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Background: There is a growing body of evidence to support the prognostic and predictive relevance of ctDNA in patients (pts) with early stage colorectal cancer (CRC). Relatively little is known about the real-world (rw) utilization of tumor-informed, personalized ctDNA assays in this population. We described the uptake of ctDNA testing over time as well as how results correlate with other biomarkers and the development of specific sites of metastasis (SOM). Methods: Pts with stage I-III CRC diagnosed after 1/1/2018 and a commercial ctDNA test in the early stage setting were selected using machine learning models from the Flatiron Health nationwide EHR-derived, de-identified database with a data cutoff of 10/31/23. Pts were considered ctDNA positive (ctDNA+) if they had at least one positive test. Odds ratios (OR) were calculated using logistic regression, adjusting for age, race, stage, practice type, insurance, and adjuvant treatment. Median time to metastasis (mets) for the ctDNA+ cohort (indexed to first positive test) was estimated using the Kaplan Meier estimator. Differences in minimal residual disease (MRD) in MTM/mL were compared using a Wilcox rank-sum test using maximum MRD. Results: In a cohort of 78,046 pts with stage I-III disease, 17,209 ctDNA tests were performed in 5,005 pts (median 3 per pt) with the majority in stage III pts (54.2%). 11% of pts (1652 / 14803) diagnosed between 1/1/21 and 4/1/22 received ctDNA testing compared to 14% of pts (1610 / 11412) diagnosed between 4/1/22 and 4/1/23. Among tested pts, 1,729 (34.5%) had at least one positive test. Pts with ctDNA+ tests were more likely to have tumor mutations in TP53 (OR: 1.69 [95% CI: 1.37, 2.08]) and KRAS (OR: 1.78 [95% CI: 1.10, 1.72]) than pts with ctDNA- tests. No differences were found in NRAS, BRAF or HER2. Progression to metastatic disease was observed in 365 (21.1%) pts with ctDNA+ tests vs 93 (2.8%) pts with ctDNA- tests (OR: 8.84 [95% CI: 6.95, 11.26]). The median time from first ctDNA+ to mets was 24.2 [95% CI: 21.7, NR] months. In those who developed mets, pts with ctDNA+ tests were significantly more likely to have liver mets compared to pts with ctDNA- tests (OR: 1.89 [95% CI: 1.12, 3.19]). Pts with liver mets had higher levels of MRD compared to non-liver SOM. (p <0.001). Conclusions: This is the largest study to date of early stage CRC ctDNA testing in routine practice. Results suggest that pairing ctDNA and NGS testing has the potential to predict risk for liver mets and other pt outcomes. Future work is needed to translate these findings into clinically actionable insights and treatment strategies.