Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan.
OBJECTIVE
The antiepidermal growth factor receptor antibody cetuximab shows activity in irinotecan-refractory metastatic colorectal cancer (mCRC), mainly in wild-type KRAS tumors. Cetuximab may also exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC) in which antibody Fc portion interacts with Fc receptors (FcgammaRs) expressed by immune cells. ADCC is influenced by FcgammaRIIa-H131R and FcgammaRIIIa-V158F polymorphisms that are clinically relevant in follicular lymphoma and metastatic breast cancer treated with rituximab and trastuzumab, respectively. We investigated the association of FcgammaR polymorphisms and KRAS mutation with the outcome of irinotecan-refractory mCRC patients treated with cetuximab plus irinotecan.


METHODS
Tumor and normal tissues from 69 patients were screened for KRAS mutations using a sensitive multiplex assay and genotyped for FcgammaRIIa and FcgammaRIIIa polymorphisms by direct sequencing and multiplex allele-specific polymerase chain reaction, respectively. The results were correlated with response and progression-free survival (PFS).


RESULTS
KRAS mutations were associated with lower response rate (4% v 27% in nonmutated patients; P = .021) and shorter PFS (3.0 v 5.3 months; P = .021). Patients with FcgammaRIIa-131H/H and/or FcgammaIIIa-158V/V genotypes had longer PFS than 131R and 158F carriers (5.5 v 3.0 months; P = .005). The difference remained significant for mutated-KRAS patients. By multivariate analysis, KRAS mutation and FcgammaR combined status were independent risk factors for PFS.


CONCLUSIONS
Combined FcgammaRIIa/FcgammaRIIIa polymorphisms are prognostic factors for disease progression in mCRC patients treated with cetuximab plus irinotecan. As these polymorphisms are also clinically relevant in mutated-KRAS mCRC, an important role of ADCC in cetuximab efficacy is presumed.
Bibeau
Frédéric
F
Département de Pathologie, Centre Régional de Lutte Contre le Cancer Val d'Aurelle-Paul Lamarque, 208 rue des Apothicaires, Parc Euromédecine, 34298 Montpellier Cedex 05 France. fbibeau@valdorel.fnclcc.fr
Lopez-Crapez
Evelyne
E
Di Fiore
Frédéric
F
Thezenas
Simon
S
Ychou
Marc
M
Blanchard
France
F
Lamy
Aude
A
Penault-Llorca
Frédérique
F
Frébourg
Thierry
T
Michel
Pierre
P
Sabourin
Jean-Christophe
JC
Boissière-Michot
Florence
F
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D017452:Receptors, IgG / Q000235:genetics*; D012189:Retrospective Studies; D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C080568:Fc gamma receptor IIA; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002166:Camptothecin