Fast track — ArticlesTreatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial
Introduction
The human epidermal growth factor receptor 2 (HER2) gene is amplified, overexpressed, or both in 15–25% of breast cancers1, 2 and is associated with aggressive disease.3 Trastuzumab (Herceptin; F Hoffmann-La Roche, Basel, Switzerland), a humanised monoclonal antibody that targets the extracellular domain of the HER2 receptor,4 has established clinical benefits in women with HER2-positive breast cancer in metastatic and early disease settings.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15
The Herceptin Adjuvant (HERA) trial (Breast International Group 01-01) is an ongoing, international, multicentre, randomised, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant/adjuvant chemotherapy in women with HER2-positive early breast cancer. 5102 women were enrolled into the HERA trial, and a planned interim analysis at a median follow-up of 1 year showed that the addition of trastuzumab to standard adjuvant chemotherapy significantly improved disease-free survival compared with chemotherapy alone (hazard ratio [HR] 0·54; 95% CI 0·43–0·67).9 These results led to a protocol amendment, which allowed patients in the observation group with left ventricular ejection fraction (LVEF) of 55% or greater who had not relapsed to cross over to treatment with trastuzumab. An updated intention-to-treat analysis at a median follow-up of 2 years showed that addition of trastuzumab was associated with a significant improvement in disease-free survival (HR 0·64; 95% CI 0·54–0·76) and overall survival (HR 0·66; 95% CI 0·47–0·91) compared with chemotherapy alone.12
We report new data on the HERA trial 1-year trastuzumab versus observation comparison at a median follow-up of 4 years, and assess the effect on outcome measures of the extensive crossover of patients from the observation group to treatment with trastuzumab.
Section snippets
Participants
The HERA trial design, eligibility criteria, randomisation, treatment plan, follow-up and monitoring, and statistical analyses have been described elsewhere.9, 12 Briefly, from Dec 7, 2001, to June 20, 2005, the study recruited 5102 women with HER2-positive (centrally confirmed overexpression or amplification) early-stage invasive breast cancer who had completed locoregional therapy (surgery with or without radiotherapy) and received at least four cycles of chemotherapy (neoadjuvant, adjuvant,
Results
Figure 1 shows the flow of patients in the observation group on May 16, 2005. The HERA trial population in our report comprises 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. In the observation arm, 1354 patients were alive and disease free as of May 16, 2005, and, therefore, eligible for selective crossover to trastuzumab. Of these patients, 885 (65%) crossed over to trastuzumab, corresponding to 52% (885 of 1698) of those randomly assigned
Discussion
The HERA trial results confirm that treatment with adjuvant trastuzumab for 1 year is associated with persisting benefits in women with HER2-positive early breast cancer (panel). The significant disease-free survival benefit originally reported at 1-year median follow-up is sustained at 4-year median follow-up, despite the substantial crossover of patients in the observation group to treatment with trastuzumab. The overall-survival benefit is no longer statistically significant by
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