Circulating tumor cell technologies.
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ABSTRACT:
SUBMITTER: Ferreira MM
PROVIDER: S-EPMC5528969 | biostudies-other | 2016 Mar
REPOSITORIES: biostudies-other
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Project description:The potential clinical utility of circulating tumor cells (CTCs) in the diagnosis and management of cancer has drawn a lot of attention in the past 10 years. CTCs disseminate from tumors into the bloodstream and are believed to carry vital information about tumor onset, progression, and metastasis. In addition, CTCs reflect different biological aspects of the primary tumor they originate from, mainly in their genetic and protein expression. Moreover, emerging evidence indicates that CTC liquid biopsies can be extended beyond prognostication to pharmacodynamic and predictive biomarkers in cancer patient management. A key challenge in harnessing the clinical potential and utility of CTCs is enumerating and isolating these rare heterogeneous cells from a blood sample while allowing downstream CTC analysis. That being said, there have been serious doubts regarding the potential value of CTCs as clinical biomarkers for cancer due to the low number of promising outcomes in the published results. This review aims to present an overview of the current preclinical CTC detection technologies and the advantages and limitations of each sensing platform, while surveying and analyzing the published evidence of the clinical utility of CTCs.
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Project description:Circulating tumor cells (CTCs) are cancer cells that circulate in the blood stream after being naturally shed from original or metastatic tumors, and can lead to a new fatal metastasis. CTCs have become a hotspot research field during the last decade. Detection of CTCs, as a liquid biopsy of tumors, can be used for early diagnosis of cancers, earlier evaluation of cancer recurrence and chemotherapeutic efficacy, and choice of individual sensitive anti-cancer drugs. Therefore, CTC detection is a crucial tool to fight against cancer. Herein, we classify the currently reported CTC detection technologies, introduce some representative samples for each technology, conclude the advantages and limitations, and give a future perspective including the challenges and opportunities of CTC detection.
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Project description:Circulating tumour cells (CTCs) are the precursor cells for the formation of metastatic disease. With a simple blood draw, liquid biopsies enable the non-invasive sampling of CTCs from the blood, which have the potential to provide important insights into cancer detection and monitoring. Since gaining FDA approval in 2004, the CellSearch system has been used to determine the prognosis of patients with metastatic breast, prostate and colorectal cancers. This utilises the cell surface marker Epithelial Cell Adhesion Molecule (EpCAM), to enrich CTCs, and many other technologies have adopted this approach. More recently, the role of mesenchymal-like CTCs in metastasis formation has come to light. It has been suggested that these cells are more aggressive metastatic precursors than their epithelial counterparts; however, mesenchymal CTCs remain undetected by EpCAM-based enrichment methods. This has prompted the development of a variety of 'label free' enrichment technologies, which exploit the unique physical properties of CTCs (such as size and deformability) compared to other blood components. Here, we review a wide range of both immunocapture and label free CTC enrichment technologies, summarising the most significant advantages and disadvantages of each. We also highlight the important characteristics that technologies should possess for routine clinical use, since future developments could have important clinical implications, with the potential to direct personalised therapies for patients with cancer.
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Project description:AbstractBreast cancer (BC) represents the most commonly diagnosed cancer among females worldwide. Although targeted therapy has greatly improved the efficacy of treating BC, a large proportion of BC patients eventually develop recurrence or metastasis. Traditional invasive tumor tissue biopsy is short of comprehensiveness in tumor assessment due to heterogeneity. Liquid biopsy, an attractive non-invasive approach mainly including circulating tumor cell and circulating tumor DNA (ctDNA), has been widely utilized in a variety of cancers with the advances of sequencing technologies in recent years. The ctDNA that is found circulating in body fluids refers to DNA released from tumor cells and has shown clinical utility in metastatic breast cancer (MBC). With the results of genomic variants detection, ctDNA could be used to predict clinical outcomes, monitor disease progression, and guide treatment for patients with MBC. Moreover, the drug resistance problem may be addressed by ctDNA detection. In this review, we summarized the technological developments and clinical applications of ctDNA in MBC.
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Project description:PurposeDue to their minimal-invasive yet potentially current character circulating tumor cells (CTC) might be useful as a "liquid biopsy" in solid tumors. However, successful application in metastatic renal cell carcinoma (mRCC) has been very limited so far. High plasticity and heterogeneity of CTC morphology challenges currently available enrichment and detection techniques with EpCAM as the usual surface marker being underrepresented in mRCC. We recently described a method that enables us to identify and characterize non-hematopoietic cells in the peripheral blood stream with varying characteristics and define CTC subgroups that distinctly associate to clinical parameters. With this pilot study we wanted to scrutinize feasibility of this approach and its potential usage in clinical studies.Experimental designPeripheral blood was drawn from 14 consecutive mRCC patients at the West German Cancer Center and CTC profiles were analyzed by Multi-Parameter Immunofluorescence Microscopy (MPIM). Additionally angiogenesis-related genes were measured by quantitative RT-PCR analysis.ResultsWe detected CTC with epithelial, mesenchymal, stem cell-like or mixed-cell characteristics at different time-points during anti-angiogenic therapy. The presence and quantity of N-cadherin-positive or CD133-positive CTC was associated with inferior PFS. There was an inverse correlation between high expression of HIF1A, VEGFA, VEGFR and FGFR and the presence of N-cadherin-positive and CD133-positive CTC.ConclusionsPatients with mRCC exhibit distinct CTC profiles that may implicate differences in therapeutic outcome. Prospective evaluation of phenotypic and genetic CTC profiling as prognostic and predictive biomarker in mRCC is warranted.
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Project description:Analysis of circulating tumor DNA (ctDNA) is emerging as a powerful tool for guiding targeted therapy and monitoring tumor evolution in patients with non-small cell lung cancer (NSCLC), especially when representative tissue biopsies are not available. Here, we have compared the ability of four leading technology platforms to detect epidermal growth factor receptor (EGFR) mutations (L858R, exon 19 deletion, T790M and G719X) in ctDNA from NSCLC patients. Two amplification refractory mutation systems (cobas-ARMS and ADx-ARMS), a droplet digital polymerase chain reaction (ddPCR) and a next-generation sequencing (Firefly NGS) platform were included in the comparison. Fifteen EGFR mutations across twenty NSCLC patients were identified. Firefly NGS, cobas-ARMS and ddPCR all displayed superior sensitivity while ADx-ARMS was better suited for the qualitative detection of EGFR mutations with allele frequency higher than 1% in plasma and tissue samples. We observed high coincidence between the plasma and tissue EGFR mutational profiles for three driver mutations (L858R, exon 19 deletion and G719X) that are known targets of first generation EGFR-TKI therapies among patients who relapsed. Discrepancies between tissue and plasma EGFR mutational profiles were mainly attributable to spatial and temporal tumor heterogeneity, mutation inhibition due to therapy response and drug resistance (T790M). This study illustrates the challenges associated with selection of a technology platform for EGFR ctDNA analysis in the context of treatment evaluation and drug resistance detection.
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Project description:Advances in the enrichment and analysis of rare cells from the bloodstream have allowed for detection and characterization of circulating tumor cells (CTCs) from patients with cancer. The analysis of CTCs has provided significant insight into the metastatic process. Studies on the biology of CTCs have begun to elucidate the molecular mechanisms of CTC generation, intravasation, survival, interactions with components of the blood, extravasation, and colonization of distant organs. Additionally, the study of CTCs has exposed dramatic intrapatient and interpatient heterogeneity and their evolution over time. In this review, we focus on the current knowledge of CTC biology and the potential clinical implications.
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Project description:The presence of circulating tumor cells (CTCs) in the blood of cancer patients may guide the use of therapy. We investigated how to evaluate a reduction in the number of CTCs after administration of therapy. CTCs were enumerated with the CellSearch system in 111 metastatic breast and 185 metastatic prostate cancer patients before start of a new line of chemotherapy and after initiation of therapy. Different means to express changes in CTC counts were evaluated with respect to overall survival (OS). A static CTC cutoff is the best method to determine whether a therapy is effective. This is exemplified by the highest Cox hazard ratio of 2.1 for OS; three methods to express relative differences performed worse. A lookup table is provided from which the significance of a change in CTCs can be derived. The aim of therapy should be the elimination of all CTCs. A period of 10 to 12 weeks of therapy is needed to reach the treatment effect on CTCs.
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Project description:PURPOSE:The purpose of this study was to directly compare mutation profiles in multiple single circulating tumor cells (CTC) and cell-free DNA (cfDNA) isolated from the same blood samples taken from patients with metastatic breast cancer (MBC). We aimed to determine whether cfDNA would reflect the heterogeneity observed in 40 single CTCs. EXPERIMENTAL DESIGN:CTCs were enumerated by CELLSEARCH. CTC count was compared with the quantity of matched cfDNA and serum CA15-3 and alkaline phosphatase (ALP) in 112 patients with MBC. In 5 patients with ?100 CTCs, multiple individual EpCAM-positive CTCs were isolated by DEPArray and compared with matched cfDNA and primary tumor tissue by targeted next-generation sequencing (NGS) of about 2,200 mutations in 50 cancer genes. RESULTS:In the whole cohort, total cfDNA levels and cell counts (?5 CTCs) were both significantly associated with overall survival, unlike CA15-3 and ALP. NGS analysis of 40 individual EpCAM-positive CTCs from 5 patients with MBC revealed mutational heterogeneity in PIK3CA, TP53, ESR1, and KRAS genes between individual CTCs. In all 5 patients, cfDNA profiles provided an accurate reflection of mutations seen in individual CTCs. ESR1 and KRAS gene mutations were absent from primary tumor tissue and therefore likely either reflect a minor subclonal mutation or were acquired with disease progression. CONCLUSIONS:Our results demonstrate that cfDNA reflects persisting EpCAM-positive CTCs in patients with high CTC counts and therefore may enable monitoring of the metastatic burden for clinical decision-making. Clin Cancer Res; 23(1); 88-96. ©2016 AACR.
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Project description:Renal cell carcinoma is a highly malignant cancer that would benefit from non-invasive innovative markers providing early diagnosis and recurrence detection. Circulating tumor cells are a particularly promising marker of tumor invasion that could be used to improve the management of patients with RCC. However, the extensive genetic and immunophenotypic heterogeneity of cells from RCC and their trend to transition to the mesenchymal phenotype when they circulate in blood constitute a challenge for their sensitive and specific detection. This review analyzes published studies targeting CTC in patients with RCC, in the context of the biological, pathological, and molecular complexity of this particular cancer. Although further analytical and clinical studies are needed to pinpoint the most suitable approach for highly sensitive CTC detection in RCC patients, it is clear that this field can bring a relevant guide to clinicians and help to RCC patients. Furthermore, as described, a particular subtype of RCC-the ccRCC-can be used as a model to study the relationship between cytomorphological and genetic cellular markers of malignancy, an important issue for the study of CTC from any type of solid cancer.
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