Predictive values of 5-fluorouracil pathway genes for S-1 treatment in patients with advanced gastric cancer

Abstract

Determination of significant associations between gene expression and predefined endpoints might improve treatment tailoring for advanced gastric cancer. We investigated the mRNA expression of 5-fluorouracil (5-FU) pathway genes in prechemotherapeutic tumor samples of primary gastric cancer to try to predict the treatment outcome of S-1 monotherapy. 5-FU pathway genes, dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), and thymidine phosphorylase (TP), were analyzed using quantitative real-time PCR of RNA extracted from archived formalin-fixed paraffin-embedded tissues. We selected the median value for each gene as a cutoff to separate patients into high and low gene expression groups. High OPRT gene expression was significantly associated with tumor response (P = 0.014). In a combined analysis including OPRT, patients with high OPRT and TP showed a higher overall response rate than did the remaining patients (40 vs. 10%, respectively; P = 0.002). For survival, patients with high OPRT and low TS levels showed prolonged survival in both progression-free survival (3.4 vs. 2.4 months, P = 0.024) and overall survival (11.0 vs. 8.2 months, P = 0.007). In a multivariate analysis, the combinations of OPRT and TP for response and OPRT and TS for both progression-free survival and overall survival were independent variables. To conclude, mRNA expression levels of molecular markers in formalin-fixed paraffin-embedded specimens of primary gastric tumors can be useful for identifying patients with advanced gastric cancer who would most likely benefit from S-1 treatment.

Predictive Biomarker Candidates for The Response Of Gastric Cancer to Targeted And Cytotoxic Agents

“…Among the fluoropyrimidine-metabolizing enzymes, TYMS mRNA overexpression is most consistently associated with poor response to f luorouracil-based chemotherapy [60,64,65].…”

Predictive V16alue of Thymidylate Synthase Expression in Gastric Cancer: A Systematic Review with Meta-analysis

“…In six studies assigned TS expression by reverse transcriptase polymerase chain reaction (RTPCR) (Ichikawa et al, 2004;Ichikawa et al, 2006;Hua et al, 2007;Akamoto et al, 2008;Ichikawa Ishido et al, 2009;Jeung et al, 2011), threshold was defined as the median observed ratio, while in the remaining three studies a maximal χ 2 method determined the optimal cut-off value (Matsubara et al, 2008;Wei et al, 2008;Koizumi et al, 2010).…”

“…Fifteen eligible studies assessed survival or treatment response in the advanced disease setting (Boku et al, 1998;Yeh et al, 1998;Miyamoto et al, 2000;Ichikawa et al, 2004;Tahara et al, 2004;Ichikawa et al, 2006;Boku et al, 2007;Kwon et al, 2007;Akamoto et al, 2008;Matsubara et al, 2008;Wei et al, 2008;Koizumi et al, 2010;Choi et al, 2011;Jeong et al, 2011;Jeung et al, 2011), with a total of 844 patients available for pooling (median: 62, range: 21-76). All studieds used fluoropyrimidine-containing regimens, either combination chemotherapy or monotherapy.…”

Impact of 5-fluorouracil metabolizing enzymes on chemotherapy in patients with resectable colorectal cancer

“…Therefore, it is important to evaluate the activities of these enzymes to better understand the antitumor effects of 5-FU. Although there are several reports on the correlation between these enzymes and response to 5-FU (14–23), such a correlation has not been prospectively investigated in the adjuvant chemotherapy setting.…”