1. Hereditary breast and ovarian cancer Who should be screened and How? Symposium on Cancer Waterloo Inn October 31, 2007 Mala Bahl, MD, MSc

2. 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

3. This presentation contains no conflicts of interest

4. General population risk Breast cancer –10.6% –1 in 9 women Ovarian Cancer –1.5% –1 in 70 women

5. 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 !

6. Contribution of Family History 15-20% have an affected 1 st /2 nd degree relative ~5% -Family history suggests high-risk gene mutation Majority are “sporadic” 5-10% ~15-20%

7. Two hit hypothesis Sporadic cancer ? age 30-50 ?age 50-70

8. Two hit hypothesis Sporadic cancer Hereditary cancer ? age 30-50 ?age 50-70

9. 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

10. Jean Cervical 39 Fred 41Susan 37Lori 33Michael 30 John 65 Mary Breast 60 Charles 74 Prostate 68 Louise d.62 Colon 59 Agnes Breast 76 Familial Cancer

11. 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!)

12. Hereditary ASCO l May appear to “skip” generations (penetrance) l Inheritance of cancer susceptibility genes not cancer Normal Carrier, affected Susceptible Carrier Sporadic Ovary, 40 Breast, 45 Colon, 67Breast,50 Ovary 50 Breast, 35

13. Factors that Influence Phenotype Penetrance –Gender –Co-morbidites –Lifestyle –Environment –Modifier genes –Risk-Reduction

14. ASCO Causes of Hereditary Breast Cancer GeneBRCA1BRCA2 TP53 Li-Fraumenni PTEN Cowden’s CHEK2 Undiscovered genes % of Hereditary Breast Cancer 20%–40%10%–30%<1%<1%<1%30%–70% BOCS

15. 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 BRCA1 identified in 1994 –>600 mutations BRCA2 in 1995 –~ 450 mutations

16. 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

17. Hereditary Breast and Ovarian Cancer: BRCA1 Breast ca risk by age 50: 50% Risk for Male Breast Cancer Unclear Risk for Male Breast Cancer Unclear  Risk for Prostate Cancer if < 65  Risk for Prostate Cancer if < 65 Breast cancer 85% Second primary breast cancer 40%-60% Ovarian cancer 20%-40% Adapted from ASCO

18. Hereditary Breast and Ovarian Cancer: BRCA2 prostate cancer(12-18%) prostate cancer(12-18%) melanoma (  2.5x) melanoma (  2.5x) bile duct (5x), pancreas ca (~5%) bile duct (5x), pancreas ca (~5%) breast cancer (30%-85%) ovarian cancer (10%-20%) male breast cancer(6.7%) Adapted from ASCO

19. 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

20. 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

21. Clinical Management Options Screening and other interventions

22. Who needs what? Family History Assessment Personalized prevention recommendations Referral for genetic evaluation Standard prevention recommendations Intervention Average Moderate (“Familial”) High (Genetic) Risk

23. 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

24. 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

25. 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

26. Options for High Risk Patients Increased surveillance Prophylactic surgery Lifestyle changes Chemo prevention

27. Surveillance: BRCA1/2 Breast –Annual mammogram from age 30 (digital) –Annual Breast MRI from 30 –CBE q6-12mos from age 18 –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 Class I Class B Class E

28. Other Heightened male breast screening –Chest wall exams, visual Consider PSA at age 40 Monitor skin and general health Pancreatic screening research (BRCA2)

29. 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%

31. 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%

32. 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

33. Your Role Detailed family history –Cancer status in 1 st and 2 nd degree relatives –Type of primary cancer(s) in each relative –Age of disease onset –Cancer status in both sides of the family –Ethnic background on both sides –Other medical findings – benign tumors, etc.

34. Referral opportunities Referral forms available at our website www.grandriverhospital.on.ca follow links to GRRCC, then Treatments & Services then Genetic Counseling Service