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Risk Appraisal Forum 2009 Westman

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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 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:
      • 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.  
    • 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
    • 11.  
    • 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
    • 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 Hereditary BRCA1 (62%) Other genes (16%) BRCA2 (32%) 7-10%
    • 16. 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
    • 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%)
    • 20.  
    • 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
    • 23.  
    • 24.  
    • 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/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
    • 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 + 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.
    • 48.