ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer

Breast Cancer Res. 2012 Mar 14;14(2):R46. doi: 10.1186/bcr3145.


Introduction: Estrogen receptor-α (ER) and human epidermal growth factor receptor 2 (HER2) positivity are inversely correlated by standard criteria. However, we investigated the quantitative relation between ER and HER2 expression at both RNA and protein levels in HER2+ve and HER2-ve breast carcinomas.

Methods: ER and HER2 levels were assessed with immunohistochemistry (IHC) and (for HER2) fluorescent in situ hybridization (FISH) and by quantitative reverse transcription-polymerase chain reaction (q-RT-PCR) in formalin-fixed primary breast cancers from 448 patients in the National Cancer Research Institute (NCRI) Adjuvant Breast Cancer Trial (ABC) tamoxifen-only arm. Relations at the RNA level were assessed in 1,139 TransATAC tumors.

Results: ER and HER2 RNA levels were negatively correlated as expected in HER2+ve (IHC 3+ and/or FISH-amplified) tumors (r = -0.45; P = 0.0028). However, in HER2-ve tumors (ER+ve and ER-ve combined), a significant positive correlation was found (r = 0.43; P < 0.0001), HER2 RNA levels being 1.74-fold higher in ER+ve versus ER-ve tumors. This correlation was maintained in the ER+veHER2-ve subgroup (r = 0.24; P = 0.0023) and confirmed in this subgroup in 1,139 TransATAC tumours (r = 0.25; P < 0.0001). The positive relation extended to IHC-detected ER in ABC: mean ± 95% confidence interval (CI) H-scores were 90 ± 19 and 134 ± 19 for 0 and 1+ HER2 IHC categories, respectively (P = 0.0013). A trend toward lower relapse-free survival (RFS) was observed in patients with the lowest levels of ER and HER2 RNA levels within the ER+veHER2-ve subgroup both for ABC and TransATAC cohorts.

Conclusions: ER and HER2 expression is positively correlated in HER2-ve tumors. The distinction between HER2+ve and HER2-ve is greater in ER-ve than in ER+ve tumors. These findings are important to consider in clinical trials of anti-HER2 and anti-endocrine therapy in HER2-ve disease.

Trial registration: Clinical trial identifier: ISRCTN31514446.

Publication types

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

MeSH terms

  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Predictive Value of Tests
  • Prognosis
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-2 / metabolism*
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Tamoxifen / therapeutic use


  • Receptors, Estrogen
  • Tamoxifen
  • ERBB2 protein, human
  • Receptor, ErbB-2

Associated data

  • ISRCTN/ISRCTN31514446