Circulating tumor DNA-based minimal residual disease-guided adjuvant therapy in solid tumors: Current evidence, clinical trial frameworks, and future directions.

The postoperative management of resectable solid tumors depends on clinicopathological risk stratification. However, these static criteria often fail to identify occult minimal residual disease (MRD), resulting in suboptimal adjuvant treatment characterized by either overtreatment or undertreatment. Circulating tumor DNA (ctDNA)-based MRD detection has emerged as a transformative molecular strategy to bridge this gap, allowing for the identification of residual disease at extremely low molecular abundance. Recent technological advances in ultra-sensitive assays have enabled the clinical translation of ctDNA assessment across diverse solid malignancies. Increasing evidence indicates that postoperative MRD status offers superior prognostic stratification and identifies molecular recurrence significantly earlier than conventional imaging. Furthermore, MRD is increasingly being evaluated as a dynamic tool to tailor adjuvant therapy, facilitating treatment intensification for MRD-positive cohorts and potential de-escalation for MRD-negative populations. This review summarizes the evolution of ctDNA-based MRD detection technologies and the clinical evidence supporting MRD-guided adjuvant strategies. We critically examine the nuances between tumor-informed and tumor-agnostic approaches. Additionally, cancer-specific variations in ctDNA shedding and clinical evidence maturity are highlighted, along with the integration of MRD into prospective interventional trial designs. We argue that MRD is currently best utilized as a biological stratification and trial-enabling tool, rather than a definitive standalone criterion for routine practice. Furthermore, technical, biological, and clinical hurdles hindering widespread implementation, including sensitivity thresholds, background noise, and standardization gaps, are addressed. Results from ongoing interventional trials will be pivotal in defining optimal thresholds and monitoring frameworks, ultimately determining whether MRD-guided precision management improves survival outcomes.