RESUMO
PURPOSE: To investigate the association between single nucleotide polymorphisms (SNPs) in endothelial nitric oxide synthase (eNOS) and interleukin-8 (IL-8) genes and risk of developing bevacizumab-related adverse events in metastatic breast cancer (mBC) patients. PATIENTS AND METHODS: mBC patients candidate to receive bevacizumab-based chemotherapy were enrolled in this pharmacogenetic study. eNOS c.-813C>T and c.894G>T, and IL-8 c.-251A>T were analyzed by real time PCR on genomic DNA extracted from peripheral blood. Univariate analysis was performed to test the association between each SNP and treatment-related toxicities. RESULTS: Seventy-six mBC patients were enrolled in the present study. Patients carrying the homozygous variant eNOS c.-813TT genotype showed a statistically significant occurrence of any grade proteinuria when compared to CT or CC genotypes (p = 0.004). No significant association of proteinuria with IL-8 SNP or hypertension with selected eNOS and IL-8 SNPs was found. CONCLUSIONS: These findings suggest an association between the eNOS c.-813C>T polymorphism and the development of proteinuria in mBC patients receiving a bevacizumab-based chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/genética , Proteinúria/induzido quimicamente , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Hipertensão/induzido quimicamente , Hipertensão/epidemiologia , Hipertensão/genética , Interleucina-8/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Intervalo Livre de Progressão , Proteinúria/epidemiologia , Proteinúria/genética , Proteinúria/urinaRESUMO
PURPOSE: To investigate the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) combined to Cyclophosphamide (CTX) and followed by weekly Paclitaxel, in older patients (≥65 years) with diagnosis of high risk breast cancer. The main end point of this prospective study was the detection of early episodes of symptomatic congestive heart failure (CHF). METHODS: The cardiac function was evaluated by left ventricular ejection fraction (LVEF) measurements with repeated echocardiograms, performed 2 weeks before the beginning of chemotherapy and every 6 months, until 30 months after the study entry; then yearly for at least 5 years. RESULTS: Forty-seven patients were enrolled from two Italian Divisions of Medical Oncology. Final results revealed no early episodes of symptomatic CHF within the first 12 months from the enrolment. Only two cardiac events were observed: an episode of atrial flutter after the first cycle of NPL-DOX and CTX, with a quick return to normal rhythm, and a grade 3 (scored to NCI-CTCAE, version 3.0) CHF episode, 18 months later chemotherapy start. No other relevant toxicities were reported. CONCLUSIONS: This adjuvant combination including NPL-DOX in elderly patients, resulted in a low rate of cardiac toxic effects. Comparative trials should be encouraged to confirm these findings.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Insuficiência Cardíaca/induzido quimicamente , Coração/efeitos dos fármacos , Fatores Etários , Idoso , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante/efeitos adversos , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Ecocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Humanos , Metástase Linfática , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Polietilenoglicóis/administração & dosagem , Estudos Prospectivos , Volume SistólicoRESUMO
AIM: To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1 and TSP-1 SNPs and their role on progression-free survival in a population of metastatic breast cancer patients treated with bevacizumab in combination with first-line paclitaxel. PATIENTS & METHODS: Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time polymerase chain reaction technique. The multifactor dimensionality reduction methodology was applied to investigate the interaction between SNPs. RESULTS: One hundred and thirteen patients were enrolled from eight Italian Oncology Units ( clinicaltrial.gov : NCT01935102). The multifactor dimensionality reduction software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGFR-2 rs11133360 and IL-8 rs4073 genotypes. The median progression-free survival was 14.1 months (95% CI: 11.4-16.8) and 10.2 months (95% CI: 8.8-11.5) for the favorable and the unfavorable genetic profile, respectively (HR: 0.44, 95% CI: 0.29-0.66, p < 0.0001). CONCLUSION: The pharmacogenetic statistical interaction between VEGFR-2 rs11133360 and IL-8 rs4073 genotypes may identify a population of patients with a better outcome.
Assuntos
Neoplasias da Mama/genética , Interleucina-8/genética , Farmacogenética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Bevacizumab , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Estudos de Associação Genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Polimorfismo de Nucleotídeo Único , Trombospondina 1/genética , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/genéticaAssuntos
Antineoplásicos Alquilantes/administração & dosagem , Ciclofosfamida/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Celecoxib , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Dexametasona/administração & dosagem , Humanos , Masculino , Pirazóis/administração & dosagem , Estudos Retrospectivos , Sulfonamidas/administração & dosagemRESUMO
Recent data reported an association between VEGF-A genotype of tumors and median overall survival as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer. In the present case we report a discordant VEGF-A genotype between tumor and normal tissue in a patient with a responsive hepatic lesion of chemoresistant breast cancer treated with bevacizumab and paclitaxel. Moreover, we show that, despite the very low VEGF-A protein expression, the neoplastic lesion was well vascularized and responded to bevacizumab therapy. The discordance of VEGF-A polymorphisms in tumor and germline DNA may suggest the importance of obtaining both information in order to predict a superior overall survival or a lower risk of hypertension in patients treated with taxanes and bevacizumab.
