Presentation Authors: Gitte Kristensen*, Copenhagen, Denmark, Siri H. Strand, Aarhus, Denmark, Martin Andreas Røder, Kasper Drimer Berg, Birgitte Grønkær Toft, Copenhagen, Denmark, Søren Høyer, Michael Borre, Karina Dalsgaard Sørensen, Aarhus, Denmark, Klaus Brasso, Copenhagen, Denmark
Introduction: Discovery of biomarkers could refine treatment of and follow-up programs for men with prostate cancer (PCa). Validation of potential biomarkers for PCa aggressiveness is essential to move biomarkers into clinical use. _x000D_
Epigenetic modifications of the human genome are important in the development of cancer. We have previously shown that high levels of the epigenetic mark 5-hydroxymethylcytosine (5hmC) in tumor tissue is a significant adverse predictor for biochemical failure (BF) following radical prostatectomy (RP) in patients with ERG negative PCa._x000D_
This study aimed to validate the predictive value of 5hmC levels in men undergoing RP for PCa in two independent Danish institutions.
Methods: The study included 592 PCa patients from two historical RP cohorts (cohort A: RP from 1998 to 2009 at Department of Urology, Aarhus University Hospital, Denmark; cohort B: RP from 2002 to 2005, at Department of Urology, Rigshospitalet, Denmark)._x000D_
5hmC and ERG protein levels were analyzed using immunohistochemistry (anti-5hmC: 39769, Active Motif; anti-ERG: EPR3864, Epitomics (cohort A) and EPR3864, Roche Ventana (cohort B)) on sections from tissue arrays based on RP specimens. 5hmC levels were dichotomized as low and high based on the predominant staining intensity. ERG expression was categorized as negative or positive. Evaluation of the biomarkers was done blinded._x000D_
Risk of BF, defined as PSA â‰¥ 0.2ng/ml, was analyzed using cumulative incidences and multiple cause-specific Cox regression. Death without BF was treated as a competing event.
Results: The median time of follow-up after RP was 10.0 years (95% CI: 9.5-10.2). In total, 246 patients (41.6%) had low and 346 patients (58.4%) had high 5hmC levels, whereas 238 patients (40.2%) were ERG negative and 354 patients (59.8%) were ERG positive._x000D_
The 10-year cumulative incidence of BF was 47.1% (95% CI: 42.8-51.4). No association between 5hmC or ERG levels and time to BF was found (p=0.2 and p=1.0, respectively). However, for those with ERG negative tumors, the 10-year cumulative incidence of BF was 42.4% (95% CI: 33.6-51.2) in the 5hmC low group compared to 55.4% (95% CI: 45.2-65.6) in the 5hmC high group (p=0.01). Furthermore, in the ERG negative population, multiple cause-specific Cox regression analysis adjusted for age, PSA, pT stage, Gleason score, and margin status showed that high 5hmC level was associated with time to BF (HR: 1.8; 95% CI: 1.2-2.7; p=0.003).
Conclusions: A high 5hmC level is an adverse predictor for BF following RP for patients with ERG negative PCa, which is consistent with previous results.
Source of Funding: The Danish Cancer Society