Exploratory biomarker analysis of RAS/BRAF somatic mutations and gene expression signatures for predicting treatment effects of aflibercept in the velour trial
- Author(s)
- Pu, T; Peddle, AM; Wirapati, P; Tsantoulis, P; Wu, Q; Hong, Y; Samuel, L; Desai, J; Riener, M; Saridaki, Z; Cunningham, D; Tejpar, S;
- Journal Title
- NPJ Precision Oncology
- Publication Type
- Online publication before print
- Abstract
- The phase III VELOUR trial demonstrated improved outcomes with aflibercept plus FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin-based regimens. We retrospectively evaluated the prognostic and predictive impact of RAS/BRAF mutations, intrinsic consensus molecular subtype (iCMS), and tumour sidedness in 439 profiled patients. Targeted sequencing identified RAS mutations in 57.5% and BRAF mutations in 10.0% of evaluable tumours; 34.2% of tumours with complete genotyping were RAS/BRAF wild-type. Transcriptomic profiling classified 66.5% of tumours as iCMS2 and 33.5% as iCMS3. RAS/BRAF wild-type tumours showed numerically improved overall survival (OS) and progression-free survival (PFS) with aflibercept, whereas no clear benefit was observed in RAS-mutant tumours. iCMS subtyping was strongly prognostic, with iCMS2 patients demonstrating longer OS and PFS than iCMS3 (OS HR 0.57, 95%CI 0.45-0.72; PFS HR 0.70, 95%CI 0.56-0.88). Exploratory integrated analyses suggested OS benefit in RAS/BRAF wild-type iCMS2 tumours (HR 0.56, 95%CI 0.33-0.96) and a significant PFS advantage in bevacizumab-pretreated iCMS3 tumours (HR 0.41, 95%CI 0.20-0.85, q = 0.032). Right-sided tumours were associated with poorer OS, but no significant treatment interaction was observed. These findings support integrating genomic and transcriptomic biomarkers to refine patient selection for anti-VEGF therapy, warranting validation in prospective studies. ClinicalTrials.gov number: NCT00561470, registered 15 November 2007.
- Department(s)
- Medical Oncology
- Publisher's Version
- https://doi.org/10.1038/s41698-025-01253-5
- Open Access at Publisher's Site
https://doi.org/10.1038/s41698-025-01253-5- Terms of Use/Rights Notice
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Creation Date: 2026-01-23 03:46:43
Last Modified: 2026-01-23 03:52:13