title: Impact of insulin-like growth factor-1 receptor and amphiregulin expression on survival in patients with stage II/III gastric cancer enrolled in the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer.
abstract: BACKGROUND
  Exploratory biomarker analysis was conducted to identify factors related to the outcomes of patients with stage II/III gastric cancer using data from the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer, which was a randomized controlled study comparing the administration of an orally active combination of tegafur, gimeracil, and oteracil with surgery alone.
  
  
  METHODS
  Formalin-fixed paraffin-embedded surgical specimens from 829 patients were retrospectively examined, and 63 genes were analyzed by quantitative real-time RT-PCR after TaqMan assay-based pre-amplification. Gene expression was normalized to the geometric mean of GAPDH, ACTB, and RPLP0 as reference genes, and categorized into low and high values based on the median. The impact of gene expression on survival was analyzed using 5-year survival data. The Benjamini and Hochberg procedure was used to control the false discovery rate.
  
  
  RESULTS
  IGF1R and AREG were most strongly correlated with overall survival, which was significantly worse in high IGF1R patients than low IGF1R patients, but better in high AREG patients than low AREG patients. The hazard ratio for death in the analysis of overall survival (S-1 vs. surgery alone) was reduced in the high IGF1R group compared with the low IGF1R group and in the low AREG group compared with the high AREG group. There were no significant interaction effects.
  
  
  CONCLUSIONS
  IGF1R gene expression was associated with poor outcomes after curative resection of stage II/III gastric cancer, whereas AREG gene expression was associated with good outcomes. No significant interaction effect on survival was evident between S-1 treatment and gene expression.
authors.affiliation: Division of Medical Oncology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa, 227-8501, Japan. wataru@med.showa-u.ac.jp.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ichikawa
authors.affiliation: Division of Gastric Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Terashima
authors.affiliation: Pathology Division, Exploratory Oncology Research and Clinical Trial Center, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
authors.affiliation: Department of Surgery, National Hospital Organization Fukuyama Medical Center, 4-14-17 Okinogami-cho, Fukuyama, Hiroshima, 720-8520, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kitada
authors.affiliation: Data Innovation Center, iAnalysis, Inc., 2-2-15-1403 Minamiaoyama. Minato-ku, Tokyo, 107-0062, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Kurahashi
authors.affiliation: Department of Surgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sakuramoto
authors.affiliation: Gastric Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo, Tokyo, 104-0045, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Katai
authors.affiliation: Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sano
authors.affiliation: Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibahara-cho, Toyonaka, Osaka, 560-8565, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imamura
authors.affiliation: Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sasako
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D066258:Amphiregulin / Q000235:genetics*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010094:Oxonic Acid / Q000627:therapeutic use*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics*; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D015996:Survival Rate; D005641:Tegafur / Q000627:therapeutic use*
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D004338:Drug Combinations; C000597236:IGF1R protein, human; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D017526:Receptor, IGF Type 1
keywords: ACTS-GC study; AREG; Gastric cancer; IGF1R