1. BRCA1 and BRCA2 Mutations and Breast Cancer: An Integrated Approach Using Four Epidemiologic Parameters Monica McClain, PhD. Assistant Director, Biometry and Epidemiology Foundation for Blood Research Scarborough, Maine Email: mcclain@fbr.org

2. Epidemiologic Parameters

3. Cumulative Incidence By Age 45By Age 70 1.19%9.67% Proportion of women that will develop breast cancer by a given age DevCan: Probability of developing or dying of cancer software. Version 5.1: Statistical Research and Application Branch, National Cancer Institute; 2003.

4. Clinical Sensitivity By Age 45 (Adjusted for methodologic underascertainment) By Age 70 3.7 to 12.6% 2 to 10% Hopper et al. Cancer Epidemiol Biomarkers Prev. 1999. Loman et al. J Natl Cancer Inst. 2001. Malone et al. Cancer. 2000. Peto et al. J Natl Cancer Inst. 1999. Anglian Breast Cancer Study Group. Br J Cancer. 2000. Newman et al. JAMA. 1998. Anton-Culver et al. Eur J Cancer. 2000. Claus et al. Cancer. 1996. Easton et al. Am J Hum Genet. 1993. Easton et al. Am J Hum Genet. 1995. Newman et al. Epidemiol Rev. 1997. Peto et al. J Natl Cancer Inst. 1999. Szabo and King. Am J Hum Genet. 1997. Whittemore et al. Am J Hum Genet. Mar 1997. Proportion of women with breast cancer by a given age carrying a BRCA1/2 mutation

5. Penetrance Proportion of women with a BRCA1/2 mutation that develops breast cancer by a given age By Age 45By Age 70 BRCA1 alone20 to 40%35 to 85% BRCA2 alone10 to 25%45 to 85% BRCA1 and BRCA2 (approximate weighted average) 15 to 30% 35 to 65% Anglian Breast Cancer Study Group. Br J Cancer. 2000; Easton et al. Am J Hum Genet. 1995; Antoniou et al. Am J Hum Genet. 2003; Antoniou et al. Br J Cancer. 2002; Antoniou et al. Genet Epidemiol. 2000; Brose et al. J Natl Cancer Inst. 2002; Ford et al. Am J Hum Genet. 1998; Schubert et al. Am J Hum Genet. 1997.

6. Carrier Rate BRCA1 alone1 in 800to1 in 1,400 BRCA2 alone1 in 450to1 in 800 BRCA1 and BRCA2 1 in 300to1 in 450 The rate of BRCA1/2 mutation carriers in the general population Anglian Breast Cancer Study Group. Br J Cancer. 2000; Antoniou et al. Br J Cancer. 2002; Antoniou et al. Genet Epidemiol. 2000; Ford et al. Am J Hum Genet. 1995; Peto et al. J Natl Cancer Inst. 1999; Whittemore et al. Am J Hum Genet. Mar 1997.

7. Meta-analysis for each parameter to calculate a point estimate but Heterogeneity Wide ranges, broad confidence intervals Not internally consistent

8. Integrated Approach CR= Carrier Rate (1 in N) CI = Cumulative incidence (N out of 1,000,000) CS = Clinical sensitivity (%) P = Penetrance (%) =CR 1 (( CI * CS ) / P ) / 1,000,000

9. Integrated Approach: Results By Age 70 (assuming a cumulative incidence of 9.67%) Penetrance 1%1.25%1.5%1.75%2% 35% 1 in 360 1 in 2901 in 2401 in 2051 in 180 45% 1 in 4651 in 370 1 in 3101 in 2651 in 235 55%1 in 570 1 in 4551 in 3801 in 325 1 in 285 65%1 in 6701 in 540 1 in 4501 in 3951 in 335 Yellow indicates plausible combinations C l i n i c a l S e n s i t i v i t y

10. 1,000,000 followed from age 20 to age 70 96,700 will develop breast cancer 1,000,000 * 9.67 % Apply Cumulative Incidence of 9.67 % Applying the integrated approach to a hypothetical cohort of 1,000,000 women

11. 1,000,000 followed age 20 to age 70 96,700 will develop breast cancer 903,300 will not develop breast cancer Con’t 1,000,000 - 96,700 Calculate those that will not develop breast cancer

12. 1,000,000 followed age 20 to age 70 96,700 will develop breast cancer 903,300 will not develop breast cancer 1,450 BRCA1/2 + Con’t 96,700 * 1.5 % Apply clinical sensitivity of 1.5 %

13. 1,000,000 followed age 20 to age 70 96,700 will develop breast cancer 903,300 will not develop breast cancer 1,450 BRCA1/2 + 95,250 BRCA1/2 - Con’t Calculate non-BRCA1/2 mutation carriers in women with breast cancer 96,700 - 1,450

14. 1,000,000 followed age 20 to age 70 96,700 will develop breast cancer 903,300 will not develop breast cancer 1,186 BRCA1/2 + 1,450 BRCA1/2 + Con’t Calculate BRCA1/2 mutation carriers in women without breast cancer (penetrance = 55%) (1,450 / 0.55) – 1,450 95,250 BRCA1/2 -

15. 1,000,000 followed age 20 to age 70 96,700 will develop breast cancer 903,300 will not develop breast cancer 1,186 BRCA1/2 + 902,114 BRCA1/2 - 1,450 BRCA1/2 + 95,250 BRCA1/2 - Con’t Calculate non-BRCA1/2 mutation carriers in women without breast cancer

16. 1,000,000 followed age 20 to age 70 96,700 will develop breast cancer 903,300 will not develop breast cancer 1,186 BRCA1/2 + 902,114 BRCA1/2 - 1,450 BRCA1/2 + 95,250 BRCA1/2 - Con’t Carrier Rate: 2,636 / 1,000,000 or 1 in 380

17. A Comparison Among Commonly Used Information Sources Epidemiologic Parameter MyriadAMAPDQ Gene Review Cumulative Incidence (%) 7Not given Clinical Sensitivity (%) 662Not given Penetrance (%)56 to 87 36 to 8536 to 86 Carrier Rate (1 in N) 500Not given500250 to 500 www.myriad.com www.ama-assn.org www.cancer.gov/cancerinfo/pdq www.genetests.org

18. Calculated parameters using our integrated approach Epidemiologic Parameter MyriadAMAPDQ Gene Review Cumulative Incidence (%) 1.9 to 2.9?3.6 to 8.5? Clinical Sensitivity (%) 1.6 to 2.5??? Penetrance (%) >100?? ? Carrier Rate (1 in N) 133 to 207??? Each epidemiologic parameter is calculated by setting the other three parameters listed by the same information source as constants in our integrated approach

19. What’s next? Expand the approach to incorporate family history

20. Epidemiologic parameters needed when family history is used as a screening test VariablePoint EstimateRange Cumulative Incidence (%)9.67+/- 10 Clinical sensitivity (%)1.51 - 2 BRCA mutation carrier rate1 in 4001 in 300 to 450 Penetrance (%) (BC | BRCA+)58 *35 – 65 Strong family history (%)1 0.5 - 10 Clinical sensitivity in strong FmHx (%) 30 26 - 64 FmHx penetrance (%) (BC | FmHx+ & BRCA+) 75 70 - 85 Fm Hx risk ratio3.2 ** 2 - 5 * value fixed by the first three variables ** risk ratio computed using the other 6 variables Lancet. Oct 27 2001 Pharoah et al. Int J Cancer. 1997

21. 3000 Yes 10,000 Positive 1,000,000 Women followed from age 20 to 70 990,000 Negative Strong Family History Develops Breast Cancer 7000 No BRCA1/2 Mutation Present 93,700 Yes 900 Yes 2100 No 300 Yes 6700 No 550 Yes 93,150 No 896,300 No 750 Yes 895,550 No Relationship Between Strong Family History, Breast Cancer and BRCA1/2 Mutation Status

22. What’s next? Expanded approaches –Family history –Ovarian cancer –Breast and ovarian cancer –Race/ethnicity (Ashkenazi Jewish) –Mutation location (BRCA1, BRCA2, OCCR) Other conditions with a genetic component

23. Acknowledgment Support for this study was provided by a cooperative agreement (UR/CCU319352) with the Centers for Disease Control and Prevention, Office of Genomics and Disease Prevention.