title: Immunohistochemical analysis of RTKs expression identified HER3 as a prognostic indicator of gastric cancer.
abstract: Standard treatment in Japan for the 13th Japanese Gastric Cancer Association stage II/III advanced gastric cancer is postoperative adjuvant S-1 administration after curative surgery. High expression of receptor type tyrosine kinases (RTKs) has repeatedly represented poor prognosis for cancers. However it has not been demonstrated whether RTKs have prognostic relevance for stage II/III gastric cancer with standard treatment. Tumor tissues were obtained from 167 stage II/III advanced gastric cancer patients who underwent curative surgery and received postoperative S-1 chemotherapy from 2000 to 2010. Expression of the RTKs including EGFR, HER2, HER3, IGF-1R, and EphA2 was analyzed using immunohistochemistry (IHC). Analysis using a multivariate proportional hazard model identified the most significant RTKs that represented independent prognostic relevance. When tumor HER3 expression was classified into IHC 1+/2+ (n = 98) and IHC 0 (n = 69), the cumulative 5-year Relapse Free Survival (5y-RFS) was 56.5 and 82.9%, respectively (P = 0.0034). Significant prognostic relevance was similarly confirmed for IGF-1R (P = 0.014), and EGFR (P = 0.030), but not for EphA2 or HER2 expression. Intriguingly, HER3 expression was closely correlated with IGF-1R (P < 0.0001, R = 0.41), and EphA2 (P < 0.0001, R = 0.34) expression. Multivariate proportional hazard model analysis identified HER3 (IHC 1+/2+) (HR; 1.53, 95% CI, 1.11-2.16, P = 0.0078) as the sole RTK that was a poor prognostic factor independent of stage. Of the 53 patients who recurred, 40 patients (75.5%) were HER3-positive. Thus, of the RTKs studied, HER3 was the only RTK identified as an independent prognostic indicator of stage II/III advanced gastric cancer with standard treatment.
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ema
authors.forename: Keishi
authors.initials: K
authors.lastname: Yamashita
authors.forename: Hideki
authors.initials: H
authors.lastname: Ushiku
authors.forename: Ken
authors.initials: K
authors.lastname: Kojo
authors.forename: Naoko
authors.initials: N
authors.lastname: Minatani
authors.forename: Mariko
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mieno
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Moriya
authors.forename: Kei
authors.initials: K
authors.lastname: Hosoda
authors.forename: Natsuya
authors.initials: N
authors.lastname: Katada
authors.forename: Shiro
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000368:Aged; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis*; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics* / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology
chemical_list: C581292:ERBB3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D020893:Receptor, ErbB-3
keywords: Advanced gastric cancer; HER3; S-1; prognosis; receptor type tyrosine kinases (RTKs)