Genomic correlates of clinical outcome in advanced prostate cancer

Significance

The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been well-defined, but the association of genomic findings with patient clinical outcomes and with other characteristics including histology and transcriptional pathway activity remains poorly understood. Here, we describe comprehensive integrative analysis of genomic and transcriptomic profiles, histology, and clinical outcomes for 429 patients with mCRPC. Of all the molecular factors we examined, alterations in RB1 had the strongest association with poor outcome. Our study identifies molecularly defined groups of patients who may benefit from a more aggressive treatment approach, with the genomic and outcome data made available to the research community for further interrogation.

Abstract

Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor ( AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.