title: 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.affiliation: Department of Medical Oncology, Istituto Clinico Humanitas IRCCS, Milan University, Rozzano, Italy. federico.cappuzzo@humanitas.it
authors.forename: F
authors.initials: F
authors.lastname: Cappuzzo
authors.forename: M
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: G
authors.initials: G
authors.lastname: Finocchiaro
authors.forename: M
authors.initials: M
authors.lastname: Skokan
authors.forename: S
authors.initials: S
authors.lastname: Gajapathy
authors.forename: C
authors.initials: C
authors.lastname: Carnaghi
authors.forename: L
authors.initials: L
authors.lastname: Rimassa
authors.forename: E
authors.initials: E
authors.lastname: Rossi
authors.forename: C
authors.initials: C
authors.lastname: Ligorio
authors.forename: L
authors.initials: L
authors.lastname: Di Tommaso
authors.forename: A J
authors.initials: AJ
authors.lastname: Holmes
authors.forename: L
authors.initials: L
authors.lastname: Toschi
authors.forename: G
authors.initials: G
authors.lastname: Tallini
authors.forename: A
authors.initials: A
authors.lastname: Destro
authors.forename: M
authors.initials: M
authors.lastname: Roncalli
authors.forename: A
authors.initials: A
authors.lastname: Santoro
authors.forename: P A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D017978:Receptors, Growth Factor / Q000235:genetics; D017451:Receptors, Somatomedin / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D017451:Receptors, Somatomedin; D014157:Transcription Factors; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab