The Role of Liquid Biopsy in Detecting KRAS, NRAS, and BRAF Mutations in Metastatic Colorectal Cancer: A Systematic Review

Abstract

Introduction: Metastatic colorectal cancer (mCRC) is a leading cause of cancer-related mortality, with molecular profiling of KRAS, NRAS, and BRAF mutations essential for guiding first-line therapy. Although liquid biopsy using circulating tumor DNA (ctDNA) offers a promising non-invasive alternative to tissue biopsy, its diagnostic accuracy and clinical utility in treatment-naïve mCRC remain under investigation. To evaluate the diagnostic accuracy and clinical utility of liquid biopsy in detecting KRAS, NRAS, and BRAF mutations in treatment-naïve metastatic colorectal cancer, using tissue biopsy as the reference standard. Method: A literature search was conducted in PubMed and ScienceDirect between January 10, 2025, and February 11, 2025, following the PRISMA guidelines, to identify studies on liquid biopsy for detecting KRAS, NRAS, and BRAF mutations in treatment-naïve or anti-EGFR–naïve adult patients with metastatic colorectal cancer. Risk of bias was assessed using QUADAS-2 and the Newcastle–Ottawa Scale. Eligible studies compared ctDNA-based and tissue-based mutation testing. Results: A total of 40 studies (24 diagnostic, 16 observational) involving 5,744 mCRC patients, of whom 5,432 were treatment-naïve, were analyzed. Liquid biopsy showed high concordance with tissue biopsy (75–97.3%), with RAS mutation sensitivity ≥ 90% and specificity > 95% across platforms, while BRAF detection was less sensitive but improved in advanced disease. ctDNA metrics, including levels and minor allele frequency, correlated with prognosis, and liquid biopsy offered faster turnaround (7–10 days) and lower failure rates than tissue testing. Conclusion: Liquid biopsy is a reliable alternative to tissue biopsy for baseline KRAS, NRAS, and BRAF testing in mCRC, offering high diagnostic accuracy, faster turnaround, and lower failure rates. It holds substantial clinical potential, though standardized protocols and further validation are still required.