Impact of Gene Expression in 5-FU Metabolic Pathways on Outcomes in Patients Enrolled in JCOG1202

Results of JCOG1202 led to recognition of the oral fluoropyrimidine derivative, S-1, as standard of care for adjuvant therapy in Japanese patients with curatively resected biliary tract cancer. Expression of enzymes involved in 5-FU metabolic pathways is related to the efficacy of 5-FU–based therapies. These enzymes include thymidylate synthase, thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), and dihydropyrimidine dehydrogenase (DPD) and are possibly related to the efficacy of S-1. Dr Shuichi Mitsunaga presented results from a study aimed at evaluating the impact of the expression of these enzymes on the outcomes of patients from JCOG1202.

Of the 440 randomly assigned patients in JCOG1202, 183 patients were included in this analysis: 94 who had surgery alone and 89 who received adjuvant S-1. Of the 94 patients who underwent surgery alone, 49 were included in the exploratory cohort and 45 were included in the validation cohort. Of the 89 patients who received S-1, 47 were included in the exploratory cohort and 42 were included in the validation cohort. Key end points included the predictive values of the 4 genes for the efficacy of adjuvant S-1 on overall survival and relapse-free survival (RFS). Messenger RNA (mRNA) expression cutoff levels were selected in the training set, which minimized the bootstrap P values (2000 samples) of an interaction term of treatment (surgery alone or S-1) and mRNA expression in a Cox regression model. In all 183 patients, RFS after adjuvant S-1 was better than after surgery alone (hazard ratio [HR], 0.790; 95% confidence interval [CI], 0.524-1.192). In patients with low mRNA DPD levels (n = 107), RFS was better with adjuvant S-1 compared to surgery alone, suggesting that lower 5-FU catabolic activity of the tumor cell may be related to the efficacy of 5-FU–based therapy (HR, 0.440 [95% CI, 0.216-0.898] in training set and 0.748 [0.334-1.675] in validation set). However, no differences were seen in RFS between adjuvant S-1 and surgery alone in patients with high DPD (n = 76), suggesting that higher 5-FU catabolic activity may reduce the efficacy of 5-FU–based therapy. RFS was also better with adjuvant S-1 than surgery alone in patients with low TP (HR, 0.709 [95% CI, 0.388-1.296] in training set and 0.602 [0.287-1.262] in validation set) and with high OPRT (HR, 0.520 [95% CI, 0.152-1.779] in training set and 0.609 [0.161-2.304] in validation set).

RFS was improved with adjuvant S-1 in patients with low DPD, low TP, and high OPRT, suggesting that these biomarkers may be able to aid in predicting therapeutic benefit in certain patients with S-1 therapy.

Source: Mitsunaga S, Ikeda M, Nomura S, et al. Effects of gene expressions of 5-FU metabolic pathway in a phase III trial evaluating adjuvant S-1 compared to surgery alone following curative resection for biliary tract cancer (JCOG1202A1). Poster presented at: ASCO Gastrointestinal Cancers Symposium, January 19-21, 2023; San Francisco, CA. Abstract 732.