title: Evaluation of antibody-dependent cell-mediated cytotoxicity activity and cetuximab response in KRAS wild-type metastatic colorectal cancer patients.
abstract: OBJECTIVE
  To investigate the prognostic role of invariant natural killer T (iNKT) cells and antibody-dependent cell-mediated cytotoxicity (ADCC) in wild type KRAS metastatic colorectal cancer (mCRC) patients treated with cetuximab.
  
  
  METHODS
  Forty-one KRAS wt mCRC patients, treated with cetuximab and irinotecan-based chemotherapy in II and III lines were analyzed. Genotyping of single nucleotide polymorphism (SNP)s in the FCGR2A, FCGR3A and in the 3' untranslated regions of KRAS and mutational analysis for KRAS, BRAF and NRAS genes was determined either by sequencing or allelic discrimination assays. Enriched NK cells were obtained from lymphoprep-peripheral blood mononuclear cell and iNKT cells were defined by co-expression of CD3, TCRVα24, TCRVβ11. ADCC was evaluated as ex vivo NK-dependent activity, measuring lactate dehydrogenase release.
  
  
  RESULTS
  At basal, mCRC patients performing ADCC activity above the median level (71%) showed an improved overall survival (OS) compared to patients with ADCC below (median 16 vs 8 mo; P = 0.026). We did not find any significant correlation of iNKT cells with OS (P = 0.19), albeit we observed a trend to a longer survival after 10 mo in patients with iNKT above median basal level (0.382 cells/microliter). Correlation of OS and progression-free survival (PFS) with interesting SNPs involved in ADCC ability revealed not to be significant. Patients carrying alleles both with A in FCGR2A and TT in FCGR3A presented a trend of longer PFS (median 9 vs 5 mo; P = 0.064). Chemotherapy impacted both iNKT cells and ADCC activity. Their prognostic values get lost when we analysed them after 2 and 4 mo of treatment.
  
  
  CONCLUSIONS
  Our results suggest a link between iNKT cells, basal ADCC activity, genotypes in FCGR2A and FCGR3A, and efficacy of cetuximab in KRAS wt mCRC patients.
authors.affiliation: Cristiana Lo Nigro, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lo Nigro
authors.affiliation: Cristiana Lo Nigro, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Ricci
authors.affiliation: Cristiana Lo Nigro, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vivenza
authors.affiliation: Cristiana Lo Nigro, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Monteverde
authors.affiliation: Cristiana Lo Nigro, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Strola
authors.affiliation: Cristiana Lo Nigro, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lucio
authors.affiliation: Cristiana Lo Nigro, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Tonissi
authors.affiliation: Cristiana Lo Nigro, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Miraglio
authors.affiliation: Cristiana Lo Nigro, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Granetto
authors.affiliation: Cristiana Lo Nigro, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Fortunato
authors.affiliation: Cristiana Lo Nigro, Daniela Vivenza, Martino Monteverde, Federica Tonissi, Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy.
authors.forename: Marco Carlo
authors.initials: MC
authors.lastname: Merlano
keywords: Antibody-dependent cell-mediated cytotoxicity; Cetuximab; Invariant natural killer T cells; Metastatic colorectal cancer; RAS family; Single nucleotide polymorphism in Fc-γ receptors