Associations of radiotherapy receipt with lung cancer risk by histological subtype among breast cancer survivors in the United States

Radiotherapy for breast cancer has been associated with an increased risk of secondary malignancies, including primary lung cancer. Whether this association varies by histological subtype of lung cancer remains unknown. Based on the data from 12 Surveillance, Epidemiology, and End Results registries, we examined the association between radiotherapy receipt and the risk of subtype-specific subsequent primary lung cancer (SPLC) among female first primary breast cancer cases diagnosed between ages 20 and 84 from 1992 to 2020. More than half (53%) of the 550,007 breast cancer survivors identified had undergone radiotherapy as part of their initial breast cancer treatment. Over an average follow-up of 9.7 years, 8014 survivors developed SPLCs. For small-cell carcinoma, the standardized incidence ratio (SIR) compared with the general population was higher for survivors who received radiotherapy (SIR = 1.15, 95% confidence interval [CI] = 1.06-1.25) but similar for those who did not receive radiotherapy (SIR = 1.00, 95% CI = 0.91-1.09), with the difference in SIRs being statistically significant (p = .003). Similar associations were found for squamous cell carcinoma (SIRyes = 1.16, 95% CI = 1.08-1.24 vs. SIRno/unknown = 1.06, 95% CI = 0.98-1.15; p = .07). The increased risks were confined to ipsilateral SPLC, with the greatest SIRs for small-cell carcinoma occurring 5-10 years since breast cancer diagnosis (SIR = 1.83, 95% CI = 1.53-2.19) and for squamous cell carcinoma with a latency of 10 years or more (SIR = 1.64, 95% CI = 1.42-1.88). In contrast, the risk of developing adenocarcinoma did not vary by radiotherapy receipt (SIRyes = 1.23, 95% CI = 1.18-1.28 vs. SIRno/unknown = 1.17, 95% CI = 1.12-1.22; p = .18), indicating additional risk factors in play. The findings suggest a distinct carcinogenic pathway of radiation-induced lung cancer across histological subtypes and may inform risk-stratified surveillance guidelines for SPLC.