TY - JOUR
T1 - Prospective evaluation of cetuximab-mediated antibody-dependent cell cytotoxicity in metastatic colorectal cancer patients predicts treatment efficacy
AU - Trotta, Anna Maria
AU - Ottaiano, Alessandro
AU - Romano, Carmela
AU - Nasti, Guglielmo
AU - Nappi, Anna
AU - De Divitiis, Chiara
AU - Napolitano, Maria
AU - Zanotta, Serena
AU - Casaretti, Rossana
AU - D'Alterio, Crescenzo
AU - Avallone, Antonio
AU - Califano, Daniela
AU - Iaffaioli, Rosario Vincenzo
AU - Scala, Stefania
PY - 2016
Y1 - 2016
N2 - Cetuximab is a monoclonal antibody to the EGFR that induces antibody-dependent cell cytotoxicity (ADCC) through Fcg receptors on immune cells. Although SNPs in genes encoding Fcg receptors are functionally relevant to cetuximab-mediated ADCC in colorectal cancer, a direct correlation between in vitro ADCC and clinical response to cetuximab is not defined. We therefore enrolled 96 consecutive metastatic colorectal cancer (mCRC) patients at diagnosis in a study that assessed FcγR status and cetuximab-mediated ADCC. Patients carrying the FcγRIIa H alleles 131H/H and 131H/R had significantly higher ADCC compared with patients with the 131R/R alleles (P = 0.013). Patients carrying FcγRIIIa genotypes with the V alleles 158V/V and 158V/F displayed higher ADCC compared with patients carrying the 158F/F genotype (P = 0.001). Progression-free survival of patients with an FcγRIIIa 158V allele was significantly longer compared with patients carrying 158F/F (P = 0.05), whereas no significant difference was observed for overall survival. Twentyeight of 50 mCRC patients with wild-type KRAS received cetuximab. The average ADCC-mediated killing was 30% of assay targets for patients who experienced cetuximab complete or partial response, 21% in patients with stable disease and 9% in patients with progressive disease. To characterize basal natural killer (NK) activity, cytotoxicity was evaluated in 39 of 96 mCRC patients. Patients who responded to first-line treatment had higher NK-cell cytotoxicity. Thus, although limited to this cohort of patients, in vitro cetuximab-mediated ADCC correlated with FcgR polymorphisms and predicted cetuximab responsiveness.
AB - Cetuximab is a monoclonal antibody to the EGFR that induces antibody-dependent cell cytotoxicity (ADCC) through Fcg receptors on immune cells. Although SNPs in genes encoding Fcg receptors are functionally relevant to cetuximab-mediated ADCC in colorectal cancer, a direct correlation between in vitro ADCC and clinical response to cetuximab is not defined. We therefore enrolled 96 consecutive metastatic colorectal cancer (mCRC) patients at diagnosis in a study that assessed FcγR status and cetuximab-mediated ADCC. Patients carrying the FcγRIIa H alleles 131H/H and 131H/R had significantly higher ADCC compared with patients with the 131R/R alleles (P = 0.013). Patients carrying FcγRIIIa genotypes with the V alleles 158V/V and 158V/F displayed higher ADCC compared with patients carrying the 158F/F genotype (P = 0.001). Progression-free survival of patients with an FcγRIIIa 158V allele was significantly longer compared with patients carrying 158F/F (P = 0.05), whereas no significant difference was observed for overall survival. Twentyeight of 50 mCRC patients with wild-type KRAS received cetuximab. The average ADCC-mediated killing was 30% of assay targets for patients who experienced cetuximab complete or partial response, 21% in patients with stable disease and 9% in patients with progressive disease. To characterize basal natural killer (NK) activity, cytotoxicity was evaluated in 39 of 96 mCRC patients. Patients who responded to first-line treatment had higher NK-cell cytotoxicity. Thus, although limited to this cohort of patients, in vitro cetuximab-mediated ADCC correlated with FcgR polymorphisms and predicted cetuximab responsiveness.
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U2 - 10.1158/2326-6066.CIR-15-0184
DO - 10.1158/2326-6066.CIR-15-0184
M3 - Article
AN - SCOPUS:84978255425
VL - 4
SP - 366
EP - 374
JO - Cancer immunology research
JF - Cancer immunology research
SN - 2326-6066
IS - 4
ER -