A Metastatic Biology Gene Expression Assay to Predict the Risk of Distant Metastases in Patients With Localized Prostate Cancer Treated With Primary Radical Treatment

Abstract

Approximately 20% of patients with organ confined prostate cancer (PCa) will develop disease recurrence following radical treatment (surgery or external beam radiotherapy (EBRT)). We hypothesized that a molecular subgroup of early PCa may have metastatic potential at presentation, resulting in disease recurrence. Using unsupervised hierarchical clustering of gene expression from a PCa dataset we identified a novel molecular subgroup with a transcriptional profile similar to metastatic disease. We developed a 70-gene expression assay to prospectively identify patients within the subgroup from formalin fixed and paraffin embedded tissue (FFPE). Initial assessment found the assay to be prognostic in three independent publicly available prostatectomy datasets. We therefore assessed the prognostic value of the assay in FFPE clinical samples collected from multiple international sites. FFPE tumor resections and tumor biopsy specimens were obtained from 322 surgical patients and 248 patients treated with EBRT. Regions of highest Gleason grade were identified for macrodissection, RNA extraction, and gene expression analysis. Samples were dichotomized as metastatic biology assay positive or negative using a pre-specified cut-off. The association of assay results with biochemical failure (BF) and distant metastases (DM) was tested on multivariate (MVA). The assay was significantly associated with BF on MVA (HR = 1.59 [1.11-2.29]; P = 0.0128), (HR = 1.86 [1.07-3.22]; P = 0.0277) and DM on MVA (HR = 3.09 [1.70-5.61]; P = 0.0002), (HR = 2.83 [1.13-7.11]; P = 0.0273) for surgery and EBRT cohorts respectively. Importantly, in a combined model, the assay demonstrated additional information to the commonly used CAPRA clinical tool for prediction of DM, HR = 2.72 [2.10-3.51]; P < 0.0001, and HR = 2.72 [1.42-5.20]; P = 0.0026 (Prostate Metastatic Assay combined with CAPRA-S and CAPRA, respectively). The metastatic biology assay predicts BF and DM in PCa patients treated with surgery or EBRT. The assay may help to select patients at risk of metastatic disease for additional treatment aimed at preventing disease recurrence.