Genome-wide copy number analysis of circulating tumor cells in breast cancer patients with liver metastasis

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Abstract

The genome-wide copy number analysis of circulating tumor cells (CTCs) provides a promising prognostic biomarker for survival in breast cancer liver metastasis (BCLM) patients. The present study aimed to confirm the prognostic value of the presence of CTCs in BCLM patients. We previously developed an assay for the genome-wide pattern differences in copy number variations (CNVs) as an adjunct test for the routine imaging and histopathologic diagnosis methods to distinguish newly diagnosed liver metastases and recurrent liver metastases. Forty-three breast cancer patients were selected for this study in which 23 newly diagnosed and 20 recurrent liver metastases were diagnosed by histopathology and ¹⁸F-FDG PET/CT imaging. CTCs were counted from all patients using the CellSearch system and were confirmed by cytomorphology and three-color immunocytochemistry. Genomic DNA of single CTCs was amplified using multiple annealing and looping based amplification cycles (MALBAC). Then, we compared the CTC numbers of newly diagnosed and recurrent BCLM patients using Illumina platforms. A high CTC frequency (>15 CTCs/7.5 ml blood) was found to be correlated with disease severity and metastatic progression, which suggests the value for CTCs in the diagnosis of BCLM in comparison with pathohistology and PET/CT imaging (P>0.05). Moreover, CTCs isolated from BCLM patients remained an independent prognostic detection factor associated with overall survival (P=0.0041). Comparison between newly diagnosed and recurrent liver metastases revealed different frequencies of CNVs (P>0.05). Notably, the CNV pattern of isolated CTCs of recurrent BCLM patients was similar to recurrent liver metastases (nearly 82% of the gain/loss regions). Functional enrichment analysis identified 25 genes as a CNV signature of BCLM. Among them, were defensin and β-defensin genes, which are significantly associated with anti-angiogenesis and immunomodulation signaling pathways. High CTC frequencies are effective in the evaluation and differentiation between newly diagnosed liver metastases from recurrent liver metastases. Future clinical studies will be necessary to fully determine the prognostic potential of CTC cluster signatures in patients with BCLM.

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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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The detection of EpCAM+ and EpCAM– circulating tumor cells

Sanne de Wit, Guus van Dalum, Aufried T. M. Lenferink … (2015)

EpCAM expressing circulating tumor cells, detected by CellSearch, are predictive of short survival in several cancers and may serve as a liquid biopsy to guide therapy. Here we investigate the presence of EpCAM+ CTC detected by CellSearch and EpCAM– CTC discarded by CellSearch, after EpCAM based enrichment. EpCAM– CTC were identified by filtration and fluorescent labelling. This approach was validated using different cell lines spiked into blood and evaluated on blood samples of 27 metastatic lung cancer patients. The majority of spiked EpCAM+ cells could be detected with CellSearch, whereas most spiked cells with EpCAMlow or EpCAM– expression were detected using filtration. Five or more CTC were detected in 15% of the patient samples, this increased to 41% when adding the CTC detected in the discarded blood. The number of patients with CTC and the number of CTC detected were doubled by the presence of EpCAM– CTC. In this pilot study, the presence of EpCAM+ CTC was associated with poor outcome, whereas the EpCAM– CTC were not. This observation will need to be confirmed in larger studies and molecular characterization needs to be conducted to elucidate differences between EpCAM– and EpCAM+ CTC.

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Circulating giant macrophages as a potential biomarker of solid tumors.

Daniel Adams, Stuart Martin, R Alpaugh … (2014)

Tumor-associated macrophages (TAMs) derived from primary tumors are believed to facilitate circulating tumor cell (CTC) seeding of distant metastases, but the mechanisms of these processes are poorly understood. Although many studies have focused on the migration of CTCs, less attention has been given to TAMs that, like CTCs, derive from tumor sites. Using precision microfilters under low-flow conditions, we isolated circulating cancer-associated macrophage-like cells (CAMLs) from the peripheral blood of patients with breast, pancreatic, or prostate cancer. CAMLs, which are not found in healthy individuals, were found to express epithelial, monocytic, and endothelial protein markers and were observed bound to CTCs in circulation. These data support the hypothesis that disseminated TAMs can be used as a biomarker of advanced disease and suggest that they have a participatory role in tumor cell migration.

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Author and article information

Journal

Journal ID (nlm-ta): Oncol Rep

Journal ID (iso-abbrev): Oncol. Rep

Title: Oncology Reports

Publisher: D.A. Spandidos

ISSN (Print): 1021-335X

ISSN (Electronic): 1791-2431

Publication date (Print): September 2020

Publication date (Electronic): 18 June 2020

Publication date PMC-release: 18 June 2020

Volume: 44

Issue: 3

Pages: 1075-1093

Affiliations

[1 ]Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China

[2 ]Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417614411, Iran

[3 ]Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran 1916893813, Iran

[4 ]Department of Biology, Faculty of Science, University of Zanjan, Zanjan 4537138791, Iran

[5 ]Sichuan Provincial Center for Gynaecology and Breast Disease, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China

[6 ]School of Humanities and Management Science, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China

[7 ]The Postdoctoral Research Station, School of Medicine, Nankai University, Tianjin 300071, P.R. China

[8 ]Department of Medical Equipment, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China

Author notes

Correspondence to: Professor Leisheng Zhang, The Postdoctoral Research Station, School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, P.R. China, E-mail: leisheng_zhang@ 123456163.com

Professor Gang Chen, Department of Medical Equipment, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, 25 Taiping Street, Jiangyang, Luzhou, Sichuan 646000, P.R. China, E-mail: chengang@ 123456swmu.edu.cn

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Publisher ID: OR-44-03-1075

DOI: 10.3892/or.2020.7650

PMC ID: 7388446

PubMed ID: 32705227

SO-VID: 58b2c808-66eb-46d8-be25-d3b0a3b0e006

License:

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Genome-wide copy number analysis of circulating tumor cells in breast cancer patients with liver metastasis

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Karger: Oncology

Most cited references 57

Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer.

The detection of EpCAM+ and EpCAM– circulating tumor cells

Circulating giant macrophages as a potential biomarker of solid tumors.

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