Cetuximab is a monoclonal antibody to the epidermal growth factor receptor (EGFR) that induces antibody-dependent cell cytotoxicity (ADCC) through Fcγ receptors on immune cells. Although single nucleotide polymorphisms in genes encoding Fcγ receptors are functionally relevant to cetuximab-mediated ADCC in colorectal cancer (CRC), a direct correlation between in vitro ADCC and clinical response to cetuximab is not defined. We therefore enrolled 96 consecutive metastatic CRC (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 to 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 to patients carrying the 158F/F genotype (P = 0.001). Progression-free survival of patients with an FcγRIIIa 158V allele was significantly longer compared to patients carrying 158F/F (P = 0.05), whereas no significant difference was observed for overall survival. Twenty-eight 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 NK activity, cytotoxicity was evaluated in 39/96 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 FcγR polymorphisms and predicted cetuximab responsiveness.
- Received July 27, 2015.
- Revision received October 20, 2015.
- Accepted December 10, 2015.
- Copyright © 2016, American Association for Cancer Research.