Validation of miR-31-3p expression to predict cetuximab efficacy when used as first-line treatment in RAS wild-type metastatic colorectal cancer

Abstract

Purpose: MiR-31-3p expression has been shown to be associated with response to anti-EGFR therapy. We investigated the predictive role of this biomarker in the FIRE-3 study population, including its ability to differentiate outcomes between patients receiving anti-EGFR and anti-VEGF therapy. Experimental Design: MiR-31-3p expression was measured in primary tumors obtained from 340 patients with RAS WT mCRC enrolled in the FIRE-3 Trial. This included 164 patients randomized to receive FOLFIRI plus cetuximab (FOLFIR-IþCetux) and 176 to FOLFIRI plus bevacizumab (FOLFIR-IþBeva). Patients were divided into subgroups defined by low or high miR-31-3p expression using a prespecified cut-off and by treatment arm. Analyses were performed to assess treatment efficacy by subgroup. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan–Meier curves and Cox regression models. Investigator-assessed objective response (iOR), early tumor shrinkage at 6 weeks (ETS), and centrally reviewed objective response (cOR) were analyzed using logistic regression models. The predictive value of miR-31-3p expression level was assessed through a treatment interaction test using multivariate models adjusted for potential confounding factors. Results: Low miR-31-3p expressers benefited from cetuximab compared with bevacizumab for PFS [HR, 0.74; 95% confidence interval (CI), 0.55–1.00; P ¼ 0.05], OS (HR, 0.61; 95% CI, 0.41–0.88; P < 0.01), iOR (OR, 4.0; 95% CI, 1.9–8.2; P < 0.01), ETS (OR, 4.0; 95% CI, 2.1–7.7; P < 0.01 and cOR (OR, 4.9; 95% CI, 2.3–10.5; P < 0.01) in multivariate analyses. There was no difference in outcomes for high expressers between treatment arms. MiR-31-3p expression level was predictive of treatment effect for PFS (P ¼ 0.03), OS (P ¼ 0.05), iOR (P ¼ 0.02), ETS (P ¼ 0.04), and cOR (P < 0.01). Conclusions: MiR-31-3p expression level was validated as a predictive biomarker of cetuximab therapy efficacy for patients with RAS WT mCRC.