Elsevier

The Lancet

Volume 382, Issue 9897, 21–27 September 2013, Pages 1021-1028
The Lancet

Articles
2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial

https://doi.org/10.1016/S0140-6736(13)61094-6Get rights and content

Summary

Background

Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The standard of care is 1 year of adjuvant trastuzumab, but the optimum duration of treatment is unknown. We compared 2 years of treatment with trastuzumab with 1 year of treatment, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in 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 chemotherapy, adjuvant chemotherapy, or both in 5102 patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. The comparison of 2 years versus 1 year of trastuzumab treatment involved a landmark analysis of 3105 patients who were disease-free 12 months after randomisation to one of the trastuzumab groups, and was planned after observing at least 725 disease-free survival events. The updated intention-to-treat comparison of 1 year trastuzumab treatment versus observation alone in 3399 patients at a median follow-up of 8 years (range 0–10) is also reported. This study is registered with ClinicalTrials.gov, number NCT00045032.

Findings

We recorded 367 events of disease-free survival in 1552 patients in the 1 year group and 367 events in 1553 patients in the 2 year group (hazard ratio [HR] 0·99, 95% CI 0·85–1·14, p=0·86). Grade 3–4 adverse events and decreases in left ventricular ejection fraction during treatment were reported more frequently in the 2 year treatment group than in the 1 year group (342 [20·4%] vs 275 [16·3%] grade 3–4 adverse events, and 120 [7·2%] vs 69 [4·1%] decreases in left ventricular ejection fraction, respectively). HRs for a comparison of 1 year of trastuzumab treatment versus observation were 0·76 (95% CI 0·67–0·86, p<0·0001) for disease-free survival and 0·76 (0·65–0·88, p=0·0005) for overall survival, despite crossover of 884 (52%) patients from the observation group to trastuzumab therapy.

Interpretation

2 years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer. 1 year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the standard of care.

Funding

F Hoffmann-La Roche (Roche).

Introduction

About 15–20% of breast cancers exhibit overexpression or amplification of the HER2 oncogene. Trastuzumab substantially reduces disease recurrence and death in patients with this type of early breast cancer and is now used widely in the adjuvant setting. Initial trials compared 1 year of trastuzumab treatment with a no trastuzumab control group.1, 2, 3 Further follow-up confirmed a persistent benefit of 1 year of treatment compared with observation alone.4, 5, 6 The HERceptin Adjuvant (HERA) trial is unique in that it also included randomisation of patients to 2 years of trastuzumab to allow comparison of two different durations of treatment. We report the first results of the comparison of 2 years versus 1 year of adjuvant trastuzumab, and update the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years.

Section snippets

Study design and participants

The HERA trial design, eligibility criteria, randomisation, treatment plan, follow-up and monitoring, and statistical analyses have been described elsewhere.1, 5 Briefly, between Dec 7, 2001, and June 20, 2005, a total of 5102 patients were randomly allocated to three groups: observation, trastuzumab for 1 year, and trastuzumab for 2 years. All patients included had locally assessed HER2-positive early-stage invasive breast cancer confirmed by the central laboratory (in Kassel, Germany), and

Results

Figure 1 shows the trial profile. Three patients with no record of written informed consent were excluded from analyses. The cohorts for comparison in the landmark analysis were well balanced in terms of demographics and baseline disease characteristics, including tumour size, node status, and hormone-receptor status (table 1). Overall, local laboratory analysis of hormone receptors showed that about half of the patients had hormone-receptor-positive disease (table 1). 1471 (92·6%) of the 1588

Discussion

Patients with HER2-positive early breast cancer given adjuvant trastuzumab have shown substantial improvements in disease-free and overall survival outcomes compared with those given no trastuzumab.10 Trastuzumab is the most effective targeted drug in breast cancer since tamoxifen. Findings from the HERA trial have supported the beneficial effects of trastuzumab, and this report extends the evidence of a substantial improvement in disease-free and overall survival to a median of 8 years'

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