Practical Guide to Hereditary Breast and Ovarian Cancer : Annual Meeting of the Japanese Organization of Hereditary Breast and Ovarian Cancer 2021

Contents 5 Part I: Breast 7 Establishment of a Medical System with HBOC in Mind 8 1 Introduction 8 1.1 History of BRCA1/2 Clinical Practice in Japan 9 1.2 BRCA1/2 Genetic Test 10 1.3 Risk Reduction Surgery 11 1.4 Surveillance 12 1.5 PARP Inhibitor 13 1.6 Chemoprevention 14 1.7 Beyond HBOC 15 1.8 Genetic Test for Family 15 2 Conclusion 16 References 16 Guidelines for Diagnosis and Treatment of HBOC: Methods and Products 19 1 Purpose of the Guidelines 19 2 Significance of Guideline Creation 20 3 Method of Preparation of These Guidelines 21 3.1 Preparation Members 21 3.2 Establishment of Clinical Queries 21 3.3 Systematic Review and Evidence Synthesis 21 3.4 Recommendation-Making 22 4 Type of Recommendation 22 5 External Evaluation 23 6 Summary 23 HBOC from a Plastic Surgeon’s Perspective 24 1 Breast Reconstruction in Japan 24 2 RRM and Breast Reconstruction for HBOC in the Era of Self-Funded Treatment 26 3 BIA-ALCL and the “Allergan Crisis” in Japan 27 4 Properly Fearing BIA-ALCL 28 5 Breast Reconstruction After RRM After Insurance Coverage of RRM 28 6 Fat Grafting 30 7 Lifestyle and Life Stage 31 References 32 Part II: Gynecology 34 Serous Tubal Intraepithelial Carcinoma (STIC) and Precancerous Lesions in Risk-Reducing Salpingo-oophorectomy (RRSO) Specimens 35 1 Introduction 35 2 HBOC and Ovarian Cancer 36 3 Significance of RRSO and Pathological Examination 37 4 Occult Cancer in RRSO Specimens 37 5 Precancerous Lesions in RRSO Specimens 38 5.1 STIC 38 5.1.1 STIC in RRSO Specimens 38 5.1.2 STIC Coexisting with HGSC 42 5.1.3 STIC in Benign Gynecological Specimens 42 5.2 STIL, p53 Signature 42 5.2.1 Frequencies of STIL and p53 Signature (Table 1) 43 5.2.2 Significance of p53 Signature and STIL 43 6 Future Prospective 43 References 44 Mutual Feedback Between Gynecological HBOC Practice and Cancer Genomic Medicine 48 1 Introduction 48 2 Characteristics of HBOC Ovarian Cancer 49 3 PARP Inhibitor 49 4 Biomarkers of PARP Inhibitors 50 4.1 Platinum-Sensitivity Status 50 4.2 BRCA1/2 Testing 51 4.3 SNP-Based Genomic Scar Assays 51 5 New Candidates for Evaluating HRD Status 52 5.1 Homologous Recombination Repair (HRR)-Related Gene Mutations 52 5.2 Mutation Signatures 53 6 Clinical Use of PARP Inhibitors for Ovarian Cancer in Japan 54 7 Conclusion 55 References 55 Part III: Basic Science 58 Heterogeneities in Hereditary Cancer Genes as Revealed by a Large-Scale Genome Analysis 59 1 Background 59 1.1 Limited Information on Personalized Medicine for BRCA1 and BRCA2 59 1.2 Importance of Large-Scale Data 61 2 Risk and Frequency of Pathogenic Variants in 27 Hereditary Cancer Genes 61 2.1 BioBank Japan 61 2.2 Sequencing 62 2.3 Clinical Interpretation of Genetic Variants 64 2.4 Unified Analysis of >66,000 Individuals with Five Cancer Types 64 2.5 Risk and Frequency of Pathogenic Variants 65 2.6 Variants of Uncertain Significance 68 3 Heterogeneity 70 3.1 Between Genes 70 3.2 Between Cancer Types 71 3.3 Between Populations 72 4 Future Directions of Research 72 4.1 Integrated Estimation of Disease Risk with Genetic and Environmental Factors 72 4.2 Identification of More Genes with Moderate or High Risk 73 5 Conclusions 74 References 74 New Functions of BRCA1/2 in Regulating Carcinogenesis and Drug Sensitivity 79 1 Introduction 80 2 Structure of BRCA1/2 81 3 Functions of BRCA1/2 82 3.1 HR 82 3.2 Stabilization of Replication Forks 84 3.3 Prevention of R-Loop Accumulation 84 3.4 Centrosome Regulation 84 3.5 Other Functions 85 4 Evaluation of HR Activity 86 4.1 Evaluation of HR Activity in HBOC 86 4.2 Novel Assay to Evaluate HR Activity in Cells 86 4.3 A Novel HR Assay to Detect Intermediate HR Activity 86 4.4 Role of HR Activity in Cancer Treatment 87 4.5 Mechanisms Underlying Resistance to PARP Inhibitors 88 4.6 A Novel Mechanism of Resistance to PARP Inhibitors 88 4.7 BRCA1/ATF1-Mediated Transactivation Confers Resistance to Cisplatin 90 5 Conclusions 91 References 91 Part IV: Health and Labor Sciences Research Grant 96 Hereditary Breast and Ovarian Cancer and the National Health Insurance in Japan 97 1 Current State of Public Health Insurance Coverage for HBOC in Japan 97 2 Definition of HBOC and Approach to Resolving Uninsured Matters 99 3 Issues That Japan Needs to Solve in Order to Aim for Seamless HBOC Medical Care 99 3.1 The Restriction on BRCA1/2 Genetic Testing for Confirming the Diagnosis of HBOC for Those Who Have Already Developed Breast or Ovarian Cancer Should Be Lifted 99 3.2 Removal of Restrictions on Breast Surveillance Only for Those Who Have Already Developed Breast or Ovarian Cancer 100 3.3 Canceling the Limitation of Ovarian Surveillance to Those Who Have Already Developed Breast Cancer 100 3.4 The Limitation of Risk-Reducing Salpingo-oophorectomy to Patients with Existing Breast Cancer Should Be Lifted 100 4 Risk-Reducing Mastectomy Should Be Lifted from Being Limited to Women with Pre-existing Breast or Ovarian Cancer 101 4.1 Remove the Restriction on Intractable Diseases for Remote Genetic Counseling Covered by Public Insurance 101 5 Toward Introducing Multigene Panel Testing (MGPT) 101 6 Conclusion 102 References 102 Current Status and Future Issues of the Activities of the Relevant Organizations 104 1 Introduction 105 2 Awareness and Educational Activities for the Public and HBOC Patients 106 3 Cosponsoring and Cooperating With Related Seminars to Strengthen Public Awareness Efforts 108 4 Guidebook for Treatment and Understanding of HBOC: PPI and Products 108 4.1 Content and Typical Questions [2] 109 4.2 For Creation and Editing 109 4.3 Introduction to Patient and Public Involvement (PPI) 110 5 Other Research Projects 111 5.1 Genetic Cancer Support Program(GCSP)/HBOC Peer Support [3, 4] 111 5.2 Future Genetic Medicine That HBOC Patients and Their Families Want 112 6 About “Clavis Arcus” 112 7 About “Genetic Alliance JP” 113 References 113 Part V: Congress Award 114 Significance of Understanding HBOC for At-Risk Relatives in Prostate and Pancreatic Cancer Patients Who Tested Positive on the Germline BRCA1/2 Genetic Testing in the Current Japanese Healthcare System 115 1 Introduction 116 2 Brief History of Germline BRCA1/2 Genetic Testing in the Japanese Healthcare System 116 2.1 Prior to the Public Health Insurance Coverage 116 2.2 Insurance Coverage for Breast Cancer and Ovarian Cancer 117 2.3 Insurance Coverage for HBOC 117 2.4 Insurance Coverage for Prostate Cancer and Pancreatic Cancer 118 3 Prostate Cancer Patients and HBOC 118 3.1 Background of Those Who Take the Germline BRCA1/2 Testing 118 3.2 Patients’ Accurate Understanding of HBOC 118 3.3 Influences on Family 119 3.3.1 Genetic Counseling with Family 120 3.3.2 Communication With Extended Family 120 4 Pancreatic Cancer Patients and HBOC 121 4.1 Background of Those Who Take the BRCA1/2 Testing 121 4.2 Accurate Understanding of HBOC 121 4.3 Influences on Family 121 5 Roles of Genetic Counseling Department 122 6 Conclusion 122 References 123 Handling Germline Findings in Ovarian Cancer Cases 124 1 Introduction 125 2 How to Evaluate Hereditary Predisposition to Cancer in Patients Undergoing CGP 125 2.1 Presumed Germline Pathogenic Variants 125 2.2 Genes Recommended for Reporting to Patients 126 2.3 Interpretation of Variants for Clinical Significance 128 2.4 Genetic Counseling–Referral Flow in CGP-Performed Patients 128 2.5 Personal and Family History in the Evaluation for Hereditary Predisposition 129 3 Clinical Utility of Germline Findings for Patients with Ovarian Cancer 130 3.1 Cancer Treatment 130 3.2 Identification of a Family of Hereditary Ovarian Cancer 131 4 Barriers for Confirmatory Germline Genetic Testing 132 5 Conclusion 133 References 133 Part VI: JOHBOC Registration 137 Registration Data of Japanese Organization of Hereditary Breast and Ovarian Cancer Till 2020 138 1 Japanese Organization of Hereditary Breast and Ovarian Cancer (JOHBOC) Registry 139 2 Summary of the Nationwide Registry Data Collection Results 140 2.1 Results of the BRCA1/2 Genetic Tests 140 2.2 Clinical Background of the BRCA1/2 Pathogenic Variant Carriers 141 2.3 Registered Variants 143 3 Recent JOHBOC Data Results 144 4 Future Outlook 145 References 147 This book shares cutting-edge evidence on Hereditary Breast and Ovarian Cancer (HBOC) treatment, delivering facts on breast cancer, gynecologic oncology, and basic research to contribute to clinicians' practices. Each chapter presents the latest clinical techniques, basic experimental results, and the best-chosen research findings. The book is based on the works presented at the Japanese Organization of Hereditary Brest and Ovarian Cancer (JOHBOC) and a special chapter delivers a study based on the extensive data from the Japanese HBOC patients registered in the society's database, presenting novel evidence for further advancement in the field. The practice for HBOC has been rapidly increasing due to the clinical development of poly(ADP-ribose) polymerase inhibitors and the spread of companion diagnostics. In addition, the insurance coverage of a part of HBOC treatment raised social awareness in Japan, and the book illustrates not only clinical efforts but also issues related to the social system and the efforts of the association of related organizations. Hereditary Breast and Ovarian Cancer – Annual meeting of JOHBOC will be of interest to breast surgeons, obstetricians and gynecologists, pancreatic cancer surgeons, and urologists engaged in HBOC treatment through the implementation of companion diagnostics for PARP inhibitors administration. Also, physicians occupied in genetic medicine who perform genetic testing and medical staff practicing HBOC will find this book insightful. It is also for HBOC patients and their families, medical administrators in the social system of HBOC practice. Editors and authors hope to contribute to the equalization and widespread of HBOC practice and serve as a foundation for future advances in the disease's treatment and medical practice.