Abstract LB-018: Defining a molecular subclass of treatment-resistant prostate cancer
Authors: Beltran Himisha , Prandi Davide , Mosquera Juan Miguel , Giannopoulou Eugenia , Puca Loredana , Marotz Clarisse , Nanus David M. , Tagawa Scott T. , Elemento Olivier , Van Allen Eliezer , Sboner Andrea , Garraway Levi , Rubin Mark A. , Demichelis Francesca 
Published: August 2015

Abstract
Background: A subset of advanced prostate cancers can progress from an androgen driven state to androgen receptor (AR) independence, often associated with low or absent AR expression and extensive neuroendocrine differentiation. Once neuroendocrine prostate cancer (NEPC) develops, patients typically demonstrate an aggressive clinical course, resistance to AR therapies, and poor overall survival. Early diagnosis is important but remains challenging as the clinical and pathologic features associate with AR independence and NEPC are currently poorly defined.
Methods: To address this gap in knowledge, we performed whole exome sequencing (WES) of 124 metastatic tumors from 81 patients including 35 with morphologic features of NEPC. Patients with serial or synchronous samples were included to characterize disease heterogeneity and the transition from adenocarcinoma to NEPC. Immunohistochemistry was performed for neuroendocrine markers and AR in all cases. Computational analysis of clonality and allele specific quantification of copy number were performed using CLONET. Expression profiling (RNA-seq and/or quantitative assessment of a targeted panel of AR signaling genes by Nanostring) and DNA methylation were evaluated in the context of genomic changes.
Results: The mutational landscape of NEPC and castration resistant prostate cancer (CRPC) did not differ significantly by rate of non-synonymous mutations or copy number burden (on average &gt;40% of the genome was aberrant), and polyploidy was frequently detected together with common allelic imbalances. Comparative analysis at the DNA and mRNA level identified significant decrease in AR signaling in NEPC and a range of AR signaling in CRPC, enrichment of copy number losses (including RB1 and multiple genes on 16q) in NEPC, and focal high level AR amplification in CRPC in contrast to NEPCs (p-val = 0.0007). DNA allele specific analysis of multi-sample cases including patient matched adenocarcinoma-NEPC tumors suggested diverse genomic state of key lesions including aberrations in MYCN and CDKN1B.
Conclusions: This is largest study to date focused on the molecular landscape of the NEPC resistance phenotype. NEPC is characterized by a molecular profile defined by distinct genomic alterations and decreased AR signaling. A subgroup of CRPC demonstrates lower AR signaling and molecular overlap with NEPC. This study supports clonal evolution of prostate adenocarcinoma to NEPC, provides new insight into NEPC biology and disease heterogeneity, and may aid in the detection of AR independence and emergence of the NEPC subclass of treatment resistance.
Citation Format: Himisha Beltran, Davide Prandi, Juan Miguel Mosquera, Eugenia Giannopoulou, Loredana Puca, Clarisse Marotz, David M. Nanus, Scott T. Tagawa, Olivier Elemento, Eliezer Van Allen, Andrea Sboner, Levi Garraway, Mark A. Rubin, Francesca Demichelis. Defining a molecular subclass of treatment-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-018. doi:10.1158/1538-7445.AM2015-LB-018