Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study‡

Ann Oncol. 2018 Dec 1;29(12):2328-2333. doi: 10.1093/annonc/mdy414.

Abstract

Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy.

Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety.

Results: A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001).

Conclusions: This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse.

Trial registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Equivalence Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anthracyclines / administration & dosage
  • Anthracyclines / adverse effects
  • Antineoplastic Agents, Immunological / administration & dosage*
  • Antineoplastic Agents, Immunological / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / standards
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • Bridged-Ring Compounds / administration & dosage
  • Bridged-Ring Compounds / adverse effects
  • Cardiotoxicity / epidemiology*
  • Cardiotoxicity / etiology
  • Chemotherapy, Adjuvant / adverse effects
  • Chemotherapy, Adjuvant / methods
  • Chemotherapy, Adjuvant / standards
  • Disease-Free Survival
  • Drug Administration Schedule
  • Female
  • Humans
  • Mastectomy
  • Middle Aged
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Receptor, ErbB-2 / metabolism
  • Taxoids / administration & dosage
  • Taxoids / adverse effects
  • Time Factors
  • Trastuzumab / administration & dosage*
  • Trastuzumab / adverse effects

Substances

  • Anthracyclines
  • Antineoplastic Agents, Immunological
  • Bridged-Ring Compounds
  • Taxoids
  • taxane
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab

Associated data

  • ClinicalTrials.gov/NCT00629278
  • EudraCT/2007-004326-25