Pretreatment KRAS-Mutant Circulating Tumor DNA Predicts Incidence and Patterns of Recurrence in Patients Undergoing Radiofrequency Ablation for Colorectal Liver Metastases: A Prospective Analysis.

Abstract

This prospective study aimed to evaluate the prognostic significance of pretreatment <i>KRAS</i>-mutant circulating tumor DNA (ctDNA) in predicting recurrence incidence and patterns in patients with colorectal liver metastasis (CRLM) undergoing radiofrequency ablation (RFA). Seventy-eight patients with CRLM treated with curative-intent RFA were enrolled. Pretreatment plasma ctDNA was analyzed using droplet digital polymerase chain reaction for <i>KRAS</i> mutations. Clinicopathologic data, recurrence patterns, and progression-free survival (PFS) were correlated with ctDNA and KRAS status. Transcriptomic profiling of tumor tissues was performed to explore biological mechanisms. Pretreatment ctDNA was detected positive in 26.9% (21/78) of patients. Patients who harbored <i>KRAS</i>-mutant ctDNA exhibited significantly higher recurrence rates (71.4% <i>v</i> 31.6%, <i>P</i> = .004) and shorter median PFS (352 days <i>v</i> not reached, <i>P</i> < .001). Multivariate Cox analysis confirmed that >3 hepatic lesions (adjusted hazard ratio [HR], 7.66 [95% CI, 2.70 to 21.8], <i>P</i> < .001) and positive ctDNA status (adjusted HR, 3.20 [95% CI, 1.60 to 6.42], <i>P</i> = .001) were independent predictors of recurrence. Moreover, ctDNA-positive patients predominantly developed lung metastases (60%), while ctDNA-negative patients showed liver-dominant recurrence (61.1%). Transcriptomic analysis linked ctDNA positivity to epithelial-mesenchymal transition and DNA repair pathways, with elevated nicotinamide N-methyltransferase expression correlating with aggressive phenotypes. Pretreatment <i>KRAS</i>-mutant ctDNA predicts higher recurrence risk and shows an association with lung-predominant metastasis in patients with CRLM after RFA. Integrating ctDNA and <i>KRAS</i> profiling enhances risk stratification and supports personalized surveillance strategies.