MiR-31-3p is a predictive biomarker of cetuximab response in FIRE3 clinical trial

Abstract

Background: MiR-31-3p expression has been shown to be predictive of cetuximab efficacy on survival in RAS wild-type (WT) mCRC patients receiving anti-EGFR theray in the FIRE-3 clinical trial. Patients were defined as low or high miR-31-3p expressors based on a cutoff threshold defined in a previous study. When treated with cetuximab, patients with low miR-31-3p expression have a better survival than patients with high expression. We aimed to investigate the miR-31-3p predictivity on clinical endpoints for response. Methods: MiR-31-3p expression was measured by qRTPCR after extraction from 370 RAS WT paraffin embedded tumor samples. 191 patients were treated with FOLFIRI plus bevacizumab and 179 FOLFIRI plus cetuximab in first line therapy. Objective response and disease control were analyzed in clinical centers based on RECIST criteria. An independent centralized radiological review reassessed patients for early tumor shrinkage (ETS) and Depth of response (DoR). ETS was defined as a diminution of 20% of the diameter at the first CT scan at 6 weeks after baseline. Response rates by treatment arms were compared through odds ratios estimated using logistic regression multivariate models. MiR-31-3p predictivity on response was assessed by testing interaction of treatment effect with miR-31-3p expression in low or high expressors groups (α = 0.10). When heterogeneity of treatment effect was detected, analyses were performed separately in both groups. Results: A benefit of cetuximab therapy on objective response was seen only in low miR-31-3p expressors patients (OR = 3.37 [1.70-6.67], p = 0.0005 versus OR = 1.25 [0.56-2.77], p = 0.6 in high expressors). In low expressors, objective response rate was 70% in patients treated with cetuximab and 57% in patients treated with bevacizumab. Disease control rate were similar in the cetuximab arm and bevacizumab arms (80% and 86% respectively), and homogeneous across miR-31-3p expression groups. MiR-31-3p expression is predictive of the DoR and ETS (interaction test: p = 0.0001 and p = 0.02 respectively). Conclusions: Benefit of cetuximab on response is restricted to patients with low miR-31-3p expression. MiR-31-3p could be clinically useful to select patients for first line anti-EGFR therapy.