The Impact of Immunotherapy on Incidence of Second Primary Malignancies: A Surrogate for Anti-Tumor Surveillance Activation

Background: Immunotherapy (IT) is widely used across multiple cancer types, yet its impact on second primary cancers (SPCs) remains poorly understood. It is unclear whether IT enhances immune surveillance that prevents progression of pre-clinical malignancies into clinically apparent cancers. Methods: We conducted a retrospective cohort study of adult cancer patients treated between 2010 and 2022 across Cleveland Clinic Ohio centers. Patients (≥18 years) with cancers eligible for first-line IT were included. After excluding ineligible patients, 5,576 patients were included. Patients who received IT (with or without additional systemic therapy or radiation) were compared with those who did not. Multivariable Cox models treated IT as a time-dependent covariate and adjusted for confounders. Follow-up continued until death or loss to follow-up. Results: Among 5,576 patients, 1,296 (23%) received first-line and 948 (17%) received subsequent-line IT, predominantly anti-PD-1/PD-L1 and/or anti-CTLA-4 agents (99.9%). Over a median follow-up of 47.5 months (IQR 27.4-75.4), 264 SPCs were diagnosed. Two- and four-year SPC-free probabilities were 97% (95% CI 96-98) and 94% (95% CI 92-97) in the first-line IT group versus 95% (95% CI 94-96) and 92% (95% CI 91-93) in the non-IT group (log-rank P<0.01). In multivariable analysis, IT was associated with a lower hazard of SPC (HR 0.57, 95% CI 0.41-0.79; P<0.001). Conclusions: Treatment of primary cancer with IT was associated with a reduced clinical incidence of SPCs. These findings support further investigation into the potential of IT as a cancer prevention strategy in both cancer survivors and high-risk, cancer-free individuals.