1. BRCA1/2 Mutation Testing and Breast/Ovarian Cancer in the Ashkenazi Jewish Population Glenn E Palomaki, B.S. Foundation for Blood Research Scarborough, Maine (207) 883-4131 palomaki@fbr.org

2. p (1,000,000) Cumulative incidence (N) = cs (cf) CF= Carrier Frequency (carrier rate as a percentage) CS = Clinical sensitivity (%) P = Penetrance (%) Use consensus estimates/ranges for each variable. Integrated Approach

3. Carrier Rate The rate of three founder BRCA1/2 mutation carriers among the Ashkenazi Jewish population 6174delT (BRCA2) All three combined 5382insC (BRCA1) 185delAG (BRCA1) 1 in 66 to 1 in 111 1 in 33 to 1 in 56 1 in 250 to 1 in 833 1 in 92 to 1 in 130 Fodor et al., 1998; Hartge et al., 1999; Oddoux et al., 1996; Roa et al., 1996; Struewing et al., 1995; Struewing et al., 1997.

4. Clinical Sensitivity At any age 7 to 12 % Proportion of Ashkenazi Jewish women with breast cancer at any age carrying a BRCA1/2 mutation Fodor et al., 1998; Hartge et al., 1999; Oddoux et al., 1996; Roa et al., 1996; Struewing et al., 1995; Struewing et al., 1997.

5. Penetrance Proportion of Ashkenazi Jewish women with a founder mutation that develops cancer by age 70 30 to 70% BRCA1 & BRCA2 (weighted average) 26 to 74%BRCA2 alone 36 to 69%BRCA1 alone Warner et al., 1999; Satagopan et al., 2001; King et al., 2003; Fodor et al., 1998; Struewing et al., 1997; Moslehi et al, 2000.

6. Cumulative Incidence Caucasian Women 10.1% Proportion of Ashkenazi Jewish women that will develop breast cancer by age 70 DevCan Software: Probability of developing or dying of cancer. Version 5.1: Statistical Research and Application Branch, National Cancer Institute; 2003. Ashkenazi Jewish women similar?

7. Cumulative Incidence of Breast Cancer by Age 70 (Among Ashkenazi Jewish women using a carrier rate of 1 in 40) 121110987 Penetrance (%) 70 60 50 40 30 Yellow indicates combinations with cumulative incidences within 10% of the overall rate for Caucasians 146,000159,000175,000194,000219,000250,000 125,000136,000150,000167,000188,000214,000 104,000114,000125,000139,000156,000179,000 83,00091,000100,000111,000125,000143,000 62,00068,00075,00083,00094,000107,000 Clinical Sensitivity (%)

8. Breast and Ovarian Cancer Risks due to Inherited Mutations in BRCA1 and BRCA2 (Mary-Claire King et al., Science, Oct 2003) Studied a cohort of 1,008 Ashkenazi women with breast cancer (index cases), regardless of family history Family members of those carrying a mutation were genotyped and cancer history collected Reported that – half of all mutation carriers had no family history – clinical sensitivity is 10.3% – 2.5% of Ashkenazi Jewish women carry a mutation – the BRCA1/2 penetrance to age 70 is 71%

9. 1,000,000 followed age 20 to age 70 25,000 (2.5%) have a BRCA1/2 mutation 975,000 do not have a BRCA1/2 mutation 159,750 develop cancer 815,240 do not develop cancer 71% develop cancer (17,750) 7,250 do not develop cancer Evaluate Finding Using the Integrated Approach Cumulative Incidence is 177,500 - 80% higher than the rate expected in Caucasians

10. Comparison of Three Studies of Breast Cancer in Ashkenazi Jewish Women ComponentKingWarnerSatagopan Clin Sensitivity10.3%11.6%10.1% Penetrance (by 70) 71% 50% 40% Carrier Rate-- assumed to be 1:40 -- Cumulative Incidence * 178,000104,000100,000 * Computed cumulative incidence per million women by age 70. In Caucasian women, the SEER rate is 96,000.

11. Acknowledgments Work was supported by a cooperative agreement with the CDC, Office of Genomics and Disease Prevention (CCU319352) Background information collected as part of an ACCE Review: Breast/Ovarian Cancer and BRCA1/2 Mutations (available on the CDC website)