Trastuzumab in The Adjuvant Treatment of Breast Cancer: New Evidence from The HERA Study

Abstract & Commentary

By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: Trastuzumab has previously been demonstrated to be active against HER2 positive breast cancer when used in the metastatic setting. In a large multicenter clinical trial (HERA) in which trastuzumab was used after chemotherapy in an adjuvant setting, after a median two years follow-up, a significant benefit was observed for treated patients compared to the observational group treated with chemotherapy alone. A survival advantage in this setting demonstrable at only two years is a notable finding and is indicative of the importance of this agent in the treatment of HER2 positive breast cancer.

Source: Smith I, et al. Lancet. 2007;369:29-36.

The gene for HER2, a transmembrane growth factor, has been shown to be amplified in 15-25% of women with early breast cancer and is considered a marker of aggressive disease.1,2 Trastuzumab (Herceptin®), a humanized monoclonal antibody against the extracellular domain of the HER2 receptor, has been shown to provide overall survival benefit to women with HER2-positive metastatic breast cancer either administered alone3,4 or in combination with chemotherapy.5,6 The Herceptin Adjuvant (HERA) trial is one of several large trials conducted by the Breast International Group (0101) designed to test the efficacy of trastuzumab in the adjuvant setting for women with HER2-positive disease. Results for a first planned interim analysis with a median 1 year follow-up showed that trastuzumab given every 3 weeks for 1 year after adjuvant (or neo-adjuvant) chemotherapy achieved a significant improvement in disease-free survival compared with women treated with adjuvant chemotherapy alone.7 Several other trials have reported similar results.8, 9 The current report is an analysis of the HERA trial in terms of overall survival at a median follow-up of two years.

The HERA trial is an international intergroup open-label phase III randomized trial involving women with centrally-confirmed HER2 positive early stage invasive breast cancer who had completed local regional therapy and a minimum of four courses of predefined standard adjuvant (or neoadjuvant) chemotherapy. Eligibility criteria included node-positive disease (or node negative if the pathological tumor size was larger than 1 cm). Patients with locally advanced disease were excluded. Enrolled patients were randomized to receive trastuzumab at an initial dose of 8 mg/kg and maintenance dose of 6 mg/kg every 3 weeks for either 2 years (n = 1701 patients) or 1 year (n = 1703 patients. A third group received no trastuzumab. Patients enrolled on the two-year trastuzumab arm continue on therapy and are not included in this report.

Disease-free survival is the primary endpoint of the HERA trial and overall survival a secondary endpoint. Analysis of the overall survival data at two years, however, indicates a small, but significant improvement. There were 59 deaths in the trastuzumab group compared with 90 in the control group. The unadjusted hazard ratio (HR) for the risk of death with trastuzumab compared with observation alone was 0.66 (95% confidence interval 0.47-0.91; p = 0.0115). Furthermore, there were 218 disease-related events (distant, CNS, locoregional, contralateral breast, second malignancy) with trastuzumab compared with 321 in the control group, and the unadjusted HR for the risk of an event with trastuzumab compared with observation alone was 0.64 (0.54-0.76; p < 0.0001).

Commentary

It has become quite apparent that trastuzumab is an effective treatment for metastatic breast cancer. Now, data from the HERA study lends additional evidence for its use in the adjuvant setting. The demonstration that one year of treatment with trastuzumab following adjuvant chemotherapy is of benefit in terms of both disease-free7 and overall survival, and the latter being demonstrable after only two years of follow-up is a testament to the advisability of this approach. Of all the adjuvant chemo/hormonal treatments for breast cancer, only Tamoxifen revealed a survival advantage as early as two years.10

There remain two critical issues with regard to trastuzumab use in the adjuvant setting. The first relates to whether it should be used concurrently with chemotherapy, as typically prescribed in the US, or sequentially as in the HERA trial. It is conceivable that the delay of several months (average 8.5 months in the HERA trial) could influence the overall efficacy in a negative way. In fact, preliminary analysis of NCCTG N9831 presented at ASCO 2005 suggested concurrent (ie, trastuzumab with chemotherapy) may be more effective than sequential treatment (Perez, et al.), but a more complete analysis from this important trial remains forthcoming.

The second question concerns the duration of trastuzumab treatment. As mentioned, the third arm of the HERA trial includes women treated for two years rather than one. Yet, it may turn out that even shorter treatment duration is equally efficacious. In this context it is notable that in a relatively small trial (232 patients) a significant disease-free survival benefit was observed after only 9 weeks of trastuzumab treatment given concurrently with chemotherapy in the adjuvant setting.9

References

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10. Baum M, Brinkley DM, Dossett JA, et al. Improved survival among patients treated with adjuvant tamoxifen after mastectomy for early breast cancer. Lancet. 1983;2(8347):450.