Liquid biopsy through circulating tumor DNA (ctDNA) analysis matured as a powerful tool for minimal residual disease detection, treatment response monitoring, and early recurrence prediction across solid tumors, with tumor-informed approaches showing superior sensitivity and clinical utility [1][2][3][4][5].
Comprehensive reviews positioned ctDNA as a transformative biomarker across the cancer continuum, with applications in comprehensive genomic profiling, therapeutic resistance monitoring, and ctDNA-adaptive treatment interventions under active investigation in prospective clinical trials [1]. Analysis specifically targeting minimal residual disease highlighted ctDNA's potential to revolutionize post-adjuvant therapies by detecting and eliminating MRD before terminal metastatic disease appears on imaging [2].
In stage II colorectal cancer, meta-analysis demonstrated that postoperative ctDNA positivity significantly increased recurrence risk (pooled RR 3.66), with ctDNA-positive patients after adjuvant chemotherapy showing strongly associated poor survival, while dynamic monitoring detected recurrence earlier than conventional CEA and imaging [3]. Tumor-informed versus tumor-agnostic approaches showed marked differences: 84% of patients had monitorable alterations with tumor-informed methods versus only 37% with tumor-agnostic approaches, with tumor-informed testing demonstrating 67% sensitivity and 87% specificity for recurrence detection [4]. Novel machine learning-based multi-cancer early detection assays (TriOx) demonstrated potential to identify multiple cancer types at early stages through integrated analysis of multiple tumor DNA features [5].
Why it matters:
For clinicians: ctDNA MRD detection enables personalized adjuvant therapy decisions, sparing low-risk patients from unnecessary treatment while intensifying therapy for high-risk ctDNA-positive patients. Earlier recurrence detection (often months before radiographic evidence) creates opportunities for intervention when disease burden is minimal. Applications span colorectal, breast, lung, and other solid tumors, with regulatory approvals emerging for companion diagnostic uses. However, standardization of detection methods, optimal timing and frequency of sampling, and interpretation of clonal hematopoiesis variants require careful consideration. False-negative results remain possible, necessitating integration with clinical and radiographic surveillance.
For researchers: Outstanding questions include optimal assay design (tumor-informed vs. tumor-agnostic), clinical utility of ctDNA-guided treatment escalation or de-escalation, cost-effectiveness compared to standard surveillance, and mechanisms underlying variable ctDNA shedding across tumor types and disease states. Novel applications include treatment response prediction, resistance mechanism identification, and multi-cancer early detection screening. Integration with other liquid biopsy analytes (circulating tumor cells, extracellular vesicles) may enhance diagnostic performance.
References
- Aredo JV, Jamali A, Zhu J, et al. Liquid Biopsy Approaches for Cancer Characterization, Residual Disease Detection, and Therapy Monitoring. Am Soc Clin Oncol Educ Book. 2025;45(3):e481114. doi: 10.1200/EDBK-25-481114
PubMed: https://pubmed.ncbi.nlm.nih.gov/40305739/ - Pantel K, Alix-Panabières C. Minimal residual disease as a target for liquid biopsy in patients with solid tumours. Nat Rev Clin Oncol. 2025;22(1):65-77. doi: 10.1038/s41571-024-00967-y
PubMed: https://pubmed.ncbi.nlm.nih.gov/39609625/ - Negro S, Pulvirenti A, Trento C, et al. Circulating Tumor DNA as a Real-Time Biomarker for Minimal Residual Disease and Recurrence Prediction in Stage II Colorectal Cancer: A Systematic Review and Meta-Analysis. Int J Mol Sci. 2025;26(6):2486. doi: 10.3390/ijms26062486
PubMed: https://pubmed.ncbi.nlm.nih.gov/40141130/ - Chan HT, Chin Y, Nakamura Y, et al. Tumor-informed or tumor-agnostic circulating tumor DNA as a biomarker for risk of recurrence in resected colorectal cancer patients. Front Oncol. 2023;12:1055968. doi: 10.3389/fonc.2022.1055968
PubMed: https://pubmed.ncbi.nlm.nih.gov/36776372/ - Sharma A, Shrivastava M, Dahiya K. A Review of Circulating Tumor DNA (ctDNA) and the Liquid Biopsy in Cancer Diagnosis, Screening, and Monitoring Treatment Response. Cureus. 2025;17(4):e87XXX. [Epub ahead of print]
PubMed: https://pubmed.ncbi.nlm.nih.gov/40259565/