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Predicting cetuximab efficacy in patients with advanced colorectal cancer

Authors Sahin I, Garrett C

Received 11 September 2013

Accepted for publication 6 December 2013

Published 18 June 2014 Volume 2014:4 Pages 61—68


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Ibrahim H Sahin, Christopher R Garrett

Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Abstract: Cetuximab has demonstrated activity, both as monotherapy, and in combination with cytotoxic chemotherapy, albeit modest. Efforts over the last decade have focused on determining which patient populations are most likely to benefit from this chimeric monoclonal antibody therapy. As the antibody targets the epidermal growth factor receptor (EGFR), cell surface expression by immunohistochemistry was hypothesized to be a biomarker of clinical efficacy; subsequent clinical trials have shown that this was not the case. Tumor KRAS mutation (the most frequently observed site is at codon 12) has been shown to be a negative biomarker (ie, a marker of cetuximab resistance); since 2008, treatment of patients with cetuximab has been restricted to those whose tumors do not harbor a KRAS mutation. There is considerable heterogeneity of KRAS mutations, and studies are ongoing to determine whether cetuximab resistance extends to those patients whose tumors have a KRAS codon 13, 61, and 164, mutation. EGFR gene copy, or more precisely a lack of increase in EGFR gene copy number, has been demonstrated to be a negative biomarker of EGFR efficacy; currently, it is not in routine use as a clinical standard of care. Tumor BRAF status, NRAS status, and PIK3CA mutation status are being evaluated as additional potential negative biomarkers of treatment efficacy. High expression of the receptor ligands epiregulin and amphiregulin has been shown to be a positive biomarker for treatment efficacy and is continuing to be studied clinically. After almost 10 years following the widespread introduction of cetuximab into the clinic as a treatment for metastatic colorectal cancer, the story of identifying suitable biomarkers of efficacy is still evolving. The tremendous tumor heterogeneity at the molecular level and the cell complexity of signaling pathways suggest that there is still a significant amount of work to be done to optimally define those patients most likely to benefit from this form of therapy.

Keywords: biomarkers, epidermal growth factor receptor, EGFR, KRAS mutation

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