Circulating Tumor Cell-Based Molecular Classifier for Predicting Resistance to Abiraterone and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer.

Abstract

While circulating tumor cell (CTC)-based detection of AR-V7 has been demonstrated to predict patient response to second-generation androgen receptor therapies, the rarity of AR-V7 expression in metastatic castrate-resistant prostate cancer (mCRPC) suggests that other drivers of resistance exist. We sought to use a multiplex gene expression platform to interrogate CTCs and identify potential markers of resistance to abiraterone and enzalutamide. 37 patients with mCRPC initiating treatment with enzalutamide (n = 16) or abiraterone (n = 21) were prospectively enrolled for CTC collection and gene expression analysis using a panel of 89 prostate cancer-related genes. Gene expression from CTCs was correlated with PSA response and radioclinical progression-free survival (PFS) using Kaplan-Meier and Cox regression analyses. Twenty patients (54%) had detectable CTCs. At a median follow-up of 11.3 months, increased expression of the following genes was significantly associated with shorter PSA PFS and radioclinical PFS: AR, AR-V7, PSA, PSCA, TSPAN8, NKX3.1, and WNT5B. Additionally, high SPINK1 expression was associated with increased PFS. A predictive model including all eight genes gave an area under the curve (AUC) of 0.84 for PSA PFS and 0.86 for radioclinical PFS. In comparison, the AR-V7 only model resulted in AUC values of 0.65 and 0.64.These data demonstrate that clinically relevant information regarding gene expression can be obtained from whole blood using a CTC-based approach. Multigene classifiers in this setting may allow for the development of noninvasive predictive biomarkers to guide clinical management.

• Authors: Jae-Seung Chung, Yugang Wang, James Henderson, Udit Singhal, Yuanyuan Qiao, Alexander B Zaslavsky, Daniel H Hovelson, Daniel E Spratt, Zachery Reichert, Ganesh S Palapattu, Russell S Taichman, Scott A Tomlins, Todd M Morgan
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 21 Issue 8 Pg. 802-809 (08 2019) ISSN: 1476-5586 [Electronic] United States
• PMID: 31276932 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Androstenes
• Benzamides
• Biomarkers, Tumor
• Nitriles
• Phenylthiohydantoin
• enzalutamide
• abiraterone

Topics

• Aged
• Aged, 80 and over
• Androstenes (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Benzamides
• Biomarkers, Tumor
• Computational Biology (methods)
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Profiling
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Grading
• Neoplasm Metastasis
• Neoplasm Staging
• Neoplastic Cells, Circulating (metabolism, pathology)
• Nitriles
• Phenylthiohydantoin (administration & dosage, analogs & derivatives)
• Prognosis
• Proportional Hazards Models
• Prostatic Neoplasms, Castration-Resistant (diagnosis, drug therapy, genetics, mortality)
• Treatment Outcome