What’s New in Hereditary Breast and Ovarian Cancer?

1. What’s New in HereditaryBreast and Ovarian Cancer? Steven A. Narod, MD Canada Research Chair in Breast Cancer

2. 1968-2008 • Genetic basis of hereditary cancer • Somatic mutations in cancer and cancer progression

3. Genetic Basis of Hereditary Cancer Familial Associations • Single site: -Prostate • Multi-site: -retinoblastoma- osteosarcoma -breast-ovary -colon-endometrium-ovary -pancreas-melanoma -breast/sarcoma/adrenocortical

4. Genetic basis for cancer - Somatic mutations • General chromosome instability • Specific chromosomal abnormalities -translocations -deletions -amplifications • Point mutations -oncogene activation • Tumour suppressor genes -two hit theory: retinoblastoma -1985-1995 loss of heterozygosity: e.g. DCC • Microsatellite instability -mismatch repair phenotype -HNPCC spectrum • Microdeletions/ fusion proteins: e.g. TMPRSS-ERG prostate cancer fusion

5. For a genetic test to reach the clinic: • Disease must be relatively common • Personal concern regarding risk • Reasonable proportion of positive tests (>5%) • Physician awareness • Prevention or screening available Currently: breast, ovary, colon, melanoma

6. Breast Cancer Genes: 1990: P53 <1% of hereditary bc 1994: BRCA1 20% of hereditary bc 1995: BRCA2 20% of hereditary bc 1997: PTEN <1% of bc 1998: ATM <1% of bc 2002: Chek2 1% of bc 2007: BRIP1 0.7% of hereditary bc 2007: PALB2 1.1% of hereditary bc 2007: eCADHERIN 1 of 23 familial lobular cancers 2007: FGFR2 OR=1.6 freq.=0.14 (homo)

7. Nature Genetics 2007 June 28;447:1087-93

8. Hereditary Breast Cancer Syndromes • Breast/ovarian cancer Syndrome • Cowden Syndrome • Li-Fraumeni Syndrome

9. Who to test for BRCA1 and BRCA2 mutations? • All triple-negative breast cancers under age 40 • All familial breast cancers • All male breast cancers • Multiple primary breast and ovary cancers • All Jewish women with breast cancers • All French-Canadian women with breast cancers • All invasive ovarian cancers • At risk relatives!

10. Approach to the BRCA Population • Identify unaffected carriers • Prevent breast and ovarian cancer • If not, then find cancers at an early stage • Treat cancers appropriately

11. Mutation Positives in WCH2004 - 2008

12. Topics to Discuss • Update on screening • Update on prevention • Update on treatment

13. MRI and Breast Cancer Detection in BRCA Carriers - Sensitivity

17. Odds Ratio for Advanced Breast Cancer OR = 0.30 (0.12 – 0.72) P = 0.007

18. Carrier Database 2008 N=9043 • No cancer 3806 • Breast cancer 4097 • Ovarian cancer 1262 • Both 401 • Other cancer 826 • BRCA1 6838 • BRCA2 2092 • Both mutations 33

19. Breast Ovarian Cancer Cancer BRCA1 80% 25 - 50% BRCA2 80% 10 - 25% Risks of Cancer to Age 70 Among Carriers of BRCA1 or BRCA2 Mutations

20. Weight Gain Breast feeding Mastectomy Coffee Oophorectomy Tamoxifen Pregnancy Oral Contraceptives Hormone Replacement Therapy Prevention of Breast Cancer Factors to consider:

21. Prophylactic Mastectomy Preventive removal of both breasts prior to the development of breast cancer Approximately 95% risk reduction (Hartmann, 1999) 2 types: • Total mastectomy • Subcutaneous mastectomy

22. Average four years of follow-up Prophylactic Number of Number of Mastectomy Subjects New Breast Cancers Yes 174 0 No 1134 76 expected—9.5 p=0.00005 Prophylactic Mastectomy and Breast Cancer

23. Prophylactic Mastectomy by Country

24. The Risk of Contralateral Breast Cancer in BRCA Mutation Carriers

25. Contralateral Mastectomy by Country

26. Association Between Age at Oophorectomy and Breast Cancer (BRCA1) Case-Control Study *Adjusted for OC, parity

27. Prophylactic Oophorectomy by Country

28. Is HRT safe following prophylactic mastectomy?

29. Risk of Breast Cancer with HT use by type of menopause in BRCA carriers

30. Contralateral Breast Cancer Associated with Tamoxifen

31. Tamoxifen by Country(unaffected carriers)

32. Why the Reluctance? • Belief in effectiveness • Lack of data on primary cancer • ER-negative cancers • Side effects • Dependency on screening

33. Tamoxifen and the risk of primary breast cancer No Tamoxifen Tamoxifen Breast Cancer 1010 1010 No Breast Cancer 1973 47 2020 OR = 0.32 p-value = 0.001

34. Genes responsible for hereditary ovarian cancer • BRCA1 • BRCA2 • MSH2 • MLH1

35. Frequency of BRCA1/BRCA2 Mutations Among Patients with Cancer in Ontario • 1372 incident Cases of Ovarian Cancer • Population-based Series • Mixed ethnicities • Invasive only • PTT Performed on Exons 11 of BRCA1, 10 and 11 of BRCA2 • DGGE (BRCA1) • DhPLC (BRCA2) • Direct Sequencing • 179 mutations identified • 110 in BRCA1 (8%) • 69 in BRCA2 (5%) • 10 MLPA (6% of mutations, < 1% of cases) • estimated frequency, incl. MLPA (13.0%)

36. Prevalence of Mutations in Patients with Ovarian Cancer by Age

37. Prevalence of Mutations in Patients with Ovarian Cancer by Histology

39. North American Prospective Study of Oophorectomy • 1828 carriers followed for 3.5 years • 50 cancers diagnosed (fallopian/ovarian/peritoneal) No oophorectomy: 32 cases 1.0% per year Oophorectomy: 7 cases 0.2% per year Risk Reduction= 80% (HR=.20, 95% CI, 0.07-0.58, p=0.003)

40. Cancer of the Peritoneum Following Prophylactic Salpingo-oophorectomy (n=12)

41. Odds Ratios for Reproductive Factors and Hereditary Ovarian Cancer: BRCA1

42. Odds Ratios for Reproductive Factors and Hereditary Ovarian Cancer: BRCA2

43. Recommendations • Test all non-mucinous cancer patients • Oral contraceptives 3 yrs (30-35) • Oophorectomy 35 yrs old • HRT 5 yrs • Breast Feeding (BRCA1) 12 months

44. Uptake of clinical genetic testing for ovarian cancer in Ontario • What proportion of women who are eligible for testing are actually offered testing? • In 2001, genetic testing for BRCA1 and BRCA2 became freely available to all women in Ontario with a diagnosis of invasive ovarian cancer. • Identified using the Ontario Cancer Registry • Asked if they had been offered testing by doctors • Asked if they wished to be tested.

45. Uptake of clinical genetic testing for ovarian cancer in Ontario • 550 women contacted • 80 women (19%) had undergone previous clinical genetic testing for BRCA1 and BRCA2. • 24 mutations detected • 491 requested genetic testing (89%) • total of 41 mutations • 17 of 41 mutations had been missed

46. Do carriers of BRCA1 mutations have a different response to specific chemotherapy agents compared to non-carriers?

47. BRCA1 protein is a key component in the repair of double-strand DNA breaks (homologous recombination) • BRCA1 mutation is associated with impaired DNA repair • Agents that induce double strand breaks used as chemotherapy including mitomycin C, cis-platinum, radiotherapy • Loss of heterozygosity renders cancer cells particularly sensitive • Pre-clinical studies in cells with null BRCA1 show these cells are highly sensitive • Synthetic lethality

48. Polish Study Neo-adjuvant Therapy in BRCA1 Carriers • Database of 6903 women with breast cancer below 50 years • Three founder mutations with BRCA 1 • 400 mutation carriers • 102 were treated with neo-adjuvant therapy • Endpoint: pathologic complete response (PCR)

49. Numbers of patients treated with, and responding to different chemotherapy regimens C: cyclophosphamide M: methotrexate F: 5-flourouracil A: adriamycin T: docetaxel CMF category includes four patients with CMFP and two patients with CMFVP