Plasma cell-free chromatin state kinetics as a predictor of early treatment response in gastric cancer.

e16073 Background: Early and reliable assessment of treatment response across heterogeneous gastric cancer (GC) regimens remains an unmet need. Circulating cell-free chromatin retains tissue-encoded epigenetic information that can be quantified longitudinally. We developed a plasma-based framework to compute cell-free epigenetic clearance rates from serial cell-free chromatin signals (integrating six core histone modifications) and evaluated its value for cross-regimen response assessment, benchmarking against standard clinical evaluation. Methods: We profiled a prospective cohort of 31 GC patients sampled at six longitudinal timepoints across peri-treatment and peri-operative windows, treated with XELOX chemotherapy, RC48 (HER2-targeted antibody–drug conjugate), or JS001 (PD-1 blockade). Using cf-EpiTracing plasma chromatin profiling (≤100 µL plasma; automated workflow), we quantified trajectory-based clearance kinetics and compared regimen-specific response patterns as assessed by (i) routine clinical evaluation (radiographic/clinical assessment and peri-operative pathology including ypTNM where available) and (ii) cf-EpiTracing-derived clearance metrics. Associations with recurrence and prognosis were analyzed during follow-up. Results: Clinical evaluation revealed differential response patterns across regimens in this cohort, and plasma cell-free epigenetic clearance kinetics recapitulated these between-regimen differences, enabling early discrimination of higher- versus lower-benefit treatment courses. Across regimens, clearance kinetics separated respondents from non-respondents at early on-treatment timepoints and provided an orthogonal, quantitative measure consistent with clinical response assessment. In peri-operative settings, clearance-derived metrics supported pre-surgical prediction of pathological outcomes, including identification of ypT0N0M0 status. Clearance trajectories further stratified recurrence risk; 5/31 patients developed recurrence within two-year follow-up. In a small independent pilot validation, the clearance metric showed concordant directionality with clinical outcomes. Conclusions: Longitudinal plasma epigenetic clearance kinetics offer a minimally invasive, quantitative approach for early response monitoring and for comparing treatment effectiveness across GC regimens in a small clinical cohort, while also providing preliminary real-world evidence on outcomes under newer regimens. Clinical trial information: CTR20233553.