Therapeutic. Handbook of. Biomarkers

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3 Therapeutic Handbook of Biomarkers IN CANCER

6 Published by Pan Stanford Publishing Pte. Ltd. Penthouse Level, Suntec Tower 3 8 Temasek Boulevard Singapore editorial@panstanford.com Web: British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Handbook of Therapeutic Biomarkers in Cancer Copyright 2013 by Pan Stanford Publishing Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the publisher. For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy is not required from the publisher. ISBN (Hardcover) ISBN (ebook) Printed in the USA

7 Contents Preface xix 1. Overview: Therapeutic Biomarkers in Cancer 1 Sherry X. Yang and Janet E. Dancey 1.1 Introduction Classification of Therapeutic Biomarkers Chemotherapy Agents and Therapeutic Biomarkers Targeted Cancer Therapeutics and Biomarkers Targeted Cancer Therapeutics Biomarker Validation Therapeutic Biomarkers of Targeted Therapy Direct drug targets as therapeutic biomarkers Indirect drug targets as therapeutic biomarkers Anti-angiogenesis therapy and biomarkers Targeted Therapeutics in Combination with Chemotherapy and Therapeutic Biomarkers Multi-Gene Expression or Signatures for Cancer Prognosis and Treatment Diagnostic Techniques for Therapeutic Biomarkers Conclusions and Perspectives Statistical Considerations in the Development and Evaluation of Therapeutic Biomarkers in Cancer 31 Lisa M. McShane, Edward L. Korn, and Boris Freidlin 2.1 Introduction Analytical Performance of a Biomarker-Based Test Prognostic versus Predictive Biomarkers 37

8 vi Contents 2.4 Biomarker Evaluations in Phase I Trials Biomarker Evaluations in Phase II Trials Designs Involving Single Biomarkers Designs Involving Multiple Biomarkers Biomarker Evaluations in Phase III Trials Biomarker-Stratified Designs Enrichment Designs Biomarker-Strategy Designs Designs in Which the Biomarker Has Not Been Completely Specified Summary Role of Biomarkers in Clinical Development of Cancer Therapies 59 Helen X Chen 3.1 Introduction A Few Definitions and General Concepts Role of Biomarkers in the Different Stages of Drug Development Use of PD Markers in Phase I and Early-Stage Proof of Principle Studies Role of PD markers in verifying target engagement Role of PD markers in decisions on the recommended phase II dose (RP2D): value and limitations Use of distal PD markers to measure the biological and molecular consequences of target inhibition Incorporation and Exploration of Patient Selection Markers in Early Clinical Trials Trial design for patient selection markers Scientific and technical challenges of predictive markers Conclusions and Future Directions 73

9 Contents vii 4. HER-2 as a Prognostic and Predictive Biomarker in Cancer 77 Suparna B. Wedam and Stanley Lipkowitz 4.1 Introduction Biology of HER HER-2 Amplification and Overexpression: Methods of HER-2 Measurement HER-2 Amplification as a Prognostic Biomarker in Breast Cancer HER-2 Amplification as a Predictive Biomarker for Response to HER-2 Targeted Agents in Breast Cancer Trastuzumab Lapatinib Pertuzumab HER-2 Amplification as a Predictive Biomarker for Response to Chemotherapy in Breast Cancer HER-2 Amplification as a Predictive Biomarker for Response to Hormonal Therapy in Breast Cancer Serum HER-2 Extracellular Domain (ECD) as a Biomarker in Breast Cancer HER-2 Amplification as a Prognostic Biomarker and a Predictive Biomarker for Response to HER-2 Targeted Agents in Other Cancers Gastric Cancer Ovarian Cancer Non-Small Cell Lung Cancer (NSCLC) Transitional Cell Carcinoma (TCC) of the Urothelium Colorectal Cancer Other Tumors Conclusions Hormone Receptors and Endocrine Therapy in Breast Cancer 121 Sherry X. Yang 5.1 Introduction Biology of Hormone Receptors 122

10 viii Contents 5.3 ER/PgR as Prognostic and Therapeutic Biomarkers ER and PgR as Prognostic Factors in Breast Cancer ER and PgR as Therapeutic Biomarkers in Breast Cancer ER/PgR Targeted Therapy for Breast Cancer Adjuvant Endocrine Therapy Premenopausal patients Postmenopausal patients Endocrine Therapy for Recurrent and Metastatic Disease Neoadjuvant Endocrine Therapy Endocrine Therapy Resistance Diagnostic Tests for ER and PgR Methods for Evaluation of ER/PgR Expression Immunohistochemical Testing for ER and PgR Conclusions Predictive Biomarkers for Epidermal Growth Factor Receptor Agents in Non-Small Cell Lung Cancer 155 John Hilton, Penelope A. Bradbury, and Janet Dancey 6.1 Introduction The Epidermal Growth Factor Receptor Family Signal Transduction Pathways Controlled by the Activation of EGFR EGFR Inhibitors for the Management of NSCLC Activating EGFR Receptor Mutations Biomarkers for Acquired Resistance to EGFR TKIs EGFR Gene Amplification and Increased Protein Levels K-Ras Mutations and Anti-EGFR Therapy EGFR Ligands Polymorphism Studies and Anti-EGFR Therapy Circulating Tumor Cells in NSCLC Biomarker Research Conclusions 174

11 Contents ix 7. Markers of Sensitivity and Resistance to EGFR Inhibitors in Colorectal Cancer 183 Jose G. Monzon and Janet Dancey 7.1 Introduction The Epidermal Growth Factor Receptor (EGFR) Pathway and Colorectal Cancer RAS/RAF/MAPK Pathway PI3K/AKT Pathway EGFR Inhibitors Used in Metastatic Colorectal Cancer (mcrc) Determinants of Sensitivity and Resistance to EGFR Targeting moabs Clinical Features EGFR inhibitor induced-skin rash Potential predictive Genetic Alterations of the EGFR pathway in patients with mcrc KRAS mutations KRAS mutation detection Specimen selection for KRAS mutation testing Prognostic significance of KRAS mutation status Predictive significance of KRAS mutation status BRAF mutations in patients with mcrc BRAF mutation detection in patients with mcrc Specimen selection for BRAF mutation testing Prognostic and predictive role of BRAF mutations KRAS Let-7 single nucleotide polymorphism Genetic Mutations Affecting the EGFR Gene Somatic EGFR gene mutations EGFR gene copy number 208

12 x Contents Measuring EGFR gene copy number Specimen selection for EGFR gene copy number Prognostic value of EGFR gene copy number Predictive role of EGFR gene copy number PIK3CA mutations Measuring PIK3CA mutations Specimen selection for PIK3CA mutation testing Predictive role of PIK3CA mutation testing Potential Predictive Alterations in Gene Expression of the EGFR Pathway EGFR protein expression EGFR ligands: amphiregulin and epiregulin PTEN loss of expression Measuring PTEN expression Predictive role of loss of PTEN expression Future Directions Targeting BCR-ABL for Molecular Therapy of Chronic Myelogenous Leukemia 233 Shamudheen Rafiyath, Guoqing Wei, and Delong Liu 8.1 Pathogenesis Structure of BCR-ABL Mechanism of CML Essential Features of BCR-ABL Targeted Therapies of Chronic Myeloid Leukemia First-Generation Tyrosine Kinase Inhibitors Imatinib mesylate Monitoring 240

13 Contents xi Toxicity Imatinib resistance Mutation analysis Second-Generation Tyrosine Kinase Inhibitors Dasatinib Nilotinib Management of Resistance to First-Line TKIs Bosutinib Bafetinib (INNO-406) Future Horizons in the Treatment of CML T315I Kinase Inhibitors Aurora Kinase Inhibitor Omacetaxine Mepesuccinate Conclusions and Future Directions Gastrointestinal Stromal Tumors: From Molecular Pathogenesis to Therapy 267 Joaquina Baranda, Rashna Madan, and Andrew K. Godwin 9.1 Introduction Molecular Pathogenesis of GIST Mutations in RTKS: KIT Mutations in RTKs: PDGFRA BRAF Mutation Hereditary, Syndromic and Variant GISTs Hereditary/Familial GISTs Neurofibromatosis I (NF1)-Associated GISTs Carney s Triad-associated GISTs Carney Stratakis Syndrome (Carney s Dyad) Pediatric GISTs Risk Assessment Treatment of GIST Imatinib Mesylate Efficacy of imatinib in patients with advanced GIST Dose and efficacy 279

14 xii Contents Duration of therapy Management of toxicities Sunitinib Management of sunitinib toxicities Sorafenib and Other Tyrosine Kinase Inhibitors Assessment of response to therapy Adjuvant therapy Biomarkers That Predict Benefit, Response, and Resistance to Therapy Response predictors in GIST Imatinib plasma levels Drug interactions Imatinib resistance and intolerance Benefit of imatinib as a function of risk stratification Molecular biomarkers of therapeutic response Summary PML/RARα Fusion Gene and Response to Retinoic Acid and Arsenic Trioxide Treatment 313 Alicja M. Gruszka and Myriam Alcalay 10.1 Introduction Description of Acute Promyelocytic Leukaemia Modern Therapeutic Approaches Treatment Complications and Prognosis Molecular Pathogenesis Translocation (15;17) and Cloning of the Fusion Gene Partner Genes and Their Physiological Function Mechanisms of Action of PML/RARα Global transcriptional repression 319

15 Contents xiii Transcriptional activation Deregulation of other haematopoietic transcription factors Protein misfolding Consequences of the Expression of PML/RARα Differentiation block Enhanced self-renewal Apoptosis resistance The Role of Cooperating Mutations Mechanisms of Action of ATRA and Arsenic Trioxide Mechanisms of ATRA Action Mechanisms of Arsenic Trioxide Action Synergy Between ATRA and Arsenic Trioxide Conclusions Dihydropyrimidine Dehydrogenase Deficiency and 5-Fluorouracil Toxicity 337 Eva Gross and André B. P. van Kuilenburg 11.1 Introduction Variability of the DPYD Gene Epigenetic and Non-Genetic Effects on DPYD Dysregulation Functional Testing of the DPD Status Conclusion UGT1A1 Polymorphisms and Mutations Lead to Irinotecan-Induced Toxicity 353 K. M. Reece and W. D. Figg 12.1 Irinotecan The UGT1A Gene Complex Pharmacogenetics of UGT1A Ethnic Differences in UGT1A1 Variants Crigler Najjar Syndrome Gilbert s Syndrome Conclusion 363

16 xiv Contents 13. The 21-Gene Recurrence Score and Benefit of Chemotherapy in Estrogen Receptor-Positive Breast Cancer 369 Petra Rietschel and Joseph A. Sparano 13.1 Introduction Genomics Development and Validation of Multiparameter Assays Development of the 21-Gene Recurrence Score Recurrence Score and Prognosis Recurrence Score and Prediction of Chemotherapy Benefit Impact of RS on Clinical Decision Making Gene Expression Profiles and Expert Panels Prospective Clinical Trials Evaluating Multiparameter Assays Conclusion MammaPrint for Individualized Recurrence Risk Assessment and Treatment Recommendations for Early-Stage Breast Cancer Patients 387 Sonal J. Desai and Tianhong Li 14.1 Introduction Discovery of MammaPrint Retrospective Clinical Validation Analytic Development for MammaPrint as a Diagnostic Test Prospective Clinical Validation of MammaPrint Biologic Implication of MammaPrint Results Understanding of Tumor Biology Revealing New Therapeutic Targets Prediction for Response or Resistance to Chemotherapy Elucidation of Resistant Mechanisms to Chemotherapy Potential Advantages of MammaPrint as a Prognostic Test Challenges in Clinical Application of MammaPrint Summary and Perspectives 408

17 Contents xv 15. BRCA Mutation and PARP Inhibitors 417 Marcie K. Weil, Shivaani Kummar, James H. Doroshow, and Alice Chen 15.1 Introduction BRCA Poly (ADP-Ribose) Polymerase (PARP) PARP Inhibitors as Single Agents to Induce Synthetic Lethality in BRCA Tumor Cells PARP Inhibitors in Combination with Cytotoxic Therapy PARP Inhibitors in Combination with Ionizing Radiation (XRT) Clinical Development of PARP Inhibitors Olaparib (AZD 2281, KU ) BRCA-mutation ovarian cancer and olaparib BRCA-mutation associated breast cancer and olaprib Veliparib (ABT888) BRCA breast and ovarian cancers and TNBC with veliparib Rucaparib (AG014699, PF ) Iniparib (BSI 201, NSC ; IND-71677) Niraparib (MK 4827) Acquired Resistance to PARP Inhibitors Future Directions EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer 449 Vimal Patel and Biren Saraiya 16.1 Introduction The Identification of EML4-ALK in NSCLC The Structure and Function of EML The Structure and Function of ALK The ALK Gene Rearrangements in Cancer The Structure of EML4-ALK and Other Non-EML4 Translocation Partners 454

18 xvi Contents The Transforming Activity of EML4-ALK Clinical and Pathologic Features of EML4-ALK Methods of Detection Reverse Transcriptase-PCR Based Detection Immunohistochemistry Based Detection Fluorescence in situ Hybridization Based Detection Potential Concerns Independent of the Method of Detection Outcomes with Current Standard NSCLC Therapies Preclinical ALK Targeted Therapies in NSCLC Clinical Studies with Crizotinib Resistance to Crizotinib and Emergence of New ALK Inhibitors Future Directions BRAF-Targeted Therapy in Metastatic Melanoma 473 Noori Kim and April Deng 17.1 Introduction BRAF and the MAPK Pathway BRAF V600E Mutation in Melanoma Sorafenib and PLX Other RAF Inhibitors BRAF Inhibition Resistance Mechanisms The Role of RAF Isoforms The Role of IGF-1R and PI3K-AKT Pathway Amplification of Cyclin-Dependent Kinase The Role of Growth Factors The Role of Cytokines Final Thoughts 485 Index 491

19 Preface The advent of the era of the molecularly targeted therapy in oncology in addition to conventional multimodality management signifies more hope for cancer patients. The discovery, validation, and clinical applications of biomarkers of prognosis and prediction are advancing the promise of personalized medicine. The clinically validated therapeutic (predictive) biomarkers for targeted and chemotherapy agents approved for use or having potential to be approved by the regulatory agencies such as the United States Food and Drug Administration facilitate the evolution of empiric therapy to individually tailored treatment. In essence, therapeutic biomarkers and appropriately validated clinical assays facilitate treatment decision-making. We have clearly entered the epoch that patients can receive the right drugs with the right doses at the right time with greater assurance of maximal benefits and reduced risks. In editing and organizing the Handbook of Therapeutic Biomarkers in Cancer, we have made every attempt to cover the growing numbers of promising predictive biomarkers and associated assays in the fields of oncology and cancer research. We hope that many readers oncologists, health professionals, patients, scientists involved in basic, translational, and clinical research, educators, and students both medical and undergraduate will find each chapter of this book a valuable source of information and guidance. It has been a great privilege to be involved in editing this book. We express our sincere thanks to all authors who have contributed their expertise, experience, and hard work to this book for publication. In addition, we welcome comments for planning future editions. Sherry X. Yang Janet E. Dancey

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