A clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer.

BackgroundNeuroendocrine prostate cancer (NEPC) is an aggressive subtype, the presence of which changes the prognosis and management of metastatic prostate cancer.MethodsWe performed analytical validation of a Circulating Tumor Cell (CTC) multiplex RNA qPCR assay to identify the limit of quantification (LOQ) in cell lines, synthetic cDNA, and patient samples. We next profiled 116 longitudinal samples from a prospectively collected institutional cohort of 17 patients with metastatic prostate cancer (7 NEPC, 10 adenocarcinoma) as well as 265 samples from 139 patients enrolled in 3 adenocarcinoma phase II trials of androgen receptor signaling inhibitors (ARSIs). We assessed a NEPC liquid biomarker via the presence of neuroendocrine markers and the absence of androgen receptor (AR) target genes.ResultsUsing the analytical validation LOQ, liquid biomarker NEPC detection in the longitudinal cohort had a per-sample sensitivity of 51.35% and a specificity of 91.14%. However, when we incorporated the serial information from multiple liquid biopsies per patient, a unique aspect of this study, the per-patient predictions were 100% accurate, with a receiver-operating-curve (ROC) AUC of 1. In the adenocarcinoma ARSI trials, the presence of neuroendocrine markers, even while AR target gene expression was retained, was a strong negative prognostic factor.ConclusionOur analytically validated CTC biomarker can detect NEPC with high diagnostic accuracy when leveraging serial samples that are only feasible using liquid biopsies. Patients with expression of NE genes while retaining AR-target gene expression may indicate the transition to neuroendocrine differentiation, with clinical characteristics consistent with this phenotype.FundingNIH (DP2 OD030734, 1UH2CA260389, R01CA247479, and P30 CA014520), Department of Defense (PC190039 and PC200334), and Prostate Cancer Foundation (Movember Foundation - PCF Challenge Award).

The Journal of clinical investigation. 2022 Nov 01*** epublish ***

Shuang G Zhao, Jamie M Sperger, Jennifer L Schehr, Rana R McKay, Hamid Emamekhoo, Anupama Singh, Zachery D Schultz, Rory M Bade, Charlotte N Stahlfeld, Cole S Gilsdorf, Camila I Hernandez, Serena K Wolfe, Richel D Mayberry, Hannah M Krause, Matt Bootsma, Kyle T Helzer, Nicholas Rydzewski, Hamza Bakhtiar, Yue Shi, Grace Blitzer, Christos E Kyriakopoulos, David Kosoff, Xiao X Wei, John Floberg, Nan Sethakorn, Marina Sharifi, Paul M Harari, Wei Huang, Himisha Beltran, Toni K Choueiri, Howard I Scher, Dana E Rathkopf, Susan Halabi, Andrew J Armstrong, David J Beebe, Menggang Yu, Kaitlin E Sundling, Mary-Ellen Taplin, Joshua M Lang

Department of Human Oncology and., Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA., Moores Cancer Center, University of California, San Diego, La Jolla, California, USA., Wisconsin State Lab of Hygiene, Madison, Wisconsin, USA., Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA., Genitourinary Oncology Service, Department of Medicine and., Department of Biostatistics and Bioinformatics and., Duke Cancer Institute Center for Prostate and Urologic Cancers, Department of Medicine, Duke University, Durham, North Carolina, USA., Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA.