Metabolomic signatures of physical activity in treatment-naive patients with early-onset vs. late-onset colorectal cancer: Results from the ColoCare Study

Introduction : Emerging studies link physical inactivity to early-onset colorectal cancer (EOCRC), but most rely on subjective measures of physical activity (PA). Metabolite signatures may offer an objective measure of PA that also captures the systemic metabolic response to activity. We assessed a previously validated PA metabolomic signature in patients with recently diagnosed colorectal cancer (CRC) and compared profile scores between patients with EOCRC (<50 yrs) vs. non-EOCRC ( > 50 yrs). Methods: We examined baseline (pre-surgery) data from 122 stage I-III patients with CRC in the ColoCare Study at Huntsman Cancer Institute (Utah) and Heidelberg University Hospital (Germany). PA for the previous year was measured with the International Physical Activity Questionnaire-Short Form. Untargeted serum metabolites and complex lipids were profiled at the West Coast Metabolomics Center. We calculated a 24-metabolite PA signature developed in >6,000 cancer-free individuals (Papadimitriou et al., CEBP, 2025) consisting of acylcarnitines, glycerophospholipids, monosaccharides, amino acids, and sphingolipids. Following metabolite pre-processing, normalization, and scaling, we performed multivariable linear regression on 20 metabolites available in our dataset, adjusting for age, sex, tumor stage, and body mass index (BMI). Metabolite scores were calculated for each participant by multiplying normalized metabolite concentrations by the previously developed PA metabolite signature coefficients and were then compared between EOCRC vs. non-EOCRC survivors. Results : Compared to patients with non-EOCRC (67±9 years, N=102), those with EOCRC (39±10 years, N=20) were diagnosed with higher stages (55% vs. 43% stage III), had lower prevalence of obese BMI (25% vs. 37%), and were more physically active (16±17 metabolic equivalent (MET) hrs/week vs. 11±17 MET hrs/week), p>0.05. Patients with EOCRC were more likely to meet PA guidelines ( > 150 min/week of moderate to vigorous PA; 60% vs. 38%) compared to those with non-EOCRC, p>0.05. Among the 20 metabolites investigated in our data, 15 showed a consistent direction of association with the previously developed PA signature. Patients with EOCRC had higher scores of the PA metabolite signature (0.04±0.09) than older patients (-0.01±0.10), t=2.3, p=0.03. This modest association remained significant after adjustment for stage, sex, and BMI (beta=0.05, p=0.048). Conclusions : A PA metabolite signature showed comparable associations to questionnaire-derived PA measures in our CRC survivor cohort, consistent with findings in healthy individuals. Patients with EOCRC reported a higher level of PA compared to those with non-EOCRC and had a significantly higher PA metabolite signature score. The metabolite response to PA may clarify how physical inactivity influences EOCRC risk and outcomes.