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

Abstract

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).

Targeted Therapy and Local Control: The Dynamic Duo

“…early breast cancer. 7 Similar results were seen in a combined analysis of data from the North Central Cancer Treatment Group (NCCTG) N9831 Intergroup and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trials, with significantly improved disease-free survival (HR 0.52) at 4 years among patients with operable HER2? disease treated with adjuvant trastuzumab.…”

“…cancers, resulting in a notable reduction in disease recurrences. [7][8][9] The Herceptin Adjuvant (HERA) randomized trial showed a significant reduction in risk of a disease-free survival event (hazard ratio [HR] 0.76) and death (0.74) at 11 years of follow-up with the receipt of 1 year of adjuvant trastuzumab compared with observation among 5,099 patients with HER2? early breast cancer.…”

A Critical Review of Economic Evaluations of Trastuzumab in the Treatment of Early Stage HER2 Positive Breast Cancer

“…Such a review should assess the quality of model based assessments against established criteria for the production of economic models, heterogeneity in the interpretation of the term "early stage" and seek to identify the source of variation in reported ICERs. Second, some 11 years after the approval for use of Trastuzumab in the treatment of early stage HER2 positive breast cancer, longer term follow up data on cost and survival now exist [77]. A model based analysis that avails of data outside a trial setting with the potential inherent biases this might generate not seems timely.…”

Trastuzumab in Female Breast Cancer Patients With Reduced Left Ventricular Ejection Fraction

“…In most recent clinical trials, the proportion of patients developing symptomatic HF during trastuzumab has been relatively low (0.6% to 3.8%) 27, 30, 31, 32, 33. In fact, the HERA (HERceptin Adjuvant) trial showed an HF incidence of only 0.8% and decreases in LVEF of ≥10% from baseline to an LVEF of <50% in only 7.2% of patients 34.…”