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

3. The cancer family history is the key to: l Accurate risk assessment l Effective genetic counseling l Appropriate medical follow- up

4. Taking a cancer family history Obtain at least a three-generation pedigree Ask about all individuals in the family and record: –age at cancer diagnosis, age at and cause of death –primary vs metastatic cancer –precursor lesions, bilateral cancer Record ethnicity and race Verify with medical records when possible

5. Breast Cancer Best model for risk assessment

6. Cancer Risk Assessment (for high risk breast cancer) Attempts to assist patient in understanding: –Medical facts –Mode of inheritance –Risk of getting breast and/or ovarian cancer (again) –Implications for daily life Options for dealing with the risk –Breast surveillance –DNA testing –Prophylactic mastectomy and/or oophorectomy –Chemoprevention (tamoxifen, SERM, OCP)

7. Gail model Breast Cancer Detection and Demonstration Project –2852 cases, 3146 matched controls –J Natl Cancer Inst 81:1879-86, 1989 Used to determine lifetime breast cancer occurrence risk Used to determine appropriateness for prophylactic tamoxifen therapy Incorporates –Age –Reproductive history –Benign breast disease history –Breast cancers in mother or sisters

9. Pitfalls of Gail model Does not include other cancers in model –Ovarian, pancreatic, thyroid, male breast Does not include second-degree relatives –Aunts, uncles, grandparents Does not include paternal side Does not include age of breast cancer diagnosis in relatives

10. Cancer and Steroid Hormone Study

12. Three-generation pedigree Breast Ca, dx 41 35 German/PolishEnglish/Irish Breast Ca, dx 49 d. 80 6755 65 Diabetes, dx 45 52 30 d. 70 d. 85 59 62 d. 52

13. Claus risk for breast cancer Claus table for two second-degree relatives Probability to age 79 = 20.9% –To age 39 = 2.4% –To age 49 = 6.1% –To age 59 = 11.4% –To age 69 = 16.9% Risk can be “used up” –A 59 year old woman with no cancer 20.9% risk of breast cancer by age 79? Or 9.5% risk of breast cancer by age 79?

14. MYTHS: “Cancer on the father’s side of the family doesn’t count.” “Ovarian cancer in the family history is not a factor in breast cancer risk.” “The most important thing in the family history is the number of women with breast cancer.” Misconceptions about family history TRUTHS: Half of all women with hereditary risk inherited it from their father. Ovarian cancer is an important indicator of hereditary risk, although it is not always present. Age of onset of breast cancer is more important than the number of women with the disease.

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

16. ASCO Features that indicate increased likelihood of having BRCA mutations Multiple cases of early onset breast cancer Ovarian cancer (with family history of breast or ovarian cancer) Breast and ovarian cancer in the same woman Bilateral breast cancer Ashkenazi Jewish heritage Male breast cancer

17. ASCO BRCA1-Associated Cancers: Lifetime Risk 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. ASCO BRCA1-Linked Hereditary Breast and Ovarian Cancer Noncarrier BRCA1-mutation carrier Affected with cancer Breast, dx 59 Breast, dx 45 d. 89 9286 7368 Ovary, dx 59 d. 62 71 Breast, dx 36 36

19. ASCO BRCA2-Associated Cancers: Lifetime Risk 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, 18Renal, 51 Brain, 12

25. Who to test? Use software tool (BRCAPro) –Individual’s cancer status –History of breast and ovarian cancer in 1 st and 2 nd degree relatives –Number of affected vs unaffected in family –Risk >10% with clear benefit Person affected with cancer –Early onset breast preferably –Ovarian at any age Any Ashkenazi Jewish or Icelandic person Any person in family with known mutation Most health insurers have published guidelines

26. Who to test? Breast Ca, dx 41 35 German/PolishEnglish/Irish Breast Ca, dx 49 d. 80 6755 65 Diabetes, dx 45 52 30 d. 70 d. 85 59 62 d. 52

27. Risk assessment 35 year old daughter –Claus, 19.5% lifetime risk for breast cancer –Risk of carrying BRCA gene = 2-9% 67 year old father –Risk of carrying BRCA gene = 5-9% 62 year old aunt, cancer at 41 –Risk of carrying BRCA gene = 9-15% Upper risk figures from Myriad Laboratory, lower from BRCAPro

28. Use of pathology to refine risk BRCA1 breast tumors –80% basal subtype (triple negative) –DCIS rare in carriers vs controls (now under reconsideration) BRCA2 breast tumors –Typical distribution of molecular subtypes Ovary –Predominantly papillary serous adenocarcinoma –Prognosis may be better than for sporadic ovarian cancer Narod SA, Offit K J Clin Oncol 2005; 23:1656-1663

29. BRCA risk modifiers Family history alone –3-7%, breast –23% with pancr With path –7-10% Breast, 70s Pancr, 73 Breast, 35 basal

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

31. Primary prevention of breast cancer Prevents cancers from occurring in the first place Prophylactic mastectomy Lifestyle changes –Breast feeding (BRCA1) –Small family size (BRCA2) –Exercise, maintain stable weight Pre-menopausal oophorectomy (~40 years) Chemoprevention

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

33. Secondary prevention of breast cancers in BRCA1/2 carriers Early detection of tumors when surgery alone would be feasible Early clinical surveillance (begin at age 25) –Clinical breast exams every 6-12 months –Annual mammography –Monthly breast self-exams Breast MRI instead of mammography Narod SA, Offit K J Clin Oncol 2005; 23:1656-1663

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 -

36. Other breast cancer syndromes Li Fraumeni syndrome –Clearance of individual if mutation negative and mutation is known in family –Few prophylactic options available for mutation positive Cowden syndrome –Clearance of individual if mutation negative and mutation is known in family –Few prophylactic options available for mutation positive

37. Colorectal Cancer

38. Colorectal cancer 5% strongly inherited risk –Familial adenomatous polyposis –MUTYH-associated polyposis –Lynch syndrome (hereditary nonpolyposis colorectal cancer) Colon cancer, predominately right sided early onset (60%) Endometrial cancer (50% of women) Ovarian cancer (10-15% of women) Genetic testing available for all

39. Risk alteration in hereditary CRC Clearance if individual is mutation negative and mutation is known in family Mutation positive –FAP Prophylactic colectomy, other sites problematic –MAP Prophylactic colectomy, not known to affect other sites –Lynch Annual colonoscopy, hysterectomy/oophorectomy

40. Cancer and Life Insurance

41. Actuarial fairness Usually, lower premiums for women vs men In breast cancer risk –Higher premium for women with higher risks of dying from breast cancer Adverse selection –Individuals with known high risk purchase more insurance –Individuals with known lower risk do not purchase as much insurance

42. Philadelphia group Pricing term insurance in BRCA1/2 Markov model Both written when more medical uncertainty present about BRCA1/2 risks –Used 65% lifetime breast cancer risk –Used 40% lifetime ovarian cancer risk Suggest gathering as much information about family history as possible during the underwriting process –Include all relatives with cancer and ages of onset Subramanian K et al (1999), J Risk Insur 66:531; Lemaire J et al (2000), N Am Actuarial 4:75

43. “Genetic testing, adverse selection, and the demand for life insurance” Salt Lake City 105 women in large BRCA1 family, 18-55 yr old, no personal cancer hx, no employer life insurance –27% tested positive for BRCA1 mutation –62% employed –66% with life insurance $83,750 average policy –No correlation with immediate family history or mutation status No evidence of adverse selection Zick et al (2000), Am J Med Genet 93:29

44. “Life insurance and breast cancer risk assessment” (2003) Philadelphia group again 636 women with risk assessment (72% insured) –238 underwent testing –109 individuals with positive BRCA1/2 55% with significant fear of life insurance discrimination No reports of denial or cancellation after counseling 27 increased coverage (4%) –9 pos, 5 neg, 13 untested 6 decreased (1%) –1 pos, 2 neg, 3 untested K Armstrong et al (2003), Am J Med Genetics 120A:359

45. Genetic Information Nondiscrimination Act (2008) Prevents health insurers from denying coverage, adjusting premiums, or otherwise discriminating on the basis of genetic information. –Group and self-insured policies Health insurers may not request that an individual undergo a genetic test. Employers cannot use genetic information to make hiring, firing, compensation, or promotion decisions. Sharply limits a health insurer's or employer's right to request, require, or purchase someone's genetic information. Language for life insurers?

46. Points to ponder (1) Unfounded fear of life insurance discrimination may reduce use of risk assessment and preventive services In the absence of genetic testing results, family history of first- and second-degree relatives is effective in establishing risk. First-degree relatives alone are insufficient.

47. Points to ponder (2) Mutation negative individuals should be considered for standard underwriting. Risk reduction intervention in mutation positive individuals may cause reduction in overall mortality, benefitting patients and insurers alike. Use of primary prevention methods could facilitate standard underwriting for mutation positive individuals.