Cancer Risk Assessment

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Cancer Risk Assessment

• Judith A Westman MD
• Clinical Director
• Division of Human Genetics

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Cancer risk assessment is a multi-step process
Provide post-test counseling and follow-up
Disclose results
Select and offer test
Provide informed consent
Identify hereditary risk patients
Provide risk assessment
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The cancer family history is the key to

• Accurate risk assessment
• Effective genetic counseling
• Appropriate medical follow-up

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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

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Breast Cancer

• Best model for risk assessment

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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)

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Gail model

• Breast Cancer Detection and Demonstration Project
• 2852 cases, 3146 matched controls
• J Natl Cancer Inst 811879-86, 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

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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

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Cancer and Steroid Hormone Study
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Three-generation pedigree
German/Polish
English/Irish
d. 52
d. 70
d. 85
d. 80
Breast Ca, dx 49
59
67
55
65
52
62
Breast Ca, dx 41
Diabetes, dx 45
35
30
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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?

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Misconceptions about family history

• MYTHS
• Cancer on the fathers side of the family
  doesnt 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.

• 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.

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Hereditary Breast and Ovarian Cancer
Sporadic
Hereditary
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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
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BRCA1-Associated Cancers Lifetime Risk
Breast cancer 50?85 (often early age at onset)
Second primary breast cancer 40?60
Ovarian cancer 15?45
Possible increased risk of other cancers (eg,
prostate, colon)
ASCO
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BRCA1-Linked Hereditary Breast and Ovarian Cancer
Breast, dx 59
BRCA1-mutation carrier
ASCO
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BRCA2-Associated Cancers Lifetime Risk
breast cancer (50?85)
male breast cancer (6)
ovarian cancer (10?20)
Increased risk of prostate, laryngeal, and
pancreatic cancers (magnitude unknown)
ASCO
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Westman experience (1996-2009) 5 positive
results
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TP53 mutation R181C
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Who to test?

• Use software tool (BRCAPro)
• Individuals cancer status
• History of breast and ovarian cancer in 1st and
  2nd degree relatives
• Number of affected vs unaffected in family
• Risk gt10 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

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Who to test?
German/Polish
English/Irish
d. 52
d. 70
d. 85
d. 80
Breast Ca, dx 49
59
67
55
65
52
62
Breast Ca, dx 41
Diabetes, dx 45
35
30
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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
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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 231656-1663
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BRCA risk modifiers

• Family history alone
• 3-7, breast
• 23 with pancr
• With path
• 7-10

Breast, 70s
Pancr, 73
Breast, 35 basal
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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
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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

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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 2006118(9)2281-4
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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
231656-1663
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Cancer risk reduction with prophylactic surgery
Domchek and Weber, Oncogene 2006 255825-5831
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Modifying risk for relatives
d. 49 Breast, 44
BRCA1
BRCA1 -
BRCA1
58 Fallopian tube, 53
56, Breast, 51 Ovarian, 51
BRCA1 -
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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

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Colorectal Cancer
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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

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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

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Cancer and Life Insurance
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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

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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 66531
Lemaire J et al (2000), N Am Actuarial 475
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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 9329
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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
120A359
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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?

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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.

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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.

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