[Predictive value of orotate phosphoribosyltransferase in chemoresistant patients with gastric carcinoma who underwent S-1-based neoadjuvant/adjuvant chemotherapy]

Abstract

S-1, a most effective DPD-inhibitory fluoropyrimidine, used as neoadjuvant/adjuvant chemotherapy has recently been shown to improve clinical outcome in patients with stage II and III advanced stage gastric carcinoma. Orotate phosphoribosyltransferase(OPRTEC 2.4.2.10)is a primary enzyme involved in the first-step phosphorylation process of 5-fluorouracil and is an important enzyme that possibly enables to predict sensitivity to S-1 irrespective of tissue DPD levels. To test the hypothesis that a low OPRT level in gastric carcinoma tissue is an indicator of chemoresistance to S-1-based chemotherapy, the predictive value of OPRT levels in chemoresistance was evaluated in patients with gastric carcinoma undergoing S-1-based-neoadjuvant/adjuvant chemotherapy using survival analyses. A total of 67 patients with advanced-stage gastric carcinoma who underwent S-1-based neoadjuvant/adjuvant chemotherapy were subjected to the study. The OPRT level was determined by an enzyme-linked immunosorbent assay(ELISA)that has recently been developed. Postoperative cumulative survival rates were determined by the Kaplan-Meier method. The patients who underwent S-1-based adjuvant/neoadjuvant chemotherapy(n=67)were divided into 2 groups using various cut-off values to determine the prognostic significance of the OPRT level. The prognostic significance of OPRT levels was analyzed using Cox's proportional hazard model. The P value of the survival rate between the groups of low and high OPRT levels was the lowest(p=0.0018), when 2.0 ng/mg protein was used as a cut-off value for the OPRT level. The 3-year survival rate of Group L and Group H was 0% and 60%, respectively. In particular, there was a significant difference in the survival rates between Group L and Group H in stage III patients(p<0.05 by logrank test). T he survival rate of Group L(OPRT<2.0 ng/mg protein)was significantly lower than that of group H(OPRT> or =2.0 ng/mg protein)(p<0.05 by logrank test). The multivariate analysis using Cox' proportional hazard model indicated that venous invasion of carcinoma(>v2), lymph node metastasis(>5), and low OPRT level (OPRT<2.0 ng/mg protein) were significant prognostic factors in patients who were underwent S-1-based neoadjuvant/adjuvant chemotherapy. These results suggest that patients with a low OPRT level(OPRT<2.0 ng/mg protein)are non-responders to S-1- based adjuvant/neoadjuvant chemotherapy. The determination of OPRT levels in gastric carcinoma tissue enables to predict the response to S-1-based neoadjuvant/adjuvant chemotherapy.