title: Multicenter large-scale study of prognostic impact of HER2 expression in patients with resectable gastric cancer.
abstract: BACKGROUND
  Although some small-scale studies have suggested that human epidermal growth factor receptor 2 (HER2)-positive status in gastric cancer is associated with poor outcomes, the prognostic value of HER2 is still controversial. Since intratumoral HER2 heterogeneity is also an important issue, a multicenter large-scale study was conducted to evaluate the prognostic impacts of HER2 expression and intratumoral heterogeneity in gastric cancer.
  
  
  METHODS
  This study included 1,148 gastric cancer patients who underwent gastrectomy in 11 institutions. HER2 expression was centrally evaluated with immunohistochemistry and fluorescence in situ hybridization, and intratumoral HER2 heterogeneity was evaluated for HER2-positive tumors. Overall survival was compared between HER2-positive and HER2-negative patients and between the homogeneous and heterogeneous groups.
  
  
  RESULTS
  The HER2-positive rate was 15.7 %, and HER2 expression was significantly associated with histological type. HER2 expression scores obtained by immunohistochemistry showed a distinct influence on survival, and HER2-positive patients showed much poorer survival than HER2-negative patients [hazard ratio (HR) 1.59, 95 % confidence interval (CI) 1.24-2.02; P < 0.001). The subgroup analysis by pathological tumor stage showed a similar trend of poor survival in HER2-positive patients. Both intestinal type and diffuse type showed significant poor survival in HER2-positive patients. Cox multivariate analysis revealed that HER2 expression was an independent prognostic factor (HR 1.96, 95 % CI 1.51-2.55; P < 0.001). HER2 heterogeneity was observed in 75.4 % of HER2-positive cases, but the prognosis in the heterogeneous group was similar to that in the homogeneous group.
  
  
  CONCLUSIONS
  Our study demonstrated that HER2 overexpression is an independent prognostic factor in patients with any stage of resectable gastric cancer. Intratumoral HER2 heterogeneity did not affect prognosis.
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan. ykurokawa@gesurg.med.osaka-u.ac.jp.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Kurokawa
authors.affiliation: Department of Molecular Pathology, Osaka University Graduate School of Medicine and Health Science, Osaka, Japan.
authors.forename: Nariaki
authors.initials: N
authors.lastname: Matsuura
authors.affiliation: Department of Surgery, Sakai Municipal Hospital, Osaka, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Department of Surgery, Ikeda City Hospital, Osaka, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Adachi
authors.affiliation: Department of Surgery, NTT West Osaka Hospital, Osaka, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Fujita
authors.affiliation: Department of Surgery, Toyonaka Municipal Hospital, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imamura
authors.affiliation: Department of Surgery, Kinki Central Hospital, Itami, Hyogo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Molecular Pathology, Osaka University Graduate School of Medicine and Health Science, Osaka, Japan.
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Yokoyama
authors.affiliation: Department of Molecular Pathology, Osaka University Graduate School of Medicine and Health Science, Osaka, Japan.
authors.forename: Mohammed Nouri
authors.initials: MN
authors.lastname: Shaker
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Takiguchi
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: ERBB2; Epidermal growth factor receptor 2; Heterogeneity; Human epidermal growth factor receptor 2; Trastuzumab