Oncotarget

Research Papers:

Improving circulating tumor cells enumeration and characterization to predict outcome in first line chemotherapy mCRPC patients

Luis León-Mateos, Helena Casas, Alicia Abalo, María Vieito, Manuel Abreu, Urbano Anido, Antonio Gómez-Tato, Rafael López, Miguel Abal and Laura Muinelo-Romay _

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Oncotarget. 2017; 8:54708-54721. https://doi.org/10.18632/oncotarget.18025

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Abstract

Luis León-Mateos1,*, Helena Casas2,*, Alicia Abalo2,3, María Vieito6, Manuel Abreu2,3, Urbano Anido3, Antonio Gómez-Tato4, Rafael López2,3,5, Miguel Abal3 and Laura Muinelo-Romay3

1Axencia Galega de Coñecemento en Saúde (ACIS), SERGAS, Santiago de Compostela, Spain

2Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), CIBERONC, Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela, Spain

3Translational Medical Oncology Group, Health Research Institute of Santiago (IDIS), CIBERONC, Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela, Spain

4School of Mathematics, University of Santiago de Compostela (Campus Vida), Santiago de Compostela, Spain

5Roche-Chus Joint Unit for Precision Oncology, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela, Spain

6Research Unit for Molecular Therapy of Cancer, CNS Tumors, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain

*Co first-authors

Correspondence to:

Luis León-Mateos, email: [email protected]

Laura Muinelo-Romay, email: [email protected]

Keywords: prostate cancer, circulating tumour cells (CTCs), prognostic markers, taxanes resistance

Received: January 17, 2017     Accepted: May 02, 2017     Published: May 19, 2017

ABSTRACT

Introduction: There is a critical need of new surrogate markers for improving the therapeutic selection and monitoring of metastatic prostate cancer patients. Nowadays clinical management of these patients is been driven by biochemical and clinical parameters without enough accuracy to allow a real personalized medicine. The present study was conducted to go insight the molecular profile of circulating tumor cells (CTCs) isolated from advanced metastatic castration-resistant prostate cancer (mCRPC) with the aim of identifying prognostic marker with potential utility for therapy selection and monitoring.

Materials and Methods: CTCs isolation was carried out in peripheral blood samples from 29 mCRPC patients that undergo systemic chemotherapy based on taxanes (docetaxel/cabazitaxel) and 19 healthy controls using in parallel CellSearch and an alternative EpCAM-based immunoisolation followed by RT-qPCR analysis to characterize the CTC population. A panel of 17 genes related with prostate biology, hormone regulation, stem properties, tumor aggressiveness and taxanes responsiveness was analysed to identify an expression signature characterizing the CTCs.

Results: Patients with ≥ 5 CTCs/7.5ml of peripheral blood at baseline and during the treatment showed lower progression free survival (PFS) and overall survival (OS). Changes of CTCs levels during the treatment were also associated with the patient’s outcome. These results confirmed previous data obtained using CellSearch in mCRPC. In addition, we found a CTC profile mainly characterized by the expression of relevant genes for the hormone dependent regulation of PCa such as AR and CYP19 together with genes strongly implicated in PCa progression and resistance development such as BIRC5, TUB1A, GDF15, RAB7 and SPINK1. Our gene-expression profiling also permitted the identification of valuable prognostic biomarkers. Thus, high levels of AR, CYP19 and GDF15 were associated with poor PFS rates while AR, GDF15 and BIRC5 were also found as reliable predictors of OS. Besides, a logistic model using KLK3 and BIRC5 showed a high specificity and sensitivity compared to CellSearch to discriminate patients with a more aggressive evolution.

Conclusions: The molecular characterization of CTCs from advanced mCRPC patients provided with a panel of specific biomarkers, including genes related to taxanes resistance, with a promising applicability as “liquid biopsy” for the management of these patients.


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