Handbook of Therapeutic Biomarkers in Cancer

Sherry X. Yang, Janet E. Dancey, Sherry X. Yang, Janet E. Dancey

• Publisher: Jenny Stanford Publishing
• Year: 2021
• Print ISBN: 9789814877008
• eBook ISBN: 9781000367539
• Edition: 2
• Topic: Medicine
• Subtopic: Immunology

This book provides a comprehensive overview of the fast-evolving subject of clinical application of cancer therapeutic biomarkers. The second edition captures significant progress of cancer immunotherapy and emphasizes the genetic basis for selective cancer treatment. It covers an in-depth insight on biomarkers across a broad area of cancer research and oncology with a wealth of integrated genetic and molecular information about specific therapies by a multidisciplinary team of internationally recognized experts. Each chapter focuses on a class of targeted, immunologic, or chemotherapy agents and their companion biomarkers that predict response, benefit or resistance, and severe adverse event. The book will serve as a handbook for health professionals and scientists on the current applicable biomarkers in the management of cancer. The vision into the systemic classification and statistical consideration of therapeutic biomarkers summarized by the book editors and chapter authors will help advance precision medicine—a precisely tailored cancer treatment strategy for cancer patient care.

Chapter 1

Overview of Therapeutic Biomarkers in Cancer

Sherry X. Yang^a and Janet E. Dancey^b

^aDivision of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA

^bCanadian Cancer Trials Group, Queen’s University, 10 Stuart Street, Kingston, Ontario, K7L3N6, Canada [email protected], [email protected]

Cancer affects people of all ages and remains one of the leading causes of death worldwide. About 1.8 million new cancer diagnosis, and 606, 520 cancer death are expected to occur in 2020 in the United States [1]. Encouragingly, a significant reduction of cancer death has been achieved over the past two to three decades [2]. Overall cancer mortality rate continues to decline in men, women and children [3].

The achievement is attributed to our growing understanding of cancer genetics and biology, cancer prevention, and improvements in cancer diagnosis and treatment. An expanding body of molecular solutions in the treatment of cancer has led to a tailored management. These have created significant needs for predictive (therapeutic) biomarkers as companion diagnostics to identify subsets of patients who are most likely or unlikely to benefit or distinguish those at high risk for serious side effects from a treatment. This book covers current advances on the therapeutic biomarkers that predict response, benefit, or adverse events from a given antineoplastic treatment and, to a lesser degree, on biomarkers of prognosis that influence the choice of treatments. This review volume, in general, does not cover markers for cancer diagnosis, staging of any cancer types, and classification of extent of disease or disease monitoring. Each chapter provides a comprehensive overview of the molecular target or genetic alteration, a class of anti-cancer drugs and in-depth insights of the relevant therapeutic biomarkers.

1.1 Introduction

A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological or pathologic process, and pharmacologic response to a therapeutic intervention [4, 5]. The biomarkers can be genetic aberrations including gene mutation and amplification or chromosomal aberrations, amino and nucleic acids, lipids, carbohydrates, proteins, cells, enzymes or hormones, which are measured through a type of tests such as genomic, biochemical or immunologic. A prognostic factor provides information about overall clinical outcome irrespective of therapy, and a predictive marker predicts differential effect of a therapeutic intervention [6]. The latter is frequently utilized in making treatment recommendations, and thus is also referred to as a therapeutic biomarker. It serves as an indicator of likelihood of benefit, at risk developing severe adverse events, or chance of response or resistance. For example, breast cancer patients with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive tumors—hormone receptor (HR) positive—most likely respond to and benefit from endocrine therapy, whereas patients with HR-negative tumors derive little benefit. Over the past 5 years, matching treatment to a molecular target or genetic aberration—precision medicine—has entered the central stage for the treatment of cancer in clinical trials and in the clinic. The type of treatment leads to more efficacy, longer duration of remission, and survival in a larger proportion of patients, as compared to about 25% with chemotherapy. Hence, therapeutic biomarkers aid in selection of which patient receives or spares from a treatment or receives a normal or lower dose of a drug before initiation of treatment.

It is widely recognized in oncology that genetic basis of cancer is important as to whether a patient will derive benefit or a greater benefit. Since the publication ofthe first edition in 2013, an increasing number of companion biomarkers in the context of drug label related to the germ-line, somatic gene mutations or polymorphisms, difference in gene expression, and chromosomal abnormalities have been approved by the US Food and Drug Administration (FDA) and other drug regulatory agencies in other countries. In this edition, progress has been made on the therapeutic biomarkers and their companion therapy (Tables 1.1 and 1.2).

Table 1.1 Therapeutic biomarkers and their companion cancer therapy by chapter

Bio marker	Application	Drug^*	Chapter
ALK and ROS1 positivity	Treatment with ALK kinase inhibitor for metastatic NSCLC and systemic anaplastic large cell lymphoma	Crizotinib	16
BCR-ABL fusion gene (Ph+) or resistant BCR-ABLT315I mutation	Newly diagnosed Ph+CML, Ph+ALL; Ph+CML and ALL with resistance or intolerance to prior therapy	Imatinib, dasatinib; or ponatinib	8
BRAF^V600 mutation	Selective BRAF^V600 kinase inhibitor for metastatic melanoma	Vemurafenib	17
BRAF^V600 mutation, or EGFR or ALK mutations; PD-L1 expression or MSI-H	Nivolumab treatment of BRAF V600 mutation-positive or-wildtype unresectable or metastatic melanoma as a single agent or patients with EGFR or ALK genomic tumor aberrations after disease progression on FDA-approved therapy for these aberrations; PD-Ll expression or MSI-H for pembrolizumab treatment of advanced NSCLC	Nivolumab, Pembrolizumab	14
BRCA1/2 mutations	Metastatic ovarian cancer with germline and/or somatic BRCA mutations; metastatic breast cancer with germline BRCA mutations	Olaparib	15
CD20 expression or 17p deletion	CD20 antibody therapy in CLL and NHL	Rituximab; venetoclax	18
DPD deficiency	Rarely, unexpected, severe toxicity associated with 5-fluorouracil has been attributed to DPD deficiency	5-Fluorouracil	11
EGFR mutations or resistant EGFRT790M mutation	Treatment with EGFR TKI for locally advanced, unresectable or metastatic NSCLC	Erlotinib; or osimertinib	6
EGFR expression or KRAS mutations	Treatment with EGFR antibodies for KRAS-wildtype metastatic colorectal cancer	Cetuximab, panitumumab	7
ER and/or PR expression	Endocrine therapy for early and metastatic breast cancer; cyclin-dependent kinase inhibitor in combination with endocrine therapy; everolimus in combination with exmestane therapy	Tomoxifen, Palbociclib, everolimus	5
HER2 overexpression or gene amplification KIT positivity	Anti-HER2 agents for early and metastatic breast cancer; treatment of metastatic gastric or gastroesophageal junction adenocarcinoma KIT (CD117)-positive unresectable or metastatic malignant GIST; Adjuvant treatment of adult patients following resection of Kit-positive GIST	Trastuzumab, or lapatinib Imatinib	4 9
Oncotype DX assay or MammaPrint test	Adjuvant chemotherapy plus endocrine therapy for high risk breast cancer and adjuvant endocrine therapy for low risk node-negative or few-node-positive ER-positive invasive breast cancer	Chemotherapy ortamoxifen	13
PML/RARα	Treatment with ATRA may be based on its expression for acute promyelocytic leukemia	ATRA; arsenic oxide	10
UGT1A1 polymorphisms and mutation	A reduced initial dose forhomozygous UGT1A1^* 28 allele	Irinotecan	12

* Prototypedrug.Abbreviations: ALK, anaplastic lymphoma kinase; ALL, acute lymphocytic leukemia; APL, acute promyelocytic leukemia; ATRA, all trans retinoic acid; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; DPD, dihydropyrimine dehydrogenase; EGFR, epidermal growth factor receptor; ER, estrogen receptor; GIST, gastrointestinal stromal tumors; HER2, human epidermal growth receptor 2; NSCLC, non-small cell lung cancer; PARP, poly-ADP ribose polymerase; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PML/RAR(α), promyelocytic leukemia/ retinoic acid receptor alpha Ph+, Philadelphia-positive chromosome; PR, progesterone receptor; TPMT, thiopurine S-methyltransferase; UGT1A1, UDP-glucuronosyltransferase 1 family, polypeptide 1.

Table 1.2 Therapeutic biomarker categories based on their application

Biomarker/drug /Indication	Response or benefit	Resistance	Toxicity	Risk identification
ALK and ROS1 positivity/ALKinhibitors/metastatic NSCLC and systemic anaplastic large cell lymphoma	X
BCR-ABL (Ph+)/BCR-ABL TKIs/CML, ALL	X
BCR-ABL (Ph-)/Blinatumomab/Ph- relapsed or refractory Ph+ALL	X
BCR-ABLT315I mutation/ BCR-ABL TKIs/CML, Ph+ ALL		X
BRAF mutations/BRAF and MEK inhibitors /mutation+ metastatic melanoma, NSCLC and anaplastic thyroid cancer	X
BRAF^V60...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Contents
• Preface
• 1. Overview of Therapeutic Biomarkers in Cancer
• 2. Statistical Considerations in the Development and Evaluation of Therapeutic Biomarkers in Cancer
• 3. Role of Biomarkers in Clinical Development of Cancer Therapies
• 4. HER-2 as a Prognostic and Predictive Biomarker in Cancer
• 5. Hormone Receptors and Endocrine Therapy in Breast Cancer
• 6. Predictive Biomarkers for Epidermal Growth Factor Receptor Agents in Non-Small Cell Lung Cancer
• 7. Markers of Sensitivity and Resistance to EGFR Inhibitors in Colorectal Cancer
• 8. Targeting BCR-ABL in Chronic Myelogenous Leukemia
• 9. Gastrointestinal Stromal Tumors: From Molecular Pathogenesis to Therapy
• 10. PML/RARa Fusion Gene and Response to Retinoic Acid and Arsenic Trioxide Treatment
• 11. Dihydropyrimidine Dehydrogenase Deficiency and Fluoropyrimidine-Toxicity
• 12. UGT1A1 Polymorphisms and Mutations Affect Anticancer Drug Therapy
• 13. Multiparameter Gene Expression Assays and Breast Cancer Management
• 14. Biomarkers for the Immune Checkpoint Inhibitors
• 15. BRCA Mutation and PARP Inhibitors
• 16. EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer
• 17. Biomarkers for the Management of Malignancies with BRAF Mutation
• 18. Anti-CD20 Monoclonal Antibody Treatment in Follicular Lymphoma and Chronic Lymphocytic Leukemia
• Index