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 RAS WT mCRC patients enrolled in the FIRE-3 Trial. This included 164 patients randomized to receive FOLFIRI plus cetuximab (FOLFIRI+Cetux) and 176 to FOLFIRI plus bevacizumab (FOLFIRI+Beva). Patients were divided into subgroups defined by low or high miR-31-3p expression using a pre-specified 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 to bevacizumab for PFS (HR=0.74 [0.55;1.00];P=0.05), OS (HR=0.61 [0.41;0.88];P<0.01), iOR (OR=4.0 [1.9;8.2];P<0.01), ETS (OR=4.0 [2.1;7.7];P<0.01) and cOR (OR=4.9 [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=0.03), OS (P=0.05), iOR (P=0.02), ETS (P=0.04) and cOR (P<0.01). Conclusion: MiR-31-3p expression level was validated as a predictive biomarker of cetuximab therapy efficacy for RAS WT mCRC patients.
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