Evidence-Based Medicine
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Feb 15, 2016; 8(2): 222-230
Published online Feb 15, 2016. doi: 10.4251/wjgo.v8.i2.222
Evaluation of antibody-dependent cell-mediated cytotoxicity activity and cetuximab response in KRAS wild-type metastatic colorectal cancer patients
Cristiana Lo Nigro, Vincenzo Ricci, Daniela Vivenza, Martino Monteverde, Giuliana Strola, Francesco Lucio, Federica Tonissi, Emanuela Miraglio, Cristina Granetto, Mirella Fortunato, Marco Carlo Merlano
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
Vincenzo Ricci, Emanuela Miraglio, Cristina Granetto, Marco Carlo Merlano, Medical Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy
Giuliana Strola, Laboratory Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy
Francesco Lucio, Radiotherapy Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy
Mirella Fortunato, Pathology Department, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy
Author contributions: Lo Nigro C, Ricci V and Merlano MC designed the study; Ricci V, Miraglio E and Granetto C enrolled the patients and collected clinical data; Vivenza D, Monteverde M and Tonissi F performed ADCC assays and genotyping analyses; Strola G performed all the cytofluorimetric studies; Fortunato M selected patient’s tumoral samples; Vivenza D and Lucio F performed the statistical analysis; Lo Nigro C, Ricci V and Merlano MC critically visioned the results and were equally involved in the writing of the paper with Vivenza D.
Conflict-of-interest statement: The authors declare no conflicts of interest regarding this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Cristiana Lo Nigro, PhD, Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, Via Carle 25, 12100 Cuneo, Italy. lonigro.c@ospedale.cuneo.it
Telephone: +39-0171-616338 Fax: +39-0171-616331
Received: July 29, 2015
Peer-review started: July 31, 2015
First decision: September 29, 2015
Revised: November 27, 2015
Accepted: December 9, 2015
Article in press: December 11, 2015
Published online: February 15, 2016
Abstract

AIM: 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.

CONCLUSION: 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.

Keywords: Metastatic colorectal cancer, Single nucleotide polymorphism in Fc-γ receptors, Cetuximab, RAS family, Antibody-dependent cell-mediated cytotoxicity, Invariant natural killer T cells

Core tip: A high number of invariant natural killer T (iNKT) cells and a high antibody-dependent cell-mediated cytotoxicity (ADCC) activity, evaluated before therapy, do correlate significantly with a longer overall survival in metastatic colorectal cancer patients treated with irinotecan-based chemotherapy and cetuximab in II and III lines. Chemotherapy impacted both iNKT cells and ADCC activity. The prognostic value of ADCC above the median basal level, get lost when we analysed those parameters after 2 and 4 mo of treatment. Correlation of overall survival and progression-free survival with interesting single nucleotide polymorphisms reported as involved in ADCC ability, either in the FCGR2A, FCGR3A or in the 3’ untranslated regions of KRAS gene, revealed not to be significant.