MiR-31 as a predictive biomarker of cetuximab efficacy in metastatic colorectal cancer patients: systematic review

Abstract Background Cetuximab is an EGFR inhibitor used in metastatic colorectal cancer (mCRC). It demonstrates significant response variability even among RAS wild-type patients, with only ~65% objective response rates as first-line therapy. Current biomarkers, including RAS and BRAF mutation status, are insufficient to fully predict cetuximab efficacy. MicroRNA-31 (miR-31-3p and miR-31-5p) has emerged as a potential predictive biomarker through its role in activating the RAS signaling pathway by suppressing RAS p21 GTPase activating protein 1 (RASA1). This systematic review evaluates the evidence on miR-31 as a predictive biomarker for cetuximab response in mCRC. Methods A systematic literature search was conducted using PubMed/MEDLINE and Google Scholar through May 2026. Original studies evaluating miR-31 expression in relation to cetuximab response in mCRC were included. Data extraction was performed by two independent reviewers. Quality was assessed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk-of-Bias tool for clinical trials. The study followed PRISMA 2020 guidelines. Results Eleven studies (3 clinical trials, 8 observational/retrospective studies; sample sizes 26–370) were included, with moderate to high quality scores. Low miR-31-3p expression was consistently associated with improved cetuximab outcomes. In the FIRE-3 trial, low miR-31-3p expressers demonstrated superior overall survival (HR: 0.61; P = 0.01), progression-free survival (HR: 0.74; P = 0.05), and overall response rate (OR: 4.0; P = 0.01) with cetuximab versus bevacizumab. The PROSPECT-C trial showed better response rates (58.3% vs. 22.2%; P = 0.029) and longer progression-free survival with low expression. Conversely, elevated miR-31 expression was associated with shorter progression-free survival. Notably, miR-31-3p did not predict anti-EGFR efficacy in right-sided tumors. Conclusion MiR-31-3p is a promising predictive biomarker for cetuximab response in RAS wild-type mCRC, with low expression consistently associated with improved outcomes. However, tumor sidedness may modulate its predictive value. Prospective validation studies with standardized assays are needed before clinical implementation. Integration of miR-31-3p with existing markers could help identify patients unlikely to benefit from anti-EGFR therapy.