Circulating tumor cells, tumor-derived extracellular vesicles and plasma cytokeratins in castration-resistant prostate cancer patients
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Afroditi Nanou1, Frank A.W. Coumans2, Guus van Dalum3, Leonie L. Zeune1,4, David Dolling6, Wendy Onstenk5, Mateus Crespo6, Mariane Sousa Fontes6,7, Pasquale Rescigno6,7, Gemma Fowler6, Penny Flohr6, Christoph Brune4, Stefan Sleijfer5, Johann S. de Bono6,7 and Leon W.M.M. Terstappen1
1Department of Medical Cell BioPhysics, MIRA Institute, University of Twente, Enschede, the Netherlands
2Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, the Netherlands
3Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University, Düsseldorf, Germany
4Department of Applied Mathematics, MIRA Institute and Faculty of EEMCS, University of Twente, Enschede, the Netherlands
5Department of Medical Oncology, Erasmus MC – Cancer Institute, Rotterdam, The Netherlands
6Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom
7Prostate Cancer Targeted Therapies Group, The Royal Marsden NHS Foundation Trust, London, United Kingdom
Afroditi Nanou, email: [email protected]
Leon W.M.M. Terstappen, email: [email protected]
Keywords: circulating tumor cells (CTCs); tumor-derived Extracellular Vesicles (tdEVs); cytokeratin 18 (CK18); caspase-cleaved cytokeratin 18 (ccCK18); castration-resistant prostate cancer (CRPC)
Received: November 07, 2017 Accepted: March 17, 2018 Published: April 10, 2018
Purpose: The presence of Circulating Tumor Cells (CTCs) in Castration-Resistant Prostate Cancer (CRPC) patients is associated with poor prognosis. In this study, we evaluated the association of clinical outcome in 129 CRPC patients with CTCs, tumor-derived Extracellular Vesicles (tdEVs) and plasma levels of total (CK18) and caspase-cleaved cytokeratin 18 (ccCK18).
Experimental Design: CTCs and tdEVs were isolated with the CellSearch system and automatically enumerated. Cut-off values dichotomizing patients into favorable and unfavorable groups of overall survival were set on a retrospective data set of 84 patients and validated on a prospective data set of 45 patients. Plasma levels of CK18 and ccCK18 were assessed by ELISAs.
Results: CTCs, tdEVs and both cytokeratin plasma levels were significantly increased in CRPC patients compared to healthy donors (HDs). All biomarkers except for ccCK18 were prognostic showing a decreased median overall survival for the unfavorable groups of 9.2 vs 21.1, 8.1 vs 23.0 and 10.0 vs 21.5 months respectively. In multivariable Cox regression analysis, tdEVs remained significant.
Conclusions: Automated CTC and tdEV enumeration allows fast and reliable scoring eliminating inter- and intra- operator variability. tdEVs provide similar prognostic information to CTC counts.
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