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

Abstract

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).

Conflict of interest statement

Declaration of interests

DC reports grants and other from Novartis, and other from BIOENSIS, outside the submitted work. RDG reports grants as support for his academic salary from the Breast International Group (BIG) and F Hoffman-La Roche Ltd (Roche) during the conduct of the study; and grants as support for his academic salary from GlaxoSmithKline (GSK), Pfizer, Merck, Celgene, and Novartis, outside the submitted work. EdA reports grants and other from Roche. IS reports grants and other from Novartis, outside the submitted work. LG reports grants and other from Novartis, outside the submitted work. NA-S reports grants and other from Roche, outside the submitted work; and employment relationship. SL reports personal fees from Roche, during the conduct of the study; personal fees from Roche, outside the submitted work. EM reports other from Frontier Science (Scotland) Ltd, during the conduct of the study; and other from Novartis, AstraZeneca, Roche, and GSK, outside the submitted work. BL-J reports he was a member of a Scientific Advisory Board pertaining to biosimilars of Herceptin within the past year. RB reports personal fees from Roche, outside the submitted work. MD reports grants from Roche/Genetech, during the conduct of the study; and grants and personal fees from Roche/Genetech, outside the submitted work. MJP-G reports personal fees from Roche outside the submitted work. MP reports that her institution received funding from Roche to conduct the study. AG, GC, MU, JB, and CJ declare no competing interests.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Trial profile

IHC=immunohistochemistry. FISH=fluorescence in-situ hybridisation. LVEF=left ventricular ejection fraction. ITT=intention to treat.

Figure 2. Kaplan-Meier and cumulative incidence plots for DFS

Kaplan-Meier plots of disease-free survival (DFS) over time are shown for all the intention-to-treat (ITT) population (A), for patients with hormone-receptor-positive disease (C), and for patients with hormone-receptor-negative disease (E). Cumulative incidence plots for breast cancer and non-breast cancer competing risks are shown for all the ITT population (B), for the hormone-receptor-positive cohort (D), and the hormone-receptor-negative cohort (F). Non-breast cancer DFS events are non-breast malignancy and death without previous event. HR=hazard ratio.

Figure 3. 1 year trastuzumab versus observation, in the ITT population

Disease-free survival (DFS) for the entire intention-to-treat (ITT) population (A), for patients with hormone-receptor-positive disease (C), and those with hormone-receptor-negative disease (E). Overall survival for the entire ITT population (B), for the hormone-receptor-positive cohort (D), and for the hormone-receptor-negative cohort (F). These ITT analyses are affected by selective crossover in 884 (52%) patients from the observation group who received trastuzumab after the first trial results were published in 2005. HR=hazard ratio. *The percentages are of follow-up time in the ITT analysis that was accrued after selective crossover for patients assigned to the observation group. Figure reproduced and modified from Goldhirsch and colleagues, by permission of Elsevier.

Figure 4. Cumulative incidence of cardiac endpoints

Competing risk analysis showing the cumulative incidence of cardiac endpoints with disease-free survival events considered as competing risks. Primary (severely symptomatic) cardiac endpoint (A) and primary and secondary cardiac endpoints (B).