Association of Changes in Cancer Therapy over 3 Decades with Risk of Subsequent Breast Cancer among Female Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study (CCSS)

Importance: Breast cancer is the most common invasive subsequent malignant disease in childhood cancer survivors, though limited data exist on changes in breast cancer rates as primary cancer treatments have evolved. Objective: To quantify the association between temporal changes in cancer treatment over 3 decades and subsequent breast cancer risk. Design, Setting, and Participants: Retrospective cohort study of 5-year cancer survivors diagnosed when younger than 21 years between 1970 and 1999, with follow-up through December 5, 2020. Exposures: Radiation and chemotherapy dose changes over time. Main Outcomes and Measures: Breast cancer cumulative incidence rates and age-specific standardized incidence ratios (SIRs) compared across treatment decades (1970-1999). Piecewise exponential models estimated invasive breast cancer and ductal carcinoma in situ (DCIS) risk and associations with treatment exposures, adjusted for age at childhood cancer diagnosis and attained age. Results: Among 11550 female survivors (median age, 34.2 years; range 5.6-66.8 years), 489 developed 583 breast cancers: 427 invasive, 156 DCIS. Cumulative incidence was 8.1% (95% CI, 7.3%-9.0%) by age 45 years. An increased breast cancer risk (SIR, 6.6; 95% CI, 6.1-7.2) was observed for survivors compared with the age-sex-calendar-year-matched general population. Changes in therapy by decade included reduced rates of chest (34% in the 1970s, 22% in the 1980s, and 17% in the 1990s) and pelvic radiotherapy (26%, 17%, and 13% respectively) and increased rates of anthracycline chemotherapy exposures (30%, 51%, and 64%, respectively). Adjusting for age and age at diagnosis, the invasive breast cancer rate decreased 18% every 5 years of primary cancer diagnosis era (rate ratio [RR], 0.82; 95% CI, 0.74-0.90). When accounting for chest radiotherapy exposure, the decline attenuated to an 11% decrease every 5 years (RR, 0.89; 95% CI, 0.81-0.99). When additionally adjusted for anthracycline dose and pelvic radiotherapy, the decline every 5 years increased to 14% (RR, 0.86; 95% CI, 0.77-0.96). Although SIRs of DCIS generally increased over time, there were no statistically significant changes in incidence. Conclusions and Relevance: Invasive breast cancer rates in childhood cancer survivors have declined with time, especially in those younger than 40 years. This appears largely associated with the reduced use of chest radiation therapy, but was tempered by concurrent changes in other therapies..