Clinical Applications of Liquid Biopsy in Colorectal Cancer: A Focus on Registered Clinical Trials

Background/Objectives: Early detection through minimally invasive approaches is critical for timely patient stratification and optimal therapeutic decision-making in colorectal cancer (CRC). Liquid biopsy, based on the analysis of tumor-derived components in blood and other body fluids, has emerged as a promising strategy to overcome current limitations in CRC diagnosis and follow-up. This review evaluates the current landscape of liquid biopsy clinical trials in CRC, focusing on predictive biomarker detection, prognostic assessment, and disease monitoring. Methods: ClinicalTrials.gov was searched using the terms "colorectal cancer" and "liquid biopsy" yielding 153 registered trials. After manual screening, 44 trials were excluded for not using liquid biopsy for CRC management, leaving 109 trials for analysis. Of these, 25 were completed, and 13 had publicly available results related to liquid biopsy. Results: The included trials were conducted across 27 countries on four continents. Overall, 119 biomolecules assessments and 167 different endpoints were reported across 109 clinical trials. Because individual trials could evaluate multiple biomolecules and endpoints, counts exceed the total number of trials. Cell-free DNA (cfDNA) was evaluated in 92/109 trials (84%) and accounting for 77% of all biomolecule assessments. Circulatingtumor cells (CTCs) were analyzed in 9/109 trials (8%, representing 8% of all the biomolecules analyzed), and microRNAs (miRNAs) in 8/109 (7%, representing 7% of all the biomolecules analyzed). Treatment sensitivity was the most common endpoint (57/109, 52% of the clinical trials; representing 34% of all the 167 different endpoints analyzed), followed by disease progression (28/109, 26%; representing 17% of all the different endpoints analyzed) and diagnostic applications (21/109, 19%; representing 12% of all the different endpoints analyzed). Among the 25 completed studies, 10/25 (40%) were interventional and 15/25 (60%) observational, spanning 14 countries. The majority of completed trials (21/25, 84%) used cfDNA. Interventional studies were predominantly phase II (5/10), with fewer phase III trials (2/10), primarily evaluating treatment response, particularly in relation to EGFR inhibitors and RAS/BRAF mutation status. Four observational studies (4/15) investigated emerging biomarkers, including long noncoding RNAs and miRNAs. Conclusions: Current clinical trials highlight cfDNA as the dominant and most clinically advanced liquid biopsy biomarker in CRC, primarily used for treatment guidance and disease monitoring. In contrast, CTCs and RNA-based biomarkers remain underrepresented. The limited number of randomized late-phase trials, heterogeneity in study design, and technical challenges associated with emerging biomarkers underscore the need for standardized methodologies and robust validation before routine clinical implementation.