Prediction of clinical outcome of S-1-based chemotherapy for gastric cancer patients

S-1, an oral fluoropyrimidine has been considered to be a key drug in the treatment of advanced gastric cancer in Japan as a standard chemotherapy option. Individual variations in the enzyme activity of the 5-FU metabolic pathway can affect the extent of 5-FU metabolism and affect the efficacy of S-1 based chemotherapy. In this review, the role of genetic factors in affecting the therapeutic efficacy of S-1 is discussed, with special emphasis on enzymes involved in the 5-FU metabolic pathway. The gene expressions of thymidylate synthase, thymidine phosphorylase, and orotate phosphoribosyltransferase, in particular, are discussed in relation to the efficacy of S-1 monotherapy. The predictive values of these candidate genes may, however, be overcome when other drugs are combined with S-1. In gastric cancer patients, pharmacogenetic studies, based on either the pathway approach or a global approach, are promising for identifying both survival benefit and clinical benefit more accurately than studies based on a candidate approach, especially for the new era of S-1 combination therapy as the standard regimen. However, large controlled studies are needed to justify changes in chemotherapeutic strategies; from a “one-size fits all” to a “tailor-made” approach.