1. Clinical Utility of BRCA Testing Mark Robson, MD September 7, 2012 1

2. Pharoah PD et al. N Engl J Med 2008;358:2796-2803. 2

3. Risk Factors Not modifiable – Age – Gender – Age menarche – Age menopause – Histologic RF (eg ADH) – Mammo density Potentially modifiable – Age FFTP – Breast feeding – Obesity – Alcohol – HRT – Radiation exposure 3

4. Importance of family history Pharoah et al, Int J Cancer 1997; 71: 800 4

5. Mechanisms of familial risk Chance Shared socio-cultural risk factors Shared environmental exposures 5

6. Dx 45 d. 89 9286 7368 Dx 59 d. 62 Dx 72 Dx 36 36 71 * ** * * * 6

7. 7

8. Causes of Hereditary Breast Cancer BRCA1 & BRCA2 PTEN TP53 CDH1 LKB1/STK11 8

9. BRCA1 and BRCA2 mutations in BC Kurian et al, CEBP 2009;18:1084-91 Category ACategory B Category A: BC <35, B/L BC with first before 50, prior OC, 1+ FDR with BC or OC 9

10. BRCA1 and BRCA2 mutations in OC Zhang et al, Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol 2011;121:353 10

11. NCCN Criteria for BRCA testing Personal History of BC Dx ≤ 45 Dx ≤ 50 with: – 1 or more relative with BC ≤ 50 or – 1 or more relative with OC Bilateral with first ≤ 50 TNBC ≤ 60 Any age with 2+ relatives with breast or ovary any age Any age with 2+ relatives with pancreas Any age with relative with male BC Any age if Ashkenazi No Personal History of BC Epithelial ovarian cancer Male BC Pancreas with 2+ relatives with breast, ovary, or pancreas cancer Unaffected with FDR or SDR meeting criteria 11

12. Impact on management of affected Choice of local therapy Choice of systemic therapy Surgical prevention of second primaries 12

13. Risks to unaffected carriers Chen & Parmigiani JCO 2007;25:1329 BreastOvary 13

14. Management of breast cancer risk 14

15. Author N cancers/ N screened % detected by modality MMGUSMRI Kriege45/190940%71% Warner22/23636%33%77% Kuhl43/52933%39%91% Lehman4/36725%100% Leach33/64940%77% Lehman6/17133%17%100% Sardanelli18/27859%65%94% MRI surveillance in women at risk 15

16. Diagnostic yield of surveillance strategies Kuhl et al, J Clin Oncol 2010;28:1450 True positive diagnoses per 1000 screens 16

17. Management of ovarian cancer risk 17

18. Risk-Reducing Salpingo-Oophorectomy Peritoneal cancers may occur Unexpected cancers in ~4% Also ↓ breast cancer risk Survival benefit 18

19. Risk-Reducing Salpingo-Oophorectomy Peritoneal cancers may occur Unexpected cancers in ~4% Also ↓ breast cancer risk Survival benefit 19

20. Impact of RRSO 20

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22. Potential impact of intervention 22

23. Potential impact of intervention 23