RESUMO
Platinum-based chemotherapy is the standard treatment for NSCLC patients with EGFR wild-type, and as alternative to failure to EGFR inhibitors. However, this treatment is aggressive and most patients experience grade 3-4 toxicities. ERCC1, ERCC2, ERCC5, XRCC1, MDM2, ABCB1, MTHFR, MTR, SLC19A1, IL6 and IL16 gene polymorphisms may contribute to individual variation in toxicity to chemotherapy. The aim of this study was to evaluate the effect of these polymorphisms on platinum-based chemotherapy in NSCLC patients. A prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR Real-Time with Taqman(®) probes and sequencing. Patients with ERCC1 C118T-T allele (p=0.00345; RR=26.05; CI95%=4.33, 515.77) and ERCC2 rs50872-CC genotype (p=0.00291; RR=4.06; CI95%=1.66, 10.65) had higher risk of general toxicity for platinum-based chemotherapy. ERCC2 Asp312Asn G-alelle, ABCB1 C1236T-TT and the IL1B rs12621220-CT/TT genotypes conferred a higher risk to present multiple adverse events. The subtype toxicity analysis also revealed that ERCC2 rs50872-CC genotype (p=0.01562; OR=3.23; CI95%=1.29, 8.82) and IL16 rs7170924-T allele (p=0.01007; OR=3.19; CI95%=1.35, 7.97) were associated with grade 3-4 hematological toxicity. We did not found the influence of ERCC1 C8092A, ERCC2 Lys751Gln, ERCC2 Asp312Asn, ERCC5 Asp1104His, XRCC1 Arg194Trp, MDM2 rs1690924, ABCB1 C3435T, ABCB1 Ala893Ser/Thr, MTHFR A1298C, MTHFR C677T, IL1B rs1143623, IL1B rs16944, and IL1B rs1143627 on platinum-based chemotherapy toxicity. In conclusion, ERCC1 C118T, ERCC2 rs50872, ERCC2 Asp312Asn, ABCB1 C1236T, IL1B rs12621220 and IL16 rs7170924 polymorphisms may substantially act as prognostic factors in NSCLC patients treated with platinum-based chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Variantes Farmacogenômicos , Polimorfismo Genético , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Farmacogenética , Testes Farmacogenômicos , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
The aim of this study was to investigate the influence of clinical and genetic factors on response to tocilizumab (TCZ) response, remission, low disease activity (LDA) and DAS28 improvement. A retrospective cohort study in 79 RA patients treated with TCZ during 6/18 months of therapy was conducted. CD69(rs11052877), GALNT18(rs4910008), CLEC2D(rs1560011), KCNMB1(rs703505), ENOX1(rs9594987), rs10108210, and rs703297 gene polymorphisms, identified in a recent GWAS as putative predictors of TCZ response, were analysed. Variables independently associated to satisfactory EULAR response at 6 months were GALNT18-CC genotype (ORCC/T-:12.8; CI95%:1.5,108.7; p=0.02), CD69 gene polymorphism (ORAA/GG:17.2; CI95%:2.5,119.6; p=0.004) and lower number of previous biological therapy, BT (OR: 0.45; CI95%:0.3, 0.7; p=0.001). The factors independently associated to higher remission were lower number of previous BT (OR:0.56; CI95%:0.38, 0.82; p=0.003), and GALNT18 CC genotype (ORCT/CC:0.09; CI95%:0.02,0.45;p=0.004; ORTT/CC:0.14; CI95%:0.02,0.79; p=0.026). The A-allele of CD69 (ORA_/GG:6.68;CI95%:1.68,26.51;p=0.007) and lower number of previous BT (OR:0.50; CI95%:0.32,0.77; p=0.002) were independent factors capable to predict higher LDA rates at 6 months. Independent factors associated to higher improvement in DAS28 at 6 months were CD69-AA genotype (B=-0.56; CI95%:-1.09, -0.03; p=0.039), GALNT18-CC genotype (B=-0.88;CI95%:-1.49, -0.27; p=0.005), subcutaneous administration (B=1.03; CI95%:0.44,1.62; p=0.001) and higher baseline DAS28 (B=0.82; CI95%:0.59, 1.05; p=4.9×10(-10)). Lower number of previous BT was the only independent predictor of satisfactory EULAR response (OR:0.60; CI95%:0.34,0.88; p=0.010) and higher remission (OR:0.65; CI95%:0.46,0.93; p=0.018) at 18 months. The C-allele of GALNT18 (ORC-/TT:4.60; CI95%:1.16, 18.27; p=0.03) and lower number of previous BT (OR:0.47; CI95%:0.29,0.74; p=0.001) were independent factors capable to predict higher LDA rates at 18 months. In conclusion, RA patients treated with TCZ showed better EULAR response, remission, LDA and DAS28 improvement rates in patients carrying the GALNT18 C-allele or the CD69 A-allele, particularly when lower number of BT were previously administered.
