Early ctDNA stratifies survival in locally advanced and oligometastatic lung cancer treated with radiotherapy.

PURPOSE: Circulating tumor fraction estimate (ctFE) is a machine learning-derived composite metric of circulating tumor DNA (ctDNA) burden. We hypothesized that pre- and early on-treatment ctFE could robustly risk-stratify patients with locally advanced and oligometastatic non-small cell lung cancer (NSCLC) treated with radiotherapy. EXPERIMENTAL DESIGN: In a prospective phase II clinical trial (NCT03916419), 26 patients with unresectable stage IIB-III NSCLC received MR-guided hypofractionated chemoradiation (chemoRT) followed by immunotherapy. Plasma ctDNA was profiled at baseline and mid-treatment (day 10-14) to derive ctFE and maximum variant allele frequency (Max VAF). A burden-based ctFE threshold derived from baseline samples was applied unchanged to mid-treatment samples and validated in two external cohorts: locally advanced NSCLC treated with chemoRT (LA-RW; n = 94) and oligometastatic NSCLC treated with radiotherapy (OM-RW; n = 309). RESULTS: Pre- and mid-treatment ctFE burden strongly stratified overall survival (OS) and progression-free survival (PFS), markedly outperforming Max VAF and ctFE detectability. Baseline ctFE was prognostic for OS (HR 5.93, p = 0.005) and PFS (HR 11.08, p < 0.001) and remained significant at mid-treatment (OS: HR 7.08; PFS: HR 12.06; both p < 0.001). Early ctFE dynamics defined three molecular response groups with striking OS separation (median OS 60.8 vs. 13.0 vs. 2.9 months; p < 0.001). ctFE remained associated with survival in both validation cohorts. CONCLUSIONS: Early ctFE derived from a clinically available, tumor-naïve ctDNA assay enables noninvasive risk stratification in locally advanced and oligometastatic NSCLC treated with radiotherapy, supporting its use as a practical biomarker for precision treatment adaptation.