Abstract 3695: A mechanistic model of ctDNA shedding and its relevance for clinical interpretation

Abstract Circulating tumor DNA (ctDNA) in plasma is a key biomarker of tumor dynamics, yet the quantitative relationship between ctDNA levels and clinical variables—such as tumor volume, vascularization, and cell death—remains unclear. The release of ctDNA is thought to depend on cell death mechanisms and the transport of extracellular tumor DNA (excDNA) to blood vessels. We hypothesized that ctDNA concentrations are modulated by the interplay between proximity to blood vessels and excDNA transport kinetics. To test this hypothesis, we develop a spatial mechanistic model to first predict hypoxia-mediated cell death based on blood vessel distribution and then assess the amount of excDNA reaching blood vessels after release, incorporating diffusion and degradation parameters within empirically plausible ranges. In our model, we find that ctDNA concentration in plasma depends on both vascularization and transport dynamics. For example, when diffusion dominates, ctDNA yield is high, and increasing hypoxic cell death from 0 to 80% leads to a tenfold increase in ctDNA. When degradation dominates, ctDNA yield is much lower and the same change in hypoxia results in a tenfold decrease. When both terms are relevant, ctDNA depends nonlinearly on vascularization. These findings suggest that the relationship between blood vessel proximity and ctDNA is highly sensitive to excDNA transport dynamics, underscoring the importance of experimental validation of key parameters, which may vary significantly according to site and release mechanism. Citation Format: Thomas Rachman, Patrick Wagner, William LaFramboise, David Bartlett, Russell Schwartz, Oana Carja. A mechanistic model of ctDNA shedding and its relevance for clinical interpretation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3695.