Abstract 4942: Associations of smoking with the risk of second primary cancer in adults with a history of various cancer types

Importance: Smoking increases the risk of developing second primary cancers (SPCs) among individuals with a history of cancer. However, most evidence comes from survivors of smoking-related first primary cancers (FPC) with limited data available for a range of FPC types. Objective: Examine the association between smoking and the risk of developing SPC by FPC types. Design, Setting, and Participants: In the Cancer Prevention Study II Nutrition Cohort, we identified 28,272 participants who were diagnosed with first primary invasive, non-metastatic cancer between January 1, 1992, and June 30, 2015, and survived for 1+ year, and followed them for SPC diagnoses until June 30, 2018. Exposures: Smoking status and years since quitting, assessed shortly (mean=1.6 years; SD=1.4) before FPC diagnosis. Main Outcome: Self-reported SPCs (excluding those at the same site as FPC), defined as smoking-related cancers by the IARC Working Group on the Evaluation of Carcinogenic Risks to Humans Measures: Multi-variable adjusted hazard ratio (HR) using Cox proportional hazards model Results: Approximately 59% were male and 49% were in their 70s at their FPC diagnosis (mean=72.2; SD=7.08). The most common FPCs were prostate (32.8%), breast (18.5%), colorectal (9.0%), and non-Hodgkin lymphoma (8.3%). Smoking prevalence was highest among those with FPC of the lung (88.2%), esophagus (78.3%), and bladder (75.3%) and lowest among those with uterine corpus (38.5%) and ovarian (38.2%) cancers. During a median follow-up of 7.0 years, 1,926 individuals (7%) developed smoking-related SPCs. In multivariable models, former (HR=1.62, 95%CI=1.46-1.80) and current (HR=3.77; 95%CI=3.22-4.41) smokers were more likely than never-smokers to develop smoking-related SPCs. The HRs for current smokers varied across FPC types: 5.84 (95%CI=2.51-13.6) for uterine corpus, 4.93 (95%CI=2.60-9.33) for colorectum, 4.07 (95%CI=3.12-5.31) for prostate, 3.87 (95%CI=1.41-10.6) for melanoma, 3.27 (95%CI=2.24-4.75) for breast, 3.11 (95%CI=1.65-5.89) for non-Hodgkin lymphoma, and 2.77 (95%CI=1.50-5.15) for bladder. Among former smokers overall, HRs declined with years since quitting from 2.56 (95%CI=2.17-3.02) for <10 years to 1.30 (95%CI=1.14-1.48) for 30+ years before FPC diagnosis. The risk reduction was most marked for uterine cancer survivors after 10+ years (HR=0.80, 95% CI=0.37-1.74) and breast cancer survivors after 20+ years since quitting (HR=0.88, 95% CI=0.63-1.22), although a lower-level risk persisted for several other FPCs. Conclusions and Relevance: Associations between smoking and the risk of SPC are evident across various FPC types, even when the first cancer is not smoking-related. The finding highlights the importance of smoking cessation efforts in reducing the burden of second primary cancers in the expanding population of cancer survivors. Citation Format: Hyuna Sung, Christina C. Newton, W. Ryan Diver, Ellen Mitchell, Emily Deubler, Kieran Kelly, J. Lee Westmaas, Lauren Teras, Ahmedin Jemal, Alpa Patel, Clara Bodelon. Associations of smoking with the risk of second primary cancer in adults with a history of various cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4942.