Hereditary Breast Cancer The Implications

1. Hereditary Breast CancerThe Implications Kelly-Anne Phillips MBBS MD FRACP CCV Colebatch Clinical Research Fellow Medical Oncologist Peter MacCallum Cancer Centre

2. Background • Approx 13,000 Australians diagnosed each year • Approx 650 due to genetic susceptibility. Identification of these important because: • Their clinical management may differ • It may lead to identification of female family members who are at increased cancer risk and who can be targeted for prevention

3. Breast Cancer Genes Gene% of Hereditary BC BRCA1 20% BRCA2 10% CHEK2 1-5% P53 <1% PTEN <1% ATM <1% Unknown 65%

4. BRCA1 and BRCA2 Cancer Risks Breast cancer 50%-85% (often early age at onset) Second primary breast cancer Ovarian cancer 10-60% Increased risk of other cancers (prostate, pancreas, melanoma)

5. Family History Is The Main Clue • BC and / or OC in > 2 close relatives on the same side of the family (maternal or paternal) • Bilateral breast cancer • Early-onset breast cancer • Male breast cancer • Associated cancers (ovarian) • Ethnicity (eg Jewish)

7. BC Pathology Is Another Clue • BC in BRCA1 carriers are usually: • Basal phenotype • Hormone receptor negative • HER2 negative • High grade (high mitotic index) • BRCA2-associated BCs do NOT have such a specific phenotype.

11. Additional Criteria Based On Pathology • Young (< 40yo) with breast cancer with BRCA1 phenotype • Hormone receptor negative • HER2 negative • Basal markers CK5/6

13. Relevance to Woman With Recent BC Diagnosis BRCA1/2 mutation • If pre-menopausal, HR positive BC, may consider salpingo-oophorectomy as part of BC treatment, to reduce risk of subsequent BC and OC • If post-menopausal, may consider salpingo-oophorectomy to prevent subsequent OC BRCA1/2 mutation and/or strong FHx • If prior WLE, may consider completion mastectomy and contralateral risk-reducing mastectomy rather than adjuvant radiation. • If retaining breast tissue, may be eligible for medicare funded MRI for ongoing screening

14. Contralateral Breast Cancer In BRCA1 and BRCA2 mutation Carriers

15. Age of 1st BC Diagnosis and Risk of Contralateral BC In Carriers Malone et al JCO 2010

17. Background • Contralateral risk-reducing mastectomy reduces contralateral BC risk by up to 95% • Internationally uptake of CRRM for BRCA1 and BRCA2 mutation carriers is reported to vary between 5-38%* • What is the prevalence and predictors of CRRM in Australasian women with familial BC? *Metcalfe K, et al. Int J Cancer 2008;122: 2017-22

18. Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer • Resource for research • Ascertains high risk families with breast and ovarian cancer from Family Cancer Clinics • Collect epidemiological data and biological material (fresh tissue, blood ) • Collection complete from 1,350 breast cancer families – average 9 participants per family.

20. kConFab Follow-Up Project • Follow-up women in kConFab every 3 years • Collect data on lifestyle factors, prophylactic surgery and cancer outcomes etc using self-administered questionnaire

21. Results • 1018 women with personal history of BC, 30% mutation carriers, median follow-up 11 years • 15% underwent CRRM • Only 49% who underwent CRRM had breast reconstruction • Most (73%) reconstructions occurred within 12 months of CRRM • 177 contralateral BCs in 864 women (20%) not electing CRRM • 1 chest wall event in 154 women post-CRRM (0.6%) • Event rate: 15/1000 women years (no-CRRM) v 0.7/1000 women years (CRRM); p<0.0001

22. Predictors of CRRM *excludes 22 documented mutation carriers unable to recall if they learnt their mutation status before or after CRRM

23. Conclusions • Younger women with more recently diagnosed BC treated with mastectomy are more likely to elect CRRM • Neither BRCA1 or BRCA2 mutation status, nor the risks of BC recurrence and death, appears to influence decision making

24. Treatment of BC in BRCA1 and BRCA2 Carriers – should it be different?

25. Rationale • BRCA1 and BRCA2 involved in DNA repair • Thus BCs that have no functioning BRCA1 or BRCA2 gene protein, might be more sensitive to chemotherapy agents that break double stranded DNA • Also carriers might get more toxicity from treatment that breaks DNA, such as RT and some chemo agents

26. Breast Cancer Prognosis In BRCA1 and BRCA2 Mutation Carriers Results from an International, Prospective, Population-Based Cohort Study Kelly-Anne Phillips* Frances O’Malley Pamela Goodwin Roger Milne Dee West Irene Andrulis Marguerite Ennis Michael Friedlander John Hopper Teri Longacre Esther M. John Funded by the NHMRC (#145684)U.S National Institutes of Health, (1 RO1 CA102740-01A2, 5 RO1 CA102740-02, 5 RO1 CA102740-03) * Supported by the Cancer Council Victoria, Colebatch Clinical Research Fellowship

27. BRCA Prognosis Study Primary Aim • To determine whether mutation carriers with BC do better or worse than other women and is that influenced by the type of treatment they receive?

28. Prognosis in Hereditary Breast Cancer Population Assembly

29. Prognosis in Hereditary Breast Cancer BRCA1 Survival Effects

30. Prognosis in Hereditary Breast Cancer BRCA 2 Survival Effects

31. Prognosis in Hereditary Breast Cancer Clinical Implications • Outcome in BRCA2 carriers was worse than in sporadic cases but this appeared to be explained by them having more adverse traditional prognostic features (node positivity, higher grade) • Perhaps BRCA2 carriers should consider preventive approaches rather than relying on screening for early-detection

32. Key Points • BRCA1/2 carriers appear to have equivalent survival compared with non-carriers • No excess toxicity of treatment in mutation carriers* • Early clinical and preclinical data suggest BRCA1/2 associated BCs may have enhanced susceptibility to platinum agents, but more data are required • PARP inhibitors have shown good clinical activity in BRCA1/2 associated BCs in early phase clinical trials • BUT CURRENTLY, mutation carriers should receive standard adjuvant systemic therapy, based on features of their tumor, until results of prospective trials available *Shanley et al Clin Cancer Res 2006

33. Management of Unaffected Family Members Who Carry a BRCA1 or BRCA2 Mutation

34. Strategies for Reducing Breast Cancer Risk In Mutation Carriers

35. Medicare Funding of Breast MRI for High Risk Women Medicare item number 63464. Annual MRI Pt must be: • referred by specialist • <50 years old • High risk according to NBOCC criteria

36. Efficacy of Medical Prevention

37. Side-Effects of Medical Prevention Reversible / non serious • Hot flushes, vaginal discharge/itching, change in periods Serious • Venous thrombosis • Endometrial cancer (post-menopausal only)

38. Weighing up the Risks vs Benefits • For high risk women benefits clearly outweigh risks • For 1000 postmenopausal woman at 4% risk of BC over the next 5 years tamoxifen will: • For premenopausal woman risks even less, because no endometrial Ca risk • Decision aid urgently needed to help individual women assess risk vs benefit, depending on her own personal risk

39. Miss Jane Hypothetical • 32 yo single magazine editor • No medical problems • Strong FHx of BC

40. 64 57 75 6 6 70 12 60 67 59 76 78 58 Ovarian(56) Breast(42) Bowel(58) Breast(62) (+) + ?Bowel(67) 44 41 44 40 32 38 42 Breast (40) _ _ _ + + + + 12 12 10 8 3172 BRCA2 2bp del 6503 (TT)

41. Management of Jane Current, age 32 • Doesn’t want surgery. Not confident to rely on screening alone  tamoxifen & screening (annual MRI and mammo, 6 monthly CBE) Age 42 – • Completed 5 yrs tamoxifen. Now married with 2yo twin sons. Not planning further kids, needs contraception. Not keen on mastectomy but undergoes RRSO to reduce both her BC and gynaecologic cancer risk

42. What are Australasian BRCA1 and BRCA2 Mutation Carriers Doing To Reduce Their Risk?

44. Uptake of Prevention Options Not using prevention option 26% Not using prevention option 43% BO 54% BO 39% BM 3% BO and BM 16% BO and chemoprevention 1% BO and chemoprevention 1% BM 6% BO and BM 11%

45. Risk-Reducing BM 17% underwent BM Average age at BM = 41 years (range 27-66 years) 89% underwent reconstruction No malignancy found in surgical specimens Mastectomy type

46. Prophylactic Mastectomy Uptake COUNTRY UPTAKE (%) n NUMBER OF WOMEN 36.3% 115 317 U.S.A 32.7% 18 55 Netherlands 25.0% 1 4 France 22.4% 88 393 Canada 20.0% 5 25 Austria 17% 29 166 Australia 10.0% 2 20 Italy 4.5% 6 135 Norway 4.2% 4 95 Israel 2.7% 9 339 Poland Metcalfe et al Int J Cancer 2008

47. Take Home Points • Assessing FHx cancer in a woman newly diagnosed with BC is important because there may be management implications for her and her family • Effective prevention options exist for women at high risk of breast cancer • Mx of women at high risk should consider all the surgical and medical prevention options (not just screening!) • Mx is complex, changes over time and should be multidisciplinary and evidence-based • The Breast Care Nurse can play a vital role in identification of high risk women

48. Genetic Susceptibility to Breast Cancer

49. Extra slides

50. Do SERMS Reduce BC Risk For BRCA1/2 Mutation Carriers? Perhaps not • SERMS appeared to only reduce risk of ER positive BCs in the RCTs. BRCA2 BCs usually ER positive but BRCA1 BCs usually ER negative1 • In NSABP-P1 trial no statistically significant protective effect of tamoxifen (very underpowered analysis)2: BRCA1 HR 1.67 (95% CI: 0.32-10.7) BRCA2 HR 0.38 (95% CI: 0.06-1.56) 1Phillips JCO 2000 2King et al JAMA 2001