Genomic correlates of clinical outcome in advanced prostate cancer

Wassim Abida(Memorial Sloan Kettering Cancer Center), Joanna Cyrta(University of Bern), Glenn Heller(Memorial Sloan Kettering Cancer Center), Davide Prandi(University of Trento), Joshua Armenia(Memorial Sloan Kettering Cancer Center), Ilsa M. Coleman(University of Washington), Marcin Cieślik(University of Michigan), Matteo Benelli(University of Trento), Dan R. Robinson(University of Michigan), Eliezer M. Van Allen(Broad Institute), Andrea Sboner(Cornell University), Tarcisio Fedrizzi(University of Trento), Juan Miguel Mosquera(Cornell University), Brian D. Robinson(Cornell University), Navonil De Sarkar(University of Washington), Lakshmi P. Kunju(University of Michigan), Scott A. Tomlins(University of Michigan), Yi Mi Wu(University of Michigan), Daniel Nava Rodrigues(National Health Service), Massimo Loda(Cornell University), Anuradha Gopalan(Memorial Sloan Kettering Cancer Center), Victor E. Reuter(Memorial Sloan Kettering Cancer Center), Colin C. Pritchard(University of Washington), Joaquı́n Mateo(National Health Service), Diletta Bianchini(National Health Service), Susana Miranda(National Health Service), Suzanne Carreira(National Health Service), Pasquale Rescigno(National Health Service), Julie Filipenko(Cancer Clinic), Jacob Vinson(Cancer Clinic), Bruce Montgomery(University of Washington), Himisha Beltran(Cornell University), Elisabeth I. Heath(Wayne State University), Howard I. Scher(Memorial Sloan Kettering Cancer Center), Philip W. Kantoff(Memorial Sloan Kettering Cancer Center), Mary‐Ellen Taplin(Dana-Farber Cancer Institute), Nikolaus Schultz(Memorial Sloan Kettering Cancer Center), Johann S. de Bono(National Health Service), Francesca Demichelis(University of Trento), Peter S. Nelson(University of Washington), Mark A. Rubin(University of Bern), Arul M. Chinnaiyan(Howard Hughes Medical Institute), Charles L. Sawyers(Memorial Sloan Kettering Cancer Center)
Proceedings of the National Academy of Sciences
May 6, 2019
10.1073/pnas.1902651116
Cited by 1,399Open Access
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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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