Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study.
BACKGROUND
The antiepidermal growth factor receptor (antiEGFR) monoclonal antibodies cetuximab and panitumumab have good clinical activity in about 10% of patients with metastatic colorectal cancer that is resistant to chemotherapy. The molecular mechanisms underlying clinical response or resistance to these agents are unknown.


METHODS
Tumours from 31 patients with metastatic colorectal cancer who had either an objective response (n=10) or stable disease or progressive disease (n=21) after treatment with cetuximab or panitumumab were screened for genetic changes in EGFR or its immediate intracellular effectors. Specifically, we assessed the EGFR copy number and the mutation profile of the EGFR catalytic domain and of selected exons in KRAS, BRAF, and PIK3CA.


RESULTS
Eight of nine of patients with objective responses who were assessable by fluorescence in-situ hybridisation (FISH) had an increased EGFR copy number. By contrast, one of 21 non-responders assessable by FISH had an increased EGFR copy number (p<0.0001 for responders vs non-responders, Fisher's exact test). The mutation status of the EGFR catalytic domain and its immediate downstream effectors PIK3CA, KRAS, and BRAF did not correlate with disease response. In colorectal-cancer cell lines, the concentration of cetuximab that completely inhibited proliferation of cells with amplified EGFR copy number did not affect proliferation of cells with unamplified EGFR.


CONCLUSIONS
We propose that the response to antiEGFR treatment has a genetic basis and suggest that patients might be selected for treatment on the basis of EGFR copy number.
Moroni
Mauro
M
The Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda, Milan, Italy.
Veronese
Silvio
S
Benvenuti
Silvia
S
Marrapese
Giovanna
G
Sartore-Bianchi
Andrea
A
Di Nicolantonio
Federica
F
Gambacorta
Marcello
M
Siena
Salvatore
S
Bardelli
Alberto
A
D000368:Aged; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000068818:Cetuximab; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics* / Q000276:immunology*; D005260:Female; D018628:Gene Dosage; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009362:Neoplasm Metastasis; D000077544:Panitumumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077544:Panitumumab; D000077146:Irinotecan; D066246:ErbB Receptors; D000068818:Cetuximab; D002166:Camptothecin