MicroRNA expression profiling identifies miR-31-5p/3p as associated with time to progression in wild-type RAS metastatic colorectal cancer treated with cetuximab
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Jitka Mlcochova1, Petra Faltejskova-Vychytilova1,2, Manuela Ferracin3, Barbara Zagatti3, Lenka Radova1, Marek Svoboda2, Radim Nemecek2, Stanislav John4, Igor Kiss2, Rostislav Vyzula2, Massimo Negrini3, Ondrej Slaby1,2
1Central European Institute of Technology, Masaryk University, Brno, Czech Republic
2Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Masaryk University, Faculty of Medicine, Brno, Czech Republic
3Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
4Department of Oncology and Radiotherapy, Faculty Hospital Hradec Kralove, Hradec Kralove, Czech Republic
Ondrej Slaby, e-mail: [email protected]
Massimo Negrini, e-mail: [email protected]
Keywords: microRNA, metastatic colorectal cancer, EGFR, cetuximab, panitumumab
Received: May 17, 2015 Accepted: October 08, 2015 Published: October 20, 2015
The aim of our study was to investigate whether microRNAs (miRNAs) could serve as predictive biomarkers to anti-EGFR therapy (cetuximab, panitumumab) in patients with RAS wild-type (wt-RAS) metastatic colorectal cancer (mCRC). Historical cohort of 93 patients with mCRC (2006–2009) was included and further divided into exploratory and validation cohorts. MiRNAs expression profiling was performed on the exploratory cohort of 41 wt-KRAS mCRC patients treated with cetuximab to identify miRNAs associated with time to progression (TTP). The validation was performed on two independent cohorts: 28 patients of wt-RAS mCRC treated with cetuximab and 24 patients of wt-RAS mCRC treated with panitumumab. We identified 9 miRNAs with significantly different expression between responders and non-responders to cetuximab therapy (P ≤ 0.01). These 9 miRNAs were further evaluated in two independent cohorts of patients and miR-31-3p (P < 0.001) and miR-31-5p (P < 0.001) were successfully confirmed as strongly associated with TTP in wt-RAS mCRC patients treated with cetuximab but not panitumumab. When evaluated on the complete cohort of cetuximab patients (N = 69), miR-31-3p (HR, 5.10; 95% CI, 2.52–10.32; P < 0.001) and miR-31-5p (HR, 4.80; 95% CI, 2.50–9.24; P < 0.001) were correlated with TTP on the comparable level of significance. There was no difference in miR-31-5p/3p expression levels in RAS mutated and wild-type tumor samples. MiR-31-5p/3p are promising predictive biomarkers of cetuximab response in wt-RAS mCRC patients.
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