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

Abstract

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).

• Authors: 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 132 Issue 21 (11 01 2022) ISSN: 1558-8238 [Electronic] United States
• PMID: 36317634 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Receptors, Androgen
• Biomarkers

Topics

• Humans
• Male
• Receptors, Androgen (genetics, metabolism)
• Prostatic Neoplasms (diagnosis, genetics, metabolism)
• Adenocarcinoma (diagnosis, genetics, pathology)
• Biomarkers
• Signal Transduction
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic