Combined RAS and SMAD4 Mutations and Microsatellite Instability Predict Outcomes in Colorectal Lung Metastases Treated with Image-Guided Thermal Ablation.

[BACKGROUND] Image-guided thermal ablation (IGTA) is a minimally invasive alternative to colorectal cancer lung metastases (CRLM) for non-surgical candidates. This study evaluated whether combined RAS/SMAD4 mutational status and microsatellite instability (MSI) predict outcomes after IGTA in CRLM, addressing the current controversy over prognostic biomarkers.

[METHODS] This multicenter retrospective study analyzed 412 CRLM patients undergoing computed tomography (CT)-guided IGTA (March 2014 to December 2022). The patients were stratified by microsatellite status (MSS vs MSI) and RAS/SMAD4 genotype (concurrent mutations ["double"], single mutation, or wild type). The primary endpoints were local tumor progression (LTP), progression-free survival (PFS), and overall survival (OS).

[RESULTS] In multivariable analysis, poorer OS was independently predicted by maximum lesion diameter ≥20 mm, three or more lesions, synchronous metastases, MSI, and RAS mutation, whereas shorter PFS was predicted by RAS and SMAD4. In MSI tumors, concurrent RAS/SMAD4 double mutations were associated with significantly worse OS and PFS than wild type (both p < 0.05), whereas in MSS tumors, even single RAS or SMAD4 mutations portended inferior survival compared with wild type. Relative to MSS, MSI status was independently associated with higher mortality risk (hazard ratio, 1.67; 95 % confidence interval, 1.16-2.41; p = 0.005).

[CONCLUSION] Concurrent RAS and SMAD4 alterations and MSI status identify high-risk CRLM patients after IGTA. Integrating these molecular markers into clinical decision-making may enhance risk stratification and guide personalized treatment strategies.