title: Prognostic and predictive value of ERβ1 and ERβ2 in the Intergroup Exemestane Study (IES)-first results from PathIES†.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
authors.forename: V
authors.initials: V
authors.lastname: Speirs
authors.affiliation: Department of Pathology, European Institute of Oncology and University of Milan, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Viale
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London.
authors.forename: K
authors.initials: K
authors.lastname: Mousa
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool.
authors.forename: C
authors.initials: C
authors.lastname: Palmieri
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London.
authors.forename: S N
authors.initials: SN
authors.lastname: Reed
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London.
authors.forename: H
authors.initials: H
authors.lastname: Nicholas
authors.affiliation: Institute of Cancer Research-Clinical Trials and Statistics Unit, Institute of Cancer Research, Sutton, UK.
authors.forename: M
authors.initials: M
authors.lastname: Cheang
authors.affiliation: Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Jassem
authors.affiliation: Section of Oncology, Institute of Clinical Medicine, University of Bergen, Bergen; Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: P E
authors.initials: PE
authors.lastname: Lønning
authors.affiliation: Institute of Cancer Research-Clinical Trials and Statistics Unit, Institute of Cancer Research, Sutton, UK.
authors.forename: E
authors.initials: E
authors.lastname: Kalaitzaki
authors.affiliation: Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: C J H
authors.initials: CJH
authors.lastname: van de Velde
authors.affiliation: Department of Pathology, Herlev Hospital, Herlev, Denmark.
authors.forename: B B
authors.initials: BB
authors.lastname: Rasmussen
authors.affiliation: Department of Oncology, AZ Klina Hospital, Brasschaat, Belgium.
authors.forename: D M
authors.initials: DM
authors.lastname: Verhoeven
authors.affiliation: Department of Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Shaaban
authors.affiliation: Ontario Institute of Cancer Research, Toronto, Canada.
authors.forename: J M S
authors.initials: JMS
authors.lastname: Bartlett
authors.affiliation: Institute of Cancer Research-Clinical Trials and Statistics Unit, Institute of Cancer Research, Sutton, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Bliss
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London. Electronic address: c.coombes@imperial.ac.uk.
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
mesh_terms: D000368:Aged; D000730:Androstadienes / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D018572:Disease-Free Survival; D004311:Double-Blind Method; D047629:Estrogen Receptor beta / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D047629:Estrogen Receptor beta; D013629:Tamoxifen; C056516:exemestane
keywords: aromatase inhibitor; biomarker; breast cancer; oestrogen receptor beta; prognosis; tamoxifen