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 RB1AR, 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.

Several studies have described the genomic landscape of primary and metastatic castration-resistant prostate cancer (mCRPC), revealing distinct genomic subtypes in primary localized disease, including ETS fusion-positive and SPOP-mutated prostate cancer (15), and subsets of patients with advanced disease who harbor potentially clinically actionable alterations in their tumor or in the germline (46). Based on these findings, prospective trials are currently enrolling patients with defined genomic alterations, including PARP inhibitor studies for patients with alterations in BRCA2/1ATM, and other DNA repair genes (NCT02952534NCT02987543NCT02854436), and AKT inhibitor studies for men with PI3K pathway alterations (NCT02525068NCT03310541).

In addition, various genomic and histologic features of prostate cancer have been described as conferring a worse prognosis. Among these are the presence of neuroendocrine or small-cell characteristics in tumors, sometimes referred to as aggressive variant prostate cancer or neuroendocrine prostate cancer (79), the detection of androgen receptor (AR) splice variant 7 in circulating tumor cells (1011), and the presence of genomic alterations in TP53, RB1, DNA repair genes, AR, and PI3K pathway genes in circulating tumor DNA (1213). However, studies that comprehensively examine all of these characteristics—histology, genomics, and transcriptomics—and their association with outcomes in mCRPC are lacking.

Here, we expand a foundational genomic resource of mCRPC tumors (5) from 150 to 429 patients (444 tumors), and integrate the analysis of whole-exome sequencing, gene expression, and histopathology with clinical outcomes, including survival and time on treatment with the next-generation androgen signaling inhibitors (ARSIs) enzalutamide and abiraterone acetate to identify the most important prognostic markers in mCRPC within a single large multiinstitutional genomic dataset, with tumor- and patient-level data made available for additional correlative analyses.