MicroRNA expression profiling identifies miR-31-5p/3p as associated with time to progression in wild-type RAS metastatic colorectal cancer treated with cetuximab

• Published in: Oncotarget Vol. 6; no. 36; pp. 38695 - 38704
• Main Authors: Mlcochova, Jitka, Faltejskova-Vychytilova, Petra, Ferracin, Manuela, Zagatti, Barbara, Radova, Lenka, Svoboda, Marek, Nemecek, Radim, John, Stanislav, Kiss, Igor, Vyzula, Rostislav, Negrini, Massimo, Slaby, Ondrej
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 17-11-2015
• Subjects: Adult; Aged; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Cetuximab - therapeutic use; Cohort Studies; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Female; HCT116 Cells; HT29 Cells; Humans; Male; MicroRNAs - biosynthesis; MicroRNAs - genetics; Middle Aged; ras Proteins - genetics; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Research Paper; cetuximab; metastatic colorectal cancer; microRNA; panitumumab; EGFR
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5735

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.