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Modeling EV Kinetics for Use in Early Cancer Detection.

ABSTRACT: Tumor-derived extracellular vesicles (EVs) represent promising biomarkers for monitoring cancers. Technological advances have improved the ability to measure EV reliably in blood using protein, RNA, or lipid detection methods. However, it is less clear how efficacious current EV assays are for the early detection of small and thus curable tumors. Here, a mathematical model is developed to estimate key parameter values and future requirements for EV testing. Tumor volumes in mice correlate well with increases in total number of circulating EV allowing the researchers to calculate EV shed rates for four different published cancer models. Model extrapolations to human physiology show good agreement with published clinical data. Specifically, it is shown that current bulk EV detection systems are ≈10⁴ -fold too insensitive to detect human cancers of ≈1 cm³ . Conversely, it is predicted that emerging single EV methods will allow blood-based detection of cancers of <1 mm³ in humans.

SUBMITTER: Ferguson S

PROVIDER: S-EPMC7658022 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Modeling EV Kinetics for Use in Early Cancer Detection.

Ferguson Scott S Weissleder Ralph R

Advanced biosystems 20200512 12

Tumor-derived extracellular vesicles (EVs) represent promising biomarkers for monitoring cancers. Technological advances have improved the ability to measure EV reliably in blood using protein, RNA, or lipid detection methods. However, it is less clear how efficacious current EV assays are for the early detection of small and thus curable tumors. Here, a mathematical model is developed to estimate key parameter values and future requirements for EV testing. Tumor volumes in mice correlate well w ...[more]

PMID: 32394646

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Project description:The benefits of cancer early detection depend on various factors, including cancer type, screening method performance, stage at diagnosis, and subsequent treatment. Although numerous studies have evaluated the effectiveness of screening interventions for identifying cancer at earlier stages, there is no quantitative analysis that studies the optimal early detection time interval that results in the greatest mortality benefit; such data could serve as a target and benchmark for cancer early detection strategies. In this study, we focus on pancreatic ductal adenocarcinoma (PDAC), a cancer known for its lack of early symptoms. Consequently, it is most often detected at late stages when the 5-year survival rate is only 3%. We developed a PDAC population model that simulates an individual patient's age and stage at diagnosis, while replicating overall US cancer incidence and mortality rates. The model includes "cancer sojourn time," serving as a proxy for the speed of cancer progression, with shorter times indicating rapid progression and longer times indicating slower progression. In our PDAC model, our hypothesis was that earlier cancer detection, potentially through a hypothetical screening intervention in the counterfactual analysis, would yield reduced mortality as compared to a no-screening group. We found that the benefits of early detection, such as increased life-years gained, are greater when the sojourn time is shorter, reaching their maximum when identification is made 4-6 years prior to clinical diagnosis (e.g., when a symptomatic diagnosis is made). However, when early detection occurs even earlier, for example 6-10 years prior to clinical diagnosis, the benefits significantly diminish for shorter sojourn time cancers, and level off for longer sojourn time cancers. Our study clarifies the potential benefits of PDAC early detection that explicitly incorporates individual patient heterogeneity in cancer progression and identifies quantitative benchmarks for future interventions.

Dataset Information

Modeling EV Kinetics for Use in Early Cancer Detection.

Publications

Modeling EV Kinetics for Use in Early Cancer Detection.

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