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.
ABSTRACT
A phase II study was conducted to evaluate the safety and efficacy of the combination GIP (gemcitabine, ifosfamide, and cisplatin) for the treatment of patients with advanced non-small-cell lung cancer (NSCLC). Thirty patients with stage III B/IV NSCLC were treated with a combination of GIP. Patients received gemcitabine 1,000 mg/m2 administered intravenously on days 1 and 8, ifosfamide 3,500 mg/m2 on day 2, and cisplatin 80 mg/m2 on day 2, repeated every 21 days. Two of the 30 patients (7%) showed a complete response and 14 patients (46%) showed a partial response. The overall response rate was 53%. The estimated median survival for all patients was 60 weeks. All patients enrolled onto the study were eligible for toxicity assessment. Toxicities were treatable and included World Health Organization grade III or IV leukopenia (29%), thrombocytopenia (18%), anemia (7%) and nausea, and vomiting (6%). Febrile neutropenia occurred in 3 of 30 patients. There were no treatment-related deaths. The combination therapy of GIP is active, well tolerated, and easy to administer on an outpatient basis in advanced NSCLC.
