The temporal evaluation of RAS mutation by liquid biopsy at progression after bevacizumab-based treatment in patients with metastatic colorectal cancer
Clinical and Translational Oncology, 2026 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Publication Date: 2026
- Doi Number: 10.1007/s12094-026-04441-2
- Journal Name: Clinical and Translational Oncology
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, EMBASE, MEDLINE, DIALNET, Health Research Premium Collection (ProQuest)
- Keywords: Circulating tumor DNA, ctDNA, Liquid biopsy, Metastatic colorectal cancer, RAS mutation
- Hacettepe University Affiliated: Yes
Abstract
Background: Expanded RAS analysis is essential for guiding targeted therapy in metastatic colorectal cancer (mCRC), as RAS mutations predicts resistance to anti-EGFR agents. This study aimed to evaluate the plasma RAS mutation status using liquid biopsy at disease progression and to assess the prognostic significance of RAS mutation clearance. Methods: In this prospective study, 58 patients with mCRC harboring RAS mutations in baseline tumor tissue were enrolled. All patients experienced disease progression following first-line chemotherapy combined with bevacizumab. Plasma samples collected at progression were analyzed using the Idylla™ PCR-based system for detection of KRAS and NRAS mutations in circulating tumor DNA (ctDNA). Survival outcomes were estimated using the Kaplan–Meier method and compared with the log-rank test. Results: The median age was 60 years (IQR 35–83), and 60.3% of patients were male. The primary tumors were left sided in 81.0% of cases. At baseline, 94.8% of the patients had KRAS and 5.2% had NRAS mutations. At progression, ctDNA analysis revealed KRAS mutations in 56.9% and NRAS mutations in 3.4% of patients, while 39.7% showed no detectable RAS mutation in plasma. No significant differences in clinicopathological characteristics were observed between patients with persistent RAS mutations and those with RAS clearance. However, overall survival was significantly longer in patients with RAS wild-type conversion compared to those with persistent RAS mutations (44.3 vs. 19.6 months, p = 0.002). Conclusion: This study demonstrated that dynamic changes in plasma RAS mutation status may occur during disease progression in patients with mCRC, potentially reflecting tumor clonal evolution. The observed survival advantage in patients with RAS mutation clearance suggests potential prognostic relevance. Reassessment of RAS status using liquid biopsy at disease progression may provide clinically relevant information; however, these findings should be considered exploratory and require prospective validation in larger cohorts.