When Blood Speaks Before the Scan: The Role of ctDNA in Real-time CRC Care.

Background/Aim: Colorectal cancer (CRC) recurrence, especially in stage III disease, remains a clinical challenge. Circulating tumor DNA (ctDNA) has emerged as a minimally invasive biomarker for detecting minimal residual disease (MRD) and predicting recurrence. The Signatera assay is a personalized, tumor-informed ctDNA test reported in mean tumor molecules per milliliter (MTM/ml), offering dynamic monitoring beyond traditional mutant allele frequency methods. The objective of the current study was to demonstrate the clinical utility of Signatera in managing four patients with stage III CRC, particularly in detecting recurrence earlier than imaging and informing curative interventions. Case Report: We conducted a retrospective case series of four patients with histologically confirmed stage III CRC who underwent curative-intent surgery, completed adjuvant chemotherapy, and received longitudinal Signatera ctDNA testing for at least 12 months. ctDNA was assessed every three months, and imaging was performed every six months or sooner if ctDNA became positive. We documented trends in ctDNA, recurrence patterns, imaging results, and treatment changes. All patients initially achieved a disease-free status. In all cases, ctDNA positivity preceded radiographic detection of recurrence. Each had isolated liver metastases, which were detected early and treated surgically. Post-surgical ctDNA clearance was associated with improved outcomes, and one patient remained ctDNA-negative without additional chemotherapy. Conclusion: Serial ctDNA monitoring with Signatera enabled earlier detection of recurrence and guided timely interventions in stage III CRC. These findings support its clinical integration, pending further validation in prospective trials.