The Genetic Epidemiology of Second Primary Breast Cancer*

It is well established that women with a family history of breast cancer run a higher risk of breast cancer than do women without a family history. The evidence, however, is less clear regarding a possible association between a family history of breast cancer and risk of second primaries. The purpose of this prospective study was to estimate the risk for second primary breast cancer associated with having a family history of breast, endometrial, and ovarian cancers. A cohort of 4,660 women with a first primary breast cancer diagnosed between 1980 and 1982 were interviewed as part of the Cancer and Steroid Hormone Study, a multi-center population-based case-control study, and followed through eight Surveillance, Epidemiology, and End Results (SEER) program registries for 4 to 6 years. Of these women, 136 developed a second primary breast cancer in the contralateral breast at least 6 months after diagnosis of the first primary. Cox proportional hazards modeling techniques were used to model the time to onset of second primary breast cancer while adjusting for multiple predictors. The risk of contralateral breast cancer was elevated among cohort members who reported a history of breast cancer in a first-degree relative (multivariable-adjusted rate ratio (RR) = 1.91, 95% confidence interval (CI) = 1.22-2.99). Early age at onset (< 46 years) in the relative further increased the risk of developing contralateral breast cancer (sister: multivariable-adjusted RR = 3.36, 95% CI 1.62-6.98; mother: multivariable-adjusted RR = 2.35, 95% CI 1.02-5.43). Bilateral breast cancer in mothers was also associated with more than a two and a half-fold increase in risk (multivariable-adjusted RR = 2.55, 95% CI 1.02-6.35). The association between family history of breast cancer and risk of contralateral breast cancer did not vary substantially according to age at onset of the first primary breast cancer. The age-adjusted rate ratio for development of a second primary breast cancer among women with a first-degree relative with endometrial cancer was 2.13 (95% CI 1.04-4.35), while the corresponding rate ratio among women with a family history of ovarian cancer was 1.69 (95% CI 0.42-6.83). There was little evidence that age at onset among the relatives with endometrial or ovarian cancer affected the risk. Some of these findings have not been previously reported and need replication in future studies.