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DAVID W. SCOTT FIGURE 2. Immunohistochemistry-Based Assays for COO Assignment The four immunohistochemistry-based algorithms that were trained against gold standard gene expression profiling are shown. Accuracy is defined as the concordance with the gold standard. Sensitivity and specificity are shown for the ABC subtype--as they are binary assays, the specificity for ABC is the sensitivity for GCB, whereas the sensitivity for ABC is the specificity for GCB. The positive predictive value (PPV) and negative predictive value (NPV) are for the ABC subtype. The performance values are determined from independent validation cohorts, except where marked with an *, where they are from the training cohort and thus may overestimate the performance of the assay. e462 2015 ASCO EDUCATIONAL BOOK | asco.org/edbook
COO IN DLBCL: ARE THE ASSAYS READY FOR CLINIC? pathologist improved. However, the level of agreement with regards to COO was still suboptimal at 77% ( statistic of 0.62). This level of agreement was improved if stains were excluded if no positive internal control was seen, but this resulted in a substantial rise in the failure rate of the assays. In response to the technical issues identifıed with BCL6, it has been suggested that the Hans and Choi classifıers be modifıed to exclude the BCL6 antibody. 26 More recently, Coutinho et al 32 examined the level of agreement across the IHC-based assays showing that the concordance between the assays was generally low. The study of Gutiérrez-Garcia et al directly addressed the accuracy of the IHC-based assays comparing the COO assignments by the Hans, Choi, and Tally algorithms with those from GEP on matched fresh frozen tissue using Affymetrix microarrays. 33 The results were disappointing, with concordance rates between 59% and 65% for the three IHC-based assays compared with the gold standard. The issues with reproducibility and the variable agreement with the gold standard COO likely play major roles in the observation that, although COO by GEP is prognostic in the R-CHOP era, the literature is highly discordant when COO is assigned by IHC-based assays. A meta-analysis of the IHC-based studies and the GEP-based studies has recently been published illustrating this point. 34 In aggregate, despite the careful studies that defıned the assays and the wide availability of IHC, the accumulated evidence indicates that IHC-based methods are not ready to guide clinical care at this time. If IHC-based assays are to be used to make management decisions, there will have to be a shift away from individual laboratory–developed tests and toward defıned kits, where standardized antibodies, laboratory techniques, and agreement on scoring may improve reproducibility and accuracy, with reproducible observer scoring representing the most formidable obstacle to standardize. This approach is currently being used with the Hans algorithm providing the patient selection for a phase III, randomized, controlled trial assessing the effıcacy of adding ibrutinib to R-CHOP in non-GCB DLBCL (ClinicalTrials.gov Identifıer NCT01855750). Gene Expression–Based Assays Over the last decade, technologies have been developed that allow GEP employing the highly degraded RNA that is extracted from FFPET. Since 2010, a number of GEP-based assays have been described capitalizing on these advances. The generally high degree of accuracy of these assays is a testament to the very distinct gene expression patterns between ABC and GCB, and the robustness of the COO algorithm on which most of these assays are based. The fırst demonstration of robust COO assignment using GEP on RNA from FFPET came from techniques that make this degraded RNA suitable for GEP using standard microarray technology. Williams et al compared the results of applying the Wright algorithm to GEP using RNA from FFPET compared with that of matched fresh frozen tissue. 35 When unclassifıable cases were excluded, there was one frank misclassifıcation out of 44 cases, giving a concordance of 98%. This approach has subsequently been used to assign COO in a large cohort of patients with de novo DLBCL treated with R-CHOP, 27 with the expected survival difference observed between the GCB and ABC groups. A range of other technology platforms have subsequently been used as the basis of COO assays, including quantitative nuclease protection assay, 36 multiplex reverse transcription (RT)–polymerase chain reaction (PCR), 37-39 DASL, 40 and NanoString. 41-43 In studies in which the comparator was the gold standard of GEP in fresh frozen tissue, concordance was typically high at approximately 95%, when unclassifıed cases are removed. 36,37,41,43 Two studies will be discussed in more detail below as these assays are now supporting phase III randomized controlled trials. Barrans et al have developed an assay for DLBCL COO based on the cDNA-mediated Annealing, Selection, extension, and Ligation (DASL) platform (Illumina, San Diego, CA), which provides genome-wide GEP in degraded RNA samples. 40 This technology, in combination with a new tool for COO assignment based on balanced voting between four machine-learning tools, 44 was used to assign COO in a population-based cohort of 172 patients with DLBCL. 40 The COO assignments in this population were 48% GCB, 31% ABC, and 21% type 3 (presumably equivalent to unclassifıed). Although there was no comparison with the gold standard COO assignment from fresh frozen material, the characteristics of the ABC and GCB groups were consistent with previous reports, with inferior outcomes following treatment in the ABC group. This assay is currently being used to stratify patients for a phase III, randomized, controlled trial assessing the effıcacy of adding bortezomib to R-CHOP in patients with DLBCL (ClinicalTrials.gov Identifıer NCT01324596). The randomization to the treatment arms, stratifıed by COO to ensure equal proportions of patients with ABC and GCB in each arm, occurs after one cycle of R-CHOP to allow patients to commence treatment in a timely fashion while awaiting the GEP results. The LLMPP used the NanoString platform to develop a parsimonious gene expression–based COO assay for RNA from FFPET. 43 We took advantage of the ability of this platform to quantitate up to 800 RNA species in multiplex to build a model that most accurately replicated the larger GEP model described in Lenz et al. 6 In brief, 93 genes that were most differentially expressed between ABC and GCB on Affymetrix microarray data from fresh frozen tissue were quantifıed in RNA extracted from matched FFPET biopsies on the NanoString platform. Genes were then selected based on the degree of correlation of the expression between the two platforms (and across the sources of RNA). In total, 15 genes (Fig. 3A) were suffıcient to accurately replicate the model from Lenz et al 6 with the addition of further genes resulting in negligible increase in assay accuracy. The low-density assay, comprising only these 15 genes and fıve house-keeping genes, was applied to samples that contributed to the training of the Lenz et al model, the fınal model was built and then “locked.” This assay, named the Lymph2Cx, was then tested asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK e463
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AMERICAN SOCIETY OF CLINICAL ONCOLO
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American Society of Clinical Oncolo
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Controversies in Neoadjuvant Therap
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Clinical Trials of Precision Medici
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Managing Ovarian Cancer in the Olde
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Updates in the Multimodality Manage
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PEDIATRIC ONCOLOGY Real-Time Molecu
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2015 ASCO Annual Meeting Disclosure
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2015 Educational Book Expert Panel
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James Marshall, PhD Roswell Park Ca
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2015 Annual Meeting Supporters* MIS
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David Yurman Corporate Allies Conqu
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INVITED ARTICLES This year’s invi
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WONG, CAPASSO, AND ECKHARDT 3 3 sc
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WONG, CAPASSO, AND ECKHARDT terize
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WONG, CAPASSO, AND ECKHARDT for mul
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STEPHEN T. SONIS portantly, patient
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STEPHEN T. SONIS elements of a clus
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STEPHEN T. SONIS Defıning the clin
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STEPHEN T. SONIS predict oral mucos
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HUSSAIN AND DIPAOLA TABLE 1. U.S. F
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HUSSAIN AND DIPAOLA mizing use of p
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INVITED ARTICLES DIAGNOSTICS The Fu
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EDWARD S. KIM TABLE 1. Selected Umb
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EDWARD S. KIM platform that plans t
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INVITED ARTICLES HEAD AND NECK CANC
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GROSS AND COHEN treatments are poor
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GILBERT ET AL tional scholars, lead
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ENG ET AL colorectal cancer. Indeed
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INVITED ARTICLES BREAST CANCER I Wi
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WILLIAM M. SIKOV gational treatment
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BREAST CANCER Controversies in Neoa
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BREAST CANCER Individualizing the A
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CANCER PREVENTION, GENETICS, AND EP
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ADDRESSING BARRIERS TO BREAST CANCE
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DECISION MAKING IN THE CONTEXT OF B
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REFORMING THE BUY-AND-BILL CHEMOTHE
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CARE DELIVERY AND PRACTICE MANAGEME
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THE PATIENT-CENTERED MEDICAL HOME c
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INTEGRATING ICD-10 IN YOUR PRACTICE
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CENTRAL NERVOUS SYSTEM TUMORS Brain
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AHLUWALIA AND WINKLER TARGETING ANG
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MAWRIN, CHUNG, AND PREUSSER Biology
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DEVELOPMENTAL THERAPEUTICS AND TRAN
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ESTEVA, MILLER, AND TEICHER TARGETS
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STUART M. LICHTMAN include a Geriat
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STUART M. LICHTMAN an outcome of ca
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BARRIOS, WERUTSKY, AND MARTINEZ-MES
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CHRISTINE M. LOVLY TKIs have been t
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CHRISTINE M. LOVLY MAP2K1, which en
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ZARDAVAS AND PICCART-GEBHART TABLE
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ZARDAVAS AND PICCART-GEBHART mutati
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MICHAEL A. POSTOW Managing Immune C
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MICHAEL A. POSTOW diarrhea symptoms
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MICHAEL A. POSTOW tion. One of thes
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MICHAEL A. POSTOW nitis during ipil
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GASTROINTESTINAL (COLORECTAL) CANCE
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PRECISION THERAPY FOR RECTAL CANCER
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PRECISION THERAPY FOR RECTAL CANCER
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GASTROINTESTINAL (COLORECTAL) CANCE
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MARWAN FAKIH TABLE 1. Biologicals i
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MARWAN FAKIH TABLE 3. EGFR Targetin
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MARWAN FAKIH TABLE 6. EGFR Targetin
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PUNT, SIMKENS, AND KOOPMAN 5-FU/LV
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PUNT, SIMKENS, AND KOOPMAN TABLE 1.
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CERCEK, CUSACK, AND RYAN Treatment
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CERCEK, CUSACK, AND RYAN leagues pe
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GASTROINTESTINAL (NONCOLORECTAL) CA
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ABOU-ALFA ET AL sess liver function
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ABOU-ALFA ET AL tinuing liver injur
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ABOU-ALFA ET AL mors including HCC,
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ABOU-ALFA ET AL HCC (Anti-Programme
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AHN ET AL Making Sense of Current a
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AHN ET AL Pancreatic cancer has bee
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AHN ET AL Disclosures of Potential
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EGIDIO DEL FABBRO tion of precachex
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EGIDIO DEL FABBRO FIGURE 3. Mechani
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EGIDIO DEL FABBRO II RCT of ghrelin
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EGIDIO DEL FABBRO 22. Tan BH, Birds
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THE SPECTRUM OF NEUROENDOCRINE TUMO
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CHALLENGING THE TREATMENT PARADIGM
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STAGE I TESTICULAR GERM CELL CANCER
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STAGE I TESTICULAR GERM CELL CANCER
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GERM CELL TUMORS: LOOKING TO THE FU
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SALVAGE CHEMOTHERAPY Salvage Therap
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SALVAGE CHEMOTHERAPY References 1.
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EARLY CHEMOTHERAPY IN MEN WITH META
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RADIUM 223 AND METASTATIC CASTRATIO
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RADIUM 223 AND METASTATIC CASTRATIO
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IMMUNOTHERAPY FOR PROSTATE TUMORS I
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IMMUNOTHERAPY FOR PROSTATE TUMORS T
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IMMUNOTHERAPY FOR PROSTATE TUMORS a
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EVOLVING IMMUNOTHERAPY STRATEGIES I
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NOVEL IMMUNOTHERAPY AGENTS IN METAS
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PROMISING STRATEGIES IN BLADDER CAN
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GYNECOLOGIC CANCER Cervical Cancer
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MACKAY, WENZEL, AND MILESHKIN In th
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MACKAY, WENZEL, AND MILESHKIN admin
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MACKAY, WENZEL, AND MILESHKIN TABLE
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MACKAY, WENZEL, AND MILESHKIN ing s
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MACKAY, WENZEL, AND MILESHKIN 59. F
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GYNECOLOGIC CANCER Managing Ovarian
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DUSKA, TEW, AND MOORE KEY POINTS A
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DUSKA, TEW, AND MOORE FIGURE 2. Sur
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DUSKA, TEW, AND MOORE FIGURE 3. Che
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DUSKA, TEW, AND MOORE FIGURE 4. Ger
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DUSKA, TEW, AND MOORE 10. Griffıth
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GYNECOLOGIC CANCER Treatment of the
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CHEMOTHERAPY FOR PATIENTS WITH BMOC
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PROGRESS IN HEAD AND NECK SQUAMOUS
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HEAD AND NECK CANCER PI3-Kinase: Ge
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ISAACSSON VELHO, CASTRO JR, AND CHU
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SHARON H. GIORDANO Comparative Effe
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SHARON H. GIORDANO measured confoun
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SHARON H. GIORDANO These databases
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HEALTH SERVICES RESEARCH AND QUALIT
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INDUSTRY AND ONCOLOGY KEY POINTS F
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INDUSTRY AND ONCOLOGY has been “l
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INDUSTRY AND ONCOLOGY by (covered)
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INDUSTRY AND ONCOLOGY 42. World Hea
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CANCER CARE QUALITY: CURRENT STATE
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MANAGING OLDER PATIENTS WITH ALL Th
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MANAGING OLDER PATIENTS WITH ALL TA
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MANAGING OLDER PATIENTS WITH ALL FI
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MANAGING OLDER PATIENTS WITH ALL FI
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MANAGING OLDER PATIENTS WITH ALL ra
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TREATMENT OF PHILADELPHIA CHROMOSOM
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CD19 CAR THERAPY FOR ALL FIGURE 1.
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CD19 CAR THERAPY FOR ALL 5. Zhou G,
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NEW TARGETED THERAPIES FOR iNHL New
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NEW TARGETED THERAPIES FOR iNHL TAB
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NEW TARGETED THERAPIES FOR iNHL a P
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HEMATOPOIETIC CELL TRANSPLANTATION
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LEUKEMIA, MYELODYSPLASIA, AND TRANS
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MICHAEL W. DEININGER TABLE 1. Defin
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MICHAEL W. DEININGER the ATP-bindin
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MICHAEL W. DEININGER broad range ef
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MICHAEL W. DEININGER 30. Hughes T,
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PEMMARAJU AND MOLITERNO TABLE 1. Ac
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PEMMARAJU AND MOLITERNO drome (BCS)
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PEMMARAJU AND MOLITERNO 13. Xing S,
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THERAPIES AND INDICATIONS FOR PH-NE
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LEUKEMIA, MYELODYSPLASIA, AND TRANS
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RECENT UPDATES IN MDS AND MDS/MPNS
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LUNG CANCER Beyond Second-Line Trea
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BEYOND SECOND-LINE TREATMENT FOR LU
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BEYOND SECOND-LINE TREATMENT FOR LU
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LUNG CANCER New Therapies for Histo
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GERBER, PAIK, AND DOWLATI a tumor t
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GERBER, PAIK, AND DOWLATI squamous
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GERBER, PAIK, AND DOWLATI FIGURE 2.
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GERBER, PAIK, AND DOWLATI TABLE 1.
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Page 626 and 627: WOODARD AND JABLONS FIGURE 1. Molec
Page 628 and 629: NASSER HANNA Current Standards and
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Page 632 and 633: NASSER HANNA culty of this task. Va
Page 634 and 635: LYMPHOMA AND PLASMA CELL DISORDERS
Page 636 and 637: NOWAKOWSKI AND CZUCZMAN sociated wi
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Page 644 and 645: DAVID W. SCOTT Cell-of-Origin in Di
Page 646 and 647: DAVID W. SCOTT FIGURE 1. The Origin
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Page 660 and 661: CHEAH, OKI, AND FANALE TABLE 3. Sel
Page 662 and 663: CHEAH, OKI, AND FANALE eral T cell
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Page 686 and 687: BHUTANI, LANDGREN, AND USMANI FIGUR
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Page 690 and 691: MOREAU AND TOUZEAU Multiple Myeloma
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LYMPHOMA AND PLASMA CELL DISORDERS
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MANAGEMENT OF CLL Up-Front Manageme
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MANAGEMENT OF CLL than 17p-/TP53mut
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MANAGEMENT OF CLL could be associat
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MANAGEMENT OF CLL tion by nonmalign
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MANAGEMENT OF CLL fludarabine and c
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MANAGEMENT OF CLL lymphocytic leuke
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PROGNOSTIC FACTORS AND ADJUVANT RAD
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MERKEL CELL CARCINOMA Merkel Cell C
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MERKEL CELL CARCINOMA tions in PIK3
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MERKEL CELL CARCINOMA treating MCC
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MERKEL CELL CARCINOMA 32. Leonard J
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MELANOMA/SKIN CANCERS Locoregional
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PERFUSION AND INFUSION IN THE ERA O
Page 730 and 731:
Page 732 and 733:
Page 734 and 735:
NEOADJUVANT THERAPY OF MELANOMA Neo
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NEOADJUVANT THERAPY OF MELANOMA TAB
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NEOADJUVANT THERAPY OF MELANOMA ity
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NEOADJUVANT THERAPY OF MELANOMA 4.
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MELANOMA/SKIN CANCERS Targeted Mole
Page 744 and 745:
SULLIVAN ET AL FIGURE 1. Relevant S
Page 746 and 747:
SULLIVAN ET AL Resistance to BRAF i
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SULLIVAN ET AL TABLE 1. Clinical Tr
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SULLIVAN ET AL 17. Halait H, Demart
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SULLIVAN ET AL NRAS-mutant melanoma
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KLEPIN, RODIN, AND HURRIA Treating
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KLEPIN, RODIN, AND HURRIA plication
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KLEPIN, RODIN, AND HURRIA plan was
Page 760 and 761:
KLEPIN, RODIN, AND HURRIA patient-s
Page 762 and 763:
KLEPIN, RODIN, AND HURRIA 62. Blanc
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PERIPHERAL NEUROTOXICITY IN CANCER
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Page 768 and 769:
Page 770 and 771:
Page 772 and 773:
PARTRIDGE, JACOBSEN, AND ANDERSEN C
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PARTRIDGE, JACOBSEN, AND ANDERSEN c
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PARTRIDGE, JACOBSEN, AND ANDERSEN w
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PARTRIDGE, JACOBSEN, AND ANDERSEN v
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LESLIE R. SCHOVER Sexual Healing in
Page 782 and 783:
LESLIE R. SCHOVER tinuous ADT in pr
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LESLIE R. SCHOVER 12. Potosky AL, H
Page 786 and 787:
CATHERINE H. VAN POZNAK TABLE 1. Wo
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CATHERINE H. VAN POZNAK (tamoxifen,
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CATHERINE H. VAN POZNAK TABLE 3. FD
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CATHERINE H. VAN POZNAK premenopaus
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SHARI GOLDFARB KEY POINTS Brea
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SHARI GOLDFARB and friction with va
Page 798 and 799:
SHARI GOLDFARB importance both duri
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PATIENT AND SURVIVOR CARE Moving Su
Page 802 and 803:
MAYER ET AL TABLE 1. Quality Metric
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MAYER ET AL to enhance the quality
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MAYER ET AL FIGURE 2. (A) Infertili
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MAYER ET AL efıcial suggests that
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PATIENT AND SURVIVOR CARE The Chall
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BRUERA AND PAICE Choice of Opioid a
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BRUERA AND PAICE toxicity and proce
Page 816 and 817:
BRUERA AND PAICE effective. Basic s
Page 818 and 819:
PEDIATRIC ONCOLOGY Real-Time Molecu
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CARROLL, RAETZ, AND MEYER KEY POINT
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CARROLL, RAETZ, AND MEYER most are
Page 824 and 825:
CARROLL, RAETZ, AND MEYER markers a
Page 826 and 827:
PEDIATRIC ONCOLOGY Translating Surv
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REDUCING THE BURDEN OF LATE EFFECTS
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Page 832 and 833:
Page 834 and 835:
Page 836 and 837:
PROFESSIONAL DEVELOPMENT The Challe
Page 838 and 839:
ADVANCES IN WEBSITE INFORMATION RES
Page 840 and 841:
Page 842 and 843:
Page 844 and 845:
Page 846 and 847:
COMMUNICATION AND TECHNOLOGY: IT’
Page 848 and 849:
Page 850 and 851:
Page 852 and 853:
PATIENT-REPORTED OUTCOMES IN ONCOLO
Page 854 and 855:
PATIENT-REPORTED OUTCOMES IN ONCOLO
Page 856 and 857:
PROFESSIONAL DEVELOPMENT Trends, An
Page 858 and 859:
CLINICAL ONCOLOGY PRACTICE 2015 FIG
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CLINICAL ONCOLOGY PRACTICE 2015 (6.
Page 862 and 863:
CLINICAL ONCOLOGY PRACTICE 2015 Pro
Page 864 and 865:
ADJUVANT/NEOADJUVANT MEDICAL THERAP
Page 866 and 867:
Page 868 and 869:
Page 870 and 871:
INDICATIONS FOR ADJUVANT RADIATION
Page 872 and 873:
Page 874 and 875:
Page 876 and 877:
Page 878 and 879:
SARCOMA Latest Advances in Systemic
Page 880 and 881:
SYSTEMIC THERAPY FOR OSTEOSARCOMA A
Page 882 and 883:
SYSTEMIC THERAPY FOR OSTEOSARCOMA A
Page 884 and 885:
RETHINKING TREATMENT FOR CHONDROSAR
Page 886 and 887:
Page 888 and 889:
Page 890 and 891:
Page 892 and 893:
BONE SARCOMAS IN ADULTS local disea
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BONE SARCOMAS IN ADULTS structure a
Page 896 and 897:
SARCOMA Well-Differentiated and Ded
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ABBAS MANJI ET AL ticular region. 7
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ABBAS MANJI ET AL MYXOID (ROUND CEL
Page 902 and 903:
ABBAS MANJI ET AL versus doxorubici
Page 904 and 905:
SHLUSH AND HERSHKOVITZ Clonal Evolu
Page 906 and 907:
SHLUSH AND HERSHKOVITZ FIGURE 1. Ti
Page 908 and 909:
TUMOR BIOLOGY New Strategies to Und
Page 910 and 911:
KNAPP, DHAWAN, AND OSTRANDER in dog
Page 912 and 913:
KNAPP, DHAWAN, AND OSTRANDER TABLE
Page 914 and 915:
KNAPP, DHAWAN, AND OSTRANDER 14. Fe
Page 916 and 917:
SOURBIER, SRINIVASAN, AND LINEHAN M
Page 918 and 919:
SOURBIER, SRINIVASAN, AND LINEHAN F
Page 920 and 921:
SOURBIER, SRINIVASAN, AND LINEHAN T
Page 922:
Author Index Abbas Manji, Gulam ...
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