title: ERG protein expression in diagnostic specimens is associated with increased risk of progression during active surveillance for prostate cancer.
abstract: BACKGROUND
  Compelling biomarkers identifying prostate cancer patients with a high risk of progression during active surveillance (AS) are needed.
  
  
  OBJECTIVE
  To examine the association between ERG expression at diagnosis and the risk of progression during AS.
  
  
  METHODS
  This study included 265 patients followed on AS with prostate-specific antigen (PSA) measurements, clinical examinations, and 10-12 core rebiopsies from 2002 to 2012 in a prospectively maintained database. ERG immunohistochemical staining was performed on diagnostic paraffin-embedded formalin-fixed sections with a ready-to-use kit (anti-ERG, EPR3864). Men were characterised as ERG positive if a minimum of one tumour focus demonstrated ERG expression.
  
  
  METHODS
  Overall AS progression was defined as clinical progression: increased clinical tumour category ≥cT2b by digital rectal examination and ultrasound, and/or histopathologic progression: upgrade of Gleason score, more than three positive cores or bilateral positive cores, and/or PSA progression: PSA doubling time <3 yr. Risk of progression was analysed using multiple cause-specific Cox regression and stratified cumulative incidences (Aalen-Johansen method). Curatively intended treatment, watchful waiting, and death without progression were treated as competing events.
  
  
  CONCLUSIONS
  A total of 121 of 142 ERG-negative and 96 of 123 ERG-positive patients had complete diagnostic information. In competing risk models, the ERG-positive group showed significantly higher incidences of overall AS progression (p<0.0001) and of the subgroups PSA progression (p<0.0001) and histopathologic progression (p<0.0001). The 2-yr cumulative incidence of overall AS progression was 21.7% (95% confidence interval [CI], 14.3-29.1) in the ERG-negative group compared with 58.6% (95% CI, 48.7-68.5) in the ERG-positive group. ERG positivity was a significant predictor of overall AS progression in multiple Cox regression (hazard ratio: 2.45; 95% CI, 1.62-3.72; p<0.0001). The main limitation of this study is its observational nature.
  
  
  CONCLUSIONS
  In our study, ERG positivity at diagnosis can be used to estimate the risk of progression during AS. If confirmed, ERG status can be used to individualise AS programmes.
  
  
  RESULTS
  The tissue biomarker ERG identifies active surveillance patients with an increased risk of disease progression.
authors.affiliation: Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: kasperdrimerberg@gmail.com.
authors.forename: Kasper Drimer
authors.initials: KD
authors.lastname: Berg
authors.affiliation: Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ben
authors.initials: B
authors.lastname: Vainer
authors.affiliation: Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Frederik Birkebæk
authors.initials: FB
authors.lastname: Thomsen
authors.affiliation: Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: M Andreas
authors.initials: MA
authors.lastname: Røder
authors.affiliation: Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas Alexander
authors.initials: TA
authors.lastname: Gerds
authors.affiliation: Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Birgitte Grønkær
authors.initials: BG
authors.lastname: Toft
authors.affiliation: Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Klaus
authors.initials: K
authors.lastname: Brasso
authors.affiliation: Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Iversen
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm; D015415:Biomarkers / Q000097:blood*; D051517:Digital Rectal Examination; D018450:Disease Progression; D006801:Humans; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000097:blood* / Q000473:pathology; D012306:Risk; D015534:Trans-Activators / Q000097:blood*; D000071230:Transcriptional Regulator ERG
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D017430:Prostate-Specific Antigen
keywords: Active surveillance; Biopsy; Competing risk; Disease progression; ERG expression; Pathology; Prostate cancer; TMPRSS2-ERG