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

Shuang G Zhao ^1,2,3, Jamie M Sperger ^2,4, Jennifer L Schehr ²

¹Department of Human Oncology and.
²Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
³William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA.
⁴Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁵Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.
⁶Wisconsin State Lab of Hygiene, Madison, Wisconsin, USA.
⁷Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁸Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁹Genitourinary Oncology Service, Department of Medicine and.
¹⁰Biomarker Development Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
¹¹Department of Biostatistics and Bioinformatics and.
¹²Duke Cancer Institute Center for Prostate and Urologic Cancers, Department of Medicine, Duke University, Durham, North Carolina, USA.
¹³Department of Biomedical Engineering and.
¹⁴Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA.

⁰Department of Human Oncology and.

The Journal of Clinical Investigation +

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November 1, 2022

View abstract on PubMed

Summary

A new liquid biopsy test accurately detects aggressive neuroendocrine prostate cancer (NEPC) by analyzing circulating tumor cells. Serial testing of patients with metastatic prostate cancer achieved 100% diagnostic accuracy, improving prognosis and management.

Area Of Science

Oncology
Molecular Diagnostics
Genetics

Background

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype impacting metastatic prostate cancer prognosis and treatment.
Distinguishing NEPC from adenocarcinoma is critical for patient management.

Purpose Of The Study

To analytically validate a circulating tumor cell (CTC) multiplex RNA qPCR assay for NEPC detection.
To develop and assess a NEPC liquid biomarker using serial liquid biopsies.
To evaluate the prognostic value of neuroendocrine markers in prostate cancer patients treated with androgen receptor signaling inhibitors (ARSIs).

Main Methods

Analytical validation of a CTC multiplex RNA qPCR assay to determine the limit of quantification (LOQ).
Profiling of 116 longitudinal samples from 17 metastatic prostate cancer patients (7 NEPC, 10 adenocarcinoma).
Analysis of 265 samples from 139 patients in 3 adenocarcinoma ARSI phase II trials.
NEPC biomarker assessment based on neuroendocrine marker expression and androgen receptor (AR) target gene absence.

Main Results

Per-sample sensitivity and specificity for the liquid biomarker were 51.35% and 91.14%, respectively.
Incorporating serial liquid biopsy data achieved 100% per-patient diagnostic accuracy (ROC AUC of 1).
In adenocarcinoma patients on ARSI therapy, NE marker expression was a negative prognostic factor, even with retained AR target gene expression.

Conclusions

An analytically validated CTC biomarker offers high diagnostic accuracy for NEPC using serial liquid biopsies.
Serial testing with this biomarker is feasible and improves NEPC detection.
Neuroendocrine gene expression in ARSI-treated patients may signal transition to NEPC, indicating a distinct clinical phenotype.

Keywords:

Oncology Prostate cancer