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

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.

• Authors: F Cappuzzo, M Varella-Garcia, G Finocchiaro, M Skokan, S Gajapathy, C Carnaghi, L Rimassa, E Rossi, C Ligorio, L Di Tommaso, A J Holmes, L Toschi, G Tallini, A Destro, M Roncalli, A Santoro, P A Jänne
• Journal: British journal of cancer (Br J Cancer) Vol. 99 Issue 1 Pg. 83-9 (Jul 08 2008) ISSN: 1532-1827 [Electronic] England
• PMID: 18577988 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• KRAS protein, human
• Nuclear Proteins
• PI3KCA protein, human
• Proto-Oncogene Proteins
• Receptors, Growth Factor
• Receptors, Somatomedin
• Transcription Factors
• ErbB Receptors
• MET protein, human
• Proto-Oncogene Proteins c-met
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins p21(ras)
• ras Proteins
• Cetuximab

Topics

• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (therapeutic use)
• Cetuximab
• Colorectal Neoplasms (drug therapy, genetics)
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (genetics)
• Female
• Humans
• In Situ Hybridization, Fluorescence
• Male
• Middle Aged
• Nuclear Proteins (genetics)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins B-raf (genetics)
• Proto-Oncogene Proteins c-met
• Proto-Oncogene Proteins p21(ras)
• Receptors, Growth Factor (genetics)
• Receptors, Somatomedin (genetics)
• Transcription Factors (genetics)
• ras Proteins (genetics)