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Cancer Risk Assessment

Cancer Risk Assessment . Judith A Westman MD Clinical Director Division of Human Genetics. Cancer risk assessment is a multi-step process. Provide post-test counseling and follow-up. Disclose results. Select and offer test. Provide informed consent. Identify hereditary risk patients.

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Cancer Risk Assessment

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  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 Disclose results Select and offer test Provide informed consent Identify hereditary risk patients Provide risk assessment

  3. The cancer family history is the key to: • Accurate risk assessment • Effective genetic counseling • 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

  8. 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

  9. Cancer and Steroid Hormone Study

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

  11. 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?

  12. 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. 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.”

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

  14. 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 ASCO

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

  16. 92 Breast, dx 45 d. 89 86 Noncarrier Ovary, dx 59 d. 62 73 68 71 Affected with cancer Breast, dx 36 36 BRCA1-Linked Hereditary Breast and Ovarian Cancer Breast, dx 59 BRCA1-mutation carrier ASCO

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

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

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

  20. Who to test? • Use software tool (BRCAPro) • Individual’s cancer status • History of breast and ovarian cancer in 1st and 2nd 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

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

  22. 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

  23. 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

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

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

  26. 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

  27. 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

  28. 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

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

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

  31. 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

  32. Colorectal Cancer

  33. 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

  34. 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

  35. Cancer and Life Insurance

  36. 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

  37. 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

  38. “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

  39. “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

  40. 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?

  41. 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.

  42. 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.

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