Risk Appraisal Forum 2009 Westman

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

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 55 65 Diabetes, dx 45 52 30 d. 70 d. 85 59 62 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 Hereditary BRCA1 (62%) Other genes (16%) BRCA2 (32%) 7-10%

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 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%

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

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%)

Westman experience (1996-2009): 5 positive results

TP53 mutation R181C BrCa dx 43 Lymphoma, 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 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

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

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
62 year old aunt, cancer at 41
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 cancer
Narod 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 Increased surveillance Prophylactic surgery 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, 51 Ovarian, 51 d. 49 Breast, 44 58 Fallopian 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.

Risk Appraisal Forum 2009 Westman

by fondas vak on Jan 31, 2010

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Risk Appraisal Forum 2009 Westman — Presentation Transcript