TMPRSS2-ERG Status Is Not Prognostic Following Prostate Cancer Radiotherapy: Implications for Fusion Status and DSB Repair

Abstract

Background: Preclinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers, may be a surrogate for DNA repair status and therefore a biomarker for DNA-damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT).Methods: Pretreatment biopsies from two cohorts of patients with intermediate-risk prostate cancer [T1/T2, Gleason score (GS) < 8, prostate-specific antigen (PSA) < 20 ng/mL; >7 years follow-up] were analyzed: (i) 126 patients [comparative genomic hybridization (CGH) cohort] with DNA samples assayed by array CGH (aCGH) for the TMPRSS2-ERG fusion; and (ii) 118 patients [immunohistochemical (IHC) cohort] whose biopsy samples were scored within a defined tissue microarray (TMA) immunostained for ERG overexpression (known surrogate for TMPRSS2-ERG fusion). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir þ 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using a Cox proportional hazards model.Results: TMPRSS2-ERG fusion by aCGH was identified in 27 (21%) of the cases in the CGH cohort, and ERG overexpression was found in 59 (50%) patients in the IHC cohort. In both cohorts, TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analysis.Conclusions: In two similarly treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these prostate cancers have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response.

The TMPRSS2–ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition

“…Here we extend these observations by showing that there was no difference in DNA damage initiation as indicated by activation of ATM and Comet assays. Clinical data indicating that TMPRSS2-ERG is not prognostic for following PCa radiotherapy (44) support this conclusion. A recent study found that ERG expression conferred a small enhancement in radio-sensitization (45).…”

Recurrent Prostate Cancer Genomic Alterations Predict Response to Brachytherapy Treatment

“…In a recent publication, Dal Pra and colleagues (42) looked at ERG status alone in pretreatment biopsies in patients with prostate cancer treated by image-guided radiotherapy (IGRT), and identified no association between ERG status and biochemical-free relapse rate. Another study reported that tumors with c-MYC amplification alone, or combined with PTEN loss, were prognostic for BCR after IGRT (32).…”

ETS fusion genes in prostate cancer

“…So far, no specific inhibitors of ERG function have been described. In a recent report two independent cohorts of over 100 patients were treated with external beam radiotherapy (Dal Pra et al 2013). Although preclinical studies predicted that TMPRSS2-ERG tumors might be more sensitive to radiation (Brenner et al 2011), the presence of the gene fusion showed no association with biochemical recurrence-free survival in the clinical study.…”