Radiotherapy and increased risk of second primary cancers in breast cancer survivors: An epidemiological and large cohort study

BACKGROUND: Radiotherapy (RT) for breast cancer (BC) may raise the risk of second primary cancers (SPCs), a relationship inadequately studied. METHODS: We analyzed 248268 female BC patients from 9 SEER registries, 1988-2018, identifying SPCs >5 years after initial treatment, comparing SPC risks between RT and non-RT cohorts using Fine-Gray and Poisson regressions. RESULTS: Of all participants, 55.4 % received surgery and RT. The RT group had a higher SPC incidence, with excess incidence significantly dropped from 6.9 % in 1990 to 0.2 % in 2012. The 30-year SPC incidence was 24.69 % in the RT cohort and 18.11 % in the NRT cohort. RT increased the risk of SPCs(HR, 1.29 [95%CI,1.26-1.33]; P < 0.001), BC(HR, 1.58[1.52-1.64]; P < 0.001), cancer of respiratory system(HR, 1.21[1.13-1.30]; P = 0.013), skin cancer(HR, 1.26[1.10-1.44]; P < 0.001), leukemia(HR, 1.30[1.11-1.54]; P = 0.001), soft tissue cancer(HR, 1.78[1.34-2.37]; P < 0.001), and eye & orbit cancer(HR, 2.21[1.02-4.80]; P = 0.044), except for reducing the risk of multiple myeloma (HR 0.76). Notably, RT-related risks(RR) for BC declined with increasing age and the year of BC diagnosed, increased with longer latency, but the dynamic RR for cancer of respiratory system presented the almost opposite trends. The RT cohort had higher standardized incidence ratios for SPCs compared to both the NRT cohort and the general population overall. Although 15-year overall survival for SPCs was similar between RT and NRT cohorts, SPC presence significantly lowered 30-year survival from 35.64 % to 23.90 %. CONCLUSIONS: RT might increase susceptibility to SPC in breast, respiratory system, skin, soft tissue, eye and orbit, and leukemia in BC survivors. Efforts should be made to timely diagnose SPCs based on their specific patterns to improve patient's quality of life.