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Br J Cancer. 2008 Jul 8;99(1):83-9. doi: 10.1038/sj.bjc.6604439. Epub 2008 Jun 24.

Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients.

Author information

1
Department of Medical Oncology, Istituto Clinico Humanitas IRCCS, Milan University, Rozzano, Italy. federico.cappuzzo@humanitas.it

Abstract

The impact of KRAS mutations on cetuximab sensitivity in epidermal growth factor receptor fluorescence in situ hybridisation-positive (EGFR FISH+) metastatic colorectal cancer patients (mCRC) has not been previously investigated. In the present study, we analysed KRAS, BRAF, PI3KCA, MET, and IGF1R in 85 mCRC treated with cetuximab-based therapy in whom EGFR status was known. KRAS mutations (52.5%) negatively affected response only in EGFR FISH+ patients. EGFR FISH+/KRAS mutated had a significantly lower response rate (P=0.04) than EGFR FISH+/KRAS wild type patients. Four EGFR FISH+ patients with KRAS mutations responded to cetuximab therapy. BRAF was mutated in 5.0% of patients and none responded to the therapy. PI3KCA mutations (17.7%) were not associated to cetuximab sensitivity. Patients overexpressing IGF1R (74.3%) had significantly longer survival than patients with low IGF1R expression (P=0.006), with no difference in response rate. IGF1R gene amplification was not detected, and only two (2.6%) patients, both responders, had MET gene amplification. In conclusion, KRAS mutations are associated with cetuximab failure in EGFR FISH+ mCRC, even if it does not preclude response. The rarity of MET and IGF1R gene amplification suggests a marginal role in primary resistance. The potential prognostic implication of IGF1R expression merits further evaluation.

PMID:
18577988
PMCID:
PMC2453041
DOI:
10.1038/sj.bjc.6604439
[Indexed for MEDLINE]
Free PMC Article

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