Temporal dynamics of RAS mutations in circulating tumor DNA in metastatic colorectal cancer: clinical significance of mutation loss during treatment

Abstract Purpose In metastatic colorectal cancer (mCRC), RAS mutation loss may occur during the standard-of-care regimen. In this study, we aimed to investigate the temporal dynamics of the RAS gene and its clinical significance. Methods This was a retrospective, single-center study that included 82 patients with tissue RAS -mutant ( RAS -MT) mCRC who underwent circulating tumor DNA (ctDNA) RAS monitoring between January, 2013–April, 2023. Patients were analyzed for the rate of change over time to acquired RAS mutation loss (a RAS -ML) and clinicopathological factors. The prognostic relevance of mutation loss was assessed. Results a RAS -ML was detected in 33 (40.2%) patients, 32 of whom had a mutation loss in the first ctDNA RAS assay. Patients with a RAS mutation detected in the first assay had a median time of 8 months until the second ctDNA RAS assay, with 4.5% cases newly converted to a RAS -ML; no new conversions were detected at the third assay. The a RAS -ML group exhibited more single-organ metastases in the target organ during ctDNA measurement (a RAS -ML: 84.8% vs. RAS -MT: 59.2%, p = 0.02). Of the 33 patients with a RAS -ML, seven (21.2%) received anti-epidermal growth factor receptor (EGFR) therapy, with a median progression-free survival of 8 months. Multivariate analysis revealed that persistent ctDNA RAS mutation was an independent prognostic factor for overall survival (hazard ratio: 2.7, 95% confidence interval: 1.1–6.3, p = 0.02). Conclusion The rate of ctDNA mutation loss in patients with RAS -MT mCRC decreases over time. Therefore, using a ctDNA RAS assay early in treatment will assist in challenging the use of EGFR regimens.