title: Prognostic impact of HER2, EGFR, and c-MET status on overall survival of advanced gastric cancer patients.
abstract: BACKGROUND
  This study was conducted to investigate whether human epidermal growth factor receptor 2 (HER2) status, epidermal growth factor receptor (EGFR) status, and c-MET status are independent prognostic factors for advanced gastric cancer patients who received standard chemotherapy.
  
  
  METHODS
  Unresectable or recurrent gastric or gastroesophageal junction cancer patients with histologically confirmed adenocarcinoma treated with S-1 plus cisplatin as first-line chemotherapy were eligible. Formalin-fixed paraffin-embedded tumor samples were examined for HER2, EGFR, and c-MET status using immunohistochemistry (IHC). Additionally, gene amplification was examined using fluorescent in situ hybridization (FISH) for HER2. Positivity was defined as an IHC score of 3+ or an IHC score of 2+/FISH positive for HER2, and an IHC score of 2+ or 3+ for both EGFR and c-MET.
  
  
  RESULTS
  Of the 293 patients from nine institutions, 43 (15%) were HER2 positive, 79 (27%) were EGFR positive, and 120 (41%) were c-MET positive. Ten patients (3%) showed positive co-expression of HER2, EGFR, and c-MET. After a median follow-up time of 58.4 months with 280 deaths, there was no significant difference in overall survival (OS) in terms of HER2 and EGFR status. However, there was a significant difference in OS between c-MET-positive and c-MET-negative patients [median, 11.9 months vs 14.2 months; hazard ratio, 1.31 (95% confidence interval, 1.03-1.67); log-rank P = 0.024]. Multivariate analysis also showed that c-MET positivity was still a prognostic factor for OS [hazard ratio, 1.30 (95% confidence interval, 1.02-1.67); P = 0.037].
  
  
  CONCLUSIONS
  The study suggested that c-MET-positive status had poor prognostic value. These data could be used as the basis for future clinical trials for targeting agents for advanced gastric cancer patients.
authors: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. nofuse@east.ncc.go.jp.
authors: Nozomu
authors: N
authors: Fuse
authors: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors: Yasutoshi
authors: Y
authors: Kuboki
authors: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan.|Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors: Takeshi
authors: T
authors: Kuwata
authors: Department of Gastrointestinal Medical Oncology, Shikoku Cancer Center, Matsuyama, Japan.
authors: Tomohiro
authors: T
authors: Nishina
authors: Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
authors: Shigenori
authors: S
authors: Kadowaki
authors: Gastroenterological Internal Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Eiji
authors: E
authors: Shinozaki
authors: Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Nagaizumi, Japan.
authors: Nozomu
authors: N
authors: Machida
authors: Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan.
authors: Satoshi
authors: S
authors: Yuki
authors: Department of Gastroenterology, Saitama Cancer Center Hospital, Ina, Japan.
authors: Akira
authors: A
authors: Ooki
authors: The Third Department of Internal Medicine, University of Toyama, Toyama, Japan.
authors: Shinya
authors: S
authors: Kajiura
authors: Department of Gastroenterology and Oncology, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Tetsuo
authors: T
authors: Kimura
authors: Department of Biostatistics, National Cancer Center, Kashiwa, Japan.|Department of Biostatistics, Yokohama City University, Yokohama, Japan.
authors: Takeharu
authors: T
authors: Yamanaka
authors: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors: Kohei
authors: K
authors: Shitara
authors: Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors: Akiko Kawano
authors: AK
authors: Nagatsuma
authors: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors: Takayuki
authors: T
authors: Yoshino
authors: Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors: Atsushi
authors: A
authors: Ochiai
authors: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
authors: Atsushi
authors: A
authors: Ohtsu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D004338:Drug Combinations; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D004943:Esophagogastric Junction / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000008:administration & dosage; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D005641:Tegafur / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D002945:Cisplatin; D004338:Drug Combinations; D066246:ErbB Receptors; D010094:Oxonic Acid; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; D005641:Tegafur; C079198:S 1 (combination); C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: Epidermal growth factor receptor; Gastric cancer; Gastroesophageal junction cancer; Human epidermal growth factor receptor 2; c-MET