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Open Access Highly Accessed Research article

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

Leonie JM Mekenkamp12, Jolien Tol1, Jeroen R Dijkstra2, Inge de Krijger2, M Elisa Vink-Börger2, Shannon van Vliet2, Steven Teerenstra3, Eveline Kamping4, Eugène Verwiel4, Miriam Koopman5, Gerrit A Meijer6, J Han JM van Krieken2, Roland Kuiper4, Cornelis JA Punt7 and Iris D Nagtegaal2*

Author Affiliations

1 Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

2 Department of Pathology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

3 Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

4 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

5 Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands

6 Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

7 Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

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BMC Cancer 2012, 12:292  doi:10.1186/1471-2407-12-292

Published: 17 July 2012

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.