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

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)83-89
Number of pages7
JournalBritish Journal of Cancer
Issue number1
Publication statusPublished - Jul 8 2008


  • BRAF
  • Cetuximab
  • EGFR
  • IGF1R
  • KRAS
  • MET

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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