1. Cancer Risk Assessment Judith A Westman MD Clinical Director Division of Human Genetics

2. Cancer risk assessment is a multi-step process Provide post-test counseling and follow-up Identify hereditary risk patients Provide risk assessment Provide informed consent Select and offer test Disclose results

5. Breast Cancer Best model for risk assessment

10. Cancer and Steroid Hormone Study

12. Three-generation pedigree Breast Ca, dx 41 35 German/Polish English/Irish Breast Ca, dx 49 d. 80 67 55 65 Diabetes, dx 45 52 30 d. 70 d. 85 59 62 d. 52

15. Hereditary Breast and Ovarian Cancer Sporadic Hereditary BRCA1 (62%) Other genes (16%) BRCA2 (32%) 7-10%

17. BRCA1 -Associated Cancers: Lifetime Risk ASCO Possible increased risk of other cancers (eg, prostate, colon) Breast cancer 50%  85% (often early age at onset) Second primary breast cancer 40%  60% Ovarian cancer 15%  45%

18. BRCA1 -Linked Hereditary Breast and Ovarian Cancer ASCO BRCA1 -mutation carrier Breast, dx 59 Noncarrier Affected with cancer Breast, dx 45 d. 89 92 86 73 68 Ovary, dx 59 d. 62 71 Breast, dx 36 36

19. BRCA2 -Associated Cancers: Lifetime Risk ASCO Increased risk of prostate, laryngeal, and pancreatic cancers (magnitude unknown) breast cancer (50%  85%) ovarian cancer (10%  20%) male breast cancer (6%)

21. Westman experience (1996-2009): 5 positive results

22. TP53 mutation R181C BrCa dx 43 Lymphoma, 9 Brain, 46 Renal Ca, 81 Bone, 18 Renal, 51 Brain, 12

26. Who to test? Breast Ca, dx 41 35 German/Polish English/Irish Breast Ca, dx 49 d. 80 67 55 65 Diabetes, dx 45 52 30 d. 70 d. 85 59 62 d. 52

30. Clinical Management of BRCA Mutation-Positive Patient Positive BRCA1 or BRCA2 test result Possible testing for other adult relatives Increased surveillance Prophylactic surgery Lifestyle changes Chemo- prevention ASCO

32. Chemoprevention of Breast Cancer in BRCA1/2 Carriers Tamoxifen Risk reduction of 50% or more in both BRCA1 and BRCA2 carriers Gronwald J et al, Int J Cancer 2006;118(9):2281-4

34. Cancer risk reduction with prophylactic surgery Domchek and Weber, Oncogene 2006; 25:5825-5831

35. Modifying risk for relatives 56, Breast, 51 Ovarian, 51 d. 49 Breast, 44 58 Fallopian tube, 53 BRCA1 + BRCA1 + BRCA1 - BRCA1 -

37. Colorectal Cancer

40. Cancer and Life Insurance