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Cancer Risk Assessment
Judith A Westman MD
Clinical Director
Division of Human Genetics
Cancer risk assessment is a multi-step process
Provide Provide post-test post-test counselincounselin
g and g and follow-upfollow-up
Identify Identify hereditarhereditar
y risk y risk patientspatients
Provide Provide risk risk
assessmenassessmentt
Provide Provide informed informed consentconsent
Select and Select and offer testoffer test
Disclose Disclose resultsresults
The cancer family history is the key to:
Accurate risk assessment
Effective genetic counseling
Appropriate medical follow-up
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
Breast Cancer
Best model for risk assessment
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)
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
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
Cancer and Steroid Hormone Study
Three-generation pedigree
Breast Ca,
dx 41
35
German/Polish English/Irish
Breast Ca, dx 49
d. 80
67 5565Diabetes,
dx 45
52
30
d. 70 d. 85
5962
d. 52
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?
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.
Hereditary Breast and Ovarian Cancer
Sporadic
BRCA1 (62%) Other Other
genesgenes
(16%)(16%)
BRCA2 (32%)
7-10%7-10%
Hereditary
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
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%
ASCO
BRCA1-Linked Hereditary Breast and Ovarian Cancer
Noncarrier
BRCA1-mutation carrier
Affected with cancer
Breast, dx 59
Breast, dx 45d. 89
92 86
73 68 Ovary, dx 59d. 62
71
Breast, dx 36
36
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%)
Westman experience (1996-2009): 5 positive results
TP53 mutation R181C
BrCadx 43Lymphoma,
9
Brain, 46
Renal Ca, 81
Bone, 18 Renal, 51
Brain, 12
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
Who to test?
Breast Ca,
dx 41
35
German/Polish English/Irish
Breast Ca, dx 49
d. 80
67 5565Diabetes,
dx 45
52
30
d. 70 d. 85
5962
d. 52
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
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
cancerNarod SA, Offit K J Clin Oncol 2005;
23:1656-1663
BRCA risk modifiers
• Family history alone– 3-7%, breast– 23% with pancr
• With path– 7-10%
Breast, 70s
Pancr, 73
Breast, 35
basal
Clinical Management of BRCA Mutation-Positive Patient
Positive BRCA1 or BRCA2 test result
Possible testing for other adult relatives
Increasedsurveillance
Prophylacticsurgery
Lifestyle changes
Chemo-prevention
ASCO
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
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
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
Cancer risk reduction with prophylactic surgery
Domchek and Weber, Oncogene 2006; 25:5825-5831
Modifying risk for relatives
56, Breast, 51Ovarian, 51
d. 49Breast, 44
58Fallopian tube,
53
BRCA1 +BRCA1 + BRCA1 -
BRCA1 -
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
Colorectal Cancer
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
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
Cancer and Life Insurance
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
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
“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
“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
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?
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.
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.