Personalized Genomic Approaches and Pathway Identification for Individualized Prostate Cancer Therapy


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Robert Bristow
Ontario Cancer Institute/Princess Margaret Cancer Center & University of Toronto, Canada

Abstract

Up to 40% of patients with intermediate-risk prostate cancer will fail radical prostatectomy or precision image-guided radiotherapy (IGRT). Additional genetic prognosticators are needed to triage these patients towards intensified combination therapy with novel targeted therapeutics to improve both local and systemic control rates. To address these questions, we are performing genomic analyses (for mutations and copy number alterations (CNAs) using comparative genomic hybridization and whole genome sequencing) of tumour DNA derived from frozen needle biopsies of 126 men with intermediate-risk disease who underwent image-guided radiotherapy (IGRT) to a mean dose of 76.4Gy or men undergoing radical prostatectomy.

Patients whose tumours had CNAs in both PTEN and c-MYC, NKX.1 and StAR/HSD17B2 had significantly increased genetic instability (percent genome alteration; PGA). We demonstrate that c-MYC gain alone, or combined c-MYC gain and PTEN loss, were increasingly prognostic for relapse on multivariable analyses (hazard ratios (HR) of 2.58/p=0.005 and 3.21/p=0.0004; respectively). Other loci were also prognostic for biochemical disease-free relapse (StAR: HR=2.84, 95% CI: 1.44-5.61, p=0.00269; HSD17B2: HR=1.97, 95% CI: 1.06-3.64, p=0.031 and, NKX3.1 haploinsufficiency was associated with bRFR when tested alone (HR=3.05, 95% CI:1.46-6.39, p=0.0030) or when combined with c-MYC gain (HR=3.88, 95% CI:1.78-8.49, p=0.00067)). All aCGH hits were also positive for outcome on multivariate analyses in prostate cancer surgery patients. Similar findings exist for important members of the DNA Damage Response (DDR) pathway (e.g. loss of NBS1, ATR and RB) and for loci at fragile sites within the genome.

Our data from primary human specimens suggest that triaging patients by the use of personalized genetics may allow for better use of systemic therapies to target sub-clinical metastases or locally recurrent disease. This personalized approach will improve clinical outcome.

(Supported by Prostate Cancer Canada, the Ontario Institute for Cancer Research and the PMH Prostate Cancer Research Program/Campbell Family Research Institute)