Familial breast and ovarian cancer risks and BRCA1 germline mutations in two population-based studies

Abstract

9532 Background: A family history of breast or ovarian cancer is related to risk for breast and ovarian cancer and possibly other site-specific cancers, but little is known about specific causes of these associations. Methods: We studied 1978 female first-degree relatives (FDRs) of 670 unselected Caucasian invasive breast cancer cases (probands) recruited to a population-based family study. Probands were administered the same questionnaire. Recruited to a similarly designed study of ovarian cancer, 342 FDRs of 1848 unselected Caucasian ovarian cancer probands also were studied. By extensive mutation testing, 18 breast cancer and 29 ovarian cancer probands were identified as BRCA1 mutation carriers (BRCA1-positive). Standardized incidence ratios were calculated using referent five-year age- and calendar year-specific U.S. cancer incidence rates. Results: Risks of breast and ovarian cancer in female FDRs of BRCA1-positive breast cancer cases were 10.6 (95% confidence interval (CI): 6.0–18.9) and 7.9 (95% CI: 1.6–3.9) times the U.S. population risk, respectively. Risks of breast and of ovarian cancer to age 85 years in female FDRs of BRCA1+ ovarian cancer cases were 3.2 (95% CI: 2.6–3.9) and 11.1 (95% CI: 10.2–12.0) times the U.S. population risk, respectively. Only breast cancer risk in female FDRs of BRCA1-negative breast cancer probands was statistically significant. However, ovarian cancer risk in FDRs of BRCA1-negative ovarian cancer cases was significant at 2.0 (95% CI: 1.6–2.7) times the referent population risk. If the breast cancer proband was younger than age 40 years at diagnosis, then their FDRs' breast and ovarian cancer risks were elevated at 3.3 (95% CI: 2.8–3.8) and 4.7 (95% CI: 3.9–5.6) times, respectively. If the younger breast cancer proband was also BRCA1-negative, these risks remained elevated at 3.1 (95% CI: 2.0–3.5) and 3.9 (95% CI: 2.9–5.2), respectively. Conclusions: The extent of familial breast and ovarian cancer risks is related to the specific cancer type in the cancer proband. Mutations in genes other than BRCA1 may be associated with a high risk of breast cancer, especially in young women. No significant financial relationships to disclose.