Prognostic Relevance of ctDNA RAS Mutation in Patients With Metastatic Colorectal Cancer Treated With Cetuximab.

Background: RAS mutations are important biomarkers for predicting the efficacy of anti-EGFR treatment in metastatic colorectal cancer (mCRC). The emergence of RAS mutations is a known resistance mechanism. This study aimed to evaluate the prognostic significance of circulating tumor DNA (ctDNA) RAS mutations in patients with mCRC treated with cetuximab, focusing on the temporal dynamics of RAS mutation emergence.

Patients and methods: Patients with tissue-confirmed RAS wild-type mCRC were included in the study. ctDNA samples were collected at baseline, every 8 weeks during treatment, and after the final cetuximab dose. Cetuximab, combined with FOLFOX or FOLFIRI, was administered as first-line therapy. The primary objective was to assess the impact of emergent ctDNA RAS mutations on progression-free survival (PFS) during cetuximab-based treatment in the first-line setting.

Results: A total of 49 patients contributed at least 1 ctDNA sample, with 320 samples collected in total. The baseline concordance rate between ctDNA and tissue RAS status was 89.1% (41/46). Among 41 baseline RAS wild-type cases, 22 (53.7%) demonstrated emergent RAS mutations. The median time to RAS emergence was 12.8 months, and the median PFS was 12.7 months. Temporal analysis revealed that a single detection of RAS mutation was not consistently associated with poor PFS and could resolve in subsequent tests. However, time-dependent analysis indicated that the presence of ctDNA RAS mutations at any time point was significantly associated with poorer PFS (adjusted HR = 2.24, P = .02).

Conclusion: The emergence of ctDNA RAS mutations during cetuximab-based first-line therapy exhibits temporal variability. Nevertheless, the presence of ctDNA RAS mutations at any time point is collectively associated with reduced PFS.