HEREDITARY BREAST AND OVARIAN CANCER PRESENTATION

hereditary breast and ovarian cancer

1. HEREDITARY BREAST AND OVARIAN CANCER Presenter: Dr Sireesha

2. Overview Definition Genetics Genetic testing Interpretation of results Implications

3. Definition According to the National Cancer Institute, HBOC is defined as “An inherited disorder in which the risk of breast cancer (especially before the age of 50 years) and ovarian cancer is higher than normal.”

4. Hereditary Breast and Ovarian Cancer(HBOC) The BRCA1 and BRCA2 genes were first identified and cloned in the early 1990s. Genotype Ovarian Cancer Breast Cancer No mutation 1.5% 12% BRCA1 mutation 20-60% (57%) 65-85% BRCA2 mutation 10-40% (27%) 45-85% Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 1998;62:676–89

5. Why? When? Where? Who? How?

6. Whom to test?

7. Testing criteria -NCCN Individuals with any blood relative with a known pathogenic/ likely pathogenic variant in a cancer susceptibility gene personal history of cancer Epithelial ovarian cancer ( incl fallopian tube, peritoneal cancer) at any age Exocrine pancreatic cancer at any age Prostate cancer at any age with Metastatic, intraductal / cribriform pathology NCCN risk group with family history BRCA1, BRCA 2, CDH1,PALB2, PTEN,P53

8. Personal history of breast cancer with one of the following Diagnosed at age < 45 yr Diagnosed between 46-50yr Unknown or limited family history Second breast cancer diagnosed at any age > 1 close relative with breast, ovarian, pancreatic/ prostatic cancer at any age Diagnosed at < 60 yr with triple negative breast cancer Any age with male breast cancer Diagnosed at any age with Ashkenazi jewish ancestry > 1 close blood relative with breast ca < 50yr / ovarian , pancreatic, metastatic prostate ca > 3 total diagnosis of breast ca in patient and/ close relatives

9. FAMILY PEDIGREE CHART Raby BA, Kohlmann W. Genetic counselling: Family history interpretation and risk assessment. UptoDate

10. NCCN version 1.2022 The decision to offer genetic testing involves three related stages: It is recommended that a genetic counsellor, clinical geneticist, oncologist, surgeon, oncology nurse, or other health professional with expertise and experience in cancer genetics be involved in any stage whenever possible.

11. Consent Detailed family history atleast upto three generation including genetic testing, types of cancer, age at diagnosis, and pathology report confirmation Detailed medical and surgical history Discussion of testing, risks, benefits, limitations , sensitivity and specificity Potential results like inconclusive or unexpected results should be discussed with further management . Discuss possible management options if a mutation is identified Discuss cost of genetic testing P rivacy of genetic information

12. Tests Multigene panel testing- Implemented for sequencing only a few genes (e.g., hereditary breast cancer panels) . Whole exome sequencing- all of the coding regions of DNA . Whole genome sequencing- entire DNA sequence including both coding and noncoding regions Pic courtesy: Whole exome sequencing. GC Genome Overseas Biz, June 11, 2020

13. Methods Volume Mutations PCR Few Genes Known genes FISH Limited genes Known genes Microarray All genes Known genes Sanger sequencing Few genes Known and unknown genes NGS All genes Known and unknown genes Available molecular methods for genetic testing: 3 methods detect known mutation 2 methods detect unknown mutations Molecular testing methods

14. When to order which test? Type of cancer Family history If someone in the family already tested Affordable cost

15. Interpretation of results The American College of Medical Genetics and Genomics (ACMG) has published guidelines for labs to use in their interpretation and scoring of genetic variation. East K, Chung W, Foreman K, Gilmore M, Gornick M et al. Guide to interpreting genomic reports: A genomics tookit . Page 5.

16. Implication of results and further counselling Results on NGS If Positive- Confirm with Sanger sequencing If Negative- do MLPA (multiplex ligation probe amplification) for large mutations Federici and soddu . Variant of uncertain significance in the era of high-throughput genomic sequencing: a lesson learnt from breast and ovary cancers. (2020) 39:46

17. If no deleterious germline mutation…

18. Post Test Counselling : Discussion of report Doctor/counsellor should be well versed about result and its implications. Sufficient time should be given to address patient’s concerns. Address psychosocial consequences. I nterpretation of results in context of personal and family history of cancer. D iscuss about recommended medical management options including screening, life style modifications and risk reducing surgeries and chemoprevention. importance of notifying and testing at risk family members. available resources such as high-risk clinics, disease-specific support groups and research studies.

19. Clinical implications and management of Genetic mutations

20. Clinical Implications of testing

21. Implications in HBOC Pathogenic/Likely pathogenic VUS Likely Benign/Benign a.Prognosis High platinum response ↑OS/PFS with HIPEC PARPi b.Cascade testing c. Preventive strategies Risk of OC BRCA 1:35-46% BRCA 2:13-23% Patient taken as proband No role of cascade testing If later variant classified as pathogenic/benign-convey to patient and relatives and manage accordingly No lab reports it as it may have fallacies

22. FDA approved PARP inhibitors

23. Management and risk reducing strategies in BRCA pathogenic/likely pathogenic variant-positive BREAST CANCER ◊ From 18 years of age- Awareness ◊ From 25 years of age- Clinical breast exam, every 6–12 months ◊ Age 25–29 years, annual breast MRI with contrast (or mammogram) or individualized based on family history if a breast cancer diagnosis before age 30 is present. ◊ Age 30–75 years, annual mammogram with consideration of tomosynthesis and breast MRI screening with contrast. ◊ Age >75 years, management should be considered on an individual basis. Mastectomy by 25 years ↓ BC by 90 % without BSO ↓ BC by 99 % with BSO Contralateral prophylactic mastectomy Not recommended in advanced Ca ovary Chemoprevention - Tab tamoxifen – Up to 62% reduction in BRCA 2 mutated cancers Contralateral breast cancer prevention in advanced breast Ca Counsel regarding reproductive desires, extent of cancer risk, degree of protection for breast and ovarian cancer, management of menopausal symptoms, hormone replacement therapy, and related medical issues.

24. Management and risk reducing strategies in BRCA pathogenic/likely pathogenic variant-positive OVARIAN CANCER ENDOMETRIAL CANCER ◊ Recommend RRSO BRCA 1: 35-40 yrs. BRCA 2: 40-45 yrs. RAD51C/RAD51D/BRIP1: 45-50 yrs. Other HRD: only if risk is > 5% Efficacy: BRCA1 ↓ BC 56% BRCA 2 ↓ BC 42% BRCA 1<2 ↓ OC by 96 % ◊ Patients without RRSO, TVS & CA-125, may be considered at the clinician’s discretion starting at age 30–35 y. Chemoprevention - In a meta-analysis, use of OCP significantly reduced the risk for ovarian cancer by ~ 50% for both the carriers of P/LP BRCA1/2 variant. Timing: Prior to first pregnancy: Interval between pregnancies After child bearing till RRSO Slight increase in risk of serous uterine carcinomas. Discuss risks and benefits of concurrent hysterectomy at the time of RRSO prior to surgery HRT after risk reducing hysterectomy- Estrogen -alone Combined estrogen and progesterone when uterus is left in situ

25. Conclusion: Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.

26. Conclusions:  Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer ; risk-reducing salpingo -oophorectomy was associated with a lower risk of ovarian cancer , first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality. M ulticenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. 

27. RRSO- in P/LP variant in an ovarian cancer susceptibility gene Decision to carry out RRSO not light, given the impact of premature menopause. A 1% to 4.3% residual risk for a primary peritoneal carcinoma has been reported. Technical considerations at RRSO- Peritoneal washing to be taken Entire ovary and fallopian tube removed. IPL ligated at least 2 cm from its insertion into ovary Occult gynecologic neoplasia were identified in 4.5% to 9% of cases in RRSO specimen- fine pathologic assessment of ovaries and fallopian tubes (SEEFIM) recommended. Lifetime risk Recommendation >= 10% Discussion regarding RRSO recommended 5% ( eg , PALB2) RRSO may be considered based on family history

28. Options for reproductive age group female Prenatal diagnosis: Early embryo- chorionic villi/amniotic fluid 12-16 weeks of gestation: couple counseled about MTP if needed Preimplantation genetic testing: 1-2 cells from embryos in early stage of development (6-8 weeks) IVF must even in fertile women Considerations Ethical, cultural and religious beliefs Socio-economic factors Availability of technology O'Connor, C. (2008) Prenatal screen detects fetal abnormalities.  Nature Education  1(1):106

29. Thank you

30. References Raby BA, Kohlmann W. Genetic counselling: Family history interpretation and risk assessment. UptoDate Whole exome sequencing. GC Genome Overseas Biz, June 11, 2020 East K, Chung W, Foreman K, Gilmore M, Gornick M et al. Guide to interpreting genomic reports: A genomics tookit . Page 5. Federici and soddu . Variant of uncertain significance in the era of high-throughput genomic sequencing: a lesson lerant from breast and ovary cancers. (2020) 39:46 Turashvii G, Colgan T, McLachlin M, Lin H and Gharbaran R. 2022. Lynch syndrome Screening of Women with Endometrial cancer: Feasibility and Outcomes in a community program. Journal of Obstetrics and Gynaecology Canada, 44(2),pp.142-147. Cancer risk for women carrying BRCA mutations was originally published by National Cancer Institute. https://www.cancer.gov/news-events/cancer-currents-blog/2017/brca-mutation-cancer-risk