Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
Clin. transl. oncol. (Print) ; 24(10): 1975–1985, octubre 2022. graf
Artigo em Inglês | IBECS | ID: ibc-207953

RESUMO

Purpose: Lung cancer is one of the most common carcinomas with the highest mortality in the world. Non-small cell lung carcinoma has a large proportion of epidermal growth factor receptor (EGFR) mutations, of which rare EGFR mutations account for about 10%–20%. Currently, tyrosine kinase inhibitors (TKIs) therapy is a standard treatment for patients with non-small cell lung carcinoma with EGFR mutations. To date, the toxicological effects of the EGFR L861Q variant (less than 2%) have been rarely reported, so further investigation of its sensitivity to six first-in-class TKIs is of great clinical interest.MethodsIn this study, two EGFR L861Q variants cell lines (EGFR L861Q variant and EGFR L861Q + exon 19 deletion variant) were established by CRISPR-Cas9 gene-editing technology. The steady-state plasma concentrations of six TKIs (gefitinib/erlotinib/icotinib, the first generation; dacomitinib/afatinib, the second generation; and osimertinib, the third generation) were tested, respectively. The change of cell viability, proliferation, cloning ability, mitochondrial membrane potential and apoptosis were detected by MTT assay, EdU staining assay, colony formation assay, mitochondrial membrane potential and apoptosis test. TUNEL and Annexin V / PI staining were used to detect cell apoptosis, and flow cytometry was employed to explore the sensitivity of two variants to six TKIs.ResultsOur study indicated that the six TKIs inhibited the viability of the two cell lines in a time-dependent manner, and the inhibitory time of six TKIs on proliferation was different between the two cell lines. The proliferation and cloning ability of two cell lines were inhibited by six TKIs. The cytoskeleton morphology, microfilament structure and distribution of the two cell lines were changed by six TKIs. (AU)


Assuntos
Humanos , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Cloridrato de Erlotinib , Gefitinibe , Neoplasias Pulmonares , Mutação
3.
Clin. transl. oncol. (Print) ; 20(2): 140-149, feb. 2018. tab, graf
Artigo em Inglês | IBECS | ID: ibc-170553

RESUMO

Background. Erlotinib has been approved for the management of NSCLC patients after failure of the first or subsequent line of chemotherapy. Although the efficacy of erlotinib is clearly associated with the presence of EGFR mutations, there is a subset of patients with EGFR wild-type (EGFRwt) tumors who impressively respond. Patients and methods. Patients with EGFRwt NSCLC who received salvage (≥2nd line) treatment with erlotinib for a prolonged period (>6 months), were sought from the database of the Hellenic Oncology Research Group. We retrospectively analyzed the clinical, pathological and molecular characteristics of the patients with available tumor material. Results. Forty-four patients that received erlotinib for >6 months (median 10.1 months) were enrolled in the study. The majority of them were male, never-smokers with adenocarcinoma histology and a good performance status. KRAS and PIK3CA mutations were detected in 21% (9/42 tested) and 13% (4/30 tested) of the patients, respectively. The ALK-EML4 translocation was found in 10% (2/20 tested); there was no patient with HER2 or BRAF mutated tumor. Twelve (54.5%) tumor specimens were considered positive for EGFR-overexpression. Eleven patients experienced a partial response (objective response rate 25%; 95% CI 12-38%) and the remaining 33 had stable disease. The median progression-free survival and overall survival were 10.1 (95% CI 8.6-11.6 months) and 24.1 (95% CI 11.2-37 months), respectively. Conclusions. Treatment with erlotinib significantly improves the clinical outcome in a subset of NSCLC patients with EGFRwt tumors. Further molecular analysis of such tumor specimens could provide a more comprehensive characterization of this particular group of patients. Nevertheless, the presence of other mutations should not prevent the treating physician from using erlotinib at later lines of salvage therapy for NSCLC patients (AU)


No disponible


Assuntos
Humanos , Genes erbB-1/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Cloridrato de Erlotinib/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Estudos Retrospectivos , Resultado do Tratamento
4.
Rev. esp. patol. torac ; 29(4): 247-252, dic. 2017. ilus
Artigo em Espanhol | IBECS | ID: ibc-170402

RESUMO

Se presenta el caso de una paciente con antecedentes de ser fumadora de baja intensidad, con índice acumulado de tabaco menor de 5 paquetes/año y sin otros antecedentes personales de interés. Acudió en diversas ocasiones durante 2 meses a urgencias, refiriendo cefalea difusa, opresiva e intermitente y diplopía acompañada de visión borrosa ocasional, siendo diagnosticada de parálisis isquémica del IV par craneal del ojo izquierdo e iniciando tratamiento con antiagregante. A pesar del tratamiento, a la semana acudió de nuevo a urgencias, ya que progresivamente había ido presentado mareos, inestabilidad en la marcha, pérdida de visión con predominio en ojo izquierdo y mayor sensación de debilidad en miembros superiores, Finalmente, se decidió ingreso en Neurología ante la sospecha de meningoencefalitis subaguda tuberculosa, pero tras diversas pruebas diagnósticas se llegó a la conclusión de que se trataba de un adenocarcinoma pulmonar, que debutó en forma de carcinomatosis meníngea sin haber presentado sintomatología respiratoria asociada


A case is presented of a patient with a history of low-intensity smoking, with an accumulated tobacco index of less than 5 packs-year and without other personal history of interest. She went to the emergency room several times over 2 months, complaining of a diffuse, oppressive and intermittent headache and diplopia accompanied by occasional blurred vision, being diagnosed with ischemic paralysis of the fourth cranial nerve of the left eye and initiating treatment with antiplatelets. Despite treatment, she returned to the emergency room within a week, as she had been suffering from progressive dizziness, instability when walking, loss of vision mainly in the left eye and a greater feeling of weakness in the upper limbs. Finally, admission to Neurology was decided upon with the suspicion of subacute tuberculous meningoencephalitis. However, after various diagnostic tests, it was concluded that it was a pulmonary adenocarcinoma, which began as meningeal carcinomatosis without presenting associated respiratory symptoms


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Carcinomatose Meníngea/diagnóstico por imagem , Adenocarcinoma/complicações , Adenocarcinoma/diagnóstico por imagem , Radiografia Torácica/instrumentação , Neoplasias Pulmonares/tratamento farmacológico , Carcinomatose Meníngea/etiologia , Diplopia/complicações , Paralisia , Punção Espinal/métodos , Eletroencefalografia , Tomografia por Emissão de Pósitrons , Cloridrato de Erlotinib , Genes erbB-1 , Genes erbB-1/genética
6.
Med. clín (Ed. impr.) ; 146(supl.1): 7-11, abr. 2016. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-155621

RESUMO

Afatinib, junto con gefitinib y erlotinib, está aprobado para el tratamiento de primera línea del cáncer de pulmón de célula no pequeña avanzado con mutaciones activadoras del receptor del factor de crecimiento epidérmico (EGFR). Se trata de un inhibidor irreversible de la familia ErbB, que actúa sobre EGFR (HER1, ErbB1), ErbB2 (HER2) y ErbB4 (HER4). Su unión covalente a los residuos de cisteína en el dominio catalítico de EGFR, HER2 y ErbB4, inhibe la actividad tirosincinasa (ITK) de estos receptores, disminuyendo la auto y la transfosforilación entre los dímeros ErbB y bloqueando, por tanto, la actividad de diferentes vías de señalización intracelular relacionadas con el crecimiento y la supresión de la apoptosis celular. En los modelos preclínicos, esto se ha traducido en una reducción del tamaño tumoral. Además se sugiere que por su mecanismo de acción podría ser más potente que los EGFR ITK de primera generación (gefitinib y erlotinib) e incluso podría ser capaz de revertir la resistencia adquirida a dichos tratamientos. Por último, el sinergismo demostrado con otros agentes diana y quimioterápicos lo convierten en un fármaco de interés para potenciar su desarrollo clínico en combinación (AU)


Afatinib, together with gefitinib and erlotinib, is approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). This is an irreversible inhibitor of the ErbB family, acting on EGFR (HER1, ErbB1), ErbB2 (HER2) and ErbB4 (HER4). Covalent attachment to cysteine residues in the catalytic domain of EGFR, HER2 and ErbB4 inhibits the tyrosine kinase activity (TKIs) of these receptors, decreasing auto- and transphosphorylation between ErbB dimers, and thus blocking the activity of downstream signalling pathways related to growth and apoptosis suppression. In preclinical models, this has resulted in a reduction in tumour size. Furthermore, due to its mechanism of action, afatinib may be more potent than the first-generation EGFR TKIs (gefitinib and erlotinib) and may even be able to overcome acquired resistance to such treatments. Finally, because of the demonstrated synergism with other chemotherapeutic and target agents, it could be interesting to enhance its clinical development in combination with other drugs (AU)


Assuntos
Humanos , Masculino , Feminino , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/administração & dosagem , Receptores ErbB/uso terapêutico , Receptor ErbB-3/uso terapêutico , Receptores ErbB/análise , Apoptose , Técnicas In Vitro/instrumentação , Técnicas In Vitro , Cetuximab/uso terapêutico , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Fosforilação , Fosforilação/fisiologia , Proteínas Tirosina Quinases/análise , Receptor ErbB-3/administração & dosagem
7.
Med. clín (Ed. impr.) ; 146(supl.1): 12-18, abr. 2016. tab, graf, ilus
Artigo em Espanhol | IBECS | ID: ibc-155622

RESUMO

El descubrimiento de las mutaciones del receptor de factor de crecimiento epidérmico (EGFR) ha creado las bases para la medicina personalizada en el carcinoma de pulmón no microcítico (CPNM). Los inhibidores de la tirosincinasa (ITK) de primera generación, gefitinib y erlotinib, demostraron en ensayos fase III mayor eficacia comparados con la quimioterapia en los pacientes con mutaciones de EGFR, consiguiendo una supervivencia libre de progresión de 8-13,5 meses. Afatinib, un inhibidor irreversible pan-ErbB de segunda generación, es el primer ITK que ha mostrado un beneficio en la supervivencia global comparado con la quimioterapia en pacientes con CPNM con mutación de EGFR tratados en primera línea. La deleción en el exón 19 (Del19) y la mutación puntual en el exón 21 (L858R) constituyen las denominadas mutaciones activadoras, por conferir sensibilidad a los ITK, y representan aproximadamente el 90% de las mutaciones de EGFR en CPNM. Se ha observado diferente sensibilidad a los ITK según el tipo de mutación, observándose mayor supervivencia libre de progresión en pacientes con la Del19 de EGFR frente a quimioterapia. El análisis de supervivencia global de los ensayos LUX-Lung 3 y LUX-Lung 6 mostró un incremento estadísticamente significativo de la supervivencia en los pacientes tratados con afatinib y que presentaban Del19, mientras que este no fue significativo en los pacientes con mutación L858R. La comparación directa de afatinib y gefitinib en primera línea de tratamiento (ensayo LUX-Lung 7) mostró un aumento estadísticamente significativo de la supervivencia libre de progresión (hazard ratio: 0,73; intervalo de confianza del 95%, 0,57-0,95; p = 0,0165) a favor del afatinib. En el análisis por tipo de mutación, el beneficio se observó tanto para la Del19 como para la mutación L858R (AU)


The discovery of endothelial growth factor receptor (EGFR) mutations has laid the foundations for personalized medicine in non-small cell lung carcinoma (NSCLC). In phase III trials, the first-generation tyrosine kinase inhibitors (TKI), gefitinib and erlotinib, demonstrated greater efficacy compared with chemotherapy in patients with EGFR mutations, achieving progression-free survival of 8-13.5 months. Afatinib, a second-generation irreversible pan-ErbB inhibitor, is the first TKI that has shown a benefit in overall survival (OS) compared with chemotherapy in EGFR mutation-positive NSCLC when used as first-line treatment. Exon 19 deletion (Del19) and the single-point substitution mutation (L858R) in exon 21, called activating mutations due to their ability to confer sensitivity to TKI, represent approximately 90% of the EGFR mutations in NSCLC. Distinct sensitivity to TKI has been observed depending on the type of mutation, with greater progression-free survival in patients with the Del19 mutation. The analysis of OS in the LUX-Lung 3 and LUX-Lung 6 trials showed a statistically significant increase in survival in afatinib-treated patients with the Del 19 mutation, but no significant increase in that of patients with the L858R mutation. Direct comparison of afatinib and gefitinib as first-line therapy (LUX-Lung 7 trial) showed a statistically-significant increase in progression-free survival (hazard ratio: 0.73; 95% confidence interval, 0.57-0.95; p=0.0165) with afatinib. In the analysis by type of mutation, this benefit was observed for both the Del19 and the L858R mutations (AU)


Assuntos
Humanos , Masculino , Feminino , Proteínas Tirosina Quinases/análise , Neoplasias Pulmonares/tratamento farmacológico , Genes erbB-1 , Ensaios Clínicos Fase III como Assunto/métodos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Mutação , Cloridrato de Erlotinib/uso terapêutico , Resultado do Tratamento , Avaliação de Eficácia-Efetividade de Intervenções
8.
Med. clín (Ed. impr.) ; 146(supl.1): 19-24, abr. 2016. tab
Artigo em Espanhol | IBECS | ID: ibc-155623

RESUMO

Tras la descripción de la importancia de las mutaciones en EGFR en el carcinoma de pulmón no microcítico y una vez comprobado que los inhibidores de la tirosincinasa superan el beneficio producido por quimioterapia en pacientes con tumores EGFR+, el tratamiento con uno de estos fármacos se ha convertido en la recomendación estándar. A pesar de este avance, los pacientes acaban progresando, por lo que es necesario buscar alternativas de tratamiento. Existen estudios que han analizado la actividad de afatinib después de un tratamiento con un inhibidor de la tirosincinasa de primera generación e incluso de la administración también de quimioterapia convencional. Produce una tasa de respuestas y un tiempo de control de la enfermedad significativos tras la aparición de resistencia clínica, que son independientes de la existencia de la mutación de resistencia T790M y que podemos atribuir a mantener el control pan-HER. Además del ensayo clínico inicial, LUX-Lung 1, tenemos datos de utilización en la práctica clínica habitual dentro de programas de uso expandido. En conjunto, podemos esperar tasas de respuesta de entre el 7 y el 15% con una duración de alrededor de 24 semanas y una mediana del tiempo hasta progresión de unos 4 meses. Un estudio que lo combina con cetuximab ha obtenido una alta tasa de respuestas. La toxicidad de afatinib en segunda línea es semejante a cuando se utiliza en primera (fundamentalmente mucocutánea y diarreas) y manejable con las medidas habituales. En conjunto hay que considerar afatinib como una opción de tratamiento en pacientes con mutación de EGFR que progresan tras un primer inhibidor de la tirosincinasa (AU)


After description of the importance of EGFR mutations in non-small cell lung cancer and confirmation that tyrosine-kinase inhibitors are more beneficial than chemotherapy in patients with EGFR+ tumours, treatment with one of these drugs has become the standard recommendation. Despite this advance, patients continue to progress and consequently there is a need to search for alternative treatments. Some studies have analysed afatinib activity after first-generation TKI therapy, as well as its administration in combination with conventional chemotherapy. Afatinib produces significant response rates and progression-free survival times after the development of clinical resistance, which are independent of the presence of the T790M resistance mutation and can be attributed to continued pan-HER inhibition. In addition to the initial clinical trial, LUX-LUNG-1, data are available from the use of afatinib in routine clinical practice, within extended use programs. Overall, response rates of between 7 and 15% can be expected with a duration of approximately 24 months and a median progression-free time of about 4 months. A study combining afatinib with cetuximab has obtained a high response rate. Afatinib toxicity in second-line treatment is similar to that appears when the drug is used as first-line therapy (mainly mucocutaneous and diarrhoea) and can be managed with routine measures. In conclusion, afatinib should be considered as a treatment option in patients with EGFR mutations who show disease progression after a first tyrosine-kinase inhibitor (AU)


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/análise , Receptores ErbB/uso terapêutico , Proteínas Tirosina Quinases/uso terapêutico , Cloridrato de Erlotinib/uso terapêutico , Medicina Baseada em Evidências/métodos , Genes erbB-1 , Genes erbB-1/genética , Carcinoma/tratamento farmacológico , Pemetrexede/uso terapêutico , Qualidade de Vida
9.
Med. clín (Ed. impr.) ; 146(supl.1): 25-29, abr. 2016. graf
Artigo em Espanhol | IBECS | ID: ibc-155624

RESUMO

El carcinoma escamoso de pulmón (SCC) representa un 30% del cáncer de pulmón de célula no pequeña (CPCNP). Docetaxel y el inhibidor de la tirosincinasa (ITK) del EGFR, erlotinib, han sido los 2 únicos fármacos aprobados para el tratamiento de segunda línea del SCC avanzado. La sobreexpresión de EGFR puede explicar la sensibilidad de SCC a ITK. Erlotinib demostró beneficio significativo en supervivencia global (SG) en líneas sucesivas en CPCNP, incluyendo histología escamosa. La magnitud de este beneficio es similar a la de la QT. Afatinib es un inhibidor irreversible de toda la familia ErbB (EGFR, HER2-4), que ha sido aprobado recientemente para su indicación actual, CPCNP avanzado con mutación de EGFR, y tiene una toxicidad básicamente gastrointestinal y cutánea, bien definida y manejable. El ensayo LUX-Lung 8 fue un estudio fase III aleatorizado en pacientes con CPCNP con histología escamosa en segunda línea, que comparó erlotinib frente a afatinib. Se incluyeron 795 pacientes y se observó beneficio significativo para afatinib en supervivencia libre de progresión (2,7 frente a 1,9 meses; HR: 0,79; IC del 95%, 0,68-0,91; p = 0,0012) y en SG (7,9 frente a 6,8 meses; HR: 0,81; IC del 95%, 0,69-0,95; p = 0,0077), así como mejoría significativa en SG a 12 y 18 meses. Se observó más diarrea y estomatitis con afatinib y más exantema con erlotinib, pero la proporción global de toxicidad fue similar en cada grupo. Afatinib ofreció mejores resultados en calidad de vida. En resumen, afatinib es una opción de tratamiento en segunda línea en CPCNP escamocelular sobre la base de los resultados de mejoría en supervivencia respecto a erlotinib (AU)


Squamous cell carcinoma (SCC) of the lung represents 30% of non-small cell lung cancers (NSCLC). Docetaxel and the EGFR tyrosine kinase inhibitor (TKI), erlotinib, are the only two drugs approved for second-line treatment of advanced SCC. The sensitivity of SCC to TKIs can be explained by EGFR overexpression. Erlotinib demonstrated a significant benefit in terms of overall survival (OS) in successive lines in NSCLC, including squamous histology. The magnitude of this benefit is similar to that of chemotherapy. Afatinib is an irreversible inhibitor of the entire ErbB family (EGFR, HER2-4) that has recently been approved for its current indication, advanced EGFR mutation-positive NSCLC and has well-defined and manageable toxicity, mainly gastrointestinal and cutaneous. The LUX-Lung 8 study was a phase III randomized trial in patients with NSCLC with squamous histology that compared erlotinib versus afatinib as second-line treatment. A total of 795 patients were included and a significant benefit was observed for afatinib in progression-free survival (2.7 vs 1.9 months (HR 0.79 [95%CI 0.68-0.91]; p=0.0012) and in OS (7.9 vs 6.8 months (HR 0.81 [95%CI 0.69-0.95]; p=0.0077), as well as a significant improvement in OS at 12 and 18 months. More diarrhoea and stomatitis was observed with afatinib and more rash with erlotinib, but the overall proportion of toxicity was similar in each group. Afatinib offered better results in quality of life. In summary, afatinib is a second-line treatment option in squamous NSCLC based on its survival advantage over erlotinib (AU)


Assuntos
Humanos , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/uso terapêutico , Cloridrato de Erlotinib/uso terapêutico , Proteínas Tirosina Quinases/uso terapêutico , Genes erbB-2 , Diarreia/complicações , Diarreia/diagnóstico , Diarreia/tratamento farmacológico , Estomatite/complicações , Estomatite/tratamento farmacológico , Qualidade de Vida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...