Ryan Smith, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 13, 2003
Presenter: Nicholas Robert, MD Affiliation: US Oncology Research Network
The HER family of oncogenes are prevalent in breast cancers. This has allowed for the development of trastuzumab, a monoclonal antibody against the HER2 oncoprotein. Alone or with other agents, trastuzumab has improved survival of many patients with breast cancer that overexpress HER2. This was shown in a trial published in the New England Journal of Medicine in 2001. This trial had two subgroups-one with patients who had prior anthracycline therapy and one with patients who were not treated with anthracyclines previously. In the subgroup with no anthracycline treatment, patients were randomized to receive AC chemotherapy with or without trastuzumab. In the arm of patients who had received prior anthracycline chemotherapy, randomization was between paclitaxel with or without trastuzumab. Noted was an increase in overall response rate (50% vs. 32%), median time to progression (7.4 mo vs. 4.6 mo) and median survival time (25.1 mo vs. 20.3 mo).
These results are encouraging, and there are attempts to combine trastuzumab with other chemotherapeutic agents. It has been shown that there is a synergistic effect of trastuzumab with vinorelbine, gemcitabine, and platinum containing agents. A phase II trial was recently conducted which showed a response rate to cisplatin when trastuzumab was added. This was especially encouraging as cisplatin alone has virtually no activity in metastatic beast cancer. This led to the phase III trial reported in this presentation.
Patients with HER2+ metastatic breast cancer were randomized to two arms. They were stratified by extent of IHC positivity (2+ or 3+). The two arms were paclitaxel (175 mg/m2) with trastuzumab vs. paclitaxel (175 mg/m2) + carboplatin (AUC=6) + trastuzumab. Both arms were maintained on trastuzumab until disease progression. Overall response rate was better in the carboplatin arm (52% vs. 36% (p=.04)). Time to progression was 11.9 months in the carboplatin arm vs. 6.8 months in the paclitaxel trastuzumab arm. Survival was not statistically significant, but showed a trend of benefit in the carboplatin arm (42.1 months vs 33.3 months, p=.11). Toxicity data was comparable between both arms.
The authors concluded from this study that there is an improved response rate and prolonged time to progression with the addition of carboplatin. The only adverse effects of adding carboplatin were neutropenia and thrombocytopenia, without an increase in clinically significant toxicity. A confirmation study using docetaxel instead of paclitaxel is underway. This represents an additional step forward in the treatment of metastatic breast cancer in patients who overexpress the HER2 oncogene. These results should again be built upon, investigating newer schedules, combinations with other chemotherapeutic agents, and even adding trastuzumab into the adjuvant treatment regimen in selected patients. These trials are currently underway. Care must be taken in terms of cardiotoxicity when combining it with anthracyclines. Otherwise, trastuzumab seems to be very well tolerated.