Speaker
Description
Plasma cell-free DNA (cfDNA) shows promise as a predictive biomarker of treatment resistance in cancer patients. However, the mechanisms governing its production, fragmentation, elimination, and their relationships with tumor burden and disease progression, remain poorly understood. We developed a mechanistic model jointly describing the dynamics of short (75-<580 bp) and long (≥580-1650 bp) cfDNA fragments alongside tumor kinetics in 112 advanced cancer patients receiving immune checkpoint inhibition, using a population modeling approach, to characterize inter-individual variability in cfDNA kinetic parameters. The model captured complex longitudinal cfDNA patterns, including early treatmentassociated spikes. Analysis revealed substantial inter-patient variability and demonstrated a 7.4-fold higher shedding rate for short versus long fragments. A model-derived parameter estimated at 6 weeks of treatment—reflecting increased release or reduced elimination of short fragments—was significantly associated with progression-free survival (PFS, HR=1.6, 95% CI: 1.2–2.2, p=0.001). Incorporating this parameter to baseline clinical variables significantly improved PFS prediction (C-index: from 0.78 [95% CI: 0.73-0.89] to 0.80 [95% CI: 0.74-0.90], p<0.0001). This framework provides quantitative insights into cfDNA biology and o ers a noninvasive approach for early prediction of treatment resistance, with implications for adaptive therapeutic strategies from longitudinal liquid biopsy.
Bibliography
@article{nguyen_phuong_computational_2025,
title = {Computational {Modeling} for {Circulating} {Cell}-{Free} {DNA} in {Clinical}
{Oncology}},
url = {https://ascopubs.org/doi/10.1200/CCI-24-00224},
doi = {10.1200/CCI-24-00224},
number = {9},
urldate = {2025-04-07},
journal = {JCO Clinical Cancer Informatics},
publisher = {Wolters Kluwer},
author = {Nguyen Phuong, Linh and Salas, Sébastien and Benzekry, Sébastien},
month = feb,
year = {2025},
pages = {e2400224},
}
@unpublished{nguyen_phuong_schism_2026,
title = {The {SChISM} study: {Circulating} cell-free {DNA} size profiles as
predictors of progression in advanced carcinoma treated with immune-checkpoint
inhibitors},
shorttitle = {The {SChISM} study},
url = {https://inria.hal.science/hal-05238567},
urldate = {2026-03-09},
author = {Nguyen Phuong, Linh and Fina, Frederic and Greillier, Laurent and
Tomasini, Pascale and Deville, Jean-Laurent and Zakrasjek, Romain and Della-Negra,
Lucie and Boutonnet, Audrey and Ginot, Frédéric and Garcia, Jean-Charles and
Benzekry, Sébastien and Salas, Sébastien},
month = feb,
year = {2026},
}
@unpublished{nguyen_phuong_mechanistic_2025,
title = {Mechanistic {Modeling} of {cfDNA} {Fragmentome} {Dynamics} {Predicts}
{Progression} to {Immunotherapy}},
url = {https://inria.hal.science/hal-05241421},
urldate = {2026-03-09},
author = {Nguyen Phuong, Linh and Fina, Frédéric and Greillier, Laurent and
Tomasini, Pascale and Deville, Jean-Laurent and Boutonnet, Audrey and Ginot, Frédéric
and Garcia, Jean-Charles and Salas, Sebastien and Benzekry, Sébastien},
year = {2025},
keywords = {liquid biopsy, cell-free DNA, biomarker, cancer, mechanistic
modeling., size profile, tumor size},
}
