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      Detection of Circulating Tumor Cells and Circulating Tumor Microemboli in Gastric Cancer 1

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          Abstract

          PURPOSE: Gastric cancer studies indicated a potential correlation between circulating tumor cells (CTCs) in peripheral blood and tumor relapse/metastasis. The prevalence and significance of circulating tumor microemboli (CTM) in gastric cancer remain unknown. We investigated the prevalence and prognostic value of CTCs and CTM for progression-free survival (PFS) and overall survival (OS) in gastric cancer patients. METHODS: Eighty-one gastric cancer patients consented to provide 5 ml of peripheral blood before systematic therapy. CTCs and CTM were isolated using isolation by size of epithelial tumor cells and characterized by cytopathologists. For 41 stage IV gastric cancer patients, CTM was investigated as a potential biomarker to predict prognosis. RESULTS: CTCs were detected in 51 patients; the average count was 1.81. In clinical stage I, II, III, and IV patients, the average CTC counts were 1.40, 0.67, 1.24, and 2.71, respectively. CTM were detected in 3 of 33 clinical stage I to IIIb patients, at an average of 0.12 (0-2). CTM were detected in 13 of 53 clinical stage IIIc to IV patients, at an average of 1.26 (0-22). In stage IV patients, CTM positivity correlated with the CA125 level. PFS and OS in CTM-positive patients were significantly lower than in CTM-negative patients ( P < .001). CTM positivity was an independent factor for determining the PFS ( P = .016) and OS ( P = .003) of stage IV patients in multivariate analysis. Using markers of the epithelial-mesenchymal transition, single CTCs were divided into three phenotypes including epithelial CTCs, biphenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs. For CTM, CK−/Vimentin+/CD45− and CK+/Vimentin+/CD45− phenotypes were observed, but the CK+/Vimentin−/CD45− CTM phenotype was not. CA125 was detected in gastric cancer cell lines BGC823 and MGC803. CONCLUSIONS: In stage IV patients, CTM positivity was correlated with serum CA125 level. CTM were an independent predictor of shorter PFS and OS in stage IV patients. Thus, CTM detection may be a useful tool to predict prognosis in stage IV patients.

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          Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer.

          Johann de Bono, Howard Scher, R. Montgomery … (2008)
          A method for enumerating circulating tumor cells (CTC) has received regulatory clearance. The primary objective of this prospective study was to establish the relationship between posttreatment CTC count and overall survival (OS) in castration-resistant prostate cancer (CRPC). Secondary objectives included determining the prognostic utility of CTC measurement before initiating therapy, and the relationship of CTC to prostate-specific antigen (PSA) changes and OS at these and other time points. Blood was drawn from CRPC patients with progressive disease starting a new line of chemotherapy before treatment and monthly thereafter. Patients were stratified into predetermined Favorable or Unfavorable groups ( or =5 CTC/7.5mL). Two hundred thirty-one of 276 enrolled patients (84%) were evaluable. Patients with Unfavorable pretreatment CTC (57%) had shorter OS (median OS, 11.5 versus 21.7 months; Cox hazard ratio, 3.3; P 26 to 9.3 months). CTC are the most accurate and independent predictor of OS in CRPC. These data led to Food and Drug Administration clearance of this assay for the evaluation of CRPC.
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            Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer.

            Matthew G Krebs, Robert Sloane, Lynsey J.C. Priest … (2011)
            Lung cancer is the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) lacks validated biomarkers to predict treatment response. This study investigated whether circulating tumor cells (CTCs) are detectable in patients with NSCLC and what their ability might be to provide prognostic information and/or early indication of patient response to conventional therapy. In this single-center prospective study, blood samples for CTC analysis were obtained from 101 patients with previously untreated, stage III or IV NSCLC both before and after administration of one cycle of standard chemotherapy. CTCs were measured using a semiautomated, epithelial cell adhesion molecule-based immunomagnetic technique. The number of CTCs in 7.5 mL of blood was higher in patients with stage IV NSCLC (n = 60; range, 0 to 146) compared with patients with stage IIIB (n = 27; range, 0 to 3) or IIIA disease (n = 14; no CTCs detected). In univariate analysis, progression-free survival was 6.8 v 2.4 months with P < .001, and overall survival (OS) was 8.1 v 4.3 months with P < .001 for patients with fewer than five CTCs compared with five or more CTCs before chemotherapy, respectively. In multivariate analysis, CTC number was the strongest predictor of OS (hazard ratio [HR], 7.92; 95% CI, 2.85 to 22.01; P < .001), and the point estimate of the HR was increased with incorporation of a second CTC sample that was taken after one cycle of chemotherapy (HR, 15.65; 95% CI, 3.63 to 67.53; P < .001). CTCs are detectable in patients with stage IV NSCLC and are a novel prognostic factor for this disease. Further validation is warranted before routine clinical application.
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              Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition

              Tobias Gorges, Ingeborg Tinhofer, Michael Drosch … (2012)
              Background Circulating tumour cells (CTCs) have shown prognostic relevance in metastatic breast, prostate, colon and pancreatic cancer. For further development of CTCs as a biomarker, we compared the performance of different protocols for CTC detection in murine breast cancer xenograft models (MDA-MB-231, MDA-MB-468 and KPL-4). Blood samples were taken from tumour bearing animals (20 to 200 mm2) and analysed for CTCs using 1. an epithelial marker based enrichment method (AdnaTest), 2. an antibody independent technique, targeting human gene transcripts (qualitative PCR), and 3. an antibody-independent approach, targeting human DNA-sequences (quantitative PCR). Further, gene expression changes associated with epithelial-to-mesenchymal transition (EMT) were determined with an EMT-specific PCR assay. Methods We used the commercially available Adna Test, RT-PCR on human housekeeping genes and a PCR on AluJ sequences to detect CTCs in xenografts models. Phenotypic changes in CTCs were tested with the commercially available “Human Epithelial to Mesenchymal Transition RT-Profiler PCR Array”. Results Although the AdnaTest detects as few as 1 tumour cell in 1 ml of mouse blood spiking experiments, no CTCs were detectable with this approach in vivo despite visible metastasis formation. The presence of CTCs could, however, be demonstrated by PCR targeting human transcripts or DNA-sequences - without epithelial pre-enrichment. The failure of CTC detection by the AdnaTest resulted from downregulation of EpCAM, whereas mesenchymal markers like Twist and EGFR were upregulated on CTCs. Such a change in the expression profile during metastatic spread of tumour cells has already been reported and was linked to a biological program termed epithelial-mesenchymal transition (EMT). Conclusions The use of EpCAM-based enrichment techniques leads to the failure to detect CTC populations that have undergone EMT. Our findings may explain clinical results where low CTC numbers have been reported even in patients with late metastatic cancers. These results are a starting point for the identification of new markers for detection or capture of CTCs, including the mesenchymal-like subpopulations.
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                Author and article information

                Contributors
                Tao Zhang
                Journal
                Journal ID (nlm-ta): Transl Oncol
                Journal ID (iso-abbrev): Transl Oncol
                Title: Translational Oncology
                Publisher: Neoplasia Press
                ISSN (Electronic): 1936-5233
                Publication date PMC-release: 25 April 2017
                Publication date Collection: June 2017
                Publication date (Electronic): 25 April 2017
                Volume: 10
                Issue: 3
                Pages: 431-441
                Affiliations
                [* ]Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China
                [† ]Wuhan YZY Medical Science & Technology Co., Ltd., biolake, No.666 Gaoxin Road, Wuhan, China
                Author notes
                [* ]Address all correspondence to: Tao Zhang, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology1277 Jiefang AveWuhan430022China taozhang66@ 123456outlook.com
                [2]

                Xiumei Zheng and Li Fan have contributed equally to this work.

                Article
                Publisher ID: S1936-5233(16)30276-5
                DOI: 10.1016/j.tranon.2017.02.007
                PMC ID: 5406582
                PubMed ID: 28448959
                SO-VID: 7fc19efe-a4e0-49ff-92d5-7667ca4f8bea
                Copyright © © 2017 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 15 December 2016
                Date revision received : 14 February 2017
                Date accepted : 14 February 2017
                Categories
                Subject: Original article

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