Use of genetic instability to predict biochemical recurrence in intermediate-risk prostate cancer.

Abstract

42 Background: Biomarkers of local and systemic recurrence are needed to individualize patient risk categories and better define treatment. We hypothesized that genomic instability, as measured by percent genome alteration (PGA), can predict for biochemical failure in intermediate- risk prostate cancer. Methods: High-resolution array comparative genomic hybridization (arrayCGH) was used to identify PGA in frozen biopsies from 120 intermediate-risk prostate cancer patients. Our cohort included 39 T1c tumors, 78 T2 tumors and 2 T3 tumors. The Gleason score was 6 in 32 tumors, 7 in 82 tumors and 8–9 in 6 tumors. PSA ranged from 2.1–33 (median 8.0). Patients were treated with intensity-modulated radiotherapy (IMRT) with doses of 75.6–79.8 Gy in 1.8–2Gy fractions, or 60–66 Gy in 3 Gy fractions.. Twenty-five percent of patients also received neoadjuvant-concurrent bicalutamide (150mg po od). 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: Array CGH showed variable PGA ranging from <1% to 35% (median 6.7%). PSA and the use of hormonal therapy independently influenced biochemical relapse, and formed a baseline clinical model to which PGA was added. PGA was found to be a strong predictor of biochemical relapse (p<0.0001) independent of the clinical prognostic factors (pre-treatment PSA, Gleason score and T-category). PGA was also found to be associated with unique tumour suppressor and oncogene gene loci clusters involved in genetic stability (e.g. loss of PTEN, p53, RB, NKX3.1, ATM, PARP-1 and gain of c-MYC; validated by in situ FISH). Conclusions: This is the first report to show genetic instability can independently predict for biochemical recurrence in intermediate-risk prostate cancer. Current studies are associating specific gene loci regions with clinical outcome. Our results could provide a way forward for individualized medicine for non-indolent prostate cancer based on initial daignostic biopsy material. Supported by Prostate Cancer Canada, The Terry Fox Foundation and the Canadian Cancer Society. No significant financial relationships to disclose.