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.
Proceedings of the National Academy of Sciences of the United States of America. 2019 May 06 [Epub]
Wassim Abida, Joanna Cyrta, Glenn Heller, Davide Prandi, Joshua Armenia, Ilsa Coleman, Marcin Cieslik, Matteo Benelli, Dan Robinson, Eliezer M Van Allen, Andrea Sboner, Tarcisio Fedrizzi, Juan Miguel Mosquera, Brian D Robinson, Navonil De Sarkar, Lakshmi P Kunju, Scott Tomlins, Yi Mi Wu, Daniel Nava Rodrigues, Massimo Loda, Anuradha Gopalan, Victor E Reuter, Colin C Pritchard, Joaquin Mateo, Diletta Bianchini, Susana Miranda, Suzanne Carreira, Pasquale Rescigno, Julie Filipenko, Jacob Vinson, Robert B Montgomery, Himisha Beltran, Elisabeth I Heath, Howard I Scher, Philip W Kantoff, Mary-Ellen Taplin, Nikolaus Schultz, Johann S deBono, Francesca Demichelis, Peter S Nelson, Mark A Rubin, Arul M Chinnaiyan, Charles L Sawyers
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Department of Pathology, Weill Medical College of Cornell University, New York, NY 10021., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Fred Hutchinson Cancer Center, University of Washington, Seattle, WA 98109., Department of Pathology, University of Michigan, Ann Arbor, MI 48109., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215., Institute of Cancer Research, London SW7 3RP, United Kingdom., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Prostate Cancer Clinical Trials Consortium, New York, NY 10065., Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201., Fred Hutchinson Cancer Center, University of Washington, Seattle, WA 98109; ., Department of Pathology, Weill Medical College of Cornell University, New York, NY 10021; ., Department of Pathology, University of Michigan, Ann Arbor, MI 48109; ., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; .