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

Abstract

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.

Keywords: Breast cancer; Cumulative incidence; Radiotherapy; Radiotherapy-related risk; Second primary cancer; Standardized incidence ratio.

Fig. 1

The study design, the flowchart of the study design, and RT proportion and SPC proportion. (A) The study design and conceptual framework. (B) The screening flowchart for study cohorts. (C) RT proportion in entire cohort and SPC proportion in RT cohort and NRT cohort between 1988 and 2013.

Fig. 2

Kaplan-Meier plots of cumulative incidence rate to SPC of different types of systems: total SPCs (A), breast cancer (B), cancer in respiratory system (C), skin cancer (D), leukemia (E), myeloma (F), soft tissue cancer (G), and eye & orbit cancer (H). RT radiotherapy, NRT no radiotherapy.

Fig. 3

Dynamic RT-associated Risk (RR) Plots of SPC population of different types of systems: breast cancer based on age at diagnosis (A), time of diagnosis (B), and latency period (C); cancer in respiratory system based on age at diagnosis (D), time of diagnosis (E), and latency period (F); skin cancer based on age at diagnosis (G), time of diagnosis (H), and latency period (I). Dynamic standardized incidence ratio (SIR) for: BC in age-SIR plot (J), in diagnosis time-SIR plot (K), and in latency-SIR plot (L); cancer in respiratory system in age-SIR plot (M), in diagnosis time-SIR plot (N), and in latency-SIR plot (O); skin cancer in age-SIR plot (P), in diagnosis time-SIR plot (Q), and in latency-SIR plot (R). Adjusted RRs and 95 % CIs of SPC in different types of systems in patients treated with RT vs patients treated without RT are plotted. Adjusted SIRs and 95 % CIs of developing breast cancer, cancer in in respiratory system, and skin cancer in RT population versus the US general population are plotted, as well as NRT population versus the US general population, and the incidence in the background US population is represented by the gray line (at y = 1).

Fig. 4

Overall survival curves of SPC population of different types of systems: breast cancer before (A) and after PSM(D); cancer in respiratory system before (B) and after PSM (E); skin cancer before (C) and after PSM (F); leukemia before (G) and after PSM (J); myeloma (H), soft tissue cancer (I) and eye & orbit cancer (K) before PSM.