Liquid biopsy for minimal residual disease and monitoring in early-stage non-small cell lung cancer: current clinical utility and implementation challenges

This review summarizes recent developments in circulating tumor DNA (ctDNA)-based liquid biopsy for the detection and monitoring of minimal residual disease (MRD) in early-stage solid tumors. MRD assessment has emerged as a promising biomarker for predicting recurrence and guiding adjuvant therapy, particularly in non-small cell lung cancer (NSCLC). Advances in ultra-sensitive next-generation sequencing (NGS), digital PCR, and methylation-based assays have enabled detection of molecular relapse with variant allele frequencies as low as 0.004%. Numerous prospective studies have demonstrated that ctDNA positivity after curative-intent treatment is strongly associated with early relapse and can precede radiographic recurrence by several months. While ctDNA-based MRD testing has begun to influence clinical decision-making in selected settings—particularly in research-driven centers and prospective trials—its broader clinical implementation remains limited by challenges related to assay standardization, pre-analytical variability, and interpretation of MRD positivity. Ongoing efforts to establish consensus thresholds, filter clonal hematopoiesis, and validate predictive value in large-scale trials are essential for routine adoption. This review discusses both the current state and the future direction of MRD-guided oncology, highlighting emerging strategies such as longitudinal ctDNA monitoring, artificial intelligence-based interpretation, and multi-omics integration. Together, these developments may enable more precise and adaptive treatment strategies in the perioperative setting, ultimately facilitating the transition of MRD assessment from investigational use to clinical standard-of-care.