Abstract
Introduction: Colorectal cancer (CRC), a global health concern, requires effective treatments. Anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies are used for RAS wild-type and BRAFV600 mutation-negative metastatic CRC (mCRC) but are not indicated for RAS mutant CRC. Evidence suggests CRC patients with sub-clonal RAS/BRAF mutations in tumor tissue may benefit from anti-EGFRs. We assessed the outcomes of patients with sub-clonal RAS/BRAF mutated advanced/mCRC receiving anti-EGFRs using liquid-based GuardantINFORM real-world clinical-genomic analysis. Patients and Methods: GuardantINFORM analyzed US patients with advanced CRC with BRAFV600/KRAS/NRAS mutations who received anti-EGFR therapies within 90 days after a Guardant360 test. Primary endpoints were time-to-next treatment (TTNT) and overall survival (OS) (compared across RAS/BRAF mutation clonality cut-offs of 0.3–0.8 using the Cox proportional hazards model). Results: In GuardantINFORM, 446 patients initiated anti-EGFR therapy within 90 days after the Guardant360 test, and 11%, 9%, and 1% had BRAFV600E, KRAS, or NRAS mutations, respectively; median distribution of RAS/BRAF clonality was 0.84 (IQR, 0.57-1.00). The data show that patients harboring sub-clonal RAS/BRAF mutations benefited from anti-EGFR therapy to a degree similar to patients without RAS/BRAF mutations. For cut-offs of 0.3 to 0.8, sub-clonal RAS/BRAF had similar TTNT to patients without RAS/BRAF mutations, while clonal RAS/BRAF had a significantly shorter TTNT. For cut-offs of 0.3 to 0.7, sub-clonal RAS/BRAF had similar OS to RAS/BRAF mutations not detected, while clonal RAS/BRAF had a significantly shorter OS. Conclusion: Consistent with tumor tissue biopsy data, patients with CRC harboring sub-clonal RAS/BRAF mutations as assessed by liquid biopsy may derive benefit from anti-EGFR therapy, warranting further investigation.
Document Type
Journal Article
Date of Publication
1-1-2025
Volume
24
Issue
3
Publication Title
Clinical Colorectal Cancer
Publisher
Elsevier
School
School of Medical and Health Sciences
Funders
Merck KGaA, Darmstadt, Germany (10.13039/100009945)
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
First Page
352
Last Page
361
Comments
Gibbs, P., Abubaker, K., Wang, D., Feng, Z., Hamad, J., Liao, J., Stroh, C., Vlassak, S., Heinrich, K., Khattak, A., & Scheuenpflug, J. (2025). Clinical impact of sub-clonal RAS/BRAF alterations in liquid biopsies from patients with advanced or metastatic CRC. Clinical Colorectal Cancer, 24(3), 352-361. https://doi.org/10.1016/j.clcc.2025.03.004