Evaluation of circulating tumor DNA (ctDNA) burden, detected mutations, and clinical outcomes in metastatic colorectal cancer (mCRC) using real-world data (RWD).

3659 Background: ctDNA is a promising prognostic biomarker in colorectal cancer; however, there is limited RWD on its prognostic value in mCRC. We leveraged RWD to assess pre-treatment (Tx) ctDNA burden and gene mutations, and evaluated the association between ctDNA burden and clinical outcomes in patients (pts) with mCRC. Methods: Pts with mCRC identified in the GuardantINFORM database who underwent Guardant 360 comprehensive genomic profiling between June 1, 2014 to June 30, 2023 were included. First metastatic diagnosis date was used as the index date. ctDNA burden (% max variant allele fraction ctDNA levels) was categorized as below limit of detection (no ctDNA), ≤ median value (low ctDNA), and > median value (high ctDNA). ctDNA burden and gene mutations/alterations detected prior to 1L systemic therapy were summarized. Associations with OS, time to next Tx (TTNT), and time to Tx discontinuation (TTD) were assessed using Cox proportional hazards models for the overall cohort and by microsatellite instability (MSI) status, stratified by 1L and 2L Tx. Results: There were 3273 pts with mCRC included (non-MSI-high H, n = 2750; MSI-H, n = 100; missing, n = 423). Mean ctDNA burden was 19.9% overall, 20.7% in non-MSI-H, and 14.6% in MSI-H cohorts. Top 3 gene mutations were TP53 (65.8% and 67.2%), APC (59.7% and 60.7%), and KRAS (40.6% and 41.2%) in the overall and non-MSI-H cohorts; and, ARIDIA (71.0%), TP53 (67.0%), and APC (65.0%) in the MSI-H cohort. Top 3 specific variants were EGFR AMP (23.7% and 25.3%), KRAS G12D (11.3% and 11.4%), and KRAS G12V (8.2% and 8.5%) in the overall and non-MSI-H cohorts; and BRAF V600E (39.0%), ARIDIA D1850fs (22.0%), and PIK3CA H1047R (21.0%) in the MSI-H cohort. In the overall cohort, high ctDNA compared to low ctDNA was statistically significantly associated with shorter OS (HR 95% CI: 1L, 1.63 1.43-1.87; 2L, 1.42 1.19-1.70) and TTNT (1L, 1.43 1.27-1.60; 2L, 1.39 1.19-1.63) after adjusting for confounders. Conversely, no ctDNA compared to low ctDNA was statistically significantly associated with longer OS (0.70 0.53-0.91) and TTNT (0.75 0.58-0.97) in the 1L setting after adjusting for confounders; these associations were also observed when stratified by MSI status. ctDNA burden was not statistically significantly associated with TTD in 1L regardless of MSI status. In 2L, high ctDNA was associated with shorter TTD compared to low ctDNA overall (1.19 1.05-1.34), with similar findings in the non-MSI-H cohort. Conclusions: High ctDNA burden prior to 1L and 2L therapy was associated with shorter OS and TTNT, suggesting a higher disease burden or more aggressive disease. The absence of detectable ctDNA was associated with improved survival and may identify pts with better prognosis or slower-growing tumors. These findings provide growing evidence for ctDNA as a potential prognostic biomarker in mCRC.