Perioperative blood staging based on personalized ctDNA assay for recurrence prediction in NSCLC

Abstract Circulating tumour DNA (ctDNA) is a valuable biomarker for relapse monitoring. However, current personalized approaches are unable to detect emerging clones, and perioperative ctDNA dynamics remain to be defined. We prospectively validated Hi-SECURE, a tumour-informed MRD assay, in 132 NSCLC patients (POEM cohort). Analytical performance was benchmarked against reference standards and a fixed 158-gene panel. A perioperative blood (PB) staging system was proposed and externally validated. Hi-SECURE achieves a limit of detection of 0.005% with a DNA input of 20 ng. At the landmark time point, ctDNA positivity predicted recurrence with a hazard ratio (HR) of 17.14 (95% CI: 3.06–96.11). Hi‑SECURE outperformed the fixed panel, especially in stage IA (25.0% vs 6.8% detection rate, p = 0.020). Pre‑ and postoperative ctDNA status enabled PB staging, which showed strong prognostic discrimination (log rank p < 0.001), was validated across external cohorts. Moreover, Hi-SECURE’s core panel identified drug-resistant mutations (e.g., EGFR -T790M) during follow-up, enabling timely therapeutic adjustments. In conclusion, Hi‑SECURE is a highly sensitive and specific personalized MRD assay. The proposed PB staging system provides a functional, dynamic complement to anatomical TNM staging, enabling precise prognostic stratification and offering potential guidance for adjuvant therapy, resistance monitoring, and immunotherapy candidate selection.