Hereditary Breast and Ovarian Cancer: Molecular Mechanism and Clinical Practice

Preface
Contents
1: History, Advancements, and Future Strategies
	1.1	 History of Hereditary Breast Cancer (Fig. 1.1)
		1.1.1	 How It All Started
		1.1.2	 BRCA1 and BRCA2 in the Clinical Setting
	1.2	 Current Developments (Fig. 1.2)
		1.2.1	 Multi-gene Panel Testing and Non-BRCA Genes
		1.2.2	 Target Therapy
	1.3	 Future Strategies (Fig. 1.5)
	1.4	 Conclusion
	References
2: Molecular Basis of BRCA1 and BRCA2: Homologous Recombination Deficiency and Tissue-Specific Carcinogenesis
	2.1	 Introduction
	2.2	 Structure and Binding Partners of BRCA1/BRCA2 Proteins
	2.3	 BRCA1/BRCA2 Functions in HR and the Synthetic Lethality of PARP Inhibitors
		2.3.1	 HR Mediated by BRCA1/BRCA2 and a Backup Pathway Mediated by PARP1/PARP2
		2.3.2	 Essential Role of BRCA1/BRCA2 in DNA Replication with PARP Trapping
	2.4	 Hypotheses for Tissue-Specific Carcinogenesis
		2.4.1	 Tissue-Specific DNA Damage Induced by ERα-Mediated Transcription
		2.4.2	 Tissue-Specific Growth Signaling by Estrogen in BRCA1-Defective Progenitor Cells
		2.4.3	 Tissue-Specific Survival Mediated by Estrogen
	2.5	 Perspectives
	References
3: Genetic Testing
	3.1	 Introduction
	3.2	 Aim of the Genetic Testing
		3.2.1	 Diagnosis of Hereditary Cancer and Companion Diagnostics for Certain Drugs in Cancer Patients
			3.2.1.1	 Appropriate Medical Care for Cancer
			3.2.1.2	 Prevention Against Cancer Risk of Other Organs That Are Not Currently Affected
			3.2.1.3	 Clarify the Possibility of Inheritance to Relatives
		3.2.2	 Diagnosis of Relatives
		3.2.3	 Secondary Findings (SF) (Germline Findings)
	3.3	 Best Test Candidate
	3.4	 Variants of BRCA1/BRCA2 Genes
	3.5	 Analytical Methods
		3.5.1	 Sanger Sequencing
		3.5.2	 Fragment Analysis
		3.5.3	 Array Comparative Genomic Hybridization (Array-CGH)
		3.5.4	 Next-Generation Sequencing (NGS)
	3.6	 Companion Diagnostics (CDx)
		3.6.1	 CDx
		3.6.2	 HRD
	3.7	 Quality Control
		3.7.1	 Preanalytic Phase
		3.7.2	 Analytic Phase
		3.7.3	 Postanalytic Phase
		3.7.4	 Validation
		3.7.5	 Internal Quality Control
		3.7.6	 External Quality Assessment
		3.7.7	 Certification Programs
			3.7.7.1	 Clinical Laboratory Improvement Amendments (CLIA)
			3.7.7.2	 Laboratory Accreditation Program (LAP)
			3.7.7.3	 ISO15189
	3.8	 Interpretation
	3.9	 VUS
	3.10	 Summary
	References
4: Variants of Uncertain Significances in Hereditary Breast and Ovarian Cancer
	4.1	 Introduction
	4.2	 Guidelines for Variant Classification
	4.3	 VUS in BRCA1 and BRCA2
	4.4	 Functional Assays to Evaluate the Effects of VUS
		4.4.1	 Functional Assays of BRCA1
		4.4.2	 Functional Assays of BRCA2
		4.4.3	 Perspective on Functional Assays of BRCA1 and BRCA2
		4.4.4	 Utility of BRCA1 and BRCA2 Functional Assays
	4.5	 In Silico Prediction Tools
	4.6	 Multi-gene Panel Testing
	4.7	 Conclusions
	References
5: Genetic Counseling in Hereditary Breast and Ovarian Cancer
	5.1	 Introduction
	5.2	 Subjects of Genetic Counseling and BRCA1/BRCA2 Genetic Testing
	5.3	 Contents in Genetic Counseling
		5.3.1	 Family History and Risk Assessment
		5.3.2	 First Person in the Family to Be Tested
		5.3.3	 Interpretation of BRCA1/BRCA2 Genetic Testing Results
		5.3.4	 Sharing Genetic Information with Relatives
		5.3.5	 Risk of Discrimination
		5.3.6	 Presenting an Option of Not Undergoing Genetic Testing
		5.3.7	 Psychosocial Assessment
		5.3.8	 Reproductive Issues
	5.4	 Risk Communication
	5.5	 Future Outlook for Genetic Counseling
	References
6: Hereditary Breast Cancer
	6.1	 Introduction
	6.2	 BRCA1-/BRCA2-Related Breast Cancer
	6.3	 What Is the Appropriate Surgical Management for BRCA1-/BRCA2-Related Breast Cancer?
		6.3.1	 Breast Conserving Surgery or Mastectomy
		6.3.2	 Nipple-Sparing Mastectomy
		6.3.3	 Contralateral Risk-Reducing Mastectomy
	6.4	 Can RT Be Recommended for BRCA1-/BRCA2-Related Breast Cancer?
		6.4.1	 Breast Radiation After BCS
		6.4.2	 Postmastectomy Radiation Therapy
		6.4.3	 RT-Related Toxicity
	6.5	 What Is the Role of Chemotherapy (Platinum) for BRCA1-/BRCA2-Related Breast Cancer?
		6.5.1	 Early Breast Cancer
		6.5.2	 Metastatic Breast Cancer
	6.6	 BRCA1-/BRCA2-Related Breast Cancer Has Worse Prognosis?
	6.7	 TP53-Related Breast Cancer
	6.8	 PTEN-Related Breast Cancer
	6.9	 CDH1-Related Breast Cancer
	6.10	 PALB2-Related Breast Cancer
	6.11	 CHEK2-Related Breast Cancer
	6.12	 ATM-Related Breast Cancer
	6.13	 STK11-Related Breast Cancer
	6.14	 Conclusion
	References
7: Hereditary Ovarian Cancer
	7.1	 Overview of Ovarian Cancer
		7.1.1	 Symptoms
		7.1.2	 Histologic Subtypes
		7.1.3	 Risk Factors
		7.1.4	 Screening
		7.1.5	 Treatment
	7.2	 Hereditary Ovarian Cancer
		7.2.1	 Ovarian Cancer in HBOC
			7.2.1.1	 Frequency of HBOC in Ovarian Cancer
			7.2.1.2	 Germline Testing for Ovarian Cancer Patients
			7.2.1.3	 Penetrance of BRCA1/BRCA2 Variant Carriers in Ovarian Cancer
			7.2.1.4	 Histology of Ovarian Cancer in HBOC
			7.2.1.5	 Ovarian Cancer Initiation in HBOC
			7.2.1.6	 Prognosis of BRCA1/BRCA2 Variant Carriers with Ovarian Cancer
			7.2.1.7	 Chemosensitivity and HRD of Ovarian Cancer in HBOC
			7.2.1.8	 Surveillance for Ovarian Cancer
		7.2.2	 Ovarian Cancer in Lynch Syndrome
		7.2.3	 Other Germline Variants Associated with Ovarian Cancer
			7.2.3.1	 RAD51C, RAD51D, BRIP1
			7.2.3.2	 NBN, ATM, PALB2
	References
8: Risk-Based Breast Cancer Screening
	8.1	 Introduction
	8.2	 Comparison Between Japan and the USA
		8.2.1	 Definition of “High Risk”
		8.2.2	 Role of Breast Imaging Radiologists in the USA
		8.2.3	 High-Risk Program Clinic in the USA
	8.3	 Appropriate Clinical Management for High-Risk Women in Japan
		8.3.1	 The New Era of Personalized, Risk-Based Screening
		8.3.2	 Risk-Based Imaging Management
			8.3.2.1	 Clinical and Imaging Features of Women at High Risk for Breast Cancer
				Features of BRCA1/BRCA2 Germline Mutation Carriers
				Breast Density
				Background Parenchymal Enhancement (BPE)
			8.3.2.2	 Imaging Modality Choice
				Mammography: Limitations of Mammography
				Ultrasound: Differences Between Japan and the USA
				Pursuit of Quality-Assured MRI
			8.3.2.3	 Suggestions for Risk-Based Screening Management
	8.4	 Training of Breast Imaging Experts in Japan
		8.4.1	 Necessity of Breast Imaging Specialists
		8.4.2	 Communication with Patients via Outpatient Clinics and Reporting
		8.4.3	 Team-Based Care for Women at High Risk for Breast Cancer
	8.5	 Conclusion
	References
9: Chemoprevention for Breast Cancer
	9.1	 Introduction
	9.2	 Chemopreventive Drugs for Breast Cancer
		9.2.1	 Selective Estrogen Receptor Modulators
		9.2.2	 Aromatase Inhibitors
		9.2.3	 Denosumab
		9.2.4	 Poly ADP-Ribose Polymerase Inhibitors
		9.2.5	 Nonsteroidal Anti-inflammatory Drugs
		9.2.6	 Retinoids
	9.3	 Future Challenges
	References
10: Chemoprevention for Ovarian Cancer
	10.1	 Introduction
	10.2	 Methods
		10.2.1	 Literature Search
	10.3	 Results
		10.3.1	 Risk Management Options for Ovarian Cancer
		10.3.2	 Impact of Chemoprevention on Ovarian Cancer Risk
		10.3.3	 Biological Diversity of OC
	10.4	 Discussion
	References
11: Risk-Reducing Mastectomy (RRM)
	11.1	 Introduction
	11.2	 History of RRM
	11.3	 Risk Reduction of Developing Breast Cancer
		11.3.1	 BRRM
		11.3.2	 CRRM
	11.4	 Survival Benefit
		11.4.1	 BRRM
		11.4.2	 CRRM
	11.5	 Occult Cancer
	11.6	 Psychological Relief
	11.7	 Cost Effectivity
	11.8	 Disadvantages
		11.8.1	 Surgical Procedure Risk
		11.8.2	 Morbidity and Physical Consequences
		11.8.3	 Psychological Consequences
	11.9	 Conclusion
	References
12: Risk-Reducing Salpingo-oophorectomy (RRSO)
	12.1	 Significance of RRSO
	12.2	 Standard RRSO Procedure
	12.3	 Surgical Options when Performing RRSO: Concurrent Hysterectomy and Two-Stage Surgery
	12.4	 Pathological Examination of RRSO Samples
	12.5	 Post-RRSO Health Care
	12.6	 Current State of RRSO and Future Prospects
	References
13: Panel Testing
	13.1	 Introduction
	13.2	 Cancer Genome Panel Tests
	13.3	 Types of Panel Tests
	13.4	 Purpose of the Gene Panel Test
	13.5	 Report Structure of the F1CDx
	13.6	 Report Structure of the NCC Oncopanel Test
	13.7	 C-CAT Report Structure
	13.8	 Expert Panel Configuration
	13.9	 Handling of Germline Findings in Panel Testing
	13.10	 Gene Panel Testing for Germline Variants
	References
14: Germline Findings Through Precision Oncology for Ovarian Cancer
	14.1	 Introduction
	14.2	 Germline Findings when Targeting the Tumor Genome
	14.3	 Why Are Germline Findings Important?
	14.4	 Candidates for Germline Genetic Testing
	14.5	 Report of Germline Findings
	14.6	 Testing Methods for Germline Pathogenic Variants and Presumed Germline Pathogenic Variants
		14.6.1	 Tumor-Normal Paired Testing with Germline Variant Subtraction
		14.6.2	 Tumor-Normal Paired Testing with Established Analyses of Genes Associated with Germline Cancer Predisposition
		14.6.3	 Tumor-Only Testing
	14.7	 Recognition of PGPVs Through Tumor-Only Testing
	14.8	 Clinical Utility of Tumor Genomic Profiling for Ovarian Cancer
	14.9	 Summary
	References
15: Germline Findings from Genetic Testing for Breast Cancer
	15.1	 Breast Cancer in Japanese Women
	15.2	 Patients Suspected of Having Hereditary Breast Cancer
	15.3	 Japanese BRCA1/2 Database
	15.4	 Multigene Testing (MGT)
	15.5	 Breast Cancer-Related Genes Other Than BRCA1/2
	15.6	 Companion Diagnosis
	15.7	 Cancer Genome Profiling
	15.8	 Problems in Japan’s Genetic Medicine System
		15.8.1	 Repeat Genetic Testing
		15.8.2	 Additional Charge for Genetic Counseling
		15.8.3	 Providing Medical Care to Presymptomatic Mutation Carriers
	15.9	 The Future of Hereditary Tumor Treatment Under Japan’s System
	References
16: Hereditary Breast and Ovarian Cancer (HBOC) Database in Japan
	16.1	 Introduction: Importance of a Registry in Hereditary Tumors
	16.2	 History of the HBOC Registry in Japan
	16.3	 Outline of the Current Japanese Registry System
	16.4	 Research Using Registry Data
	16.5	 Future Perspectives
	References
17: Ethical Issues: Overview in Genomic Analysis and Clinical Context
	17.1	 Introduction: Genomic Medicine/Research and Ethical Issues
		17.1.1	 The Right to Know/the Right Not to Know: A Basic Ethical Principle in Genetic/Genomic Analysis
		17.1.2	 Shared Decision-Making Model: Collaboration of Medical Professionals and Patients for Better Decision-Making
		17.1.3	 Incidental/Secondary Findings (IFs/SFs)
		17.1.4	 Secondary Germline Findings in Genomic Tumor Profiling and Public Attitudes
		17.1.5	 Data Sharing and Privacy Issues in Genomic Research and Public Attitudes
	17.2	 Clinical Ethics in the Diagnosis and Treatment of Hereditary and Other Cancers
		17.2.1	 Clinical Ethics in Cancer Treatment: Perspective Based on Quality of Life
		17.2.2	 Prophylactic Surgery: Decision-Making and Follow-Up
		17.2.3	 What Method May Be Useful in the Clinical Setting? Four-Quadrant Approach of Clinical Ethics
		17.2.4	 Patient Confidentiality and Disclosure of Genetic Information to At-Risk Relatives
		17.2.5	 Communication of Genetic Risk Within the Family
	References
18: PARP Inhibitors: Mechanism of Action
	18.1	 Introduction
	18.2	 Synthetic Lethality with PARP Inhibitors
		18.2.1	 Function of PARPs
		18.2.2	 PARP Inhibitor-Induced DNA Double-Strand Break
		18.2.3	 DSB Repair Inhibition After Replication Fork Collapse
	18.3	 Mechanisms of Resistance to PARP Inhibitors
		18.3.1	 Restoration of HR Repair
			18.3.1.1	 Secondary Mutation
			18.3.1.2	 Loss of DNA End Protection Potential
		18.3.2	 HR Repair-Independent Acquired Resistance
			18.3.2.1	 Replication Fork Stability
			18.3.2.2	 Loss of PARP Trapping
			18.3.2.3	 Drug Efflux
	18.4	 Development of PARP Inhibitors
	18.5	 Perspective
	References
19: PARPi: Efficacy in Hereditary Breast Cancer
	19.1	 Introduction
	19.2	 Traditional Anthracycline- and Taxane-Based Regimens
		19.2.1	 Neoadjuvant Setting
		19.2.2	 Advanced or Metastatic Setting
	19.3	 Alkylating Agents
	19.4	 Platinum Agents
		19.4.1	 Neoadjuvant Setting
		19.4.2	 Advanced or Metastatic Setting
	19.5	 PARP Inhibitors
		19.5.1	 Olaparib
			19.5.1.1	 Neoadjuvant Setting
			19.5.1.2	 Adjuvant Setting
			19.5.1.3	 Advanced or Metastatic Setting
		19.5.2	 Niraparib
		19.5.3	 Rucaparib
			19.5.3.1	 Advanced or Metastatic Setting
		19.5.4	 Talazoparib
			19.5.4.1	 Neoadjuvant Setting
			19.5.4.2	 Advanced or Metastatic Setting
		19.5.5	 Veliparib
			19.5.5.1	 Neoadjuvant Setting
			19.5.5.2	 Advanced or Metastatic Breast Cancer
		19.5.6	 Potential Mechanisms of Resistance to PARP
		19.5.7	 Combination with Immune Checkpoint Inhibitors
			19.5.7.1	 Advanced or Metastatic Setting
	19.6	 Future Direction
	References
20: Efficacy of Poly(ADP-Ribose) Polymerase Inhibitors for Hereditary Ovarian Cancer
	20.1	 About this Chapter
	20.2	 First Line
		20.2.1	 Monotherapy
		20.2.2	 Combination
	20.3	 Platinum-Sensitive Recurrence
		20.3.1	 Monotherapy as Switch Maintenance Therapy
		20.3.2	 Monotherapy as Salvage Treatment for Patients with Multiple Sensitive Relapses
		20.3.3	 Combination
	20.4	 Platinum-Resistant Recurrence
		20.4.1	 Monotherapy
		20.4.2	 Combination
	20.5	 Ongoing Studies
	References