Herceptin: increasing survival in metastatic breast cancer

Abstract

Growth factors and their receptors play an important role in the pathogenesis of human cancer. The human epidermal growth factor receptor-2 (HER2) is overexpressed in approximately 30% of breast cancers and this is associated with poor clinical outcome. Overexpression of HER2 has been demonstrated to play a direct role in oncogenic transformation. Murine monoclonal antibodies (muMAbs) targeting the extracellular domain of the HER2 receptors suppress HER2-positive cancer cell growth, with muMAb 4D5 having particularly potent activity. A humanized form of muMAb 4D5 was generated by converting all but the antigen-binding region of muMAb 4D5 into human IgG consensus sequences. The humanized monoclonal antibody, Herceptin, preferentially targets HER2-overexpressing cells, produces responses in breast cancer patients and is well tolerated. In a pivotal phase III trial, Herceptin administered in combination with chemotherapy (anthracycline/cyclophosphamide or paclitaxel) was compared with chemotherapy alone. The combination was found to produce significant survival benefits in HER2-positive metastatic breast cancer patients. These results have led to the approval of Herceptin for clinical use in the USA and elsewhere.