Impacts of fluorouracil-metabolizing enzymes on the outcomes of patients treated with S-1 alone or S-1 plus cisplatin for first-line treatment of advanced gastric cancer.
A phase III trial of S-1 plus cisplatin (SP) versus S-1 alone, for first-line treatment of advanced gastric cancer (SPIRITS trial), has shown that overall survival was better in patients treated with SP than with S-1 alone. In the present retrospective biomarker study, we aimed to develop a methodology to identify the patients with advanced gastric cancer who would respond better to S-1 alone than SP. We studied 120 patients who received S-1 alone or SP for first-line chemotherapy for advanced gastric cancer, and quantitatively evaluated mRNA levels of thymidylate synthase (TS), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase, vascular endothelial growth factor-A, and epidermal growth factor receptor in paraffin-embedded specimens of primary tumors. Multivariate survival analysis in patients who received S-1 monotherapy (66 patients) demonstrated that low TP expression (hazard ratio: 2.55 (95% CI: (1.33 to 4.89)), low TS (2.71 (1.36 to 5.37)), and high OPRT (0.33 (0.13 to 0.86)) were significant predictors of long overall survival. In patients with lower expression of both TP and TS (n = 23) than their cutoff values, the S-1 alone group (n = 15) had longer overall survival than the SP group (n = 8; median overall survival, 18.2 months vs. 9.4 months), whereas the frequency of overall adverse events in the S-1 alone group tended to be lower than that in SP group. Our results suggest that these biomarkers are useful for selection of patients with advanced gastric cancer in whom treatment with S-1 alone will yield survival benefit.
Koizumi
Wasaburo
W
Department of Internal Medicine, Kitasato University School of Medicine, 2-1-1 Asamizodai, Sagamihara, Kanagawa 228-8520, Japan. koizumi@med.kitasato-u.ac.jp
Tanabe
Satoshi
S
Azuma
Mizutomo
M
Ishido
Kenji
K
Nishimura
Ken
K
Sasaki
Tohru
T
Nakatani
Kento
K
Higuchi
Katsuhiko
K
Nakayama
Norisuke
N
Katada
Chikatoshi
C
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D004338:Drug Combinations; D004798:Enzymes / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D016019:Survival Analysis; D005641:Tegafur / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D004798:Enzymes; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D002945:Cisplatin; D005472:Fluorouracil