title: KIR Genes and Their Ligands Predict the Response to Anti-EGFR Monoclonal Antibodies in Solid Tumors.
abstract: Killer-cell immunoglobulin-like receptors (KIRs) regulate the killing function of natural killer cells, which play an important role in the antibody-dependent cell-mediated cytotoxicity response exerted by therapeutic monoclonal antibodies (mAbs). However, it is unknown whether the extensive genetic variability of KIR genes and/or their human leukocyte antigen (HLA) ligands might influence the response to these treatments. This study aimed to explore whether the variability in KIR/HLA genes may be associated with the variable response observed to mAbs based anti-epidermal growth factor receptor (EGFR) therapies. Thirty-nine patients treated with anti-EGFR mAbs (trastuzumab for advanced breast cancer, or cetuximab for advanced colorectal or advanced head and neck cancer) were included in the study. All the patients had progressed to mAbs therapy and were grouped into two categories taking into account time to treatment failure (TTF ≤6 and ≥10 months). KIR genotyping (16 genetic variability) was performed in genomic DNA from peripheral blood by PCR sequence-specific primer technique, and HLA ligand typing was performed for HLA-B and -C loci by reverse polymerase chain reaction sequence-specific oligonucleotide methodology. Subjects carrying the KIR/HLA ligand combinations KIR2DS1/HLAC2C2-C1C2 and KIR3DS1/HLABw4w4-w4w6 showed longer TTF than non-carriers counterparts (14.76 vs. 3.73 months,p< 0.001 and 14.93 vs. 4.6 months,p= 0.005, respectively). No other significant differences were observed. Two activating KIR/HLA ligand combinations predict better response of patients to anti-EGFR therapy. These findings increase the overall knowledge on the role of specific gene variants related to responsiveness to anti-EGFR treatment in solid tumors and highlight the importance of assessing gene polymorphisms related to cancer medications.
authors.affiliation: Medical Oncology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba , Cordoba , Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Morales-Estevez
authors.affiliation: Medical Oncology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: De la Haba-Rodriguez
authors.affiliation: Immunology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba , Cordoba , Spain.
authors.forename: Barbara
authors.initials: B
authors.lastname: Manzanares-Martin
authors.affiliation: Medical Oncology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba , Cordoba , Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Porras-Quintela
authors.affiliation: Medical Oncology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rodriguez-Ariza
authors.affiliation: Medical Oncology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba , Cordoba , Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Moreno-Vega
authors.affiliation: Medical Oncology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba , Cordoba , Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ortiz-Morales
authors.affiliation: Medical Oncology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba , Cordoba , Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Gomez-España
authors.affiliation: Medical Oncology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba , Cordoba , Spain.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Cano-Osuna
authors.affiliation: Medical Oncology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba , Cordoba , Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Lopez-Gonzalez
authors.affiliation: Medical Oncology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba , Cordoba , Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Chia-Delgado
authors.affiliation: Immunology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba , Cordoba , Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Gonzalez-Fernandez
authors.affiliation: Medical Oncology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Aranda-Aguilar
keywords: KIR receptor; KIR/HLA ligands; advanced cancer; anti-EGFR; natural killer cells; solid tumor