Abstract 2136: Combined 8q gain and 10q loss predicts for relapse following radical radiotherapy in intermediate risk prostate cancer

Abstract

Abstract Introduction: Gains on 8q with amplification of c-MYC and loss of 10q and PTEN have been associated with aggression in a number of cancers, including prostate cancer. Pre-clinical studies support that altered PTEN and c-MYC expression can alter cellular radiosensitivity. A definitive study of genetic loci containing PTEN deletions and c-Myc as potential predictors of relapse following radiotherapy has not been reported. We hypothesized that increased radiotherapy relapse was associated with 10q deletion and 8q gain (associated with loss of PTEN and amplification of c-MYC). Methods Biopsies were derived from 115 men with intermediate risk prostate cancer (T1-T2 disease and a Gleason score 7 and PSA less than 20 ng/ml, or a Gleason score less than 7 and PSA between 10 and 20 ng/ml). We used high-resolution array comparative genomic hybridization (arrayCGH) to identify copy number alterations (CNAs) in intermediate risk prostate cancer patients treated with 75.6 or 79.8 Gy of conformal radiotherapy. Biochemical failure, defined by Phoenix criteria or the initiation of salvage therapy, was observed in 35 patients after median follow-up of 5.4 years (range 0.9-8.8). Results: In our cohort, the percentage of a patient's genome which is altered (PGA) ranges from <1% to 35% (median 6.7%). Multiple high-frequency CNAs were observed, including del8p23.1-8p21.1 in 55%, del21q22.2 in 28% (containing the TMPRSS2:ERG fusion transcript), del10q23.31 in 24% (containing PTEN), and amplification at 8q21.3-24.3 in 30% (containing c-Myc). Patients with 8q and 10q alterations had significantly increased CNA values. There was a trend towards CNA associating with increased Gleason score in patients with 8q gains, but not with 10q deletions. In a multivariate model when adjusting for the clinical factors of pre-treatment PSA, T-stage and Gleason Score, we observed that increased CNA predicted for relapse following radiotherapy (Hazard Ratio (HR): 1.11; p = 0.00016). Additionally, patients with 8q gain and 10q deletion (c-MYC + PTEN alterations) had increased relapse following radiotherapy (HR: 2.52; p= 0.016). Conclusions: This is the first report of altered loci pertaining to the PTEN and c-MYC genes as determinants of radiotherapy outcome in intermediate risk prostate cancer. Future goals are directed towards using all aCGH hits and FISH validation to stratify the same patients into responders and non-responders. If validated in other radical radiotherapy series, PTEN-cMYC status could be used to individualize patient therapy for localized prostate cancer. (Supported by grants from CCSRI, the Terry Fox Foundation, PCC and CFI). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2136.