Abstract 1004: Higher circulating tryptophan metabolites are associated with improved survival among patients with stage I-III colorectal cancer: results from the FOCUS consortium

Abstract

Abstract Introduction: Dysregulation of the tryptophan metabolic pathway has been linked to colorectal cancer (CRC) development. While circulating levels of tryptophan metabolites have been associated with a decreased risk of CRC, epidemiological studies assessing tryptophan metabolites in relation to CRC outcomes are limited. In this study, we investigated associations between biomarkers of the tryptophan metabolism and clinical outcomes in prospectively followed, non-metastatic CRC patients. Materials and Methods: A total of 2,102 patients with stage I-III CRC participated in six cohorts in the international FOCUS (folate dependent 1-carbon metabolism in colorectal cancer recurrence and survival) consortium. Preoperative circulating concentrations of tryptophan and its metabolites (kynurenine, kynurenic acid (KA), xanthurenic acid (XA), 3-hydroxy-anthralinic acid (HAA), anthranilic acid (AA), and picolinic acid (PA)) were measured by liquid chromatography-tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of tryptophan metabolites with overall survival (OS) and disease-free survival (DFS). Models were adjusted for patient age, sex, circulating creatinine levels, tumor site, tumor stage, and study site. Results: After a median follow-up of 3.2 years for OS, higher tryptophan levels were associated with a 25-44% better overall and disease-free survival (hazard ratio, HROS, 0.56; 95% confidence interval (CI), 0.41-0.76, HRDFS, 0.75; 95% CI, 0.57-0.99). Furthermore, the tryptophan metabolites XA and PA were associated with a better OS and DFS (XA: HROS, 0.74; 95% CI, 0.64-0.85, HRDFS, 0.84; 95% CI, 0.75-0.94; PA: HROS, 0.76; 95% CI, 0.64-0.92, HRDFS, 0.86; 95% CI, 0.75-0.99). No statistically significant associations were found between kynurenine, KA, HAA, and AA concentrations and OS and DFS. The kynurenine-to-tryptophan ratio was positively associated with worse CRC survival (HROS, 2.12; 95% CI, 1.57-2.88, HRDFS, 1.32; 95% CI, 1.01-1.73). Conclusion: Higher preoperative circulating tryptophan and its metabolites XA and PA are associated with improved OS and DFS. Furthermore, the kynurenine-to-tryptophan ratio may represent a promising predictor for survival among stage I-III CRC patients. Citation Format: Victoria Damerell, Stefanie Brezina, Jennifer Ose, Anne JMR Geijsen, Arve Ulvik, Eline H. van Roekel, Andreana N. Holowatyj, Dieuwertje E. Kok, Fränzel JB van Duijnhoven, Christopher I. Li, Nina Habermann, Alexis B. Ulrich, Ellen Kampman, Matty P. Weijenberg, Andrea Gsur, Per M. Ueland, Martin Schneider, Cornelia M. Ulrich, Biljana Gigic, FOCUS Consortium. Higher circulating tryptophan metabolites are associated with improved survival among patients with stage I-III colorectal cancer: results from the FOCUS consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1004.