Journal Article

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

Roncalli, M, Santoro, A, Jänne, P A, Varella-Garcia, M, Di Tommaso, L, Tallini, G, Cappuzzo, F, Rimassa, L, Toschi, L, Destro, A, Rossi, E, Ligorio, C, Holmes, A J, Skokan, M, Gajapathy, S, Carnaghi, C, Finocchiaro, G

2008

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Antibodies, Monoclonal - therapeutic use / Antibodies, Monoclonal, Humanized / Antineoplastic agents / Antineoplastic Agents - therapeutic use / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cetuximab / Clinical Study / Colorectal cancer / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Drug Resistance / Drug Resistance, Neoplasm - genetics / Epidemiology / Epidermal growth factor / Ethanol / Female / Gene amplification / Humans / Immunotherapy / In Situ Hybridization, Fluorescence / Kinases / Male / Medical research / Medical sciences / Metastasis / Middle Aged / Molecular Medicine / Mutation / Nuclear Proteins - genetics / Oncology / Patients / Pharmacology. Drug treatments / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins c-met / Proto-Oncogene Proteins p21(ras) / ras Proteins - genetics / Receptor, Epidermal Growth Factor - genetics / Receptors, Growth Factor - genetics / Receptors, Somatomedin - genetics / Response rates / Transcription Factors - genetics / Tumors