Many subsequent studies, whether in founder or predominantly outbred populations, have estimated breast cancer risks by age 70 years of approximately 60% or lower and ovarian cancer risks of approximately 40% or lower, though often with large confidence limits because, even in studies of founder populations, the number of identified mutation carriers is relatively small. A meta-analysis of ten studies estimates risks among BRCA1 and BRCA2 mutation carriers of 57% and 49% for breast cancer and 40% and 18% for ovarian cancer. Most studies have done molecular testing on the proband only and have done no,[46,52,55,61,86,103,108,111,113,115,116] or limited,[109,112] testing among relatives. Instead, the mutation status of relatives is modeled on simple Mendelian principles that on average, one-half of FDRs of mutation carriers will themselves be carriers. Such modeling may lead to imprecision in the penetrance estimates; by chance, more than or less than half the relatives of some families will be carriers. In the New York Breast Cancer Study of 104 mutation-positive Ashkenazi Jews with breast cancer, penetrance estimates were based only on relatives whose mutation status was known. These estimates were 69% and 74% for breast cancer by age 70 years for BRCA1 and BRCA2 mutation carriers, respectively, and 46% and 12% for ovarian cancer for BRCA1 and BRCA2, respectively.
The largest study to date to estimate penetrance involved a pooled analysis of 22 studies of over 8,000 breast and ovarian cancer cases unselected for family history. Subjects were from 12 different countries and had a broad spectrum of mutations. Using modified segregation analysis on the families of the nearly 500 cases found to carry a BRCA1/BRCA2 mutation, the cumulative risk of breast cancer by age 70 years was 65% (95% CI, 44%-78%) for BRCA1 and 45% (95% CI, 31%-56%) for BRCA2.
Data are emerging that the penetrance estimates for cancer in these families are somewhat higher for BRCA1 mutation carriers than for BRCA2 mutation carriers. For example, while the original estimates of breast cancer penetrance in the Ashkenazi Jewish population were similar for mutations in both BRCA1 and BRCA2, at least two case-control studies among Ashkenazi Jewish families have found a significant difference in rates, with BRCA1 conferring a twofold increase in penetrance of breast cancer compared with BRCA2 mutations.[86,113] A similar difference has been observed for ovarian cancer penetrance. A case series of 491 women with stage I or stage II breast cancer and a known or suspected deleterious BRCA1/BRCA2 mutation was reviewed for incidence of ovarian cancer. The actuarial risk of developing ovarian cancer at 10 years following diagnosis of breast cancer was 12.7% for BRCA1 mutation carriers and 6.8% for BRCA2 mutation carriers. Eight of 83 cancer deaths (9.6%) in this series were because of ovarian cancer. Systemic treatment for the primary breast cancer did not alter these findings. Several studies have suggested that cancer risks in BRCA1/BRCA2 mutation carriers are affected by the type of cancer of the index case. Relatives of breast cancer index cases were more likely to develop breast cancer, and relatives of ovarian cancer index cases were more likely to develop ovarian cancer.[103,118,119,120] Risk of breast cancer before age 50 years in mutation carriers appears to be higher in more recent birth cohorts; one study reported a 67% risk of breast cancer by age 50 years among women born after 1940 compared with a 24% risk among those born before 1940.