Advancing gastrointestinal cancer diagnosis and treatment: a narrative review of circulating tumor DNA in gastrointestinal malignancies

Background and Objective: Gastrointestinal (GI) cancers represent a substantial global health burden due to their high morbidity and mortality rates. These cancers are often diagnosed at advanced stages, leading to poor prognosis and limited treatment options. Early detection and personalized treatment strategies are critical to improving outcomes, yet traditional diagnostic methods, such as tissue biopsies and imaging, often fall short in sensitivity, specificity and the ability to capture tumor heterogeneity. Circulating tumor DNA (ctDNA), which comprises small fragments of tumor-derived DNA shed into the bloodstream, has emerged as a transformative tool in the diagnosis and management of GI cancers. This review aims to summarize the clinical and utility of ctDNA in GI cancers and highlight areas for future research. Methods: This narrative review integrates findings from recent studies evaluating ctDNA in GI malignancies. In doing so, we searched PubMed/MEDLINE, Google Scholar, ClinicalTrials.gov, and the Cochrane Library between October 1, 2024 and August 5, 2025. Eligible studies were restricted to English-language articles without geographic limitations to the USA. Key Content and Findings: ctDNA enables non-invasive, real-time monitoring of tumor burden, treatment response, and resistance mechanisms, making it a valuable tool for precision oncology. Evidence supports its use across colorectal, pancreatic, hepatobiliary, and esophageal cancers, with the most established role in colorectal cancer. While ctDNA offers potential to improve patient outcomes, challenges remain, including technical limitations, variability in detection methods, and issues related to cost and standardization. Conclusions: ctDNA is a promising biomarker in GI oncology, with potential to advance early detection, treatment monitoring, and prognostication. A clearer understanding of existing limitations will be critical to unlocking its full potential and establishing ctDNA as a reliable tool in the management of GI cancers.