3521
Background: MicroRNAs (MiRNAs) are post-transcriptional regulators that bind to complementary sequences on target messenger RNA transcripts, usually resulting in gene silencing. Microarray technology is a powerful high-throughput tool capable of monitoring the expression of thousands of small noncoding RNAs at once. In the present study we aimed to investigate whether MiRNA signature was predictive for sensitivity to anti-EGFR monoclonal antibodies in mCRC. Methods: A total of 183 mCRC from two independent cohorts (cohort 1: 74 cases; validation cohort: 109 cases) treated with cetuximab/panitumumab either alone (n=19) or in combination with chemotherapy (n=164) were included onto the study. MiRNA arrays were analysed using Agilent’s miRNA platform. Results: MiRNA array analyses identified the cluster miR-99a/Let7c/miR-125b located on 21p11.1 as associated with different outcome to anti-EGFR therapies. In the first cohort, individuals with high signature (n=25, 33.8%) had a significantly longer progression free survival (PFS, 6.1 versus 2.3 months, p=0.01, HR=0.42) and overall survival (OS, 29.8 versus 7.0 months, p=0.04, HR=0.39) than patients with low signature (n=25, 33.8%). Similar results were observed in the validation cohort. Patients with high signature (n=60, 32.8%) had a significantly longer PFS and longer OS than individuals with low signature (PFS 8.2 versus 4.2 months, p=0.04, HR=0.52; OS 12.8 versus 6.8 months, p=0.09, HR=0.65). To further assess the potential confounding effect of KRAS and BRAF mutations, we analyzed the outcome of patients with high and low signature in the 75 cases with KRAS or BRAF mutation and in 90 cases KRAS and BRAF wild-type. In the wild-type population, high signature patients (n=29, 32.2%) had a significantly longer PFS (8.8 versus 4 months, p=0.002, HR:0.46) and longer OS (17.7 versus 10 months, p=0.015, HR=0.62) than low signature individuals, with no difference in the KRAS or BRAF mutated patients. Conclusions: MiR-99a/Let7c/miR-125b signature is useful for improving selection of KRAS/BRAF wild-type mCRC patients candidate for anti-EGFR strategies.