani, S<br />
P1‐14‐08, P1‐14‐12<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
600s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
Author Index<br />
Ohuchi, N P1‐06‐02, P2‐10‐43,<br />
P6‐05‐14, P6‐07‐27<br />
Oikawa, M<br />
P1‐01‐27<br />
Ojeda, H<br />
P4‐01‐13, P4‐13‐13<br />
Ojutkangas, M‐L<br />
P2‐12‐09<br />
Okada, M<br />
P6‐07‐26<br />
Okamura, R<br />
P3‐13‐04<br />
Okamura, T P2‐05‐08, P3‐13‐02<br />
Okino, T<br />
P3‐13‐04<br />
Oktay, MH<br />
P6‐02‐04<br />
Okubo, F<br />
OT1‐1‐01<br />
Okuno, T<br />
P6‐07‐39<br />
Oldervoll, L<br />
P6‐09‐03<br />
O’Leary, K<br />
P4‐06‐10<br />
O’Leary, KA<br />
P2‐04‐04<br />
Oliff, I<br />
P6‐10‐01<br />
Olivares, K<br />
P5‐07‐02<br />
Oliveira, M P6‐13‐03, OT2‐3‐02<br />
Oliver, KA<br />
P6‐12‐02<br />
Oliveras, G<br />
P4‐09‐10,<br />
P4‐09‐11, P6‐11‐02<br />
Oliveria, CT<br />
P5‐20‐01<br />
Olivo, MS S6‐6<br />
Ollila, DW S2‐1<br />
Olsauskas‐Kuprys, R P2‐05‐15<br />
Olsen, JH<br />
P1‐09‐01<br />
Olsen, L<br />
PD08‐04<br />
Olsen, S<br />
P5‐18‐11<br />
Olson, E<br />
P5‐18‐03<br />
Olson, EM P2‐11‐07, P5‐18‐17<br />
Olson, J<br />
PD07‐01<br />
Olsson, H<br />
P2‐10‐28,<br />
P2‐10‐36, P2‐10‐37<br />
Olszewski, AJ<br />
P6‐07‐34<br />
Olvera, N<br />
PD04‐05, PD05‐02<br />
Omagari, T<br />
P1‐01‐27<br />
O’Malley, B<br />
P4‐08‐09<br />
O’Meara, WP P2‐11‐13, P2‐11‐14<br />
Omene, CO<br />
P5‐20‐05<br />
Omer, Z<br />
P4‐11‐03<br />
Omoto, Y<br />
P2‐14‐03<br />
Onega, TL<br />
P4‐01‐15<br />
O’Neill, A<br />
P5‐17‐01<br />
O’Neill, V<br />
OT3‐4‐04<br />
Ong, EYY<br />
P2‐05‐16<br />
Ong, K‐W<br />
P3‐08‐09<br />
Onishi, N<br />
P2‐04‐01<br />
Onoda, T<br />
P1‐14‐08, P6‐07‐38<br />
Onodera, Y<br />
P6‐05‐14<br />
Onstenk, W<br />
P2‐01‐09<br />
Onsum, M<br />
P1‐07‐03<br />
Onyekwelu, O<br />
P4‐14‐11<br />
Ookubo, F<br />
P1‐14‐06<br />
Oosterkamp, HM<br />
P1‐15‐05<br />
Oosterwijk, JC P3‐02‐09, P4‐11‐05<br />
Opdam, M<br />
PD01‐02,<br />
PD01‐03, P1‐15‐05<br />
Opdyke, KM P3‐02‐07, P5‐14‐02<br />
Openshaw, T<br />
P2‐16‐04<br />
Ordaz, D<br />
P4‐06‐19, P6‐04‐29<br />
Ordentlich, P P2‐09‐01, P6‐04‐23<br />
Orlandi, R<br />
P4‐06‐09<br />
Orr, N<br />
P3‐08‐04<br />
Orsini, C<br />
OT3‐3‐10<br />
Ortega, V P6‐13‐03, OT3‐3‐06<br />
Ortiz, C<br />
P5‐07‐06<br />
Ortiz, J<br />
P5‐07‐06<br />
Ortmann, O<br />
P2‐12‐06<br />
Ortmann, U<br />
OT1‐1‐10<br />
Osada, T<br />
P4‐08‐07<br />
Osaki, A<br />
P6‐04‐27<br />
Osako, T<br />
P1‐01‐12<br />
Osaku, M<br />
P4‐09‐08<br />
Osborne, CK S5‐8, PD01‐01, P4‐06‐02<br />
Osborne, CRC<br />
P5‐20‐03<br />
Osborne, K P2‐16‐02, P6‐10‐03<br />
Osborne, KC<br />
P2‐16‐03<br />
Osborne, MP<br />
P4‐15‐03<br />
O’Shaughnessy, J P1‐12‐02, P1‐12‐07,<br />
P3‐06‐12, P5‐20‐04, OT2‐3‐11<br />
Oshitanai, R<br />
P3‐13‐02<br />
Osin, P<br />
P1‐01‐10, P1‐01‐11<br />
Osipo, C<br />
P2‐05‐15, P4‐08‐06<br />
Ossher, L S6‐3<br />
Osterby, KR<br />
P6‐12‐02<br />
Osumi, S<br />
P2‐13‐04<br />
Oswald, M<br />
P5‐10‐13<br />
Ota, D<br />
PD07‐01<br />
Otani, S<br />
P4‐01‐05<br />
O’Toole, J P6‐09‐04, OT3‐2‐02<br />
O’Toole, M P2‐05‐15, P4‐08‐06<br />
Otremba, B<br />
P1‐15‐02<br />
Otsubo, R<br />
P1‐01‐27<br />
Ottesen, RA<br />
P1‐13‐05<br />
Otteson, R<br />
P1‐01‐13<br />
Ottewell, PD<br />
PD07‐08<br />
Oudard, S<br />
P5‐17‐04<br />
Oudot, A<br />
P4‐02‐06<br />
Ouhtit, A<br />
P4‐06‐14, P4‐06‐16<br />
Ould‐Kaci, M<br />
OT1‐1‐15<br />
Oura, S<br />
P1‐12‐01, P6‐07‐16<br />
Overgaard, J<br />
P3‐04‐03<br />
Overmoyer, B<br />
P5‐02‐01<br />
Overmoyer, BA P3‐10‐06, P4‐06‐01<br />
Owen, R<br />
S4‐1, P3‐06‐09<br />
Owonikoko, TK<br />
PD09‐06<br />
Oxley, P<br />
P4‐17‐08<br />
Oyama, T<br />
P3‐06‐29<br />
Ozanne, EM P3‐02‐12, P4‐01‐15,<br />
P4‐11‐03, P4‐13‐13, P5‐15‐01<br />
Ozmen, V<br />
P5‐02‐02<br />
Pacchiarotti, A<br />
P1‐01‐25<br />
Pachmann, K P1‐07‐16, P5‐03‐13<br />
Pachmann, U<br />
P5‐03‐13<br />
Pachter, JA P6‐11‐07, P6‐11‐09<br />
Pacia, E<br />
PD06‐03<br />
Padfield, D<br />
P3‐05‐06<br />
Padhani, AR<br />
P1‐06‐01<br />
Padval, MV<br />
P6‐11‐07<br />
Paepke, D<br />
P1‐13‐13<br />
Paepke, S<br />
S3‐1, P1‐14‐01,<br />
OT1‐1‐13, OT3‐3‐11<br />
Pagani, G<br />
PD03‐01<br />
Pagani, O<br />
OT2‐2‐01<br />
Page, J<br />
P1‐15‐01<br />
Page, K<br />
P1‐09‐07<br />
Paik, J‐Y<br />
P6‐01‐05<br />
Paik, N<br />
P4‐03‐11<br />
Paik, S<br />
S1‐10, S1‐11, S5‐5,<br />
OT1‐1‐12, OT2‐2‐04<br />
Paik, SS<br />
P2‐10‐39<br />
Paillocher, N<br />
P1‐14‐21<br />
Paily, AJ<br />
P4‐14‐05<br />
Paladini, L<br />
P5‐10‐01<br />
Pallaud, C<br />
P3‐06‐34<br />
Palles, C<br />
P3‐08‐04<br />
Palmer, G S3‐6, PD05‐01, PD05‐03<br />
Palmieri, C P2‐02‐03, P2‐10‐22,<br />
P2‐14‐06, P3‐02‐04, P3‐06‐13<br />
Palmisano, G<br />
P3‐04‐05<br />
Pan, H S1‐2<br />
Panageas, KS<br />
P3‐07‐09<br />
Panday, H<br />
P4‐08‐08<br />
Pandiella, A P4‐06‐17, P6‐05‐04<br />
Pandita, T<br />
P4‐08‐08<br />
Pankratz, VS<br />
P4‐12‐03<br />
Panneerdoss, S<br />
P5‐10‐14<br />
Pannu, H<br />
P5‐18‐04<br />
Pantel, K P2‐01‐02, OT1‐1‐10<br />
Papadaki, M<br />
P2‐01‐03<br />
Papadaki, MA<br />
P2‐01‐07<br />
Papadimitriou, C<br />
P5‐18‐21<br />
Papamichail, M<br />
P5‐16‐05<br />
Papoutsakis, D<br />
P6‐11‐06<br />
Paquet, A<br />
P2‐05‐06,<br />
P2‐10‐16, P2‐10‐31<br />
Paquet, L<br />
P2‐11‐10, P3‐04‐11<br />
Paragas, V<br />
P1‐07‐03<br />
Pardo, I<br />
P1‐03‐02<br />
Parham, LR<br />
PD10‐05<br />
Paridaens, R P2‐10‐12, P5‐18‐19,<br />
P6‐05‐05, P6‐07‐04, P6‐07‐19,<br />
P6‐07‐29, P6‐09‐07<br />
Parise, C<br />
P3‐09‐01, P3‐09‐02<br />
Parisini, E<br />
P4‐10‐01<br />
Parissenti, A<br />
P1‐14‐13<br />
Park, B‐W P1‐01‐23, P2‐05‐03<br />
Park, CC P1‐05‐08, P4‐01‐04, P4‐06‐05<br />
Park, H<br />
PD03‐09, P4‐13‐13<br />
Park, HS<br />
P1‐01‐23, P2‐05‐03<br />
Park, H‐S<br />
PD09‐05<br />
Park, HY<br />
P1‐01‐24<br />
Park, IA<br />
P2‐05‐20<br />
Park, J<br />
P2‐05‐01<br />
Park, JH<br />
P1‐12‐04<br />
Park, JM<br />
P1‐01‐23, P2‐05‐03<br />
Park, JW P2‐01‐05, P4‐16‐07, P6‐01‐05<br />
Park, M<br />
P6‐02‐03<br />
Park, S<br />
P1‐01‐23, P2‐05‐02,<br />
P2‐05‐03, P6‐04‐13<br />
Park, S‐J<br />
P1‐14‐19<br />
Park, SY<br />
P4‐06‐01, P5‐04‐03<br />
Park, Y<br />
P3‐07‐04<br />
Park, YH<br />
P2‐05‐20, P4‐06‐13<br />
Parker, BA P2‐06‐01, P4‐13‐13<br />
Parker, CA<br />
OT2‐3‐10<br />
Parker, J<br />
P6‐07‐10<br />
Parker, JS S6‐1<br />
Parker, S<br />
P2‐15‐02, OT3‐1‐02<br />
Parkes, EE<br />
P6‐07‐24<br />
Parmar, M S6‐5<br />
Partridge, A<br />
P6‐08‐03<br />
Partridge, AH<br />
P4‐01‐09<br />
Pasick, R<br />
P4‐13‐05<br />
Paskett, LA<br />
P6‐11‐12<br />
Pasqualini, R<br />
P3‐10‐09<br />
Pasquier, F<br />
P2‐13‐10<br />
Pasula, S<br />
P1‐05‐21<br />
Patel, R S1‐6<br />
Patel, V<br />
P1‐05‐23<br />
Pathania, S<br />
P4‐10‐01<br />
Pathiraja, T<br />
P2‐09‐02<br />
Patil, R<br />
P5‐16‐02<br />
Patil, S P2‐08‐01, P2‐11‐05, P2‐12‐05,<br />
P5‐18‐04, P5‐18‐20, P6‐05‐01,<br />
P6‐05‐02, OT3‐1‐01<br />
Patl, S<br />
P5‐20‐07<br />
Patre, M<br />
P5‐18‐05<br />
Patrick‐Miller, L<br />
P6‐08‐01<br />
Patt, D<br />
P2‐11‐16, P4‐11‐04<br />
Patterson, RE<br />
P2‐11‐09<br />
Paul, BA<br />
P5‐06‐01<br />
Paul, D<br />
P3‐06‐12<br />
Paula Junior, W<br />
P2‐12‐04<br />
Pauletti, G<br />
P2‐08‐02<br />
Paulino, AC<br />
P6‐07‐11<br />
Paulose, C<br />
P4‐08‐04<br />
Pauporte, I S5‐3<br />
Pauwels, P P2‐01‐08, P2‐01‐09<br />
Pavdal, M<br />
P6‐11‐09<br />
Pavlou, MP P2‐05‐11, P6‐05‐09<br />
Pawaskar, M<br />
P3‐07‐08<br />
Pazdur, R S1‐11<br />
Peacock, DL<br />
P1‐05‐15<br />
Peacock, N<br />
P5‐20‐10<br />
Peccatori, FA<br />
P6‐07‐14<br />
Pechan, J<br />
P2‐01‐12<br />
Peck, AR S1‐8<br />
Peck, KA<br />
P2‐11‐15<br />
Pectasides, D<br />
P1‐07‐15<br />
Pedersen, HC<br />
P1‐07‐05<br />
Pedersen, RC<br />
P3‐10‐07<br />
Pedrini, JL S1‐4<br />
Peeters, DJ P2‐01‐08, P2‐01‐09<br />
Peeters, J<br />
P3‐06‐11<br />
Peeters, M P2‐01‐08, P2‐01‐09<br />
Peeters, S<br />
P2‐10‐12,<br />
P6‐05‐05, P6‐07‐29<br />
Peg, V<br />
P1‐01‐29<br />
Peisker, U<br />
P1‐07‐16<br />
Peixoto, J‐E P3‐01‐07, P3‐02‐13<br />
Peksa, R<br />
P3‐12‐09, P3‐13‐03<br />
Pelissier, S<br />
OT3‐4‐05<br />
Pellegrini, M<br />
P5‐01‐10<br />
Peltier, S S6‐3<br />
Peluffo, G<br />
P4‐06‐01<br />
Peluzio, MCG<br />
P3‐07‐12<br />
Pemberton, K<br />
OT1‐1‐17<br />
Penault‐Llorca, F PD05‐08, P2‐08‐04,<br />
P3‐05‐07, P3‐06‐20,<br />
P3‐14‐03, P5‐21‐01<br />
Pendergrass, K S1‐4<br />
Pendleton, CS<br />
P6‐05‐03<br />
Pendyala, P<br />
P2‐01‐05<br />
Penedo, FJ<br />
PD08‐05<br />
Peoples, GE P5‐16‐02, P5‐16‐05<br />
Pepels, MJ<br />
PD07‐06<br />
Perea, F<br />
P1‐14‐13<br />
Perea, S<br />
P1‐14‐10, P5‐18‐15<br />
Perelló, A<br />
P1‐07‐18,<br />
P2‐01‐06, P3‐12‐08<br />
Peretz‐Yablonski, T OT1‐1‐02<br />
Perey, L<br />
P6‐04‐05<br />
Perez, C<br />
PD10‐02, P1‐02‐01<br />
Pérez, D P1‐07‐18, P1‐14‐10, P2‐01‐06<br />
Perez, E<br />
P1‐13‐01<br />
Perez, EA S5‐4, S5‐5, S6‐6, PD10‐04,<br />
P1‐05‐24, P1‐12‐06, P2‐10‐01<br />
Perez, J<br />
P1‐07‐19<br />
Perez, SA<br />
P5‐16‐05<br />
Perez‐Bueno, F<br />
P4‐09‐11<br />
Perez‐Garcia, J<br />
P6‐13‐03<br />
Perez‐Plasencia, C<br />
PD08‐06<br />
Perez‐Stable, EJ<br />
PD08‐05<br />
Pérez‐Tenorio, G<br />
P6‐07‐12<br />
Perin, T<br />
P5‐10‐17<br />
Periyasamy, M<br />
P1‐04‐04<br />
Permaul, E<br />
P1‐09‐04<br />
Perou, C<br />
S1‐11, P6‐07‐10<br />
Perou, CM S6‐1, P2‐10‐01, P5‐19‐01,<br />
P6‐02‐09, P6‐03‐01<br />
Perre, CI<br />
P4‐14‐08<br />
Perree, M<br />
P3‐06‐28<br />
Perren, T<br />
P4‐01‐14<br />
Perry, A<br />
P4‐17‐06<br />
Perry, M‐C<br />
P5‐18‐08<br />
Pertsemlidis, A<br />
P5‐10‐14<br />
Peters, A<br />
P3‐12‐03<br />
Peters, FPJ<br />
P6‐07‐32<br />
Peters, NAJB<br />
P6‐07‐32<br />
Peters, U<br />
PD03‐09<br />
Petersen, V<br />
P5‐21‐02<br />
Peterson, LM<br />
P6‐04‐03<br />
Petit, A<br />
P1‐01‐29<br />
Petit, T<br />
P2‐13‐10, P3‐06‐20<br />
Peto, J<br />
P3‐08‐04<br />
Peto, R S1‐2<br />
Petrcich, W<br />
P3‐11‐03<br />
Petrella, G<br />
P4‐15‐04<br />
Petrella, TM<br />
P2‐12‐03<br />
Petricoin, EF P3‐04‐01, P3‐04‐02<br />
Petropoulos, C P2‐10‐16, P2‐10‐31<br />
Petrowsky, C<br />
P1‐12‐04<br />
Petrucelli, N<br />
PD03‐09<br />
Petruse, A<br />
P4‐13‐13<br />
Petruzelka, L S1‐4<br />
Petry, C<br />
S4‐3, P2‐10‐11<br />
Pettke, E<br />
P3‐02‐11<br />
Peyrat, J‐P<br />
P5‐21‐01<br />
Peyro Saint Paul, HP OT3‐3‐10<br />
Pfalzer, LA P2‐11‐13, P2‐11‐14<br />
Pfeiler, G<br />
P1‐15‐10, P2‐13‐01<br />
Pham, T<br />
P2‐01‐10<br />
Pham, TND<br />
P6‐04‐24<br />
Pharoah, PD P3‐08‐02, P3‐08‐05<br />
Phillips, K‐A<br />
P4‐13‐10<br />
Phipps, EA<br />
P5‐08‐01<br />
Piccart, M S1‐11, S4‐4, S6‐2, P1‐07‐08,<br />
P2‐14‐01, P3‐04‐10, P3‐05‐02,<br />
P3‐05‐03, P5‐18‐19, P6‐04‐02,<br />
P6‐07‐14, P6‐07‐22<br />
Piccart‐Gebhart, M<br />
OT1‐1‐16<br />
Piccart‐Gebhart, MJ S5‐2, P5‐18‐02<br />
Picquenot, JM<br />
P3‐14‐03<br />
Pidgeon, GP<br />
P6‐01‐02<br />
Pieczynska, B P3‐12‐09, P3‐13‐03<br />
Piede, JA<br />
P4‐08‐07<br />
Pienkowski, T<br />
P5‐02‐02<br />
Pierga, JY<br />
P3‐06‐04<br />
Pierga, J‐Y<br />
S5‐3, P1‐01‐07,<br />
P1‐01‐19, P1‐14‐03, P1‐14‐18,<br />
P2‐01‐01, P2‐01‐04, P2‐01‐13,<br />
P5‐21‐03, OT2‐3‐05,<br />
OT3‐4‐05, OT3‐4‐06<br />
Pietenpol, JA P3‐05‐09, P6‐05‐03<br />
Pietrarota, P<br />
P4‐16‐08<br />
www.aacrjournals.org 601s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Pietras, RJ<br />
PD03‐04<br />
Pigeonnat, S<br />
P3‐08‐07<br />
Pigorsch, S S4‐2<br />
Piha‐Paul, S<br />
P5‐20‐09<br />
Pijnappel, RM P4‐14‐08, P5‐01‐11<br />
Pikiel, J<br />
P5‐18‐21<br />
Pillai, MM<br />
PD01‐07<br />
Pillai, S<br />
P2‐04‐02<br />
Pina, L<br />
P5‐16‐03<br />
Pinder, S<br />
P2‐10‐29<br />
Pinna, G<br />
P5‐03‐01<br />
Pinotti, M<br />
P3‐02‐14<br />
Pinter, T S1‐6<br />
Pintilie, M<br />
P2‐10‐33<br />
Pinto, JA S3‐6, P6‐07‐20, P6‐07‐21<br />
Pinto, RR<br />
P3‐11‐04, P6‐07‐44<br />
Pinto, W<br />
P1‐01‐29<br />
Piper, T S1‐5<br />
Pircher, M<br />
P5‐20‐11<br />
Pirolli, M<br />
P2‐13‐03<br />
Pitcher, B<br />
P6‐08‐05<br />
Pitcher, BN<br />
P2‐10‐01<br />
Pivot, X<br />
S5‐3, S6‐5,<br />
P5‐15‐07, P5‐18‐22<br />
Pizon, M<br />
P5‐03‐13<br />
Platero, S<br />
P5‐01‐09<br />
Plevritis, S<br />
P2‐09‐03<br />
Plichta, JK<br />
P1‐02‐01<br />
Pluard, T<br />
PD07‐01<br />
Plyler, JR<br />
P5‐10‐16<br />
Poggi, LE<br />
P6‐12‐02<br />
Pogorelic, Z<br />
P4‐04‐04<br />
Pohorelic, B P4‐09‐07, P6‐07‐17<br />
Poillot, M‐L<br />
P3‐08‐07<br />
Polgar, C<br />
P4‐15‐01<br />
Polistena, A<br />
P1‐01‐25<br />
Pollak, MN<br />
P1‐07‐13<br />
Polley, M‐YC S4‐6<br />
Polyak, K P3‐05‐04, P4‐06‐01<br />
Polyzos, A<br />
P1‐13‐09<br />
Pond, G<br />
P6‐09‐02<br />
Poniewierski, MS P1‐15‐04, P3‐06‐07<br />
Ponniah, S P5‐16‐02, P5‐16‐05<br />
Popova, T<br />
P5‐02‐03<br />
Porcher, R<br />
P4‐13‐03<br />
Port, D<br />
PD08‐06<br />
Porta, R<br />
P4‐09‐10<br />
Porter, C<br />
P2‐11‐17<br />
Porter, D<br />
P6‐11‐06<br />
Porter, DA<br />
P4‐01‐10<br />
Portielje, JEA<br />
P1‐12‐05<br />
Portier, BP PD02‐04, P6‐07‐45<br />
Portillo, RM<br />
P3‐06‐12<br />
Posse, S<br />
P3‐03‐01<br />
Postma, EL<br />
P4‐01‐17,<br />
P5‐01‐14, P5‐15‐03<br />
Potemski, P<br />
P5‐18‐21<br />
Potter, BM<br />
P1‐01‐04<br />
Potter, S<br />
P4‐17‐03<br />
Potvin, K<br />
P1‐14‐13<br />
Potyka, I S4‐2<br />
Pouget, N<br />
P3‐08‐07<br />
Poulet, B<br />
P6‐07‐03<br />
Poulikakos, P<br />
P4‐08‐02<br />
Pourmand, N<br />
P2‐06‐05<br />
Powathil, GG<br />
P5‐05‐02<br />
Powell, CA<br />
P1‐05‐17<br />
Power, S<br />
P4‐13‐06<br />
Pradeep, S<br />
P5‐10‐03<br />
Prager‐van der Smissen, WJC P6‐04‐08<br />
Prasad, N<br />
P5‐18‐13<br />
Prat, A P6‐05‐04, P6‐07‐10, OT3‐3‐06<br />
Prathap, P<br />
P6‐07‐13<br />
Pratt, C<br />
PD09‐01<br />
Prendergast, BM<br />
P5‐17‐07<br />
Prendergast, GC<br />
P4‐09‐12<br />
Prenois, F<br />
P5‐13‐02<br />
Presant, C<br />
P3‐06‐28<br />
Press, M<br />
PD02‐01<br />
Press, MF<br />
P4‐08‐05<br />
Price, A<br />
P4‐01‐07<br />
Price, JT<br />
P6‐07‐17<br />
Price, KN<br />
OT2‐2‐01<br />
Priego, V<br />
P1‐14‐14<br />
Prinzler, J<br />
S4‐5, P3‐06‐05<br />
Prior, WW P4‐07‐01, P5‐19‐02<br />
Pritchard, K<br />
P1‐13‐01,<br />
P2‐12‐03, P6‐08‐04<br />
Pritchard, KI P1‐07‐13, P2‐13‐02<br />
Privat, M<br />
P3‐06‐20<br />
Procter, M S5‐2<br />
Proctor, I<br />
PD04‐08<br />
Protter, AA<br />
P2‐14‐02<br />
Prové, A<br />
P2‐01‐08<br />
Prowell, T S1‐11<br />
Prudente, R<br />
P6‐04‐12<br />
Pruneri, G PD03‐01, PD04‐07,<br />
PD06‐06, P3‐05‐03<br />
Psyrri, A S5‐4<br />
Pu, M<br />
P2‐06‐01<br />
Puccio, A<br />
PD03‐01<br />
Pugh, TW<br />
P4‐12‐05<br />
Puglisi, F<br />
OT1‐1‐02<br />
Puhalla, SL<br />
PD09‐06,<br />
P6‐07‐02, OT1‐1‐11<br />
Puig, T P4‐09‐10, P4‐09‐11, P6‐11‐02<br />
Puig‐Vives, M<br />
P4‐09‐11<br />
Pulhalla, S<br />
OT2‐3‐07<br />
Puntoni, M PD03‐01, PD06‐06<br />
Pupa, SM<br />
P5‐18‐10<br />
Purdie, CA<br />
PD03‐02<br />
Purnomosari, D<br />
P3‐01‐08<br />
Purshouse, K<br />
P2‐02‐03<br />
Purushotham, A<br />
P2‐10‐29<br />
Pusztai, L<br />
S6‐7, P2‐10‐10,<br />
P2‐10‐17, P5‐10‐01<br />
Putney, JL<br />
OT2‐1‐04<br />
Putter, H<br />
PD07‐06<br />
Qamri, Z<br />
P1‐05‐17<br />
Qian, J<br />
P6‐04‐12, OT2‐3‐07<br />
Qin, J<br />
P4‐09‐09<br />
Qin, L<br />
P6‐04‐25<br />
Qin, L‐X<br />
PD05‐02<br />
Qiong, P<br />
P4‐16‐10<br />
Quach, D<br />
P2‐13‐03<br />
Quadt, C<br />
P6‐10‐07<br />
Quigley, DA<br />
P5‐05‐03<br />
Quigley, J<br />
P2‐13‐03<br />
Quijano, Y P1‐14‐10, P5‐18‐15<br />
Quinaux, E<br />
PD02‐01<br />
Quintanar‐Jurado, V P5‐10‐12<br />
Quintayo, MA<br />
P1‐07‐17<br />
Quintyn‐Ranty, M‐L P3‐05‐07<br />
Raafat, A<br />
P2‐04‐08<br />
Rabaglio, M<br />
P2‐13‐02<br />
Rabeneck, L<br />
P3‐02‐10<br />
Rabenstein, C<br />
P5‐03‐13<br />
Rabinovitch, R<br />
OT1‐2‐01<br />
Rack, B<br />
P2‐10‐25, P3‐06‐05,<br />
P5‐14‐06, P5‐15‐04, P6‐07‐05<br />
Rack, BJ<br />
P2‐01‐11<br />
Rack, BK<br />
P2‐01‐02,<br />
P4‐13‐11, OT1‐1‐10<br />
Radecka, B<br />
P2‐10‐31,<br />
P3‐12‐09, P3‐13‐03<br />
Radisky, DC P4‐12‐03, P6‐06‐01<br />
Radosevic‐Robin, N P5‐21‐01<br />
Radovich, M PD05‐06, P1‐03‐02<br />
Ragaz, J<br />
P4‐13‐04, P6‐07‐43<br />
Raghavendra, A<br />
P4‐01‐11<br />
Raguin, O<br />
P4‐02‐06<br />
Rahal, RMS<br />
P3‐02‐13<br />
Rahnenführer, J<br />
P2‐10‐13<br />
Rai, Y<br />
P1‐12‐01, P5‐18‐16<br />
Raj, V<br />
P3‐06‐30<br />
Rajan, P<br />
P1‐02‐01<br />
Rajput, A<br />
P3‐03‐01<br />
Rakha, E<br />
P3‐06‐09<br />
Rakovitch, E<br />
P1‐07‐17<br />
Ramadan, D<br />
P5‐18‐07<br />
Ramalingam, SS<br />
PD09‐06<br />
Raman, D<br />
P1‐05‐01<br />
Raman, S<br />
P2‐11‐07<br />
Ramaswamy, B<br />
P2‐11‐07<br />
Ramaswamy, S<br />
P2‐01‐14<br />
Ramirez, AG<br />
PD08‐05<br />
Ramirez, E<br />
P5‐07‐06<br />
Ramirez, J<br />
P2‐11‐05<br />
Ramirez, O<br />
P4‐04‐06<br />
Ramirez Ardila, DE<br />
P3‐06‐01<br />
Ramkumar, A P4‐06‐14, P4‐06‐16<br />
Ramnarain, A<br />
P1‐15‐07<br />
Ramos, K<br />
P4‐04‐05<br />
Ramos, M S1‐7<br />
Rampaul, R<br />
P4‐17‐06<br />
Ramteke, VK<br />
P4‐02‐02<br />
Randolph, S S1‐6<br />
Rangel, LBA P5‐01‐15, P6‐11‐13<br />
Rao, M P5‐04‐04, P5‐10‐14, P5‐10‐16<br />
Rao, R<br />
S3‐7, P1‐07‐04<br />
Rappold, E<br />
PD10‐05<br />
Raro, P P1‐01‐21, P1‐14‐21, OT2‐1‐01<br />
Rastegar, R<br />
P4‐17‐08<br />
Rastogi, P S1‐11, S5‐5, OT2‐2‐04<br />
Rathbone, EJ S6‐4<br />
Rattay, T<br />
P1‐14‐15<br />
Raubitschek, AA<br />
P2‐05‐10<br />
Rauch, P<br />
P6‐08‐01<br />
Raum, N<br />
P2‐16‐01<br />
Ravichandran, P<br />
P6‐07‐41<br />
Ravnsbaek, A<br />
P6‐07‐08<br />
Ray, P<br />
OT2‐1‐04<br />
Ray‐Coquard, I<br />
P5‐17‐04<br />
Rayson, D<br />
OT1‐1‐07<br />
Razis, E<br />
P1‐07‐15<br />
Rea, D S1‐5<br />
Ready, N<br />
P2‐10‐03, P3‐06‐07<br />
Rebollar‐Vega, RG<br />
P5‐10‐12<br />
Rechoum, Y<br />
P4‐08‐09<br />
Reddick, C<br />
OT2‐2‐03<br />
Reddy, J<br />
PD03‐06<br />
Redmond, W<br />
P4‐04‐02<br />
Reed, J<br />
P6‐07‐10<br />
Reed, JP<br />
P2‐10‐01<br />
Reedijk, M<br />
PD03‐05<br />
Rees, B<br />
P6‐07‐18<br />
Rees, H<br />
P2‐10‐09<br />
Rees, R<br />
P6‐07‐09<br />
Reeves, KJ<br />
PD07‐08<br />
Refice, S PD03‐03, P1‐09‐02, P4‐02‐07<br />
Refinetti, AP P1‐09‐03, P4‐01‐07<br />
Regan, M<br />
S4‐4, PD10‐03<br />
Regan, MM P1‐07‐07, P3‐10‐06,<br />
P5‐18‐02, OT2‐2‐01<br />
Rege, J<br />
P1‐12‐02, P1‐13‐11,<br />
P5‐20‐04, P6‐11‐14<br />
Regehr, G<br />
P5‐12‐01<br />
Regondi, V<br />
P5‐18‐10<br />
Reich, SD<br />
OT1‐1‐05<br />
Reichow, J P2‐15‐02, OT3‐1‐02<br />
Reid, I<br />
P4‐14‐13<br />
Reid, J<br />
PD10‐08<br />
Reid, R<br />
P4‐14‐09<br />
Reidunsdatter, RJ<br />
P6‐09‐03<br />
Reijm, EA<br />
P6‐04‐08<br />
Reinholz, MM<br />
PD10‐04<br />
Reintgen, D<br />
OT3‐4‐02<br />
Reis‐Filho, J<br />
P3‐06‐09<br />
Reis‐Filho, JS<br />
PD05‐08<br />
Reiter, BE<br />
P6‐04‐18<br />
Re‐Louhau, F<br />
P4‐06‐17<br />
Renne, G<br />
P6‐07‐14<br />
Rennert, G<br />
P6‐14‐03<br />
Rennert, HS<br />
P6‐14‐03<br />
Renshaw, L<br />
P3‐06‐23,<br />
P6‐04‐09, P6‐04‐10<br />
Resch, A<br />
P4‐15‐01<br />
Ressler, S<br />
P5‐20‐11<br />
Reuben, JM PD03‐08, P2‐01‐01,<br />
P2‐01‐12, P2‐03‐01, P2‐10‐32,<br />
P3‐10‐05, P3‐10‐10, P5‐03‐05,<br />
P5‐03‐09, P5‐04‐06, P5‐10‐02,<br />
OT2‐3‐01<br />
Reuter‐Lorenz, PA S6‐3<br />
Rey, J‐B<br />
P5‐17‐04<br />
Reyal, F<br />
P1‐01‐19<br />
Reyes, ME<br />
P5‐03‐09<br />
Reynolds, C<br />
P1‐01‐22<br />
Reyre, J<br />
P3‐05‐07<br />
Rezai, M<br />
P1‐14‐01,<br />
P2‐10‐14, P2‐10‐25<br />
Rezende, LCD<br />
P5‐01‐15<br />
Riabowol, K<br />
P4‐09‐07<br />
Ribas, R<br />
PD01‐05<br />
Ribeiro, IM<br />
P3‐02‐14<br />
Ribeiro, MKA<br />
P2‐12‐04<br />
Ribeiro, R<br />
P3‐01‐03<br />
Ricart, AD<br />
OT1‐1‐05<br />
Ricci, D<br />
P5‐01‐09<br />
Ricci, F<br />
P1‐01‐25<br />
Richardson, A<br />
PD01‐08<br />
Richardson, AL<br />
P1‐07‐07<br />
Richardson, E<br />
P1‐07‐13<br />
Richer, JK P2‐14‐02, P5‐10‐04,<br />
P5‐10‐05, P5‐10‐06<br />
Richmond, A<br />
P1‐05‐01<br />
Ricker, C<br />
P4‐01‐11<br />
Rief, W<br />
P6‐09‐08<br />
Riegel, AT<br />
P6‐05‐07<br />
Riehle, K<br />
P6‐05‐12<br />
Rifa, J<br />
P3‐12‐08<br />
Rigal, O<br />
P1‐15‐08<br />
Rijna, H<br />
P4‐11‐01<br />
Riley, L<br />
P2‐06‐04<br />
Rimareix, F<br />
P4‐14‐12<br />
Rimawi, M<br />
P5‐18‐24<br />
Rimawi, MF<br />
S5‐8, P2‐16‐02<br />
Rimm, D<br />
S5‐4, P3‐14‐01<br />
Rimm, DL<br />
PD02‐01,<br />
P2‐10‐06, P3‐06‐25<br />
Ring, A<br />
P6‐07‐05<br />
Ring, JE<br />
P6‐11‐07<br />
Rinnerthaler, G<br />
P5‐20‐11<br />
Rino, Y<br />
P1‐01‐20<br />
Rios, M<br />
P1‐13‐04<br />
Ritchie, C<br />
P2‐12‐14<br />
Rivain, A‐L<br />
P1‐01‐19<br />
Rivaux, G<br />
P4‐14‐10<br />
Rivera, E<br />
OT3‐3‐01<br />
Rix, P<br />
P6‐04‐12<br />
Ro, J PD09‐05, P5‐18‐26, OT1‐1‐16<br />
Roarty, K<br />
P5‐03‐08<br />
Robbins, D<br />
P3‐13‐05<br />
Robert, NJ<br />
P3‐06‐12<br />
Robertson, C P4‐13‐07, P4‐13‐08<br />
Robertson, FM<br />
P4‐06‐03,<br />
P5‐04‐05, P6‐10‐04<br />
Robertson, S<br />
P2‐10‐09<br />
Robertson, SJ<br />
P5‐01‐01<br />
Robidoux, A<br />
S3‐2, P6‐07‐06<br />
Robinson, A S3‐3<br />
Robinson, BD<br />
P6‐02‐04<br />
Robinson, M<br />
OT2‐3‐11<br />
Robinson, P<br />
PD10‐02<br />
Robinson, PA<br />
P1‐12‐04<br />
Roblyer, D<br />
P4‐02‐04<br />
Robson, M<br />
OT2‐3‐07<br />
Roca, L<br />
P1‐13‐04<br />
Rocha, RM<br />
P1‐06‐03<br />
Roche, H<br />
P1‐13‐04, P3‐04‐04<br />
Roche, N<br />
P1‐01‐10, P1‐01‐11<br />
Roche‐Comet, I<br />
P5‐21‐01<br />
Rocque, GB<br />
P2‐11‐15<br />
Rodenhuis, S<br />
P4‐02‐01<br />
Rodier, J‐F<br />
P1‐01‐21<br />
Rodón, J<br />
OT2‐3‐06<br />
Rodrigues, DCN<br />
P3‐02‐13<br />
Rodrigues, DN PD05‐08, P3‐06‐09<br />
Rodriguez, AA<br />
P3‐06‐14,<br />
P5‐03‐03, P6‐07‐11<br />
Rodriguez, CA<br />
P2‐10‐11<br />
Rodriguez, EM<br />
P1‐04‐01<br />
Rodriguez, JG<br />
OT1‐1‐08<br />
Rodríguez‐Antona, C OT3‐3‐05<br />
Rodriguez‐Cuevas, S P5‐10‐12<br />
Rodriguez‐Lescure, A P2‐10‐11<br />
Rodriguez‐Peralto, JL P5‐10‐11<br />
Rodriguez‐Spiteri, N P5‐16‐03<br />
Rodriguez‐Teja, M<br />
P2‐02‐03<br />
Rodrik‐Outmezguine, V P4‐08‐02<br />
Rody, A<br />
P2‐10‐17<br />
Roepman, P<br />
P4‐09‐05<br />
Roessl, E<br />
P4‐03‐06<br />
Rogers, AN<br />
P2‐05‐04<br />
Rogers, K<br />
P3‐06‐28<br />
Rogers, N<br />
P4‐01‐10<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
602s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
Author Index<br />
Rogowski, W P3‐12‐09, P3‐13‐03<br />
Rohan, TE<br />
P6‐02‐04<br />
Rojas, LA<br />
P5‐18‐13<br />
Rojas, M<br />
P5‐13‐03<br />
Rojas, PA<br />
P4‐06‐15<br />
Rokutanda, N P2‐05‐07, P3‐06‐29<br />
Rollot, F<br />
OT3‐3‐10<br />
Roloff, T<br />
PD01‐06<br />
Romeder, F<br />
P5‐20‐11<br />
Rømer, M P3‐06‐32, P3‐06‐35<br />
Romero, A<br />
P5‐07‐06<br />
Romero, Q<br />
PD03‐07<br />
Romero‐Cordoba, SL P5‐10‐12<br />
Romics, L<br />
P4‐14‐13<br />
Romieu, G<br />
S5‐3, P3‐12‐01<br />
Romieux, G<br />
OT3‐3‐10<br />
Romond, E<br />
S5‐5, P2‐14‐05<br />
Roncadin, M<br />
S4‐2, P5‐10‐17<br />
Rong, H‐M<br />
P2‐08‐02<br />
Rose, C<br />
PD03‐07<br />
Rose, J<br />
P3‐02‐07<br />
Rosen, DB<br />
P6‐07‐31<br />
Rosen, J<br />
P4‐02‐08, P5‐03‐08<br />
Rosen, N PD04‐05, P4‐08‐02, P5‐18‐04<br />
Rosen, RB<br />
P6‐05‐10<br />
Rosenberg, AL S1‐8<br />
Rosenberg, CA<br />
PD03‐09<br />
Rosenblad, A<br />
P2‐12‐09<br />
Rosenstock, J P4‐13‐07, P4‐13‐08<br />
Rosenthall, RE<br />
P2‐10‐27<br />
Roskelly, C<br />
P1‐05‐05<br />
Ross, G<br />
S5‐1, S6‐7,<br />
P5‐18‐01, P5‐18‐26<br />
Ross, GM<br />
P3‐08‐04<br />
Ross, J<br />
PD02‐07, PD05‐01<br />
Ross, L<br />
P4‐07‐01<br />
Ross, LB<br />
P5‐19‐02<br />
Roth, S<br />
P1‐14‐04<br />
Rothé, F S6‐2<br />
Rothstein, R<br />
P4‐07‐05<br />
Rotkiss, M<br />
OT3‐4‐03<br />
Rotmensz, N PD04‐07, P6‐07‐14<br />
Rouanet, P<br />
OT2‐1‐01<br />
Roussi, P<br />
P6‐09‐05<br />
Roussou, P<br />
P6‐11‐08<br />
Rouzier, R P1‐01‐07, P1‐01‐14,<br />
P1‐01‐19, P4‐14‐12<br />
Rowan, B<br />
P6‐08‐01<br />
Rowland, C<br />
PD10‐03<br />
Rowland, Jr., KM<br />
P1‐12‐06<br />
Roy, S<br />
PD10‐07<br />
Roy, SS PD09‐07, P5‐04‐04, P6‐04‐07<br />
Royce, M<br />
P3‐03‐01<br />
Roylance, R<br />
P6‐07‐15<br />
Rubin, P<br />
P5‐20‐08<br />
Rubio, I<br />
P1‐01‐29, OT3‐3‐06<br />
Ruckhäberle, E<br />
P2‐10‐17<br />
Rudas, M<br />
S4‐3, P2‐10‐02<br />
Ruddy, KJ<br />
P4‐01‐09<br />
Rüdiger, T S4‐5<br />
Rudlowski, C<br />
OT2‐2‐05<br />
Rudraraju, B P2‐10‐22, P3‐06‐13<br />
Rueda, OM P2‐10‐20, P3‐08‐05<br />
Ruffini, P<br />
OT2‐3‐01<br />
Rugo, H PD09‐03, P1‐01‐13, P1‐13‐01,<br />
P6‐04‐02, P6‐05‐02, P6‐13‐01<br />
Rugo, HS S3‐5, P1‐13‐05, P2‐01‐05,<br />
P2‐12‐11, P2‐12‐12, P4‐01‐13,<br />
P4‐16‐07, OT2‐3‐04<br />
Rugowski, DE<br />
P2‐04‐04<br />
Rui, H S1‐8, P2‐05‐21, P5‐01‐07<br />
Ruigrok‐Ritstier, K P3‐06‐01, P6‐04‐08<br />
Ruiz, A<br />
P2‐10‐11, OT1‐1‐09<br />
Ruiz, M<br />
P1‐07‐18, P2‐01‐06<br />
Ruiz‐Borrego, M<br />
P2‐10‐11<br />
Ruiz‐Esparza, GU<br />
P6‐11‐03<br />
Rukazenkov, Y S1‐4<br />
Rumas, N<br />
P1‐02‐01<br />
Ruppert, AS<br />
P2‐11‐07<br />
Rusby, J<br />
P1‐01‐10<br />
Rusby, JE<br />
P1‐01‐11<br />
Ruschke, K<br />
P2‐10‐38<br />
Russell, J<br />
P3‐03‐01<br />
Russell, K<br />
P3‐06‐21<br />
Russell, NS<br />
P2‐10‐42<br />
Russnes, HG<br />
P3‐05‐04<br />
Russo, L<br />
P3‐05‐02<br />
Russo, LM<br />
P5‐01‐10<br />
Rutgers, E<br />
P3‐05‐02<br />
Rutgers, EJ P3‐02‐09, P4‐11‐01<br />
Rutgers, EJT<br />
P2‐10‐42,<br />
P3‐02‐01, P4‐02‐01<br />
Ruth, K<br />
P1‐01‐16<br />
Rutkowski, T P3‐12‐09, P3‐13‐03<br />
Rutledge, J<br />
P3‐06‐28<br />
Rutqvist, L‐E<br />
P6‐14‐01<br />
Rutten, A<br />
P2‐01‐08, P2‐01‐09<br />
Ryabin, N<br />
OT1‐1‐11<br />
Ryan, J<br />
P5‐12‐03<br />
Ryan, PD<br />
PD09‐03<br />
Rydén, L PD03‐07, P2‐10‐28, P2‐10‐36<br />
Ryder, D<br />
P2‐14‐06<br />
Rye, IH<br />
P3‐05‐04<br />
Ryvo, L<br />
P5‐20‐06<br />
Saad, O<br />
P5‐18‐11<br />
Saadatmand, S<br />
P3‐02‐09<br />
Saadjian, H P2‐16‐02, P2‐16‐03<br />
Sabe, H<br />
P1‐05‐08<br />
Sabine, VS S1‐5<br />
Sabol, JL<br />
P4‐09‐12<br />
Sacchini, V<br />
OT3‐1‐01<br />
Sachdev, JC<br />
OT3‐3‐07<br />
Sackey, H<br />
P3‐07‐03<br />
Sadat, F<br />
P2‐07‐01<br />
Sadewa, AH<br />
P3‐01‐08<br />
Sadik, H<br />
P2‐09‐01, P4‐08‐08<br />
Saeki, T<br />
P4‐02‐04, P6‐04‐27<br />
Sætersdal, A<br />
P3‐05‐04<br />
Saez, R<br />
P5‐20‐10, OT3‐4‐02<br />
Safgren, S<br />
PD10‐08<br />
Safra, T<br />
P5‐20‐06<br />
Sagan, C<br />
P3‐14‐03<br />
Sagara, Y<br />
P6‐07‐16<br />
Saghatchian, M P4‐09‐05, P5‐13‐02<br />
Sahadevan, M<br />
P4‐12‐04<br />
Sahebjam, S<br />
P2‐10‐23<br />
Sahin, A<br />
P1‐07‐06<br />
Sahin, S<br />
P3‐08‐01<br />
Sahium, RC<br />
P3‐02‐14<br />
Sahmoud, T<br />
P6‐04‐02<br />
Sahoo, R<br />
PD07‐07<br />
Sai‐Girdhar, P<br />
P1‐01‐18<br />
Saini, K<br />
P3‐05‐03<br />
Sainsbury, R<br />
PD04‐08<br />
Saito, M P1‐12‐01, P4‐14‐07, P6‐07‐16<br />
Saito, Y<br />
P3‐13‐02<br />
Saiz, E<br />
P4‐09‐10<br />
Saji, S P3‐02‐06, P3‐06‐18, P6‐04‐27<br />
Sakahara, H<br />
P4‐03‐05<br />
Sakai, Y<br />
PD02‐05<br />
Sakata, S<br />
P3‐13‐04<br />
Sakr, BJ<br />
P6‐07‐34<br />
Sakr, R<br />
P5‐18‐04<br />
Sakr, RA<br />
PD04‐05, PD05‐02<br />
Salari, R<br />
PD05‐09<br />
Salat, C<br />
P5‐18‐21<br />
Salazar, LG<br />
P2‐15‐02,<br />
P5‐16‐04, OT3‐1‐02<br />
Salazar, N<br />
P5‐07‐01<br />
Saleh, MN<br />
P6‐10‐01<br />
Saleh, SM<br />
P6‐02‐03<br />
Salem, M<br />
P2‐10‐08<br />
Salgado, E<br />
P5‐16‐03<br />
Salgado, R<br />
S6‐2, P1‐07‐08,<br />
P3‐04‐10, P3‐05‐03<br />
Salihi, R<br />
P6‐07‐29<br />
Salim, A<br />
P2‐11‐06<br />
Salmon, R<br />
PD07‐04<br />
Salomon, A<br />
P1‐01‐07<br />
Salvador, J P1‐07‐18, P2‐01‐06<br />
Salvadori, B<br />
P5‐17‐06<br />
Samant, M P5‐18‐06, P5‐18‐24<br />
Sammel, MD<br />
P4‐13‐01<br />
Sampath, D P4‐07‐01, P5‐19‐02<br />
Sample, D<br />
P5‐16‐01<br />
Samra, F<br />
P4‐14‐03, P4‐17‐07<br />
Samson, S S3‐8<br />
<strong>San</strong>born, JZ<br />
P2‐06‐05<br />
<strong>San</strong>chez, F<br />
P5‐07‐06<br />
Sánchez, S<br />
P5‐03‐07<br />
<strong>San</strong>chez‐Olle, G<br />
P6‐13‐03<br />
<strong>San</strong>cho de Salas, M<br />
P1‐01‐29<br />
<strong>San</strong>dbach, J<br />
P4‐11‐04<br />
<strong>San</strong>ders, L<br />
OT3‐2‐01<br />
<strong>San</strong>ders, ME<br />
S3‐6, P4‐01‐03,<br />
P6‐05‐03, P6‐10‐05<br />
<strong>San</strong>ders, MS<br />
P2‐14‐04<br />
<strong>San</strong>dhu, H<br />
P3‐09‐05<br />
<strong>San</strong>dler, DP<br />
P3‐08‐03<br />
<strong>San</strong>ds, C<br />
P6‐08‐01<br />
<strong>San</strong>ft, T<br />
P2‐11‐08<br />
<strong>San</strong>gai, T<br />
P6‐11‐03, P6‐11‐11<br />
<strong>San</strong>Miguel, SA<br />
PD08‐05<br />
<strong>San</strong>o, Y<br />
P6‐01‐03<br />
<strong>San</strong>sano, I<br />
P1‐01‐29<br />
<strong>San</strong>tarpia, L<br />
P5‐10‐01<br />
<strong>San</strong>tiago, S<br />
P5‐07‐06<br />
<strong>San</strong>tibanez, M<br />
PD08‐06<br />
<strong>San</strong>tillana, S<br />
OT1‐1‐08<br />
<strong>San</strong>tisteban, M P5‐03‐07, P5‐16‐03<br />
<strong>San</strong>toro, M<br />
P5‐17‐06<br />
<strong>San</strong>tos, CS<br />
P6‐06‐05<br />
<strong>San</strong>tos, LFG<br />
P3‐02‐14<br />
<strong>San</strong>tos, N<br />
P4‐06‐19, P6‐04‐29<br />
<strong>San</strong>z, JL<br />
OT3‐3‐05<br />
Sapunar, F<br />
P5‐18‐21<br />
Saralli, E<br />
P1‐01‐25<br />
Saranathan, M<br />
P4‐01‐06<br />
Sareddy, GR PD09‐07, P6‐04‐07<br />
Sarode, V<br />
P1‐07‐04<br />
Sarosiek, T<br />
P5‐18‐21<br />
Sartorius, C<br />
PD01‐07<br />
Sartorius, CA<br />
P6‐05‐10<br />
Saruwatari, A<br />
P3‐06‐26<br />
Sasano, H P1‐06‐02, P1‐14‐02,<br />
P5‐01‐02, P6‐05‐14<br />
Sasi, W<br />
P1‐04‐03<br />
Sasso, M<br />
P4‐06‐09<br />
Sastre‐Garau, X PD05‐08, P1‐01‐19,<br />
P5‐01‐04, P5‐02‐03<br />
Satele, DV<br />
P2‐11‐01<br />
Sato, A<br />
P2‐05‐07, P3‐06‐29<br />
Sato, F<br />
P5‐10‐09<br />
Sato, K<br />
PD06‐02<br />
Sato, N<br />
P1‐12‐01, P1‐14‐02,<br />
P1‐14‐08, P3‐02‐02, P6‐07‐16<br />
Sato, T<br />
P3‐06‐22<br />
Sattlberger, C<br />
P5‐20‐11<br />
Sau, A<br />
PD09‐01<br />
Sauder, CAM<br />
P1‐03‐02<br />
Sauer, R<br />
P1‐14‐04<br />
Saunders, C S4‐2<br />
Saura, C<br />
P6‐10‐07, P6‐13‐03,<br />
OT2‐3‐02, OT2‐3‐06<br />
Savage, JE<br />
P6‐01‐03<br />
Savage, T<br />
P4‐04‐02<br />
Savin, M<br />
P2‐05‐06<br />
Sawaki, M P1‐02‐02, P3‐12‐06<br />
Sawyer, E<br />
P3‐08‐04<br />
Saya, H<br />
P2‐04‐01<br />
Scala, T<br />
P1‐01‐25<br />
Scaltriti, M S5‐7, P1‐07‐19, P4‐08‐02<br />
Schaefer, R<br />
P2‐10‐24<br />
Schafer, JM<br />
P6‐05‐03<br />
Schaffer, M<br />
P5‐01‐09<br />
Schaffrik, M<br />
P1‐15‐02<br />
Schaid, DJ<br />
PD10‐05<br />
Schalper, KA<br />
P3‐06‐25<br />
Schaper, C<br />
P2‐10‐02<br />
Schapira, L<br />
P3‐06‐27<br />
Schedin, P<br />
P4‐04‐03<br />
Schem, C<br />
P3‐06‐05<br />
Schenk, K<br />
P6‐08‐02<br />
Scherer, SJ<br />
P3‐06‐34<br />
Scheri, R<br />
P4‐13‐06<br />
Scheurer, M<br />
P2‐16‐02<br />
Scheurer, ME<br />
P2‐16‐03<br />
Schiff, R<br />
S5‐8, PD01‐01,<br />
PD09‐08, P4‐06‐02, P6‐04‐25,<br />
P6‐05‐12, P6‐10‐03<br />
Schimmer, AA<br />
P1‐04‐05<br />
Schindlbeck, C<br />
P2‐01‐11<br />
Schipper, R‐J<br />
P3‐02‐08<br />
Schlehe, B<br />
P6‐07‐05<br />
Schlichting, E<br />
P3‐01‐01<br />
Schlom, J<br />
P5‐16‐06<br />
Schmid, P P1‐14‐05, P4‐06‐10<br />
Schmidheiser, H<br />
P6‐08‐01<br />
Schmidt, M S1‐6, PD10‐06, P1‐13‐13,<br />
P1‐15‐02, P2‐10‐13, P2‐10‐17<br />
Schmidt, MK<br />
P3‐02‐01<br />
Schmidt, P<br />
P5‐21‐02<br />
Schmidt, T<br />
OT3‐2‐01<br />
Schmitt, M<br />
P1‐13‐13<br />
Schmitz, KJ<br />
P2‐11‐17<br />
Schnabel, CA S1‐9, P1‐07‐13, P2‐10‐15<br />
Schnabel, F P1‐09‐03, P4‐01‐07<br />
Schnadig, I<br />
P2‐11‐16<br />
Schneeweiss, A S3‐1, S3‐4, P1‐14‐01,<br />
P2‐01‐02, P3‐06‐08, P3‐06‐19,<br />
P5‐18‐26, OT1‐1‐02, OT1‐1‐10,<br />
OT1‐1‐13, OT3‐3‐11<br />
Schneider, BP<br />
PD05‐06<br />
Schneider, R<br />
P5‐20‐05<br />
Schneider, RJ<br />
P5‐03‐02<br />
Schneider, S P1‐15‐07, P6‐08‐06,<br />
P6‐11‐04<br />
Schnell, C<br />
P4‐08‐01<br />
Schnell, FM<br />
P5‐20‐08<br />
Schnitt, S<br />
PD01‐08<br />
Schoenegg, W S1‐7<br />
Scholtens, D<br />
P2‐10‐30<br />
Scholz, C<br />
P2‐01‐02<br />
Schott, AF OT2‐2‐04, OT2‐3‐01<br />
Schrader, I<br />
P2‐10‐25<br />
Schrama, JG<br />
P1‐12‐05<br />
Schrenk, P S2‐2<br />
Schubert, EK<br />
P6‐04‐03<br />
Schueller, K<br />
P2‐01‐02<br />
Schuler, LA<br />
P2‐04‐04<br />
Schulz, WC<br />
P1‐12‐04<br />
Schulz‐Wendtland, R PD07‐02<br />
Schusterbauer, C<br />
P6‐10‐02<br />
Schütte, M<br />
PD07‐02<br />
Schwab, LP<br />
P1‐05‐15<br />
Schwab, RB<br />
P2‐06‐01<br />
Schwartz, L<br />
P6‐08‐01<br />
Schwartz, MR<br />
P6‐07‐11<br />
Schwartz, MW<br />
P5‐18‐07<br />
Schwartz, S<br />
P4‐01‐07<br />
Schwartzberg, L P1‐12‐02, P5‐20‐04,<br />
P6‐09‐06, OT3‐3‐07<br />
Schwartzberg, LS P1‐15‐12, P2‐05‐06,<br />
P3‐12‐04, P5‐20‐08<br />
Schwarz, JL<br />
P6‐07‐20<br />
Schwarz, LJ<br />
P6‐07‐21<br />
Schwba, LP<br />
P5‐03‐10<br />
Scott, GK<br />
P2‐05‐04<br />
Scott, JH<br />
P2‐01‐05<br />
Scott, RJ<br />
P4‐10‐02<br />
Scott, SM<br />
P2‐16‐04<br />
Seagroves, TN P1‐05‐15, P5‐03‐10<br />
Seah, D<br />
P5‐18‐03<br />
Seah, DS<br />
P2‐16‐04, P6‐08‐03<br />
Searleman, AC S5‐6<br />
Sears, AK P5‐16‐02, P5‐16‐05<br />
Sebbagh, S<br />
P4‐13‐14<br />
Sedgewick, AJ<br />
P2‐06‐06<br />
Sediyama, CMNO<br />
P3‐07‐12<br />
Sedlacek, S<br />
P3‐06‐12<br />
Sedlackova, T<br />
P2‐01‐12<br />
Sedletcaia, A<br />
P1‐04‐02<br />
Seewaldt, V P1‐03‐01, P4‐13‐06<br />
Seferina, SC<br />
P5‐21‐04<br />
Segal‐Eiras, A<br />
P3‐07‐13<br />
Seguí, MA P1‐07‐18, P2‐01‐06<br />
Seidman, A P5‐18‐04, P6‐11‐10<br />
Seidman, AD<br />
P1‐13‐11<br />
Seif, MW<br />
P2‐14‐06<br />
Seifert, M P1‐15‐10, P2‐13‐01<br />
Seki, H<br />
P4‐09‐08<br />
Selder, S<br />
P5‐20‐01<br />
Selfors, LM<br />
P4‐08‐05<br />
Semiglazov, V S1‐11, P5‐18‐01,<br />
P5‐18‐26, OT3‐3‐01<br />
Semiglazova, T<br />
P5‐02‐02<br />
www.aacrjournals.org 603s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Sen, S<br />
P2‐04‐05<br />
Sen, SK<br />
P6‐11‐06<br />
Sener, S<br />
P4‐01‐11<br />
Sengoku, N<br />
P2‐12‐13<br />
SenGupta, SK<br />
P2‐10‐09<br />
Senn‐Reeves, JN<br />
P2‐11‐01<br />
Sensintaffar, J<br />
P6‐04‐12<br />
Senter, L<br />
P4‐13‐02<br />
Seo, S<br />
P1‐05‐03<br />
Sepkovic, DW<br />
P1‐10‐02<br />
Seppo, A<br />
P3‐05‐05, P3‐05‐06<br />
Sepúlveda, JM P5‐10‐11, OT3‐3‐05<br />
Sequeira, GR<br />
P4‐06‐15<br />
Sequist, LV<br />
P2‐01‐14<br />
Serganova, I<br />
P6‐01‐01<br />
Sergeant, J<br />
P1‐09‐05<br />
Sergenson, N S3‐3<br />
Serin, D<br />
P1‐13‐04<br />
Seroczynska, B<br />
P5‐04‐01<br />
Serra, V<br />
P1‐07‐19<br />
Serrano, D PD04‐07, PD06‐06<br />
Serrero, G P2‐10‐40, P6‐04‐19<br />
Serroyen, JL OT2‐1‐02, OT2‐1‐03<br />
Serrurier, KM P2‐12‐11, P2‐12‐12<br />
Seruga, B P2‐10‐23, P6‐09‐02<br />
Servent, V P2‐13‐10, OT3‐3‐10<br />
Serzhanova, VA<br />
P1‐05‐03<br />
Sestak, I<br />
S1‐9, P2‐10‐15<br />
Sesto, ME<br />
P2‐11‐15<br />
Setoguchi, Y<br />
OT1‐1‐01<br />
Sevenet, N<br />
PD05‐04<br />
Severson, TM<br />
PD01‐03<br />
Sevinc, A<br />
OT1‐1‐08<br />
Sexton, KR<br />
P3‐10‐01<br />
Seynaeve, C<br />
S1‐5, P1‐12‐05<br />
Sezgin, C<br />
OT1‐1‐08<br />
Sfondrini, L<br />
P5‐18‐10<br />
Sgroi, D<br />
P1‐07‐13, P2‐01‐14<br />
Sgroi, DC<br />
S1‐9, P2‐10‐15<br />
Shabaan, A<br />
P4‐01‐14<br />
Shah, AM<br />
P2‐01‐14<br />
Shah, C<br />
P1‐15‐09, P4‐16‐03<br />
Shah, KN<br />
P3‐12‐07<br />
Shah, RR<br />
P1‐07‐09<br />
Shaheen, S<br />
P4‐04‐08<br />
Shai, A<br />
P6‐14‐03<br />
Shaitelman, SF P4‐15‐02, P4‐16‐03<br />
Shak, S<br />
S1‐10, P2‐10‐08<br />
Shaker, H<br />
P1‐01‐26<br />
Shakeraneh, S<br />
P4‐13‐04<br />
Shamill, E<br />
P2‐10‐29<br />
Shan, Q<br />
P1‐01‐09<br />
Shan, T<br />
P2‐05‐10<br />
Shane, ES<br />
P6‐12‐03<br />
Shanmuganathan, S P4‐06‐14, P4‐06‐16<br />
Shao, G<br />
P6‐04‐12<br />
Shao, T P3‐08‐08, P6‐07‐34, P6‐12‐03<br />
Shao, X‐Y P2‐05‐05, P4‐09‐09<br />
Shao, Z<br />
P6‐04‐26<br />
Shao, Z‐M P1‐13‐07, P2‐06‐07,<br />
P3‐01‐05, P3‐06‐14,<br />
P6‐07‐35, P6‐07‐36, P6‐07‐42<br />
Shapira, I<br />
P5‐10‐13, P6‐07‐31<br />
Shapiro, AJ<br />
P3‐12‐02<br />
Shapiro, CL<br />
P2‐11‐04,<br />
P2‐11‐07, P5‐18‐17<br />
Shapiro, IM P6‐11‐07, P6‐11‐09<br />
Shapiro, R P4‐14‐03, P4‐17‐07<br />
Sharaiha, Y<br />
P1‐01‐18<br />
Sharma, A<br />
P1‐04‐03<br />
Sharma, AK P1‐04‐07, P1‐04‐08,<br />
P1‐04‐09<br />
Sharma, N<br />
P4‐01‐14<br />
Sharma, P<br />
S3‐7, PD09‐02<br />
Sharp, M<br />
P5‐01‐09<br />
Shastry, M P1‐14‐14, P5‐17‐05,<br />
P5‐20‐10, OT3‐3‐08<br />
Shaw, J<br />
P2‐10‐22, P3‐06‐13<br />
Shay, JW<br />
P4‐06‐06<br />
Shea, LD<br />
P6‐04‐24<br />
Shea, M<br />
PD01‐01<br />
Sheeba, I<br />
P2‐10‐29<br />
Sheehan, C<br />
PD02‐07<br />
Shen, D S5‐6<br />
Shen, H<br />
P6‐13‐02<br />
Shen, W S5‐6<br />
Shen, Y<br />
P3‐12‐04<br />
Shen, Z<br />
P6‐07‐35<br />
Shenouda, M<br />
P6‐09‐04<br />
Shepherd, L<br />
P1‐13‐01<br />
Shepherd, LE P1‐07‐13, P2‐13‐02<br />
Shepherd, SP PD09‐06, OT2‐3‐07<br />
Sherman, KA P4‐17‐04, P6‐09‐05<br />
Sherman, ME<br />
P3‐08‐02<br />
Sherman, ML P3‐06‐33, P5‐20‐03<br />
Sheshadri, N<br />
P5‐04‐09<br />
Sheth, P<br />
P4‐01‐11<br />
Shetty, G<br />
P4‐14‐11<br />
Shi, A<br />
P5‐03‐14<br />
Shi, JM<br />
P3‐08‐06<br />
Shia, A<br />
P4‐06‐10<br />
Shiau, C‐W<br />
P6‐11‐05<br />
Shiau, C‐Y<br />
P3‐12‐10<br />
Shibata, K<br />
P1‐01‐27<br />
Shidfar, A<br />
P3‐04‐08<br />
Shien, T<br />
P3‐07‐10<br />
Shigechi, T<br />
P3‐06‐26<br />
Shigekawa, T<br />
P6‐04‐27<br />
Shigematsu, H<br />
P6‐07‐26<br />
Shigeoka, Y PD07‐05, P6‐07‐39<br />
Shih, T<br />
P3‐12‐04<br />
Shih, Y‐C<br />
P3‐07‐11<br />
Shimizu, C P2‐11‐02, P6‐04‐27<br />
Shimizu, K<br />
P5‐10‐09<br />
Shimizu, S<br />
P1‐01‐20<br />
Shimizu, T<br />
OT1‐1‐01<br />
Shimozuma, K P1‐13‐10, P4‐14‐07<br />
Shin, H‐C<br />
P1‐14‐19<br />
Shin, I‐s<br />
P1‐01‐03<br />
Shin, YK<br />
P2‐05‐02<br />
Shipley, D<br />
P5‐17‐05<br />
Shiraki, N<br />
P4‐12‐06<br />
Shirato, H<br />
P1‐05‐08<br />
Shiroiwa, T<br />
P4‐14‐07<br />
Shklovskaya, J<br />
P1‐09‐07<br />
Shoemaker, M<br />
P3‐08‐04<br />
Shofoluwe, AI<br />
P6‐14‐04<br />
Shokuhi, S<br />
P1‐14‐15<br />
Shorter, R<br />
P6‐08‐01<br />
Shou, J<br />
P6‐10‐03<br />
Shparyk, Y S1‐6<br />
Shriver, CD PD02‐02, P1‐05‐09,<br />
P2‐05‐21, P3‐04‐06, P3‐04‐07,<br />
P3‐09‐03, P5‐01‐07, P6‐02‐08<br />
Shtivelband, M<br />
P6‐11‐08<br />
Shu, L<br />
P1‐05‐18<br />
Shu, S<br />
P4‐06‐01<br />
Shuai, Y<br />
P6‐07‐02<br />
Shumak, R<br />
P3‐02‐10<br />
Shumway, NM<br />
P5‐16‐05<br />
Shuping, JL<br />
P1‐01‐04<br />
Shvetsov, YB<br />
P4‐12‐02<br />
Shyamala, M S5‐7<br />
Shyr, Y‐M<br />
P3‐12‐10<br />
Sicilia, P<br />
P6‐08‐01<br />
Sicking, I<br />
P2‐10‐13<br />
Sideras, K<br />
PD10‐08<br />
Sidow, A<br />
PD05‐09<br />
Sieberova, G<br />
P2‐01‐12<br />
Sieffert, MR<br />
P3‐10‐07<br />
Siegel, PM<br />
P1‐05‐22<br />
Sieuwerts, AM P2‐01‐09, P6‐04‐08<br />
Sigal, B<br />
P1‐14‐18, P3‐06‐04<br />
Sigal‐Zafrani, B P1‐01‐19, P5‐02‐03<br />
Sigurdson, ER<br />
P1‐01‐16<br />
Sikora, MJ<br />
P6‐04‐20<br />
Sikov, W PD05‐05, P4‐01‐02, P6‐07‐34<br />
Sillerud, L<br />
P3‐03‐01<br />
Silva, DJ<br />
P2‐12‐04<br />
Silva, IV<br />
P5‐01‐15<br />
Silva, TRMA<br />
P2‐12‐04<br />
Silver, S<br />
P1‐01‐13<br />
Silvera, D<br />
P5‐03‐02<br />
Sima, CS<br />
P3‐07‐09<br />
Simak, A<br />
P3‐06‐13<br />
Simmons, P<br />
PD07‐09<br />
Simmons, S S4‐1<br />
Simoes, RV<br />
P6‐01‐01<br />
Simon, I<br />
P3‐06‐01<br />
Simon, MS<br />
PD03‐09<br />
Simon, R<br />
P6‐05‐13<br />
Simondi, C<br />
OT3‐4‐06<br />
Simone, B<br />
P6‐01‐03<br />
Simone, NL<br />
P6‐01‐03<br />
Simpson, G<br />
P3‐08‐04<br />
Simpson, PT<br />
P6‐10‐06<br />
Sims, A<br />
P3‐06‐23<br />
Sims, AH<br />
P6‐04‐09, P6‐04‐10<br />
Sing, AP S1‐10<br />
Singel, SM<br />
P4‐06‐06<br />
Singer, C<br />
P2‐10‐02,<br />
P2‐10‐31, P2‐13‐01<br />
Singer, CF<br />
S4‐3, P1‐15‐10<br />
Singer, G<br />
P4‐03‐06<br />
Singh, B<br />
P2‐10‐01<br />
Singh, G<br />
P1‐07‐06<br />
Singh, JC<br />
P5‐20‐05<br />
Singh, NK<br />
P5‐16‐06<br />
Singh, R<br />
P4‐04‐05<br />
Singh, RK<br />
P5‐07‐01<br />
Singh, S<br />
S5‐7, P4‐06‐08<br />
Singhal, S<br />
S6‐2, P1‐07‐08,<br />
P3‐05‐03, P6‐07‐22<br />
Sinha, SP<br />
P4‐01‐04<br />
Sinn, P<br />
P3‐06‐08, P3‐06‐19<br />
Sirtoli, GM<br />
P5‐01‐15<br />
Sitarik, M<br />
P2‐11‐16<br />
Sivaraman, I<br />
P4‐12‐04<br />
Sivasubramanian, PS P1‐09‐02<br />
Siziopikou, KP P5‐03‐11, OT1‐2‐01<br />
Sjöström, M<br />
P2‐10‐07<br />
Skaland, I<br />
P2‐10‐19<br />
Sklarin, N<br />
P5‐18‐20<br />
Skolny, MN P6‐09‐04, OT3‐2‐02<br />
Skoog, L<br />
P1‐05‐07, P6‐07‐12<br />
Skripkauskas, S<br />
P1‐09‐07<br />
Slaets, L S1‐11, P3‐02‐01, P3‐05‐02<br />
Slamon, D<br />
PD02‐01<br />
Slamon, DJ<br />
S1‐6, P2‐08‐02,<br />
P4‐08‐01, P4‐08‐05<br />
Sledge, G<br />
P2‐13‐02<br />
Sledge, GW<br />
PD05‐06,<br />
PD10‐04, P5‐17‐01<br />
Sledge, Jr., GW S5‐5<br />
Sleijfer, S P3‐06‐01, P6‐04‐08<br />
Slimane, K<br />
P6‐04‐14<br />
Sloane, BF<br />
P1‐05‐11<br />
Slone, S<br />
P2‐14‐05<br />
Slota, M<br />
P5‐16‐04<br />
Smalle, N<br />
P1‐13‐08<br />
Smas, ME<br />
P2‐01‐14<br />
Smeets, A<br />
P2‐10‐12,<br />
P6‐05‐05, P6‐07‐29<br />
Smeets, D<br />
P3‐05‐03<br />
Smid, M P3‐06‐32, P3‐06‐35, P6‐04‐08<br />
Smidt, M<br />
P3‐02‐08<br />
Smidt, ML<br />
P5‐01‐13,<br />
OT2‐1‐02, OT2‐1‐03<br />
Smilde, TJ P1‐14‐07, P6‐07‐32<br />
Smirnova, I S1‐4<br />
Smit, VTHBM<br />
PD07‐06<br />
Smith, BD S2‐3<br />
Smith, DA<br />
P6‐11‐10<br />
Smith, DL P5‐03‐05, P5‐03‐10<br />
Smith, I<br />
S5‐2, P5‐18‐02<br />
Smith, IE<br />
PD07‐07<br />
Smith, JA<br />
P5‐20‐05<br />
Smith, ML<br />
P6‐09‐11<br />
Smith, ND<br />
P6‐04‐12<br />
Smith, PD P4‐14‐09, P4‐17‐01<br />
Smith, R<br />
PD04‐03<br />
Smith, II, JW<br />
P4‐11‐04<br />
Smitt, M<br />
P5‐18‐06<br />
Smorenburg, CH<br />
P1‐12‐05<br />
Snider, J<br />
P6‐07‐10<br />
Snider, JE<br />
P2‐10‐01<br />
Snider, JN<br />
OT3‐3‐07<br />
Sninsky, J<br />
PD10‐03<br />
Snuderl, M<br />
P3‐12‐03<br />
Snyder, KA<br />
P1‐05‐05<br />
Soares, C<br />
OT1‐1‐08<br />
Soares, F<br />
P4‐02‐03<br />
Soares, FA P1‐06‐03, P2‐05‐17<br />
Soeling, U<br />
P2‐10‐25<br />
SoFEA and EFECT<br />
Investigators<br />
P2‐14‐01<br />
Sohl, J<br />
P2‐16‐04, P5‐18‐03<br />
Sohn, J<br />
PD09‐05<br />
Sola, JJ<br />
P5‐16‐03<br />
Solbach, C<br />
P2‐10‐13<br />
Soler, CMJ<br />
P6‐04‐08<br />
Solid, C<br />
P1‐15‐01<br />
Soliman, H<br />
OT3‐4‐01<br />
Solin, LJ<br />
P5‐15‐01<br />
Solomayer, EF<br />
OT1‐1‐10<br />
Solomon, S<br />
OT3‐1‐01<br />
Soloway, MG S6‐1<br />
Solti, M<br />
P4‐11‐04<br />
Soltys, SG<br />
P4‐16‐11<br />
Somaiah, N<br />
P3‐06‐09<br />
Somarelli, J<br />
P4‐06‐07<br />
Somera, AL<br />
OT2‐1‐04<br />
Somlo, G<br />
P2‐14‐08, P3‐06‐11<br />
Sommariva, M<br />
P5‐18‐10<br />
Sommer, HL<br />
P2‐01‐02<br />
Son, BH<br />
P3‐01‐02, P3‐12‐05<br />
Son, G‐T<br />
P1‐01‐05, P3‐03‐02<br />
Song, BJ<br />
P2‐05‐02, P4‐03‐01<br />
Song, D<br />
P2‐05‐19<br />
Song, J<br />
P3‐07‐05<br />
Song, X<br />
P2‐11‐10, P3‐04‐11,<br />
P3‐13‐05, P5‐01‐01<br />
Song, Y P3‐12‐03, P4‐03‐12, P5‐01‐16<br />
Sonis, ST<br />
P1‐15‐12<br />
Sonoo, H<br />
P2‐10‐18<br />
Sood, AK<br />
P5‐10‐03<br />
Soori, GS<br />
P1‐12‐06<br />
Sorensen, BS<br />
P6‐04‐18<br />
Sørlie, T<br />
P3‐04‐03<br />
Sosa, EV<br />
P2‐01‐05<br />
Sosinska‐Mielcarek, K P3‐12‐09,<br />
P3‐13‐03<br />
Sotiriou, C S4‐4, S6‐2, P1‐07‐08,<br />
P3‐04‐10, P3‐05‐03,<br />
P6‐07‐14, P6‐07‐22<br />
Soubeyrand, M‐S<br />
P5‐21‐01<br />
Souichirou, I<br />
P4‐04‐08<br />
Souleimanova, M<br />
P6‐02‐03<br />
Soulié, P<br />
P1‐14‐21, OT3‐3‐04<br />
Soundararajan, A<br />
P4‐06‐08<br />
Spagnoli, GC<br />
P4‐04‐04<br />
Span, P<br />
P3‐06‐01<br />
Spano, J‐P<br />
P5‐17‐04<br />
Specht, JM<br />
P6‐04‐03<br />
Specht, M<br />
P3‐06‐27<br />
Specht, MC<br />
OT3‐2‐02<br />
Speck, RM<br />
P4‐13‐01<br />
Spector, N<br />
P4‐08‐07<br />
Spector, NL<br />
P4‐08‐03<br />
Spector, T<br />
OT3‐3‐01<br />
Speer, V<br />
P1‐14‐04<br />
Speers, C PD04‐02, P4‐16‐01,<br />
P4‐16‐02, P4‐16‐04<br />
Speirs, C<br />
P1‐05‐13<br />
Speirs, V<br />
P6‐02‐06<br />
Spencer, P<br />
P3‐13‐05<br />
Sperinde, J P2‐10‐16, P2‐10‐31<br />
Sperk, E S4‐2<br />
Speyer, J<br />
P5‐20‐05<br />
Spicer, D<br />
P1‐09‐06<br />
Spoelstra, NS<br />
P5‐10‐04,<br />
P5‐10‐05, P5‐10‐06<br />
Sposato, V<br />
P2‐16‐01<br />
Sposto, R<br />
P4‐01‐11<br />
Spraggs, CF<br />
PD10‐05<br />
Spyratos, F<br />
PD07‐04<br />
Squires, M<br />
OT2‐2‐03<br />
Sridhara, R S1‐11<br />
Srikrishnan, R<br />
P4‐06‐08<br />
Sroussi, J<br />
P1‐01‐19<br />
Stacy, T<br />
P6‐14‐05<br />
Stadler, ZK<br />
P2‐16‐04<br />
Staebler, A S2‐2<br />
Stål, O<br />
P2‐10‐28, P6‐07‐12<br />
Stallard, S<br />
P4‐14‐13<br />
Stallings‐Mann, ML P6‐06‐01<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
604s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
Author Index<br />
Stamatovic, L<br />
P5‐02‐02<br />
Stambolic, V PD03‐02, PD03‐05<br />
Stampanoni, M<br />
P4‐03‐06<br />
Standish, L<br />
OT3‐1‐02<br />
Stanford, JC<br />
P6‐02‐01<br />
Starczynski, J<br />
P1‐07‐17<br />
Stark, A<br />
P4‐13‐12<br />
Stark, G<br />
P1‐04‐06<br />
Staroslawska, E<br />
P5‐18‐21<br />
Starr, A<br />
P2‐05‐06<br />
START Trialists S4‐1<br />
Stasi, I<br />
P5‐17‐06<br />
Staudigl, C<br />
P1‐15‐10<br />
Stearns, V PD09‐03, PD10‐08,<br />
P3‐04‐08, P4‐12‐04,<br />
P6‐05‐02, P6‐07‐33<br />
Stebbing, J P1‐04‐04, P6‐04‐15<br />
Stecklein, S<br />
S3‐7, PD09‐02<br />
Steding, CE<br />
P5‐18‐13<br />
Steding‐Jessen, M<br />
P1‐09‐01<br />
Steelman, L<br />
OT2‐3‐11<br />
Steffens, C‐C<br />
P1‐15‐02<br />
Steger, G S6‐5<br />
Stein, R S3‐3<br />
Steinberg, MS<br />
P3‐06‐12<br />
Steinberg, SM<br />
P5‐16‐06<br />
Steiner, M<br />
P6‐14‐03<br />
Steiner, P<br />
P4‐07‐05<br />
Steinkohl, O P5‐14‐06, P5‐15‐04<br />
Stella, PJ<br />
P1‐12‐06<br />
Stemmer, SM P5‐17‐03, P5‐20‐01<br />
Stenvang, J P3‐06‐32, P3‐06‐35<br />
Stepansky, A<br />
P3‐14‐01<br />
Stephant, G<br />
P3‐06‐24<br />
Stephens, P PD02‐07, PD05‐01<br />
Stephens, PJ S3‐6<br />
Stern, DF<br />
P3‐14‐01<br />
Stern, LH P4‐02‐09, P4‐02‐10<br />
Stern, M‐H<br />
P5‐02‐03<br />
Stessin, A<br />
P4‐03‐09<br />
Stevens, M<br />
P2‐14‐05<br />
Stevens, MG<br />
P6‐04‐08<br />
Steyerberg, EJ<br />
P4‐11‐05<br />
Stineman, MG<br />
P4‐13‐01<br />
Stitt, L<br />
P2‐13‐08<br />
Stockerl‐Goldstein, K S3‐5<br />
Stoeber, K<br />
PD04‐08<br />
Stokoe, C<br />
P3‐06‐12<br />
Stoller, RG<br />
PD09‐06<br />
Stolley, M<br />
P5‐13‐03<br />
Stone, A<br />
P6‐08‐06<br />
Stopeck, A<br />
P6‐10‐01<br />
Stoppa‐Lyonnet, D<br />
P5‐02‐03<br />
Storer, CL<br />
P5‐07‐02<br />
Storhoff, J<br />
P2‐10‐02<br />
Stork‐Sloots, L P3‐05‐01, P3‐05‐02,<br />
P3‐06‐11, OT3‐4‐01,<br />
OT3‐4‐02, OT3‐4‐03<br />
Storniolo, AMV<br />
P1‐03‐02<br />
Storz, P<br />
P1‐05‐24<br />
Stott, SL<br />
P2‐01‐14<br />
Stout, NL<br />
P2‐11‐13, P2‐11‐14<br />
Stover, AC<br />
P4‐16‐07<br />
Strand, C<br />
P2‐10‐19, P2‐10‐28<br />
Strang, P<br />
P2‐12‐09<br />
Strasak, A<br />
P5‐18‐05<br />
Straube, W<br />
P6‐13‐01<br />
Stravodimou, A<br />
P6‐04‐05<br />
Strickland, S<br />
P1‐15‐07<br />
Strigel, R<br />
P3‐02‐11<br />
Strina, C<br />
PD07‐03<br />
Strobbe, LJA P5‐01‐13, OT2‐1‐02,<br />
OT2‐1‐03<br />
Strzelecka, M P3‐12‐09, P3‐13‐03<br />
Stuller, KA<br />
P2‐11‐04<br />
Sturge, J<br />
P2‐02‐03<br />
Sturrock, M<br />
P5‐05‐06<br />
Styles, AL<br />
P5‐18‐12<br />
Su, F<br />
P1‐01‐09<br />
Su, J‐C<br />
P6‐11‐05<br />
Su, N<br />
PD02‐04<br />
Suarez, A<br />
P1‐14‐10, P5‐18‐15<br />
Subbarayalu, P<br />
P5‐10‐16<br />
Sue, GR<br />
P3‐14‐05<br />
Suen, DTK<br />
P3‐11‐02<br />
Suganuma, N<br />
P1‐01‐20<br />
Sugiura, H<br />
P4‐12‐06<br />
Sukenick, G<br />
P6‐01‐01<br />
Sukov, WR<br />
PD02‐05<br />
Sukumar, S P2‐02‐01, P2‐09‐01,<br />
P3‐04‐08, P4‐08‐08, P4‐12‐04,<br />
P6‐04‐13<br />
Sullivan, R<br />
P2‐04‐04<br />
Suman, V<br />
PD07‐01, PD10‐08<br />
Suman, VJ S2‐1, S5‐5<br />
Summa, B<br />
OT3‐2‐01<br />
Sun, G<br />
P4‐03‐12, P5‐01‐16<br />
Sun, L P1‐05‐18, P2‐04‐07, P4‐03‐12,<br />
P5‐01‐16, P5‐03‐04, P5‐03‐06,<br />
P5‐04‐04, P6‐11‐10<br />
Sun, S<br />
P6‐11‐01<br />
Sun, W<br />
P4‐14‐09, P4‐17‐01<br />
Sun, X<br />
P2‐10‐16<br />
Sun, X‐Y<br />
P1‐14‐17<br />
Sun, Y PD09‐09, P3‐07‐05, P5‐19‐03,<br />
P6‐04‐11<br />
Sun, Z<br />
P1‐05‐24<br />
Sundaram, S<br />
P6‐02‐09<br />
Sung, J<br />
OT3‐1‐01<br />
Sunpaweravong, P<br />
P5‐18‐01<br />
Suter, T S6‐5<br />
Sutterlin, M S4‐2<br />
Suwa, H<br />
P3‐13‐04<br />
Suzuki, K P4‐09‐08, P6‐07‐23<br />
Suzuki, T<br />
P4‐03‐05, P6‐05‐14<br />
Suzuki, Y P2‐05‐08, P3‐13‐02<br />
Svedman, C<br />
P6‐07‐03<br />
Swain, S<br />
P5‐18‐11<br />
Swain, SM<br />
S1‐11, S5‐1, S5‐5,<br />
P5‐18‐01, P5‐18‐26<br />
Swanton, C P6‐07‐15, OT1‐1‐14<br />
Sweeney, KJ P1‐01‐15, P5‐10‐07<br />
Sweep, F<br />
P3‐06‐01<br />
Sweep, FCGJ<br />
P1‐13‐13<br />
Swerdlow, A<br />
P3‐08‐04<br />
Sydenham, M<br />
S4‐1, P3‐06‐09<br />
Syldor, A<br />
P5‐18‐04, P5‐18‐20<br />
Symmans, F P1‐07‐08, P2‐10‐17<br />
Symmans, WF S2‐1, P1‐07‐06,<br />
P1‐07‐09, P2‐10‐10, P3‐06‐14<br />
Szade, J<br />
P5‐04‐01<br />
Szalkucki, L<br />
P3‐02‐11<br />
Szallasi, Z<br />
P6‐07‐15<br />
Szasz, AM<br />
P3‐05‐08<br />
Szostakiewicz, B<br />
P2‐10‐31<br />
Sztupinszki, Z<br />
P2‐10‐24<br />
T. Dorsam, R P1‐05‐23<br />
Taback, B S2‐1, PD03‐03, P4‐02‐07<br />
Tabarsi, N<br />
P4‐16‐01<br />
Tabouret, E<br />
P3‐12‐11<br />
Tafra, L<br />
OT2‐1‐04<br />
Taghian, AG P6‐09‐04, OT3‐2‐02<br />
Tagliabue, E P4‐06‐09, P5‐18‐10<br />
Taioli, E<br />
P5‐10‐13<br />
Taira, N<br />
P3‐07‐10, P4‐14‐07<br />
Tait, N<br />
P2‐13‐05<br />
Takada, M P3‐06‐18, P3‐13‐04<br />
Takagi, K<br />
P6‐05‐14<br />
Takahashi, F<br />
P1‐14‐02<br />
Takahashi, M P1‐14‐08, P1‐14‐09,<br />
P3‐02‐06, P3‐06‐22,<br />
P4‐03‐03, P4‐09‐08, P6‐07‐39<br />
Takahashi, S<br />
P4‐12‐06<br />
Takahashi, Y<br />
P3‐02‐02<br />
Takahasi, S<br />
P2‐10‐43<br />
Takamoto, Y<br />
P2‐04‐01<br />
Takanaka, T<br />
P4‐16‐13<br />
Takano, T<br />
P1‐14‐08<br />
Takao, S<br />
PD07‐05, P5‐18‐16,<br />
P6‐07‐30, P6‐07‐39<br />
Takata, D<br />
P2‐05‐07, P3‐06‐29<br />
Takatsuka, Y P2‐13‐04, P2‐13‐07<br />
Takei, H<br />
P1‐14‐06, P2‐10‐18,<br />
P5‐15‐06, P6‐04‐17<br />
Takei, J<br />
P6‐07‐23<br />
Takeyama, H P4‐03‐10, P5‐04‐02<br />
Takeyoshi, I P1‐14‐06, P2‐05‐07,<br />
P3‐06‐29<br />
Takizawa, S<br />
P5‐10‐09<br />
Talavera, GG<br />
PD08‐05<br />
Talcott, S<br />
P5‐07‐03<br />
Talcott, SM<br />
P5‐07‐03<br />
Tallet, A<br />
P3‐12‐11<br />
Tamaki, K P1‐06‐02, P6‐05‐14<br />
Tamaki, N<br />
P1‐06‐02<br />
Tamimi, RM<br />
P5‐01‐03<br />
Tamura, K<br />
P3‐02‐06<br />
Tamura, N<br />
P2‐11‐02<br />
Tan, B<br />
P3‐08‐09<br />
Tan, CH<br />
P4‐16‐12<br />
Tan, M‐H<br />
P3‐08‐09<br />
Tan, PH<br />
P4‐16‐12<br />
Tan, P‐H<br />
P3‐08‐09<br />
Tan, Q<br />
P4‐09‐04<br />
Tan, Y PD09‐08, P4‐07‐04, P6‐04‐25<br />
Tanaka, F<br />
P3‐13‐04<br />
Tanaka, RMN<br />
P3‐01‐07<br />
Tanaka, S<br />
P3‐02‐02, P3‐09‐04<br />
Tandon, V<br />
P4‐04‐01<br />
Tanei, T<br />
P5‐03‐03<br />
Tang, G S1‐10<br />
Tang, J<br />
P4‐08‐10, P5‐10‐10<br />
Tang, L<br />
P6‐05‐03<br />
Tang, S<br />
S1‐11, P4‐01‐11<br />
Tani, T<br />
P1‐15‐11<br />
Taniguchi, H<br />
P1‐01‐27<br />
Tanimoto, A<br />
P4‐03‐03<br />
Tanino, H<br />
PD07‐05<br />
Tanioka, M<br />
P6‐07‐30<br />
Tannock, I<br />
P2‐05‐12<br />
Tannock, IF<br />
P6‐09‐02<br />
Tannous, BA<br />
P3‐12‐03<br />
Tao, J S5‐7<br />
Tao, S<br />
P5‐15‐07<br />
Taran, T<br />
P6‐04‐02<br />
Tarco, E<br />
P1‐07‐06<br />
Tarpin, C<br />
OT2‐3‐05<br />
Tarter, P<br />
P4‐15‐03<br />
Tas, P<br />
P3‐14‐03<br />
Tashima, R<br />
PD06‐07<br />
Tatla, R<br />
P2‐12‐07<br />
Tauer, KW<br />
P5‐20‐08<br />
Tautchin, M<br />
P5‐16‐01<br />
Tawbi, H<br />
PD09‐06<br />
Tawfik, OW<br />
PD09‐02<br />
Taylor, CT<br />
OT1‐1‐05<br />
Taylor, JA<br />
P3‐08‐03<br />
Taylor, NJ<br />
P1‐06‐01<br />
Tea, M‐K<br />
P1‐15‐10<br />
Teh, BS<br />
P6‐07‐11<br />
Teh, B‐T<br />
P3‐08‐09<br />
Teixeira, SF<br />
P6‐11‐13<br />
Tejedo, S<br />
P5‐13‐03<br />
Tekmal, RR P5‐04‐04, P6‐04‐07<br />
Telang, NT<br />
P1‐10‐02<br />
Telli, ML<br />
PD09‐04<br />
Tembo, O<br />
P1‐14‐03<br />
Tenniswood, MPR<br />
P3‐10‐02<br />
Teo, WW<br />
P2‐02‐01, P6‐04‐13<br />
Tepperberg, J<br />
P3‐10‐10<br />
Ter Haar‐van Eck, SA P6‐08‐02<br />
Terada, M<br />
P3‐13‐02<br />
Terao, M<br />
P3‐13‐02<br />
Tereffe, W P3‐10‐07, P4‐15‐02<br />
Terhaar, AR<br />
P2‐11‐15<br />
Terrell, KL<br />
P5‐10‐04<br />
Tesch, H<br />
S4‐5, PD06‐01,<br />
P1‐14‐01, P2‐10‐25<br />
Tessari, A<br />
P2‐12‐08<br />
Tevaarwerk, AJ<br />
P2‐11‐15,<br />
P3‐02‐11, P6‐12‐02<br />
TEX Study Group<br />
P1‐05‐07<br />
Thakur, S<br />
P4‐09‐07<br />
Theodoropoulos, PA P2‐01‐07<br />
Theodoulou, M<br />
P5‐18‐20<br />
Therrien, B S6‐3<br />
Thery, J‐C<br />
P5‐17‐04<br />
Theunissen, EB<br />
P4‐11‐01<br />
Thomalla, J<br />
P2‐11‐11<br />
Thomas, F<br />
PD03‐09<br />
Thomas, J<br />
OT3‐3‐09<br />
Thomas, M S6‐7<br />
Thomassin‐Piana, J<br />
P5‐03‐01<br />
Thompson, A S4‐2, P1‐05‐14, P5‐05‐02<br />
Thompson, AE<br />
P1‐05‐24<br />
Thompson, AM PD03‐02, P4‐06‐10,<br />
P5‐05‐05, P5‐05‐06<br />
Thompson, D<br />
P4‐11‐05<br />
Thompson, EA<br />
PD10‐04<br />
Thompson, J<br />
P2‐13‐05<br />
Thompson, MO<br />
P4‐01‐12<br />
Thompson, PA<br />
PD08‐04<br />
Thompson, SL<br />
P2‐11‐01<br />
Thomson, E P2‐14‐07, P5‐20‐12<br />
Thomssen, C<br />
S3‐4, P1‐13‐13,<br />
P2‐10‐08, P2‐10‐38<br />
Thor, AD<br />
P5‐10‐04, P5‐10‐05<br />
Thorat, M<br />
PD04‐08<br />
Thorén, L<br />
PD10‐09<br />
Thorne, A<br />
OT3‐1‐01<br />
Thorsen, C<br />
P4‐11‐03<br />
Thorsen, CM P3‐02‐12, P4‐01‐15<br />
Thuler, LCS P3‐11‐04, P6‐07‐44<br />
Thummala, AR S1‐6<br />
Thune, I<br />
P3‐01‐01<br />
Thürlimann, B S1‐1<br />
Thyparambil, S<br />
P1‐07‐19<br />
Tibbitts, P<br />
P6‐04‐21<br />
Tice, D<br />
P4‐07‐05<br />
Tice, J<br />
P4‐13‐05<br />
Tiersten, A<br />
P5‐20‐05<br />
Tilanus‐Linthorst, MM P3‐02‐09<br />
Tilanus‐Linthorst, MMA P4‐11‐05<br />
Tiller, GE<br />
P3‐08‐06<br />
Tillett, R<br />
P4‐17‐03<br />
Timar, J<br />
P2‐10‐24<br />
Timcheva, C<br />
P5‐02‐02<br />
Timmerman, D<br />
OT2‐2‐02<br />
Timmermans, M P3‐06‐32, P3‐06‐35<br />
Timms, K<br />
PD09‐04<br />
Timotheadou, E<br />
P1‐07‐15<br />
Timpson, P<br />
P1‐05‐13<br />
Tin, S P2‐03‐01, P2‐10‐32, P5‐04‐06<br />
Ting, DT<br />
P2‐01‐14<br />
Tirona, KM P6‐09‐01, P6‐09‐02<br />
Tizon, X<br />
P4‐02‐06<br />
Tjan‐Heijnen, VCG P1‐14‐07,<br />
P5‐21‐04, P6‐07‐32,<br />
OT2‐1‐02, OT2‐1‐03<br />
Tkaczuk, K<br />
P2‐13‐05<br />
Tkaczuk, KR<br />
P2‐10‐40<br />
Tobias, JS S4‐2<br />
Tobin, H<br />
P2‐04‐03<br />
Tobin, NP<br />
PD06‐08<br />
Tobler, J<br />
OT1‐1‐08<br />
Toelg, C<br />
P1‐05‐20<br />
Toesca, A<br />
PD06‐06<br />
Toffoli, S<br />
P3‐04‐04<br />
Toi, M<br />
S6‐5, P1‐14‐02,<br />
P1‐14‐08, P3‐06‐18, P3‐13‐04,<br />
P5‐01‐02, P5‐10‐09<br />
Tokes, A‐M<br />
P3‐05‐08<br />
Tokin, CA<br />
P4‐01‐13<br />
Tokiniwa, H P2‐05‐07, P3‐06‐29<br />
Tokuda, Y<br />
P2‐05‐08,<br />
P3‐13‐02, P5‐18‐16<br />
Tolaney, S<br />
P6‐05‐02<br />
Toledo, C<br />
P4‐02‐03<br />
Tollenaar, RA<br />
P3‐02‐09<br />
Toller, I<br />
P5‐18‐25<br />
Tomczyk, K<br />
P3‐08‐04<br />
Tomic, S<br />
P4‐04‐04<br />
Tomida, K<br />
P1‐15‐11<br />
Tomita, S<br />
P2‐14‐03<br />
Tomlinson, DC<br />
P6‐02‐06<br />
Tomlinson, I<br />
P3‐08‐04<br />
Toner, M<br />
P2‐01‐14<br />
Tonetti, DA<br />
P6‐04‐24<br />
Tong, L<br />
P4‐08‐01<br />
Toriumi, Y P4‐03‐10, P5‐04‐02<br />
Torrecabota, J<br />
P3‐12‐08<br />
Torrejon‐Castro, D<br />
P6‐13‐03<br />
Torres, A<br />
P5‐07‐06<br />
Torres, R S1‐4<br />
Tost, J<br />
P5‐05‐03<br />
Tosteson, AN<br />
P4‐01‐15<br />
www.aacrjournals.org 605s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Totobenazara, J‐L<br />
P4‐16‐10<br />
Toy, KA<br />
P1‐04‐11<br />
Toyama, T<br />
P4‐12‐06<br />
Tozuka, K P2‐05‐07, P3‐06‐29<br />
Traina, T<br />
PD09‐03<br />
Traina, TA P1‐13‐11, P6‐05‐01,<br />
P6‐05‐02, P6‐11‐10<br />
Tralau‐Stewart, C<br />
P4‐06‐12<br />
Tramm, T<br />
P3‐04‐03<br />
Trappey, AF<br />
P5‐16‐05<br />
Trassard, M<br />
PD07‐04<br />
Tredan, O<br />
P3‐06‐20<br />
Treekitkarnmongkol, W P2‐04‐05<br />
Tresca, P<br />
OT3‐4‐06<br />
Triolo, R<br />
P5‐01‐10<br />
Tripathi, M<br />
P4‐02‐02<br />
Tripathy, D<br />
P4‐01‐11<br />
Trippel, M<br />
P4‐03‐06<br />
Triulzi, T<br />
P4‐06‐09, P5‐18‐10<br />
Trivedi, MV<br />
S5‐8, P4‐06‐02<br />
Troester, MA<br />
P6‐02‐09<br />
Tromberg, B<br />
P4‐02‐04<br />
Troxell, M<br />
PD05‐09<br />
Troxell, ML<br />
P2‐08‐03<br />
Trucu, D<br />
P1‐05‐14<br />
Trudeau, M P2‐12‐03, P5‐18‐14<br />
Truglia, M<br />
P5‐10‐01<br />
Tsai, K<br />
P3‐07‐08<br />
Tsai, W‐Y<br />
P2‐11‐03<br />
Tsai, Y‐CS<br />
P4‐16‐05<br />
Tsai, Y‐F<br />
P3‐12‐10<br />
Tse, CH<br />
P1‐07‐01<br />
Tseng, L‐M<br />
P3‐12‐10,<br />
P6‐11‐05, OT1‐1‐17<br />
Tsimberidou, A<br />
P5‐20‐09<br />
Tsou, M‐H<br />
P4‐16‐05<br />
Tsuboi, M<br />
P1‐14‐06<br />
Tsuda, B<br />
P2‐05‐08, P3‐13‐02<br />
Tsuda, H<br />
P1‐01‐12,<br />
P5‐01‐02, P6‐04‐27<br />
Tsugawa, K<br />
P1‐01‐12<br />
Tsujimoto, G<br />
P5‐10‐09<br />
Tsujimoto, M<br />
P2‐10‐18<br />
Tsukamoto, F<br />
P2‐10‐18<br />
Tsuyuki, S P1‐14‐08, P3‐13‐04<br />
Tubbs, RR PD02‐04, P6‐07‐45<br />
Tubiana‐Mathieu, N P3‐06‐20,<br />
OT3‐4‐05<br />
Tuchman, L<br />
P6‐08‐01<br />
Tucker, N<br />
P2‐12‐05<br />
Tullis, I<br />
P2‐10‐29<br />
Tun, MT<br />
P2‐11‐15<br />
Tunon de Lara, C PD05‐04, P1‐01‐21,<br />
P3‐14‐03, OT2‐1‐01<br />
Turdo, F<br />
P4‐06‐09<br />
Turk, M<br />
P3‐05‐01<br />
Turley, EA<br />
P1‐05‐20<br />
Turman, YJ S6‐1<br />
Turnbull, A<br />
P3‐06‐23<br />
Turnbull, AK P6‐04‐09, P6‐04‐10<br />
Turner, B<br />
OT3‐4‐04<br />
Turnwald, B<br />
P2‐11‐16<br />
Turpeenniemi‐Hujanen, T PD10‐06<br />
Tursz, T<br />
P4‐09‐05<br />
Tusquets, I P1‐07‐18, P2‐01‐06<br />
Tuttle, K<br />
P2‐10‐40<br />
Tuyls, S<br />
P2‐10‐12, P6‐05‐05<br />
Tweardy, D<br />
P5‐03‐08<br />
Twelves, C<br />
S6‐6, P6‐11‐14<br />
Tyldesley, S<br />
PD04‐02,<br />
P4‐16‐01, P4‐16‐02<br />
Tzeng, C‐H<br />
P3‐12‐10<br />
Tzonis, P<br />
P5‐16‐05<br />
Uchida, K P4‐03‐10, P5‐04‐02<br />
Uchida, S<br />
P2‐05‐07<br />
Uchiyama, K P3‐02‐02, P3‐09‐04<br />
Udovitsa, D<br />
OT1‐1‐17<br />
Ueda, N<br />
P3‐06‐26<br />
Ueda, S<br />
P4‐02‐04<br />
Ueda, Y<br />
P4‐03‐05<br />
Uehara, K<br />
P1‐06‐02<br />
Ueno, N<br />
P3‐10‐09<br />
Ueno, NT PD03‐06, PD03‐08, P2‐03‐01,<br />
P2‐10‐32, P3‐10‐01, P3‐10‐05,<br />
P3‐10‐10, P5‐03‐05, P5‐03‐09,<br />
P5‐03‐10, P5‐04‐06, P5‐10‐02,<br />
P5‐20‐13, OT2‐3‐10<br />
Ueno, T P1‐14‐02, P1‐14‐08, P3‐06‐18,<br />
P5‐01‐02, P5‐10‐09<br />
Uhlén, M<br />
PD03‐07<br />
Uhrhammer, N<br />
P3‐06‐20<br />
Uleer, C<br />
P2‐10‐08<br />
Ullman, E<br />
P5‐04‐09<br />
Umbricht, C<br />
P2‐02‐01<br />
Umeda, T<br />
P1‐15‐11<br />
Umphrey, H<br />
P3‐03‐03<br />
Uncu, D<br />
OT1‐1‐08<br />
Unger, HA<br />
P1‐04‐02<br />
Untch, M S1‐11, S2‐2, S3‐1, S3‐4,<br />
S5‐2, P1‐14‐01, P3‐06‐05, P5‐18‐02,<br />
P5‐18‐11, OT1‐1‐13, OT3‐3‐11<br />
Untch, S<br />
OT3‐4‐01<br />
Unzeitig, G<br />
PD07‐01<br />
Unzeitig, GW<br />
P4‐14‐01<br />
Upadhyaya, G<br />
P3‐06‐28<br />
Urban, P<br />
P6‐11‐08<br />
Urist, M<br />
P1‐01‐06, P3‐03‐03<br />
Urist, MM<br />
P5‐17‐07<br />
Urruticoechea, A P6‐11‐02, P6‐11‐08<br />
Ursin, G<br />
P3‐01‐01<br />
Ursini‐Siegel, J<br />
P1‐05‐22<br />
Ushio, A<br />
P1‐02‐02, P3‐12‐06<br />
Uslu, R<br />
OT1‐1‐08<br />
Utama, FE S1‐8<br />
Utsumi, T<br />
P3‐02‐05<br />
Uttenreuther‐Fischer, M OT1‐1‐16,<br />
OT1‐1‐17<br />
Uzan, C<br />
P4‐12‐01, P4‐14‐12<br />
Uzan, S<br />
P4‐14‐12<br />
Vach, W<br />
P4‐09‐04<br />
Vachon, CM<br />
P4‐12‐03<br />
Vadakkan, T<br />
P4‐02‐08<br />
Vadlamudi, RK PD09‐07, P1‐05‐10,<br />
P5‐04‐04, P6‐04‐07<br />
Vahdat, L P1‐12‐02, P1‐15‐07,<br />
P5‐20‐04, P6‐11‐14<br />
Vahdat, LT P6‐10‐01, P6‐11‐04<br />
Vaidya, JS S4‐2<br />
Valachis, A<br />
P5‐18‐18<br />
Valadão, IC<br />
P6‐11‐13<br />
Valagussa, P S1‐11, S6‐7<br />
Valdés Olmos, RA<br />
P4‐02‐01<br />
Valdimarsdottir, H<br />
P4‐11‐01<br />
Valencia, A<br />
P5‐12‐03<br />
Valent, A<br />
P2‐08‐04<br />
Valente, AL<br />
PD02‐02<br />
Valero, V P2‐10‐32, P3‐10‐05, P5‐10‐02,<br />
P5‐15‐02, P5‐20‐02, P5‐20‐13,<br />
OT2‐3‐10<br />
Vallejos, CS P6‐07‐20, P6‐07‐21<br />
Vallier, A‐L OT1‐1‐03, OT3‐3‐09<br />
Valo, I<br />
P1‐14‐21<br />
van Asperen, CJ<br />
P4‐11‐05<br />
Van Bree, R<br />
P2‐13‐06<br />
Van Calster, B P2‐10‐12, P6‐07‐04,<br />
P6‐07‐05, P6‐07‐19, OT2‐2‐02<br />
Van Calsteren, K<br />
P6‐07‐05<br />
van Dalen, T P4‐11‐01, P4‐14‐08,<br />
OT2‐1‐02, OT2‐1‐03<br />
van Dam, PA P2‐01‐08, P2‐01‐09<br />
van Dam, P‐J<br />
P2‐01‐08<br />
van de <strong>San</strong>dt, L<br />
P2‐10‐13<br />
van de Velde, CJH S1‐5, PD07‐06<br />
van de Ven, AL<br />
P6‐11‐12<br />
van de Ven, S<br />
PD07‐06<br />
Van de Vijver, KKBT P5‐01‐13<br />
van de Wouw, AJ P5‐21‐04, P6‐07‐32<br />
van Decker, S<br />
P6‐08‐01<br />
van den Akker, J<br />
P3‐05‐02<br />
van den Berkmortel, F P5‐21‐04,<br />
P6‐07‐32<br />
van den Bosch, MA P4‐01‐17,<br />
P4‐14‐08, P5‐01‐11,<br />
P5‐01‐14, P5‐15‐03<br />
Van den Eynden, GG P2‐01‐08,<br />
P2‐01‐09<br />
van den Tol, P<br />
PD04‐01<br />
Van den Wyngaert, T P3‐13‐01<br />
van der Groep, P P2‐06‐02, P5‐01‐06,<br />
P6‐05‐08<br />
van der Hage, J OT2‐1‐02, OT2‐1‐03<br />
van der Luijt, RB<br />
P4‐11‐01<br />
van der Pol, CC<br />
P5‐01‐11<br />
van der <strong>San</strong>den‐Melis, J P4‐11‐01<br />
van der Wall, E P2‐06‐02, P5‐01‐06,<br />
P6‐05‐08<br />
van Deurzen, CHM<br />
P5‐01‐13<br />
van Diest, PJ PD02‐03, P2‐06‐02,<br />
P4‐01‐17, P5‐01‐06, P5‐01‐11,<br />
P5‐01‐14, P6‐05‐08, P6‐05‐13<br />
van Gastel, SM<br />
P1‐14‐07<br />
van Geer, M<br />
P1‐15‐05<br />
van Goethem, M<br />
P3‐02‐08<br />
van Golen, CM<br />
P3‐10‐04<br />
van Golen, K P1‐04‐10, P6‐06‐03<br />
van Golen, KL P3‐10‐04, P3‐10‐08<br />
van Hillegersberg, R P4‐01‐17,<br />
P5‐01‐14, P5‐15‐03<br />
Van Huffel, S<br />
P4‐06‐11<br />
van IJcken, WFJ<br />
P6‐04‐08<br />
van Kampen, RJW P5‐21‐04, P6‐07‐32<br />
van Laar, R P2‐10‐05, P6‐02‐08<br />
van Laarhoven, HW<br />
P1‐14‐07<br />
van Laarhoven, HWM PD07‐06<br />
Van Laere, S P3‐06‐01, P3‐10‐08<br />
Van Laere, SJ P2‐01‐08, P2‐01‐09,<br />
P3‐10‐04<br />
van Leeuwen‐Stok, E PD07‐06<br />
van Leeuwen‐Stok, EAE P1‐12‐05<br />
Van Limbergen, E P2‐10‐12, P4‐15‐01,<br />
P6‐05‐05, P6‐07‐04,<br />
P6‐07‐19, P6‐07‐29<br />
Van Loo, P<br />
P5‐05‐03<br />
van Ooijen, B<br />
P4‐11‐01<br />
Van Poznak, CH<br />
OT1‐1‐11<br />
van Puyvelde, K<br />
P6‐09‐07<br />
van Riel, JMGH<br />
P6‐07‐32<br />
van Roozendaal, L<br />
P3‐02‐08<br />
van Roozendaal, LM OT2‐1‐02,<br />
OT2‐1‐03<br />
van Roye, C<br />
P2‐11‐11<br />
van Slooten, H‐J<br />
PD02‐03<br />
van Spronsen, DJ<br />
P1‐14‐07<br />
van Tinteren, H<br />
P1‐12‐05<br />
van Warmerdam, LJ PD07‐06, P1‐14‐07<br />
Van Zee, KJ<br />
PD04‐05<br />
van’t Veer, L<br />
P2‐05‐01,<br />
P3‐04‐01, P3‐04‐02, P3‐05‐02,<br />
P3‐06‐11, P4‐13‐13, P5‐05‐01<br />
van’t Veer, LJ P2‐10‐42,P3‐02‐01,<br />
P4‐09‐02, P4‐09‐05<br />
Vanbeckevoort, D<br />
P6‐05‐05<br />
Vandenberg, E<br />
P1‐13‐01<br />
Vandenberg, T<br />
P1‐14‐13<br />
Vandergrift, JL<br />
P1‐13‐05<br />
Vanderhaegen, J P2‐13‐06, P5‐18‐19,<br />
P6‐05‐05, P6‐07‐29<br />
Vandermeer, L P2‐05‐13, P3‐13‐05<br />
Vanderschueren, D<br />
P2‐13‐06<br />
Vanderstichele, A P2‐10‐12, P6‐05‐05<br />
VandeWydeven, K<br />
P5‐13‐03<br />
vanDiest, PJ PD01‐02, PD01‐03<br />
Vanlemmens, L<br />
P2‐13‐10,<br />
P2‐13‐10, P3‐06‐20<br />
Vanni, G<br />
P4‐15‐04<br />
Vanzulli, SI<br />
P4‐06‐15<br />
Varadan, V PD05‐05, P4‐01‐02<br />
Vareslija, D<br />
P6‐04‐21<br />
Vargas, W<br />
P5‐07‐06<br />
Varma, S<br />
PD05‐09<br />
Varoqueaux, N<br />
P4‐02‐06<br />
Varricchio, C<br />
PD04‐07<br />
Vaske, CJ P2‐06‐05, P2‐06‐06<br />
Vasovics, S<br />
P5‐02‐02<br />
Vásquez, J<br />
P6‐07‐21<br />
Vassilakopoulou, M S5‐4<br />
Vaughan‐Briggs, C<br />
P5‐14‐03<br />
Vaysse, C<br />
P1‐01‐19<br />
Vaz‐Luis, I<br />
P5‐18‐03<br />
Vedell, P<br />
P1‐08‐02<br />
Veiseh, M<br />
P1‐05‐20<br />
Vejborg, I<br />
P3‐02‐03<br />
Velasco, V<br />
P3‐14‐03<br />
Veldman, T<br />
P2‐10‐03<br />
Velikova, G<br />
S3‐3, P4‐01‐14<br />
Venables, K S4‐1<br />
Venat Bouvet, L<br />
PD07‐04<br />
Vendel, Y<br />
P2‐13‐10<br />
Vente, JP<br />
P4‐11‐01<br />
Venuto, T<br />
P5‐03‐02<br />
Venzon, D<br />
P1‐09‐04<br />
Vergote, I<br />
P2‐10‐12,<br />
P6‐05‐05, P6‐07‐29<br />
Verhaeghe, J<br />
P2‐13‐06<br />
Verhoef, S<br />
P4‐11‐01<br />
Verhoeven, D S1‐4<br />
Verkooijen, HM P2‐11‐06, P4‐01‐17,<br />
P4‐14‐08, P5‐01‐11,<br />
P5‐01‐14, P5‐15‐03<br />
Verma, R<br />
P1‐13‐08<br />
Verma, S P2‐11‐10, P2‐12‐03, P2‐12‐07,<br />
P3‐12‐04, P5‐13‐01, P6‐07‐33<br />
Vermeulen, PB P2‐01‐08, P2‐01‐09,<br />
P3‐10‐04, P3‐10‐08<br />
Vermorken, JB<br />
PD01‐03<br />
Verriele, V<br />
P1‐14‐21<br />
Verril, M<br />
P1‐13‐03<br />
Verrill, M S3‐3<br />
Vetter, M<br />
P1‐13‐13, P2‐10‐38<br />
Veyret, C<br />
P1‐13‐13, P1‐15‐08<br />
Veys, I<br />
S4‐4, P3‐05‐03<br />
Viñas, G P4‐09‐10, P4‐09‐11, P6‐11‐02<br />
Viale, G<br />
S1‐1, S4‐4, S4‐6,<br />
PD04‐07, PD10‐03, P3‐05‐02,<br />
P3‐05‐03, P6‐07‐14<br />
Vicente Conesa, AM P3‐06‐15<br />
Vicente García, V<br />
P3‐06‐15<br />
Vicini, F<br />
P1‐15‐09<br />
Vicini, FA P4‐16‐03, P4‐16‐09<br />
Vickery, T P2‐10‐01, P6‐07‐10<br />
Victor, C<br />
P2‐12‐07<br />
Vidal, CM P6‐11‐07, P6‐11‐09<br />
Vidal, L<br />
P6‐11‐06<br />
Vidal, M<br />
P6‐13‐03<br />
Vidaurre, T<br />
P6‐07‐21<br />
Vieites, B<br />
P1‐01‐29<br />
Viens, P<br />
P1‐13‐04, P3‐12‐11,<br />
P5‐03‐01, OT2‐3‐05<br />
Vierkant, RA P4‐12‐03, P5‐01‐08<br />
Vigil, CE<br />
P6‐07‐20<br />
Vijayakrishn, GK<br />
P6‐04‐03<br />
Vila‐Caballer, M<br />
P6‐06‐05<br />
Vilardell, F<br />
P1‐01‐29<br />
Villanueva, C<br />
P5‐18‐22<br />
Villanueva, O<br />
P4‐06‐19<br />
Villarin, E<br />
P2‐01‐10<br />
Villarreal‐Garza, C<br />
PD08‐06<br />
Vinayak, S<br />
PD09‐04<br />
Vincent, A PD01‐02, PD01‐03<br />
Vincent, D S6‐2, P1‐07‐08, P3‐05‐03<br />
Vincent‐Salomon, A PD05‐08,<br />
P1‐01‐19, P2‐01‐04, P5‐01‐04,<br />
P5‐02‐03, P5‐21‐03, P6‐04‐14<br />
Vingiani, A<br />
PD03‐01<br />
Violante, A<br />
P1‐01‐25<br />
Viqueira, A<br />
P6‐11‐02<br />
Virador, VM<br />
P2‐04‐08<br />
Virani, S<br />
PD04‐02<br />
Virnig, BA<br />
P4‐01‐15<br />
Viscusi, RK<br />
P3‐10‐07<br />
Visram, H<br />
P3‐11‐03<br />
Visscher, DW<br />
P4‐12‐03,<br />
P5‐01‐08, P6‐06‐01<br />
Visvanathan, K S3‐5, P2‐02‐01<br />
Vo, H‐T<br />
PD02‐04<br />
Voduc, D P4‐16‐02, P4‐16‐04, P6‐07‐10<br />
Vogel, C<br />
OT2‐3‐11<br />
Vogel, CL<br />
P1‐12‐03<br />
Vogel, VG<br />
P4‐13‐12<br />
Vogel, WV<br />
P4‐02‐01<br />
Vojnovic, B<br />
P2‐10‐29<br />
Vollan, HKM<br />
P2‐10‐20<br />
Volm, M<br />
P5‐20‐05<br />
Volta, V<br />
P5‐03‐02<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
606s<br />
<strong>Cancer</strong> Research
December 4-8, 2012<br />
Author Index<br />
von der Assen, A<br />
P5‐21‐02<br />
von Euler‐Chelpin, M P3‐02‐03<br />
Von Euw, E<br />
P4‐08‐01<br />
von Minckwitz, G S1‐7, S2‐2, S3‐1,<br />
S4‐5, PD06‐01, P1‐13‐13, P1‐14‐01,<br />
P3‐06‐05, P6‐07‐05, OT1‐1‐13,<br />
OT2‐2‐05, OT3‐3‐11<br />
von Schoultz, E<br />
P6‐14‐01<br />
vonMincwitz, G S1‐11<br />
Voogd, AC P5‐21‐04, P6‐07‐32<br />
Vos, S<br />
P5‐01‐06<br />
Voss, A<br />
P3‐06‐21<br />
Voytko, NL S1‐6<br />
Vrancken Peeters, M‐JTFD P4‐02‐01<br />
Vrbanec, D<br />
P5‐02‐02<br />
Vreeland, TJ P5‐16‐02, P5‐16‐05<br />
Vriens, B<br />
PD07‐06<br />
Vriens, BE<br />
P1‐14‐07<br />
Vrigneaud, J‐M<br />
P4‐02‐06<br />
Vrouenraets, BC<br />
P4‐11‐01<br />
Wa, A<br />
P4‐11‐02<br />
Wachsmann, G S1‐7<br />
Wactawski‐Wende, J PD03‐09<br />
Wada, N<br />
P3‐02‐06<br />
Wada, R<br />
P5‐18‐11<br />
Wada, Y<br />
P3‐13‐04<br />
Wagle, N<br />
P5‐18‐03<br />
Wagner, J<br />
P1‐07‐06<br />
Wagner, K‐U S1‐8<br />
Wahdan‐Alaswad, RS P5‐10‐04<br />
Wahdan‐Alsawad, RS P5‐10‐05<br />
Waheed, S P1‐01‐10, P1‐01‐11<br />
Wai, ES<br />
PD04‐02<br />
Waisman, J<br />
P5‐16‐04<br />
Wakita, K<br />
P6‐07‐39<br />
Walker, K<br />
P3‐08‐04<br />
Walker, M<br />
P5‐20‐08<br />
Walker, MS<br />
P1‐15‐12<br />
Wallace, AM<br />
P2‐06‐01<br />
Wallden, B<br />
P3‐06‐03<br />
Wallecha, A<br />
P4‐04‐05<br />
Walley, B P1‐13‐01, OT2‐2‐01<br />
Wallin, J<br />
P5‐19‐02<br />
Wallin, JJ<br />
P4‐07‐01<br />
Wallon, UM<br />
P4‐09‐12<br />
Wallwiener, D<br />
P6‐09‐08<br />
Wals, J<br />
P1‐14‐07<br />
Walsh, CA<br />
P6‐04‐01<br />
Walsh, FJ<br />
PD02‐05<br />
Walsh, T<br />
P6‐07‐10<br />
Walter, HS<br />
P4‐14‐14<br />
Walters, EA<br />
P4‐06‐18<br />
Walz, T<br />
P1‐05‐07<br />
Wan, Y<br />
P6‐09‐06<br />
Wanders, J<br />
S6‐6, P6‐11‐14<br />
Wang, A<br />
PD03‐03, PD10‐03<br />
Wang, B P5‐18‐11, P5‐18‐24, P6‐11‐01<br />
Wang, D<br />
P5‐03‐04, P5‐03‐06<br />
Wang, D‐Y<br />
P2‐10‐34<br />
Wang, F<br />
P4‐16‐07<br />
Wang, FQ<br />
P4‐16‐12<br />
Wang, H<br />
PD02‐04<br />
Wang, J<br />
P2‐10‐30, P3‐04‐08,<br />
P4‐05‐01, P6‐11‐01<br />
Wang, K<br />
S3‐6, P4‐03‐12<br />
Wang, L<br />
OT3‐4‐04<br />
Wang, N<br />
PD07‐08<br />
Wang, Q<br />
P2‐09‐05<br />
Wang, S<br />
P2‐05‐05, P4‐06‐18<br />
Wang, T<br />
S5‐8, P4‐08‐07<br />
Wang, X PD09‐08, P5‐10‐10, P6‐04‐25<br />
Wang, X‐j P2‐05‐05, P4‐09‐09<br />
Wang, Y P2‐11‐16, P3‐06‐12, P4‐11‐04<br />
Wang, YC S5‐8<br />
Wang, Y‐L<br />
P3‐12‐10<br />
Wang, Y‐S<br />
P1‐14‐17<br />
Wang, Z<br />
PD02‐04, P4‐03‐06,<br />
P5‐10‐09, P6‐07‐45<br />
Wani, NA<br />
P1‐05‐17<br />
Wantanabe, A<br />
P1‐05‐04<br />
Wanyo, CM<br />
P3‐06‐27<br />
Wapnir, I S3‐2<br />
Wapnir, IL<br />
P6‐07‐06<br />
Ward, J<br />
P4‐17‐03<br />
Ward, M<br />
P1‐15‐07<br />
Ward, MM<br />
P6‐11‐04<br />
Ward, P<br />
P5‐20‐10<br />
Wardley, A<br />
S3‐3, P1‐13‐03<br />
Wardley, AM P2‐14‐06, OT1‐1‐03<br />
Warm, M<br />
PD07‐02<br />
Warnecke, R<br />
P5‐13‐03<br />
Warner, E<br />
P2‐12‐03,<br />
P3‐02‐10, P6‐08‐04<br />
Warr, R<br />
P4‐17‐03<br />
Warren, LE<br />
P3‐10‐06<br />
Warren, M<br />
P2‐12‐15<br />
Warren, R<br />
P1‐09‐04<br />
Warren, RM<br />
P4‐13‐09<br />
Warren Peled, A P4‐14‐04, P4‐16‐07<br />
Warrick, A<br />
P2‐08‐03<br />
Warwick, J<br />
P3‐08‐01<br />
Wasser, MNJM<br />
PD07‐06<br />
Watanabe, G<br />
P2‐10‐43<br />
Watanabe, J<br />
P1‐12‐01,<br />
P5‐18‐16, P6‐07‐16<br />
Watanabe, K<br />
P6‐07‐39<br />
Watanabe, M<br />
P2‐10‐43,<br />
P2‐12‐13, P6‐05‐14<br />
Watanabe, T P1‐13‐10, P2‐13‐04,<br />
P2‐13‐07, P4‐14‐07<br />
Waters, PS P1‐01‐15, P2‐05‐09<br />
Waterworth, A<br />
P3‐01‐06<br />
Watson, AP<br />
P1‐05‐16<br />
Watson, M PD07‐01, P2‐04‐02<br />
Wauters, CAP<br />
P5‐01‐13<br />
Waxman, J<br />
P2‐02‐03<br />
Waynick, C<br />
P2‐14‐05<br />
Waynick, S<br />
P2‐14‐05<br />
Wazer, D<br />
P4‐16‐03<br />
Wazir, U<br />
P1‐04‐07, P1‐04‐08,<br />
P1‐04‐09, P6‐05‐11<br />
Weaver, J<br />
P3‐05‐01<br />
Weaver, R<br />
P6‐10‐01<br />
Webb, C<br />
P1‐14‐14<br />
Webb, P<br />
P4‐08‐09, P5‐07‐02<br />
Webber, V<br />
P6‐04‐10<br />
Weber, B<br />
P3‐06‐20<br />
Weber, D<br />
OT2‐3‐08<br />
Weber, HA S5‐2<br />
Weber, JJ<br />
P1‐01‐17<br />
Weber, KE<br />
S4‐3, P2‐10‐11<br />
Webster, MA<br />
P1‐07‐10<br />
Webster, S<br />
P1‐07‐05<br />
Weeks, J<br />
P1‐01‐13<br />
Weeks, JC<br />
S3‐5, P1‐13‐05<br />
Wefel, JS<br />
OT1‐1‐11<br />
Wei, W P4‐02‐08, P5‐03‐08, P5‐10‐10<br />
Wei Shi, W<br />
P2‐10‐33<br />
Weide, R<br />
P2‐11‐11<br />
Weideman, PC<br />
P4‐13‐10<br />
Weidler, J<br />
P2‐05‐06,<br />
P2‐10‐16, P2‐10‐31<br />
Weidner, SM<br />
P1‐15‐12<br />
Weigelt, B<br />
PD05‐08<br />
Weigert, JM P4‐02‐09, P4‐02‐10<br />
Weigert, R<br />
P1‐05‐23<br />
Weiler‐Mithoff, E P4‐14‐13, P4‐17‐03<br />
Weinstein, P<br />
P5‐20‐08<br />
Weinstein, S<br />
P4‐01‐08<br />
Weir, L<br />
P4‐16‐01<br />
Weiss, E<br />
P2‐10‐25<br />
Weiss, HL<br />
P2‐14‐05<br />
Weiss, JE<br />
P4‐01‐15<br />
Weiss, L<br />
P4‐13‐13<br />
Weiss, MS<br />
P6‐04‐24<br />
Weisser, B<br />
OT3‐2‐01<br />
Weitsman, G<br />
P2‐10‐29<br />
Weitzel, JN<br />
PD08‐06<br />
Welch, RS<br />
P2‐14‐06<br />
Wells, C<br />
P4‐01‐13<br />
Wells, MN<br />
P2‐01‐14<br />
Welm, AL<br />
P6‐04‐20<br />
Welnicka‐Jaskiewicz, M P5‐04‐01<br />
Weltens, C P2‐10‐12, P6‐05‐05,<br />
P6‐07‐04, P6‐07‐19, P6‐07‐29<br />
Weltz, B<br />
P2‐10‐24<br />
Weltzien, E<br />
P3‐07‐05<br />
Wemhoff, G<br />
P4‐06‐03<br />
Wen, YH<br />
P2‐08‐01<br />
Weng, Z<br />
PD05‐09<br />
Wenger, N<br />
P4‐13‐13<br />
Wennmalm, K<br />
PD06‐08<br />
Wenz, F S4‐2<br />
Werner, L<br />
P1‐07‐07<br />
Werner Hartman, L<br />
P2‐10‐37<br />
Wesolowski, R<br />
P2‐11‐07<br />
Wesseling, J<br />
PD01‐03,<br />
P2‐10‐42, P3‐05‐01<br />
Wessels, H<br />
P5‐01‐11<br />
West, DW P3‐11‐02, P4‐11‐02<br />
West, RB<br />
PD05‐09<br />
Westbrook, TF<br />
PD01‐01<br />
Westenend, PJ<br />
P6‐07‐05<br />
Wetzel, L<br />
P4‐07‐05<br />
Wevers, MR<br />
P4‐11‐01<br />
Wey, A<br />
P1‐14‐11<br />
Wey, D<br />
P2‐11‐11<br />
Wheatley, D<br />
PD07‐09<br />
Wheeler, A<br />
P4‐11‐04<br />
Whelan, T<br />
P1‐13‐01<br />
Wheler, J<br />
P5‐20‐09<br />
White, A<br />
P3‐02‐04<br />
White, CB<br />
P6‐09‐11<br />
White, J<br />
P4‐06‐11<br />
Whitford, DL<br />
P6‐08‐07<br />
Whitman, B<br />
P6‐08‐09<br />
Whitworth, P PD07‐01, P1‐15‐09,<br />
P3‐06‐28, OT3‐4‐03<br />
Wicha, M<br />
OT2‐3‐01<br />
Wicinski, J<br />
P5‐03‐01<br />
Wickerham, DL S1‐10<br />
Wickerham, L S1‐11<br />
Wickham, T<br />
P1‐07‐03,<br />
P4‐02‐05, P5‐18‐09<br />
Wiegmann, DA<br />
P2‐11‐15<br />
Wienert, S<br />
PD06‐01<br />
Wiest, W<br />
P1‐13‐13<br />
Wiktor, AE<br />
PD02‐05<br />
Wildiers, H P2‐10‐12, P3‐13‐01,<br />
P6‐05‐05, P6‐07‐04,<br />
P6‐07‐05, P6‐07‐19, P6‐07‐29,<br />
P6‐09‐07, OT2‐2‐02<br />
Wilke, L<br />
P3‐02‐11<br />
Wilke, LG S2‐1<br />
Wilkens, LR<br />
P4‐12‐02<br />
Wilkerson, MD S6‐1<br />
Wilking, N<br />
P6‐14‐01<br />
Wilkins, M<br />
P4‐10‐02<br />
Wilkinson, JB<br />
P4‐16‐03<br />
Wilks, S<br />
P5‐20‐04<br />
Willems, SM<br />
P5‐01‐14<br />
Willey, J<br />
P3‐10‐05<br />
Willey, JS P5‐20‐13, OT2‐3‐10<br />
Willey, SC<br />
P4‐14‐01<br />
Williams, G<br />
PD04‐08<br />
Williams, K<br />
P3‐14‐04<br />
Williams, KE<br />
PD04‐06<br />
Williams, NR S4‐2<br />
Willianson, J<br />
P3‐08‐04<br />
Wilson, BC<br />
P4‐03‐04<br />
Wilson, C<br />
S6‐4, P2‐02‐04<br />
Wilson, G<br />
P2‐14‐06<br />
Wilson, J<br />
P1‐01‐13<br />
Wilson, JL<br />
P1‐13‐05<br />
Wilson, K<br />
P4‐13‐04<br />
Wilson, M<br />
P3‐01‐04<br />
Wilson, S<br />
P4‐17‐03<br />
Wilson‐Edell, KA<br />
P2‐05‐04<br />
Winchester, D<br />
PD04‐04<br />
Winchester, L<br />
P4‐01‐01<br />
Winczura, P P3‐12‐09, P3‐13‐03<br />
Winer, E S1‐1, S5‐5, P3‐05‐03,<br />
P5‐18‐03, P6‐08‐03, P6‐10‐05,<br />
OT1‐1‐07, OT2‐3‐06<br />
Winer, EP PD09‐03, PD10‐04,<br />
P2‐10‐01, P2‐16‐04,<br />
P6‐08‐05, OT1‐1‐11<br />
Winslow, J P2‐10‐16, P2‐10‐31<br />
Winter, A<br />
P4‐14‐13<br />
Winter, M<br />
P1‐15‐05<br />
Winter, MC<br />
P2‐02‐04<br />
Winter, W<br />
P2‐11‐16<br />
Winters, Z<br />
P4‐17‐03<br />
Wirtz, R<br />
P3‐06‐19<br />
Wirtz, RM PD10‐06, P3‐06‐08<br />
Wischnik, A P5‐14‐06, P5‐15‐04<br />
Wisell, J<br />
P6‐05‐10<br />
Wishart, GC<br />
P1‐01‐01<br />
Wisinski, KB<br />
P2‐11‐15,<br />
P3‐02‐11, P6‐12‐02<br />
Wisner, DJ<br />
P4‐01‐10<br />
Wist, EA<br />
P3‐01‐01<br />
Witkamp, AJ P4‐01‐17, P4‐11‐01,<br />
P5‐01‐11, P5‐15‐03<br />
Witteveen, PO<br />
P6‐07‐05<br />
Wittner, BS<br />
P2‐01‐14<br />
Wogu, AF P1‐15‐04, P3‐06‐07<br />
Wojciechowski, BS<br />
P4‐09‐12<br />
Wojtukiewicz, M<br />
OT1‐1‐16<br />
Wolchok, J<br />
OT3‐1‐01<br />
Wolf, D P3‐04‐01, P3‐04‐02, P4‐09‐05<br />
Wolf, DM P2‐05‐01, P4‐09‐02<br />
Wolfer, A<br />
P6‐04‐05<br />
Wolff, AC S3‐5, P1‐13‐05, P2‐02‐01,<br />
OT1‐1‐11<br />
Wolff, RA<br />
P5‐15‐02<br />
Wolmark, N S1‐10, S1‐11, S3‐2, S5‐5,<br />
P6‐07‐06, OT1‐1‐12, OT1‐2‐01<br />
Won, HH<br />
PD05‐02<br />
Wong, C<br />
P2‐14‐08<br />
Wong, CHN P3‐11‐02, P4‐11‐02<br />
Wong, CLP<br />
P4‐11‐02<br />
Wong, FY<br />
P4‐16‐12<br />
Wong, GYC<br />
P1‐10‐02<br />
Wong, H<br />
P4‐13‐04<br />
Wong, J P1‐01‐17, P3‐08‐09, P5‐01‐09<br />
Wong, KL<br />
P2‐01‐10<br />
Wong, S<br />
P4‐02‐08<br />
Wong, ST<br />
P3‐06‐14<br />
Wong, Y‐N P1‐01‐13, P1‐13‐05<br />
Wong-Brown, MW<br />
P4‐10‐02<br />
Woo, SY<br />
P2‐05‐20<br />
Woodman, N<br />
P2‐10‐29<br />
Woods, R<br />
PD04‐02, P4‐16‐01<br />
Woods, RR<br />
P3‐10‐07<br />
Woodward, W<br />
P3‐10‐10,<br />
P5‐03‐09, P5‐10‐02<br />
Woodward, WA PD03‐06, PD03‐08,<br />
P2‐03‐01, P3‐10‐01, P3‐10‐05,<br />
P5‐03‐05, P5‐03‐10, P5‐04‐06<br />
Worsham, MJ<br />
P2‐09‐04<br />
Wouters, C<br />
P3‐13‐01<br />
Wouters, K<br />
P3‐13‐01<br />
Wright, B<br />
P3‐06‐21<br />
Wright, F<br />
P6‐08‐04<br />
Wright, MC P4‐06‐03, P6‐10‐04<br />
Wright, WE<br />
P4‐06‐06<br />
Wroblewski, S<br />
OT1‐1‐04<br />
Wu, A P1‐09‐06, P5‐03‐04, P5‐03‐06<br />
Wu, C<br />
PD03‐09<br />
Wu, C‐C<br />
P4‐04‐07, P6‐05‐12<br />
Wu, E<br />
P5‐19‐02<br />
Wu, EQ<br />
P5‐15‐05, P5‐18‐12<br />
Wu, H<br />
PD05‐01<br />
Wu, J P3‐01‐05, P4‐05‐01, P6‐04‐26<br />
Wu, L<br />
P2‐09‐05<br />
Wu, M<br />
P5‐10‐10<br />
Wu, Q P3‐04‐01, P3‐04‐02, P5‐04‐06<br />
Wulfkuhle, JD P3‐04‐01, P3‐04‐02<br />
Wuyts, H<br />
P2‐01‐08<br />
Wymenga, MANM<br />
P1‐12‐05<br />
Wysocki, PJ<br />
P2‐10‐31<br />
Xerri, l<br />
P5‐03‐01<br />
Xia, G S1‐8<br />
Xia, W<br />
P4‐08‐03, P4‐08‐07<br />
Xiang, D<br />
P1‐07‐04<br />
Xiao, X<br />
P5‐10‐10<br />
Xiao, Z<br />
P4‐07‐05<br />
Xiaoyi, L<br />
P2‐10‐26<br />
Xie, H<br />
PD10‐09<br />
Xie, J<br />
P5‐15‐05<br />
Xie, X<br />
P5‐10‐10, P5‐10‐10<br />
Xie, Z<br />
P5‐10‐10<br />
Xingang, W<br />
P2‐10‐26<br />
Xu, B<br />
OT1‐1‐16<br />
Xu, J<br />
P4‐08‐10<br />
www.aacrjournals.org 607s<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012
CTRC-AACR <strong>San</strong> <strong>Antonio</strong> <strong>Breast</strong> <strong>Cancer</strong> <strong>Symposium</strong><br />
Xu, N<br />
P5‐03‐14<br />
Xu, Q<br />
P6‐11‐07, P6‐11‐09<br />
Xu, R<br />
P6‐13‐02<br />
Xu, W PD03‐06, P5‐03‐05, P5‐03‐10<br />
Xu, X<br />
P2‐01‐10<br />
Xu, X‐H<br />
P2‐05‐05<br />
Xu, X‐L<br />
P6‐07‐42<br />
Xu, XX<br />
PD08‐02<br />
Xu, Y<br />
P6‐04‐15<br />
Xu, Z P1‐03‐03, P4‐03‐12, P5‐01‐16<br />
Xue, L<br />
P2‐05‐19<br />
Xynos, Y<br />
P3‐02‐04<br />
Yadav, P<br />
P4‐06‐02<br />
Yagata, H P1‐01‐12, P5‐15‐06,<br />
P6‐07‐23, P6‐07‐38<br />
Yager, S<br />
OT3‐4‐04<br />
Yamada, J<br />
PD06‐02<br />
Yamada, Y<br />
P4‐09‐08<br />
Yamagami, K PD07‐05, P3‐13‐04<br />
Yamaguchi, T P2‐13‐04, P2‐13‐07<br />
Yamaguchi, Y<br />
P6‐04‐17<br />
Yamaki, E<br />
P4‐03‐05<br />
Yamamoto, D P1‐12‐01, P6‐07‐16<br />
Yamamoto, N<br />
P3‐02‐06<br />
Yamamoto, S<br />
P2‐11‐02<br />
Yamamoto, Y P1‐14‐02, P1‐14‐08,<br />
P2‐14‐03, P3‐06‐18,<br />
P6‐05‐06, P6‐07‐16<br />
Yamamoto‐Ibusuki, M P2‐14‐03<br />
Yamamura, J<br />
P1‐14‐08<br />
Yamamura, N<br />
P4‐03‐07<br />
Yamanaka, A<br />
P1‐01‐20<br />
Yamanaka, T<br />
P1‐01‐20<br />
Yamashige, S<br />
P5‐15‐06<br />
Yamashiro, H<br />
P3‐13‐04<br />
Yamashita, D<br />
P4‐03‐05<br />
Yamashita, H P1‐14‐02, P3‐06‐18,<br />
P3‐12‐03, P4‐12‐06<br />
Yamashita, Y<br />
P4‐03‐05<br />
Yamauch, A<br />
P3‐13‐04<br />
Yamauchi, H P1‐01‐12, P5‐15‐06,<br />
P6‐07‐23, P6‐07‐38<br />
Yan, FJ<br />
P1‐07‐17<br />
Yan, Y<br />
P3‐04‐01, P3‐04‐02<br />
Yanac, AF S1‐8<br />
Yang, C<br />
P1‐13‐07<br />
Yang, G<br />
P2‐10‐39<br />
Yang, H P5‐01‐16, P5‐03‐14, P5‐15‐05<br />
Yang, J P1‐05‐18, P2‐04‐07, P6‐06‐05<br />
Yang, JH<br />
P2‐05‐20<br />
Yang, J‐H<br />
P2‐10‐41<br />
Yang, L<br />
P5‐10‐10<br />
Yang, N S1‐8<br />
Yang, P<br />
PD03‐08<br />
Yang, S‐H<br />
P4‐03‐02<br />
Yang, S‐Y<br />
P3‐06‐02<br />
Yang, W<br />
P3‐06‐14<br />
Yang, XR<br />
P3‐08‐02<br />
Yang, Y<br />
P2‐05‐19, P2‐07‐01<br />
Yang, Z<br />
P3‐12‐12<br />
Yankeelov, TE<br />
P4‐01‐03<br />
Yano, H<br />
P1‐01‐27<br />
Yano, S<br />
P4‐07‐04<br />
Yao, K<br />
P3‐05‐01<br />
Yap, Y‐S<br />
P3‐08‐09<br />
Yardley, DA P1‐14‐14, P2‐05‐06,<br />
P3‐12‐04, P5‐17‐05, P5‐20‐10,<br />
P6‐10‐01, P6‐11‐14, OT3‐3‐08<br />
Yarnold, J<br />
P1‐13‐03<br />
Yarnold, JR<br />
S4‐1, P3‐06‐09<br />
Yasmeen, S<br />
P4‐13‐13<br />
Yau, C P2‐05‐01, P2‐10‐06, P3‐04‐01,<br />
P3‐04‐02, P4‐09‐02<br />
Ye, F<br />
P2‐05‐19<br />
Ye, L<br />
P1‐04‐03<br />
Ye, W‐w<br />
P4‐09‐09<br />
Ye, Z<br />
P4‐06‐03, P6‐10‐04<br />
Yee, D<br />
P1‐14‐11<br />
Yeh, D‐C<br />
OT1‐1‐16<br />
Yeh, E<br />
P5‐02‐01<br />
Yeh, ED P3‐10‐06, P4‐01‐09, P4‐06‐01<br />
Yeh, I‐T<br />
P5‐03‐04, P5‐03‐06<br />
Yeh, L‐C<br />
P6‐05‐15<br />
Yelensky, R<br />
S3‐6, PD02‐07<br />
Yelle, L S6‐6<br />
Yellin, MJ<br />
P6‐10‐01<br />
Yerushalmi, R<br />
P5‐20‐06<br />
Yeung, TY<br />
PD01‐08<br />
Yevtushenko, M<br />
P2‐05‐04<br />
Yi, J<br />
OT3‐4‐04<br />
Yi, J‐H<br />
P5‐18‐24<br />
Yi, M<br />
P1‐07‐09<br />
Yin, W<br />
P6‐07‐35<br />
Yip, AYS<br />
P2‐05‐16<br />
Yokota, I<br />
P2‐13‐04, P2‐13‐07<br />
Yong, W‐S<br />
P3‐08‐09<br />
Yoon, K<br />
P1‐05‐18<br />
Yoshibayashi, H<br />
P3‐13‐04<br />
Yoshida, A P1‐01‐20, P5‐15‐06,<br />
P6‐07‐23, P6‐07‐38<br />
Yoshida, K<br />
P5‐04‐02<br />
Yoshida, M<br />
P4‐03‐08<br />
Yoshida, N<br />
P1‐14‐02<br />
Yoshida, S<br />
P6‐07‐30<br />
Yoshida, T<br />
P6‐04‐13<br />
Yoshidome, K<br />
P2‐10‐18<br />
Yoshimoto, K<br />
P4‐03‐05<br />
Yoshimoto, N<br />
P4‐12‐06<br />
Yoshimura, K<br />
P5‐01‐02<br />
Yoshiyama, T<br />
P3‐06‐26<br />
Yoshizawa, C<br />
P5‐15‐06<br />
You, M<br />
P1‐08‐02<br />
You, Z<br />
P5‐17‐07<br />
Youn, HJ<br />
P1‐10‐01, P5‐07‐04<br />
Young, L<br />
P6‐04‐04, P6‐04‐21<br />
Young, LS<br />
P6‐04‐01<br />
Young, R<br />
OT3‐3‐07<br />
Younus, J<br />
P2‐13‐08<br />
Youssoufian, H<br />
P6‐11‐10<br />
Yovine, A<br />
OT2‐2‐03<br />
Yu, B‐L<br />
P4‐16‐05<br />
Yu, J<br />
P2‐08‐02<br />
Yu, J‐C<br />
P4‐04‐07<br />
Yu, JH<br />
P3‐01‐02<br />
Yu, K‐D P1‐13‐07, P2‐06‐07, P3‐06‐14<br />
Yu, M<br />
S5‐7, P2‐01‐14<br />
Yu, S<br />
P1‐09‐06<br />
Yu, T<br />
P5‐15‐06<br />
Yu, X‐y<br />
P4‐09‐09<br />
Yuan, J<br />
OT3‐1‐01<br />
Yue, B<br />
P2‐10‐40<br />
Yueh, N<br />
P4‐07‐03<br />
Yuki, S<br />
P2‐05‐08<br />
Yun, C<br />
P4‐03‐11<br />
Yvonnet, V<br />
P3‐06‐24<br />
Zabaglo, LA S4‐6<br />
Zaborek, P<br />
P5‐02‐02<br />
Zacharchuk, C<br />
OT1‐1‐05<br />
Zachariae, B<br />
P6‐07‐08<br />
Zacksenhaus, E<br />
P6‐02‐03<br />
Zaczek, AJ<br />
P5‐04‐01<br />
Zafra Poves, M<br />
P3‐06‐15<br />
Zahm, D‐M<br />
P2‐10‐25<br />
Zaman, K P6‐04‐05, OT2‐2‐02<br />
Zamani, A<br />
P2‐12‐10<br />
Zambetti, M<br />
P2‐12‐08<br />
Zamora, E<br />
P6‐13‐03<br />
Zamora, P P1‐07‐18, P2‐01‐06<br />
Zannetti, A<br />
OT3‐3‐04<br />
Zanoni, V<br />
PD07‐03<br />
Zaravinos, J<br />
P1‐12‐03<br />
Zaun, S<br />
P6‐09‐08<br />
Zebisch, M<br />
P2‐01‐11<br />
Zehnbauer, B<br />
P6‐07‐10<br />
Zeichner, SB<br />
P1‐12‐03<br />
Zelek, LH<br />
PD08‐03<br />
Zelenika, D<br />
P5‐05‐03<br />
Zellinger, J<br />
P2‐13‐01<br />
Zemba‐Palko, V<br />
P4‐09‐12<br />
Zeng, W<br />
P4‐05‐01<br />
Zhan, M<br />
P3‐06‐14, P4‐02‐08<br />
Zhang, A‐Q<br />
P2‐09‐05<br />
Zhang, B<br />
P6‐10‐02<br />
Zhang, D<br />
P5‐03‐09<br />
Zhang, DY<br />
P2‐05‐19<br />
Zhang, F<br />
P5‐10‐03<br />
Zhang, H P1‐04‐04, P1‐05‐08,<br />
P4‐06‐05, P6‐04‐07<br />
Zhang, J<br />
P6‐07‐43, P6‐11‐01<br />
Zhang, L<br />
S1‐11, P2‐12‐03<br />
Zhang, M S6‐3, P4‐02‐08, P5‐03‐08<br />
Zhang, Q P3‐12‐12, OT1‐1‐16<br />
Zhang, T<br />
P3‐03‐01<br />
Zhang, X<br />
P6‐10‐04<br />
Zhang, Y S1‐9, P1‐03‐03, P1‐07‐13,<br />
P2‐10‐15, P4‐06‐18, OT2‐2‐03<br />
Zhang, Y‐J<br />
P6‐07‐43<br />
Zhang, Y‐M<br />
P4‐09‐09<br />
Zhang, Y‐P<br />
P6‐07‐43<br />
Zhang, Z<br />
P6‐07‐33, P6‐09‐06<br />
Zhang, Z‐P<br />
P1‐14‐17<br />
Zhao, H<br />
P2‐05‐12, P2‐05‐13<br />
Zhao, J<br />
P4‐08‐10<br />
Zhao, L<br />
P2‐04‐07<br />
Zhao, S P4‐08‐03, P4‐08‐07, P6‐01‐03<br />
Zhe, J<br />
P1‐04‐05<br />
Zheng, C<br />
P1‐07‐12<br />
Zheng, CX<br />
P3‐08‐06<br />
Zheng, J<br />
P4‐02‐05<br />
Zheng, P<br />
OT1‐2‐01<br />
Zheng, Y<br />
P3‐09‐05<br />
Zheng, Y‐b<br />
P4‐09‐09<br />
Zhidong, L<br />
P2‐10‐26<br />
Zhong, S<br />
P4‐08‐10<br />
Zhou, D<br />
P5‐16‐01<br />
Zhou, J<br />
P3‐01‐04, P4‐06‐08<br />
Zhou, JZ<br />
P3‐13‐06<br />
Zhou, M<br />
P6‐07‐43<br />
Zhou, Rj<br />
P6‐07‐36<br />
Zhu, L<br />
P1‐01‐09<br />
Zhu, R<br />
P3‐06‐14<br />
Zhu, S<br />
PD05‐09<br />
Zhu, X<br />
P3‐04‐11<br />
Zhu, Y<br />
P4‐02‐08<br />
Zhuang, X<br />
P6‐04‐28<br />
Zickl, L<br />
OT2‐2‐01<br />
Zielinski, C<br />
P5‐17‐03<br />
Zignani, J<br />
P3‐01‐03<br />
Zijlstra, A<br />
P3‐05‐09<br />
Zimon, D<br />
P5‐03‐13<br />
Zingelewicz, S<br />
P3‐05‐05<br />
Ziras, N<br />
P1‐13‐09<br />
Zlobin, A<br />
P2‐05‐15, P4‐08‐06<br />
Zoeller, JJ<br />
P4‐08‐05<br />
Zoghi, B<br />
P5‐10‐14, P5‐10‐16<br />
Zohar, S<br />
P4‐14‐12<br />
Zok, J<br />
P3‐12‐09, P3‐13‐03<br />
Zong, W‐X<br />
P5‐04‐09<br />
Zrada, S<br />
P2‐05‐06<br />
Zubritsky, LM<br />
P3‐06‐33<br />
Zujewski, JA S1‐11, S5‐5<br />
Zvelebil, M PD05‐08, P3‐08‐04<br />
Zwelling, L<br />
P5‐15‐02<br />
Zwenger, A<br />
P3‐07‐13<br />
<strong>Cancer</strong> Res; 72(24 Suppl.) December 15, 2012<br />
608s<br />
<strong>Cancer</strong> Research
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