Elsevier

The Lancet Oncology

Volume 12, Issue 3, March 2011, Pages 236-244
The Lancet Oncology

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Treatment 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

https://doi.org/10.1016/S1470-2045(11)70033-XGet rights and content

Summary

Background

Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial.

Methods

The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0–56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11.

Findings

The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio [HR] 0·76; 95% CI 0·66–0·87; p<0·0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89·3% vs 87·7%, respectively; HR 0·85; 95% CI 0·70–1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5–52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51–0·90; p=0·0077). Higher incidences of grade 3–4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea.

Interpretation

Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort.

Funding

F Hoffmann-La Roche, Michelangelo Foundation.

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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