Blood-Based vs. Tissue-Based mRNA Expression of Thymidylate Synthase, Dihydropyrimidine Dehydrogenase, and Methylenetetrahydrofolate Reductase: A Prospective Study to Predict the Neoadjuvant CAPEOX Response in Advanced Colorectal Cancer

Abstract

BACKGROUND: Fluoropyrimidine-based chemotherapy is a fundamental treatment for colorectal cancer (CRC), yet its therapeutic efficacy is often limited by significant inter-individual variability. Enzymes involved in 5-fluorouracil (5-FU) metabolism thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and methylenetetrahydrofolate reductase (MTHFR) are critical determinants of drug response. This study aimed to evaluate the molecular correlation between TS, DPD, and MTHFR mRNA expression in paired tumor tissue and peripheral blood samples, while simultaneously developing and validating a non-invasive predictive nomogram to forecast therapeutic response to neoadjuvant CAPEOX (capecitabine-oxaliplatin) chemotherapy in advanced CRC. METHODS: A prospective cohort study was conducted on 36 patients with stage III-IV CRC receiving CAPEOX. mRNA expression of TS, DPD, and MTHFR was quantified using qRT-PCR from paired tumor and peripheral blood samples. Chemotherapy response was evaluated using RECIST 1.1 criteria. Statistical analyses included Spearman correlation, the Mann-Whitney U test, and multivariate logistic regression. A nomogram was constructed based on significant predictors. RESULTS: DPD and MTHFR expression levels were significantly lower in responders than in non-responders (p < 0.001), while TS expression showed no significant difference. Gene expression in tissue and blood was strongly correlated (r = 0.820 for TS, r = 0.658 for DPD, and r = 0.623 for MTHFR; all p < 0.001). Multivariate analysis identified blood-based DPD and MTHFR expression as independent predictors of response. The predictive nomogram demonstrated excellent discrimination (AUC = 0.932). CONCLUSION: Lower DPD and MTHFR expression predicts a favorable response to neoadjuvant CAPEOX in advanced CRC. These biomarkers offer a promising, non-invasive approach to personalizing treatment strategies potentially enhancing therapeutic efficacy while minimizing unnecessary toxicity.

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