Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use A Report From the Childhood Cancer Survivor Study

Question Is the combination of radiotherapy and treatment with anthracyclines associated with an increased risk of breast cancer among survivors of childhood cancer? Findings In this case-control study of 271 patients with breast cancer within the North America Childhood Cancer Survivor Study, the combination of anthracyclines and radiotherapy doses to the breast was associated with increased breast cancer risks and was greater than the sum of their effects, consistent with an additive interaction. Meaning The results of this study may help inform surveillance guidelines for childhood cancer survivors and assess potential breast cancer risks from contemporary treatment protocols. Importance Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied. Objectives To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status. Design, Setting, and Participants In a North American hospital-based nested case-control study, a retrospective cohort of 14358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (+/- 2 years). Data analysis was conducted from September 2017 to July 2018. Exposures Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents. Main Outcomes and Measures Odds ratios (ORs) for subsequent breast cancer by ER status. Results A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER- (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m(2), 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER- cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use. Conclusions and Relevance This study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER- cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors. This case-control study evaluates the risk of breast cancer in women who have survived childhood cancer treated with radiotherapy and anthracyclines.