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.

Introduction 3. Epidermal Growth Factor Receptor (EGFR) 3.1. Ras 4. Cetuximab 4.1. The role of cetuximab in refractory colorectal cancer 4.2. The role of cetuximab in first and second line in metastatic colorectal cancer 4.3. Toxicity 4.4. The role of cetuximab in adjuvant therapy of colorectal cancer 4.5. The role of neoadjuvant cetuximab in rectal cancer 5. Panitumumab 5.1. The role of panitumumab in refractory colorectal cancer 5.2. The role of panitumumab in first line in metastatic colorectal cancer 6. Dual antibody therapy 7. Perspectives 8. Acknowledgement 9.References