Abstract 7419: Polygenic risk scores and risk of second cancers among older adult cancer survivors

Abstract Background. The etiology of second primary cancers among survivors of older adult-onset cancers is largely known. There is limited data as to whether genetic predisposition increases the risk of second cancers among older adult-onset cancer survivors. Methods. This analysis was conducted among men and women enrolled in the Cancer Prevention Study II Nutrition cohort who were diagnosed with a first non-metastatic incident cancer between 1992 and 2015. Survivors were followed-up until 2017 for the diagnosis of a second primary cancer at a different organ. Analyses were restricted to participants with genetic data, younger than 85 years at their initial diagnosis, unrelated and of European ancestry. We used externally validated polygenic risk scores (PRSs) for the prediction of overall (overall-PRS; 179 variants), breast (BC-PRS; 313 variants) and prostate (PC-PRS; 451 variants) cancers in the general population. Adjusted Cox proportional regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) to estimate the risk of second primary cancers associated with the PRSs, modeled as continuous and quartile variables. Results. This cohort included 16, 356 survivors of a first primary cancer (58.1% male). The median age at this diagnosis was 73 years (interquartile range (IQR): 68, 77), with 72.2% of the cancers being localized. The most common first primary cancers were prostate (35.0%), breast (19.1%) and colorectal (9.5%). Cancer survivors were followed-up for a median of 8.6 years (IRQ: 4.1, 13.9) for the incidence of a second primary cancer. We found that the PRSs were associated with significant increased risks of second cancers. Specifically, 1-standard deviation (sd) increased of the overall-PRS increased the risk of any second cancer by 7% (HR=1.07, 95% CI: 1.03, 1.12); 1-sd increased of the BC-PRS increased the risk of breast cancer among female survivors of a non-breast cancer by 59% (HR=1.59, 95% CI: 1.35, 1.86); and 1-sd increased of the PC-PRS also increased the risk of prostate cancer in male cancer survivors of a non-prostate cancer by 59% (HR=1.59, 95% CI: 1.39, 1.82). Compared to the lowest quartiles of each of the PRSs, those in the highest quartile of the overall-PRS had a 16% increased risk of any second cancer (HR=1.16, 95% CI: 1.04, 1.30); those in the highest quartile of the BC-PRS had a 4-fold increased risk of breast cancer (HR=4.07, 95% CI: 2.43, 6.80); and those in the highest quartile of the PC-PRS had a 3-fold increased risk of prostate cancer (HR=3.05, 95% CI: 2.10, 4.43). Conclusions. In this cohort of older cancer survivors, we found that externally validated PRSs for the prediction of overall and breast and prostate cancers in the general population were associated with higher risks of developing second primary cancers. These PRSs may provide valuable information to improve clinical risk stratification among survivors and opportunities to enhance surveillance for second cancers. Citation Format: Clara Bodelon, Adriana Lori, Christina C. Newton, Ying Wang, Parichoy Pal Choudhury, Hyuna Sung, Ahmedin Jemal, Lauren R. Teras, Alpa V. Patel. Polygenic risk scores and risk of second cancers among older adult cancer survivors [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 7419.