1 The Faculty of Medicine, Aalborg University, VBN2 Aalborg University Hospital, The Faculty of Medicine, Aalborg University, VBN3 Klinik Kirurgi og Kræftbehandling, The Faculty of Medicine, Aalborg University, VBN4 Kræftbehandling (Onkologi), The Faculty of Medicine, Aalborg University, VBN5 Department of Oncology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.6 Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland.7 Department of Oncology, Odense University Hospital, Odense, Denmark.8 Department of Pathology, Herlev University Hospital, Copenhagen.9 Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium.10 Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland; Department of Oncology, University of Lausanne, Lausanne, Switzerland; Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland.11 AROS Applied Biotechnology, Aarhus, Denmark.
A Non-Invasive Biomarker for Clinical Outcome in Non-KRAS Mutant Patients Treated with 3rd Line Cetuximab and Irinotecan
INTRODUCTION: MicroRNAs (miRNAs) have important regulatory functions in cellular processes and have shown promising potential as prognostic markers for disease outcome in patients with cancer. The aim of the present study was to find miRNA expression profiles in whole blood that were prognostic for overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated with cetuximab and irinotecan. METHODS: From 138 patients with mCRC in 3rd line therapy with cetuximab and irinotecan in a prospective phase II study, 738 pretreatment miRNAs were isolated and profiled from whole blood using the TaqMan MicroRNA Array v2.0. Mutation status of KRAS, BRAF, and PI3KCA was known. RESULTS: After Bonferroni adjustment, 6 miRNAs: (miR-345, miR-143, miR-34a*, miR-628-5p, miR-886-3p and miR-324-3p), were found associated with short OS. miR-345 was the strongest prognostic miRNA, significant in the full cohort and in the non-KRAS mutant population. miR-345, as a continuous variable in the full cohort, resulted in a hazard ratio (HR) of 2.38 per IQR (CI 95%: 1.8-3.1, P-value = 2.86e-07, Bonferroni adjusted, univariable analysis) and a HR = 1.75 per IQR (CI 95%: 1.24-2.48, P-Wald = 1.45e-03) in the multivariable analysis adjusted for gender, age, KRAS, PI3KCA and performance status. miR-345 was prognostic in progression-free survival (PFS) with a HR = 1.63 per IQR (CI 95%: 1.25-2.114, P-Wald = 2.92e-4) in the multivariable analysis. In addition, high miR-345 expression was associated with lack of response to treatment with cetuximab and irinotecan. CONCLUSION: We identified miR-345 in whole blood as a potential biomarker for clinical outcome. MiR-345 was a single prognostic biomarker for both OS and PFS in all patients and also in the non-KRAS mutant population.