Handbook of Targeted Cancer Therapy and Immunotherapy

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Handbook of Targeted Cancer Therapy

and Immunotherapy Gastrointestinal Cancer

Handbook of Targeted Cancer Therapy

and Immunotherapy Gastrointestinal Cancer

Editors

Series Editors

Milind Javle, MD Professor Division of Cancer Medicine Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Mitesh J. Borad, MD Professor of Medicine Mayo Clinic College of Medicine and Science Mayo Clinic Comprehensive Cancer Center Phoenix, Arizona

Daniel D. Karp, MD Professor of Medicine Department of Investigational Cancer Therapeutics Principal Investigator of the MD Anderson Clinical & Translational Science Award (CTSA) The University of Texas MD Anderson Cancer Center Houston, Texas

Gerald S. Falchook, MD, MS Director

JoAnn D. Lim,

PharmD, BCOP Clinical Pharmacy Specialist, Phase I Division of Pharmacy Department of Investigational Cancer Therapeutics The University of Texas MD Anderson Cancer Center Houston, Texas

Drug Development Unit Sarah Cannon Research

Institute at HealthONE Presbyterian/St. Luke’s Medical Center Denver, Colorado

Acquisitions Editor: Joe Cho Development Editor: Eric McDermott Editorial Coordinator: Priyanka Alagar Marketing Manager: Phyllis Hitner Production Project Manager: Catherine Ott Manager, Graphic Arts & Design: Stephen Druding Manufacturing Coordinator: Lisa Bowling Prepress Vendor: S4Carlisle Publishing Services

This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work. This work is no substitute for individual patient assessment based upon healthcare professionals’ examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data and other factors unique to the patient. The publisher does not provide medical advice or guidance and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare professionals should consult a variety of sources. When prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use, warnings and side effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/ or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work.

All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at permissions@lww.com, or via our website at shop.lww.com (products and services).

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ISBN-13: 978-1-975162-94-8

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To my parents, Madhukar and Vimal—your love, support, and dedication have made me the man I am today. You taught me the value of education, hard work, and, most importantly, how to build a family. To my family, Michael, Sachi, and Vihan, for your patience, love, humor and for making my life complete. —Milind Javle I would like to convey my deepest gratitude for patients and their families for the privilege to help them in their cancer journey. I would also like to thank my family for their unwavering love and support. —Mitesh J. Borad

Contributors

Kavitha Balaji, PhD AstraZeneca

Arvind Dasari, MD, MS The University of Texas MD Anderson Cancer Center Timothy Philip DiPeri, MD The University of Texas MD Anderson Cancer Center Ecaterina Dumbrava, MD The University of Texas MD Anderson Cancer Center Ben George, MD Rutgers Cancer Institute of New Jersey Thorvardur R. Halfdanarson, MD Mayo Clinic Daniel M. Halperin, MD The University of Texas MD Anderson Cancer Center Nicholas James Hornstein, MD The University of Texas MD Anderson Cancer Center Ryan Huey, MD The University of Texas MD Anderson Cancer Center Filip Janku, MD, PhD The University of Texas MD Anderson Cancer Center Medical College of Wisconsin Roman Groisberg, MD

Sarah Baldwin, RN, ANP-BC, BSN, MSN The University of Texas MD Anderson Cancer Center Tamara G. Barnes, RN, MSN, CNS, AOCNS The University of Texas MD Anderson Cancer Center Laura Beatty, PA-C The University of Texas MD Anderson Cancer Center Tanios Bekaii-Saab, MD Mayo Clinic Lindsay Gaido Bramwell, MSN, RN, ACNS-BC Flatiron Health Sara Bresser, MPAS, PA-C The University of Texas MD Anderson Cancer Center Amanda Brink, DNP, APRN, FNP-BC, AOCNP The University of Texas MD Anderson Cancer Center Isabel Cepeda, MSN, RN, AGN-P The University of Texas MD Anderson Cancer Center Ian Chau, MD Royal Marsden Hospital

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Milind Javle, MD The University of Texas MD Anderson Cancer Center Daniel D. Karp, MD The University of Texas MD Anderson Cancer Center Ahmed O. Kaseb, MD The University of Texas MD Anderson Cancer Center Ed Kheder, MD The University of Texas MD Anderson Cancer Center Holly Kinahan, RN, MSN, NP-C, AOCNP The University of Texas MD Anderson Cancer Center Michael Sangmin Lee, MD The University of Texas MD Anderson Cancer Center Sunyoung S. Lee, MD The University of Texas MD Anderson Cancer Center Gregory B. Lesinski, PhD, MPH Emory University JoAnn D. Lim, PharmD, BCOP The University of Texas MD Anderson Cancer Center Shalini Makawita, MD Baylor College of Medicine Kathrina Marcelo-Lewis, PhD The University of Texas MD Anderson Cancer Center Hossein Maymani, MD Rocky Mountain Cancer Centers

Funda Meric-Bernstam, MD The University of Texas MD Anderson Cancer Center Sandra Montez, RN The University of Texas MD Anderson Cancer Center Shyamm Moorthy, PhD The University of Texas MD Anderson Cancer Center Van Karlyle Morris, MD The University of Texas MD Anderson Cancer Center Justin Moyers, MD The University of Texas MD Anderson Cancer Center University of California, Irvine College of Medicine Shubham Pant, MD The University of Texas MD Anderson Cancer Center Christine Parseghian, MD The University of Texas MD Anderson Cancer Center Amy B. Patel, MPAS, PA-C The University of Texas MD Anderson Cancer Center Maggie Phillips, BSc Emory University Rille Pihlak, MD, PhD The Royal Marsden NHS Foundation Trust Patrick Pilie, MD The University of Texas MD Anderson Cancer Center

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Kanwal Pratap Sing Raghav, MD The University of Texas MD Anderson Cancer Center

Shiraj Sen, MD, PhD Ana Stuckett, PhD

The University of Texas MD Anderson Cancer Center Gabriele Urschel, DNP, RN, FNP-C, AOCNP The University of Texas MD Anderson Cancer Center Irene S. Yu, MD The University of Texas MD Anderson Cancer Center

Matthew J. Reilley, MD University of Virginia Jordi Rodon-Ahnert, MD, PhD The University of Texas MD Anderson Cancer Center

Preface

Precision medicine, also referred to as “personalized medicine,” has led to transformative changes for patients with gastrointestinal malignancies over the past decade. The advent of next-generation sequencing, liquid biopsies, identification of cellular signaling pathways across different cancer types, and nimble mechanisms for drug development has contributed to this success. It is essential that scientific advances and novel therapeutics be easily accessible to the practicing clinician who is making quick decisions based on the clinical and molecular data. We are building on the success of Handbook of Targeted Cancer Therapy and Immunotherapy and are pleased to present a focused Handbook of Targeted Cancer Therapy and Immunotherapy: Gastrointestinal Cancer in a similar for mat. Our hope is that this book will provide a quick and easy reference guide for management deci sions in the clinic. Each chapter includes a short summary of targeted therapy approaches followed by a table of molecular targets and potential therapies as applicable to the individual cancer type along with relevant citations. We recognize that several of the proposed therapies lack level one evidence from phase III clinical trials, may need further validation, and should therefore be con sidered judiciously. Providing both a succinct and comprehensive review on different cancer types is certainly challenging, particularly when the field is changing rapidly. We were fortunate to have some of the leaders in the field coauthor this book and are extremely grateful for their contribu tions. Patients and their families are our inspiration and we look forward to making cancer history with them! Milind Javle, MD Mitesh J. Borad, MD

Acknowledgments

We are indebted to Wolters Kluwer Health for guiding us through this process and for their patience. We also thank Drs Dan Karp and Gerald Falchook for this opportunity.

Contents

Contributors �� vi Preface �� ix Acknowledgments �� x

SECTION 1 Targets by Organ Site 1 Milind Javle and Mitesh Borad, Editors

CHAPTER 1 Colorectal Cancer 2 Christine Parseghian

Targeting RAS �� 3 Cetuximab �� 3 Panitumumab �� 4 Targeting VEGF/VEGFR �� 4 Regorafenib �� 4 Bevacizumab �� 5 Targeting BRAF V600E Mutations �� 5 Targeting HER2 Overexpression �� 7 Targeting NTRK Fusions �� 8 Targeting MSI-H mCRC �� 8 Targeting Ultramutators: POLE and High Tumor Mutational Burden �� 10

CHAPTER 2 Gastric and Esophageal Cancer 18 Rille Pihlak and Ian Chau

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Introduction �� 19 HER2 �� 19 PD-L1 �� 20 FGFR �� 21 CLDN18.2 �� 21 MSI and TMB ��22 DDR Mutations ��22 Other Rare Alterations ��23

CHAPTER 3 Liver Cancer (Hepatocellular) 28 Irene S. Yu and Ahmed O. Kaseb

Introduction �� 29 Vascular Endothelial Growth Factor Pathway ��29 MET Overexpression ��30 Immune Checkpoint Inhibition ��31 Nivolumab and Combination Nivolumab/Ipilimumab ��31 Pembrolizumab �� 32 Combination Atezolizumab and Bevacizumab ��32 Combination Atezolizumab and Cabozantinib ��32 Durvalumab and Combination Durvalumab/Tremelimumab ��33 Other Immune Checkpoint Inhibitors ��33

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PI3K/AKT/mTOR Pathway ��33 Tumor Growth Factor- β Inhibition ��34 Future Directions ��34

CHAPTER 4 Biliary Tract Cancer 39 Sunyoung S. Lee and Milind Javle

Molecular Targeted Therapy ��40 IDH1 Mutation ��40 FGFR2 Gene Alterations ��40 ERBB2 (HER2) Amplification ��41 BRAF V600 ��41 Immune Checkpoint Blockade ��42 Michael Sangmin Lee, Tanios Bekaii-Saab, and Shubham Pant Introduction ��47 Germline Mutations Impacting DNA Damage Repair Pathways ��47 Microsatellite Instability ��48 KRAS Oncogenic Mutations and Targeting ��50 Genomic Aberrations Enriched in KRAS Wild-Type Cancers ��51 Additional Targetable Aberrations ��52

CHAPTER 5 Pancreatic Cancer 46

CHAPTER 6 Rare Gastrointestinal Tumors 55 Van Karlyle Morris and Ben George

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Anal �� 56 Genomic Biomarkers �� 56 Immune Biomarkers �� 57 Small Bowel Cancers �� 59 Appendiceal Cancer �� 60 Malignant Peritoneal Mesothelioma �� 65 Nicholas James Hornstein, Ryan Huey, and Kanwal Pratap Sing Raghav Introduction �� 70 Epidemiology and Prognosis �� 70 Molecular Profiling and Tissue (Site) of Origin �� 72 Empiric Treatment in CUP �� 74 Molecular Profiling and Targeted/Immune Therapy �� 74 Approved Targeted/Immune Therapies for CUP �� 76 Daniel M. Halperin and Thorvardur R. Halfdanarson Classification �� 80 Targeted Therapies �� 80 Immunotherapy �� 82 Conclusion �� 82

CHAPTER 7 Cancer of Unknown Primary 69

CHAPTER 8 Neuroendocrine Cancer 79

SECTION 2 Sequencing Technologies 85 Milind Javle, Editor CHAPTER 9 Introduction of High-Throughput Sequencing 86 Timothy Philip DiPeri and Funda Meric-Bernstam

Introduction �� 87 Sequencing the Cancer Genome �� 87 Detection of Genomic Alterations �� 88 Unveiling the Transcriptome �� 90 Personalized Cancer Therapy �� 91 Conclusion �� 92

CHAPTER 10 Liquid Biopsies in Gastrointestinal Cancers 93 Shalini Makawita and Arvind Dasari

Introduction �� 94 Colorectal Cancer �� 96 Pancreatic Cancer �� 101 Gastric Cancer �� 102 Hepatobiliary �� 103 Challenges to Liquid Biopsies �� 103

CHAPTER 11 Immune Landscape of Gastrointestinal Malignancy 105 Maggie Phillips and Gregory B. Lesinski Introduction �� 106 The Microenvironment of GI Tumors Harbors Cellular Complexity �� 106 Inflammation Shapes the Immunologic Profile of GI Tumors �� 108 Cytokines and Chemokines Perpetuate the Inflammatory Nature of GI Tumors �� 108 Redundant Mechanisms of Immune Suppression Are Evident in GI Tumors �� 110 T-Cell Intrinsic Mechanisms Can Limit Antitumor Immune Responses �� 110 T-Cell Extrinsic Mechanisms Hinder Immunity against GI Malignancy �� 111 CAFs: At the Crossroads of Communication between Tumor and Immune Cells �� 114 Future Areas of Emphasis for Advancing Our Understanding of GI Tumor Immunology �� 115 Kavitha Balaji, Ecaterina Dumbrava, Roman Groisberg, Filip Janku, Daniel D. Karp, Ed Kheder, Kathrina Marcelo-Lewis, Hossein Maymani, Sandra Montez, Shyamm Moorthy, Patrick Pilie, Matthew J. Reilley, Jordi Rodon-Ahnert, Shiraj Sen, and Ana Stuckett, Contributors An Introduction to the Organization of Cancer Cell Signaling �� 118 Signal Transduction Roadmap �� 119 VEGF and VEGFR �� 121

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SECTION 3 Molecular Targets and Pathways 117 Ecaterina Dumbrava and Jordi Rodon-Ahnert, Editors

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FGF and FGFR �� 123 PDGF and PDGFR �� 125 Angiopoietin and TIE Receptors �� 127 IGFR and Insulin Receptors �� 129 Targeting IGFR and Insulin Receptors �� 131 TGF a /SMAD �� 132 EGFR �� 135 EGFR Signaling �� 137 HER2 (Also Known as ERBB2) �� 139 MET (Also Known as HGF Receptor) �� 141 RET Receptor �� 143 ALK Receptor �� 145 KIT Receptor �� 147 ROS Receptor �� 148 Receptor Tyrosine Kinases (Activation Cascade) �� 149 Cell Signaling Pathways Rapamycin and Its Mammalian Target (mTOR) �� 151 PI3K-AKT-mTOR Pathway ��153 PI3K, AKT, PTEN, TSC in Cancer ��155 mTORC 1 , 2 �� 158 NF-Kappa B—Master Immune Regulator �� 159 NF- κ B Pathway �� 160 G-Protein-Coupled Receptors �� 161 Mitogen-Activated Protein Kinase (MAPK) �� 163 RAS/MAPK Pathway �� 164 Targeting BRAF/MEK �� 166 Rous Sarcoma Virus Oncogene (SRC) �� 167 SRC Pathway �� 168 β -Catenin–Cell Adhesion �� 170

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Wnt Pathway �� 171 Fruit Fly Mutations and Related Genes �� 173 Hedgehog Pathway �� 174 NOTCH Pathway �� 177 B-Cell Lymphoma 2 (BCL-2)/Cysteine Aspartates (CASPASES) �� 179 Janus Kinase and Signal Transducer and Transcription �� 180 JAK/STAT Pathway �� 181 Apoptosis (Greek—“Leaves Falling from a Tree”) �� 184 Death Receptors (DRs) and Apoptosis �� 185 Nuclear Factors and DNA Repair �� 188 TP53: Master Cell Cycle Regulator �� 189 Cell Regulation by RB1, CDKs �� 191 DNA Damage Response �� 193 Aurora Kinase �� 195 Overview of Angiogenic Signaling �� 196 Angiogenesis: A Hallmark of Cancer �� 197 Angiogenesis Regulators �� 199 Immunotherapy �� 200 Management of Immune-Related Adverse Events (irAEs) �� 207 Epigenetics �� 214 Targeting Epigenetics �� 216 Antibody Drug Conjugates (ADCs) Have Variable “Payloads” and Multiple Microenvironmental Targets �� 217 Tropomyosin-Related Kinases �� 219 Metabolism: Glycolysis and the TCA Cycle �� 221 Targeting Cancer Metabolism �� 222

SECTION 4 Targeted and Immunotherapy Agents 223 JoAnn D. Lim and Justin Moyers, Editors Sarah Baldwin, Tamara G. Barnes, Laura Beatty, Sara Bresser, Amanda Brink, Isabel Cepeda, Lindsay Gaido Bramwell, Holly Kinahan, JoAnn D. Lim, Justin Moyers, Amy B. Patel, and Gabriele Urschel, Contributors

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Color Key ��224 Abbreviations �� 225 Adagrasib �� 228 Afatinib Dimaleate ��228 Alectinib �� 229 Apatinib �� 229 Atezolizumab �� 230 Avelumab �� 230 Axitinib �� 231 Bemarituzumab �� 231 Bevacizumab �� 232 Binimetinib �� 232 Cabozantinib �� 233 Cetuximab �� 233 Crizotinib �� 234 Dabrafenib �� 234 Durvalumab �� 235 Encorafenib �� 235

Entrectinib ��236 Erdafitinib ��237 Erlotinib ��237 Everolimus ��238 Futibatinib ��239 Galunisertib ��239 Infigratinib ��239 Ipilimumab ��240 Ivosidenib ��241 Lapatinib Ditosylate ��241 Larotrectinib ��242 Lenvatinib Mesylate ��242 Lutetium Lu 177 Dotatate ��243 nab-Rapamycin ��243 Nivolumab ��244 Octreotide acetate ��244 Olaparib ��245 Panitumumab ��245 Pazopanib Hydrochloride ��246 Pembrolizumab ��246 Pemetrexed ��247 Pemigatinib ��247 Pertuzumab ��247 Pralsetinib ��248 Ramucirumab ��248 Regorafenib ��249 Retifanlimab ��249 Rucaparib Camsylate ��250

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Sintilimab �� 250 Sirolimus �� 251 Sorafenib �� 251 Sotorasib �� 252 Sunitinib �� 252 Surufatinib �� 252 Temsirolimus �� 253 Tislelizumab �� 253 Trametinib �� 254 Trastuzumab �� 254 Fam-trastuzumab Deruxtecan ��255 Tremelimumab �� 255 Vemurafenib �� 256 Zenocutuzumab �� 256 Zolbetuximab �� 257

Index �� 258

SECTION 2 Sequencing Technologies

CHAPTER 9 Introduction of High-Throughput Sequencing

Timothy Philip DiPeri and Funda Meric-Bernstam

87 Introduction At the turn of the millennium, one of the largest breakthroughs in contemporary med ical science was announced—the majority of the human genome had been sequenced, unveiling a new road map for human biology (1). Over the past two decades, sequencing technolo gies have advanced at a rapid pace, which has had broad implications for the detection and treat ment of human disease (2). The field of oncology has been at the forefront of these developments, considering the relevance of genetics in cancer. High-throughput sequencing, or next-generation sequencing (NGS), has made comprehensive molecular profiling of cancers feasible and has pro foundly changed our understanding of human tumor biology (3). Although NGS was once considered cost-prohibitive and utilized sparingly for research efforts, it is now commonplace in oncology practices (4). This has given rise to the era of precision oncology, which refers to a personalized approach to cancer medicine by using an individual tumor’s molec ular characteristics to guide therapeutic decision-making (5). Rapid identification of alterations in cancer-related genes, which may have diagnostic, prognostic, and/or therapeutic relevance, has revolutionized modern cancer care. In this chapter, we will introduce high-throughput sequencing by reviewing the historical context into the sequencing of the cancer genome, discussing platforms to detect alterations within the genome and transcriptome, how high-throughput sequencing data can be leveraged for the treatment of cancer patients, and challenges with integrating these data into clinical practice. Sequencing the Cancer Genome Shortly after completion of the Human Genome Project, several international efforts were launched to comprehensively profile a diverse set of cancers and to gain insight into tumorigenesis, most notably The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) (6,7). Although many oncogenic drivers/tumor suppressors had previously been identified, it was clear that an understanding of the spectrum of genomic aberrations that drive cancers was imper ative. The vision for the TCGA project, as put forth by the National Institutes of Health (NIH), was ambitious—multiple centers and a vast array of multiomics approaches were utilized to molecu larly profile > 30 different tumor types (8). Methods to acquire these data included RNA sequencing

88 (RNASeq), micro RNA sequencing (miRNASeq), DNA sequencing (DNASeq), single- nucleotide polymorphism (SNP)-based platforms, and array-based DNA methylation sequencing for nucleic acid sequencing, as well as reverse-phase protein array (RPPA) for proteomic assessment (6). Subsequently, the TCGA Pan-Cancer project was im plemented and sought to further analyze the molecular profiles of individual tumors, as well as compare genetic aberrations between tumor types (8). Similarly, the ICGC characterized > 50 cancer types, with the goal of discovering highly prevalent mutations, standardizing reporting methods on an international scale, providing granular data at the single-nucleotide level, and to make this data publicly accessible (7). Progress in the field of cancer biology that has stemmed from these efforts cannot be over stated. The field of oncology was previously predominated by a tumor-centric approach to treat ment, but it is now evident that tumors with vastly different origins can have overlapping molecular drivers, and often tumors of the same origin are molecularly distinct (8). Publicly available data from the TCGA and ICGC have allowed researchers around the globe to make progress in iden tifying biomarkers, discovering new targets for therapy, and providing an opportunity to develop bioinformatics tools to better understand the available data, which will ultimately improve the care of cancer patients (6). Detection of Genomic Alterations High-throughput DNASeq can be performed using several molecular biology techniques, including cyclic reversible termination, pyrosequencing, synthesis by ligation, and real-time sequencing (9). Sequences determined by these assays are then mapped onto the human reference genome using bioinformatics tools, which enables the calling of single-nucleotide variants, insertions/deletions, fusions, and copy number variations (Figure 9.1). These NGS technologies are advantageous over first-generation Sanger sequencing, considering that the volume of data that can be produced with one run can exceed 1 billion short reads (9). Tissue input for these assays includes solid tumor tissue, individual tumor cells, and plasma (liquid biopsy). Although fresh frozen tissue provides ad equate tissue for performing NGS, samples are often formalin fixed and paraffin embedded (FFPE), which can lead to the degradation of both DNA and RNA (10). Despite these limitations, most mod ern NGS platforms can utilize FFPE tissue for sequencing analysis.

Figure 9.1

Flowchart of genomic and transcriptomic assessment using NGS. DNA, deoxyribonucleic acid; Mb, megabase; NGS, next-generation sequencing; RNA, ribonucleic acid.

Tissue Input for NGS

Whole tumor sample Single tumor cell Plasma (liquid biopsy)

DNA Sequencing

RNA Sequencing

Targeted sequencing Small/large panel testing Whole-exome/genome sequencing

Gene Expression Signatures Splice variant expression

Somatic Alterations

Pathway under-/overexpression

Single-nucleotide variations Copy number alterations Insertions/deletions

Expression of Oncogenes/Tumor Suppressor Genes

Tumor Mutational Burden

Number of mutations/Mb

Expression of Deleterious Variants

Germline Variants

Gene Fusions

Novel/oncogenic fusions Fusion transcript expression

90 Several NGS platforms have emerged, which may be encountered by oncologists, including commercially available/adapted platforms, institutionally developed plat forms, and research-based platforms. Sequencing platforms vary widely and may refer to targeted and small panels of < 100 genes, large panels of > 100 genes, whole-exome sequencing (WES)/whole-genome sequencing (WGS), and RNASeq. Many commercial platforms have emerged for tumor or tumor-normal sequencing, including FoundationOne CDx, Caris CDx, TempusXT, and Oncomine Comprehensive Assay (11). Some institutions have also adapted these assays for in-house profiling efforts, whereas others have developed their own sequencing plat forms, such as the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform, which is a hybridization capture–based assay (12). WES and WGS are still less frequently performed but provide additional data that are not confined to genes cov ered on a single panel and are often used in a research-based setting. With the increasing prevalence of large panel testing in oncology, a question that is often en countered in practice is whether or not an alteration is germline (present in all or most tissue) or somatic (present in tumor cells but not in other tissues). Importantly, panels are not able to distin guish if a variant is germline or somatically acquired, if tumor-only testing was performed, rather than tumor paired with a matched normal sample (such as blood). Additionally, when germline variants are identified, there is a lack of consensus on which genes may warrant germline-focused analysis and, furthermore, what degree of penetrance is required to determine cancer risk. Groups such as the European Society of Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) have established guidelines for germline-focused analysis to allow oncologists to navigate

these challenging clinical questions (13). Unveiling the Transcriptome

Transcriptomics is broadly defined as the analysis of messenger RNA (mRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), micro RNA (miRNAs), and long non-coding RNAs (ncRNAs). High-throughput transcriptional sequencing by RNASeq gives precise details on base pair sequences and additional RNAs that cannot be identified with the conventional microarray technology (14). Following the isolation of RNA from a given tissue, it is then converted to complementary DNA (cDNA) by reverse

91 transcription and further amplified by polymerase chain reaction (PCR) to allow for the detection of RNA sequences (15). The clinical utility of transcriptional profiling is evolv ing and is a component of tumor biology that should be taken into consideration in parallel with genomic profiling efforts. RNASeq is advantageous as it can allow for the detection of unique isoforms/splice variants, gene expression signatures, and fusions/rearrange ments (14). Differential gene expression in cancer pathways can have downstream effects that potentiate tumor growth, often without corresponding genomic alterations, which may highlight avenues for therapeutic intervention (16). In addition to gene expression signatures, RNASeq also can identify gene fusions and fusion transcript expression, which have prognostic, and diagnostic, implications and have been emerging as some of the most compelling therapeutic targets in preci sion oncology (16). Personalized Cancer Therapy Progress in the field of genomic medicine has profoundly improved our understanding of cancer biology and ushered in the era of precision oncology. NGS is now routinely performed at both academic and community cancer centers and can inform oncologists of which molecular char acteristics are driving a tumor that may have therapeutic relevance. Early successes in preci sion oncology are highlighted by the benefits of trastuzumab in HER2-positive breast cancer (17) and vemurafenib in BRAF V600E mutant melanoma (18), among others. A study from the MD Anderson Cancer Center identified that in a phase I setting, patients treated with molecularly matched therapies had an improved overall response rate (27%) in comparison to those who received non-matched therapies (5%) (19). The phase II MyPathway study investigated if U.S. Food and Drug Administration (FDA)-approved therapies had activity across 14 different tumor types, and identified meaningful responses in 23% of patients with metastatic solid tumors when matched with agents outside of their FDA-approved indications (20). These findings are promis ing for cancer therapeutics, though a remaining challenge is the lack of FDA-approved therapies for most alterations. Basket trials are a way to address this concern through a tumor-agnostic approach to enrollment, which can facilitate the evaluation of matched therapies in patients with less common alterations.

92 The surplus of data acquired from broad-based sequencing efforts poses a set of new challenges for oncologists—how can this information be best incorporated into clinical practice to improve outcomes for patients? A survey of physicians at a National Can cer Institute (NCI)-designated comprehensive cancer center identified that physicians have varying levels of confidence regarding the incorporation of genomic data into practice (21). Although many genes have been identified that have prognostic and/or therapeutic relevance, there is a knowledge gap in determining if a particular alteration is a “driver” or “passenger,” and which alterations may be clinically “actionable,” meaning that they may be targeted directly or indirectly with investigational or approved agents (22). Integration of NGS data requires not only the accurate detection of genomic alterations but also an understanding of the clinical implications associated with an alteration, and awareness of trials that the patient may be eligible for (22). Furthermore, ac cess to both multiplex genomic profiling and molecularly targeted therapies varies widely by insti tution (23). A study by Meric-Bernstam et al. reported that few patients with actionable alterations were ultimately enrolled in genotype-matched trials (23). Efforts to address these concerns include decision support programs to assess if a variant is actionable and/or affects eligibility criteria for an ongoing clinical trial (24). Several publicly available precision oncology resources have also been established to help provide insight into the actionability of alterations, including the MD Anderson Personalized Cancer Therapy website (www.personalizedcancertherapy.org) (25), the Cornell Pre cision Medicine Knowledge Base (PMKB) website (https://pmkb.weill.cornell.edu/) (26), and the Memorial Sloan Kettering OncoKB website (https://www.oncokb.org/) (27). These findings high light the need for institutional, programmatic efforts to implement decision support for precision oncology to facilitate the enrollment of patients with actionable alterations into clinical trials. Conclusion High-throughput sequencing has revolutionized modern cancer care and enabled oncologists to routinely profile tumors in clinical practice. Clinical integration of genomic and transcriptomic data obtained from NGS is evolving, and decision support programs can be utilized to assess the functionality of a given aberration, which may facilitate clinical trial enrollment.

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