Abstract 134: Immunogenomic landscape of neuroendocrine prostate cancer (NEPC)
Authors: Ferguson Alison M. , Bhinder Bhavneet , Conteduca Vincenza , Sigouros Michael , Sboner Andrea , Nanus David , Tagawa Scott , Rickman David , Elemento Olivier , Beltran Himisha 
Published: August 2019

Abstract
Background: NEPC is a histological subtype of advanced prostate cancer, predominantly arising clonally from castrate resistant prostate adenocarcinoma (CRPC) as a mechanism of resistance. Given current immunotherapeutic strategies only showing modest clinical benefit in prostate cancer patients and NEPC having clinical features aligned with small cell lung carcinoma (SCLC) we investigated the immune landscape of NEPC in relation to prostate cancer subtypes and SCLC to identify potential targets.
Methods: We evaluated RNA-seq from a 190 patient cohort including benign prostate (n=29; 25 PCa matched), localized prostate adenocarcinoma (PCa; n=68), hormone-naïve metastatic prostate adenocarcinoma (mPCa; n=11), CRPC (n=54), NEPC (n=25; 11 de novo) with follow-up data, and SCLC (n=28) (Rudin et al., Nat Gen 2012). Additionally, 234 prostate cancer patients had tumor mutational burden (TMB) determined by WES. Unsupervised clustering of FPKMs was performed to identify a 232 gene, immune-rich cluster, used to categorize immune status and prioritize validation of targets by IHC.
Results: Prostate cancer is known to have a relatively low TMB. Similarly, the median TMB of NEPC is akin to CRPC (38.0 vs 37.0 p = 0.44) while significantly lower than SCLC (38.0 vs 142.5, p &lt;0.001). Unsupervised assessment identified a predominantly ‘cold’ immune status across subtypes, with ‘hot’ tumors (n=8) associated with metastatic tumors of the LN and bone and ‘intermediate’ NEPC tumors (n=9) associated with de novo cases. Worse overall survival was associated with intermediate vs cold T-cell immune status (66.5 mo vs 101.5 mo; p &lt;0.001). Further analysis of NEPC showed lower expression of cytokines (p&lt;0.01) as well as variation in checkpoint markers. Specifically, NEPC tumors had significantly lower expression of PD1 in relation to CRPC (p = 0.0001) and SCLC (p = &lt;0.0001), higher PDL1 expression than CRPC (p = 0.05) but comparable with SCLC (p = 0.93) and lower PDL2 expression than PCa and SCLC (p = 0.03; &lt;0.001, respectively).
Conclusion: NEPC is characterized by a relatively ‘cold’ tumor immune microenvironment similar to other metastatic prostate cancer subtypes but higher PDL1 expression comparable to SCLC. Association of colder tumors with treatment-induced disease, inverse correlation between survival outcome and immune infiltration, as well as novel expression changes in cytokines and checkpoint markers support further investigation into the immune landscape and potential targets for NEPC.
Citation Format: Alison M. Ferguson, Bhavneet Bhinder, Vincenza Conteduca, Michael Sigouros, Andrea Sboner, David Nanus, Scott Tagawa, David Rickman, Olivier Elemento, Himisha Beltran. Immunogenomic landscape of neuroendocrine prostate cancer (NEPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 134.