Genomic correlates of clinical outcome in advanced prostate cancer

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.

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Affiliated Institutions

• The Barbara Ann Karmanos Cancer Institute US
• University of Trento IT
• Fred Hutch Cancer Center US
• Institute of Cancer Research GB
• University of Bern CH
• University of Michigan US
• Dana-Farber Cancer Institute US
• Cornell University US
• University of Washington US
• Broad Institute US
• National Health Service GB
• Howard Hughes Medical Institute US
• Memorial Sloan Kettering Cancer Center US
• Wayne State University US
• Cancer Clinic US

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