Abstract 6141: Genetic risk, health-associated lifestyle, and risk of early-onset total cancer and breast cancer: A prospective cohort study

Abstract Background Early-onset cancer (diagnosed under 50 years of age) is generally more aggressive. Its rising incidence is a global concern. The associations between genetic risk, lifestyle, and the risk of early-onset cancer may inform preventive strategies. Methods We studied the association between genetic risk, lifestyle and early-onset cancers among 66308 white British participants enrolled in the UK Biobank before age 50. Genetic risk was assessed using sex-specific composite total cancer polygenic risk scores (PRSs). We calculated composite PRSs as weighted sums of previously-developed cancer site-specific PRSs using weights obtained from lasso regression. We considered a breast cancer-specific PRS for analyses on breast cancer among women. A health-associated lifestyle score (HLS) was calculated based on baseline smoking, BMI (men only), physical activity, alcohol intake, and diet. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of early-onset total cancer and breast cancer across genetic risk and HLS groups in women and men. Results A total of 1247 incident invasive early-onset cancer cases (820 in women, 427 in men) were documented, including 386 cases of early-onset breast cancer. In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs. lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in women (composite PRS HR=1. 85; 95% CI, 1. 50-2. 29), early onset total cancer in men (composite PRS HR=1. 94; 95% CI, 1. 45-2. 59), and early-onset breast cancer in women (breast-cancer PRS HR=3. 06; 95% CI, 2. 20-4. 25). The HRs (95% CI) of early-onset total cancer in women and men, and early-onset breast cancer in women associated with adopting an unfavorable lifestyle (highest vs. lowest tertile of HLS) were 1. 49 (0. 99, 2. 25), 1. 14 (0. 67, 1. 95), and 1. 78 (0. 97, 3. 24), respectively, in the total study population; 1. 85 (1. 02, 3. 36), 3. 27 (0. 78, 13. 72), and 1. 67 (0. 71, 3. 90), respectively, in those with high genetic risk; 1. 25 (0. 60, 2. 57), 1. 11 (0. 42, 2. 89), and 1. 66 (0. 54, 5. 11), respectively, in those with intermediate genetic risk; and 1. 15 (0. 44, 2. 98), 1. 16 (0. 39, 3. 40), and 2. 10 (0. 57, 7. 75), respectively, in those with low genetic risk. Compared to individuals with both low genetic risk and a favorable lifestyle, those with high genetic risk and an unfavorable lifestyle had substantially increased risks of early-onset total cancer in women (3. 07; 1. 64-5. 78) and men (2. 18; 0. 78-6. 11), and significantly higher early-onset breast cancer risk in women (4. 11; 1. 56-10. 85). Conclusion Genetic and lifestyle factors were independently associated with risks of early-onset total cancer and breast cancer. Compared to those with low genetic risk, individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer. Citation Format: Yin Zhang, Yuxi Liu, Kathryn L. Penney, Sara Lindström, Peter Kraft. Genetic risk, health-associated lifestyle, and risk of early-onset total cancer and breast cancer: A prospective cohort study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6141.