Is there an ideal way to combine trastuzumab with chemotherapy?

The human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in 15% to 20% of invasive breast cancers. Early studies with trastuzumab, a humanized monoclonal antibody directed against HER2, demonstrated significant antitumor activity as a single agent and survival benefit in patients with HER2positive metastatic breast cancer when combined with chemotherapy. Such evidence served as the basis to conduct several large, multicenter, randomized controlled clinical trials assessing sequential or concurrent administration of trastuzumab with chemotherapy in the adjuvant setting. These studies confirmed the highly significant clinical benefit of adjuvant trastuzumab in early HER2-positive breast cancer. However, as a result of the different designs of the trials and some seemingly contradictory results, it has been difficult to reach definitive conclusions about the optimal combination of trastuzumab with adjuvant chemotherapy. In the article that accompanies this editorial, Perez et al present the results of the sequential versus concurrent trastuzumab arms of the North Central Cancer Treatment Group (NCCTG) N9831 trial, the only randomized trial that prospectively compared the two approaches. In October of 2009, the NCCTG independent data monitoring committee recommended the release of all N9831 study data from the preplanned second interim analysis comparing the control (chemotherapy alone) versus the sequential trastuzumab arm (chemotherapy followed by trastuzumab) after the prespecified O’BrienFleming boundary was crossed. The data monitoring committee also recommended that data from the sequential versus concurrent trastuzumab and paclitaxel comparison be released because of the slow disease-free survival (DFS) event rate although the statistical boundary had not been reached. The primary end point of the study was DFS. As the result of a safety concern, the concurrent trastuzumab and paclitaxel arm of the trial was temporarily closed, and the statistical plan of the trial was appropriately modified. Patients randomly assigned to the sequential arm during the time that the concurrent arm was closed were excluded for the purpose of this comparison. This analysis incorporated data from 1,903 patients, with 954 randomly assigned to sequential trastuzumab and 949 randomly assigned to concurrent trastuzumab and paclitaxel. At a median follow-up of 6 years and 313 events, the 5-year DFS rates were 80.1% and 84.4% for the sequential trastuzumab and concurrent trastuzumab and paclitaxel arms, respectively. There was an increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration (hazard ratio [HR], 0.77; 99.884% CI, 0.53 to 1.11), but the P value (.02) did not cross the prespecified O’Brien-Fleming boundary (.00116) for the planned interim analysis. There were no significant differences in adverse events, including grade 2 cytopenias, neurosensory changes, neuromotor difficulties, arthralgiae, myalgiae, or nail changes. Grade 2 left ventricular ejection fraction reductions were seen in 10% of the patients in the sequential trastuzumab arm and in 11.4% of the patients in the concurrent trastuzumab and paclitaxel arm. Earlier preclinical investigations focused on evaluating the effects of the molecular interactions between trastuzumab and different cytotoxic chemotherapies. Investigators found that the magnitude of the increased cytotoxic effects of the combination were logarithmic, with mathematical computations demonstrating formal synergy between several chemotherapies and trastuzumab when tested against HER2positive breast cancer models. Additional work was done by using multiple drug effect/combination index isobologram analyses to study the efficacy of different chemotherapeutic drugs in combination with trastuzumab in four HER2-overexpressing breast cancer cell lines (SK-BR-3, BT-474, MDA-MB-361, and MDA-MB-453). Combination index values showed synergistic interactions in all cell lines for trastuzumab plus carboplatin, 4-hydroxycyclophosphamide, docetaxel, and vinorelbine. There were additive interactions in all cell lines with trastuzumab plus doxorubicin, epirubicin, and paclitaxel. Other experiments assessed the importance of the schedule of administration as well as the dose of the antibody. The investigators found that the schedule of administration was critical to elicit antibodyinduced potentiation of cisplatin cytotoxicity. Increased tumor cell kill was only observed if the antibody and the drug were administered in close temporal proximity, mimicking the simultaneous administration used in the clinical setting. What are the clinical implications of this clinical report and earlier preclinical observations? Although the study was powered to demonstrate a DFS difference, because of the low number of events, the P value did not cross the prespecified O’Brien-Fleming boundary for the planned interim analysis. However, from a clinical perspective, the increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration without corresponding increased toxicities suggests that concurrent trastuzumab and paclitaxel might be a preferred option for the adjuvant treatment of patients with HER2-positive early breast cancer. Early initiation of trastuzumab will JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S