Transcript Cancer Risk Assessment

Cancer Risk Assessment
Judith A Westman MD
Clinical Director
Division of Human Genetics
Cancer risk assessment is a
multi-step process
Identify
hereditary
risk
Provide risk
assessment patients
Provide
informed
consent
Select and
offer test
Disclose
results
Provide
post-test
counseling
and
follow-up
The cancer family history
is the key to:
Accurate risk
assessment
 Effective
genetic
counseling
 Appropriate
medical followup

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
German/Polish
d. 70
62
Breast Ca,
dx 41
English/Irish
d. 52
Breast Ca,
dx 49
67
65
d. 80
d. 85
55
59
Diabetes,
dx 45
35
30
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?
Misconceptions about family history
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.”
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
BRCA1
(62%)
Other
genes
(16%)
7-10%
Sporadic
Hereditary
BRCA2
(32%)
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
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
BRCA1-Linked Hereditary
Breast and Ovarian Cancer
92
73
68
Breast, dx 45 86
d. 89
71
Breast,
dx 36
Ovary, dx 59 Breast,
d. 62
dx 59
Noncarrier
BRCA1-mutation
carrier
Affected
with cancer
36
ASCO
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
Westman experience (1996-2009): 5 positive results
TP53 mutation R181C
Renal Ca,
81
Brain, 46
Bone, 18
Renal, 51
Brain, 12
Lymphoma,
9
BrCa
dx 43
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?
German/Polish
d. 70
62
Breast Ca,
dx 41
English/Irish
d. 52
Breast Ca,
dx 49
67
65
d. 80
d. 85
55
59
Diabetes,
dx 45
35
30
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
cancer
Narod SA, Offit K J Clin Oncol
2005; 23:1656-1663
BRCA risk modifiers
Breast,
70s
Pancr,
73
Breast,
35
basal
• Family history
alone
– 3-7%, breast
– 23% with pancr
• With path
– 7-10%
Clinical Management of
BRCA Mutation-Positive Patient
Positive BRCA1 or BRCA2
test result
Possible testing for
other adult relatives
Increased
surveillance
Lifestyle
changes
Chemoprevention
Prophylactic
surgery
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
d. 49
Breast, 44
BRCA1 +
58
Fallopian tube,
53
BRCA1 -
BRCA1 -
BRCA1 +
56,
Breast, 51
Ovarian, 51
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.