Circulating tumor DNA (ctDNA) in early-stage NSCLC: a new frontier in precision oncology

Recent advances in the management of early-stage non-small cell lung cancer (NSCLC), including perioperative immunotherapy and targeted treatments, have significantly improved outcomes. Nevertheless, a considerable proportion of patients relapse after curative-intent surgery, emphasizing the need for biomarkers that can more accurately define recurrence risk and guide individualized treatment. Circulating tumor DNA (ctDNA) has emerged as a promising, non-invasive biomarker for detecting minimal residual disease (MRD), assessing molecular response, and identifying relapse before clinical or radiologic evidence. Across retrospective and prospective studies, ctDNA detection at baseline or after treatment is consistently associated with inferior recurrence-free and overall survival, with postoperative positivity marking patients at the highest risk of relapse, often several months ahead of imaging findings. Evidence from recent pivotal trials further reinforces the prognostic significance of ctDNA dynamics in the perioperative setting. However, translation into clinical practice remains limited. ctDNA detection in early-stage disease is inherently challenging due to its low abundance and technical variability across assays. Moreover, no platform is yet validated or approved for MRD detection in this setting, and the predictive impact of ctDNA-guided treatment adaptation remains to be demonstrated. Ongoing efforts are focused on refining assay sensitivity, standardizing workflows, and conducting prospective interventional trials to establish ctDNA as a clinically actionable biomarker. This review provides an overview of current evidence, emerging technologies, and future directions toward clinical integration of ctDNA in resectable NSCLC.