BRCA1 and BRCA2 mutation testing in minority populations enrolled in the Breast Cancer Family Registry

CN06-01

Background: Although the BRCA1 and BRCA2 tumor suppressor genes were identified in the mid 1990s, information on deleterious mutations in these genesamong racial/ethnic minority populations remains limited. We report on BRCA1 and BRCA2 mutations in a population-based series of African-American, Hispanic, Asian-American, and non-Hispanic white breast cancer patients from the San Francisco Bay area that are enrolled in the Breast Cancer Family Registry (BCFR), an NCI-funded international consortium established in 1995 at six collaborating sites in the U.S., Canada and Australia.
 Methods: The California site of the BCFR has enrolled over 3,100 breast cancer families, 73% of whom are from racial/ethnic minority populations. This report is based on female patients aged <65 years diagnosed with invasive breast cancer between 1995 and 2003. Newly diagnosed patients were identified through the population-based cancer registry of the Greater San Francisco Bay area and screened by telephone to assess study eligibility, family history of breast and ovarian cancer, and self-identified race/ethnicity. Patients were recruited for the BCFR using a two-stage sampling design, with over-sampling of patients with characteristics suggesting an inherited basis of their breast cancer, as well as patients from racial/ethnic minority populations. Patients were eligible if they had a breast cancer likely to be hereditary (diagnosed before age 35 years, personal history of ovarian or childhood cancer, personal history of bilateral breast cancer with the first diagnosis before age 50 years, or family history of breast or ovarian cancer in at least one first-degree relative). All other patients aged 35-64 years with breast considered less likely to be hereditary were randomly sampled (2.5% of non-Hispanic whites and 25% of racial/ethnic minority populations). Patients participating in the BCFR completed a detailed family history questionnaire by telephone, an in-person interview on breast cancer risk factors and treatment, and provided a blood sample. Patients were tested for BRCA1 and BRCA2 mutations. For each racial/ethnic group, we compared mutation carriers to non-carriers in terms of clinical and tumor characteristics such as age at diagnosis, estrogen receptor (ER) and progesterone receptor (PR) status, tumor grade and stage at diagnosis, and self-reported family history of breast cancer. For BRCA1 mutations, we also compared the spectrum of mutations across racial/ethnic groups, and calculated weighted estimates of BRCA1 carrier prevalence and 95% confidence intervals for each racial/ethnic group.
 Results: A total of 3,218 breast cancer patients were eligible to enroll in the BCFR, including 142 proxy respondents for deceased patients. Of those alive, 76% completed the family history and risk factor questionnaires, and 58% provided a blood sample. BRCA1 mutation testing completed for 1,727 patients identified 129 patients with unclassified variants and 54 carriers of deleterious mutations (7 Ashkenazi Jewish, 15 other non-Hispanic whites, 8 African-Americans, 21 Hispanics, and 3 Asian-Americans). Overall, 35% of carriers (n=19) were aged <35 years at diagnosis, compared to 12% among non-carriers (patients without deleterious mutations or unclassified variants). Average age at diagnosis was 42 years for carriers and 49 years for non-carriers. Compared to tumors of non-carriers, those of carriers were significantly more likely to be ER- (70% vs. 23%), PR- (70% vs. 30%), and high-grade (80% vs. 34%) than non-carriers. Advanced stage at diagnosis (regional or distant disease) did not significantly differ between carriers and non-carriers (26% vs. 33%). Carriers were also more likely to report a family history of breast cancer than non-carriers (57% vs. 44%).
 Findings were similar for African-American and Hispanic carriers, the two largest racial/ethnic groups in this study. Among 8 African-American carriers, 7 (88%) had ER- and 7 (88%) had PR- tumors and all tumors were high-grade. Furthermore, 5 (63%) were diagnosed before age 35 years. Among 19 Hispanic carriers with information on ER and PR status, 15 (79%) had ER- and 14 (74%) had PR- tumors; 18 (86%) were diagnosed with high-grade tumors. Among 15 non-Hispanic white carriers without Ashkenazi Jewish ancestry, 8 (53%) had ER-, 9 (60%) had PR-, and 10 (67%) had high-grade tumors. Of the 3 Asian-American carriers, all were ER- and PR- and 2 had high-grade tumors.
 A total of 1645 breast cancer patients were tested for BRCA2 mutations, 235 had an unclassified variant and 49 were carriers of a deleterious mutation (1 Ashkenazi Jewish, 14 other non-Hispanic whites, 9 African-Americans, 12 Hispanics, 12 Asian-Americans, and 1 of mixed race). Average age at diagnosis was slightly younger for carriers than non-carriers (45 vs. 48 years). Unlike tumors of BRCA1 carriers, those of BRCA2 carriers were less likely to be ER- (18% vs. 27%) or PR- (30% vs. 35%), when compared to tumors of non-carriers. However, these differences were not statistically significant. Similar to BRCA1 carriers, BRCA2 carriers were more likely to be diagnosed with high-grade tumors than non-carriers (62% vs. 40%, p <0.01). These overall patterns were similar in specific racial/ethnic groups.
 For BRCA1, we found that the spectrum of deleterious mutations differed between racial/ethnic groups. In Hispanics, 71% of mutations were frameshift, compared to 25% in African-Americans and 36% among non-Hispanic whites. Most notably, 5 of 21 Hispanic BRCA1 carriers had the 185delAG mutation.
 The prevalence of deleterious mutations was estimated only for BRCA1, as BRCA2 testing is not complete yet in this population-based series of patients. The prevalence was highest in Ashkenazi Jewish patients (8.3%, 95% CI=3.1-20.1), followed by Hispanic patients (3.5%, 95% CI=2.1-5.8), other non-Hispanic white patients (2.2%, 95% CI=0.7-6.9), African-American patients (1.3%, 95% CI=0.6-2.6) and Asian-American patients (0.5%, 0.1-2.0). Among young patients diagnosed before age 35 years, the prevalence was particularly high among African-American patients (16.7%, 95% CI=7.1-34.4), compared to 7.2% (95% CI=3.3-15.2) among non-Ashkenazi Jewish whites and 8.9% (95% CI=3.8-19.7) among Hispanics.
 Conclusions: As has been reported for non-Hispanic white breast cancer patients, among African-American and Hispanic patients, the tumors of BRCA1 mutation carriers were predominantly ER-, PR- and high-grade compared to those of non-carriers. No such differences in ER and PR status were seen for tumors of BRCA2 mutation carriers. The higher prevalence of BRCA1 mutations in Hispanic patients as compared to non-Hispanic white patients without Ashkenazi ancestry may reflect the presence of unrecognized Jewish ancestry in this population. The high prevalence of BRCA1 mutations among young African-American patients needs confirmation.