Background: Despite standard of care management with surgery ± adjuvant chemotherapy treatment (ACT), >30% of patients (pts) with resectable CRC recur. The presence of ctDNA in plasma after resection and after ACT, has been shown to be a strong prognostic factor for the risk of recurrence, suggesting that the presence of ctDNA in blood is molecular evidence of residual disease. As such, ctDNA analysis may enable post-surgical risk stratification for ACT decision-making, as well as detection of molecular recurrence during surveillance and subsequent early intervention. The CORRECT-I study aims to validate the association of post-definitive therapy and pre-recurrence follow-up ctDNA positivity with recurrence-free interval (RFI) in pts who have undergone complete surgical resection for stage II or III CRC. Methods: This study is a prospective, observational, multicenter study, which is open in Israel, Italy, Japan, Spain, and the UK. Pts must have pathologically confirmed stage II or III CRC, have undergone complete surgical resection, and have tissue available from the primary resection. Pts may not have started ACT prior to baseline blood draw post-surgery. Pts are asked to provide serial whole blood specimens for ctDNA analysis at a) post-surgical baseline, b) pre-recurrence follow-up visits (max 15 blood draws over max 5 years), and c) clinical recurrence. ctDNA will be analyzed with an NGS-based tumor-informed MRD assay that identifies somatic genomic alterations from DNA derived from the patient’s tumor tissue and detects a selected subset of tumor-specific (bespoke) ctDNA in their blood. The primary objective of this study is to validate the association of post-definitive therapy and serial pre-recurrence follow-up ctDNA positivity with RFI, using a Cox proportional hazards regression analysis. Further objectives include the assessment of sensitivity and specificity of the ctDNA assay, the association between ctDNA at individual timepoints and RFI, ctDNA dynamics and RFI, and the time from ctDNA positivity to clinical recurrence. A multivariable model, including ctDNA, clinicopathological risk features, serial serum CEA assessments, and recurrence risk as determined by the Oncotype Colon Recurrence Score will be fit with RFI as endpoint. The primary analysis will be conducted when ≥30 histologic and/or radiographic confirmed cases of clinical recurrence have been observed. As of April 2, 2024, 158 pts of 400 have been enrolled.