Risk Appraisal Forum 2009 Westman


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  • Risk Appraisal Forum 2009 Westman

    1. 1. Cancer Risk Assessment Judith A Westman MD Clinical Director Division of Human Genetics
    2. 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. 3. The cancer family history is the key to: <ul><li>Accurate risk assessment </li></ul><ul><li>Effective genetic counseling </li></ul><ul><li>Appropriate medical follow-up </li></ul>
    4. 4. Taking a cancer family history <ul><li>Obtain at least a three-generation pedigree </li></ul><ul><li>Ask about all individuals in the family and record: </li></ul><ul><ul><li>age at cancer diagnosis, age at and cause of death </li></ul></ul><ul><ul><li>primary vs metastatic cancer </li></ul></ul><ul><ul><li>precursor lesions, bilateral cancer </li></ul></ul><ul><li>Record ethnicity and race </li></ul><ul><li>Verify with medical records when possible </li></ul>
    5. 5. Breast Cancer Best model for risk assessment
    6. 6. Cancer Risk Assessment (for high risk breast cancer) <ul><li>Attempts to assist patient in understanding: </li></ul><ul><ul><li>Medical facts </li></ul></ul><ul><ul><li>Mode of inheritance </li></ul></ul><ul><ul><li>Risk of getting breast and/or ovarian cancer (again) </li></ul></ul><ul><ul><li>Implications for daily life </li></ul></ul><ul><li>Options for dealing with the risk </li></ul><ul><ul><li>Breast surveillance </li></ul></ul><ul><ul><li>DNA testing </li></ul></ul><ul><ul><li>Prophylactic mastectomy and/or oophorectomy </li></ul></ul><ul><ul><li>Chemoprevention (tamoxifen, SERM, OCP) </li></ul></ul>
    7. 7. Gail model <ul><li>Breast Cancer Detection and Demonstration Project </li></ul><ul><ul><li>2852 cases, 3146 matched controls </li></ul></ul><ul><ul><li>J Natl Cancer Inst 81:1879-86, 1989 </li></ul></ul><ul><li>Used to determine lifetime breast cancer occurrence risk </li></ul><ul><li>Used to determine appropriateness for prophylactic tamoxifen therapy </li></ul><ul><li>Incorporates </li></ul><ul><ul><li>Age </li></ul></ul><ul><ul><li>Reproductive history </li></ul></ul><ul><ul><li>Benign breast disease history </li></ul></ul><ul><ul><li>Breast cancers in mother or sisters </li></ul></ul>
    8. 9. Pitfalls of Gail model <ul><li>Does not include other cancers in model </li></ul><ul><ul><li>Ovarian, pancreatic, thyroid, male breast </li></ul></ul><ul><li>Does not include second-degree relatives </li></ul><ul><ul><li>Aunts, uncles, grandparents </li></ul></ul><ul><li>Does not include paternal side </li></ul><ul><li>Does not include age of breast cancer diagnosis in relatives </li></ul>
    9. 10. Cancer and Steroid Hormone Study
    10. 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
    11. 13. Claus risk for breast cancer <ul><li>Claus table for two second-degree relatives </li></ul><ul><li>Probability to age 79 = 20.9% </li></ul><ul><ul><li>To age 39 = 2.4% </li></ul></ul><ul><ul><li>To age 49 = 6.1% </li></ul></ul><ul><ul><li>To age 59 = 11.4% </li></ul></ul><ul><ul><li>To age 69 = 16.9% </li></ul></ul><ul><li>Risk can be “used up” </li></ul><ul><ul><li>A 59 year old woman with no cancer </li></ul></ul><ul><ul><ul><li>20.9% risk of breast cancer by age 79? </li></ul></ul></ul><ul><ul><ul><li>Or 9.5% risk of breast cancer by age 79? </li></ul></ul></ul>
    12. 14. <ul><li>MYTHS: </li></ul><ul><li>“ Cancer on the father’s side of the family doesn’t count.” </li></ul><ul><li>“ Ovarian cancer in the family history is not a factor in breast cancer risk.” </li></ul><ul><li>“ The most important thing in the family history is the number of women with breast cancer.” </li></ul>Misconceptions about family history <ul><li>TRUTHS: </li></ul><ul><li>Half of all women with hereditary risk inherited it from their father. </li></ul><ul><li>Ovarian cancer is an important indicator of hereditary risk, although it is not always present. </li></ul><ul><li>Age of onset of breast cancer is more important than the number of women with the disease. </li></ul>
    13. 15. Hereditary Breast and Ovarian Cancer Sporadic Hereditary BRCA1 (62%) Other genes (16%) BRCA2 (32%) 7-10%
    14. 16. Features that indicate increased likelihood of having BRCA mutations <ul><li>Multiple cases of early onset breast cancer </li></ul><ul><li>Ovarian cancer (with family history of breast or ovarian cancer) </li></ul><ul><li>Breast and ovarian cancer in the same woman </li></ul><ul><li>Bilateral breast cancer </li></ul><ul><li>Ashkenazi Jewish heritage </li></ul><ul><li>Male breast cancer </li></ul>ASCO
    15. 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%
    16. 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
    17. 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%)
    18. 21. Westman experience (1996-2009): 5 positive results
    19. 22. TP53 mutation R181C BrCa dx 43 Lymphoma, 9 Brain, 46 Renal Ca, 81 Bone, 18 Renal, 51 Brain, 12
    20. 25. Who to test? <ul><li>Use software tool (BRCAPro) </li></ul><ul><ul><li>Individual’s cancer status </li></ul></ul><ul><ul><li>History of breast and ovarian cancer in 1 st and 2 nd degree relatives </li></ul></ul><ul><ul><li>Number of affected vs unaffected in family </li></ul></ul><ul><ul><li>Risk >10% with clear benefit </li></ul></ul><ul><li>Person affected with cancer </li></ul><ul><ul><li>Early onset breast preferably </li></ul></ul><ul><ul><li>Ovarian at any age </li></ul></ul><ul><li>Any Ashkenazi Jewish or Icelandic person </li></ul><ul><li>Any person in family with known mutation </li></ul><ul><li>Most health insurers have published guidelines </li></ul>
    21. 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
    22. 27. Risk assessment <ul><li>35 year old daughter </li></ul><ul><ul><li>Claus, 19.5% lifetime risk for breast cancer </li></ul></ul><ul><ul><li>Risk of carrying BRCA gene = 2-9% </li></ul></ul><ul><li>67 year old father </li></ul><ul><ul><li>Risk of carrying BRCA gene = 5-9% </li></ul></ul><ul><li>62 year old aunt, cancer at 41 </li></ul><ul><ul><li>Risk of carrying BRCA gene = 9-15% </li></ul></ul>Upper risk figures from Myriad Laboratory, lower from BRCAPro
    23. 28. Use of pathology to refine risk <ul><li>BRCA1 breast tumors </li></ul><ul><ul><li>80% basal subtype (triple negative) </li></ul></ul><ul><ul><li>DCIS rare in carriers vs controls (now under reconsideration) </li></ul></ul><ul><li>BRCA2 breast tumors </li></ul><ul><ul><li>Typical distribution of molecular subtypes </li></ul></ul><ul><li>Ovary </li></ul><ul><ul><li>Predominantly papillary serous adenocarcinoma </li></ul></ul><ul><ul><li>Prognosis may be better than for sporadic ovarian cancer </li></ul></ul>Narod SA, Offit K J Clin Oncol 2005; 23:1656-1663
    24. 29. BRCA risk modifiers <ul><li>Family history alone </li></ul><ul><ul><li>3-7%, breast </li></ul></ul><ul><ul><li>23% with pancr </li></ul></ul><ul><li>With path </li></ul><ul><ul><li>7-10% </li></ul></ul>Breast, 70s Pancr, 73 Breast, 35 basal
    25. 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
    26. 31. Primary prevention of breast cancer <ul><li>Prevents cancers from occurring in the first place </li></ul><ul><li>Prophylactic mastectomy </li></ul><ul><li>Lifestyle changes </li></ul><ul><ul><li>Breast feeding ( BRCA1 ) </li></ul></ul><ul><ul><li>Small family size ( BRCA2 ) </li></ul></ul><ul><ul><li>Exercise, maintain stable weight </li></ul></ul><ul><li>Pre-menopausal oophorectomy (~40 years) </li></ul><ul><li>Chemoprevention </li></ul>
    27. 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
    28. 33. Secondary prevention of breast cancers in BRCA1/2 carriers <ul><li>Early detection of tumors when surgery alone would be feasible </li></ul><ul><li>Early clinical surveillance (begin at age 25) </li></ul><ul><ul><li>Clinical breast exams every 6-12 months </li></ul></ul><ul><ul><li>Annual mammography </li></ul></ul><ul><ul><li>Monthly breast self-exams </li></ul></ul><ul><li>Breast MRI instead of mammography </li></ul>Narod SA, Offit K J Clin Oncol 2005; 23:1656-1663
    29. 34. Cancer risk reduction with prophylactic surgery Domchek and Weber, Oncogene 2006; 25:5825-5831
    30. 35. Modifying risk for relatives 56, Breast, 51 Ovarian, 51 d. 49 Breast, 44 58 Fallopian tube, 53 BRCA1 + BRCA1 + BRCA1 - BRCA1 -
    31. 36. Other breast cancer syndromes <ul><li>Li Fraumeni syndrome </li></ul><ul><ul><li>Clearance of individual if mutation negative and mutation is known in family </li></ul></ul><ul><ul><li>Few prophylactic options available for mutation positive </li></ul></ul><ul><li>Cowden syndrome </li></ul><ul><ul><li>Clearance of individual if mutation negative and mutation is known in family </li></ul></ul><ul><ul><li>Few prophylactic options available for mutation positive </li></ul></ul>
    32. 37. Colorectal Cancer
    33. 38. Colorectal cancer <ul><li>5% strongly inherited risk </li></ul><ul><ul><li>Familial adenomatous polyposis </li></ul></ul><ul><ul><li>MUTYH-associated polyposis </li></ul></ul><ul><ul><li>Lynch syndrome (hereditary nonpolyposis colorectal cancer) </li></ul></ul><ul><ul><ul><li>Colon cancer, predominately right sided early onset (60%) </li></ul></ul></ul><ul><ul><ul><li>Endometrial cancer (50% of women) </li></ul></ul></ul><ul><ul><ul><li>Ovarian cancer (10-15% of women) </li></ul></ul></ul><ul><li>Genetic testing available for all </li></ul>
    34. 39. Risk alteration in hereditary CRC <ul><li>Clearance if individual is mutation negative and mutation is known in family </li></ul><ul><li>Mutation positive </li></ul><ul><ul><li>FAP </li></ul></ul><ul><ul><ul><li>Prophylactic colectomy, other sites problematic </li></ul></ul></ul><ul><ul><li>MAP </li></ul></ul><ul><ul><ul><li>Prophylactic colectomy, not known to affect other sites </li></ul></ul></ul><ul><ul><li>Lynch </li></ul></ul><ul><ul><ul><li>Annual colonoscopy, hysterectomy/oophorectomy </li></ul></ul></ul>
    35. 40. Cancer and Life Insurance
    36. 41. Actuarial fairness <ul><li>Usually, lower premiums for women vs men </li></ul><ul><li>In breast cancer risk </li></ul><ul><ul><li>Higher premium for women with higher risks of dying from breast cancer </li></ul></ul><ul><li>Adverse selection </li></ul><ul><ul><li>Individuals with known high risk purchase more insurance </li></ul></ul><ul><ul><li>Individuals with known lower risk do not purchase as much insurance </li></ul></ul>
    37. 42. Philadelphia group <ul><li>Pricing term insurance in BRCA1/2 </li></ul><ul><li>Markov model </li></ul><ul><li>Both written when more medical uncertainty present about BRCA1/2 risks </li></ul><ul><ul><li>Used 65% lifetime breast cancer risk </li></ul></ul><ul><ul><li>Used 40% lifetime ovarian cancer risk </li></ul></ul><ul><li>Suggest gathering as much information about family history as possible during the underwriting process </li></ul><ul><ul><li>Include all relatives with cancer and ages of onset </li></ul></ul>Subramanian K et al (1999), J Risk Insur 66:531; Lemaire J et al (2000), N Am Actuarial 4:75
    38. 43. “ Genetic testing, adverse selection, and the demand for life insurance” <ul><li>Salt Lake City </li></ul><ul><li>105 women in large BRCA1 family, 18-55 yr old, no personal cancer hx, no employer life insurance </li></ul><ul><ul><li>27% tested positive for BRCA1 mutation </li></ul></ul><ul><ul><li>62% employed </li></ul></ul><ul><ul><li>66% with life insurance </li></ul></ul><ul><ul><ul><li>$83,750 average policy </li></ul></ul></ul><ul><ul><li>No correlation with immediate family history or mutation status </li></ul></ul><ul><li>No evidence of adverse selection </li></ul>Zick et al (2000), Am J Med Genet 93:29
    39. 44. “ Life insurance and breast cancer risk assessment” (2003) <ul><li>Philadelphia group again </li></ul><ul><li>636 women with risk assessment (72% insured) </li></ul><ul><ul><li>238 underwent testing </li></ul></ul><ul><ul><li>109 individuals with positive BRCA1/2 </li></ul></ul><ul><li>55% with significant fear of life insurance discrimination </li></ul><ul><li>No reports of denial or cancellation after counseling </li></ul><ul><li>27 increased coverage (4%) </li></ul><ul><ul><li>9 pos, 5 neg, 13 untested </li></ul></ul><ul><li>6 decreased (1%) </li></ul><ul><ul><li>1 pos, 2 neg, 3 untested </li></ul></ul>K Armstrong et al (2003), Am J Med Genetics 120A:359
    40. 45. Genetic Information Nondiscrimination Act (2008) <ul><li>Prevents health insurers from denying coverage, adjusting premiums, or otherwise discriminating on the basis of genetic information. </li></ul><ul><ul><li>Group and self-insured policies </li></ul></ul><ul><li>Health insurers may not request that an individual undergo a genetic test. </li></ul><ul><li>Employers cannot use genetic information to make hiring, firing, compensation, or promotion decisions. </li></ul><ul><li>Sharply limits a health insurer's or employer's right to request, require, or purchase someone's genetic information. </li></ul><ul><li>Language for life insurers? </li></ul>
    41. 46. Points to ponder (1) <ul><li>Unfounded fear of life insurance discrimination may reduce use of risk assessment and preventive services </li></ul><ul><li>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. </li></ul>
    42. 47. Points to ponder (2) <ul><li>Mutation negative individuals should be considered for standard underwriting. </li></ul><ul><li>Risk reduction intervention in mutation positive individuals may cause reduction in overall mortality, benefitting patients and insurers alike. </li></ul><ul><li>Use of primary prevention methods could facilitate standard underwriting for mutation positive individuals. </li></ul>