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.

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

Grant support

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.