Beyond KRAS mutation status: influence of KRAS copy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients

Leonie J M Mekenkamp, Jolien Tol, Jeroen R Dijkstra, Inge de Krijger, M Elisa Vink-Börger, Shannon van Vliet, Steven Teerenstra, Eveline Kamping, Eugène Verwiel, Miriam Koopman, Gerrit A Meijer, J Han Jm van Krieken, Roland Kuiper, Cornelis J A Punt, Iris D Nagtegaal

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. We assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab.

METHODS: Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n = 17) or poor (n = 17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR.

RESULTS: Copy number loss of the KRAS locus was observed in the tumour of 5 patients who were all good responders including patients with a KRAS mutation. Copy number gains in two wild-type KRAS tumours were associated with a poor PFS. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good PFS. In wild-type KRAS patients, miRNA expression did not correlate with PFS in a multivariate model.

CONCLUSIONS: Our results indicate that the assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of mCRC eligible for anti-EGFR therapy.

Original languageEnglish
Pages (from-to)292
JournalBMC cancer
Volume12
DOIs
Publication statusPublished - 17 Jul 2012
Externally publishedYes

Keywords

  • Antibodies, Monoclonal/administration & dosage
  • Antibodies, Monoclonal, Humanized/administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols/therapeutic use
  • Bevacizumab
  • Cetuximab
  • Chromosomes, Human, Pair 12/genetics
  • Clinical Trials, Phase III as Topic
  • Colorectal Neoplasms/drug therapy
  • DNA Copy Number Variations
  • Disease-Free Survival
  • Female
  • Humans
  • Male
  • MicroRNAs/genetics
  • Middle Aged
  • Multicenter Studies as Topic
  • Multivariate Analysis
  • Mutation
  • Neoplasm Metastasis
  • Organoplatinum Compounds/administration & dosage
  • Oxaliplatin
  • Proto-Oncogene Proteins/genetics
  • Proto-Oncogene Proteins p21(ras)
  • Randomized Controlled Trials as Topic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Treatment Outcome
  • ras Proteins/genetics

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