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.