Breast Cancer: A focus on BRCA Mutations.

It describes the prevalence of Breast Cancer among BRCA 1/2 mutations with special consideration to biological background, detection and screening, actions taken upon discovering mutation carriers and whether we have a different therapeutic algorithm than sporadic cases. Special emphasis on the role of PARP inhibitors in the management of metastatic disease.

1. A Focus on Brca mutations in breast cancer Mohamed Abdulla M.D. Prof. of Clinical Oncology Cairo University Dubai – 11/09/2015

2. Speaker Disclosures Member of Advisory Board, Consultant, and Speaker for: Amgen, Astellas, Astra Zeneca , Hoffman la Roche, Janssen Cilag, Merck Serono, Novartis, Pfizer. Speaker Disclosures:

3. Breast Cancer: The Story: Narod SA. BRCA mutations in the management of breast cancer: the state of the art. Nat Rev Clin Oncol 2010; 7:702

4. Cancer Risk in Carriers of Germ Line Mutations in BRCA1 & BRCA2 Autosomal Dominant Inheritance with High Penetrance 50% Chance of Inheritance. Lifetime Risk of Cancer = 30-70%

5. Cancer Risk in Carriers of Germ Line Mutations in BRCA1 & BRCA2 Presented by Judy Garber at 2015 ASCO Annual Meeting. 54 – 85%

6. Presented By Elizabeth Swisher at 2015 ASCO Annual Meeting Risk of Breast Cancer for Women with BRCA1 & 2 Mutations: King, Science, New York Breast Cancer Study, 2003

7. Risk of Breast Cancer for Women with BRCA1 & 2 Mutations: Claus EB, et al. The genetic attributable risk of breast and ovarian cancer. Cancer 1996;77:2318-2324.

8. Risk of Breast Cancer for Women with BRCA1 & 2 Mutations: Adapted from: Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med 2001; 344:276.

9. BRCA Genes: Basic Knowledge Eukaryotic Genome Constant Stress Endogenous Exogenous Continuous Damage Continuous Repair Misrepair Perfect Repair No Repair Mutations Apoptosis Tumor Suppressor Genes Peter J.O’Donovan and David M.Livingston .􏰀 Carcinogenesis vol.31 no.6 pp.961–967, 2010 BRCA1 & BRCA2 DNA Repair. Control of Cell Cycle Checkpoints. Control of Mitotic Activity

10. BRCA Genes: Basic Knowledge 1 2 1 2 Peter J.O’Donovan and David M.Livingston .􏰀 Carcinogenesis vol.31 no.6 pp.961–967, 2010 G , G 1 , Early S Late S, G 2

11. Mutated Non - Mutated P 2 Year 96.4% 99.3% 0.02 5 Year 85.3% 95.9% 10 Year 71.9% 87.2% Robson M, et al. J. Natl. Cancer Inst. 1999;91(24)2112-2117. BRCA-Associated Breast Cancer   Ipsilateral & Contralateral Recurrences Breast Cancer with BRCA Mutations: Poor Prognosis:

12. Breast Cancer with BRCA Mutations: Poor Prognosis: Early onset of disease  more years of lost life . High prevalence of poorly differentiated , high grade and highly proliferative lesions  more common in BRCA1 mutation cases. Higher prevalence of HR –ve and TNBC . Altered sensitivity to systemic agents:  to platinum and PARP inhibitors.  to taxanes. Chemotherapy for early small tumors might improve the outcome. Rijnsburger et al. JCO 2010;28:5265 Lee et al. Breast Cancer Res Treat 2010; 122:11 . Hemel & Domchek . Hematol Oncol Clin North Am 2010; 24:799.

13. BRCA Gene Mutations: Who Should Be Investigated for Mutations?

14. BRCA Gene Mutations: Who Should Be Investigated for Mutations?

15. BRCA Genes Mutation: Confirmed Detection: Actions Taken Cancer Surveillance Reducing Risk Therapeutic Implications Breast Self Examination. Breast Clinical Examination. Mammography/MRI. Surgical Intervention. Chemoprevention. Different Disease Entity? Locoregional Treatment? Systemic Therapy (PARP)

16. BRCA Mutation: Cancer Surveillance: Breast Self-Examination: Monthly at age of 18 years. Clinical Breast Examination: 2 – 4 times annually at age of 25 years. MRI – Breast: 2 times annually (25 – 30 Years). Alternating Mammography/MRI – Breast: annually after the age of 30. Age Mammography MRI Mammo + MRI Sens. Spec Sens. Spec Sense Spec All Ages 39.6% 93.6% 85.3% 84.7% 93.4% 80.3% < 50 40% 93% 85.7% 83.5% 93.2% 78.7% > 50 39.1% 95.9% 84.4% 88.5% 94.1% 85.3% Warner et al. Ann Intern Med. 2008;148:671. Xi PA et al. J Clin Oncol. 2015;33:349-56.

17. BRCA Mutation: Reducing Risk: Surgical Intervention: Bilateral Prophylactic Mastectomy: 90% risk reduction. Total > S.C. mastectomy. Skin sparing +/- preservation of nipple/areola complex  Better cosmoses. Immediate reconstruction. Bilateral Salpingo -oophorectomy:  77% risk reduction of all cause breast cancer mortality to age of 70 years. Ingham SL et al. Risk-reducing surgery increases survival in BRCA1/2 mutation carriers unaffected at time of family referral. Breast Cancer Res Treat 2013; 142:611. Finch AP , et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 2014; 32:1547.

18. BRCA Mutation: Reducing Risk: Chemoprevention: Tamoxifen (5 Years)  50%  of breast cancer in women with moderately increased risk: > 60 years. > 35 years with LCIS. 1.66% increased risk (Gail Method). NSABP (P-1): TAM 62%  breast cancer risk (BRCA2). Role of Raloxifen and AI. Chemoprevention < Prophylactic Surgery. No HBOC Eisen A, Weber BL. Prophylactic mastectomy for women with BRCA1 and BRCA2 mutations--facts and controversy. N Engl J Med 2001; 345:207 . Gronwald J, Tung N, Foulkes WD, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer 2006; 118:2281.

19. BRCA Mutation: Reducing Risk: Clinical Decision Making: Life Expectancy Quality of Life 30 years + BRCA1/2 Prophylactic Mastectomy  3 – 5 years gain. Oophorectomy  0.3 – 2 years gain Schrag D, et al.N Engl J Med 1997; 336:1465.

20. Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management:

21. Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management:

22. Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management: 655 Patients Stage I - III BRCA1/2 Mutation 302 Patients  BCT 353 Patients  MRM Failures: Local Regional Systemic Pierce et al. Breast Cancer Res Treat . 2010 June ; 121(2): 389–398

23. Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management: Pierce et al. Breast Cancer Res Treat . 2010 June ; 121(2): 389–398 P = < 0.0001 LR = 30% LF = 70%

24. Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management: Pierce et al. Breast Cancer Res Treat . 2010 June ; 121(2): 389–398 P = < 0.0001

25. Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management: Pierce et al. Breast Cancer Res Treat . 2010 June ; 121(2): 389–398 P = < 0.44

26. Conclusions: L.R.: BCT > MRM (Significant) Local Control: BCT + CTH = MRM . Distant Failure, DSS, OAS: No Difference. CBC: Significantly High Irrespective of RTH Use  Prophylaxis. Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management: Pierce et al. Breast Cancer Res Treat . 2010 June ; 121(2): 389–398

27. Breast Cancer with BRCA Mutation: Contralateral Breast: Int. J Cancer:136,668-677.(2015)

28. Breast Cancer with BRCA Mutation: Contralateral Breast: Int. J Cancer:136,668-677.(2015) Number 583 BRCA Mutated PBC P/HR CRRM Surveillance 242 (42%) 341 (58%) Contralateral Breast Cancer 4 (2%) 64 (19%) P = 0.001 Mortality/1000 Persons - Years of Observation 9.6% 21.6 HR = 0.49 Median Follow up = 11.2 years

29. Breast Cancer with BRCA Mutation: Systemic Therapy: Chemotherapy: Banu Arun et al. J Clin Oncol 29:3739-3746. © 2011 by American Society of Clinical Oncology 317 Patients 1997-2009 23 BRCA2 57 BRCA1 237 Non Carriers NST pCR = 22% pCR = 57% pCR = 13% P < .001

30. Breast Cancer with BRCA Mutation: Systemic Therapy: Chemotherapy: Banu Arun et al. J Clin Oncol 29:3739-3746. © 2011 by American Society of Clinical Oncology