Impact of the gene expressions of thymidylate synthase and dihydropyrimidine dehydrogenase on survival in patients enrolled in the ACTS-GC study.

Abstract

52 Background: The efficacy of 5-FU-based therapy is basically related to the expression of enzymes involved in pyrimidine metabolism, such as thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyltransferase (OPRT). Biomarker analysis was conducted to evaluate the influence of these expressions on the outcomes of patients enrolled in the ACTS-GC study, a randomized phase III trial, which demonstrated the efficacy of adjuvant treatment with S-1 after D2 dissection for stage II and III gastric cancer (Sakuramoto et al., NEJM 2007) Methods: Formalin-fixed paraffin-embedded specimens were available for 829 of a total of 1,059 (78.3%) patients. Expressions of TS, DPD, TP and OPRT were measured by RT-PCR in macrodissected tumor specimens and normalized to β-actin expression as the reference gene. The expression levels of each gene were categorized as low or high at the 33.3rd or 66.7th percentile. If the p-value of the interaction was less than 0.1, statistical significance was assumed. Results: Expressions of the 4 genes were quantifiable in 97% of the 829 specimens and the distributions were balanced across the arms. The hazard ratio (HR) for overall survival (OS) of S-1 to surgery alone was smaller in the high-TS (highest one-third) (HR, 0.370; 95%CI, 0.221-0.619) than in the low-TS group (lower two-thirds) (HR, 0.757; 95%CI, 0.563-1.018). This interaction between TS expression and OS was statistically significant (p=0.015). Similarly, the HR for OS of S-1 to surgery alone was smaller in the high-DPD (higher two-thirds) (HR, 0.520; 95%CI, 0.376-0.720) than in the low-DPD group (lowest one-third) (HR, 0.848; 95%CI, 0.563-1.276). This interaction (p=0.065) was also statistically significant. There was no interaction between the TP or OPRT expression and OS. Conclusions: This large biomarker study showed that intratumoral TS and DPD gene expressions may be predictive markers of the efficacy of S-1 in gastric cancer patients receiving postoperative adjuvant chemotherapy with S-1.