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

Abstract

regimens remains unknown. Determination of significant associations between gene expressions and defi ned clinical endpoints (e.g., survival and response) may improve the prediction of treatment success and thereby the tailoring of chemotherapy.S-1 (Taiho Pharmaceutical, Tokyo Japan) is an oral anticancer agent consisting of tegafur (FT), 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1 : 0.4 : 1 [3]. A randomized phase III study of 5-fl uorouracil (5-FU) alone versus a combination of irinotecan and cisplatin versus S-1 alone in advanced gastric cancer showed a signifi cant noninferiority of the S-1-alone to the 5-FU alone regimen (Japan Clinical Oncology Group 9912) [4]. Another randomized phase III study, of S-1 alone versus S-1 plus cisplatin in the treatment of advanced gastric cancer, demonstrated a signifi cant survival benefi t in the patients treated with S-1 plus cisplatin [5]. Based on the results obtained from these randomized phase III trials, S-1 has been considered to be a key drug in the treatment of advanced gastric cancer in Japan as a standard chemotherapy option.In this article, we address some of the latest advances in the area of pharmacogenetics as it applies to S-1 based chemotherapy for patients with gastric cancer. We focus on the factors that affect the therapeutic efficacy of S-1-based chemotherapy, with special emphasis on enzymes involved in the 5-FU metabolic pathway. Metabolic pathway of fl uoropyrimidinesTegafur is converted into 5-FU mainly by cytochrome P450 (CYP450) enzymes in the liver (Fig. 1). CYP2A6 is the main CYP450 enzyme involved in tegafur activation, but CYP1A2 and CYP2C8 also play a signifi cant role [6].In humans, 80%-90% of the administered 5-FU is catabolized rapidly to the inactive metabolite α-fl uoroAbstract S-1, an oral fl uoropyrimidine 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 effi cacy of S-1 based chemotherapy. In this review, the role of genetic factors in affecting the therapeutic effi cacy 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 effi cacy 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 benefi t and clinical benefi t 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-...