Genomic correlates of clinical outcome in advanced prostate cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 23; pp. 11428 - 11436
• Main Authors: Abida, Wassim, Cyrta, Joanna, Heller, Glenn, Prandi, Davide, Armenia, Joshua, Coleman, Ilsa, Cieslik, Marcin, Benelli, Matteo, Robinson, Dan, Van Allen, Eliezer M., Sboner, Andrea, Fedrizzi, Tarcisio, Mosquera, Juan Miguel, Robinson, Brian D., De Sarkar, Navonil, Kunju, Lakshmi P., Tomlins, Scott, Wu, Yi Mi, Rodrigues, Daniel Nava, Loda, Massimo, Gopalan, Anuradha, Reuter, Victor E., Pritchard, Colin C., Mateo, Joaquin, Bianchini, Diletta, Miranda, Susana, Carreira, Suzanne, Rescigno, Pasquale, Filipenko, Julie, Vinson, Jacob, Montgomery, Robert B., Beltran, Himisha, Heath, Elisabeth I., Scher, Howard I., Kantoff, Philip W., Taplin, Mary-Ellen, Schultz, Nikolaus, deBono, Johann S., Demichelis, Francesca, Nelson, Peter S., Rubin, Mark A., Chinnaiyan, Arul M., Sawyers, Charles L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04.06.2019
• Series: From the Cover
• Subjects: Aged; Androgen receptors; Androgens; Androstenes - therapeutic use; Benzamides; Biological Sciences; Biomarkers, Tumor - genetics; Castration; Clinical outcomes; Deoxyribonucleic acid; DNA; Drug Resistance, Neoplasm - genetics; Gene expression; Genomics; Genomics - methods; Heterogeneity; Histology; Humans; Interrogation; Male; Metastases; Metastasis; Middle Aged; Nitriles; p53 Protein; Patients; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - therapeutic use; PNAS Plus; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Receptors, Androgen - genetics; Ribonucleic acid; RNA; Transcription; Treatment Outcome; clinical outcomes; integrative genomics; castration-resistant prostate cancer; biomarkers
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1902651116

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.