Women who were nulliparous at the time of diagnosis with a first primary breast cancer were at an increased risk of radiation-induced CBC. This increase appeared to be limited to women with an early age at first breast cancer diagnosis. An increased risk was not seen in RT-exposed women who were parous at first diagnosis. Associations between RT and CBC risk did not vary by menopausal status, number of pregnancies, or history of breastfeeding. Among women who had a full-term pregnancy between first diagnosis and reference date, those who were treated with RT for their first breast cancer were at a significantly higher risk of CBC compared with those who did not have RT.
The epidemiology of radiation-induced breast cancer has been largely informed by studying the Japanese atomic bomb survivors and patients exposed to diagnostic or therapeutic medical radiation. Among Japanese A-bomb survivors, parity, first full-term pregnancy at a young age, multiple births and history of breastfeeding have all been shown to be associated with a lower excess risk of breast cancer after radiation exposure (13
). A recent study of Japanese atomic bomb survivors, however, found that once the baseline breast cancer risk was taken into account, radiation-induced breast cancer risk did not vary appreciably by whether exposure occurred before menarche, between menarche and first pregnancy, or after first pregnancy, i.e., radiation-associated breast cancer risk did not vary by reproductive status at the time of exposure (16
Women exposed to diagnostic or therapeutic radiation (i.e., RT for Hodgkin lymphoma, fluoroscopic chest x-rays for monitoring lung-collapse treatment of tuberculosis, RT for acute postpartum mastitis or diagnostic x-rays for monitoring scoliosis during the growth spurt) at an early age, prior to or around the time of first menses (9
), or while pregnant (9
) or lactating (18
), have been reported to have increased risk of radiogenic breast cancer. These time periods of high breast cell proliferation may render the breast particularly susceptible to the carcinogenic effects of radiation. Further, women treated with RT for Hodgkin lymphoma, who also received radiation to their ovaries (>5 Gy) or alkylating agents (leading to ovarian dysfunction) as part of their chemotherapy, had a lower risk of developing breast cancer compared to women who received lower RT doses to the ovaries or no alkylating agents (19
). These results suggest a role for hormonal stimulation of breast cells in radiation-induced breast cancer.
In studies of predominantly ER positive breast cancers, a transient increase in risk is seen in the years directly following a pregnancy (4
). It has been hypothesized that this initial increase could be due to the promotion of previously initiated cellular changes occurring in the breast. The protective effect of pregnancy observed in later years is thought to be due to tissue differentiation, which reduces susceptibility to subsequent exposures (3
). The results of our analysis suggest that the nulliparous, but not the parous, breast is susceptible to the carcinogenic effect of radiation exposure experienced during treatment for a first primary breast cancer. They also suggest that women who have a full-term pregnancy after RT are at an increased risk of radiation-induced CBC. We were unable to examine the impact of interval pregnancies as to whether they were the first or a subsequent pregnancy, or the impact of pregnancies by age at diagnosis, due to small sample numbers within sub-groups of RT exposure.
The relationship between parity and breast cancer risk may vary by breast cancer molecular subtype, with a protective effect of parity seen in ER or PR positive, but not triple-negative breast cancers (2
). The limited data available do not indicate heterogeneity in the relationship between radiation exposure and breast cancer risk by histological subtype or ER/PR status (20
). We were unable to examine the impact of tumor molecular subtype on the relationship between RT, reproductive factors and CBC risk due to small numbers and incomplete information on ER status of second primary breast cancers.
Strengths of this study include the population-based design, large study population and comprehensive questionnaire and medical record data. A further strength is the availability of detailed RT information allowing for dose estimation to the quadrant in the contralateral breast of cases where the second cancer arose. Limitations include an inability to account for tumor subtype, individual patient body shapes in dose estimation, the relatively short time interval of follow-up between first and second breast cancer diagnoses, and the small number of women treated around the time of pregnancy precluding an evaluation of this important period.
Women who were nulliparous at the time of RT for a first primary breast cancer were at an increased risk of radiation-induced CBC. An increased risk was not seen in similarly exposed parous women. Further, women who became pregnant after a first primary breast cancer diagnosis may have an increased risk of CBC, suggesting that hormonal stimulation of radiation-initiated cells may promote further changes toward malignancy. If confirmed in a larger study population, these results could have clinical implications on treatment decisions for women with breast cancer who are nulliparous, or still in their child-bearing years.