2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial

doi:10.1016/S0140-6736(07)60028-2

The Lancet

Volume 369, Issue 9555, 6–12 January 2007, Pages 29-36

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https://doi.org/10.1016/S0140-6736(07)60028-2 Get rights and content

Summary

Background

Trastuzumab—a humanised monoclonal antibody against HER2—has been shown to improve disease-free survival after chemotherapy in women with HER2-positive early breast cancer. We investigated the drug's effect on overall survival after a median follow-up of 2 years in the Herceptin Adjuvant (HERA) study.

Methods

HERA is an international multicentre randomised trial that compared 1 or 2 years of trastuzumab treatment with observation alone after standard neoadjuvant or adjuvant chemotherapy in women with HER2-positive node positive or high-risk node negative breast cancer. 5102 women participated in the trial; we analysed data from 1703 women who had been randomised for treatment with trastuzumab for 1 year and 1698 women from the control group, with median follow-up of 23·5 months (range 0–48 months). The primary endpoint of the trial was disease-free survival. Here, we assess overall survival, a secondary endpoint. Analyses were done on an intent-to-treat basis. This trial is registered with the European Clinical Trials Database, number 2005–002385–11.

Findings

97 (5·7%) patients randomised to observation alone and 58 (3·4%) patients randomised to 1 year of treatment with trastuzumab were lost to follow-up. 172 women stopped trastuzumab prematurely. 59 deaths were reported for trastuzumab and 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% CI 0·47–0·91; p=0·0115). 218 disease-free survival events were reported with trastuzumab compared with 321 in the control group. 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).

Interpretation

Our results show that 1 year of treatment with trastuzumab after adjuvant chemotherapy has a significant overall survival benefit after a median follow-up of 2 years. The emergence of this benefit after only 2 years reinforces the importance of trastuzumab in the treatment of women with HER2-positive early breast cancer.

Introduction

Trastuzumab (Herceptin; Roche, Basel, Switzerland) is a humanised monoclonal antibody that is targeted against the extracellular domain of the HER2 transmembrane growth factor receptor.¹ Amplification of the HER2 gene and overexpression of the receptor occurs in around 15–25% of women with early breast cancer, and is associated with an aggressive disease course.2, 3 Trastuzumab has been shown to be of overall survival benefit to women with HER2-positive metastatic breast cancer administered alone4, 5 or in combination with chemotherapy.6, 7

The Herceptin Adjuvant (HERA) trial (Breast International Group 0101) is one of several large trials designed to test the efficacy of trastuzumab in the adjuvant (ie, postsurgery) treatment of women with HER2-positive early breast cancer. Results of 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 neoadjuvant (ie, presurgery) chemotherapy achieved a significant improvement in disease-free survival compared with women treated with adjuvant chemotherapy alone, with a hazard ratio (HR) of 0·54.⁸

The combined analysis of two similar North American trials (North Central Cancer Treatment Group Trial N9831 and National Surgical Adjuvant Breast and Bowel Project B-31) has also shown a significant improvement in disease-free survival for trastuzumab given concurrently with four courses of paclitaxel either every week or every 3 weeks after a combination of doxorubicin and cyclophosphamide and continued for 1 year compared with the same chemotherapy schedule alone.⁹ A fourth adjuvant trastuzumab trial, known as BCIRG 006, has also shown much the same disease-free survival benefit when trastuzumab is given either with docetaxel after doxorubicin and cyclophosphamide or with docetaxel and carboplatin.¹⁰ Finally, a fifth, much smaller, trial has also shown an improvement in disease-free survival after only 9 weeks of trastuzumab given at the start of treatment concurrently with adjuvant chemotherapy.¹¹

The magnitude of the benefit, with a reduction in the early risk of recurrence of around 50% in all these trials, has led to the widespread use of trastuzumab as adjuvant therapy. However, this use has been criticised by some because the findings arise from interim analyses, follow-up is short, and significant overall survival benefit has not been shown in any stand alone trial.¹² Our aim is to report an analysis of overall survival, together with an updated assessment of disease-free survival, in the HERA trial with a median 2-year follow-up.

Section snippets

Patients

The study design, eligibility criteria, treatment schedules, monitoring, and statistical analysis plan have been described in detail elsewhere.⁸ Briefly, the HERA trial is an international intergroup open-label phase III randomised trial involving women with centrally confirmed HER2-positive (immunohistochemistry score 3 or fluorescence in-situ hybridisation positive) early stage invasive breast cancer who had completed local regional therapy and a minimum of four courses of predefined standard

Results

5102 women were recruited between December, 2001, and June, 2005, including 1698 in the observation group and 1703 assigned to receive 1 year of treatment with trastuzumab (figure 1). The baseline characteristics of patient tumours and treatment, updated from the original publication, are shown in table 1. 97 (5·7%) patients randomly assigned to observation alone and 58 (3·4%) patients randomly assigned to 1 year of treatment with trastuzumab were lost to follow-up.

As of May 15, 2006, 861 women

Discussion

Our results indicate that trastuzumab shows a significant overall survival benefit in early breast cancer over observation alone after chemotherapy. Such a survival benefit after only 2 years of follow-up is unusual in breast cancer trials. For example, adjuvant chemotherapy is of major importance in the treatment of breast cancer and has achieved a long-term survival benefit of 38% for younger women,¹⁴ but the key early trial for such treatment had not begun to show a substantial survival

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Articles2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

Lancet

The discovery of receptor tyrosine kinases: targets for cancer therapy

Nat Rev Cancer

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

Science

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

Science

Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer

J Clin Oncol

Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule

J Clin Oncol

Concurrent administration of anti-HER2 monoclonal antibody and first-line chemotherapy for HER2-overexpressing metastatic breast cancer. A phase III, multinational, randomised controlled trial

N Engl J Med

Randomised phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 Study Group

J Clin Oncol

Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer

N Engl J Med

Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer

N Engl J Med

Articles
2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial