Transcript The Cancer Pedigree

The Cancer Pedigree
BRCA What?
Outline
• Introduction: Understanding the weight of genetics in Ovarian
Breast Cancer
• BRCA 1 and BRCA 2 Genes
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Function
Incidence
Cancer Risk
Who should get tested?
Family History
• Genetic Testing
• A positive result
– What does it mean?
– What are your options?
Understanding the weight of genetics
in Ovarian Breast Cancer
• Association of Cancer with Germline
mutations
– Less than 10 percent of all breast cancers
– less than 15 percent of ovarian cancers
– The majority of hereditary breast and ovarian
cancers are associated with mutations in two
genes: breast cancer type 1 and 2 susceptibility
genes (BRCA1 and BRCA2) (table 1).
COMPARISON OF RISK BETWEEN FAMILY HISTORY, GENETIC MUTATION
CARRIERS and THE GENERAL POPULATION
Percent of Percent of
Population All Cases
Average
Risk to age
70
Positive Family History of Breast
cancer
10
15-20
10-13
Positive BRCA 1 or 2 mutation
0.1
5-6
50-85
General Population without
positive family history or BRCA
mutation
90
80-85
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BRCA 1 and BRCA 2
• Why are they so important?
– BRCA 1 and 2 are tumor suppressor genes
– Role:
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Maintenance of genome integrity
Repair of double strand DNA breaks
Control of cell cycle check point responses
Chromosomal segregation
– GERM LINE Mutations:
• loss of one wild type one functional allele vs two
• those with tumors usually demonstrate loss of other wild
type through somatic mutation or loss of heterozygosity
Genetics:
Random mutation rate: 1 per 106 cell divisions
• Probability of two acquired gene mutations,
same locus: 1 x 1012
• Hereditary cancers occur because one
inherited gene copy is already damaged at
birth
• Shifts prevalence and age incidence for
hereditary cancers
Cell Cycle: Made Easy
DNA
Repair
Genes:
BRCA1
BRCA2
Cell cycle image
INCIDENCE
• Estimated at 1/800- 1/1000 per gene
– Higher prevalence in individuals with personal or
family history of breast or ovarian cancer
– Usually younger onset
• Geographic/ Ethnic Variation
– Ashkenazi Jews: up to 2 %
– Also Netherlands, Sweden, Hungary, Iceland,
French Canada
Cancer Risk in Positive Individuals
• Autosomal Dominance
• High Penetrance
• Women
– Lifetime risk:
• Breast: 50-85%
• Ovarian: 15-40%
• Males (BRCA 2 data)
– Lifetime risk:
• Breast : 10%
• Prostate: 5-7 fold increase
Genetics:
Random mutation rate: 1 per 106 cell divisions
• Probability of two acquired gene mutations,
same locus: 1 x 1012
• Hereditary cancers occur because one
inherited gene copy is already damaged at
birth
• Shifts prevalence and age incidence for
hereditary cancers
Should I get tested?
Non Jewish Families
High risk Breast- ovarian: any one of the following
One case of breast cancer < 40 years old in first or second degree relative
One first or second degree relative with both breast and ovarian cancer
Two cases of breast cancer in first or second degree relative if one is diagnosed <50 years of age or is bilateral
One first or second-degree relative with breast cancer diagnosed at ≤50-years-old or bilateral and one first or second-degree
relative with ovarian cancer
Three cases of breast and ovarian cancer (at least one case of ovarian cancer) in first or second-degree relatives
Two cases of ovarian cancer in first or second-degree relative
One case of male breast cancer in a first or second-degree relative if another first or second degree relative has (male or female)
breast or ovarian cancer
Moderate risk* breast; any of the following:
Two first-degree relatives if both diagnosed between 51 and 60 years of age
One first degree and one second-degree relative (mother or sister and maternal aunt or maternal grandmother), if the sum of
their ages is ≤118-years-old
Moderate risk ovarian:
One first-degree relative with ovarian cancer
Jewish Families
High risk* breast-ovarian; any of the following:
One case of breast cancer ≤50-years-old in a first or second-degree relative
One case of ovarian cancer at any age in a first or second-degree relative
A first or second degree relative with breast cancer at any age if another first or
second degree relative has breast and/or ovarian cancer at any age
One case of male breast cancer in a first or second-degree relative
High Risk: this means you have a family history suggestive of hereditary cancer
susceptibility syndrome and may benefit from referral to a cancer genetics
professional and increased surveillance.
Note: Those women with family history and known BRCA mutation should follow
different guidelines
Moderate risk: family history not diagnostic for increased risk, but still with
increased risk for cancer and requiring increased surveillance.
General Information about the BRCA
genetic testing
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Should be done by an expert.
Expensive test  roughly $3000.00
www.genetests.org
Insurance Reimbursement: most insurance
companies cover roughly 90%
– May need letter of medical necessity
• Do the results affect my health or life insurance?
– You are protected by a federal law known as the
“Genetic Information Nondiscrimination Act (GINA)
– This prohibits health insurers and employers from
using your genetic information
What Your Result Means
• If you test positive:
– This means a deleterious mutation was identified in
BRCA1 or BRCA2
– This mutation is known to be associated with
increased risk for cancer
• If you test negative:
– If you have a family history of familial BRCA mutation,
this means your risk of developing cancer is lower
– Chances of false negative results exist, should still
undergo surveillance if coming from high risk family
What a positive test means for Cancer
• Your lifetime risk of breast cancer is:
– 55-85% for BRCA1
– 50-85% for BRCA 2
• Your lifetime risk of ovarian cancer is:
– 35-46 % for BRCA1
– 13-23% for BRCA2
You tested positive: What are your
options?
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Screening
– Starting at 18 years of age:
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Monthly Breast Self Exam: table with instructions
– Starting at 25 years of age:
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Professional Breast Exam every 6 months
Yearly mammogram
Yearly MRI
– Ovarian: less accurate than breast
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Includes blood test and pelvic ultrasound every 6 months beginning at age 35 or 5-10 years before
youngest known cancer case
Surgical Intervention: preventative
– Mastectomy: both breasts removed “bilateral prophylactic mastectomy), decreases
development of breast cancer by 90%
– Removal of ovaries:: “prophylactic bilateral salpingo-oopherectomy”. Reduces risk of cancer
development in the pelvis by 80-90 % and breast cancer by 50-60%
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Medical Management:
– Tamoxifen Therapy: reduces risk of breast cancer in women who have a BRCA mutation
– Hormonal birth control: decrease risk of ovarian cancer (however concerns regarding risk of
increased breast cancer risk)
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Combination of all 3
Bilateral Mastectomy
Robotic Surgery: TOH BOS
Ovarian Cancer Paradigm of
Illness: Future Shift
Trimodal Survival Distribution
35%
Cured
50%
Chr Disease
15%
Term Phase