Circulating tumor DNA in colorectal cancer: assay selection, clinical applications, and practical integration for gastroenterologists.

Background: Circulating tumor DNA (ctDNA) has rapidly evolved from a research tool to a clinically applicable biomarker in colorectal cancer (CRC), transforming the assessment of minimal residual disease (MRD) and recurrence risk. The growing availability of commercial assays has complicated test selection and interpretation, particularly for gastroenterologists who increasingly encounter ctDNA data in postoperative and surveillance settings. Methods: We conducted a narrative review of the literature using PubMed, Embase, and Cochrane databases from January 2015 through March 2026, prioritizing randomized controlled trials, prospective cohort studies, and clinical practice guidelines relevant to ctDNA applications in CRC. The search employed predefined keyword combinations applied independently to each database. Two authors (A.S. and S.M.) independently screened titles and abstracts against the prespecified inclusion criteria, with disagreements resolved by discussion. Results: Tumor-informed assays that analyze patient-specific mutations exhibit high specificity for MRD detection, with serial sampling sensitivity reaching 88% compared to 59% for tumor-agnostic approaches, based on a 2026 systematic review and diagnostic accuracy meta-analysis that pooled data across multiple platforms and settings; the authors note substantial study-level heterogeneity in platform design and patient populations, and results should be interpreted accordingly, but require tissue access and extended processing times. Tumor-agnostic tests are more rapid and accessible, incorporating genomic and epigenomic signals, though they exhibit site-specific sensitivity variations ranging from 100% for liver metastases to 40% for peritoneal recurrence and remain vulnerable to biological confounders such as clonal hematopoiesis (CH). Importantly, ctDNA interpretation is subject to additional biological limitations including tumor shedding variability by anatomical site and disease burden, the timing of sample collection relative to surgery or chemotherapy, platform-specific detection thresholds, and pre-analytical variables such as hemolysis and delayed plasma processing. Randomized evidence supports ctDNA-guided de-escalation of adjuvant therapy in stage II colon cancer, with 5-year follow-up from the DYNAMIC trial demonstrating comparable recurrence-free survival (88% vs. 87%) and overall survival (93.8% vs. 93.3%) despite reduced chemotherapy use. In stage III disease, ctDNA is strongly prognostic, but chemotherapy intensification based solely on molecular positivity has not improved outcomes. This review additionally addresses underexplored areas including ctDNA in rectal cancer and neoadjuvant therapy, the influence of microsatellite instability (MSI) status on assay performance, and disparities in ctDNA access across racial, socioeconomic, and geographic populations. Conclusions: For gastroenterologists encountering ctDNA results in postoperative and surveillance settings, three principles should guide practice (i): match assay selection to clinical intent - tumor-informed platforms for MRD-directed adjuvant decisions, tumor-agnostic platforms when tissue is unavailable (ii); interpret results within biological and technical context, accounting for platform-specific sensitivity limitations, biological confounders, and quantitative VAF trajectory rather than binary thresholds; and (iii) integrate ctDNA findings into multidisciplinary pathways - de-escalation is supported by high-quality randomized evidence in stage II disease (Grade A; Level I), while chemotherapy escalation based solely on ctDNA positivity in stage III disease is not supported outside clinical trials (Grade C; Level I). Standardization of assay performance benchmarks and equitable access to testing remain critical unmet needs.