No evidence of excess breast cancer risk among mutation-negative women from BRCA mutation-positive families
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This analysis addresses risk of breast cancer among women in BRCA-positive families who test negative for the family mutation. We compared the number of prospectively diagnosed breast cancers in 395 mutation-negative women from 28 BRCA1/2-positive families to an age-, race-, and calendar time-specific expected number of breast cancers derived from the SEER 9 Cancer Registry. Study participants contributed a total of 7008.1 person-years of follow-up. The mean age at study entry was 31.3 years; mean follow-up was 17.7 years. Ten women developed breast cancer yielding an observed-to-expected ratio of 0.82 (95% CI 0.39–1.51). Adjustment for possible reduction in breast cancer risk due to oophorectomy by two different methods resulted in O/E ratios in the range of 0.80–0.99. Stratification by degree of relatedness to the nearest mutation carrier did not substantially alter these results, however, women with at least one-first degree relative with breast cancer appeared to have a slightly increased, though not statistically significant, risk of breast cancer (O/E ratio = 1.33, 95% CI 0.41–2.91). 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, with a possible slight increase in risk among mutation-negative women with a family history of breast cancer in a first degree relative. Although this is the largest prospective cohort yet assembled to address this important question, the number of breast cancer events is still relatively small.
KeywordsBRCA mutation Breast cancer risk Mutation negative Cohort
We are grateful to the families who participated in National Cancer Institute protocols 78-C-0039 [NCT00004007]: Clinical, Laboratory, and Epidemiologic Characterization of Individuals and Families at High Risk of Cancer, and 02-C-0212 [NCT00045214]: Study of Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characteristics of Individuals and Families at High Risk of Breast or Ovarian Cancer. Without their sustained commitment to this research effort, this work would have been impossible. We would also like to acknowledge the contributions of June Peters, Ron Kase and Ann Carr to the study, and Dr. Mitch Gail for thoughtful comments on the manuscript. This research was supported, in part, by funding from the Intramural Research Program of the National Cancer Institute to the Clinical Genetics Branch, and by support services contracts NO2-CP-11019 and NO2-CP-65504 with Westat.
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