5‐Fluorouracil metabolic pathway genes predict recurrence risk following adjuvant S‐1 therapy: Results of an ancillary analysis from a phase III trial of resected biliary tract cancer (JCOG1202A1)

Abstract Background S‐1, an oral fluoropyrimidine derivative, is standard adjuvant therapy for resected biliary tract cancer (BTC), based on the results of the JCOG1202, a phase III trial evaluating the survival benefit with adjuvant S‐1 following curative resection for BTC compared to surgery alone. This multicenter ancillary study of the JCOG1202 aimed to evaluate the prognostic impact of the 5‐fluorouracil (5‐FU) metabolic pathway genes including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). Methods The 5‐FU metabolic pathway genes were measured in tumor cells from formalin‐fixed paraffin‐embedded resected specimens from 183 patients (surgery alone: n = 94; adjuvant S‐1: n = 89). We randomly divided them into training ( n = 96) and validation sets ( n = 87) for evaluating the interaction between gene levels and RFS benefits in the treatment arm. Results RFS benefits of adjuvant S‐1 were observed in the low DPD (HR = 0.440 and 0.748, respectively in the training and validation sets) and the low TP groups (HR = 0.709 and 0.602, respectively). Clinicopathological characteristics were well balanced between low and high DPD populations. More advanced stage tumors were observed in high TP populations as compared to those in low TP populations ( p = .0332). Conclusion The results suggest the RFS benefit of adjuvant S‐1 in resected BTC patients with low DPD and low TP gene expressions.