Anti-EGFR monoclonal antibodies have shown efficacy in the treatment of metastatic colorectal cancer (mCRC). One of the mechanism is the antibody-dependent cell-mediated cytotoxicity (ADCC) in which Fc region of the antibody binds to the Fc gamma receptors (FcγR) expressed by immune cells. The present study investigated the association between single nucleotide polymorphisms of FcγRIIa and FcγRIIIa, in vitro ADCC and clinical outcome in mCRC patients treated with anti-EGFR antibodies. Fifty-five consecutive patients with mCRC were analyzed and the genotypes were distributed as follow: 38%HH, 47%HR and 15%RR for FcγRIIa; 26%VV, 44%VF and 30%FF for FcγRIIIa. The genotype frequencies in both were in Hardy-Weinberg Equilibrium. Heterozygosis for FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms were the most common genotype detected in mCRC and in healthy subjects (n=148) . The genotype frequencies of the H131R and V158F did not significantly differ between the two groups (p= 0.626, p=0.613 respectively). ADCC-cetuximab mediated was evaluate in HT29 human colon cancer cell line through two in vitro assays (SRB assayand CytoTox96) demonstrated to be technically comparable. Interleukin-2 (IL-2) activated PBMCs (LAK) cells of 55 study cases were used to evaluate in vitro ADCC-cetuximab mediated against HT-29, human colon cancer cells. Patients carrying the Fc gamma IIIA genotypes V/V or V/F induced an higher ADCC- cetuximab mediated compared to F/F carrying patients (average value ADCC with cetuximab-ADCC without cetuximab in patients carrying VV genotype = 39%, average value ADCC with cetuximab-ADCC without cetuximab in patients carrying V/F = 21% and average value ADCC with cetuximab-ADCC without cetuximab in patients carrying F/F genotype 6% respectively;p<0.001). To investigate the role of FcγRIIIa higher expression in ADCC, FcγRIIIa mRNA expression was determined by quantitative real-time PCR in 34 mCRC patients distributed for genotype as follows 12VV, 14VF and 8FF. Although the FcγRIIIa transcript level was higher in patients with FcRIIIa-158 V/V or V/F compared to F/F, analysis of variance showed no statistically significant differences (p=0.240). The study is currently recruiting consecutive mCRC patients evaluating FcγR polymorphisms, the effective in vitro cetuximab-ADCC activity and biological tumor features to be evaluated with a prognostic/ predictive intent.
Citation Format: Anna Maria Trotta, Alessandro Ottaiano, Serena Zannotta, Maria Napolitano, Guglielmo Nasti, Rosario Vincenzo Iaffaioli, Stefania Scala. Fc gamma receptor IIIa polymorphisms correlated with antibody-dependent cell-mediated cytotoxicity (ADCC): anti-EGFR antibodies induced and clinical outcome in metastatic colorectal cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2393. doi:10.1158/1538-7445.AM2013-2393