A clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer Journal Article
| Authors: | Zhao, S. G.; Sperger, J. M.; Schehr, J. L.; McKay, R. R.; Emamekhoo, H.; Singh, A.; Schultz, Z. D.; Bade, R. M.; Stahlfeld, C. N.; Gilsdorf, C. S.; Hernandez, C. I.; Wolfe, S. K.; Mayberry, R. D.; Krause, H. M.; Bootsma, M.; Helzer, K. T.; Rydzewski, N.; Bakhtiar, H.; Shi, Y.; Blitzer, G.; Kyriakopoulos, C. E.; Kosoff, D.; Wei, X. X.; Floberg, J.; Sethakorn, N.; Sharifi, M.; Harari, P. M.; Huang, W.; Beltran, H.; Choueiri, T. K.; Scher, H. I.; Rathkopf, D. E.; Halabi, S.; Armstrong, A. J.; Beebe, D. J.; Yu, M.; Sundling, K. E.; Taplin, M. E.; Lang, J. M. |
| Article Title: | A clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer |
| Abstract: | BACKGROUND. Neuroendocrine prostate cancer (NEPC) is an aggressive subtype, the presence of which changes the prognosis and management of metastatic prostate cancer. METHODS. We 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. RESULTS. Using 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. CONCLUSION. Our 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. FUNDING. NIH (DP2 OD030734, 1UH2CA260389, R01CA247479, and P30 CA014520), Department of Defense (PC190039 and PC200334), and Prostate Cancer Foundation (Movember Foundation — PCF Challenge Award). © 2022, Zhao et al. |
| Keywords: | signal transduction; adult; controlled study; human tissue; human cell; major clinical study; genetics; area under the curve; prospective study; adenocarcinoma; biomarkers; biological marker; metabolism; metastasis; phase 2 clinical trial; gene expression; cohort analysis; cell differentiation; pathology; cell line, tumor; prostate cancer; prostatic neoplasms; gene expression regulation; gene expression regulation, neoplastic; prostate tumor; tumor cell line; androgen receptor; real time polymerase chain reaction; receptors, androgen; complementary dna; longitudinal study; neuroendocrine carcinoma; circulating tumor cell; abiraterone; clinical outcome; neuroendocrine disease; cancer prognosis; enzalutamide; limit of quantitation; humans; human; male; article; prognostic assessment; liquid biopsy; 22rv1 cell line; multiplex real time polymerase chain reaction |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 132 |
| Issue: | 21 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2022-11-01 |
| Start Page: | e161858 |
| Language: | English |
| DOI: | 10.1172/jci161858 |
| PUBMED: | 36317634 |
| PROVIDER: | scopus |
| PMCID: | PMC9621140 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
