Abstract 3421: Associations of circulating levels of tryptophan-kynurenine metabolites and inflammation biomarker neopterin with overall survival among patients with stage I-III colorectal cancer
Authors: Damerell Victoria , van Roekel Eline H. , Brezina Stefanie , Kok Dieuwertje E. , Lin Tengda , Holthuijsen Daniëlle D. , Ose Jennifer , Himbert Caroline , Eussen Simone J. P. , Ulvik Arve , van Duijnhoven Fränzel J. , Figueiredo Jane C. , Li Christopher I. , Siegel Erin M. , Schneider Martin , Shibata David , Toriola Adetunji A. , Ulrich Alexis B. , Ueland Per M. , Weijenberg Matty P. , Gsur Andrea , Kampman Ellen , Ulrich Cornelia M. , Gigic Biljana 
Published: March 2024

Introduction: Dysregulation of the kynurenine pathway of tryptophan metabolism has been linked to the development of inflammation-related chronic diseases, such as colorectal cancer (CRC). Circulating concentrations of certain kynurenine metabolites, the kynurenine/tryptophan ratio (KTR), and the pro-inflammatory marker neopterin increase during inflammation, particularly in response to interferon-gamma. However, comprehensive data on the associations between inflammation markers and kynurenine metabolites and clinical outcomes in CRC patients are lacking. To address this gap in knowledge, we investigated associations of circulating kynurenine metabolites and neopterin with overall survival (OS) in prospectively followed non-metastatic CRC patients.

Methods: Pre-surgery blood samples from 2,101 stage I-III CRC patients participating in the international FOCUS consortium were used to measure circulating levels of nine tryptophan-kynurenine pathway metabolites and neopterin using liquid chromatography-tandem mass spectrometry. Multivariable linear regression models and Spearman partial correlation analyses were conducted to quantify associations between kynurenine metabolites and neopterin. Based on the results from correlation analyses, a subset of patients (n=984) was categorized into different groups (‘kynurenine metabolite/neopterin‘: i.e. ‘low/high‘, ‘high/high‘) using the median biomarker concentration as cut-off. Associations of biomarkers with OS were assessed using Cox proportional hazards regression models. All models were adjusted for age at diagnosis, sex, tumor stage, tumor site, circulating creatine levels and cohort.

Results: Tryptophan was inversely correlated with neopterin (r=−0.21, β=−0.48, Plinear&lt;0.001). Neopterin was positively correlated with kynurenine (kyn) (r=0.25, β=0.57, Plinear&lt;0.001), the KTR (r=0.42, β=0.87, Plinear&lt;0.001), 3-hydroxykynurenine (r=0.26, β=0.32, Plinear&lt;0.001), anthranilic acid (r=0.29, β=0.36, Plinear&lt;0.001), and quinolinic acid (QA) (r=0.41, β=0.56, Plinear&lt;0.001). After a median follow-up of 3.2 years for OS, 14% (141) patients deceased. While patients with ‘high neopterin’ levels had a 43% increased risk of death (HR, 1.43, 95%CI 0.95-2.16), the ‘high kyn/high neopterin‘ patient group had a 52% increased risk of death (HR, 1.52, 95%CI 1.04-2.22). Similarly, the ‘high QA/high neopterin‘ and ‘high KTR/high neopterin‘ patient groups had a 85% and 89% increased risk of death, respectively (HRQA/Neopt, 1.85, 95%CI 1.24-2.75, HRKTR/Neopt, 1.89, 95%CI 1.27-2.80).

Conclusion: Tryptophan-kynurenine pathway activation correlates with inflammation marker neopterin in CRC. Combined associations of kynurenine metabolites and neopterin may be a promising predictor for OS among stage I-III CRC patients.

Citation Format: Victoria Damerell, Eline H. van Roekel, Stefanie Brezina, Dieuwertje E. Kok, Tengda Lin, Daniëlle D. Holthuijsen, Jennifer Ose, Caroline Himbert, Simone J. P. Eussen, Arve Ulvik, Fränzel J. van Duijnhoven, Jane C. Figueiredo, Christopher I. Li, Erin M. Siegel, Martin Schneider, David Shibata, Adetunji A. Toriola, Alexis B. Ulrich, Per M. Ueland, Matty P. Weijenberg, Andrea Gsur, Ellen Kampman, Cornelia M. Ulrich, Biljana Gigic. Associations of circulating levels of tryptophan-kynurenine metabolites and inflammation biomarker neopterin with overall survival among patients with stage I-III colorectal cancer [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(6_Suppl):Abstract nr 3421.