Hereditary breast and ovarian cancer Who should be screened and How

1. Hereditary breast and ovarian cancerWho should be screened and How? Symposium on Cancer Waterloo Inn October 31, 2007

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 Some repro are inherited and some are environmental Mention breast density Having a premenopausal 1st degree relative OR=3. If they have bilateral dz OR=9. 1st degree post meno OR=1.5Some repro are inherited and some are environmental Mention breast density Having a premenopausal 1st degree relative OR=3. If they have bilateral dz OR=9. 1st degree post meno OR=1.5

6. Contribution of Family History 15-20% have an affected 1st/2nd degree relative ~5% -Family history suggests high-risk gene mutation Majority are “sporadic” Small but very important group as we will see intervention makes a big difference 5-10% of all ovarian cancer is hereditarySmall but very important group as we will see intervention makes a big difference 5-10% of all ovarian cancer is hereditary

7. Two hit hypothesis All cancer is genetic All cancer is genetic

8. Two hit hypothesis All cancer is genetic All cancer is genetic

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 Often don’t see ovarian cancers- or other rare cancersOften don’t see ovarian cancers- or other rare cancers

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!) Ovarian cancer here is a clue as it is more rare!Ovarian cancer here is a clue as it is more rare!

12. Hereditary

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

14. Causes of Hereditary Breast Cancer Ataxia telangectasia Peutz jegers CHEK2 low penetrance Ataxia telangectasia Peutz jegers CHEK2 low penetrance

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 Tumour suppressors To activate a mutation, both maternal and paternal copies need to be altered- if one germline mut is inherited -t only take s one gene “hit”Tumour suppressors To activate a mutation, both maternal and paternal copies need to be altered- if one germline mut is inherited -t only take s one gene “hit”

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 Founder effect: population descended from a small # of ancestors with a disease in question Social religious or geographic isolation They were the key to discovery of genes Among jewish women with br ca <40, 45% are carriers of founder mutationsFounder effect: population descended from a small # of ancestors with a disease in question Social religious or geographic isolation They were the key to discovery of genes Among jewish women with br ca <40, 45% are carriers of founder mutations

17. Hereditary Breast and Ovarian Cancer: BRCA1 More often high grade cancers Often ER- Ov + fallopian tube Prostate ca risk RR 1.6 to age 65, or 8% then with gen pop. Colon ca may be involved- or mutation may increase risk of common cancers More commonly the gene for young breast cancerMore often high grade cancers Often ER- Ov + fallopian tube Prostate ca risk RR 1.6 to age 65, or 8% then with gen pop. Colon ca may be involved- or mutation may increase risk of common cancers More commonly the gene for young breast cancer

18. Hereditary Breast and Ovarian Cancer: BRCA2 Less commonly young breast cancer May be positive in up to 2% of prostate pts ?Familial pancreas ?Less commonly young breast cancer May be positive in up to 2% of prostate pts ?Familial pancreas ?

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

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 Goiter, adenomas, follicular thyroid ca 75% with benign breast diseaseGoiter, adenomas, follicular thyroid ca 75% with benign breast disease

21. Clinical Management Options Screening and other interventions

23. Ontario Screening Guidelinesfor 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

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% Mammo has reduced mortality by 16% in gen pop For ovarian screening, does not necessarily detect cancers early Ca 125 not reliable to tell benign from malignant massMammo has reduced mortality by 16% in gen pop For ovarian screening, does not necessarily detect cancers early Ca 125 not reliable to tell benign from malignant mass

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 1st and 2nd 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. Type of primary cancer(s) in each affected relative Age of disease onset in each affected relative earlier onset generally confers higher risk for close relatives Cancer status in 1st and 2nd degree relatives (often discounted) Other medical findings associated with hereditary cancer syndromes: i.e. thyroid findings, benign breast disease, lipomas, uterine fibroids, skin findings, etc. Cancer status in both sides of the family (paternal family history often overlooked when assessing risk of “female” cancers) Type of primary cancer(s) in each affected relative Age of disease onset in each affected relative earlier onset generally confers higher risk for close relatives Cancer status in 1st and 2nd degree relatives (often discounted) Other medical findings associated with hereditary cancer syndromes: i.e. thyroid findings, benign breast disease, lipomas, uterine fibroids, skin findings, etc. Cancer status in both sides of the family (paternal family history often overlooked when assessing risk of “female” cancers)

34. Referral opportunities