miR-345 in metastatic colorectal cancer: a non-invasive biomarker for clinical outcome in non-KRAS mutant patients treated with 3rd line cetuximab and irinotecan

Jakob V Schou; Simona Rossi; Benny V Jensen; Dorte L Nielsen; Per Pfeiffer; Estrid Høgdall; Mette Yilmaz; Sabine Tejpar; Mauro Delorenzi; Mogens Kruhøffer; Julia S Johansen

doi:10.1371/journal.pone.0099886

miR-345 in metastatic colorectal cancer: a non-invasive biomarker for clinical outcome in non-KRAS mutant patients treated with 3rd line cetuximab and irinotecan

PLoS One. 2014 Jun 18;9(6):e99886. doi: 10.1371/journal.pone.0099886. eCollection 2014.

Authors

Affiliations

¹ Department of Oncology, Herlev University Hospital, Herlev, Denmark.
² Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
³ Department of Oncology, Odense University Hospital, Odense, Denmark.
⁴ Department of Pathology, Herlev University Hospital, Herlev, Denmark.
⁵ Department of Oncology, Aalborg University Hospital, Aalborg, Denmark.
⁶ Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium.
⁷ 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.
⁸ AROS Applied Biotechnology, Aarhus, Denmark.

Abstract

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.

Publication types

Clinical Trial, Phase II
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized / therapeutic use*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Biomarkers, Tumor / genetics*
Camptothecin / analogs & derivatives*
Camptothecin / therapeutic use
Cetuximab
Colorectal Neoplasms / blood
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / secondary*
DNA Mutational Analysis
Disease-Free Survival
Female
Gene Expression Regulation, Neoplastic
Humans
Irinotecan
Kaplan-Meier Estimate
Male
MicroRNAs / blood
MicroRNAs / genetics*
MicroRNAs / metabolism
Middle Aged
Multivariate Analysis
Mutation / genetics
Proportional Hazards Models
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins p21(ras)
Treatment Outcome
ras Proteins / genetics

Substances

Antibodies, Monoclonal, Humanized
Biomarkers, Tumor
KRAS protein, human
MIRN345 microRNA, human
MicroRNAs
Proto-Oncogene Proteins
Irinotecan
Proto-Oncogene Proteins p21(ras)
ras Proteins
Cetuximab
Camptothecin

Grants and funding

This work was supported by grants from The Research Council at Herlev Hospital, the Danish Ministry of the Interior and Health, Merck-Serono Denmark/Sweden, and the European Union Seventh Framework Programme [FP7/2007–2013] under grant agreement no 222916 (given to MK). ST is a senior clinical investigator of the Fund for Scientific Research Flanders and is supported by Belgian National Cancer Plan. ST and SR is also supported by the Foundation Fournier-Majoie, FFMI, Belgium. MD is supported in part by the Swiss National Science Foundation (SNF; http://www.snf.ch/E/; Grant No. 320030_135421); Krebsforschung Schweiz (KFS; http://www.krebsforschung.ch/; Grant No. 02697-08-2010); and by the Fondation Medic. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.