Breast cancer risk in mutation-negative members of known BRCA1/2 mutation-positive families.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #1093 Background : Women with deleterious mutations in BRCA1 and BRCA2 have a 40-85% lifetime risk of breast cancer. Female members of BRCA1/2 mutation-positive families who do not carry the family mutation have been counseled as having a breast cancer risk similar to that of the general population. However, recent data suggest that such women may have a 2-to 5-fold increased breast cancer risk, despite being mutation-negative. Methods : We compared the number of prospectively-diagnosed breast cancers in mutation-negative women in an NCI cohort of families with known deleterious BRCA1/2 mutations to an age-, race-, calendar time-specific expected number derived from the SEER 9 Cancer Registries. The family population included all bloodline individuals within three degrees of relatedness to a known mutation carrier. Data were obtained via mailed questionnaire or in-person follow-up. Individuals were eligible for analysis if (1) we had updated cancer status from the individual or a first-, second- or third-degree relative within the past year; and (2) they were tested- or inferred-negative for the family mutation. Individual follow-up began at date of family ascertainment or at age 25 for women who were <25 at family ascertainment. Study follow-up was completed at the date of the most recent family or personal contact, date of death, date of breast cancer diagnosis or date of bilateral mastectomy. Results : We included 395 mutation-negative members from 28 BRCA1/2 positive families in this analysis. Cancer status was obtained from: subjects (33%), first-degree relatives (34%), second-degree relatives (16%), and third-degree relatives (13%). 3% of the participants did not have close family contact within the past year; their follow-up was truncated at last personal contact date. The mean age at study entry was 31.3 years. The mean length of follow-up was 17.7 years. 50 women underwent bilateral oophorectomy prior to or during study follow-up (13%). Study participants contributed a total of 6982.6 person-years of follow-up. Nine women developed breast cancer (all were invasive), yielding an observed-to-expected ratio (O/E ratio) for invasive plus in situ breast cancer of 0.75 (95% CI 0.34-1.41), O/E ratio for invasive disease only = 0.86 (95% CI 0.39–1.63). Adjusting the expected breast cancer number for the known decrease in breast cancer risk among women undergoing oophorectomy did not substantially alter these results. Conclusion : Our data suggest that breast cancer risk among mutation-negative women from BRCA1/2 mutation-positive families is similar to that observed in the general population. Although this is the largest prospective cohort yet assembled to address this important question, the number of breast cancer events is still small. Thus, we cannot exclude a small increase in breast cancer risk. Additional data are required to accurately determine risk in this population, in order to formulate evidence-based screening recommendations for this group of women. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1093.