Prognostic and predictive value of ERβ1 and ERβ2 in the Intergroup Exemestane Study (IES)-first results from PathIES†

Ann Oncol. 2015 Sep;26(9):1890-1897. doi: 10.1093/annonc/mdv242. Epub 2015 May 22.


Background: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. PathIES aimed to assess the potential prognostic and predictive value of ERβ1 and ERβ2 expression in primary tumours in order to determine benefit in the two treatment arms.

Patients and methods: Primary tumour samples were available for 1256 patients (27% IES population). ERβ1 and ERβ2 expression was dichotomised at the median IHC score (high if ERβ1 ≥ 191, ERβ2 ≥ 164). Hazard ratios (HRs) were estimated by multivariable Cox proportional hazards models adjusting for clinicopathological factors. Treatment effects with biomarker expressions were determined by interaction tests. Analysis explored effects of markers both as a continuous variable and with dichotomised cut-offs.

Results: Neither ERβ1 nor ERβ2 were associated with disease-free survival (DFS) or overall survival (OS) in the whole cohort. In patients treated with continued tamoxifen, high ERβ1 expression compared with low was associated with better DFS [HR = 0.38:95% confidence interval (CI) 0.21-0.68, P = 0.001]. DFS benefit of exemestane over tamoxifen (HR = 0.40:95% CI 0.22-0.70) was found in the low ERβ1 subgroup (interaction P = 0.01). No significant difference with treatment was observed for ERβ2 expression in either DFS or OS.

Conclusion: In the PathIES population, exemestane appeared to be superior to tamoxifen among patients with low ERβ1 expression but not in those with high ERβ1 expression. This is the first trial of its kind to report a parameter potentially predicting benefit of an aromatase inhibitor when compared with tamoxifen and an independent validation is warranted.

Keywords: aromatase inhibitor; biomarker; breast cancer; oestrogen receptor beta; prognosis; tamoxifen.

Publication types

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

MeSH terms

  • Aged
  • Androstadienes / therapeutic use*
  • Antineoplastic Agents / therapeutic use
  • Aromatase Inhibitors / therapeutic use
  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Disease-Free Survival
  • Double-Blind Method
  • Estrogen Receptor beta / biosynthesis
  • Estrogen Receptor beta / genetics*
  • Female
  • Humans
  • Middle Aged
  • Prognosis
  • Proportional Hazards Models
  • Retrospective Studies
  • Tamoxifen / therapeutic use*
  • Treatment Outcome


  • Androstadienes
  • Antineoplastic Agents
  • Aromatase Inhibitors
  • Biomarkers, Tumor
  • Estrogen Receptor beta
  • Tamoxifen
  • exemestane