Hereditary breast and ovarian cancer Who should be screened and How

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 • • • • • Age Reproductive/hormonal Lifestyle Environmental Previous breast disease The majority of cases have no identifiable risk factor! Contribution of Family History 5-10% ~15-20% Sporadic 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 ?age 50-70 Hereditary cancer Familial Vs Hereditary • Familial Clustering – – – – – – – – 2  cases in a family Not necessarily young cases (cases >60 years) Not necessarily related cancers No clear pattern seen Shared genetics Shared environment Shared lifestyle Chance Familial Cancer Agnes Breast 76 John 65 Mary Breast 60 Charles 74 Prostate 68 Louise d.62 Colon 59 Jean Fred 41 Cervical 39 Susan 37 Lori 33 Michael 30 Familial Vs Hereditary • Hereditary – – – – – 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 Ovary, 40 Normal Susceptible Carrier Breast, 45 Carrier, affected 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 Gene BRCA1 BRCA2 TP53 PTEN CHEK2 Undiscovered genes BOCS Li-Fraumenni Cowden’s % of Hereditary Breast Cancer 20%–40% 10%–30% <1% <1% <1% 30%–70% ASCO Breast and Ovarian Cancer Syndrome • • • • Refers to BRCA1 or BRCA2 AD inheritance Tumor Suppressors- a caretaker function 1 in 800 women in the general population – >600 mutations • BRCA1 identified in 1994 • BRCA2 in 1995 – ~ 450 mutations Founder mutations • 4 founder mutations among Ashkenazi Jews – Prevalence 1 in 40 • Other groups with BRCA!/2 mutation families – – – – – French-Canadian Mennonite Icelandic Scandinavian Irish – – – – 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 (6.7%) ovarian cancer (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 Intervention Standard prevention recommendations Moderate (“Familial”) High (Genetic) 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 • • • • 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 • Detailed family history – – – – – Cancer status in 1st and 2nd degree relatives Type of primary cancer(s) in each relative Age of disease onset Ethnic background on both sides Other medical findings – benign tumors, etc. – Cancer status in both sides of the family Referral opportunities Referral forms available at our website www.grandriverhospital.on.ca follow links to GRRCC, then Treatments & Services then Genetic Counseling Service