Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials

The discovery of the HER2/neu proto-oncogene and its role in the pathogenesis of breast cancer tumors, and the development of the anti-HER2 monoclonal antibody, trastuzumab (Herceptin; Genentech, South San Francisco, CA), directed against the HER2 receptor represent major milestones in the research developments in breast cancer, making trastuzumab the first monoclonal antibody available for treatment of this disease. Clinical trials in HER2-positive patients have demonstrated that the combined use of targeted therapy with trastuzumab in conjunction with cytotoxic chemotherapy is associated with improved time to disease progression and overall survival. Unfortunately, findings also demonstrate an increased risk for cardiotoxicity when trastuzumab is combined with anthracyclines. For HER2/neu-overexpressing breast cancer patients, the adjuvant use of trastuzumab will become paramount; therefore, it must be evaluated in a randomized controlled trial. There is disagreement regarding the design of such a trial, largely because of the ubiquitous use of anthracyclines in the adjuvant setting and the opposing necessity of avoiding anthracycline plus trastuzumab combinations. Combination index values for various chemotherapeutic drugs in combination with trastuzumab demonstrate dramatic synergistic interactions with the platinum agents and with docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ). The greatest level of synergy has been demonstrated with the triple-drug combination of docetaxel, platinum, and trastuzumab in which synergy is demonstrated, even at low doses. The adjuvant trial design for the Breast Cancer International Research Group uses a control arm of doxorubicin/cyclophosphamide for four cycles followed by docetaxel for four cycles and the second arm contains the addition of trastuzumab to the taxane sequence. The third arm, a non-anthracycline-containing regimen, contains docetaxel, a platinum agent (either cisplatin or carboplatin), and trastuzumab. The rationale for the selection of this three-drug regimen is based on the biology of the system and preclinical and clinical findings that demonstrate a high potential for clinical synergy.