Precision Cancer Medicine: Challenges and Opportunities

✍ Scribed by Sameek Roychowdhury (editor), Eliezer M. Van Allen (editor)

• Publisher: Springer
• Tongue: English
• Leaves: 196
• Category: Library

✦ Synopsis

Genomic sequencing technologies have augmented the classification of cancer beyond tissue of origin and towards a molecular taxonomy of cancer. This has created opportunities to guide treatment decisions for individual patients with cancer based on their cancer’s unique molecular characteristics, also known as precision cancer medicine. The purpose of this text will be to describe the contribution and need for multiple disciplines working together to deliver precision cancer medicine. This entails a multi-disciplinary approach across fields including molecular pathology, computational biology, clinical oncology, cancer biology, drug development, genetics, immunology, and bioethics. Thus, we have outlined a current text on each of these fields as they work together to overcome various challenges and create opportunities to deliver precision cancer medicine. As trainees and junior faculty enter their respective fields, this text will provide a framework for understanding the role and responsibility for each specialist to contribute to this team science approach. 

✦ Table of Contents

Contents
Chapter 1: Between Hype and Hope, on the Cutting Edge of Precision Cancer Medicine
Chapter 2: Molecular Diagnostics in Cancer: A Fundamental Component of Precision Oncology
2.1 History of Molecular Diagnostics in Cancer
2.2 Clinical Applications of Molecular Diagnostics in Cancer Care
2.2.1 Taxonomy and Molecular Biomarkers for Prediction of Therapy, Diagnosis, and Prognosis
2.2.1.1 Predictive Biomarkers
2.2.1.2 Diagnostic Biomarkers
2.2.1.3 Prognostic Biomarkers
2.2.2 Disease Monitoring
2.2.3 Cancer Prevention and Early Detection
2.3 Frontiers in Molecular Diagnostics of Cancer
2.3.1 Current State-of-the-Art Nucleic-Acid-Based Analysis: Next-Generation Sequencing
2.3.2 Liquid Biopsy
2.3.3 Current Challenges and Near Term Solutions
2.3.4 Future Perspective
References
Chapter 3: Clinical Interpretation
3.1 Introduction
3.2 History
3.3 Current Developments
3.3.1 Acquisition
3.3.2 Analysis
3.3.3 Action
3.3.4 Case Study: PHIAL
3.4 Challenges
3.4.1 Tissue Acquisition
3.4.2 Sequencing Approaches and Infrastructure
3.4.3 Clinical Adoption
3.5 Future Approaches
3.5.1 Acquisition Improvements
3.5.2 Analysis Improvements
3.5.3 Action Improvements
3.6 Conclusion
References
Chapter 4: Precision Cancer Medicine and Clinical Trial Design
4.1 Introduction
4.2 Target Discovery and Validation
4.3 Implications of Tumor Heterogeneity
4.4 Clinical Trial Paradigm
4.5 Enrichment and Adaptive Strategies
4.6 Umbrella or Master Trials
4.7 Basket Trials
4.8 N of 1 Trial
4.9 Conclusion
References
Chapter 5: Resistance to Anti-Cancer Therapeutics
5.1 Introduction
5.2 Chemotherapy Resistance
5.2.1 Introduction
5.2.2 Modulation of Drug Efflux from Cells
5.2.3 Intratumoral Heterogeneity and Cancer Stem Cells
5.2.4 DNA Damage Checkpoint and Repair Mechanisms
5.2.5 Genomic Complexity and Acquisition of Specific Mutations
5.2.6 Specific Gene Alterations
5.2.7 Other Mechanisms of Chemotherapy Resistance
5.3 Resistance to Targeted Therapies
5.3.1 BCR-ABL Inhibitors
5.3.2 EGFR Inhibitors
5.3.3 BRAF-V600E Inhibitors
5.3.4 HER2 (ERBB2) Targeted Therapies
5.3.5 ALK Inhibitors
5.3.6 Proteasome Inhibitors
5.3.7 VEGF Inhibitors
5.3.8 BTK Inhibitors
5.4 Conclusions
References
Chapter 6: Exceptional Responders
6.1 Introduction
6.2 Initial Whole Genome Sequencing (WGS) of an Exceptional Responder in Urothelial Carcinoma
6.3 Exceptional Response to mTOR Inhibitor Therapy and Pathway Convergence in Clonal Heterogeneity
6.4 Concurrent mTOR Mutations and Sensitivity to mTOR Inhibition as a Component of Combination Therapy
6.5 Curative Response to Combination Therapy in the Context of a Hypomorphic RAD50 Mutation
6.6 Analysis of Exceptional Responses to Treatment with Immunotherapy
6.7 Analysis of Exceptional Responses to Treatment with Chemotherapy
6.8 Occult Biomarkers Identified by Outlier Analysis
6.9 Mechanisms of Acquired Resistance Following Initial Exceptional Response
6.10 NCI Exceptional Responders Initiative
6.11 Conclusions and Future Steps
References
Chapter 7: Immunogenomics
7.1 Introduction and History of Immunogenomics
7.2 Preclinical Models Demonstrate Relevance of Immunogenomics to Tumor Fate
7.3 Neoantigen Prediction
7.4 Technologies to Detect a Neoantigen-Specific T Cell Response
7.5 Evidence for T-Cell Reactivity to Neoantigens in Patients Treated with Checkpoint Blockade Immunotherapy
7.6 Unanswered Questions and Future Directions
References
Chapter 8: Managing Germline Findings from Molecular Testing in Precision Oncology
8.1 Overview of Molecular Testing in Oncology
8.2 Molecular Testing in Oncology Care – Background
8.2.1 Tumor Molecular Testing for Treatment Planning
8.3 Germline Molecular Testing for Hereditary Cancer Risk
8.4 Next Generation Sequencing Technologies – Impact on Clinical Molecular Testing
8.5 How Common Are Germline Findings in Patients with Cancer?
8.6 Integrating Tumor and Germline Testing
8.7 Patient Preference, Right “Not to Know”
8.8 Informed Consent
8.9 Genetic Service Delivery
8.10 Case Examples
8.10.1 PGVs Can Have Relevance for Cancer Treatment
8.10.2 PGVs May Have Been Previously Missed
8.10.3 PGVs May Not Have Been Expected
8.11 Summary
References
Chapter 9: Ethical, Legal, and Social Implications of Precision Cancer Medicine
9.1 Introduction
9.2 Precision Cancer Medicine and Distributive Justice
9.2.1 Resource Allocation
9.2.2 Health Disparities
9.3 Informed Consent and Patient Education
9.3.1 Further Considerations in Precision Cancer Studies
9.3.2 Issues in Health Communication
9.3.3 Consenting Pediatric Participants
9.4 Return of Sequencing Results
9.4.1 Disclosing Risks for Adult-Onset Conditions in Childhood
9.4.2 Disclosing Results of Deceased Patients
9.4.3 Disclosing Risks for Diseases Other than Cancer
9.4.4 Legal Issues for Clinicians and Researchers
9.5 Conclusions
References
Chapter 10: Liquid Biopsy: Translating Minimally Invasive Disease Profiling from the Lab to the Clinic
10.1 Introduction
10.2 Circulating Tumor Cells (CTCs)
10.3 CTC Enrichment
10.4 Clinical Applications of CTCs: Enumeration
10.5 Beyond Enumeration: CTC Characterization and Analysis
10.6 Cell Free DNA (cfDNA)
10.7 Clinical Applications of cfDNA
10.8 Cell Free RNA and MicroRNA
10.9 The Rapidly Evolving Cell-Free Landscape
10.10 Extracellular Vesicles (EVs)
10.11 EV Isolation
10.12 Clinical Applications of EVs
10.13 Conclusion
References
Chapter 11: Data Portals and Analysis
11.1 The Evolution of Cancer Genomics
11.2 Navigating the Maze of Omics Data: Challenges and Opportunities
11.3 Data Portals and Public Repositories
11.3.1 Progress and Observations from Public Projects
11.3.2 Public Repositories for Cancer Genomics Data
11.3.2.1 The Cancer Genome Atlas (TCGA) [6]
11.3.2.2 Therapeutically Applicable Research to Generate Effective Treatments (TARGET) [7]
11.3.2.3 Cancer Genome Characterization Initiative (CGCI) [8]
11.3.2.4 Cancer Cell Line Encyclopedia (CCLE) [9]
11.3.2.5 International Cancer Genome Consortium (ICGC) [10]
11.3.2.6 AACR Project GENIE (Genomics Evidence Neoplasia Information Exchange) [12]
11.3.2.7 Genomic Data Commons (GDC) Data Portal [13]
11.3.2.8 Database of Genotypes and Phenotypes (dbGaP) [16]
11.3.2.9 European Genome-phenome Archive (EGA) [18]
11.3.2.10 ArrayExpress [19]
11.3.2.11 Gene Expression Omnibus (GEO) [20]
11.3.2.12 Synapse [15]
11.3.2.13 GDAC Firehose (Genome Data Analysis Center) [17]
11.3.2.14 The cBioPortal for Cancer Genomics [14]
11.4 Data Analysis Platforms
11.4.1 Bridging the Gap for Translational Cancer Research
11.4.1.1 cBioPortal for Cancer Genomics [14]
11.4.1.2 Broad Institute Firebrowse [21]
11.4.1.3 COSMIC [22]
11.4.1.4 ICGC Data Portal [10]
11.4.1.5 UCSC Xena [23]
11.4.1.6 St. Jude PeCan Data Portal [24]
11.4.1.7 Brown MAGI [25]
11.5 Clinical Actionability Resource Integration
References