title: Prospective Evaluation of Cetuximab-Mediated Antibody-Dependent Cell Cytotoxicity in Metastatic Colorectal Cancer Patients Predicts Treatment Efficacy.
abstract: Cetuximab is a monoclonal antibody to the EGFR that induces antibody-dependent cell cytotoxicity (ADCC) through Fcγ receptors on immune cells. Although SNPs in genes encoding Fcγ 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/Hand 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. 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 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 FcγR polymorphisms and predicted cetuximab responsiveness.
authors.affiliation: Molecular Immunology and Immuneregulation Functional Genomics, Naples, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Trotta
authors.affiliation: Department of Abdominal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ottaiano
authors.affiliation: Department of Abdominal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Romano
authors.affiliation: Department of Abdominal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Nasti
authors.affiliation: Department of Abdominal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Nappi
authors.affiliation: Department of Abdominal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: De Divitiis
authors.affiliation: Molecular Immunology and Immuneregulation Functional Genomics, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Napolitano
authors.affiliation: Molecular Immunology and Immuneregulation Functional Genomics, Naples, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Zanotta
authors.affiliation: Department of Abdominal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Casaretti
authors.affiliation: Molecular Immunology and Immuneregulation Functional Genomics, Naples, Italy.
authors.forename: Crescenzo
authors.initials: C
authors.lastname: D'Alterio
authors.affiliation: Department of Abdominal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Avallone
authors.affiliation: Molecular Immunology and Immuneregulation Functional Genomics, Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Califano
authors.affiliation: Department of Abdominal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Rosario Vincenzo
authors.initials: RV
authors.lastname: Iaffaioli
authors.affiliation: Molecular Immunology and Immuneregulation Functional Genomics, Naples, Italy. scalaste@gmail.com.
authors.forename: Stefania
authors.initials: S
authors.lastname: Scala
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C080568:Fc gamma receptor IIA; C117307:KRAS protein, human; D017452:Receptors, IgG; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab