Expression of Her2/neu in locally advanced bladder cancer:: Implication for a molecular targeted therapy

Purpose: The Her2/neu oncoprotein, belonging to the erbB-receptor family, is known to contribute to physiological mechanisms of cell proliferation by intrinsic tyrosine-kinase-activity. Overexpression has been shown for several tumors and is known to influence Malignant cell proliferation, metastasis and angiogenesis. The clinical use of Her2-targeting agents has emerged in clinical research. In our study, we analyzed Her2/neu expression in urothelial tumors. Materials and Methods: Her2/neu expression was evaluated immunohistochemically (IHC) in 127 patients undergoing radical cystectomy (DAKO- Herceptest (R)). Additionally, fluorescent-in-situ-hybridisation (FISH) was carried out in all immunohistochemically "2+" cases (n = 41) to assess gene amplification. After grading the Her2/neu-overall status, Her2/neu expression was correlated with clinicopathological parameters and survival data. Results: An immunohistochemical Her2/neu expression was found in 95 of 127 cases (74.8%). Of all 41 cases with,,2+" staining (32.2%), 11 cases (26.8%) showed positive amplification by FISH. Therefore, including the IHC 3+ cases, a Her2/neu overall status of 22 positive (17.3%) tumors was assessed. Correlation with clinical data showed a relation to lymph node metastasis (P=0.06), lymph vessel invasion (P=0.07) and metastasis (P=0.002). No further associations with other parameters nor with overall survival (P=0.73) or disease-free survival (P=0.63) were found. Conclusions: Her2/neu upregulation is found in invasive bladder cancer with significant differences in protein expression and gene amplification. The association with lymphogenic and distant metastases implicates a late event in carcinogenesis. Moreover, there was no further association with clinicopathological parameters and survival. The possible role of a molecular targeted therapy of advanced bladder cancer with Her2/neu targeting agents should be assessed in further clinical trials.