Clinical bottom line
Circulating tumor DNA (ctDNA) is increasingly recognized as a sensitive and minimally invasive biomarker for monitoring treatment response across various cancers. Evidence supports its utility in detecting molecular residual disease, early relapse, and therapeutic resistance, often preceding radiographic changes. While ctDNA assays show promise for real-time disease tracking and personalized therapy adjustments, variability in assay sensitivity, tumor shedding, and interpretation limits universal application. Integration of ctDNA monitoring into clinical workflows warrants further validation in prospective trials and standardization of methodologies (Schroers-Martin et al., 2023; Au et al., 2024).
What the evidence shows
Schroers-Martin et al. (2023) provide a comprehensive review of molecular monitoring in lymphomas, highlighting ctDNA’s role in assessing minimal residual disease and predicting relapse with high sensitivity. Serial ctDNA quantification correlates with treatment response and may guide therapy intensification or de-escalation.
Au et al. (2024) focus on urothelial cancer, demonstrating that ctDNA detection post-treatment predicts recurrence earlier than imaging and can stratify patients for adjuvant therapies.
Besse et al. (2025) report on EGFR-mutant non-small cell lung cancer (NSCLC) patients treated with amivantamab plus lazertinib, showing that ctDNA dynamics reflect tumor burden changes and emergence of resistance mutations, informing therapeutic decisions.
Uğur Topal et al. (2026) review hepatocellular carcinoma, underscoring ctDNA’s potential to monitor treatment efficacy and detect early progression, though challenges remain due to tumor heterogeneity and variable ctDNA shedding.
Ashida et al. (2017) provide early evidence of ctDNA utility in melanoma patients receiving anti-PD-1 immunotherapy, where ctDNA clearance correlates with durable responses.
Rizzo et al. (2020) discuss biliary tract cancers, noting that ctDNA can identify actionable mutations and monitor response, though clinical adoption is still evolving.
Caveats and uncertainty
Sensitivity of ctDNA assays varies with tumor type, stage, and burden; low-shedding tumors may yield false negatives.
Standardization of pre-analytical variables, sequencing platforms, and bioinformatics pipelines is lacking.
Interpretation of ctDNA fluctuations requires context, as transient increases may reflect tumor lysis or clonal hematopoiesis.
Prospective randomized trials demonstrating improved patient outcomes with ctDNA-guided management are limited.
Cost-effectiveness and accessibility remain barriers in routine clinical practice.
How this may change practice
Incorporation of ctDNA monitoring could enable earlier detection of treatment failure and relapse, allowing timely therapeutic modifications.
Personalized treatment strategies may be refined by tracking resistance mutations via ctDNA.
ctDNA assays may reduce reliance on invasive biopsies and frequent imaging, improving patient convenience and safety.
Multidisciplinary teams should consider integrating ctDNA results with clinical and radiologic data for comprehensive disease assessment.
Ongoing research and consensus efforts are needed to establish standardized protocols and clinical guidelines.