Prospective evaluation of cetuximab-mediated antibody-dependent cell cytotoxicity in metastatic colorectal cancer patients predicts treatment efficacy

Anna Maria Trotta, Alessandro Ottaiano, Carmela Romano, Guglielmo Nasti, Anna Nappi, Chiara De Divitiis, Maria Napolitano, Serena Zanotta, Rossana Casaretti, Crescenzo D'Alterio, Antonio Avallone, Daniela Califano, Rosario Vincenzo Iaffaioli, Stefania Scala

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)366-374
Number of pages9
JournalCancer immunology research
Volume4
Issue number4
DOIs
Publication statusPublished - 2016

ASJC Scopus subject areas

  • Cancer Research
  • Immunology

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