Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm

Pons-Belda, Oscar D.; Fernandez-Uriarte, Amaia; Diamandis, Eleftherios P.

doi:10.3390/diagnostics11122171

Cited by 34 publications

(24 citation statements)

References 46 publications

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“…As ExoArc is a size-based separation approach, it is likely that circulating cell debris or mitochondria (0.5−3 μm) 70 with similar sizes to platelets/PFs can be removed to reduce the genomic background in the detection of circulating tumor DNA. 71 To extend the separation resolution, ExoArc can couple with other microfluidic modalities like acoustophoresis 72 or membrane filtration 37 to further fractionate EV into finer subpopulations by size (e.g., 50−150 nm, 150−500 nm).…”

Section: Discussionmentioning

confidence: 99%

“…As a proof-of-concept, we successfully identified a 7-miRNA panel for NSCLC detection using ExoArc-processed PPP (AUC ∼ 0.9) from healthy and late stages (III/IV) NSCLC patients, which is comparable to other miRNA studies, − and outperforms circulating antigen tests (AUC ∼ 0.7). , Commonly reported NSCLC miRNAs like miR-21 and miR-125 , that are associated with platelets , are absent in our panel, thus highlighting the importance of identifying tumor-specific miRNA using PFP instead of PPP for cancer diagnosis. As ExoArc is a size-based separation approach, it is likely that circulating cell debris or mitochondria (0.5–3 μm) with similar sizes to platelets/PFs can be removed to reduce the genomic background in the detection of circulating tumor DNA . To extend the separation resolution, ExoArc can couple with other microfluidic modalities like acoustophoresis or membrane filtration to further fractionate EV into finer subpopulations by size (e.g., 50–150 nm, 150–500 nm).…”

Section: Discussionmentioning

confidence: 99%

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High-Throughput Microfluidic Extraction of Platelet-free Plasma for MicroRNA and Extracellular Vesicle Analysis

Leong,

Lok,

Goh

et al. 2024

ACS Nano

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Cell-free RNAs and extracellular vesicles (EVs) are valuable biomarkers in liquid biopsies, but they are prone to preanalytical variabilities such as nonstandardized centrifugation or ex vivo blood degradation. Herein, we report a high-throughput and labelfree inertial microfluidic device (ExoArc) for isolation of platelet-free plasma from blood for RNA and EV analysis. Unlike conventional inertial microfluidic devices widely used for cell sorting, a submicrometer size cutoff (500 nm) was achieved which completely removed all leukocytes, RBCs, platelets, and cellular debris based on differential lateral migration induced by Dean vortices. The single-step operation also reduced platelet-associated miRNAs (∼2-fold) compared to centrifugation. We clinically validated ExoArc for plasma miRNA profiling (39 samples) and identified a 7-miRNA panel that detects non-small cell lung cancer with ∼90% sensitivity. ExoArc was also coupled with size exclusion chromatography (SEC) to isolate EVs within 50 min with ∼10-fold higher yield than ultracentrifugation. As a proof-of-concept for EV-based transcriptomics analysis, we performed miRNA analysis in healthy and type 2 diabetes mellitus (T2DM) subjects (n = 3 per group) by coupling ExoArc and ExoArc+SEC with quantitative polymerase chain reaction (RT-qPCR) assay. Among 293 miRNAs detected, plasmas and EVs showed distinct differentially expressed miRNAs in T2DM subjects. We further demonstrated automated in-line EV sorting from low volume culture media for continuous EV monitoring. Overall, the developed ExoArc offers a convenient centrifugation-free workflow to automate plasma and EV isolation for point-of-care diagnostics and quality control in EV manufacturing.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

High-Throughput Microfluidic Extraction of Platelet-free Plasma for MicroRNA and Extracellular Vesicle Analysis

Leong,

Lok,

Goh

et al. 2024

ACS Nano

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“…Due to the low tumor fraction of cfDNA in early-stage cancers [ 11 , 12 , 13 , 14 , 15 ] it is questionable whether liquid biopsies can be used in population screening [ 16 ]. In this study, we modeled the early detection of breast cancer using liquid biopsies that were either able or unable to detect DCIS, the nonobligate precursor lesion of invasive breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…However, due to the low tumor fraction of cfDNA in early-stage cancers [ 11 , 12 , 13 , 14 , 15 ], the suitability of liquid biopsies for early detection is debated [ 16 , 17 ]. There are currently no identified clinical tumor markers for ductal carcinoma in situ (DCIS) [ 18 ], the nonobligate precursor lesion of invasive breast cancer.…”

Section: Introductionmentioning

confidence: 99%

The Early Detection of Breast Cancer Using Liquid Biopsies: Model Estimates of the Benefits, Harms, and Costs

Poort

Ravesteyn

Broek

et al. 2022

Cancers

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Breast cancer screening is associated with harms, such as false-positives and overdiagnoses, and, thus, novel screen tests can be considered. Liquid biopsies have been proposed as a novel method for the early detection of cancer, but low cell-free DNA tumor fraction might pose a problem for the use in population screening. Using breast cancer microsimulation model MISCAN-Fadia, we estimated the outcomes of using liquid biopsies in breast cancer screening in women aged 50 to 74 in the United States. For varying combinations of test sensitivity and specificity, we quantify the impact of the use of liquid biopsies on the harms and benefits of screening, and we estimate the maximum liquid biopsy price for cost-effective implementation in breast cancer screening at a cost-effectiveness threshold of USD 50,000. We investigate under what conditions liquid biopsies could be a suitable alternative to digital mammography and compare these conditions to a CCGA substudy. Outcomes were compared to digital mammography screening, and include mortality reduction, overdiagnoses, quality-adjusted life-years (QALYs), and the maximum price of a liquid biopsy for cost-effective implementation. When liquid biopsies are unable to detect DCIS, a large proportion of overdiagnosed cases is prevented but overall breast cancer mortality reduction and quality of life are lower, and costs are higher compared to digital mammography screening. Liquid biopsies prices should be restricted to USD 187 per liquid biopsy depending on test performance. Overall, liquid biopsies that are unable to detect ductal carcinoma in situ (DCIS) need to be able to detect small, early-stage tumors, with high specificity, at low costs in order to be an alternative to digital mammography. Liquid biopsies might be more suitable as an addition to digital mammography than as an alternative.

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“…[ 2 , 81 , 82 , 83 ]). In-depth profiling of cancer-specific mutations in cfDNA may enable the development of pan-cancer screening tests for at-risk groups or unsuspected healthy populations, thereby allowing early detection and prompt treatment (reviewed in [ 8 , 84 , 85 ]). As the level of cancer-specific mutations shows a high correlation with tumor size, quantitative measurements could be used as an indicator of disease stage and may even predict the clinical outcome of patients.…”

Section: Sequence Analysis Of Cfdnamentioning

confidence: 99%

New Perspectives on the Importance of Cell-Free DNA Biology

et al. 2022

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Body fluids are constantly replenished with a population of genetically diverse cell-free DNA (cfDNA) fragments, representing a vast reservoir of information reflecting real-time changes in the host and metagenome. As many body fluids can be collected non-invasively in a one-off and serial fashion, this reservoir can be tapped to develop assays for the diagnosis, prognosis, and monitoring of wide-ranging pathologies, such as solid tumors, fetal genetic abnormalities, rejected organ transplants, infections, and potentially many others. The translation of cfDNA research into useful clinical tests is gaining momentum, with recent progress being driven by rapidly evolving preanalytical and analytical procedures, integrated bioinformatics, and machine learning algorithms. Yet, despite these spectacular advances, cfDNA remains a very challenging analyte due to its immense heterogeneity and fluctuation in vivo. It is increasingly recognized that high-fidelity reconstruction of the information stored in cfDNA, and in turn the development of tests that are fit for clinical roll-out, requires a much deeper understanding of both the physico-chemical features of cfDNA and the biological, physiological, lifestyle, and environmental factors that modulate it. This is a daunting task, but with significant upsides. In this review we showed how expanded knowledge on cfDNA biology and faithful reverse-engineering of cfDNA samples promises to (i) augment the sensitivity and specificity of existing cfDNA assays; (ii) expand the repertoire of disease-specific cfDNA markers, thereby leading to the development of increasingly powerful assays; (iii) reshape personal molecular medicine; and (iv) have an unprecedented impact on genetics research.

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Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm

Cited by 34 publications

References 46 publications

High-Throughput Microfluidic Extraction of Platelet-free Plasma for MicroRNA and Extracellular Vesicle Analysis

High-Throughput Microfluidic Extraction of Platelet-free Plasma for MicroRNA and Extracellular Vesicle Analysis

The Early Detection of Breast Cancer Using Liquid Biopsies: Model Estimates of the Benefits, Harms, and Costs

New Perspectives on the Importance of Cell-Free DNA Biology

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