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      Circulating tumor cells as a response monitor in stage IV non-small cell lung cancer

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          Abstract

          Background

          Monitoring circulating tumor cells (CTC) has been shown to be prognostic in most solid malignancies. There is no CTC assay in clinical use for lung cancer therapy monitoring due to inconclusive clinical utility data. Limited data has been published outside of the standard CTC enumerations, regarding clinical significance of phenotypic heterogeneity of CTCs in late stage NSCLC and its ability to correlate with treatment outcomes.

          Methods

          In 81 patients with stage IV NSCLC, multiple timepoints for CTC analysis were collected after initiation of treatment across 139 lines of therapy using single cell high definition diagnostic pathology imaging of all nucleated cells from 362 peripheral blood samples as a liquid biopsy.

          Results

          We analyzed the subset of 25 patients with complete time series data, totaling 117 blood samples, to determine the significance of HD-CTC kinetics during the initiation of treatment. These kinetics follow three distinct patterns: an increase in HD-CTCs with therapy (mean + 118.40 HD-CTCs/mL), unchanged HD-CTCs numbers (stable; mean 0.54 HD-CTCs/mL), and a decrease in HD-CTCs numbers (mean − 81.40 HD-CTCs/mL). Patients with an increasing CTC count during the first 3 months post initiation of new treatment had a better PFS and OS compared to the other groups. There was weak correlation between the absolute number of HD-CTCs at a single time point of therapy and patient outcomes (OS p value = 0.0754). In the whole cohort of 81 patients, HD-CTCs were detected in 51 (63%) patients at initiation of therapy with a median of 2.20 (range 0–509.20) and a mean of 26.21 HD-CTCs/mL (± 15.64).

          Conclusions

          CTCs are identifiable in most patients with stage IV NSCLC. While absolute HD-CTC counts do not correlate with prognosis, the changes in CTC counts were predictive of survival in patients with metastatic lung cancer receiving chemotherapy. The level and dynamics of CTCs indicate very different biological and pharmacological phenomena at different stages of disease and timepoints of treatment, highlighting the complex role of CTCs in cancer research and clinical management.

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          Most cited references45

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

          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 tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival.

            We reported previously that >or=5 circulating tumor cells (CTC) in 7.5 mL blood at baseline and at first follow-up in 177 patients with metastatic breast cancer (MBC) were associated with poor clinical outcome. In this study, additional follow-up data and CTC levels at subsequent follow-up visits were evaluated. CTCs were enumerated in 177 MBC patients before the initiation of a new course of therapy (baseline) and 3 to 5, 6 to 8, 9 to 14, and 15 to 20 weeks after the initiation of therapy. Progression-free survival (PFS) and overall survival (OS) times were calculated from the dates of each follow-up blood draw. Kaplan-Meier plots and survival analyses were done using a threshold of >or=5 CTCs/7.5 mL at each blood draw. Median PFS times for patients with or=5 CTC, median PFS from these same time points was significantly shorter: 2.7, 1.3, 1.4, 3.0, and 3.6 months, respectively. Median OS for patients with 18.5 months. For patients with >or=5 CTC, median OS from these same time points was significantly shorter: 10.9, 6.3, 6.3, 6.6, and 6.7 months, respectively. Median PFS and OS times at baseline and up to 9 to 14 weeks after the initiation of therapy were statistically significantly different. Detection of elevated CTCs at any time during therapy is an accurate indication of subsequent rapid disease progression and mortality for MBC patients.
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              Isolation and retrieval of circulating tumor cells using centrifugal forces

              Presence and frequency of rare circulating tumor cells (CTCs) in bloodstreams of cancer patients are pivotal to early cancer detection and treatment monitoring. Here, we use a spiral microchannel with inherent centrifugal forces for continuous, size-based separation of CTCs from blood (Dean Flow Fractionation (DFF)) which facilitates easy coupling with conventional downstream biological assays. Device performance was optimized using cancer cell lines (> 85% recovery), followed by clinical validation with positive CTCs enumeration in all samples from patients with metastatic lung cancer (n = 20; 5–88 CTCs per mL). The presence of CD133+ cells, a phenotypic marker characteristic of stem-like behavior in lung cancer cells was also identified in the isolated subpopulation of CTCs. The spiral biochip identifies and addresses key challenges of the next generation CTCs isolation assay including antibody independent isolation, high sensitivity and throughput (3 mL/hr); and single-step retrieval of viable CTCs.
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                Author and article information

                Contributors
                sshishid@usc.edu
                ncarlsso@usc.edu
                Jorge.Nieva@med.usc.edu
                Bethel.Kelly@scrippshealth.org
                jameshic@usc.edu
                lbazhenova@ucsd.edu
                (213) 821-3980 , pkuhn@usc.edu
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                28 August 2019
                28 August 2019
                2019
                : 17
                : 294
                Affiliations
                [1 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, , University of Southern California, ; 1002 W Childs Way, MCB351, MC:3502, Los Angeles, CA 90089-3502 USA
                [2 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, University of Southern California, ; 1441 Eastlake Avenue, Suite 3440, Los Angeles, CA 90033 USA
                [3 ]ISNI 0000 0001 2111 8997, GRID grid.419794.6, Scripps Clinic, Department of Pathology, ; 10666 North Torrey Pines Road, MC211C, La Jolla, CA 92037 USA
                [4 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Moores Cancer Center, , University of California San Diego, ; 3855 Health Sciences Dr, La Jolla, CA 92093 USA
                Author information
                http://orcid.org/0000-0003-2629-4505
                Article
                2035
                10.1186/s12967-019-2035-8
                6714097
                31462312
                4d746ec7-c8e1-4b68-b673-56420dba467a
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 5 March 2019
                : 18 August 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: U54CA143906
                Award ID: P30CA014089
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Medicine
                non-small cell lung cancer,circulating tumor cells,hd-sca,liquid biopsy
                Medicine
                non-small cell lung cancer, circulating tumor cells, hd-sca, liquid biopsy

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