title: Molecular Biomarker Study in a Randomised Phase III Trial of Irinotecan Plus S-1 versus S-1 for Advanced Gastric Cancer (GC0301/TOP-002).
abstract: Gastric cancer is a common and heterogeneous disease; however, global standard and biomarkers for selecting chemotherapy regimens have not been established. This study was designed retrospectively to identify molecular biomarkers for irinotecan plus S-1 (IRI-S) and S-1 therapy from subset analyses in GC0301/TOP-002, a randomised phase III trial for advanced gastric cancer.
  
  
  
  Paraffin-embedded primary tumour specimens were collected from 126 of 326 randomised patients in GC0301/TOP-002. The mRNA was measured for thymidylate synthase, dihydropyrimidine dehydrogenase, topoisomerase I, excision repair cross-complementing gene 1 (ERCC1) and thymidine phosphorylase; categorised into low and high to analyse their association with efficacy end points.
  
  
  
  There was no significant difference in each mRNA between S-1 and IRI-S groups, whereas there were differences among some clinical characteristics. Multivariate analyses for overall survival showed that mRNA levels were not correlated with prognosis. By comparison, between IRI-S and S-1 arms, low thymidylate synthase, low ERCC1 and high thymidine phosphorylase were associated with better prognosis for IRI-S versus S-1 (hazard ratio = 0.653, 0.702 and 0.709, respectively; P < 0.15 for each interaction).
  
  
  
  Low thymidylate synthase, low ERCC1 and high thymidine phosphorylase are candidates for predictive biomarkers for first-line treatment in advanced gastric cancer by IRI-S. Further study is warranted to confirm these results in other clinical trials and cohort studies.
authors.affiliation: Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan. Electronic address: tuburayaa@gmail.com.
authors.forename: A
authors.initials: A
authors.lastname: Tsuburaya
authors.affiliation: Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Sugimoto
authors.affiliation: Department of Surgery, Toyonaka Municipal Hospital, Toyonaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Imamura
authors.affiliation: Department of Surgery, Osaka National Hospital, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nishikawa
authors.affiliation: Department of Surgery, Kinki University School of Medicine, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Imamoto
authors.affiliation: Department of Surgery, Kaizuka City Hospital, Kaizuka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tsujinaka
authors.affiliation: Department of Gastrointestinal and Medical Oncology, National Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Esaki
authors.affiliation: Department of Internal Medicine, Toyama Prefectural Central Hospital, Toyama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Horita
authors.affiliation: Department of Gastroesophageal Surgery, Sakai Municipal Hospital, Sakai, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Department of Surgery, Miyagi Cancer Center, Sendai, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fujiya
authors.affiliation: Department of Surgery, Itami City Hospital, Itami, Japan.
authors.forename: O
authors.initials: O
authors.lastname: Takayama
authors.affiliation: Department of Surgery, Nakano General Hospital, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Oono
authors.affiliation: Department of Surgery, Niigata Cancer Center Hospital, Niigata, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yabusaki
authors.affiliation: Department of Biostatistics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Taguri
authors.affiliation: Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Morita
authors.affiliation: Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: National University of Singapore, Cancer Science Institute of Singapore, Singapore, Singapore.
authors.forename: P
authors.initials: P
authors.lastname: Tan
authors.affiliation: Department of Surgery, Hiroshima City Hospital, Hiroshima, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ninomiya
authors.affiliation: Department of Surgery, Kinki University School of Medicine, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Furukawa
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sasako
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004264:DNA Topoisomerases, Type I / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000032:analysis; D004338:Drug Combinations; D004720:Endonucleases / Q000032:analysis; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000008:administration & dosage*; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy*; D005641:Tegafur / Q000008:administration & dosage*; D013939:Thymidine Phosphorylase / Q000032:analysis; D013940:Thymidylate Synthase / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D012333:RNA, Messenger; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D000077146:Irinotecan; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; C071447:ERCC1 protein, human; D004720:Endonucleases; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin
keywords: Excision repair cross-complementing gene 1; gastric cancer; irinotecan; predictive factor; thymidine phosphorylase; thymidylate synthase