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

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

doi:10.1186/1471-2407-12-292

Abstract

BackgroundKRAS 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.MethodsFormalin-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.ResultsCopy 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.ConclusionsOur results indicate that the assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of mCRC eligible for anti-EGFR therapy.

Highlights

KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer
We demonstrated that regulation of the KRAS oncogene at several levels might affect clinical outcome in a selected group of cetuximab-treated metastatic colorectal cancer (mCRC) patients treated in a phase III trial [34]
Our results suggest that KRAS copy number gains are associated with worse clinical outcome in wild-type KRAS mCRC patients who are treated with a cetuximab-containing first-line regimen

Summary

Introduction

KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Antibodies against the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, have shown a survival benefit in mCRC patients with KRAS wild-type tumours both as in codons 12 and 13 are tested, which comprise approximately 96% of the observed KRAS mutations [7]. Recent data suggest that a codon 13 KRAS mutation has a distinct clinical behaviour and is not associated with cetuximab resistance [8]. A mutation in the BRAF oncogene occurs in approximately 10% of mCRC patients and is restricted to KRAS wild-type tumours, and was first shown to have a negative predictive value for anti-EGFR therapy [10]. Other biomarkers in the PI3K and RAS/MAPK pathways [12,13,14,15,16], ligands to the EGFR [17,18], and germline single nucleotide polymorphisms [19,20,21] have not yet shown a predictive value that can be used in clinical practice

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