Background: Postoperative circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) is reported to be associated with a high risk of recurrence. Here, we present an updated analysis and the lead time interval (LTI) of ctDNA positivity to radiographic recurrence in patients (pts) with radically resected colorectal cancer (CRC), stage II-IV in the observational GALAXY study. Methods: Serial ctDNA was analyzed using personalized tumor-informed assay (Signatera bespoke multiplex-PCR NGS assay) at 1 (4-week MRD time point), 3, 6, 9, 12, 18, and 24 months after surgery until recurrence, and CT scans were conducted every 6 months. The primary endpoint was disease-free survival (DFS), defined as the time between the date of surgery and date of diagnosis with relapse or death due to any cause. The LTI was defined from the first ctDNA positive date at post-surgery to radiographic recurrence. Results: Among 3,615 CRC pts who were enrolled between May 2020 and April 2022 in GALAXY study, 2,083 pts that met the inclusion criteria were analyzed in this report. The median follow-up period was 16.3 months. Of 2,083 pts analyzed, 286 (14%) were ctDNA-positive at 4-weeks MRD time point and 1,797 (86%) were ctDNA-negative. Pts with ctDNA-positivity at 4-weeks MRD timepoint demonstrated an inferior DFS and were 12 times more likely to recur, compared to ctDNA-negative pts (HR:12, 95CI: 9.1-15%; p < 0.0001). We further combined ctDNA status with BRAF V600E status at 4-week MRD time point and observed that pts with ctDNA-positivity and BRAF V600E mutation showed significantly shorter DFS compared to ctDNA-positive pts with BRAF wild-type (p < 0.001). Whereas, in pts with ctDNA-negativity no significant difference in DFS was observed (p = 0.306). On performing ctDNA dynamics analysis between 4-weeks to 12 weeks, compared to pts who remained ctDNA-negative (N = 1529), a significantly shorter DFS was observed for pts who converted from ctDNA-negative to positive (N = 112, HR: 14.5, 95%CI: 8.8-23.8%, p < 0.0001) or who remained positive (N = 124, HR: 25.4, 95%CI: 18.3-35.3; p < 0.0001). Radiographic recurrence was observed in 186 pts (46%). Of these, 121 pts (65%) had CT imaging performed every 6 months, as per the protocol. The median LTI was 142 days (IQR, 43-189 days). Conclusions: Our study builds on the existing evidence from the recently published, prospective GALAXY study. ctDNA status at MRD time point post-surgery is prognostic of patient outcomes and is the most significant risk factor regardless of BRAF V600E status. ctDNA positivity predicted radiologic recurrence several months ahead of clinical recurrence. Pts with positive postoperative ctDNA should be examined carefully due to a high risk of recurrence. ctDNA-guided adjuvant strategy will further be established by ongoing randomized VEGA and ALTAIR studies in the CIRCULATE-Japan. Clinical trial information: UMIN000039205.