Low-dose ionizing radiation significantly increases the risk of breast cancer among BRCA1/2 mutation carriers in the International BRCA1/2 Carrier Cohort Study (IBCCS)

Background

Women who carry germline mutations in the BRCA1 and BRCA2 genes are at a greatly increased risk of breast cancer (BC). Numerous studies have shown that exposure to ionizing radiation is a risk factor for BC. Because of the role of the BRCA proteins in DNA repair it is plausible that women who carry mutations in these genes might be more sensitive to ionizing radiation than women in the general population. We therefore determined the role of low-dose ionizing radiation in carriers of a BRCA1 or BRCA2 mutation.

Methods

A retrospective cohort study of 1601 female BRCA1/2 carriers, of whom 879 were affected with BC at the time of interview, was performed. Exposure data were analyzed using a weighted Cox proportional hazards model. We assessed the relative risk of BC as a function of exposure to chest X-rays as assessed by questionnaire.

Results

In the entire cohort, any reported exposure to chest X-rays was associated with a significantly increased risk of BC (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.1-2.1, P = 0.007) compared with those reporting never having had an X-ray. This risk was increased in carrier women aged 40 and younger (HR = 1.97, 95% CI = 1.3-2.9, P < 0.001), and in women born after 1949 (HR = 3.6, 95% CI = 2.1-6.2, P < 0.001). Estimated risks were highest in women exposed to X-rays before age 20 only, particularly those born in later birth cohorts (HR = 4.85, 95% CI = 2.2-10.9, P < 0.001).

Conclusions

The observed patterns of risk are consistent with those found in previous studies of radiation and BC, but the extent of the risk increase in BRCA carriers appears to exceed several-fold that observed for other radiation-exposed cohorts. The results of this study have important implications for the use of X-ray imaging in BRCA1/2 carriers, particularly before age 20.