ctDNA-based detection of residual disease: implications for management of non-metastatic NSCLC

Despite advancements in perioperative and consolidative immunotherapy in early-stage to locally advanced non-small cell lung cancer (NSCLC), recurrence rates remain substantial. In this context, liquid biopsy has transformed the oncological landscape by enabling the non-invasive detection of tumor-derived components, including DNA, cells, and proteins, from biological fluids. Although plasma-based circulating tumor DNA (ctDNA) analysis is routinely used in metastatic NSCLC to identify actionable genomic alterations at diagnosis and mechanisms of acquired resistance to targeted therapies, its application in non-metastatic disease represents a pivotal challenge. Leveraging minimal residual disease (MRD) detection through ctDNA offers the potential for early risk stratification, enabling the identification of patients who may benefit from treatment escalation, such as intensified adjuvant or consolidative regimens, while sparing low-risk patients from unnecessary toxicity through de-escalation strategies. This review summarizes the biological and technological foundations underlying ctDNA-based MRD detection, including tumor-informed and non-tumor-informed approaches, and examines the current evidence supporting its clinical utility in non-metastatic NSCLC. We also highlight key technical and clinical challenges and discuss future perspectives to optimize integration of ctDNA MRD assessment into routine clinical practice.