Abstract
652 Background: Therapeutic benefits of the powerful combination of Trastuzumab and anthracyclines in the management of HER2-overexpressing metastatic breast cancer are limited by a dramatic increase in cardiac side effects. Many data indicate an important role of HER2 and its preferred cardiac heterodimerisation partner HER4 in mediating essential myocytes survival pathways. Gene targeting of either receptor leads to cardiomyocyte apoptosis and cardiomyopathy. An interaction between Trastuzumab and HER2/HER4 mediated signaling might therefore contribute to the cardiotoxic side effects. We therefore have examined possible changes in the protein expression levels of HER2 and HER4 after anthracycline treatment. Methods: We examined HER2 and HER4 protein expression as well as HER2 gene amplification in 35 cardiac specimens obtained from autopsy material of breast cancer patients with a history of anthracycline treatment. The mean cumulative Epirubicin dose was 662 mg. In addition 10 patients with anthracycline- free pretreatment were assessed. Three of them had received immunotherapy with Trastuzumab. HER2 and HER4 expression were analyzed immunohistochemically using the HercepTest (DAKO) and the polyclonal antibody c-18 (SantaCruz) respectively. Copy numbers of the HER2 gene were determined by fluorescence in situ hybridisation (Inform-Kit Ventana). Results: In the 54 cardiac biopsies with and without anthracycline pretreatment no HER2 staining could be detected. In addition, no HER2 gene amplification was observed in all specimens. A HER4 expression could be detected in 13 of the 25 anthracycline pretreated specimens witch was not significantly different from the cases without anthracycline history (6/10). No relation of HER4 expression with the cumulative anthracycline dose could be noticed. Conclusions: This study shows that an anthracycline treatment does not result in changes of the HER2 or HER4 expression levels nor in amplification of the HER2 gene in the myocardium as suspected to probably underlie the onset of heart failure in anthracycline pretreated patients receiving Trastzumab therapy. No significant financial relationships to disclose.
Published Version
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