c-erbB-2 Is of Independent Prognostic Relevance in Gastric Cancer and Is Associated With the Expression of Tumor-Associated Protease Systems

Abstract

PURPOSE: The c-erbB-2 gene (encoding the protein p185) is overexpressed in diverse human cancers and has been implicated to be of prognostic value in gastric cancer. Recent studies suggest a role of p185 in tumor progression by specifically promoting the invasive capacity of tumor cells. Therefore, the present study was conducted with the following three objectives: (1) to support the prognostic value of c-erbB-2 in gastric cancer in a large prospective series using a monoclonal antibody and a highly sensitive immunohistochemical method; (2) to determine the association of c-erbB-2 expression with the expression of invasion-related genes; and (3) to perform the first overall multivariate analysis including c-erbB-2 and the invasion-related tumor-associated protease systems. PATIENTS AND METHODS: In a consecutive prospective series of 203 gastric cancer patients (median follow-up, 42 months), expression of c-erbB-2 and a panel of tumor-associated proteases and inhibitors by tumor cells were evaluated semiquantitatively (score 0 to 3) and analyzed for correlation (χ2 test, Bonferroni-corrected). Kaplan-Meier survival analysis and multivariate Cox analysis were performed to determine the relative prognostic impact of c-erbB-2 and the invasion-related parameters. RESULTS: Kaplan-Meier analysis (log-rank statistics) revealed a significant association of increasing expression of c-erbB-2 with shorter disease-free (P = .0023) and overall survival (P = .0160). High amounts of p185 were significantly associated with a high expression of urokinase-type plasminogen activator (uPA) (P < .010), uPA-receptor (P = .030), type-1 plasminogen activator inhibitor (PAI) (P < .010), type-2 PAI (P = .021), cathepsin D (P = .036), matrix metalloproteinase-2 (P = .024), α-1-antichymotrypsin (P = .025), and α-2-macroglobulin (P = .017). Multivariate analysis considering these proteases/protease inhibitors, in addition to α-1-antitrypsin, tissue plasminogen activator, plasminogen, α-2-antiplasmin, and antithrombin III, and established prognostic parameters revealed that, in addition to surgical curability, pT stage, pN stage, and PAI-1, c-erbB-2 is an independent prognostic factor for overall survival of curatively resected patients (n = 139; P = .049; relative risk, 1.54; 95% confidence interval, 1.08 to 1.67) and all patients (P = .028; relative risk 1.33; 95% CI, 1.28 to 1.38). CONCLUSION: c-erbB-2 is confirmed as a new independent, functional prognostic parameter for overall survival in gastric cancer, even when a panel of invasion-related factors, including the strong prognostic parameter PAI-1, are considered. The significant correlation of p185 with several tumor-associated proteases supports the hypothesis that c-erbB-2 is a promoter of invasion and metastasis. This strongly suggests that c-erbB-2 may be a promising target for anti-invasive therapy in gastric cancer.