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

Publication ,  Journal Article
Zhao, SG; Sperger, JM; Schehr, JL; McKay, RR; Emamekhoo, H; Singh, A; Schultz, ZD; Bade, RM; Stahlfeld, CN; Gilsdorf, CS; Hernandez, CI; Yu, M ...
Published in: J Clin Invest
November 1, 2022

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).

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

November 1, 2022

Volume

132

Issue

21

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptors, Androgen
  • Prostatic Neoplasms
  • Male
  • Immunology
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Cell Line, Tumor
  • Biomarkers
  • Adenocarcinoma
 

Citation

APA
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MLA
NLM
Zhao, S. G., Sperger, J. M., Schehr, J. L., McKay, R. R., Emamekhoo, H., Singh, A., … Lang, J. M. (2022). A clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer. J Clin Invest, 132(21). https://doi.org/10.1172/JCI161858
Zhao, Shuang G., Jamie M. Sperger, Jennifer L. Schehr, Rana R. McKay, Hamid Emamekhoo, Anupama Singh, Zachery D. Schultz, et al. “A clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer.J Clin Invest 132, no. 21 (November 1, 2022). https://doi.org/10.1172/JCI161858.
Zhao SG, Sperger JM, Schehr JL, McKay RR, Emamekhoo H, Singh A, et al. A clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer. J Clin Invest. 2022 Nov 1;132(21).
Zhao, Shuang G., et al. “A clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer.J Clin Invest, vol. 132, no. 21, Nov. 2022. Pubmed, doi:10.1172/JCI161858.
Zhao SG, Sperger JM, Schehr JL, McKay RR, Emamekhoo H, Singh A, Schultz ZD, Bade RM, Stahlfeld CN, Gilsdorf CS, Hernandez CI, Wolfe SK, Mayberry RD, Krause HM, Bootsma M, Helzer KT, Rydzewski N, Bakhtiar H, Shi Y, Blitzer G, Kyriakopoulos CE, Kosoff D, Wei XX, Floberg J, Sethakorn N, Sharifi M, Harari PM, Huang W, Beltran H, Choueiri TK, Scher HI, Rathkopf DE, Halabi S, Armstrong AJ, Beebe DJ, Yu M, Sundling KE, Taplin M-E, Lang JM. A clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer. J Clin Invest. 2022 Nov 1;132(21).

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

November 1, 2022

Volume

132

Issue

21

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptors, Androgen
  • Prostatic Neoplasms
  • Male
  • Immunology
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Cell Line, Tumor
  • Biomarkers
  • Adenocarcinoma