Das HER2 Onkogen ist eine geeignete Zielstruktur für die adjuvante Therapie disseminierter Ösophaguskarzinome

Abstract

Background: The prognosis of operable esophageal carcinoma patients remains poor and new adjuvant therapeutic concepts are needed. To identify relevant targets on disseminated tumor cells, the progenitors of later arising métastases, we analysed their genomes directly. Methods: We screened more than 70 bone marrow samples of operable esophageal carcinoma patients with an anti-cytokeratin antibody (A45/BB3) for disseminated tumor cells (positive patients: n = 31). The detected single cells were isolated by micromanipulation and their genomes were globally amplified using the Mse-adapter PCR method. Subsequently comparative genomic hybridization (CGH) was used for genome-wide screening of chromosomal aberrations. An additional series of 60 primary tumors with clinical follow-up data of patients with adenocarcinoma of the esophagus was tested with a FISH method for HER2 amplifications. Overexpression of the HER2 protein was investigated with the HercepTest. The cytotoxic activity of Herceptin on cell lines was testet with a FACS based cytotoxic assay. Results: Among several other aberrations, 30% of the investigated tumor cell genomes displayed an amplification of 17ql2 - 21, making it to one of the most frequently affected chromosomal regions of single disseminated tumor cells in esophageal cancer. This region contains the HER2 gene and its gene product can be targeted by a therapeutic antibody (Herceptin®). In the investigated primary esophageal adenocarcinomas we found a highly significant correlation between HER2 gene-amplification and overexpression of the HER2 gene-product pi85 (p = 0.002). The correlation with prospective clinical follow-up data revealed a reduced overall survival for patients with HER2 gene-amplification (median survival: 14 vs. 34 months, p = 0.017), reflecting the aggressiveness of cells with Her-2 gene-amplification. Finally, we tested Herceptin® activity on a tumor cell line (LN1590), recently established from a micrometastasis of an esophageal carcinoma patient, that displays a HER2 gene amplification. Herceptin® induced significant antibody-dependent cell lysis (ADCC) of LN1590 with human effector cells. Conclusion: Our results demonstrate that the HER2 oncogene should be a suitable adjuvant therapeutic target for operable esophageal carcinoma patients with a positive Her-2 status.