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Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in...
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Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers

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

Deadline for manuscript submissions: closed (15 March 2021) | Viewed by 65031

Special Issue Editor

Dr. Giulia Siravegna

E-Mail Website
Guest Editor
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02114, USA
Interests: gastrointestinal cancers; liquid biopsy; circulating free DNA; targeted therapies; next-generation sequencing; non-invasive monitoring

Special Issue Information

The molecular profile of tumors evolves dynamically in space and time in response to a wide variety of endogenous and exogenous selective pressures, with several implications. Single-shot tissue biopsies do not recapitulate the molecular complexity of a tumor as a whole and cannot inform how the tumor changes as it progresses, as they cannot be performed repeatedly. Furthermore, they are sometimes difficult to obtain and require invasive procedures. Circulating free tumor DNA (ctDNA), a form of blood-based liquid biopsy, has recently emerged as a novel, non-invasive biomarker that may better represent the genetic heterogeneity of cancers. Recent studies have revealed the presence of ctDNA in other bodily fluids, such as urine, saliva, CSF, bronchial washings, and pleural fluids.

Although recent advancements in next-generation sequencing and droplet digital PCR technologies have now allowed sensitive and specific detection of very low frequency alleles in the circulation, a wide-spread use of ctDNA remains challenging.

This issue will highlight the most recent applications of ctDNA in cancer patients’ management, covering both technological and clinical aspects that will improve our understanding of its potentiality, including but not limiting to early diagnosis, detection of minimal residual disease after surgery, and monitoring tumor evolution during different drug schedules.

Dr. Giulia Siravegna
Guest Editor

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 short 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
  • Circulating tumor DNA
  • Circulating free DNA
  • Tumor evolution
  • Tumor heterogeneity
  • Clonal evolution
  • Minimal residual disease
  • Non-invasive
  • Early diagnosis
  • Cancer detection
  • Treatment monitoring
  • Bodily fluids
  • Next generation sequencing
  • Highly sensitive technologies
  • Immunotherapy
  • Targeted therapy
  • Chemotherapy

Published Papers (15 papers)

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Research

Jump to: Review, Other

19 pages, 5168 KiB  
Article
Detection of EGFR Mutations in Plasma cfDNA and Paired CTCs of NSCLC Patients before and after Osimertinib Therapy Using Crystal Digital PCR
by Aliki Ntzifa, Athanasios Kotsakis, Vassilis Georgoulias and Evi Lianidou
Cancers 2021, 13(11), 2736; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112736 - 31 May 2021
Cited by 21 | Viewed by 6986
Abstract
Circulating tumor DNA (ctDNA) analysis has clinical utility in EGFR mutant NSCLC. Circulating tumor cells (CTCs) consist a unique source of information at the cellular level. Digital PCR (dPCR) is a valuable tool for accurate and valid analysis of gene mutations in liquid [...] Read more.
Circulating tumor DNA (ctDNA) analysis has clinical utility in EGFR mutant NSCLC. Circulating tumor cells (CTCs) consist a unique source of information at the cellular level. Digital PCR (dPCR) is a valuable tool for accurate and valid analysis of gene mutations in liquid biopsy analysis. In the present study we detected EGFR mutations in ctDNA and paired CTCs under osimertinib therapy at two time points using crystal dPCR and the naica® system (Stilla Technologies). We quantified mutation allele frequencies (MAF) of EGFR mutations in 91 plasma cfDNA samples of 48 EGFR mutant NSCLC patients and in 64 matched CTC-derived genomic DNA samples, and the FDA-cleared cobas® EGFR mutation test in 80 identical plasma samples. Direct comparison between crystal dPCR and the cobas EGFR assay revealed a high concordance for all EGFR mutations. Our comparison of crystal dPCR results in ctDNA with the corresponding primary tissue has shown a strong correlation. EGFR mutations analysis in paired CTC-derived gDNA revealed a high heterogeneity. Crystal dPCR offers the unique advantages of high analytical sensitivity, precision, and accuracy for detecting and quantifying multiple EGFR mutations in plasma cfDNA and CTCs of NSCLC patients. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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12 pages, 696 KiB  
Article
Circulating Tumor DNA Early Kinetics Predict Response of Metastatic Melanoma to Anti-PD1 Immunotherapy: Validation Study
by Guillaume Herbreteau, Audrey Vallée, Anne-Chantal Knol, Sandrine Théoleyre, Gaëlle Quéreux, Emilie Varey, Amir Khammari, Brigitte Dréno and Marc G. Denis
Cancers 2021, 13(8), 1826; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081826 - 11 Apr 2021
Cited by 9 | Viewed by 1970
Abstract
The ability of early (first weeks of treatment) ctDNA kinetics to identify primary resistance to anti-PD1 immunotherapies was evaluated with a validation cohort of 49 patients treated with anti-PD1 for metastatic BRAF or NRAS-mutated melanoma, alone and pooled with the 53 patients from [...] Read more.
The ability of early (first weeks of treatment) ctDNA kinetics to identify primary resistance to anti-PD1 immunotherapies was evaluated with a validation cohort of 49 patients treated with anti-PD1 for metastatic BRAF or NRAS-mutated melanoma, alone and pooled with the 53 patients from a previously described derivation cohort. BRAF or NRAS mutations were quantified on plasma DNA by digital PCR at baseline and after two or four weeks of treatment. ctDNA kinetics were interpreted according to pre-established biological response criteria. A biological progression (bP, i.e., a significant increase in ctDNA levels) at week two or week four was associated with a lack of benefit from anti-PD1 (4-month PFS = 0%; 1-year OS = 13%; n = 12/102). Patients without initial bP had significantly better PFS and OS (4-month PFS = 78%; 1-year OS = 73%; n = 26/102), as did patients whose ctDNA kinetics were not evaluable, due to low/undetectable baseline ctDNA (4-month PFS = 80%; 1-year OS = 81%; n = 64/102). ctDNA detection at first-line anti-PD1 initiation was an independent prognostic factor for OS and PFS in multivariate analysis. Overall, early ctDNA quantitative monitoring may allow the detection of primary resistances of metastatic melanoma to anti-PD1 immunotherapies. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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12 pages, 1797 KiB  
Article
Early, On-Treatment Levels and Dynamic Changes of Genomic Instability in Circulating Tumor DNA Predict Response to Treatment and Outcome in Metastatic Breast Cancer Patients
by Adriana Aguilar-Mahecha, Josiane Lafleur, Susie Brousse, Olga Savichtcheva, Kimberly A. Holden, Nathan Faulkner, Graham McLennan, Taylor J. Jensen and Mark Basik
Cancers 2021, 13(6), 1331; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13061331 - 16 Mar 2021
Cited by 8 | Viewed by 2534
Abstract
Background: Circulating tumor DNA (ctDNA) offers high sensitivity and specificity in metastatic cancer. However, many ctDNA assays rely on specific mutations in recurrent genes or require the sequencing of tumor tissue, difficult to do in a metastatic disease. The purpose of this study [...] Read more.
Background: Circulating tumor DNA (ctDNA) offers high sensitivity and specificity in metastatic cancer. However, many ctDNA assays rely on specific mutations in recurrent genes or require the sequencing of tumor tissue, difficult to do in a metastatic disease. The purpose of this study was to define the predictive and prognostic values of the whole-genome sequencing (WGS) of ctDNA in metastatic breast cancer (MBC). Methods: Plasma from 25 patients with MBC were taken at the baseline, prior to treatment (T0), one week (T1) and two weeks (T2) after treatment initiation and subjected to low-pass WGS. DNA copy number changes were used to calculate a Genomic Instability Number (GIN). A minimum predefined GIN value of 170 indicated detectable ctDNA. GIN values were correlated with the treatment response at three and six months by Response Evaluation Criteria in Solid Tumours assessed by imaging (RECIST) criteria and with overall survival (OS). Results: GIN values were detectable (>170) in 64% of patients at the baseline and were significantly prognostic (41 vs. 18 months OS for nondetectable vs. detectable GIN). Detectable GIN values at T1 and T2 were significantly associated with poor OS. Declines in GIN at T1 and T2 of > 50% compared to the baseline were associated with three-month response and, in the case of T1, with OS. On the other hand, a rise in GIN at T2 was associated with a poor response at three months. Conclusions: Very early measurements using WGS of cell-free DNA (cfDNA) from the plasma of MBC patients provided a tumor biopsy-free approach to ctDNA measurement that was both predictive of the early tumor response at three months and prognostic. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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13 pages, 3624 KiB  
Article
The Prognostic Impact of Circulating Tumour DNA in Melanoma Patients Treated with Systemic Therapies—Beyond BRAF Mutant Detection
by Gabriela Marsavela, Peter A. Johansson, Michelle R. Pereira, Ashleigh C. McEvoy, Anna L. Reid, Cleo Robinson, Lydia Warburton, Muhammad A. Khattak, Tarek M. Meniawy, Benhur Amanuel, Michael Millward, Nicholas K. Hayward, Melanie R. Ziman, Elin S. Gray and Leslie Calapre
Cancers 2020, 12(12), 3793; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123793 - 16 Dec 2020
Cited by 12 | Viewed by 2242
Abstract
In this study, we evaluated the predictive value of circulating tumour DNA (ctDNA) to inform therapeutic outcomes in metastatic melanoma patients receiving systemic therapies. We analysed 142 plasma samples from metastatic melanoma patients prior to commencement of systemic therapy: 70 were treated with [...] Read more.
In this study, we evaluated the predictive value of circulating tumour DNA (ctDNA) to inform therapeutic outcomes in metastatic melanoma patients receiving systemic therapies. We analysed 142 plasma samples from metastatic melanoma patients prior to commencement of systemic therapy: 70 were treated with BRAF/MEK inhibitors and 72 with immunotherapies. Patient-specific droplet digital polymerase chain reaction assays were designed for ctDNA detection. Plasma ctDNA was detected in 56% of patients prior to first-line anti-PD1 and/or anti-CTLA-4 treatment. The detection rate in the immunotherapy cohort was comparably lower than those with BRAF inhibitors (76%, p = 0.0149). Decreasing ctDNA levels within 12 weeks of treatment was strongly concordant with treatment response (Cohen’s k = 0.798, p < 0.001) and predictive of longer progression free survival. Notably, a slower kinetic of ctDNA decline was observed in patients treated with immunotherapy compared to those on BRAF/MEK inhibitors. Whole exome sequencing of ctDNA was also conducted in 9 patients commencing anti-PD-1 therapy to derive tumour mutational burden (TMB) and neoepitope load measurements. The results showed a trend of high TMB and neoepitope load in responders compared to non-responders. Overall, our data suggest that changes in ctDNA can serve as an early indicator of outcomes in metastatic melanoma patients treated with systemic therapies and therefore may serve as a tool to guide treatment decisions. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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28 pages, 2717 KiB  
Article
Correlating Radiomic Features of Heterogeneity on CT with Circulating Tumor DNA in Metastatic Melanoma
by Andrew B Gill, Leonardo Rundo, Jonathan C. M. Wan, Doreen Lau, Jeries P. Zawaideh, Ramona Woitek, Fulvio Zaccagna, Lucian Beer, Davina Gale, Evis Sala, Dominique-Laurent Couturier, Pippa G. Corrie, Nitzan Rosenfeld and Ferdia A. Gallagher
Cancers 2020, 12(12), 3493; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123493 - 24 Nov 2020
Cited by 18 | Viewed by 3155
Abstract
Clinical imaging methods, such as computed tomography (CT), are used for routine tumor response monitoring. Imaging can also reveal intratumoral, intermetastatic, and interpatient heterogeneity, which can be quantified using radiomics. Circulating tumor DNA (ctDNA) in the plasma is a sensitive and specific biomarker [...] Read more.
Clinical imaging methods, such as computed tomography (CT), are used for routine tumor response monitoring. Imaging can also reveal intratumoral, intermetastatic, and interpatient heterogeneity, which can be quantified using radiomics. Circulating tumor DNA (ctDNA) in the plasma is a sensitive and specific biomarker for response monitoring. Here we evaluated the interrelationship between circulating tumor DNA mutant allele fraction (ctDNAmaf), obtained by targeted amplicon sequencing and shallow whole genome sequencing, and radiomic measurements of CT heterogeneity in patients with stage IV melanoma. ctDNAmaf and radiomic observations were obtained from 15 patients with a total of 70 CT examinations acquired as part of a prospective trial. 26 of 39 radiomic features showed a significant relationship with log(ctDNAmaf). Principal component analysis was used to define a radiomics signature that predicted ctDNAmaf independent of lesion volume. This radiomics signature and serum lactate dehydrogenase were independent predictors of ctDNAmaf. Together, these results suggest that radiomic features and ctDNAmaf may serve as complementary clinical tools for treatment monitoring. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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Review

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9 pages, 893 KiB  
Review
Detection of Tumor Recurrence via Circulating Tumor DNA Profiling in Patients with Localized Lung Cancer: Clinical Considerations and Challenges
by Bryan Ulrich, Anne Pradines, Julien Mazières and Nicolas Guibert
Cancers 2021, 13(15), 3759; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153759 - 26 Jul 2021
Cited by 12 | Viewed by 3370
Abstract
Approximately 30% of patients with non-small-cell lung cancer (NSCLC) present with localized/non-metastatic disease and are eligible for surgical resection or other “treatment with curative intent”. Due to the high prevalence of recurrence after treatment, adjuvant therapy is standard care for most patients. The [...] Read more.
Approximately 30% of patients with non-small-cell lung cancer (NSCLC) present with localized/non-metastatic disease and are eligible for surgical resection or other “treatment with curative intent”. Due to the high prevalence of recurrence after treatment, adjuvant therapy is standard care for most patients. The effect of adjuvant chemotherapy is, however, modest, and new tools are needed to identify candidates for adjuvant treatments (chemotherapy, immunotherapy, or targeted therapies), especially since expanded lung cancer screening programs will increase the rate of patients detected with localized NSCLC. Circulating tumor DNA (ctDNA) has shown strong potential to detect minimal residual disease (MRD) and to guide adjuvant therapies. In this manuscript, we review the technical aspects and performances of the main ctDNA sequencing platforms (TRACERx, CAPP-seq) investigated in this purpose, and discuss the potential of this approach to guide or spare adjuvant therapies after definitive treatment of NSCLC. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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16 pages, 682 KiB  
Review
Signed in Blood: Circulating Tumor DNA in Cancer Diagnosis, Treatment and Screening
by Jacob J. Adashek, Filip Janku and Razelle Kurzrock
Cancers 2021, 13(14), 3600; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143600 - 18 Jul 2021
Cited by 37 | Viewed by 6137
Abstract
With the addition of molecular testing to the oncologist’s diagnostic toolbox, patients have benefitted from the successes of gene- and immune-directed therapies. These therapies are often most effective when administered to the subset of malignancies harboring the target identified by molecular testing. An [...] Read more.
With the addition of molecular testing to the oncologist’s diagnostic toolbox, patients have benefitted from the successes of gene- and immune-directed therapies. These therapies are often most effective when administered to the subset of malignancies harboring the target identified by molecular testing. An important advance in the application of molecular testing is the liquid biopsy, wherein circulating tumor DNA (ctDNA) is analyzed for point mutations, copy number alterations, and amplifications by polymerase chain reaction (PCR) and/or next-generation sequencing (NGS). The advantages of evaluating ctDNA over tissue DNA include (i) ctDNA requires only a tube of blood, rather than an invasive biopsy, (ii) ctDNA can plausibly reflect DNA shedding from multiple metastatic sites while tissue DNA reflects only the piece of tissue biopsied, and (iii) dynamic changes in ctDNA during therapy can be easily followed with repeat blood draws. Tissue biopsies allow comprehensive assessment of DNA, RNA, and protein expression in the tumor and its microenvironment as well as functional assays; however, tumor tissue acquisition is costly with a risk of complications. Herein, we review the ways in which ctDNA assessment can be leveraged to understand the dynamic changes of molecular landscape in cancers. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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24 pages, 782 KiB  
Review
Assessment of Circulating Nucleic Acids in Cancer: From Current Status to Future Perspectives and Potential Clinical Applications
by Gabriella Cirmena, Martina Dameri, Francesco Ravera, Piero Fregatti, Alberto Ballestrero and Gabriele Zoppoli
Cancers 2021, 13(14), 3460; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143460 - 10 Jul 2021
Cited by 15 | Viewed by 5044
Abstract
Current approaches for cancer detection and characterization are based on radiological procedures coupled with tissue biopsies, despite relevant limitations in terms of overall accuracy and feasibility, including relevant patients’ discomfort. Liquid biopsies enable the minimally invasive collection and analysis of circulating biomarkers released [...] Read more.
Current approaches for cancer detection and characterization are based on radiological procedures coupled with tissue biopsies, despite relevant limitations in terms of overall accuracy and feasibility, including relevant patients’ discomfort. Liquid biopsies enable the minimally invasive collection and analysis of circulating biomarkers released from cancer cells and stroma, representing therefore a promising candidate for the substitution or integration in the current standard of care. Despite the potential, the current clinical applications of liquid biopsies are limited to a few specific purposes. The lack of standardized procedures for the pre-analytical management of body fluids samples and the detection of circulating biomarkers is one of the main factors impacting the effective advancement in the applicability of liquid biopsies to clinical practice. The aim of this work, besides depicting current methods for samples collection, storage, quality check and biomarker extraction, is to review the current techniques aimed at analyzing one of the main circulating biomarkers assessed through liquid biopsy, namely cell-free nucleic acids, with particular regard to circulating tumor DNA (ctDNA). ctDNA current and potential applications are reviewed as well. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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20 pages, 714 KiB  
Review
ctDNA to Guide Adjuvant Therapy in Localized Colorectal Cancer (CRC)
by Laura Masfarré, Joana Vidal, Concepción Fernández-Rodríguez and Clara Montagut
Cancers 2021, 13(12), 2869; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13122869 - 8 Jun 2021
Cited by 17 | Viewed by 3978
Abstract
Currently, the standard treatment for patients with localized colorectal cancer (CRC) includes surgical resection followed by adjuvant chemotherapy based on clinicopathological features. Recurrence risk stratification in those patients is of utmost importance to guide clinicians to avoid both under- and overtreatment. Recently, the [...] Read more.
Currently, the standard treatment for patients with localized colorectal cancer (CRC) includes surgical resection followed by adjuvant chemotherapy based on clinicopathological features. Recurrence risk stratification in those patients is of utmost importance to guide clinicians to avoid both under- and overtreatment. Recently, the concept of minimal residual disease (MRD) has emerged as the detection of circulating tumor DNA (ctDNA) carrying tumor-specific genomic or epigenomic alterations in the bloodstream of patients after surgery. Emerging studies described how the detection of MRD is a powerful prognostic biomarker to identify patients at higher risk of recurrence and who will potentially benefit the most from a systemic adjuvant treatment. Based on that unprecedented finding, several clinical trials involving stage II and III CRC patients are ongoing evaluating the impact of ctDNA guided treatment by escalating or deescalating adjuvant chemotherapy based on ctDNA MRD detection. This review provides a critical overview of current perspectives of liquid biopsy in early-stage CRC including technical, biological, and clinical key points, as well as ongoing ctDNA-based clinical trials that ultimately aim to improve clinical outcomes of patients with CRC. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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18 pages, 3973 KiB  
Review
Liquid Biopsy in the Clinical Management of High-Grade Serous Epithelial Ovarian Cancer—Current Use and Future Opportunities
by Lara Paracchini, Maurizio D’Incalci and Sergio Marchini
Cancers 2021, 13(10), 2386; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102386 - 14 May 2021
Cited by 6 | Viewed by 3429
Abstract
The lack of a sensitive and specific biomarker and the limits relating to the single primary tumor sampling make it difficult to monitor high-grade serous epithelial ovarian cancer (HGS-EOC) over time and to capture those alterations that are potentially useful in guiding clinical [...] Read more.
The lack of a sensitive and specific biomarker and the limits relating to the single primary tumor sampling make it difficult to monitor high-grade serous epithelial ovarian cancer (HGS-EOC) over time and to capture those alterations that are potentially useful in guiding clinical decisions. To overcome these issues, liquid biopsy has emerged as a very promising tool for HGS-EOC. The analysis of circulating tumor DNA appears to be feasible and studies assessing specific pathogenic mutations (i.e., TP53) or copy number alterations have shown a sufficient degree of sensitivity and specificity to be realistically used to monitor the effectiveness of antitumor therapy. Liquid biopsy can also provide potential important information on the mechanisms of sensitivity and resistance, e.g., by the determination of the reversion of BRCA mutations. Perspective studies are needed to test whether the application of liquid biopsy will significantly improve HGS-EOC management and patients’ survival. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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15 pages, 1288 KiB  
Review
ctDNA-Based Liquid Biopsy of Cerebrospinal Fluid in Brain Cancer
by Laura Escudero, Francisco Martínez-Ricarte and Joan Seoane
Cancers 2021, 13(9), 1989; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13091989 - 21 Apr 2021
Cited by 28 | Viewed by 5742
Abstract
The correct characterisation of central nervous system (CNS) malignancies is crucial for accurate diagnosis and prognosis and also the identification of actionable genomic alterations that can guide the therapeutic strategy. Surgical biopsies are performed to characterise the tumour; however, these procedures are invasive [...] Read more.
The correct characterisation of central nervous system (CNS) malignancies is crucial for accurate diagnosis and prognosis and also the identification of actionable genomic alterations that can guide the therapeutic strategy. Surgical biopsies are performed to characterise the tumour; however, these procedures are invasive and are not always feasible for all patients. Moreover, they only provide a static snapshot and can miss tumour heterogeneity. Currently, monitoring of CNS cancer is performed by conventional imaging techniques and, in some cases, cytology analysis of the cerebrospinal fluid (CSF); however, these techniques have limited sensitivity. To overcome these limitations, a liquid biopsy of the CSF can be used to obtain information about the tumour in a less invasive manner. The CSF is a source of cell-free circulating tumour DNA (ctDNA), and the analysis of this biomarker can characterise and monitor brain cancer. Recent studies have shown that ctDNA is more abundant in the CSF than plasma for CNS malignancies and that it can be sequenced to reveal tumour heterogeneity and provide diagnostic and prognostic information. Furthermore, analysis of longitudinal samples can aid patient monitoring by detecting residual disease or even tracking tumour evolution at relapse and, therefore, tailoring the therapeutic strategy. In this review, we provide an overview of the potential clinical applications of the analysis of CSF ctDNA and the challenges that need to be overcome in order to translate research findings into a tool for clinical practice. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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29 pages, 1162 KiB  
Review
Liquid Biopsy in Pancreatic Cancer: Are We Ready to Apply It in the Clinical Practice?
by Victoria Heredia-Soto, Nuria Rodríguez-Salas and Jaime Feliu
Cancers 2021, 13(8), 1986; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081986 - 20 Apr 2021
Cited by 39 | Viewed by 5707
Abstract
Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, disease monitoring, evaluation of the response and prognosis. Liquid biopsy (LB), in its different modalities, represents a particularly interesting tool for these purposes, since it is a minimally invasive and risk-free procedure that can detect both the presence of genetic material from the tumor and circulating tumor cells (CTCs) in the blood and therefore distantly reflect the global status of the disease. In this work we review the current status of the main LB modalities (ctDNA, exosomes, CTCs and cfRNAs) for detecting and monitoring PDAC. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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21 pages, 372 KiB  
Review
Detection of Microsatellite Instability: State of the Art and Future Applications in Circulating Tumour DNA (ctDNA)
by Pauline Gilson, Jean-Louis Merlin and Alexandre Harlé
Cancers 2021, 13(7), 1491; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071491 - 24 Mar 2021
Cited by 36 | Viewed by 5274
Abstract
Microsatellite instability (MSI) is a molecular scar resulting from a defective mismatch repair system (dMMR) and associated with various malignancies. MSI tumours are characterized by the accumulation of mutations throughout the genome and particularly clustered in highly repetitive microsatellite (MS) regions. MSI/dMMR status [...] Read more.
Microsatellite instability (MSI) is a molecular scar resulting from a defective mismatch repair system (dMMR) and associated with various malignancies. MSI tumours are characterized by the accumulation of mutations throughout the genome and particularly clustered in highly repetitive microsatellite (MS) regions. MSI/dMMR status is routinely assessed in solid tumours for the initial screening of Lynch syndrome, the evaluation of cancer prognosis, and treatment decision-making. Currently, pentaplex PCR-based methods and MMR immunohistochemistry on tumour tissue samples are the standard diagnostic methods for MSI/dMMR. Other tissue methods such as next-generation sequencing or real-time PCR-based systems have emerged and represent viable alternatives to standard MSI testing in specific settings. The evolution of the standard molecular techniques has offered the opportunity to extend MSI determination to liquid biopsy based on the analysis of cell-free DNA (cfDNA) in plasma. This review aims at synthetizing the standard and emerging techniques used on tumour tissue samples for MSI/dMMR determination. We also provide insights into the MSI molecular techniques compatible with liquid biopsy and the potential clinical consequences for patients with solid cancers. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
26 pages, 1183 KiB  
Review
Circulating Cell-Free DNA in Breast Cancer: Searching for Hidden Information towards Precision Medicine
by Maria Panagopoulou, Manel Esteller and Ekaterini Chatzaki
Cancers 2021, 13(4), 728; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040728 - 10 Feb 2021
Cited by 19 | Viewed by 3453
Abstract
Breast cancer (BC) is a leading cause of death between women. Mortality is significantly raised due to drug resistance and metastasis, while personalized treatment options are obstructed by the limitations of conventional biopsy follow-up. Lately, research is focusing on circulating biomarkers as minimally [...] Read more.
Breast cancer (BC) is a leading cause of death between women. Mortality is significantly raised due to drug resistance and metastasis, while personalized treatment options are obstructed by the limitations of conventional biopsy follow-up. Lately, research is focusing on circulating biomarkers as minimally invasive choices for diagnosis, prognosis and treatment monitoring. Circulating cell-free DNA (ccfDNA) is a promising liquid biopsy biomaterial of great potential as it is thought to mirror the tumor’s lifespan; however, its clinical exploitation is burdened mainly by gaps in knowledge of its biology and specific characteristics. The current review aims to gather latest findings about the nature of ccfDNA and its multiple molecular and biological characteristics in breast cancer, covering basic and translational research and giving insights about its validity in a clinical setting. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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Other

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14 pages, 1067 KiB  
Systematic Review
Circulating Tumor DNA Detection by Digital-Droplet PCR in Pancreatic Ductal Adenocarcinoma: A Systematic Review
by Marisol Huerta, Susana Roselló, Luis Sabater, Ana Ferrer, Noelia Tarazona, Desamparados Roda, Valentina Gambardella, Clara Alfaro-Cervelló, Marina Garcés-Albir, Andrés Cervantes and Maider Ibarrola-Villava
Cancers 2021, 13(5), 994; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13050994 - 27 Feb 2021
Cited by 27 | Viewed by 4262
Abstract
Pancreatic cancer (PC) is one of the most devastating malignant tumors, being the seventh leading cause of cancer-related death worldwide. Researchers and clinicians are endeavoring to develop strategies for the early detection of the disease and the improvement of treatment results. Adequate biopsy [...] Read more.
Pancreatic cancer (PC) is one of the most devastating malignant tumors, being the seventh leading cause of cancer-related death worldwide. Researchers and clinicians are endeavoring to develop strategies for the early detection of the disease and the improvement of treatment results. Adequate biopsy is still challenging because of the pancreas’s poor anatomic location. Recently, circulating tumor DNA (ctDNA) could be identified as a liquid biopsy tool with huge potential as a non-invasive biomarker in early diagnosis, prognosis and management of PC. ctDNA is released from apoptotic and necrotic cancer cells, as well as from living tumor cells and even circulating tumor cells, and it can reveal genetic and epigenetic alterations with tumor-specific and individual mutation and methylation profiles. However, ctDNA sensibility remains a limitation and the accuracy of ctDNA as a biomarker for PC is relatively low and cannot be currently used as a screening or diagnostic tool. Increasing evidence suggests that ctDNA is an interesting biomarker for predictive or prognosis studies, evaluating minimal residual disease, longitudinal follow-up and treatment management. Promising results have been published and therefore the objective of our review is to understand the current role and the future perspectives of ctDNA in PC. Full article
(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)
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