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Our study examines whether reproductive and hormonal factors prior to, at the time of, or subsequent to, radiation treatment for a first primary breast cancer, modify the risk of radiation-induced second primary breast cancer.
The Women’s Environmental, Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based study of 708 women (cases) with asynchronous contralateral breast cancer (CBC) and 1,399 women (controls) with unilateral breast cancer. Radiotherapy (RT) records, coupled with anthropomorphic phantom simulations, were used to estimate quadrant-specific radiation dose to the contralateral breast for each patient. Rate ratios (RR) and 95% confidence intervals (CI) were computed to assess the relationship between reproductive factors and risk of CBC.
Women who were nulliparous at diagnosis and exposed to ≥1 gray (Gy) to the contralateral breast, had a greater risk of CBC than matched unexposed nulliparous women (RR=2.2, 95% CI 1.2–4.0). No increased risk was seen in RT-exposed parous women (RR=1.1, 95% CI 0.8–1.4). Women treated with RT who later became pregnant (n=8 cases and 9 controls) had a greater risk of CBC (RR=6.0, 95% CI 1.3, 28.4) than unexposed women (n=4 cases and 7 controls) who also became pregnant. The association of radiation with risk of CBC did not vary by number of pregnancies, history of breastfeeding or menopausal status at the time of first breast cancer diagnosis.
Nulliparous women treated with RT were at an increased risk of CBC. Although based on small numbers, women who become pregnant after first diagnosis also appear to be at an increased risk of radiation-induced CBC.
Age at menarche, age at menopause, parity and age at first full-term pregnancy are well established factors affecting breast cancer risk (1). Young age at first full-term pregnancy is associated with a reduction in lifetime risk of estrogen receptor (ER) or progesterone receptor (PR) positive breast cancer (2) that is thought to be mediated through the induction of breast differentiation associated with lower rates of breast cell proliferation (3). In the approximately 10 years following a first full-term pregnancy before age 35 years, breast cancer risk is increased, then decreases relative to nulliparous women (4).
Ionizing radiation is an established breast cancer risk factor (5). Radiation-induced breast cancer risk depends on age at exposure, radiation dose and the time since exposure. Previously we reported that women under age 40 years who received >1.0 gray (Gy) of absorbed dose to the contralateral breast during radiotherapy (RT) for a first primary breast cancer, had a significantly higher risk of developing a second primary contralateral breast cancer (CBC) (RR= 2.5, 95% CI 1.4–4.5) compared with unexposed women. Women older than 40 years at the time of RT, however, were not at increased risk (6). We also reported that parity and age at menarche, but not age at first full-term pregnancy, were risk factors for CBC (7).
During puberty and pregnancy, breast cells are rapidly dividing and may be particularly susceptible to carcinogens, including radiation. Thus, the timing of radiation exposure relative to these hormonally-related events might be important determinants of radiation-induced breast cancer risk. Exposures during puberty (8–11) and pregnancy (9, 12) have been associated with an increased risk of radiation-induced breast cancer. Previous studies have suggested that parity, age at first full-term pregnancy, number of births and breastfeeding may modify the impact of radiation exposure on breast cancer risk (9, 12–14).
The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study is a population-based case-control study of 708 cases with asynchronous CBC and 1,399 controls with unilateral breast cancer (UBC) after comparable lengths of follow-up (15). The objective of this study is to examine whether reproductive and hormonal factors prior to, at the time of, or subsequent to, diagnosis of a first primary breast cancer, modify the risk of radiation-induced second primary CBC.
Subjects were identified through five population-based cancer registries: Los Angeles County Cancer Surveillance Program; Cancer Surveillance System of the Fred Hutchinson Cancer Research Center (Seattle); State Health Registry of Iowa; and the Cancer Surveillance Program of Orange County/San Diego-Imperial Organization for Cancer Control (Orange County/San Diego) and the Danish Breast Cancer Cooperative Group Registry, supplemented with data from the Danish Cancer Registry (15).
Eligible cases met the following criteria: a) diagnosed between 1/1/1985 and 12/31/2000 with UBC followed by a second in situ or invasive primary breast cancer in the contralateral breast, diagnosed at least 1 year later; b) resided in the same study reporting area for both diagnoses; c) no previous or intervening cancer diagnosis (except for basal or squamous cell skin cancer); d) under age 55 years at the time of diagnosis of the first primary breast cancer; e) alive and granted informed consent, completed the interview and provide a blood sample. The “at-risk” period was defined as starting one year after first diagnosis and ending at reference date: i.e., the date of second breast cancer diagnosis in cases or the corresponding date in matched controls.
WECARE Study controls met the same criteria as the cases except they had not developed a second breast cancer or undergone a prophylactic mastectomy of the contralateral breast prior to the end of the at-risk interval. Two controls were individually matched to each case on year of birth (5-year strata), year of diagnosis (4-year strata), registry region and race/ethnicity. Reproductive history was not used in defining case-control eligibility.
To improve statistical efficiency, cases and controls were counter-matched on cancer registry-recorded RT so that each triplet contained two RT-treated (exposed) women and one woman not treated with RT (unexposed). For each exposed case, one exposed and one unexposed control were selected from the relevant stratum and for each unexposed case, two exposed controls were selected. This counter-matching ensured that each triplet contributed to the analysis, avoiding the situation where all members of a matched set had the same radiation status (15).
A total of 998 women with CBC and 2,112 women with UBC were identified as being eligible for the study. Of these, 708 cases (71%) and 1,399 controls (66%) were interviewed and provided a blood sample.
The data collection protocol was approved by the institutional review board at each of the participating centers. Each woman provided written informed consent. WECARE Study participants were interviewed by telephone using a pre-tested, structured questionnaire. Medical records, radiotherapy records, pathology reports and hospital charts were used to collect information on treatment and tumor characteristics, including tumor location in the contralateral breast.
RT details were sought from the basic RT record, RT summary, RT notes, medical record notes, surgery reports (for brachytherapy) and physician correspondence. All patients in this study were treated with conventional fields, including various combinations of tangential breast, supraclavicular, axilla, direct breast, and internal mammary chain fields. The radiation absorbed dose to the quadrant in the contralateral breast where the second cancer arose (or to the equivalent breast location for UBC controls) was estimated for each woman. Representative irradiations in tissue-equivalent anthropomorphic phantoms were performed to estimate the dose from each type of field. These measures were used to estimate the dose to the contralateral breast received by each woman, based on the treatment fields and corresponding dose received as part of her treatment for a first breast cancer. The total dose for each woman was the sum of the contribution from each field. The mean dose to the quadrant location of the contralateral breast tumor or matching location for controls was 1.2 Gy (SD=0.7). Further details can be found in Stovall et al (6).
Two RT variables were created for analysis: RT (ever/never) and “RT dose”. RT (ever/never) indicates whether a woman was treated with radiation. “RT dose” is the estimated absorbed dose to the contralateral breast at the quadrant-specific location of the second breast cancer in cases or corresponding location for the matched controls. Analyses using “RT dose” were restricted to women with complete RT records, including women with no RT, and to women with known location of the second primary CBC (606 cases and 1,200 controls) (Table 1).
The influence of reproductive and hormonal factors on radiation-induced CBC risk was assessed by exploring the relationship with RT status (ever/never and dose to the contralateral breast (0, <1Gy, ≥1Gy)) stratified by: menopausal status, age at menopause (premenopausal, postmenopausal and age <45 years, postmenopausal and age ≥45 years), parity (nulliparous, parous), number of full-term pregnancies (nulliparous, 1, ≥2), and history of breastfeeding (yes, no). Only full-term (third-trimester) pregnancies were included in the analysis. We also explored the influence of RT by whether a pregnancy occurred between first diagnosis and reference date (nulliparous at reference date, parous at first diagnosis but no interval pregnancy, interval pregnancy), and by time between last full-term pregnancy and first breast cancer diagnosis among those who were parous at first diagnosis but had no interval pregnancy (full-term pregnancy <5 years prior to first diagnosis, full-term pregnancy 5–<10 years prior to first diagnosis and full-term pregnancy ≥10 years prior to first diagnosis).
To assess the relationship between reproductive factors and risk of radiation-induced CBC, rate ratios (RR) and 95% confidence intervals (CI) were computed, using conditional logistic regression models, adjusting for known risk factors for breast cancer: age at (first) diagnosis, menopausal status at first diagnosis/age at menopause, age at menarche (<13, ≥13 years), number of full-term pregnancies at first diagnosis, first-degree family history of breast cancer (no, yes, adopted), histology of first primary (lobular, other), stage of first primary breast cancer (local, regional), and treatment (hormonal and/or chemotherapy: yes, no). An offset term was incorporated to account for the sampling probability of the counter-matching (15). Age- and multivariate-adjusted models are presented.
Menopausal status was estimated by comparing the date or age a woman last reported menstruating with the date of her first diagnosis of breast cancer. If a woman reported that she was still menstruating within 2 years before first diagnosis, or was pregnant, she was classified as premenopausal at that time point. A lag of two years was used to ensure minimal misclassification due to rounding errors in the self-report of age at menopause with respect to age at breast cancer diagnosis.
All statistical analyses were conducted using SAS 9.2 (SAS Institute Inc., Cary NC).
Table 1 shows the distribution of the matching factors and selected characteristics of the WECARE Study population. Cases and controls were similar for all matching characteristics. Both had a median age at first diagnosis of 46 years and the median age at reference date was 50 years for cases and 51 years for controls. The median at-risk period length was 4 years for both cases and controls. Forty-five percent of cases and 55% of controls received chemotherapy and 28% of cases and 35% of controls received hormone therapy as part of their treatment for a first primary breast cancer.
When radiation was coded as ever/never, radiation-related CBC risk did not vary by parity, number of full-term pregnancies, history of breastfeeding and menopausal status at the time of first diagnosis (Table 2). When radiation dose (0, <1, ≥1 Gy) to the contralateral breast was taken into account, women who were nulliparous at the time of RT and received ≥1 Gy to the contralateral breast had a higher risk of CBC than unexposed nulliparous women (RR=2.2, 95% CI 1.2–4.0, p=0.01) (Table 3). No increase in risk was seen in similarly exposed parous women (RR=1.1, 95% CI 0.9–1.4, p for heterogeneity relative to parous women = 0.08).
Women treated with RT (ever/never) who had a full-term pregnancy between first diagnosis and reference date had a greater risk of CBC compared with unexposed women who also had a pregnancy during this time period (RR=6.0, 95% CI 1.3, 28.4, p=0.02) (Table 2), whereas no effect was seen in the other two groups (p for heterogeneity = 0.06). We had insufficient numbers to examine RRs by dose categories in this group of women. The 12 cases and 16 controls who had an interval pregnancy were similar with respect to median age at breast cancer diagnosis (30 years in cases, 31.5 years in controls), although cases were younger at the time of interval pregnancy (33 years for cases, 36 years for controls). This interval pregnancy was the first for 33% of cases and 29% of controls. The median number of years between initial breast cancer diagnosis and pregnancy was 2 years (range of 1–4 years) for cases and 2.5 years (range of 1–7 years) for controls, and cases with an interval pregnancy had a slightly shorter median at-risk period than controls (4 years for cases, 6 years in controls). No association was seen between time since last full-term pregnancy and radiation-induced CBC risk; again we had insufficient numbers to further stratify the interval pregnancies by time since last pregnancy.
The influence of parity at the time of first diagnosis on radiation-induced CBC risk was also examined stratified by age at first diagnosis (<45 years, ≥45 years). Nulliparous women, exposed to ≥1Gy who were <45 years old at first diagnosis, had a higher risk of CBC than unexposed women (RR=2.6, 95% CI 1.4–4.9). A similar increase was not seen in women who were ≥45 years (RR=1.7, 95% CI 0.8–3.5). The results of this stratified analysis were not statistically different (p for heterogeneity=0.61). No difference was seen in parous women stratified by age at first diagnosis (results not shown).
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 (9–11, 17), or while pregnant (9, 12) 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, 21). 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.
This research was funded by the National Cancer Institute: R01CA114236, and U01CA083178.
Conflicts of Interest: The authors declare no conflicts of interest.