Recurrence prediction using circulating tumor DNA in patients with early-stage non-small cell lung cancer after treatment with curative intent: A retrospective validation study
Authors: Milou M F Schuurbiers, Christopher G Smith, Koen J Hartemink, Robert C Rintoul, Davina Gale, Kim Monkhorst, Bas L R Mandos, Anna L Paterson, Dan van den Broek, Nitzan Rosenfeld, Michel M van den Heuvel
Journal: PLoS Medicine (2025)

Background Despite treatment with curative intent, many patients with localized non-small cell lung cancer (NSCLC) develop recurrence. The current challenge is to identify high-risk patients to guide adjuvant treatment. Identification of residual disease by detection of circulating tumor DNA (ctDNA) may allow more accurate clinical decision-making, but its reliability in NSCLC is not established. We aimed to build on previous data to validate a tissue-informed personalized ctDNA assay, to predict recurrence in patients with early-stage disease. Methods and findings Tumor tissue and plasma was collected from patients with stage 0–III NSCLC enrolled to LEMA ( L ung cancer E arly M olecular A ssessment trial, NCT02894853). Serial plasma was collected before and after definitive treatment, with the latter including key timeframes of interest (1–3 days post-treatment, between 14 and 122 days after treatment end, and ≥14 days after treatment end). Somatic mutations identified by tumor exome sequencing were used to design patient-specific assays, to analyze ctDNA. Results were compared and combined with an independent dataset (LUCID; LU ng C ancer C I rculating Tumour D na study, NCT04153526). In LEMA, 130 patients (57% male; median age 66 years (range 44–82); 69% adenocarcinoma, 22% squamous cell carcinoma (SCC); 3%/49%/19%/29% with stage 0/I/II/III) were treated with curative intent. Tumor tissue originated from surgical resection or diagnostic biopsy in 118 and 12 patients respectively. LUCID included 88 patients (51% male; median age 72 years (range 44–88); 63% adenocarcinoma, 31% SCC; 49%/28%/23% with stage I/II/III). Before treatment, ctDNA was detected in 48% LEMA and 51% LUCID patients. Sensitivity, specificity, positive and negative predictive value of ctDNA detection post-treatment (≥1 positive sample ≥14 days after treatment end) to predict recurrence were 61%, 97%, 92% and 84% for LEMA and 64%, 96%, 90% and 83% for LUCID. In the combined cohort, ctDNA detection after treatment was associated with shorter recurrence-free survival (hazard ratio (HR) 11.4 (95% confidence interval (CI) [7.0,18.7]; p &lt; 0.001)) and overall survival (HR 8.1 (95% CI [4.6,14.2]; p &lt; 0.001)), accounting for guarantee-time bias. Of note, a key limitation of this work was the irregular sample collection schedules, during routine follow-up visits, of both studies. Conclusions ctDNA detection predicted recurrence in independent retrospective cohorts with notable reproducibility, including near-identical detection rates and predictive values, confirming its ability to differentiate patients at high- versus low risk of recurrence. Our results support the potential of tissue-informed ctDNA analysis as a decision-support tool for adjuvant therapy in NSCLC.