Prognostic Utility of a Whole-blood Androgen Receptor-based Gene Signature in Metastatic Castration-resistant Prostate Cancer.

Abstract

BACKGROUND\nThe treatment paradigm for metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly in recent years. Identifying predictive and/or prognostic biomarkers in the context of this rapidly expanding therapeutic armamentarium remains a pressing and unmet clinical need.\n\n\nOBJECTIVE\nTo develop a prognostic whole-blood gene signature for mCRPC patients.\n\n\nDESIGN, SETTING, AND PARTICIPANTS\nAs part of an ongoing prospective, multicentre biomarker research study (Australian Prostate Biomarker Alliance), we enrolled 115 mCRPC patients commencing chemotherapy (n\u2009=\u200934) or androgen receptor (AR) pathway inhibitors therapy (n\u2009=\u200981) and obtained pretreatment whole-blood samples in PAXgene RNA tubes. Gene expression was assessed using reverse transcription-polymerase chain reaction.\n\n\nOUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS\nGene transcripts correlating with overall survival (OS) at p\u2009<\u20090.10 in univariate Cox regression models were incorporated into a multigene signature. Kaplan-Meier survival estimates and multivariate analyses were used to assess association with clinical outcomes. Prognostic strength of the signature was estimated using a concordance probability estimate (CPE).\n\n\nRESULTS AND LIMITATIONS\nBased on univariate analysis for OS, the following genes were incorporated into a multigene signature: AR splice variant 7 (AR-V7), and three androgen-regulated genes: GRHL2, HOXB13, and FOXA1. The number of positive transcripts clearly stratified survival outcomes (median OS: not reached vs 24.8\u2009mo vs 16.2\u2009mo for 0, 1, and ≥2 transcripts, respectively; p\u2009=\u20090.0052). Notably, this multigene signature retained prognostic significance on multivariable analysis (hazard ratio, 2.1; 95% confidence interval, 1.1-4.0; p\u2009=\u20090.019). Moreover, CPE for this model was 0.78, indicating strong discriminative capacity. Limitations include short follow-up time.\n\n\nCONCLUSIONS\nOur data demonstrate the prognostic utility of a novel whole-blood AR-based signature in mCRPC patients commencing contemporary systemic therapies. Our pragmatic assay requires minimal processing, can be performed in most hospital laboratories, and could represent a key prognostic tool for risk stratification in mCRPC.\n\n\nPATIENT SUMMARY\nWe found that expression of certain genes associated with the androgen receptor could help determine how long men with advanced prostate cancer survive after starting modern drug therapies.