title: 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.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology, Herlev University Hospital, Herlev, Denmark.
authors.forename: Jakob V
authors.initials: JV
authors.lastname: Schou
authors.affiliation: Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Department of Oncology, Herlev University Hospital, Herlev, Denmark.
authors.forename: Benny V
authors.initials: BV
authors.lastname: Jensen
authors.affiliation: Department of Oncology, Herlev University Hospital, Herlev, Denmark.
authors.forename: Dorte L
authors.initials: DL
authors.lastname: Nielsen
authors.affiliation: Department of Oncology, Odense University Hospital, Odense, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Pfeiffer
authors.affiliation: Department of Pathology, Herlev University Hospital, Herlev, Denmark.
authors.forename: Estrid
authors.initials: E
authors.lastname: Høgdall
authors.affiliation: Department of Oncology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Yilmaz
authors.affiliation: Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: 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.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: AROS Applied Biotechnology, Aarhus, Denmark.
authors.forename: Mogens
authors.initials: M
authors.lastname: Kruhøffer
authors.affiliation: Department of Oncology, Herlev University Hospital, Herlev, Denmark.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Johansen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary*; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; C561417:MIRN345 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002166:Camptothecin