Abstract
2021 Background: Low levels of the 5-Fluorouracil (5-FU) metabolic enzymes, thymidylate synthase (TS), dihydropyrimdine dehydrogenase (DPD) and thymidine phosphorylase (TP) are linked to improved survival in colorectal cancer (CRC) patients receiving 5-FU chemotherapy. However, whether they are prognostic (related to tumor biology) or predictive (drug sensitivity) indicators is not clarified. This study aimed to (1) discriminate the prognostic and predictive significance of TS, DPD and TP and (2) ascertain the clinical and molecular subtype associations of the proteins in a large sample series. Methods: Tissue arrays containing sections from 956 stage 2/3 CRC cases were stained immunohistochemically for TS, DPD and TP. Associations with clinical and molecular characteristics and survival according to treatment status were assessed by Kruskall-Wallis and Kaplan-Meier analysis. Results: Low TS levels were associated with late stage, proximal tumor location and absence of microsatellite instability, low DPD with younger age and late stage and low TP with proximal tumor location. Low levels of all three enzymes associated with absence of tumor infiltrating lymphocytes. There were no associations with gender, grade or ras and p53 mutation. In stage 2 patients treated by surgery alone, those with low DPD levels had a worse survival than those with high levels (p<0.01). Stage 3 patients treated with chemotherapy had a better survival than those without in subgroups of patients with low TS (p=0.05), DPD (p<0.01) and TP (p=0.03) but not high levels of the proteins. Conclusions: Our results suggest the improved outcome of 5FU-treated patients with low tumor TS, DPD and TP levels may be due primarily to a benefit from adjuvant treatment rather than a favorable prognosis. TS, DPD and TP levels may be useful indicators for identifying CRC patients likely to benefit from 5-FU treatment. No significant financial relationships to disclose.
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