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Annals of Oncology Advance Access originally published online on January 29, 2009
Annals of Oncology 2009 20(5):879-884; doi:10.1093/annonc/mdn712
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

gastrointestinal tumors

The importance of KRAS mutations and EGF61A>G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer

K. -L. Garm Spindler1,*, N. Pallisgaard2, A. A. Rasmussen3, J. Lindebjerg4, R. F. Andersen2, D. Crüger3 and A. Jakobsen1

1 Department of Oncology
2 Department of Biochemistry
3 Department of Clinical Genetics
4 Department of Pathology, Danish Colorectal Cancer Group South, Vejle Hospital, Vejle, Denmark

* Correspondence to: Dr K.-L. Garm Spindler, Department of Oncology, Vejle Hospital, Kabbeltoft 25, 7100 Vejle, Denmark. Tel: +45-79406002; Fax: +45-79406709; E-mail: karen-lise.garm.spindler{at}vgs.regionsyddanmark.dk

Background: The effect of anti-epidermal growth factor receptor (EGFR) antibodies (mAb) in metastatic colorectal cancer seems limited to KRAS wild-type (wt) tumours, but still a major fraction of KRASwt patients are nonresponders and supplementary selection criteria are needed. We investigated methodological aspects of KRAS testing and the predictive and prognostic value of KRAS status combined with three EGFR-related gene polymorphisms [single-nucleotide polymorphisms (SNPs)] in patients treated with cetuximab and irinotecan.

Patients and methods: The study included 71 patients referred to third-line cetuximab–irinotecan. Blood samples were analysed for SNPs. KRAS analysis was carried out by sequencing analysis and quantitative PCR (DxS kit) in primary tumour and distant metastases.

Results: There was a clear correlation between KRAS status in primary tumours and metastasis. The DxS kit presented the highest sensitivity. Response was confined to KRASwt patients (40% response rate versus 0%, P < 0.1–3), which translated into a significant difference in PFS. The EGF61A>G polymorphism showed relation to clinical outcome. A combined biomarker analysis showed a 19% progression rate in KRASwt-EGF61 homozygote patients and 60% in the EGF61A/G patients (P = 0.006) and a significant increase in overall survival (17.1 versus 5.9 months, log-rank, P = 0.002).

Conclusion: The combined biomarker analysis maybe an attractive approach to selection of patients for third-line treatment including anti-EGFR mAbs.

Key words: cetuximab–irinotecan, EGF61A>G, gene polymorphisms, KRAS, mCRC

Received for publication June 9, 2008. Revision received October 12, 2008. Revision received October 17, 2008. Accepted for publication October 20, 2008.


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