Transcript Who should be screened for hereditary breast and ovarian

Hereditary breast
and ovarian cancer
Who should be screened and
How?
Symposium on Cancer
Waterloo Inn
October 31, 2007
Mala Bahl, MD, MSc
Objectives
• Describe genetic syndromes associated with
breast and ovarian cancers
• Identify those at high risk for hereditary breast
or ovarian cancer
• Review cancer screening and risk reduction
measures relative to the general population
• Review referral opportunities for such
patients
• This presentation contains no conflicts
of interest
General population risk
• Breast cancer
– 10.6%
– 1 in 9 women
• Ovarian Cancer
– 1.5%
– 1 in 70 women
Breast Cancer Risk Factors
• Familial/genetic
– 1st degree relatives at 1.5-3 x risk
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Age
Reproductive/hormonal
Lifestyle
Environmental
Previous breast disease
The majority of cases have no identifiable risk factor!
Contribution of Family History
5-10%
Sporadic
~15-20%
Familial
clustering
75%
Hereditary
• 15-20% have an affected 1st/2nd degree relative
• ~5% -Family history suggests high-risk gene mutation
• Majority are “sporadic”
Two hit hypothesis
Sporadic cancer
? age 30-50
?age 50-70
Two hit hypothesis
Sporadic cancer
? age 30-50
Hereditary cancer
?age 50-70
Familial Vs Hereditary
• Familial Clustering
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2  cases in a family
Not necessarily young cases (cases >60 years)
Not necessarily related cancers
No clear pattern seen
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Shared genetics
Shared environment
Shared lifestyle
Chance
Familial Cancer
John 65
Agnes
Breast 76
Mary
Breast 60
Jean
Fred 41
Cervical 39
Charles 74
Prostate 68
Susan 37 Lori 33
Louise d.62
Colon 59
Michael 30
Familial Vs Hereditary
• Hereditary
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Multiple generations with same cancer
Early onset
>1 cancer / individual especially in paired organs
Pattern fits with known cancer syndrome
Presence of rare cancers
• Most are autosomal dominant with
incomplete penetrance (like BRCA1 and 2!)
Hereditary
Normal
Ovary, 40
Susceptible Carrier
Carrier, affected
Breast, 45
Sporadic
Colon, 67


Breast,50
Ovary
50
Breast, 35
May appear to “skip” generations (penetrance)
Inheritance of cancer susceptibility genes not cancer
Factors that Influence
Phenotype
• Penetrance
– Gender
– Co-morbidites
– Lifestyle
– Environment
– Modifier genes
– Risk-Reduction
Causes of Hereditary
Breast Cancer
% of Hereditary
Breast Cancer
Gene
BRCA1
BRCA2
BOCS
20%–40%
10%–30%
TP53
Li-Fraumenni
<1%
PTEN
Cowden’s
<1%
CHEK2
Undiscovered genes
<1%
30%–70%
ASCO
Breast and Ovarian Cancer
Syndrome
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Refers to BRCA1 or BRCA2
AD inheritance
Tumor Suppressors- a caretaker function
1 in 800 women in the general population
• BRCA1 identified in 1994
– >600 mutations
• BRCA2 in 1995
– ~ 450 mutations
Founder mutations
• 4 founder mutations among Ashkenazi Jews
– Prevalence 1 in 40
• Other groups with BRCA!/2 mutation families
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French-Canadian
Mennonite
Icelandic
Scandinavian
Irish
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British
Dutch
Japanese
Pakistani
Hereditary Breast and Ovarian
Cancer: BRCA1
Breast cancer 85%
Second primary breast cancer 40%-60%
Ovarian cancer 20%-40%
• Breast ca risk by age 50: 50%
• Risk for Male Breast Cancer Unclear
• Risk for Prostate Cancer if < 65
Adapted from ASCO
Hereditary Breast and Ovarian
Cancer: BRCA2
breast cancer
(30%-85%)
male breast
cancer
ovarian cancer
(6.7%)
(10%-20%)
• prostate cancer(12-18%)
• melanoma (2.5x)
• bile duct (5x), pancreas ca (~5%)
Adapted from ASCO
Clues to Breast/Ovarian Ca
Syndrome
• Breast Cancer < age 35
•  2 cases Breast ca before age 50
• Bilateral breast cancer, first <50
• Serous ovarian cancer
• Breast and ovarian cancer in the same woman
• Male breast cancer
• Ashkenazi Jewish heritage with breast cancer
ASCO
More Breast Cancer
Syndromes (<1%)
• Cowden’s – 25-50% breast ca risk
– Oral lesions, GI hamartomas, benign breast dz
– Thyroid, uterine lesions or CA, macrocephaly
• Li-Fraumeni – breast ca < age 40
– Often childhood cancers
– sarcoma, leukemia, brain adrenocortical CA
• Peutz-Jeghers - <1%
– Childhood GI hamartomas, colon CA
– Pigmentation of lips, buccal mucosa, hands/feet
Clinical Management Options
Screening and other interventions
Who needs what?
Assessment
Risk
Average
Family
History
Moderate
(“Familial”)
High
(Genetic)
Intervention
Standard prevention
recommendations
Personalized prevention
recommendations
Referral for genetic
evaluation
Ontario Screening Guidelines
for the general population
• Breast
– Mammogram every 1-2 years from 50
– Annual clinical breast exam for all women
– Monthly breast self exam for all women
– No guidelines for men
• Ovary
– No gen population screening guidelines
Moderate Risk Families
• Low risk of BRCA1/ 2 or other cancer syndromes
• Lifetime risk 10-30%
• Screening recommendations:
– BSE monthly; CBE once or twice a year
– Annual (digital) mammo from 40 or 5-10 yrs
prior to youngest cancer
• Immediate biopsy of any suspicious findings
– Explore Chemoprevention
– Lifestyle modifications
Lifestyle Modification
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Good for all risk categories!
Exercise – 30 min. or more most days
Weight control
Diet ??
– Less saturated/trans fat
– Less refined flour, sugar
– More fruits/vegetables, whole grains, legumes
• Alcohol: less than 1-2 drinks/day
• Breast feeding
Options for High Risk Patients
• Increased surveillance
• Prophylactic surgery
• Lifestyle changes
• Chemo prevention
Surveillance: BRCA1/2
• Breast
– Annual mammogram from age 30 (digital)
Class I
Class B – Annual Breast MRI from 30
– CBE q6-12mos from age 18
Class E – Monthly breast self exam from age 18
• Ovarian screening – significant limitations
– Ca-125, TV ultrasound 1-2/yr- age 25-35
– Suboptimal early detection
– high false positive
– Preferred in a research setting
Other
• Heightened male breast screening
– Chest wall exams, visual
• Consider PSA at age 40
• Monitor skin and general health
• Pancreatic screening research (BRCA2)
Challenges to Surveillance
• CBE detects few cancers missed by above
– Promotes awareness no  mortality
• Mammo
– insensitive in younger patients 26-42%
• MRI
– Sensitivity 83-100%
– Lower specificity
• TV US
– +FH, Sensitivity 92%, Specificity 97.8%
– PPV 11%; if  2 cases, PPV=20%
• CA 125 Sensitivity 35-55%
Series of 3991 high-risk pts
• 155 cancers
• 78% of cancers detected by MRI
• 38% by mammo
– 18 (10 DCIS, 8 invasive) on mammo NOT MRI
• 42% by US (<1% detected by US only)
• Interval cancer < 10% if MRI
• Of MRI detected cancers
– 12-27% DCIS
– if invasive ca 75-94% < 2 cm
– Axillary node mets seen in 17-25%
Other Management Options
BRCA1/2
• Mastectomy
– Cohort shows 96% breast ca
– Total Mastectomy, no node dissection
– Path review- cancer found in 7%
• Oophorectomy
–  ovarian ca 85%
– Breast ca by 50-66%
• Birth Control Pill
• Tamoxifen
Your Role
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Detailed family history
– Cancer status in 1st and 2nd degree relatives
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Type of primary cancer(s) in each relative
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Age of disease onset
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Cancer status in both sides of the family
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Ethnic background on both sides
– Other medical findings – benign tumors, etc.
Referral opportunities
Referral forms available at our website
www.grandriverhospital.on.ca
follow links to GRRCC,
then Treatments & Services
then Genetic Counseling Service