Circulating tumor cells, tumor-derived extracellular vesicles and plasma cytokeratins in castration-resistant prostate cancer patients

Afroditi Nanou; Frank A W Coumans; Guus van Dalum; Leonie L Zeune; David Dolling; Wendy Onstenk; Mateus Crespo; Mariane Sousa Fontes; Pasquale Rescigno; Gemma Fowler; Penny Flohr; Christoph Brune; Stefan Sleijfer; Johann S de Bono; Leon W M M Terstappen

doi:10.18632/oncotarget.25019

Circulating tumor cells, tumor-derived extracellular vesicles and plasma cytokeratins in castration-resistant prostate cancer patients

Oncotarget. 2018 Apr 10;9(27):19283-19293. doi: 10.18632/oncotarget.25019.

Authors

Afroditi Nanou¹, Frank A W Coumans², Guus van Dalum³, Leonie L Zeune^{1

4}, David Dolling⁵, Wendy Onstenk⁶, Mateus Crespo⁵, Mariane Sousa Fontes^{5

7}, Pasquale Rescigno^{5

7}, Gemma Fowler⁵, Penny Flohr⁵, Christoph Brune⁴, Stefan Sleijfer⁶, Johann S de Bono^{5

7}, Leon W M M Terstappen¹

Affiliations

¹ Department of Medical Cell BioPhysics, MIRA Institute, University of Twente, Enschede, the Netherlands.
² Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, the Netherlands.
³ Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University, Düsseldorf, Germany.
⁴ Department of Applied Mathematics, MIRA Institute and Faculty of EEMCS, University of Twente, Enschede, the Netherlands.
⁵ Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom.
⁶ Department of Medical Oncology, Erasmus MC - Cancer Institute, Rotterdam, The Netherlands.
⁷ Prostate Cancer Targeted Therapies Group, The Royal Marsden NHS Foundation Trust, London, United Kingdom.

Abstract

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.

Keywords: caspase-cleaved cytokeratin 18 (ccCK18); castration-resistant prostate cancer (CRPC); circulating tumor cells (CTCs); cytokeratin 18 (CK18); tumor-derived Extracellular Vesicles (tdEVs).