HER2 staining intensity in HER2-positive disease: relationship with FISH amplification and clinical outcome in the HERA trial of adjuvant trastuzumab

Ann Oncol. 2013 Nov;24(11):2761-6. doi: 10.1093/annonc/mdt275. Epub 2013 Jul 25.


Background: Trastuzumab treatment improves survival of HER2-positive primary breast cancer. HER2 staining intensity varies widely in HER2-positive tumours.

Patients and methods: We investigated whether differences in immunohistochemical (IHC) staining intensity for HER2 in HER2-positive tumors (IHC 3+ or FISH ratio ≥2.0) was associated with prognosis or benefit from trastuzumab treatment in patients randomized to 1 year or no trastuzumab in the HERceptin Adjuvant (HERA) trial. Median follow-up was 2 years. The nested case-control analysis, included 425 patients (cases) with a disease-free survival (DFS) event and two matched controls (no DFS event) per case. Tissue sections stained for HER2 were assessed for HER2 staining intensity by image analysis.

Results: HER2 staining intensity varied widely and correlated with HER2 gene copy number (Spearman, r = 0.498, P < 0.001) or less closely with HER2/CEP17 FISH ratio (r = 0.396, P < 0.001). We found no significant difference in DFS in the observation arm according to staining intensity (odds ratio [OR] change per 10 unit change in intensity: 1.015, 95% confidence interval [CI] 0.930-1.108) and no impact of staining intensity on benefit derived from 1-year trastuzumab (OR: 1.017, 95% CI 0.925-1.120).

Conclusions: Variability in HER2 staining in HER2-positive tumours has no role in clinical management with adjuvant trastuzumab.

Hera trial no: NCT00045032.

Keywords: HER2; HERA; IHC intensity; Trastuzumab; breast cancer.

Publication types

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

MeSH terms

  • Adult
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / pathology
  • Case-Control Studies
  • Disease-Free Survival
  • Female
  • Humans
  • In Situ Hybridization, Fluorescence
  • Middle Aged
  • Prognosis*
  • Receptor, ErbB-2 / isolation & purification*
  • Receptor, ErbB-2 / metabolism
  • Trastuzumab
  • Treatment Outcome


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab

Associated data

  • ClinicalTrials.gov/NCT00045032