Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation

Abstract

Genetic testing for mutations in BRCA1 and BRCA2 is available in Canada for women with a significant family history of breast cancer. For the majority of tested women, a BRCA1 or BRCA2 mutation is not found, and counselling regarding breast cancer risk is based on the review of the pedigree. In this prospective study, we estimate breast cancer risks in women with a family history of breast cancer and for whom the proband tested negative for a mutation in BRCA1 or BRCA2. Families with two or more breast cancers under the age of 50 years, or with three cases of breast cancer at any age, and who tested negative for a BRCA1 or BRCA2 mutation were identified. Follow-up information on cancer status was collected on all first-degree relatives of breast cancer cases. The standardised incidence ratios (SIRs) for breast cancer were calculated by dividing the observed numbers of breast cancer by the expected numbers of breast cancers, based on the rates in the provincial cancer registries. A total of 1492 women from 365 families were included in the analyses. The 1492 first-degree relatives of breast cancer cases contributed 9109 person-years of follow-up. Sixty-five women developed breast cancer, compared to 15.2 expected number (SIR=4.3). The SIR was highest for women under the age of 40 (SIR=14.9) years and decreased with increasing age. However, the absolute risk was higher for women between the age of 50 and 70 (1% per year) years than for women between 30 and 50 (0.4% per year) years of age. There was no elevated risk for ovarian, colon or any other form of cancer. Women with a significant family history of breast cancer (ie, two or more breast cancers under the age of 50 years, or three or more breast cancers at any age), but who test negative for BRCA mutations have approximately a four-fold risk of breast cancer. Women in these families may be candidates for tamoxifen chemoprevention and/or intensified breast screening with an MRI.