Tumor-naïve pre-surgical ctDNA detection is prognostic in clinical stage I lung adenocarcinoma

Abstract

We assessed pre-surgical diagnostic circulating tumor DNA (ctDNA) status in 895 patients with EGFR/ALK-wild-type, clinical stage I–II non-small-cell lung cancer using a tumor-naïve methylation-based cell-free DNA assay. Pre-surgical ctDNA detection was observed in 55/414 (13%) patients with clinical stage I lung adenocarcinoma (LUAD) and was associated with poor recurrence-free survival (RFS) (2-year RFS 69% versus 91%; log-rank P < 0.001), approaching that of clinical stage II LUAD. Pre-surgical ctDNA detection was not prognostic in patients with clinical stage II LUAD or non-LUAD. Within LUAD, tumor volume interacted with positron emission tomography avidity to predict pre-surgical ctDNA detection, and pre-surgical ctDNA detection correlated with high-grade pathological features, programmed death ligand-1 (PD-L1) positivity, and pathological upstaging. Our findings support pre-surgical ctDNA positivity as an adverse prognostic feature specifically in clinical stage I LUAD. This validated observation using a tumor-naïve assay will enable perioperative trial advances targeted toward patients with high-risk disease.