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Background: In non-metastatic colorectal cancer (CRC), we evaluated prospectively the pertinence of longitudinal detection and quantification of circulating tumor DNA (ctDNA) as a prognostic marker of recurrence., Method: The presence of ctDNA was assessed from plasma collected before and after surgery for 184 patients classified as stage II or III and at each visit during 3-4 years of follow-up. The ctDNA analysis was performed by droplet-based digital polymerase chain reaction, targeting mutation and methylation markers, blindly from the clinical outcomes. Multivariate analyses were adjusted on age, gender, stage, and adjuvant chemotherapy., Results: Before surgery, 27.5% of patients were positive for ctDNA detection. The rate of recurrence was 32.7% and 11.6% in patients with or without detectable ctDNA respectively (P = 0.001). Time to recurrence (TTR) was significantly shorter in patients with detectable ctDNA before (adjusted hazard ratio [HR] = 3.58, 95% confidence interval [CI] 1.71-7.47) or immediately after surgery (adjusted HR = 3.22, 95% CI 1.32-7.89). The TTR was significantly shorter in patients with detectable ctDNA during the early postoperative follow-up (1-6 months) (adjusted HR = 5, 95% CI 1.9-12.9). Beyond this period, ctDNA remained a prognostic marker with a median anticipated diagnosis of recurrence of 13.1 weeks (interquartile range 28 weeks) when compared to imaging follow-up. The rate of ctDNA+ might be underestimated knowing that consensus pre-analytical conditions were not described at initiation of the study., Conclusion: This prospective study confirms the relevance of ctDNA as a recurrence risk factor in stage II and III CRC before surgery and as a marker of minimal residual disease after surgery that may predict recurrence several months before imaging techniques., Competing Interests: Conflict of interest statement The authors of this work have conflicts of interest to declare: Valerie Taly: Honoraria from Raindance Technologies and Boerhinger Ingehleim; cofounder Emulseo; board Emulseo. Pierre Laurent-Puig: honoraria and board: Amgen, Merck-Serono, Boehringer Ingelheim, Sanofi, Roche, Lilly. Julien Taieb: Honoraria from Merck, Amgen, Roche, Pierre Fabre, MSD, Sanofi, Lilly, Servier, Astra-Zeneca. AZ: consulting and/or advisory boards: Roche, Merck Serono, Amgen, Sanofi, and Lilly. Olivier Bouché: honoraria and board: Merck, Amgen, Roche, Bayer, Servier, Pierre Fabre, MSD. Delphine Le Corre: Bio-Rad Employee. All remaining authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Simple Summary: Currently, methods including endoscopy, radiology, and carcinoembryonic antigen levels allow for the detection of colorectal cancer (CRC) at an early stage and the ability to follow the evolution of the disease during treatment. However, these are not always sensitive and specific enough for timely intervention. This leads, amongst other consequences, to delays in treatment or even to overtreatment. Circulating tumor DNA (ctDNA) has shown promise in filling this gap, allowing treatment to be personalized at each stage of the disease and, thus, tailored to each patient's needs. This review article focuses on the current clinical use and future direction of ctDNA for CRC management. Colorectal cancer (CRC) is the third most common cancer type worldwide, with over 1.9 million new cases and 935,000 related deaths in 2020. Within the next decade, the incidence of CRC is estimated to increase by 60% and the mortality by 80%. One of the underlying causes of poor prognosis is late detection, with 60 to 70% of the diagnoses occurring at advanced stages. Circulating cell-free DNA (ccfDNA) is probably the most promising tool for screening, diagnosis, prediction of therapeutic response, and prognosis. More specifically, the analysis of the tumor fraction within the ccfDNA (circulating tumor DNA, ctDNA) has great potential to improve the management of CRC. The present review provides an up-to-date and comprehensive overview of the various aspects related to ctDNA detection in CRC. [ABSTRACT FROM AUTHOR]