Elsevier

The Lancet

Volume 389, Issue 10075, 25–31 March 2017, Pages 1195-1205
The Lancet

Articles
11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial

https://doi.org/10.1016/S0140-6736(16)32616-2Get rights and content

Summary

Background

Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial.

Methods

HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032).

Findings

Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09–11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68–0·86) and death (0·74, 0·64–0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89–1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group.

Interpretation

1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit.

Funding

F Hoffmann-La Roche (Roche).

Introduction

15–20% of patients with early breast cancer have tumours that exhibit overexpression, amplification, or both, of the HER2 receptor or oncogene, and the use of adjuvant trastuzumab (Herceptin; Roche, Basel, Switzerland) is now the standard of care for these patients. Four large randomised trials1, 2, 3 have clearly shown that trastuzumab has a major effect in reducing recurrence and death in patients with this type of early breast cancer. Initial trials compared 1 year of trastuzumab treatment with a control group without trastuzumab.1, 2, 3 Longer follow-up confirmed a persistent benefit of 1 year of trastuzumab treatment versus observation (no trastuzumab).4, 5, 6, 7 The HERA (HERceptin Adjuvant) trial1 randomly assigned patients to one of three groups: a control group, 1 year of trastuzumab, or 2 years of trastuzumab. This trial is unique because it assigned patients to 2 years of trastuzumab. Demonstration that 2 years of trastuzumab was not more effective than 1 year of trastuzumab7 reinforced the use of 1 year of treatment as the standard of care. Long-term follow-up of patients with HER2-positive breast cancer is important to better understand the true impact of this disease, the benefits of trastuzumab, and long-term cardiovascular safety. Here we report the results of the comparison between observation, 1 year of trastuzumab, and 2 years of trastuzumab treatment at a median follow-up of 11 years of patients enrolled within the HERA trial.1

Research in context

Evidence before this study

We searched PubMed for randomised clinical trials published in English between Jan 1, 2000, and March 1, 2013, assessing long-term outcomes (>5 years' follow-up) from randomised trials of systemic therapy in patients with early breast cancer confirmed as HER2-positive, using the search terms “adjuvant”, “breast”, “randomised”, and “HER2”. We found no data in the published literature providing 10 years or more of follow-up from the use of adjuvant trastuzumab within a randomised trial.

Added value of this study

To our knowledge, this 11-year follow-up of the HERA trial provides the longest survival data of any trial that assessed the addition of anti-HER2 therapy to standard treatment for HER2-positive early breast cancer. We provide long-term patient outcome data to support the use of 1 year of adjuvant trastuzumab in this patient population, with evidence that those patients randomly assigned to receive trastuzumab (in both the 1-year and 2-years groups) sustained relative reductions in recurrence and breast cancer deaths, with the reassurance that the rate of serious toxicity does not increase over time. We also showed no evidence of a benefit of 2 years of trastuzumab compared with 1 year, and could not identify a subgroup of patients studied in the HERA trial who would not have derived long-term benefits.

Implications of all the available evidence

Patients with HER2-positive early breast cancer who meet the criteria for the HERA trial (or the other studies reported elsewhere), including the cardiac disease criteria, we believe should be offered 1 year of adjuvant trastuzumab as part of standard of care. Patients can be reassured that there are benefits in terms of better disease-free and overall survival that are sustained to at least 10 years after diagnosis, with no evidence of significant differential benefit by disease characteristics, such as nodal status or tumour hormone receptor status. Additionally, there is no evidence of late emergent side-effects, including no evidence of more cardiac endpoints emerging up to 10 years after treatment.

Section snippets

Study design, participants, and randomisation and masking

HERA is an open-label, phase 3, randomised controlled trial; full details of the trial methods have been previously reported.1, 5 Briefly, between Dec 7, 2001, and June 20, 2005, 5102 patients were recruited and randomly assigned (1:1:1) to three groups of observation (without trastuzumab), or adjuvant treatment of trastuzumab for 1 year or for 2 years.1 Methods used to generate the random allocation sequence, stratification factors, type of randomisation, approval of the protocol by local

Results

Figure 1 shows the trial profile. Three patients had no record of written informed consent and were excluded from analyses. The three groups were well balanced with respect to demographics and baseline disease characteristics including tumour size and nodal and hormone receptor status (table 1).

Overall 2571 (50%) patients had hormone-receptor-positive disease and 2528 (50%) had hormone-receptor-negative disease by local laboratory determination of hormone receptors. 2370 (92%) of the 2571

Discussion

After 11 years of median follow-up, the use of 1 year of adjuvant trastuzumab significantly improves disease outcomes when given in addition to standard of care, including chemotherapy, in patients with HER2-positive early breast cancer. The relative risk of a disease-free survival event is reduced by 24% from when trastuzumab is given in addition to standard of care, conferring an absolute benefit of 6·8% improvement in 10-year disease-free survival in those women who were randomly assigned to

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