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.

Design, setting, and participants: 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.

Outcome measurements and statistical analysis: 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.

Results and limitations: 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.

Patient summary: The tissue biomarker ERG identifies active surveillance patients with an increased risk of disease progression.

Keywords: Active surveillance; Biopsy; Competing risk; Disease progression; ERG expression; Pathology; Prostate cancer; TMPRSS2-ERG.