Women exposed to radiotherapy for an enlarged thymus during early childhood are at increased risk for breast cancer well into the 6th decade of life with a statistically significant radiation dose response relationship. This association remained even after evaluating the potential for confounding by multiple breast cancer risk factors. Incidence rate ratios for neither the entire follow-up period nor the interval since the 1985 survey were markedly different when censored for other first cancers, suggesting that the increased breast cancer incidence among thymic irradiated women did not result solely from a greater exposure to chemotherapy or secondary radiotherapy.
While our current results suggest a possible decrease in relative risk of breast cancer associated with thymic irradiation over time, the absolute excess risk appeared to increase with time. The rate ratio for treated individuals up to 1987 had been 3.6 (15
), so the new estimates, using a similar model adjusted for attained age only, of 3.05 represents a 16% reduction and of 2.54 since the 1985 survey represents a 31% reduction. The previously reported ERR/Gy of 3.48 (95%CI: 2.1-6.2) was not adjusted for attained age (15
), so similar estimates of 1.96 (95%CI: 1.18-3.08) for the entire follow-up period and of 1.64 (95% CI: 0.85-2.85) since the 1985 survey represent 44% and 53% reductions respectively. Although models suggested time since therapy would reduce ERR of breast cancer (1
), the longitudinal nature of our data collection has allowed for the confirmation of this within a single cohort. However, the unadjusted excess absolute risk increased from 5.7 (95% CI: 2.9-9.5) to 12.2 (95% CI: 8.2-17.0) cases per 104
person-years per Gy. This opposite trends in relative and absolute risk are not contradictory, because baseline breast cancer incidence increases with age offsetting the decline over time in the relative risk associated with radiation exposure (1
). While changes in dosimetry might affect comparisons with prior results, analysis using the original dose estimates suggest that any changes in dosimetry would underestimate the decrease in ERR/Gy over time, while having a less than 5% impact on EAR estimates.
To place the magnitude of the radiation-associated breast cancer risk from our study in perspective, we used the excess absolute risk model for breast cancer diagnosis by 50 years of age from a large pooled analysis of 8 cohorts by Preston et al (1
). This pooled study included this cohort with follow-up through the 1985 survey, the atomic bomb survivors cohort, and 6 others. The authors recommend using the pooled EAR model to transfer risk across different populations (1
). Using this pooled model, they estimated that in our cohort the EAR at age of 50 would be 30 per 104
person-years per Gy (95% CI: 7.7-71), which is remarkably similar to the EAR/Gy of 28.7 per 104
person-years (95% CI: 17.6-41.7) we calculated applying this model to the updated data. This would continue to place the EAR/Gy estimate from this cohort among the highest of the 8 cohorts studied. This finding is likely due to the relatively greater number of years at risk since exposure, the relatively acute nature of the radiation exposure (i.e. one or two fractions vs. multiple fractions), and the relative radiosensitivity of the breast at age of exposure (infancy) compared to other cohorts in the pooled analysis (1
Although infants are generally thought to be more radiosensitive than older children and adults (20
), in terms of breast cancer, the highest risk from radiation may be during puberty and surrounding the first pregnancy, when breast ductal cells are actively developing (2
). Comparing our results to those from the recent follow-up of U.S. Scoliosis Study cohort (40
) would suggest that breast cancer risk per Gy in infants is not as high as in adolescents and young adults. In this cohort, women received periodic X-rays for scoliosis evaluation resulting in an estimated mean dose to the breast of 0.13 Gy (range 0.00005-1.11 Gy), over a median of 24 fractions. A vast majority had some radiation exposure from screening between breast budding and first child birth, while only 23% had exposure before breast budding. The estimated EAR/Gy was 176 per 104
person-years at age 50 using the common model from the pooled cohort study compared to our estimate of 28.7. This estimate is much higher than ours strongly suggesting that the young adult female breast is more radiosensitive. Furthermore, they found that the ERR/Gy was highest for radiation exposure during the period between menarche and birth of the first child and lowest for the period before breast budding, although adjusting for period of exposure did not improve model fit (40
None of the traditional BC risk factors added significantly to model fit in our cohort. This result suggests that even at the “relatively lower” medical doses in the thymus cohort (mean 0.71 Gy; median 0.17 Gy), radiation is a much more powerful breast cancer risk factor then other established risk factors. Due to missing risk factor data, we were only able to perform multivariate adjustment using 80% of our sample. The findings from other studies on the impact of traditional breast cancer risk factors on radiation's effect are mixed (6
). In other radiation-exposed cohorts, age at first birth seems to be the most consistent independent risk factor for breast cancer though it does not directly modify the effect of a given dose of irradiation (43
). Findings in Hodgkin lymphoma survivors suggest that decreased estrogen stimulation decreases the breast cancer risk associated with a unit dose of irradiation, at least pre-menopausally (42
Three studies have suggested that family history and particular mutations may affect risk associated with irradiation (40
). Absent data on family history of breast cancer, we investigated whether Jewish ethnicity might affect risk, given the increased frequency of BRCA1 and 2 mutations in Ashkenazi Jews (48
). Jewish subjects in our cohort had also been found to have a greater risk of thyroid cancer per Gy (26
). Although significant in univariate analysis, no evidence existed for an independent or interactive effect of Jewish ethnicity in multivariate models that included thymic irradiation status or dose. This result may be due to a true absence of association, our very limited power, and/or the clustering of Jewish families in the practice that tended to use the highest radiation doses (26
Treatment/birth cohort added to model fit, with the group born or treated between 1937 and 1947 having a much higher risk than the other two groups. This cohort also had a non-significantly lower ERR/Gy of 0.63 (95% CI: 0.20-1.36) compared to the group treated before 1937 with an ERR/Gy of 1.97 (95% CI:0.75-4.49) and the group after 1947 with an ERR/Gy of 2.08 (95% CI 0.44-5.91). These results could be caused by differences in breast cancer risk factors in the different treatment/birth cohorts. However, risk factor distribution varied significantly by treatment/birth cohort but not in a consistent manner (data not shown). There was also more missing data in the earliest cohort making further analysis difficult. Nevertheless, even in our models without treatment/birth cohort, none of the traditional breast cancer risk factors significantly added to multivariate model fit.
A limitation of our study is the lower-than-desired response rate and the differential response rate between the treated and untreated women. This response pattern might lead to non-response bias, threatening internal validity. However, differences in breast cancer risk factors amongst responders and non-responders by treatment group are minimal and would tend to cancel each other out (). For age at first birth and oral contraceptive use, differences in distribution between responders and non-responders in the untreated group are similar in magnitude and direction to differences in the treated group between responders and non-responders. Thus the relative risk comparing the two groups should not be substantially biased by the difference between measured and actual distributions of these factors. Respondents also had a lower rate of smoking than non-respondents in the untreated group, but smoking is not consistently associated with breast cancer risk in other studies (49
) nor in our cohort previously (15
). Additionally, the rate ratio for thymic irradiation on breast cancer incidence up until 1987 did not differ significantly between responders and non-responders to the current survey (p= 0.25); further suggesting non-response bias is not a substantial problem in our study.
A related concern is accuracy of risk factor data collected. Although we incorporated breast cancer risk factor data from the 1985 and the current surveys into our analysis, the inclusion of the former would minimize misclassification only for those risk factors unlikely to change after 1985, when the average age was 37 years and the minimum age was 22 years. These risk factors would include age at menarche, factors regarding pregnancy, and use of oral contraceptives, which were all remarkably consistent between the two surveys at the individual level. Data on menopausal status, age at menopause, and hormone replacement therapy, however, likely changed after 1985. Thus, the effect of these factors on the association between radiation and breast cancer risk should be interpreted with caution, as there were fewer respondents to the current survey. As breast cancer risk factors were first collected in 1985, we could not adjust for these variables in the person-years provided by people who were no longer in the cohort by 1985. Finally, we note that complex radiobiological models were not applied to these data, as the linear dose model proved to fit better than linear-quadratic or pure quadratic models, and a more complex model including a term that allowed for a downturn at high doses due to ”cell sterilization“– ERR(D) = (β1
D + β2
) * [exp(-β3
)-- could not be fit statistically. The latter is probably because of the limited number of breast cancer cases.
This study has several strengths. First, to our knowledge, the median follow-up of this cohort is longer than that of any other radiation-exposed cohort, other than the atomic bomb survivors' cohort (51
). As such, it is one of the first studies of individuals exposed to medical irradiation during childhood known to have a significant proportion of breast cancer events occur after menopause. Second, the cohort has an internal comparison group made up of siblings from the same community as those exposed to irradiation. Third, although radiation received by our cohort differs from that used today in terms of dose distribution and less-precise techniques, this exposure is more similar to the therapeutic and diagnostic radiation received by patients today than is the whole-body radiation received by atomic bomb survivors with its different exposure pattern and sources of radioactivity. Our cohort also has the advantage that their radiation exposure was not due to cancer, so our findings are not confounded by the possibility that an initial malignancy may be a marker of cancer susceptibility or by chemotherapy effects.
Our results therefore highlight the potential for increased breast cancer risk from current medical practices that expose the chest to irradiation during early childhood. As previously mentioned, the higher breast doses in the thymus cohort overlap with exposures to the breast from current radiotherapy protocols for childhood Hodgkin's lymphoma, while lower doses may be consistent with scatter from treatment for other malignancies such as Wilms tumor (14
). More importantly the lower doses in this cohort are similar to those to the breast of infants from chest CT. Typical breast doses for an infant from a single chest CT range between 0.014 and 0.03 Gy (21
). Doses can be twice as high if the settings are not changed from adults levels and a substantial fraction of CT-scanned patients require multiple scan, so if both conditions are met total doses would be close to the median dose of 0.17 Gy in our cohort (55
). In fact, exposures at the lower end of the dose range in our cohort were unfractionated, and thus, may be the most like that from pediatric chest CT than in any other studied cohort to date. Recent studies suggest that an estimated 930,000 body CTs are performed on children 5 years old or younger (55
). Our findings, by adding information on breast cancer risk, support the earlier concern that the population risk of cancer from children undergoing a single CT is not negligible (20
). In fact, when we limited our analysis to breast exposures of < 1 Gy, the estimated ERR per Gy was even higher at 4.80 (95%CI: 1.71-9.56), although at lower doses the error in dose estimation is larger as a percentage of total dose, so ERR estimates may not be as accurate.
In conclusion, our study adds to the radiation-associated breast cancer literature by extending the follow-up of the Rochester, NY thymic irradiation cohort, providing the longest longitudinal follow-up of any cohort exposed to chest radiotherapy. The breast cancer incidence rate associated with the average radiation dose of 0.71 Gy remains about 3 times higher than it is among untreated women from the same communities and families. Our findings suggest that while limiting thoracic radiation exposure during childhood cancer treatment may decrease breast cancer risk, survivors will continue to have an increased cumulative incidence of breast cancer. These findings along with those of others also suggest that female infants undergoing chest CT may be at increased breast cancer risk as adults. While the risks and benefits of radiation exposure for medical purposes must be weighed on an individual basis, these results underscore the importance of limiting radiation exposure in the youngest children as much as possible.