Challenges in predicting the clinical outcome in S-1-based chemotherapy for gastric cancer patients.

S-1 has been considered to be a key drug in the treatment of advanced gastric cancer in Japan as a standard option of chemotherapy. Interindividual variation in the enzymes of the S-1 metabolic pathway can affect the extent of S-1 metabolism and impact the efficacy of S-1-based chemotherapy. In this review, the role of the "candidate" genetic factors affecting the therapeutic efficacy of S-1 is discussed with a special emphasis on polymorphism and gene expressions involved in the S-1 metabolic pathway, including CYP2A6, thymidylate synthase, thymidine phosphorylase, and orotate phosphoribosyltransferase. The predictive values of these candidates might be overcome with drugs combined with S-1. Pharmacogenetic studies based on a "global" approach by DNA microarray are promising to identify gastric cancer patients with both survival benefit and clinical benefit more accurately than those based on the "candidate" approach, especially for S-1 combination therapy. Large and controlled studies are needed to justify changes in the chemotherapeutic strategies, from "one-size fits all" to "tailor-made."