Molecular characteristics of circulating tumor cells resemble the liver metastasis more closely than the primary tumor in metastatic colorectal cancer

Abstract

// Wendy Onstenk 1 , Anieta M. Sieuwerts 1 , Bianca Mostert 1 , Zarina Lalmahomed 2 , Joan B. Bolt-de Vries 1 , Anne van Galen 1 , Marcel Smid 1 , Jaco Kraan 1 , Mai Van 1 , Vanja de Weerd 1 , Raquel Ramírez-Moreno 1 , Katharina Biermann 3 , Cornelis Verhoef 2 , Dirk J. Grünhagen 2 , Jan N.M. IJzermans 2 , Jan W. Gratama 1 , John W.M. Martens 1 , John A. Foekens 1 , Stefan Sleijfer 1 1 Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands 2 Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands 3 Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands Correspondence to: Wendy Onstenk, email: w.onstenk@erasmusmc.nl Keywords: circulating tumor cells, CTCs, CellSearch, colorectal cancer, gene expression profiling Received: April 06, 2016     Accepted: May 29, 2016     Published: June 20, 2016 ABSTRACT Background: CTCs are a promising alternative for metastatic tissue biopsies for use in precision medicine approaches. We investigated to what extent the molecular characteristics of circulating tumor cells (CTCs) resemble the liver metastasis and/or the primary tumor from patients with metastatic colorectal cancer (mCRC). Results: The CTC profiles were concordant with the liver metastasis in 17/23 patients (74%) and with the primary tumor in 13 patients (57%). The CTCs better resembled the liver metastasis in 13 patients (57%), and the primary tumor in five patients (22%). The strength of the correlations was not associated with clinical parameters. Nine genes ( CDH1 , CDH17 , CDX1 , CEACAM5 , FABP1 , FCGBP , IGFBP3 , IGFBP4 , and MAPT ) displayed significant differential expressions, all of which were downregulated, in CTCs compared to the tissues in the 23 patients. Patients and Methods: Patients were retrospectively selected from a prospective study. Using the CellSearch System, CTCs were enumerated and isolated just prior to liver metastasectomy. A panel of 25 CTC-specific genes was measured by RT-qPCR in matching CTCs, primary tumors, and liver metastases. Spearman correlation coefficients were calculated and considered as continuous variables with r=1 representing absolute concordance and r=-1 representing absolute discordance. A cut-off of r>0.1 was applied in order to consider profiles to be concordant. Conclusions: In the majority of the patients, CTCs reflected the molecular characteristics of metastatic cells better than the primary tumors. Genes involved in cell adhesion and epithelial-to-mesenchymal transition were downregulated in the CTCs. Our results support the use of CTC characterization as a liquid biopsy for precision medicine.