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Cancers
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Liquid Biopsy in Breast Cancer
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Liquid Biopsy in Breast Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 15571

Special Issue Editors

Prof. Dr. Dimitrios Mavroudis

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Guest Editor
Head, Department of Medical Oncology, University of Crete Medical School, Heraklion, Greece
Interests: biology of early breast cancer; clinical trials; circulating tumor cells; adjuvant chemotherapy; chemotherapy for metastatic breast cancer; endocrine resistance; mTOR inhibitors; CDK4/6 inhibitors
Special Issues, Collections and Topics in MDPI journals
Dr. Maria Papadaki

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Guest Editor
Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece
Interests: circulating tumor cells (CTCs); biomarkers; tumor heterogeneity; anti-tumor immunity; peripheral immune response; tumor immune evasion; immune checkpoints; breast cancer; lung cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Liquid biopsy is increasingly being recognized as a valuable non-invasive tool for the management of patients with solid tumors. It mainly includes the analysis of intact circulating tumor cells (CTCs), nucleic acids such as circulating tumor DNA (ctDNA) and circulating miRNAs, as well as exosomes/extracellular vesicles. CTC enumeration emerged as the first liquid biopsy analyte with clinical relevance in breast cancer (BC) as early as 2004, and since then, large clinical trials have verified the role of CTCs in the prediction of relapse or disease progression, as well as the survival of metastatic BC patients. Beyond enumeration, CTC characterization at the protein/RNA/DNA level has been widely used to provide information about the tumor heterogeneity and to uncover novel mechanisms of metastasis and resistance to current therapies. Moreover, different liquid biopsy analytes provide independent yet complementary information, thus their combined use can better reflect tumor heterogeneity and improve disease monitoring in real time. The analysis of ctDNA has gained significant attention mainly due to its high reproducibility, and it is increasingly utilized in BC clinical trials to monitor treatment outcomes. Recently, a PIK3CA companion diagnostic assay was approved by the FDA to detect PIK3CA mutations in the ctDNA of BC patients eligible for treatment with alpelisib. Other liquid biopsy analytes such as circulating miRNAs and exosomes/extracellular vesicles are also widely used in BC research, but their clinical validity and utility are still under investigation.

This Special Issue of Cancers welcomes contributions that present new data and address or discuss liquid biopsy biomarkers with prognostic and/or predictive relevance in BC. This Special Issue will also focus on translational research that will shed light onto the role of CTCs and other liquid biopsy analytes in BC metastatic progression, as well as resistance to endocrine therapy, chemotherapy, or targeted therapies. Studies including the development of new liquid biopsy assays are also welcome. Of great interest are reports on the longitudinal assessment of liquid biopsy, as well as studies utilizing liquid biopsy to identify potential novel therapeutic targets.

Prof. Dr. Dimitrios Mavroudis
Dr. Maria Papadaki
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • liquid biopsy
  • liquid biomarkers
  • precision oncology
  • disease monitoring
  • treatment monitoring
  • tumor heterogeneity
  • circulating tumor cells (CTCs)
  • circulating tumor DNA (ctDNA)
  • circulating miRNAs
  • exosomes
  • extracellular vesicles (EVs)

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Related Special Issue

Published Papers (6 papers)

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Research

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15 pages, 3357 KiB  
Article
Improved Characterization of Circulating Tumor Cells and Cancer-Associated Fibroblasts in One-Tube Assay in Breast Cancer Patients Using Imaging Flow Cytometry
by Anna Muchlińska, Robert Wenta, Wiktoria Ścińska, Aleksandra Markiewicz, Grażyna Suchodolska, Elżbieta Senkus, Anna J. Żaczek and Natalia Bednarz-Knoll
Cancers 2023, 15(16), 4169; https://doi.org/10.3390/cancers15164169 - 18 Aug 2023
Cited by 2 | Viewed by 2115
Abstract
Circulating tumor cells (CTCs) and circulating cancer-associated fibroblasts (cCAFs) have been individually considered strong indicators of cancer progression. However, technical limitations have prevented their simultaneous analysis in the context of CTC phenotypes different from epithelial. This study aimed to analyze CTCs and cCAFs [...] Read more.
Circulating tumor cells (CTCs) and circulating cancer-associated fibroblasts (cCAFs) have been individually considered strong indicators of cancer progression. However, technical limitations have prevented their simultaneous analysis in the context of CTC phenotypes different from epithelial. This study aimed to analyze CTCs and cCAFs simultaneously in the peripheral blood of 210 breast cancer patients using DAPI/pan-keratin (K)/vimentin (V)/alpha-SMA/CD29/CD45/CD31 immunofluorescent staining and novel technology—imaging flow cytometry (imFC). Single and clustered CTCs of different sizes and phenotypes (i.e., epithelial phenotype K+/V− and epithelial–mesenchymal transition (EMT)-related CTCs, such as K+/V+, K−/V+, and K−/V−) were detected in 27.6% of the samples and correlated with metastases. EMT-related CTCs interacted more frequently with normal cells and tended to occur in patients with tumors progressing during therapy, while cCAFs coincided with CTCs (mainly K+/V− and K−/V−) in seven (3.3%) patients and seemed to correlate with the presence of metastases, particularly visceral ones. This study emphasizes the advantages of imFC in the field of liquid biopsy and highlights the importance of multimarker-based analysis of different subpopulations and phenotypes of cancer progression-related cells, i.e., CTCs and cCAFs. The co-detection of CTCs and cCAFs might improve the identification of patients at higher risk of progression and their monitoring during therapy. Full article
(This article belongs to the Special Issue Liquid Biopsy in Breast Cancer)
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18 pages, 6461 KiB  
Article
Cell State and Cell Type: Deconvoluting Circulating Tumor Cell Populations in Liquid Biopsies by Multi-Omics
by Lisa Welter, Serena Zheng, Sonia Maryam Setayesh, Michael Morikado, Arushi Agrawal, Rafael Nevarez, Amin Naghdloo, Milind Pore, Nikki Higa, Anand Kolatkar, Jana-Aletta Thiele, Priyanka Sharma, Halle C. F. Moore, Jennifer K. Richer, Anthony Elias, Kenneth J. Pienta, Amado J. Zurita, Mitchell E. Gross, Stephanie N. Shishido, James Hicks, Carmen Ruiz Velasco and Peter Kuhnadd Show full author list remove Hide full author list
Cancers 2023, 15(15), 3949; https://doi.org/10.3390/cancers15153949 - 3 Aug 2023
Cited by 3 | Viewed by 2357
Abstract
Bi-directional crosstalk between the tumor and the tumor microenvironment (TME) has been shown to increase the rate of tumor evolution and to play a key role in neoplastic progression, therapeutic resistance, and a patient’s overall survival. Here, we set out to use a [...] Read more.
Bi-directional crosstalk between the tumor and the tumor microenvironment (TME) has been shown to increase the rate of tumor evolution and to play a key role in neoplastic progression, therapeutic resistance, and a patient’s overall survival. Here, we set out to use a comprehensive liquid-biopsy analysis to study cancer and specific TME cells in circulation and their association with disease status. Cytokeratin+, CD45- circulating rare cells (CRCs) from nine breast and four prostate cancer patients were characterized through morphometrics, single-cell copy number analysis, and targeted multiplexed proteomics to delineate cancer cell lineage from other rare cells originating in the TME. We show that we can detect epithelial circulating tumor cells (EPI.CTC), CTCs undergoing epithelial-to-mesenchymal transition (EMT.CTC) and circulating endothelial cells (CECs) using a universal rare event detection platform (HDSCA). Longitudinal analysis of an index patient finds that CTCs are present at the time of disease progression, while CECs are predominately present at the time of stable disease. In a small cohort of prostate and breast cancer patients, we find high inter-patient and temporal intra-patient variability in the expression of tissue specific markers such as ER, HER2, AR, PSA and PSMA and EpCAM. Our study stresses the importance of the multi-omic characterization of circulating rare cells in patients with breast and prostate carcinomas, specifically highlighting overlapping and cell type defining proteo-genomic characteristics of CTCs and CECs. Full article
(This article belongs to the Special Issue Liquid Biopsy in Breast Cancer)
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14 pages, 1577 KiB  
Article
Estimation of ALU Repetitive Elements in Plasma as a Cost-Effective Liquid Biopsy Tool for Disease Prognosis in Breast Cancer
by Madhumathy G. Nair, Rakesh S. Ramesh, Chandrakala M. Naidu, Apoorva D. Mavatkar, Snijesh V. P., Vishakha Ramamurthy, Vidya M. Somashekaraiah, Anupama C. E., Kiruthiga Raghunathan, Anuradha Panigrahi, Manjula Das, Sujan K. Dhar and Jyothi S. Prabhu
Cancers 2023, 15(4), 1054; https://doi.org/10.3390/cancers15041054 - 7 Feb 2023
Cited by 4 | Viewed by 3630
Abstract
Background: Liquid biopsy is widely recognized as an efficient diagnostic method in oncology for disease detection and monitoring. Though the examination of circulating tumor cells (CTC) is mostly implemented for the assessment of genomic aberrations, the need of complex methodologies for their detection [...] Read more.
Background: Liquid biopsy is widely recognized as an efficient diagnostic method in oncology for disease detection and monitoring. Though the examination of circulating tumor cells (CTC) is mostly implemented for the assessment of genomic aberrations, the need of complex methodologies for their detection has impeded its acceptance in low-resource settings. We evaluated cell-free DNA (cfDNA) as a liquid biopsy tool and investigated its utility in breast cancer patients. Methods: Total cell-free DNA was extracted from the plasma of breast cancer patients (n = 167) with a median follow-up of more than 5 years, at various stages of the disease. Quantitative PCR was performed to estimate the copy numbers of two fractions of ALU repetitive elements (ALU 115 and ALU 247), and DNA integrity (DI) was calculated as the ratio of ALU 247/115. Mutations in TP53 and PIK3CA in the cfDNA were estimated by next-gen sequencing (NGS) in a subset of samples. Associations of the levels of both the ALU fragments with various clinico-pathological factors and disease-free survival at various stages were examined. Nomogram models were constructed with clinical variables and ALU 247 levels to predict disease-free survival and the best performing model was evaluated by decision curve analysis. Results: DI and ALU 247 levels were significantly lower (p < 0.0001) in the post-operative plasma when compared to their pre-surgery levels. DI and ALU 247 were found to be significantly higher in patients with metastasis (p < 0.05). Patients with higher levels of ALU 247 in their post-operative plasma had significant poor disease-free survival (p = 0.005). Higher levels of ALU 247 in the circulation also correlated with low tumor-infiltrating lymphocytes (TIL) within their primary tumors in the ER-negative breast cancer subtype (p = 0.01). Cox proportional hazard analysis confirmed ALU 247 as an independent variable of disease-free survival both in univariate and multivariate analysis [HR 1.3 (95% CI 1.047 to 1.613, p = 0.017)]. The nomogram model showed that the addition of ALU 247 with other variables significantly improved (C-index 0.823) the predictive ability of the model. Conclusion: Our results confirm the utility of cfDNA as an evolving liquid biopsy tool for molecular analysis. Evaluation of larger fragments of cfDNA estimated through ALU 247 can provide vital information concurrent with the pathological process of disease evolution in breast cancer and warrants expansion to other cancer types. Full article
(This article belongs to the Special Issue Liquid Biopsy in Breast Cancer)
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16 pages, 2297 KiB  
Article
Investigating the Role of CTCs with Stem/EMT-like Features in Metastatic Breast Cancer Patients Treated with Eribulin Mesylate
by Maria A. Papadaki, Anastasia Mala, Aikaterini C. Merodoulaki, Maria Vassilakopoulou, Dimitrios Mavroudis and Sofia Agelaki
Cancers 2022, 14(16), 3903; https://doi.org/10.3390/cancers14163903 - 12 Aug 2022
Cited by 7 | Viewed by 1681
Abstract
We herein aimed to assess the effect of eribulin mesylate on the cancer stem cell (CSC)/EMT-like phenotype of CTCs, and to investigate the prognostic role of CTC detection and monitoring for eribulin-treated BC patients. Peripheral blood was obtained at baseline (n = [...] Read more.
We herein aimed to assess the effect of eribulin mesylate on the cancer stem cell (CSC)/EMT-like phenotype of CTCs, and to investigate the prognostic role of CTC detection and monitoring for eribulin-treated BC patients. Peripheral blood was obtained at baseline (n = 42 patients) and 8 days after treatment initiation (C1D8: n = 22), and on disease progression (PD: n = 26). PBMCs cytospins were immunofluorescently stained for Cytokeratins/ALDH1/TWIST1/DAPI and analyzed via Ariol microscopy. CTCs were detected in 33.3%, 27.3%, and 23.1% of patients at baseline, C1D8, and PD, respectively. Accordingly, partial-EMT+ CTCs represented 61.3%, 0%, and 37.5% of total CTCs, whereas the CSC-like phenotype was consistently expressed by 87.5%, 75%, and 91.7% of CTCs at the respective time points. Interestingly, the CSC+/partial-EMT+ subset prevailed at baseline, but it was eradicated on C1D8 and resurged again during PD. CTC detection at baseline was associated with reduced PFS (p = 0.007) and OS (p = 0.005), and was an independent risk factor for death (HR: 3.779, p = 0.001; multivariate analysis). The CSC+/partial-EMT+ CTCs emerged as the only subset with adverse prognostic significance, while CTC monitoring during eribulin therapy improved the prediction of disease progression. These results indicate that resistant CTC subsets persevere eribulin treatment and highlight the prognostic implications of CTC analyses for eribulin-treated BC patients. Full article
(This article belongs to the Special Issue Liquid Biopsy in Breast Cancer)
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12 pages, 2036 KiB  
Article
Detection and Characterization of Estrogen Receptor α Expression of Circulating Tumor Cells as a Prognostic Marker
by Retno Ningsi, Maha Elazezy, Luisa Stegat, Elena Laakmann, Sven Peine, Sabine Riethdorf, Volkmar Müller, Klaus Pantel and Simon A. Joosse
Cancers 2022, 14(11), 2621; https://doi.org/10.3390/cancers14112621 - 25 May 2022
Cited by 4 | Viewed by 1917
Abstract
CTCs have increasingly been used as a liquid biopsy analyte to obtain real-time information on the tumor through minimally invasive blood analyses. CTCs allow for the identification of proteins relevant for targeted therapies. Here, we evaluated the expression of estrogen receptors (ER) in [...] Read more.
CTCs have increasingly been used as a liquid biopsy analyte to obtain real-time information on the tumor through minimally invasive blood analyses. CTCs allow for the identification of proteins relevant for targeted therapies. Here, we evaluated the expression of estrogen receptors (ER) in CTCs of patients with metastatic breast cancer. From sixty metastatic breast cancer patients who had ER-positive primary tumors (range of 1–70% immunostaining) at initial cancer diagnosis, 109 longitudinal blood samples were prospectively collected and analyzed using the CellSearch System in combination with the ERα monoclonal murine ER-119.3 antibody. Prolonged cell permeabilization was found to be required for proper staining of nuclear ER in vitro. Thirty-one cases were found to be CTC-positive; an increased number of CTCs during endocrine and chemotherapy was correlated with disease progression, whereas a decrease or stable amount of CTC number (<5) during treatment was correlated with a better clinical outcome. Survival analyses further indicate a positive association of CTC-status with progression-free survival (HR, 66.17; 95%CI, 3.66–195.96; p = 0.0045) and overall survival (HR, 6.21; 95%CI, 2.66–14.47; p < 0.0001). Only one-third of CTC-positive breast cancer patients, who were initially diagnosed with ER-positive primary tumors, harbored ER-positive CTCs at the time of metastasis, and even in those patients, both ER-positive and ER-negative CTCs were found. CTC-positivity was correlated with a shorter relapse-free survival. Remarkably, ER-negative CTCs were frequent despite initial ER-positive status of the primary tumor, suggesting a switch of ER phenotype or selection of minor ER-negative clones as a potential mechanism of escape from ER-targeting therapy. Full article
(This article belongs to the Special Issue Liquid Biopsy in Breast Cancer)
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Review

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14 pages, 742 KiB  
Review
Autotaxin in Breast Cancer: Role, Epigenetic Regulation and Clinical Implications
by Andrianna Drosouni, Maria Panagopoulou, Vassilis Aidinis and Ekaterini Chatzaki
Cancers 2022, 14(21), 5437; https://doi.org/10.3390/cancers14215437 - 4 Nov 2022
Cited by 11 | Viewed by 2720
Abstract
Autotaxin (ATX), the protein product of Ectonucleotide Pyrophosphatase Phosphodiesterase 2 (ENPP2), is a secreted lysophospholipase D (lysoPLD) responsible for the extracellular production of lysophosphatidic acid (LPA). ATX-LPA pathway signaling participates in several normal biological functions, but it has also been connected [...] Read more.
Autotaxin (ATX), the protein product of Ectonucleotide Pyrophosphatase Phosphodiesterase 2 (ENPP2), is a secreted lysophospholipase D (lysoPLD) responsible for the extracellular production of lysophosphatidic acid (LPA). ATX-LPA pathway signaling participates in several normal biological functions, but it has also been connected to cancer progression, metastasis and inflammatory processes. Significant research has established a role in breast cancer and it has been suggested as a therapeutic target and/or a clinically relevant biomarker. Recently, ENPP2 methylation was described, revealing a potential for clinical exploitation in liquid biopsy. The current review aims to gather the latest findings about aberrant signaling through ATX-LPA in breast cancer and discusses the role of ENPP2 expression and epigenetic modification, giving insights with translational value. Full article
(This article belongs to the Special Issue Liquid Biopsy in Breast Cancer)
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