Quantitative ctDNA Profiling of RAS Mutations as a Prognostic Biomarker in Metastatic Colorectal Cancer

Circulating tumor DNA (ctDNA) analysis offers a non-invasive approach to molecular profiling. While RAS mutations are well-established predictive biomarkers in metastatic colorectal cancer (mCRC), the prognostic value of their variant allele frequency (VAF) remains unclear. We retrospectively analyzed individual patient data with mCRC who underwent ctDNA testing using the FoundationOne® Liquid CDx assay. The primary objective was to determine the optimal RAS VAF cutoff for overall survival (OS) prognostication. Between November 2020 and July 2024, 282 patients were enrolled. Among 265 eligible patients, 134 (50.6%) were ctRAS mutant, 25 (9.4%) ctBRAFV600E mutant, and 106 (40.0%) were ctRAS/BRAF wild-type. A RAS VAF threshold of 5% yielded the highest prognostic discrimination for OS (HR = 2.41; 95% CI 1.65–3.55; p < 0.0001; C-index = 0.601). ctRAS-high mutant tumors (VAF ≥ 5%) were associated with synchronous metastatic disease, multiple metastatic sites, higher blood tumor mutational burden, and elevated tumor fraction. ctRAS-low mutant tumors (VAF < 5%) were more frequently metachronous, presented with a single metastatic site, and showed liver involvement. High RAS VAF in ctDNA is a strong and independent prognostic marker for OS in mCRC. Quantitative ctDNA profiling may enhance risk stratification and guide personalized management strategies.