Trastuzumab With Chemo Beats Sequential Administration in Breast Cancer

The results of a trial comparing concurrent versus sequential trastuzumab and chemotherapy as adjuvant treatment of breast cancer has shown an improved efficacy without increased toxicity for the concurrent regimen. As the authors of the accompanying editorial (DOI: 10.1200/JCO.2011.38.3836) point out, this result is likely to thwart additional trials comparing the two types of administration. The editorial authors along with the authors of the research suggest that the concurrent schedule should be adopted as best standard of care. 

Ribbon diagram of the trastuzumab, a monoclonal antibody, bound to the extracellular domain of HER2

Trastuzumab was first approved in 1998 for the first-line treatment of metastatic breast cancer in combination with paclitaxel as well as a single agent for second or third-line treatment. Based on follow-up data, the median overall survival for women taking trastuzumab in combination with chemotherapy had a 4.8 month longer median overall survival compared to chemotherapy alone. Trastuzumab, a targeted antibody against the human epidermal growth factor receptor 2 (HER2) protein, was approved in 2006 for use as an adjuvant treatment for HER2-positive, node-positive breast cancer. The approval was based on results that showed a 52% reduced cancer recurrence compared to standard adjuvant therapy. Approximately one-fourth of women with breast cancer have HER2-positive disease and are eligible for treatment with trastuzumab whose brand name is Herceptin.

However, as Ana M. Gonzalez-Angulo and Gabriel N. Hortobagyi of The University of Texas MD Anderson Cancer Center discuss in their editorial on the study, randomized and controlled trials to assess whether a concurrent or sequential adjuvant treatment of trastuzumab and chemotherapy are optimal. 

The results of the latest trial, the North Central Cancer Treatment Group(NCCTG)N9831 trial, which address this question were published in JCO last week (doi: 10.1200/JCO.2011.36.7045). The trial is the only prospective trial that has compared the two treatment regiments. 

Data from 1903 patients in the study, with 954 assigned to sequential therapy, and 949 to concurrent trastuzumab and paclitaxel, show a 5-year disease free survival rate of 80.1% for sequential compared to 84.4% for concurrent treatment. The median follow up was six years and treatment duration was 52 weeks. The data showed a 33% risk reduction with concurrent versus sequential treatment. However, the p-value was .02, which did not cross the pre-specified statistical boundary set up for the planned interim analysis.

With 313 events having occurred by the cut-off point, the study, while powered to demonstrate a difference in disease-free survival, did not reach statistical significance due to the low number of events that occurred.

Gonzalez-Angulo and Hortobagyi believe that the results may be enough to state that concurrent treatment “might be a preferred option for the adjuvant treatment of patients with HER2-positive early breast cancer” from a clinical perspective. They point to the rationale for earlier trastuzumab administration to target early HER2-positive micrometastases as well as the convenience of concurrent treatment for patients. They also highlight that meta-analyses of adjuvant trials with trastuzumab have shown a reduction of CNS recurrences for those having received concurrent treatment of trastuzumab and paclitaxil that is not seen in either sequential treatment or treatment with chemotherapy alone.

As far as adverse events, the trial showed no significant differences in events, which included grade 2 cytopenias, neurosensory, changes, neuromotor difficulties, arthralgiae, myalgiae, and nail changes. Grade 2 left ventricular ejection fraction reductions were seen in 10% of sequential treatment patients compared to 11.4% of concurrent-regimen patients. 

As the authors describe in their editorial, the result that concurrent treatment appears to be more beneficial compared to a sequential regimen is also supported by preclinical evaluations that have shown more potent cell killing induced allowing the antibody to elicit “antibody-induced potentiation of cisplatin cytotoxicity” when the two agents are administered close together. 

The question of whether a shorter trastuzumab exposure is possible because of the synergistic effects of concurrent chemotherapy and the targeted antibody is still an open one. This question is currently being addressed in on-going trials with longer versus shorter durations of trastuzumab therapies.