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

PURPOSE: This prospective study aimed to evaluate the prognostic significance of pretreatment KRAS-mutant circulating tumor DNA (ctDNA) in predicting recurrence incidence and patterns in patients with colorectal liver metastasis (CRLM) undergoing radiofrequency ablation (RFA).

METHODS

Seventy-eight patients with CRLM treated with curative-intent RFA were enrolled. Pretreatment plasma ctDNA was analyzed using droplet digital polymerase chain reaction for KRAS 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.

RESULTS

Pretreatment ctDNA was detected positive in 26.9% (21/78) of patients. Patients who harbored KRAS-mutant ctDNA exhibited significantly higher recurrence rates (71.4% v 31.6%, P = .004) and shorter median PFS (352 days v not reached, P < .001). Multivariate Cox analysis confirmed that >3 hepatic lesions (adjusted hazard ratio [HR], 7.66 [95% CI, 2.70 to 21.8], P < .001) and positive ctDNA status (adjusted HR, 3.20 [95% CI, 1.60 to 6.42], P = .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.

CONCLUSION

Pretreatment KRAS-mutant ctDNA predicts higher recurrence risk and shows an association with lung-predominant metastasis in patients with CRLM after RFA. Integrating ctDNA and KRAS profiling enhances risk stratification and supports personalized surveillance strategies.