RESUMEN
INTRODUCTION: The role of IMP3, CDK4, MDM2 and ß-catenin proteins in Enchondroma and Central Chondrosarcoma is not totally understood. The aim of this study is to evaluate the immunoexpression of these proteins, associating histological grade, clinical data and prognosis to these tumors. METHODS: This is a retrospective-analytical study of 32 Enchondroma and 70 Central Chondrosarcoma. RESULTS: IMP3, CDK4, MDM2 and ß-catenin expression was observed in 22.82 %, 13.82 %, 17.17 % and in 8.8 % of cases, respectively. All Enchondromas positive for these immunomarkers were located in short tubular bones. The positivity for these antibodies is directly proportional to Chondrosarcoma's histological grade increase. No difference was found between Enchondroma and Chondrosarcoma, Grade 1 for IMP3, CDK4 and ß-catenin positivity. Significant metastasis outcome was observed for IMP3, CDK4, MDM2 and death for MDM2 expression. CONCLUSION: IMP3, CDK4, MDM2 and ß-catenin expression in Enchondromas of short bones phenotypically characterizes these tumors. Their expression has not proven to be useful either as diagnostic markers of these neoplasms or in distinguishing between Enchondroma and Chondrosarcoma, Grade 1. The significant immunoexpression of IMP3, CDK4 and MDM2 in metastatic Chondrosarcoma and the lower survival in those with positivity for MDM2 suggest a possible association of these proteins with tumor aggressiveness.
Asunto(s)
Biomarcadores de Tumor , Neoplasias Óseas , Condroma , Condrosarcoma , Quinasa 4 Dependiente de la Ciclina , Inmunohistoquímica , Proteínas Proto-Oncogénicas c-mdm2 , beta Catenina , Humanos , Condrosarcoma/patología , Condrosarcoma/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/análisis , Masculino , Femenino , Neoplasias Óseas/patología , Neoplasias Óseas/metabolismo , Persona de Mediana Edad , beta Catenina/análisis , beta Catenina/metabolismo , Adulto , Estudios Retrospectivos , Biomarcadores de Tumor/análisis , Pronóstico , Condroma/patología , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/análisis , Anciano , Adulto Joven , Adolescente , Clasificación del Tumor , Niño , Proteínas de Unión al ARNRESUMEN
PURPOSE: The optimal treatment sequence for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) after progression on first-line cyclin-dependent kinase 4/6 inhibitor (CDKi) and endocrine therapy is unclear. Clinical and biological factors influencing treatment choices and outcomes in the second-line setting need to be elucidated. MATERIALS AND METHODS: This is a retrospective analysis of a real-world cohort including patients with HR+/HER2- ABC who received CDKi and endocrine therapy in the first-line setting and progressed, requiring second-line treatment. Clinical and biological factors were analyzed to evaluate their association with daily treatment decisions and the prognostic role of progression-free survival (PFS) in the second-line setting. RESULTS: Two hundred thirty-five patients were included. Second-line treatments were hormone therapy (HT) based in 60% and chemotherapy based in 40% of patients. The second-line median PFS was 6.6 months, with no difference between treatment types. In multivariable analysis, postmenopausal status, lower Ki-67 expression, and non-de novo stage IV disease were associated with improved second-line (2L) PFS. Menopausal status significantly interacted with treatment type, with reduced PFS in premenopausal patients receiving HT-based treatments (4.7 v 8.7 months, P = .00045). CONCLUSION: In our study, treatment decisions reflected the current algorithm incorporated in our clinical guidelines, and prior treatment response was the most relevant factor to determine 2L treatment decision. Menopausal status interacted with the subsequent therapy efficacy in this setting. Hence, we consider that menopausal status should be routinely evaluated in the subgroup analysis of clinical trials.
Asunto(s)
Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Inhibidores de Proteínas Quinasas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Persona de Mediana Edad , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Estudios Retrospectivos , Argentina/epidemiología , Anciano , Adulto , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano de 80 o más Años , Receptor ErbB-2/metabolismo , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: Cyclin-dependent kinases (CDK) 4/6 inhibitors have significantly improved outcomes for patients with ER+/HER2- breast cancer. Nevertheless, they differ from each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. METHODS: We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing the prevalence of QTc prolongation as an adverse event in HR+ breast cancer patients treated with CDK4/6i vs those without CDK4/6i. We pooled relative risk (RR) and mean difference (MD) with 95% confidence interval (CI) for the binary endpoint of QT prolongation. RESULTS: We included 14 RCTs comprising 16â196 patients, of whom 8576 underwent therapy with CDK4/6i. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR = 2.35, 95% CI = 1.67 to 3.29, P < .001; I2 = 44%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a relative risk of 3.12 (95% CI = 2.09 to 4.65, P < .001; I2 = 12%), whereas the palbociclib subgroup had a relative risk of 1.51 (95% CI = 1.05 to 2.15, P = .025; I2 = 0%). CONCLUSION: Palbociclib was associated with QTc prolongation; however, the relative risk for any grade QTc was quantitively twice with ribociclib. Furthermore, grade 3 QTc prolongations were observed exclusively with ribociclib. These results are important for guiding clinical decision-making and provide reassurance regarding the overall safety profile of this drug class.
Asunto(s)
Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Síndrome de QT Prolongado , Inhibidores de Proteínas Quinasas , Femenino , Humanos , Aminopiridinas/efectos adversos , Aminopiridinas/uso terapéutico , Aminopiridinas/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Síndrome de QT Prolongado/inducido químicamente , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Purinas/efectos adversos , Purinas/uso terapéutico , Purinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Roscovitina/efectos adversosRESUMEN
INTRODUCCIÓN: Cuadro clínico: El cáncer de mama es la primera causa de muerte por neoplasia maligna en mujeres. A nivel mundial, en el 2022, se produjeron 2.3 millones de casos nuevos y 666 103 muertes por cáncer de mama. En Latinoamérica, se estimó que la tasa estandarizada de incidencia es de 48.7 casos nuevos por cada 100 000 habitantes. Sobre la carga de enfermedad, los reportes nacionales informan que el cáncer de mama tiene una incidencia de 37.6 casos nuevos por cada 100 000 habitantes y produjo 39 139 años de vida saludables perdidos (AVISA) así como 9 049 años vividos por discapacidad (AVD). Según los subtipos moleculares, el más frecuente es el subtipo RH(+) y HER2(-), representando el 58.2% de casos. No se dispone de datos específicos epidemiológicos en el Perú para mujeres pre/perimenopáusicas con cáncer de mama RH (+) HER2(-) que han fallado a primera línea de terapia endocrina. Tecnología sanitária: El ribociclib es un inhibidor de la cinasa 4 dependiente de las ciclinas (CDK4) y la cinasa 6 dependiente de ciclinas (CDK6). Estas cinasas son proteínas que inducen el crecimiento tumoral. En Perú, el ribociclib cuenta con registro sanitario (N° EE10867), otorgado por la Dirección General de Medicamentos Insumos y Drogas (DIGEMID). Actualmente, ribociclib no forma parte del Petitorio Nacional Único de Medicamentos Esenciales (PNUME). Justificación de la evaluación: Este informe de ETS-EMC se realizó a solicitud de Comité Farmacoterapéutico (CFT) del Instituto Regional de Enfermedades Neoplásicas del Sur (IREN SUR) mediante Oficio N°475- 2023-GRA/GRS/GR-IREN-SUR, en e
Asunto(s)
Humanos , Premenopausia , Perimenopausia , Quinasa 4 Dependiente de la Ciclina/uso terapéutico , Quinasa 6 Dependiente de la Ciclina/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Evaluación en Salud/economía , Eficacia , Análisis Costo-Beneficio/economíaRESUMEN
INTRODUCCIÓN: Cuadro clínico: El cáncer de mama ocurre cuando existe un crecimiento desregulado de células en cualquier componente de la mama. La mayoría de cánceres de mama son de tipo invasivo, lo que significa que se extienden más allá de los ductos y glándulas a tejidos adyacentes y nódulos linfáticos. En Perú, en el año 2022 se reportaron 7,797 casos nuevos de cáncer de mama y 1,951 muertes en pacientes con cáncer de mama. Respecto a la carga de enfermedad por cáncer de mama en el Perú en el año 2019, por cada 1,000 habitantes, el cáncer de mama causó 39,139 años de vida saludable perdidos; 9,049 años de vida vividos con discapacidad y 30,091 años de vida perdidos por muerte prematura. Tecnología sanitária: El palbociclib, es un inhibidor de las cinasas dependientes de ciclina 4 (CDK4) y 6 (CDK6); controlando así la multiplicación celular. El fulvestrant es un antagonista competitivo de la unión de estrógenos al receptor de estrógenos; bloqueando así las acciones tróficas de los estrógenos. La dosis recomendada de la combinación palbociclib más fulvestrant (PAL + FUL) es 125 mg de palbociclib una vez al día durante 21 días consecutivos, seguidos de 7 días sin tratamiento, lo que completa el ciclo de 28 días; y 500 mg fulvestrant en los días 1, 15, 29, y luego una vez al mes. Justificación de la evaluación: Este documento técnico se realiza en base al envío de una solicitud del comité farmacoterapéutico (CFT) del Hospital Nacional Daniel Alcides Carrión, en el marco del numeral 13.5 del reglamento de la Ley Nacional de Cáncer y de la décimo sexta disposición complementaria final del reglamento de la Ley Nº 31336, Ley Nacional de Cáncer aprobado mediante Decreto Supremo Nº 004-2022-SA. OBJETIVOS: Identificar, evaluar y sintetizar la mejor evidencia disponible para informar los criterios de carga de enfermedad, efectos deseables, efectos indeseables, certeza de la evidencia, balance de efectos, nivel de innovación, equidad, recursos necesarios y costo-efectividad para la evaluación multicriterio de la tecnología sanitaria PAL+ FUL en mujeres postmenopáusicas con cáncer de mama avanzado o metastásico; positivo para el receptor de hormonas (HR+); negativo para el receptor 2 de factor de crecimiento epidérmico humano (HER2-), y progresión de la enfermedad luego de tratamiento endocrino. Reportar la valoración de los criterios y la recomendación efectuada por el Grupo de trabajo de la ETS-EMC respecto al uso de PAL + FUL en mujeres postmenopáusicas con cáncer de mama avanzado o metastásico; positivo para el receptor de hormonas (HR+); negativo para el receptor 2 de factor de crecimiento epidérmico humano (HER2-), y progresión de la enfermedad luego de tratamiento endocrino. METODOLOGÍA: Pregunta clínica y graduación de desenlaces: Se validó la pregunta clínica y graduó la importancia de los desenlaces incluidos con participación de profesionales de la institución solicitante y metodólogos a cargo de la presente ETS-EMC. Efectos deseables e indeseables (eficacia y seguridad): Se realizó una búsqueda bibliográfica en Medline (vía PubMed), The Cochrane Library (CENTRAL) y LILACS (Biblioteca virtual de Salud) desde la fecha de inserción de cada base de datos hasta el 24 de enero del 2024; la cual fue actualizada con fecha 16 de febrero de 2024. El proceso de selección de estudios fue desarrollado por un solo revisor y conducido en la plataforma electrónica Rayyan. Se evalúo el riesgo de sesgo mediante la herramienta Risk of Bias (RoB) de la colaboración Cochrane. La certeza de la evidencia fue evaluada mediante el enfoque Grading of Recommendations Assessment, Development and Evaluation (GRADE). Carga de enfermedad, necesidad clínica y equidade: Para estimar la carga de enfermedad, se revisó el Observatorio Global del Cáncer (GLOBOCAN), y el reporte epidemiológico del Centro Nacional de Epidemiología, Prevención y Control de Enfermedades (CDC) del Perú. Para evaluar la necesidad clínica, se revisó el Petitorio Nacional Único de Medicamentos Esenciales (PNUME) y la lista complementaria de medicamentos para el tratamiento de enfermedades neoplásicas. Para informar el impacto sobre la equidad en salud, se realizó una búsqueda de estudios realizados en América Latina publicados en Medline/PubMed hasta el 24 de enero del 2024; la cual fue actualizada con fecha 16 de febrero de 2024. Recursos necesarios (costos): Se desarrolló un estudio de costo de enfermedad desde la perspectiva del financiador incluyendo costos de procedimientos médicos, medicamentos e insumos. Se empleó un modelo estático con horizonte temporal de un año, con estimación de costos bottom-up y enfoque epidemiológico de prevalencia. Se definieron tres variantes clínicas de acuerdo a la pregunta PICO. Costo-efectividad: Se realizó una búsqueda en el repositorio de evaluaciones económicas de la Dirección General de Medicamentos, Insumos y Drogas (DIGEMID), la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y las páginas institucionales de organismos evaluadores de tecnología sanitaria de Colombia, Brasil, Argentina y Chile. Adicionalmente, se elaboró una estrategia de búsqueda en Medline/PubMed. La fecha de búsqueda fue el 24 de enero del 2024; la cual fue actualizada con fecha 16 de febrero de 2024. Elaboración de la recomendación clínica: Se convocó a un Grupo de trabajo conformado por representantes de la Red Oncológica Nacional (RON), la Dirección General de Aseguramiento e Intercambio Prestacional (DGAIN), el Fondo Intangible Solidario de Salud (FISAL), la Dirección General de Medicamentos, Insumos y Drogas (DIGEMID), y representantes de la institución solicitante (ie. Hospital Nacional Daniel Alcides Carrión). El equipo metodológico del Centro de Evaluación de Tecnología en Salud del Instituto Nacional de Salud (CETS/INS) presentó la evidencia para la evaluación de diez criterios: carga de enfermedad, necesidad clínica, efectos deseables (eficacia), efectos indeseables (seguridad), balance de efectos, certeza de evidencia, nivel de innovación, equidad, recursos necesarios y costo-efectividad. RESULTADOS: Pregunta clínica: La pregunta PICO formulada fue la siguiente, P: Mujeres postmenopáusicas con cáncer de mama avanzado o metastásico; positivo para el receptor de hormonas (HR+); negativo para el receptor 2 de factor de crecimiento epidérmico humano (HER2-), y progresión de la enfermedad luego de tratamiento endocrino; I: Palbociclib + fulvestrant.; C: Ribociclib + fulvestrant; O: Críticos: sobrevida global, calidad de vida, eventos adversos serios. Valoración de los criterios de decisión: Necesidad clínica: El grupo de trabajo concluyó que la población de pacientes descrita en la PICO cuenta con alternativas de tratamiento disponibles para el tratamiento; por lo tanto, no existe necesidad clínica. Efectos deseables e indeseables: Solo se identificó un estudio que cumplió con los criterios de elegibilidad (Rugo et al. 2021). La evidencia mostró que no había diferencia estadísticamente significativa entre PAL + FUL y RIB + FUL en términos de sobrevida global (diferencia en el riesgo de muerte de 3.8 muertes menos por cada 1000 personas; IC 95%: 20.4 muertes menos a 17.4 muertes más). Adicionalmente, la certeza de evidencia fue calificada como muy baja. No se identificaron estudios que comparen las tecnologías sanitarias PAL + FUL versus RIB + FUL en términos de calidad de vida e incidencia de eventos adversos serios en la población descrita en la PICO. Balance de efectos deseables e indeseables: En base a lo anterior, el grupo de trabajo concluyó por mayoría que el balance entre efectos deseables e indeseables no favorece a la intervención ni al comparador. Certeza global de la evidencia: Para valorar la certeza de la evidencia global se toma en cuenta la menor certeza de la evidencia de los desenlaces críticos, por ende, la certeza de la evidencia global fue considerada muy baja. Nivel de innovación: Se considera una tecnología sanitaria como innovadora si genera una mejora significativa en los desenlaces relevantes para la salud de los pacientes, en términos de mayor eficacia o seguridad en comparación con el mejor tratamiento disponible, basado en evidencia con certeza al menos moderada. La decisión del Grupo de trabajo fue considerar a PAL + FUL como una tecnología no innovadora debido a que la certeza de la evidencia para los desenlaces de beneficio fue muy baja. Equidad: No se encontró evidencia sobre el impacto que el uso de PAL + FUL podría tener sobre la equidad en salud. El grupo de trabajo tampoco identificó que el uso de PAL + FUL, en lugar de RIB + FUL, tuviese algún impacto sobre la equidad en salud. Por lo tanto, el grupo de trabajo concluyó que el tratamiento con PAL + FUL probablemente no tenga impacto en la equidad. Recursos necesarios (costos): El análisis de costos mostró que el uso de PAL + FUL en la población descrita en la PICO genera un incremento en los costos de entre 3.641.63 y 5.609.47 soles al año por cada paciente tratado según la variante clínica de presentación. Tomando en cuenta dicha información, el grupo de trabajo concluyó que el uso de PAL + FUL, en lugar de RIB + FUL genera costos y ahorros mínimos. RECOMENDACIÓN FORMULADA POR EL GRUPO DE TRABAJO: Considerando todo lo anteriormente expuesto, el grupo de trabajo formuló la siguiente recomendación clínica: En mujeres postmenopáusicas con cáncer de mama avanzado o metastásico; positivo para el receptor de hormonas; negativo para el receptor 2 de factor de crecimiento epidérmico humano, y progresión de la enfermedad luego de tratamiento endocrino, el grupo de trabajo no recomienda el uso de palbociclib más fulvestrant (recomendación en contra basada en una certeza global de la evidencia muy baja).
Asunto(s)
Humanos , Neoplasias de la Mama/tratamiento farmacológico , Posmenopausia , Genes erbB-2 , Metástasis de la Neoplasia/tratamiento farmacológico , Evaluación en Salud/economía , Eficacia , Análisis Costo-Beneficio/economía , Quinasa 4 Dependiente de la Ciclina/uso terapéutico , Quinasa 6 Dependiente de la Ciclina/uso terapéuticoRESUMEN
INTRODUCCIÓN: Cuadro clínico: El cáncer de mama ocurre cuando existe un crecimiento desregulado de células en cualquier componentede la mama. La mayoría de los cánceres de mama son de tipo invasivo, lo que significa que se extiendenmás allá de los ductos y glándulas a tejidos adyacentes y nódulos linfáticos. En Perú, en el año 2022 sereportaron 7,797 casos nuevos de cáncer de mama y 1,951 muertes en pacientes con cáncer de mama. Respecto a la carga de enfermedad por cáncer de mama en el Perú en el año 2019, por cada 1,000 habitantes, el cáncer de mama causó 39,139 años de vida saludable perdidos; 9,049 años de vida vividoscon discapacidad y 30,091 años de vida perdidos por muerte prematura. Tecnología sanitária: El ribociclib, también conocido como Kisqali ®, es un inhibidor de las cinasas dependientes de ciclina 4 (CDK4) y 6 (CDK6); controlando así la multiplicación celular. El fulvestrant es un antagonista competitivo de la unión de estrógenos al receptor de estrógenos; bloqueando así las acciones tróficas delos estrógenos. La dosis recomendada de ribociclib + fulvestrant es: es 600 mg de ribociclib (tres comprimidos recubiertos de 200 mg) una vez al día durante 21 días consecutivos, seguidos de 7 días sin tratamiento para completar un ciclo de 28 días. Cuando fulvestrant se administra con ribocic
Asunto(s)
Humanos , Neoplasias de la Mama/tratamiento farmacológico , Posmenopausia , Genes erbB-2 , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Evaluación en Salud/economía , Eficacia , Análisis Costo-Beneficio/economíaRESUMEN
INTRODUCTION: Cyclin-dependent kinases 4/6 inhibitors (CDK 4/6i) combined with endocrine therapy have become the gold standard in hormone receptor-positive (HR +) HER2-negative (HER2-) metastatic breast cancer (MBC). However, there is a significant lack of data regarding the efficacy and safety of these treatments in elderly patients. We present the results of a real-world data (RWD) cohort stratified by age at treatment initiation (≥ 70 years compared to patients < 70 years). METHODS: Clinico-pathological data of HR + HER2- MBC patients who were candidates for CDK4/6i therapy between January 2017 and December 2020 at the Institut Català d'Oncologia (Spain) were retrospectively collected. The primary goal was to assess Progression-Free Survival (PFS), Overall Survival (OS), and safety outcomes within this patient population. RESULTS: A total of 274 patients with MBC who received CDK4/6i treatment were included in the study. Among them, 84 patients (30.8%) were aged ≥ 70 years, with a mean age of 75, while 190 patients (69.2%) were under the age of 70, with a mean age of 55.7 years. The most frequently observed grade 3-4 toxicity was neutropenia, with similar rates in both the < 70 group (43.9%) and the ≥ 70 group (47.9%) (p = 0.728). The median Progression-Free Survival (mPFS) for the first-line CDK4/6i treatment was 22 months (95% CI, 15.4-39.8) in the < 70 group and 20.8 months (95% CI 11.2-NR) in the ≥ 70 group (p = 0.67). Similarly, the median PFS for the second-line CDK4/6i treatment was 10.4 months (95% CI, 7.4-15.1) and 7.1 months (95% CI 4.4-21.3) (p = 0.79), respectively. Median overall survival (mOS) was not reached either for the first- and second-line treatment. CONCLUSIONS: Our RWD suggests that elderly patients, when compared to those under 70, experience similar survival outcomes and exhibit comparable tolerance for CDK4/6i therapy.
Asunto(s)
Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas , Receptor ErbB-2 , Receptores de Progesterona , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Factores de Edad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios RetrospectivosRESUMEN
PURPOSE: To estimate the cost-effectiveness of adding a CDK4/6 inhibitor to standard endocrine therapy in the first-line setting for advanced HR+/HER2- breast cancer in postmenopausal and premenopausal women, from the perspective of the Mexican public healthcare system. METHODS: We used a partitioned survival model to simulate relevant health outcomes in a synthetic cohort of patients with breast cancer derived from the PALOMA-2, MONALEESA-2, MONARCH-3 trials for postmenopausal patients, and from the MONALEESA-7 study for premenopausal patients. Effectiveness was measured in life years gained. Cost-effectiveness is reported through incremental cost-effectiveness ratios (ICER). RESULTS: In postmenopausal patients, palbociclib led to an increase of 1.51 life years, ribociclib of 1.58 years, and abemaciclib of 1.75 years, compared to letrozole alone. The ICER was 36,648 USD, 32,422 USD, and 26,888 USD, respectively. In premenopausal patients, ribociclib led to an increase of 1.82 life years when added to goserelin and endocrine therapy, with an ICER of 44,579 USD. In the cost minimization analysis, for postmenopausal patients, ribociclib was the treatment with the highest costs due to follow-up requirements. CONCLUSION: Palbociclib, ribociclib, and abemaciclib demonstrated a significant increase in effectiveness in postmenopausal patients, and ribociclib in premenopausal patients, when added to standard endocrine therapy for patients with advanced HR+/HER2- breast cancer. At the national stablished willingness to pay, only the addition of abemaciclib to standard endocrine therapy in postmenopausal women would be considered cost-effective. However, differences on results between therapies for postmenopausal patients were not statistically significant.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Análisis Costo-Beneficio , México , Aminopiridinas/uso terapéutico , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Receptor ErbB-2 , Quinasa 4 Dependiente de la CiclinaRESUMEN
OBJECTIVE: This study aimed to evaluate the relationship between the toxicity of cyclin-dependent kinase 4/6 inhibitors and body mass index and body surface area. METHODS: A total of 83 patients were included in the study. Patients were divided into 4 groups as 18-24.9, 25-29.9, 30-39.9, and >40 kg/m2 according to body mass index and into two groups as below and above 1.77 according to body surface area. The relationship between body mass index and body surface area and side effects was evaluated. RESULTS: No statistically significant difference was found between body mass index groups and side effects. Grade 3 neutropenia was more common in patients on palbociclib with a body surface area≤1.77. In our study, it was revealed that less hematological side effects can be encountered when body surface area is taken into account.
Asunto(s)
Neutropenia , Humanos , Quinasa 4 Dependiente de la Ciclina , Superficie Corporal , Neutropenia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
PURPOSE OF REVIEW: Sequential use of radiation therapy before cyclin-dependent kinase (CDK) inhibitors in women with early breast cancer seems reasonable and with a low toxicity rate. This study aimed to evaluate the possible interaction between RT and CDK inhibitors in the adjuvant setting for patients with positive hormone receptors and HER-2 negative, investigating toxicity and the treatment sequencing. RECENT FINDINGS: CDK inhibitors have been studied in patients with localized breast cancer and can improve invasive disease-free survival outcomes. Regarding the time of RT, all trials used CDK inhibitors after the RT. Interruptions in the CDK inhibitors were performed in 27.1% in Pallas, 17.5% in Penelope-B, and 16.6% in Monarch-E trials due to adverse events. Data from the Natalee trial are still not reported. The main adverse event grade III was neutropenia, with good resolution of the symptoms over time. CDK inhibitors applied sequentially and after RT postoperative showed a low profile of acute toxicity and suitable oncological outcomes.
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Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/radioterapia , Quinasas Ciclina-Dependientes , Supervivencia sin Enfermedad , Oncología Médica , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la CiclinaRESUMEN
BACKGROUND: Melanoma is the most lethal skin cancer, and its incidence has increased worldwide. About 10% of cases are classified as hereditary melanoma (HM). CDKN2A and CDK4 are the major high-risk genes. Families are also more prone to develop pancreatic cancer, and different forms of oncological surveillance are recommended. OBJECTIVES: Describe the prevalence of CDKN2A/CDK4 germline mutations in melanoma-prone patients and their phenotypic and histopathological features. METHODS: A total of 69 patients meeting the clinical criteria for HM were included in this cross-sectional descriptive study. Amplification by PCR and genomic sequencing were used. The variants were classified according to American College of Medical Genetics (ACMG) criteria. RESULTS: The mean age at first diagnosis of melanoma was 44.8 years (SD ± 17.83). Most patients had phototype II (44.9%), more than 50 melanocytic nevi (76.8%), atypical nevus syndrome (72.5%), history of sunburn (76.8%), and multiple primary melanomas without a family history of this tumor (74.3%). Two hundred melanomas were observed. Most tumors had a Breslow index ≤1.0 mm (84.5%), location in the trunk (60.5%), and superficial spreading histological subtype (22.5%). Four variants were found in CDKN2A exons in seven patients (c.305C>A, c.26T>A, c.361G>A e c.442G>A), two variants in the 5'UTR region in five patients (c.-25C>T and c.-33G>C), and two variants in the 3'UTR region in 21 patients (c.*29C>G and c.*69C>T). One likely pathogenic variant (c.305C>A) was identified in one patient (1.4%). No variant was found in CDK4. CONCLUSION: The prevalence of CDKN2A mutations was 1.4% in Brazilian patients meeting clinical criteria for HM.
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Melanoma , Neoplasias Cutáneas , Humanos , Adulto , Brasil/epidemiología , Estudios Transversales , Quinasa 4 Dependiente de la Ciclina/genética , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Melanoma/epidemiología , Melanoma/genética , Melanoma/patología , Mutación de Línea Germinal , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Predisposición Genética a la Enfermedad , Melanoma Cutáneo MalignoRESUMEN
Resistance to therapy remains a major obstacle in cancer management. Although treatment with hormone and CDK4/6 inhibitors is successful in luminal breast cancer, resistance to these treatments is frequent, highlighting the need for novel therapeutic strategies to delay disease progression and improve patient survival. Here, we assessed the mechanisms of acquired resistance using T47D and MCF-7 tamoxifen- and palbociclib-resistant cell-line variants in culture and as xenografts, and patient-derived cells (PDCs) obtained from sensitive or resistant patient-derived xenografts (PDXs). In these models, we analyzed the effect of specific kinase inhibitors on survival, signaling and cellular aggressiveness. Our results revealed that mTOR inhibition is more effective than PI3K inhibition in overcoming resistance, irrespective of PIK3CA mutation status, by decreasing cell proliferation and tumor growth, as well as reducing cell migration and stemness. Moreover, a combination of mTOR and CDK4/6 inhibitors may prevent pathway reactivation downstream of PI3K, interfering with the survival of resistant cells and consequent tumor escape. In conclusion, we highlight the benefits of incorporating mTOR inhibitors into the current therapy in ER + breast cancer. This alternative therapeutic strategy not only enhances the antitumor response but may also delay the emergence of resistance and tumor recurrence.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos , Línea Celular Tumoral , Recurrencia Local de Neoplasia , Serina-Treonina Quinasas TOR/metabolismo , Hormonas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la CiclinaRESUMEN
Coronavirus disease 2019 (COVID-19) outbreak has become a global pandemic. CDK4/6 inhibitor palbociclib was reported to be one of the top-scored repurposed drugs to treat COVID-19. As the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry, expression level of angiotensin-converting enzyme 2 (ACE2) is closely related to SARS-CoV-2 infection. In this study, we demonstrated that palbociclib and other methods could arrest cells in G0/G1 phase and up-regulate ACE2 mRNA and protein levels without altering its subcellular localization. Palbociclib inhibited ubiquitin-proteasome and lysosomal degradation of ACE2 through down-regulating S-phase kinase-associated protein 2 (SKP2). In addition, increased ACE2 expression induced by palbociclib and other cell cycle arresting compounds facilitated pseudotyped SARS-CoV-2 infection. This study suggested that ACE2 expression was down-regulated in proliferating cells. Cell cycle arresting compounds could increase ACE2 expression and facilitate SARS-CoV-2 cell entry, which may not be suitable therapeutic agents for the treatment of SARS-CoV-2 infection.
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COVID-19 , SARS-CoV-2 , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Proteínas Quinasas Asociadas a Fase-S , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus , Quinasa 6 Dependiente de la Ciclina/metabolismoRESUMEN
BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have been recently developed and introduced into clinical practice. METHODS: We retrospectively analyzed data from patients with confirmed HR+/HER2 metastatic breast cancer treated with hormonal therapy in combination with ribociclib (R), palbociclib (P), or abemaciclib (A). OUTCOMES: median progression-free survival (mPFS), time to treatment discontinuation (mTTD), and objective response rate (ORR). RESULTS: Between January 2016 - June 2021, 142 patients were treated with an CDK4/6i (79 P, 42 R, 21 A). The median age was 59 years and 67.6% had recurrent disease. Roughly 35.2%, 36.6%, 28.2% of the patients had 1, 2 or 3+ metastatic sites, respectively, and 55.6% of the patients received CDK4/6i as a first-line treatment. The mPFS was 28m(R) vs. 14m(P) vs. 6m(A) (P = 0.002), with a higher proportion of patients receiving R in the first-line setting. However, no difference was seen when the analysis was restricted to the first-line scenario (P = 0.193). Sixty-four patients required one dose reduction, and 19 patients required two. ORR was 76.2% (R) vs 62% (P) vs 42.9% (A). More patients achieved a complete response with R and P, with no difference in the incidence of partial response and stable disease. Adverse events occurred in 94.4% of the population, with the most common grade 3-4 AE being neutropenia (59.1%). CONCLUSIONS: Our results confirm the efficacy and tolerability of CDK4/6i in routine clinical practice. This is the first real-world data describing and comparing the efficacy and toxicity of CDK4/6i in the Brazilian population.
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Neoplasias de la Mama , Femenino , Humanos , Persona de Mediana Edad , Brasil , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
PURPOSE: Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteosome, and many others. The ubiquitin-proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins. METHODS: We performed transcriptional profiling of the HR(+) breast cancer cell lines MCF7 and T47D treated with Palbociclib. Differential expressed genes were analyzed for novel pathways enriched. The results were further validated with biochemical assays and with real world clinical database cohorts. RESULTS: We uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR(+) breast cancer cells demonstrate dependence on the UBE2C. CONCLUSIONS: Our study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer.
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Neoplasias de la Mama , Aminopiridinas , Bencimidazoles , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Femenino , Hormonas/uso terapéutico , Humanos , Fosfatidilinositol 3-Quinasas , Complejo de la Endopetidasa Proteasomal/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Purinas , ARN Mensajero , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo , Ubiquitinas/uso terapéuticoRESUMEN
PURPOSE: In recent years, unprecedented benefits have been observed with the development of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. However, there is scarce evidence of their value in specific populations, such as patients carrying germline pathogenic variants in DNA repair-related genes. PATIENTS AND METHODS: We retrospectively studied the efficacy of CDK 4/6 inhibitors plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Three cohorts were compared, including patients harboring germline pathogenic variants in DNA repair-related genes (gBRCA1/2-ATM-CHEK2 mutated), those tested without these mutations (wild type [WT]), and the nontested subgroup. Relevant prognostic factors including age, metastatic site (visceral v nonvisceral), Eastern Cooperative Oncology Group, and prior treatment with CDK 4/6 inhibitors were stratified by univariate and multivariate Cox regression models. RESULTS: Among the total population (n = 217), 15 (6.9%) patients carried gBRCA1/2 (n = 10)-ATM (n = 4)-CHEK2 (n = 1) pathogenic variants, 45 (20.7%) were WT, and 157 (72.4%) were nontested. Gene pathogenic variant carriers were younger (P < .001). Most patients (164, 75.6%) had not received prior endocrine therapy in the advanced setting. Median progression-free survival was shorter in patients with evaluated germline pathogenic variants (10.2 months [95% CI, 5.7 to 14.7]), compared with WT and nontested patients (15.6 months [95% CI, 7.8 to 23.4], and (17.6 months [95% CI, 12.9 to 22.2]; P = .002). Consistently, a worse median overall survival was observed in the subgroup with germline pathogenic variants than in the WT group (P = .006). Multivariable analysis showed that mutation status was an independent prognostic factor of progression-free survival (P = .020) and overall survival (P = .012). CONCLUSION: In this retrospective real-world study, gBRCA1/2-ATM-CHEK2 pathogenic variants were independently associated with poor outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors.
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Neoplasias de la Mama , Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/genética , Reparación del ADN/genética , Femenino , Células Germinativas/metabolismo , Humanos , Estudios RetrospectivosRESUMEN
Luminal breast cancer (BrCa) has a favorable prognosis compared with other tumor subtypes. However, with time, tumors may evolve and lead to disease progression; thus, there is a great interest in unraveling the mechanisms that drive tumor metastasis and endocrine resistance. In this review, we focus on one of the many pathways that have been involved in tumor progression, the fibroblast growth factor/fibroblast growth factor receptor (FGFR) axis. We emphasize in data obtained from in vivo experimental models that we believe that in luminal BrCa, tumor growth relies in a crosstalk with the stromal tissue. We revisited the studies that illustrate the interaction between hormone receptors and FGFR. We also highlight the most frequent alterations found in BrCa cell lines and provide a short review on the trials that use FGFR inhibitors in combination with endocrine therapies. Analysis of these data suggests there are many players involved in this pathway that might be also targeted to decrease FGF signaling, in addition to specific FGFR inhibitors that may be exploited to increase their efficacy.
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Neoplasias de la Mama/tratamiento farmacológico , Factores de Crecimiento de Fibroblastos/fisiología , Receptores de Factores de Crecimiento de Fibroblastos/fisiología , Receptores de Esteroides/fisiología , Transducción de Señal/fisiología , Animales , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/química , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Receptor alfa de Estrógeno/análisis , Femenino , Factores de Crecimiento de Fibroblastos/genética , Amplificación de Genes , Humanos , Ratones , Mutación , Receptor Cross-Talk/fisiología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/genéticaRESUMEN
Introduction: For decades, endocrine therapy has been the cornerstone of management for luminal breast cancer. Despite the substantial benefit derived by patients from endocrine therapy, primary and secondary resistances to endocrine therapy are serious clinical issues.Areas covered: Today, in the advanced setting, three distinct classes of targeted agents mTOR, CDK 4/6, and PI3K inhibitors, are approved for use. CDK 4/6 inhibitors have improved outcomes substantially, changing the natural history of advanced luminal breast cancer. Current studies seek to bring CDK 4/6 inhibitors to the early setting. This review will cover all available data on target therapy combinations with endocrine therapy for both the early and advanced settings, including approved drugs and agents in development.Expert opinion: Combined endocrine and target therapy has changed the landscape in advanced disease. In early disease, it is possible to have a large impact, particularly in patients with higher risk of relapse. Trials like ADAPTCYCLE seek to leverage neoadjuvant data to de-escalate treatment, substituting chemotherapy for CDK 4/6 inhibitors. In advanced diseases, studies such as PADA-1 point toward a future in which ctDNA will be used to define management before clinical progression occurs.
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Neoplasias de la Mama , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Quinasa 4 Dependiente de la Ciclina , Femenino , Humanos , Terapia Neoadyuvante , Recurrencia Local de Neoplasia , Fosfatidilinositol 3-Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-2RESUMEN
BACKGROUND/AIM: Genetic variations of the CDKN2A and CDK4 gene have been associated to melanoma development. In the present study we investigated the potential associations of CDKN2A and CDK4 gene variants in a colombian population diagnosed with melanoma. MATERIALS AND METHODS: DNA was extracted from whole blood samples from 85 patients diagnosed with cutaneous melanoma and 166 healthy controls. CDKN2A and CDK4 genes were genotyped using a high-resolution melting assay. RESULTS: A similar distribution of CDKN2A variants 500C>G and 540C>T was found among cases (12% and 31% respectively) and controls (15% and 31% respectively). The CDKN2A variants were present in 36% of acral lentiginous melanoma and 39.47% of lentigo maligna. The haplotype analysis showed an association with susceptibility in the development of melanoma. CONCLUSION: The presence of haplotype 500G/540C in males is associated with an increased risk of melanoma in a colombian population, especially in subjects with a family history of cancer.
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Melanoma , Neoplasias Cutáneas , Regiones no Traducidas 3' , Quinasa 4 Dependiente de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal/genética , Humanos , Masculino , Melanoma/epidemiología , Melanoma/genética , Neoplasias Cutáneas/genéticaRESUMEN
BACKGROUND: Glioblastoma (GB) remains an incurable and deadly brain malignancy that often proves resistant to upfront treatment with temozolomide. Nevertheless, temozolomide remains the most commonly prescribed FDA-approved chemotherapy for GB. The DNA repair protein methylguanine-DNA methyl transferase (MGMT) confers resistance to temozolomide. Unsurprisingly temozolomide-resistant tumors tend to possess elevated MGMT protein levels or lack inhibitory MGMT promotor methylation. In this study, cultured human temozolomide resistance GB (43RG) cells were introduced to the MGMT inhibitor O6-benzylguanine combined with temozolomide and either LY2835219 (CDK 4/6 inhibitor) or LY2157299 (TGF-ßRI inhibitor) seeking to overcome GB treatment resistance. METHODS: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot, cell viability, and cell cycle progression. RESULTS: Our in vitro study demonstrated that sequential treatment of O6-Benzylguanine with either LY2385219 or LY2157299-enhanced temozolomide enhanced sensitivity in MGMT+ 43RG cells. Importantly, normal human neurons and astrocytes remained impervious to the drug therapies under these conditions. Furthermore, LY2835219 has additional anti-proliferative effects on cell cycling, including induction of an RB-associated G (1) arrest via suppression of cyclin D-CDK4/6-Rb pathway. LY2157299 enhances anti-tumor effect by disrupting TGF-ß-dependent HIF-1α signaling and by activating both Smad and PI3K-AKT pathways towards transcription of S/G2 checkpoints. CONCLUSION: This study establishes the groundwork for the development of a combinatorial pharmacologic approach by using either LY2385219 or LY2157299 inhibitor plus O6-Benzylguanine to augment temozolomide response in temozolomide-resistant GB cells.