Predictive Role of Thymidylate Synthase, Dihydropyrimidine Dehydrogenase and Thymidine Phosphorylase Expression in Colorectal Cancer Patients Receiving Adjuvant 5-Fluorouracil

Abstract

Objective: The combined assessment of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) gene expressions in metastatic colorectal cancer has been reported to be able to predict the efficacy of fluoropyrimidine-based chemotherapy. In order to evaluate the prognostic role in the adjuvant setting, we investigated the TS, DPD and TP expression in primary tumors of colorectal cancer patients treated with 5-fluorouracil (5-FU). Methods: TS, DPD and TP expression levels were determined by immunohistochemistry in paraffin-embedded primary tumor tissues from 62 patients with Dukes’ stage B and C colorectal cancers who underwent surgery and received adjuvant systemic chemotherapy with 5-FU. The median follow-up was 90 months (range 17–127). Results: Dukes’ stage C cancer and high TS expression were independent markers of poor prognosis for disease-free survival (DFS; p = 0.0009 and p = 0.007, respectively) and overall survival (OS; p = 0.0005 and p = 0.011, respectively). By multivariate analysis, patients with high DPD expression had significantly shorter DFS (p = 0.007) and OS (p = 0.005) compared to patients with low DPD expression. In the combined analysis of 2 markers, patients with low TS and low DPD had the best outcome in terms of DFS (p = 0.007) and OS (p = 0.03). The analysis of all 3 proteins showed that the patients with low expression of all 3 markers had significantly longer DFS (p = 0.04) and OS (p = 0.01) than patients with a high value of any one of the protein expressions. However, the joint analysis of 3 markers (group with TS–/DPD–/TP–) could not identify a subgroup of patients with a better prognosis compared to the analysis of 2 markers (group with TS–/DPD–). The analysis of Dukes’ stage C cancer patients confirmed a significant benefit in terms of DFS and OS (p = 0.001 and p = 0.006, respectively) when all 3 markers had low expression. We also found a positive significant correlation between TS and TP protein expression (p = 0.033). Conclusions: This retrospective investigation suggests that the combined assessment of TS and DPD may be useful to evaluate the prognosis of patients with Dukes’ B and C colon carcinoma receiving 5-FU adjuvant chemotherapy. The role of TP as a predictor for 5-FU-based therapy needs further investigations.

Prognostic value of 5-fluorouracil metabolic enzyme genes in Dukes' stage B and C colorectal cancer patients treated with oral 5-fluorouracil-based adjuvant chemotherapy

“…As to the methodology of 5-FU metabolic pathway enzymes, protein activity, immunohistochemistry, enzymelinked immunosorbent assay (ELISA) and mRNA levels have been reported (13)(14)(15). Concerning the routine measurement of these enzymes, protein activity measurements are not technically feasible because of the complexity in the use of radioisotopes.…”

“…However, the prognostic value of these 5-FU-related metabolic enzymes in patients treated with 5-FU-based adjuvant chemotherapy is still controversial. It has been reported that a high-expression level of TS and low-expression levels of DPD were correlated with poor prognosis (13,14). In contrast, it has been reported that OPRT, though not TS and DPD have a prognostic value in patients treated with 5-FU-based adjuvant chemo-therapy (15).…”

Pharmacogenetics and biomarkers in colorectal cancer

“…Low levels or absence of DPD was associated with accumulation of 5-FU, leading frequently to significant toxicities and adverse events, even death. 55 There are studies supporting that increasing expression of DPD mRNA is associated with poor response to 5-FU and higher resistance, possibly because of a high catabolic rate. 42,56 Although low levels of DPD expose individuals to higher risk …”

Targeted therapy of cancer: new roles for pathologists in colorectal cancer

“…As a result, these enzymes have been studied extensively at the DNA, RNA, and protein levels, and high levels of expression by immunohistochemistry and mRNA associated with poor outcome. 1,[8][9][10][19][20][21][22] Recently, additional enzymes important in 5-FU effects have been identified, including mRNA expression of TNFRSF1B, SLC35F5, and orotate phosphoribosyltransferase. [23][24][25] At the DNA level, a tandem repeat of 28 bp is present in the 5 0 -untranslated region of the TS gene and is linked to its expression and enzymatic activity in tumors.…”