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

From the Department of Surgery, Klinikum Grosshadern, Ludwig Maximilians University of Munich; Institute of Pathology and Cytology, Deggendorf, Germany; and Department of Tumorbiology, M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Markus Maria Heiss, MD, Associate Professor, Department of Surgery, Klinikum Grosshadern, Ludwig Maximilians University of Munich, 81377 Munich, Germany; email heiss{at}gch.med.uni-muenchen.de

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 (² 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), -1-antichymotrypsin (P = .025), and -2-macroglobulin (P = .017). Multivariate analysis considering these proteases/protease inhibitors, in addition to -1-antitrypsin, tissue plasminogen activator, plasminogen, -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.

Rudolf Babic was supported by the Wilhelm Sander Stiftung, Neustadt, Germany.

H.A. and R.B. share first authorship.

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