New Compass for Precision Oncology: Evidence, Challenges, and Prospects of Circulating Tumor DNA in Colorectal Cancer

Circulating tumor DNA (ctDNA) has emerged as a clinically actionable biomarker for the management of colorectal cancer (CRC). Improvements in analytical accuracy and sequencing depth have expanded the role of ctDNA from early cancer detection to include molecular profiling of advanced disease, postoperative risk stratification, and real-time evaluation of therapeutic response and resistance. In screening and early detection settings, ctDNA-based assays integrating mutation analysis, methylation profiling, and fragmentomic features have demonstrated high specificity for CRC and multi-cancer early detection (MCED). Prospective studies suggest that ctDNA can identify CRC before clinical diagnosis; however, its sensitivity for advanced premalignant lesions remains limited, supporting its use as a complementary approach for individuals who do not participate in established screening rather than as a replacement for stool-based tests or colonoscopy. Postoperatively, ctDNA-based detection of minimal residual disease (MRD) is a strong independent predictor of recurrence and survival, often preceding radiographic evidence of relapse. Randomized trials have demonstrated that ctDNA-guided adjuvant strategies have the potential to reduce overtreatment and identify candidates for treatment escalation, although the impact on long-term outcomes remains under prospective validation. In metastatic disease, serial ctDNA monitoring enables early treatment–response assessment, detection of resistance mechanisms, and optimization of targeted therapy, including rechallenge strategies. The emerging concept of Neo RAS further illustrates the dynamic nature of tumor genomics and its therapeutic implications. Collectively, these advances have positioned ctDNA as a central tool in precision medicine. This narrative review summarizes recent clinical evidence supporting ctDNA-guided strategies for CRC and discusses their implications for the broader field of precision oncology.