Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab

Ann Oncol. 2011 Sep;22(9):2014-2020. doi: 10.1093/annonc/mdq706. Epub 2011 Feb 2.


Background: Patients with metastatic breast cancer (MBC) overexpressing HER2 (human epidermal growth factor receptor 2) are currently selected for treatment with trastuzumab, but not all patients respond.

Patients and methods: Using a novel assay, HER2 protein expression (H2T) was measured in formalin-fixed, paraffin-embedded primary breast tumors from 98 women treated with trastuzumab-based therapy for MBC. Using subpopulation treatment effect pattern plots, the population was divided into H2T low (H2T < 13.8), H2T high (H2T ≥ 68.5), and H2T intermediate (13.8 ≤ H2T < 68.5) subgroups. Kaplan-Meier (KM) analyses were carried out comparing the groups for time to progression (TTP) and overall survival (OS). Cox multivariate analyses were carried out to identify correlates of clinical outcome. Bootstrapping analyses were carried out to test the robustness of the results.

Results: TTP improved with increasing H2T until, at the highest levels of H2T, an abrupt decrease in the TTP was observed. KM analyses demonstrated that patients with H2T low tumors [median TTP 4.2 months, hazard ratio (HR) = 3.7, P < 0.0001] or H2T high tumors (median TTP 4.6 months, HR = 2.7, P = 0.008) had significantly shorter TTP than patients whose tumors were H2T intermediate (median TTP 12 months). OS analyses yielded similar results.

Conclusions: MBC patients with very high levels of H2T may represent a subgroup with de novo resistance to trastuzumab. These results are preliminary and require confirmation in larger controlled clinical cohorts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Cohort Studies
  • Drug Resistance, Neoplasm
  • Female
  • Gene Amplification
  • Gene Dosage
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Proportional Hazards Models
  • Prospective Studies
  • Receptor, ErbB-2 / biosynthesis*
  • Receptor, ErbB-2 / genetics
  • Trastuzumab
  • Treatment Outcome


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