Abstract 4442: Associations between pre-diagnostic plasma metabolites and biliary tract cancer risk in the prospective UK Biobank cohort

Abstract Background Annually, approximately 200, 000 people are diagnosed with biliary tract cancer (BTC). Most present with metastatic disease which encompasses a 5-year survival rate of 5%. Etiology is poorly understood though some studies suggest metabolic dysregulation may contribute to development. Previous evaluations of metabolites and BTC risk have primarily been limited to case-control studies, few metabolites, or post-diagnostic blood samples. Methods We evaluated 248, 285 adult participants with metabolite data in the UK Biobank, a prospective cohort study. Participants were excluded (6. 2%) primarily due to a baseline history of cancer. To reduce potential influences of reverse causation, those who developed cancer or died within one year after baseline blood collection were also removed. Metabolites were trimmed to two standard deviations, log-transformed (lnx+0. 5), z-scored, and evenly divided into tertiles. Cox proportional hazards regression was implemented to evaluate associations of BTC risk per 1-standard deviation (SD) and across tertiles with hazard ratios (HR) and 95% confidence intervals (95% CI). Models were adjusted for age, sex, education, income, fasting time, and statin use. A p-value of 0. 001 was considered statistically significant after multiple comparison adjustment (0. 05 divided by 50, the number of independent tests). Results The analyzed cohort includes 232, 781 UKB participants with a median age of 58, a median follow-up time of 11. 8 years, and 268 first primary incident BTC cases. Multiple metabolites were significantly associated with BTC risk using continuous variables (per 1-SD increment). High triglyceride to total lipid ratios were associated with higher BTC risk, and the strongest association was for intermediate-density lipoproteins (the HR (95% CI) was 1. 33 (1. 15-1. 54), p=0. 0001). On the other hand, high cholesterol to total lipid ratios were associated with lower BTC risk, and the strongest association was for the free cholesterol to total lipids in small very-low-density lipoproteins (VLDL) (0. 76 (0. 66-0. 88), p =0. 0002). High glutamine was associated with lower BTC risk (0. 68 (0. 69-0. 89), p =0. 0003) as was the phospholipid to total lipid ratio in small VLDL (0. 75 (0. 65-0. 87), p =0. 0002). Analysis by tertile identified additional significant associations, including a higher polyunsaturated fatty acid to total fatty acid ratio being associated with lower BTC risk (the HR (95% CI) comparing the highest to lowest tertile, 0. 50 (0. 35-0. 71), p-trend=0. 0001). Notably, within polyunsaturated fatty acids, a higher omega-6 to omega-3 ratio trended toward higher risk (1. 32 (0. 94-1. 85), p-trend=0. 11). Conclusion These findings indicate circulating metabolites may be biomarkers for BTC and suggest that triglycerides, cholesterols, fatty acids, phospholipids, and glutamine may be involved in BTC etiology. Citation Format: Valerie Gunchick, Guochong Jia, Wei Zheng. Associations between pre-diagnostic plasma metabolites and biliary tract cancer risk in the prospective UK Biobank cohort 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 4442.