Genomic correlates of clinical outcome in advanced prostate cancer

作者：Wassim Abida, Joanna Cyrta, Glenn Heller, Davide Prandi, Joshua Armenia, Ilsa M. Coleman, Marcin Cieślik, Matteo Benelli, Dan R. Robinson, Eliezer M. Van Allen, Andrea Sboner, Tarcisio Fedrizzi, Juan Miguel Mosquera, Brian D. Robinson, Navonil De Sarkar, Lakshmi P. Kunju, Scott A. Tomlins, Yi Mi Wu, Daniel Nava Rodrigues, Massimo Loda, Anuradha Gopalan, Victor E. Reuter, Colin C. Pritchard, Joaquı́n Mateo, Diletta Bianchini, Susana Miranda, Suzanne Carreira, Pasquale Rescigno, Julie Filipenko, Jacob Vinson, Bruce Montgomery, Himisha Beltran, Elisabeth I. Heath, Howard I. Scher, Philip W. Kantoff, Mary‐Ellen Taplin, Nikolaus Schultz, Johann S. de Bono, Francesca Demichelis, Peter S. Nelson, Mark A. Rubin, Arul M. Chinnaiyan, Charles L. Sawyers · 发表于：Proceedings of the National Academy of Sciences · 年份：2019 · DOI：10.1073/pnas.1902651116 · 被引用次数：1455 · 研究领域：Prostate Cancer Treatment and Research、Prostate Cancer Diagnosis and Treatment、Cancer, Lipids, and Metabolism

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.