Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial.

BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

Estrogen signaling encourages blastocyst development and implantation potential.

PURPOSE: Estrogen is well-known for preparing uterine receptivity. However, its roles in regulating embryo development and implantation are unclear. Our objective was to characterize estrogen receptor 1 (ESR1) in human and mouse embryos and determine the effect of estradiol (E2) supplementation on pre- and peri-implantation blastocyst development. METHODS: Mouse embryos, 8-cell through hatched blastocyst stages, and human embryonic days 5-7 blastocysts were stained for ESR1 and imaged using confocal microscopy. We then treated 8-cell mouse embryos with 8 nM E2 during in vitro culture (IVC) and examined embryo morphokinetics, blastocyst development, and cell allocation into the inner cell mass (ICM) and trophectoderm (TE). Finally, we disrupted ESR1, using ICI 182,780, and evaluated peri-implantation development. RESULTS: ESR1 exhibits nuclear localization in early blastocysts followed by aggregation, predominantly in the TE of hatching and hatched blastocysts, in human and mouse embryos. During IVC, most E2 was absorbed by the mineral oil, and no effect on embryo development was found. When IVC was performed without an oil overlay, embryos treated with E2 exhibited increased blastocyst development and ICM:TE ratio. Additionally, embryos treated with ICI 182,780 had significantly decreased trophoblast outgrowth during extended embryo culture. CONCLUSION: Similar ESR1 localization in mouse and human blastocysts suggests a conserved role in blastocyst development. These mechanisms may be underappreciated due to the use of mineral oil during conventional IVC. This work provides important context for how estrogenic toxicants may impact reproductive health and offers an avenue to further optimize human-assisted reproductive technology (ART) to treat infertility.

ERß1 Sensitizes and ERß2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid.

Adjuvant endocrine therapy (AET) is the treatment of choice for early-stage estrogen receptor alpha (ERα)-positive breast cancer (BC). However, almost 40% of tamoxifen-treated cases display no response or a partial response to AET, thus increasing the need for new treatment options and strong predictors of the therapeutic response of patients at high risk of relapse. In addition to ERα, BC research has focused on ERß1 and ERß2 (isoforms of ERß), the second ER isotype. At present, the impact of ERß isoforms on ERα-positive BC prognosis and treatment remains elusive. In the present study, we established clones of MCF7 cells constitutively expressing human ERß1 or ERß2 and investigated their role in the response of MCF7 cells to antiestrogens [4-hydroxytamoxifen (OHΤ) and fulvestrant (ICI182,780)] and retinoids [all-trans retinoic acid (ATRA)]. We show that, compared to MCF7 cells, MCF7-ERß1 and MCF7-ERß2 cells were sensitized and desensitized, respectively, to the antiproliferative effect of the antiestrogens, ATRA and their combination and to the cytocidal effect of the combination of OHT and ATRA. Analysis of the global transcriptional changes upon OHT-ATRA combinatorial treatment revealed uniquely regulated genes associated with anticancer effects in MCF7-ERß1 cells and cancer-promoting effects in MCF7-ERß2 cells. Our data are favorable to ERß1 being a marker of responsiveness and ERß2 being a marker of resistance of MCF7 cells to antiestrogens alone and in combination with ATRA.

Glutamine synthetase regulates the immune microenvironment and cancer development through the inflammatory pathway.

Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER+) breast cancer patients, a significant number of patients still develop metastasis or undergo recurrence. Therefore, identifying novel diagnostic and prognostic biomarkers for these patients is urgently needed. Predictive markers and therapeutic strategies for tamoxifen-resistant ER+ breast cancer are not clear, and micro (mi)RNAs have recently become a focal research point in cancer studies owing to their regulation of gene expressions, metabolism, and many other physiological processes. Therefore, systematic investigation is required to understand the modulation of gene expression in tamoxifen-resistant patients. High-throughput technology uses a holistic approach to observe differences among expression profiles of thousands of genes, which provides a comprehensive level to extensively investigate functional genomics and biological processes. Through a bioinformatics analysis, we revealed that glutamine synthetase/glutamate-ammonia ligase (GLUL) might play essential roles in the recurrence of tamoxifen-resistant ER+ patients. GLUL increases intracellular glutamine usage via glutaminolysis, and further active metabolism-related downstream molecules in cancer cell. However, how GLUL regulates the tumor microenvironment for tamoxifen-resistant ER+ breast cancer remains unexplored. Analysis of MetaCore pathway database demonstrated that GLUL is involved in the cell cycle, immune response, interleukin (IL)-4-induced regulators of cell growth, differentiation, and metabolism-related pathways. Experimental data also confirmed that the knockdown of GLUL in breast cancer cell lines decreased cell proliferation and influenced expressions of specific downstream molecules. Through a Connectivity Map (CMap) analysis, we revealed that certain drugs/molecules, including omeprazole, methacholine chloride, ioversol, fulvestrant, difenidol, cycloserine, and MK-801, may serve as potential treatments for tamoxifen-resistant breast cancer patients. These drugs may be tested in combination with current therapies in tamoxifen-resistant breast cancer patients. Collectively, our study demonstrated the crucial roles of GLUL, which provide new targets for the treatment of tamoxifen-resistant breast cancer patients.

Real-World Experience with CDK4/6 Inhibitors for Metastatic HR+/HER2- Breast Cancer at a Single Cancer Center.

BACKGROUND: A study was initiated at Roswell Park Comprehensive Cancer Center to capture the real-world experience related to the use of CDK4/6 inhibitors (Ciclibs) for the treatment of metastatic hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-). PATIENTS AND METHODS: A total of 222 patients were evaluated who received CDK4/6 inhibitors in the period from 2015 to 2021. Detailed clinical and demographic information was obtained on each patient and used to define clinical and demographic features associated with progression-free survival on CDK4/6 inhibitor-based therapies. RESULTS: In this real-world analysis, the majority of patients received palbociclib as the CDK4/6 inhibitor with letrozole or fulvestrant as the predominant endocrine therapies. The median progression-free survival (PFS) in the letrozole (27.6 months) and fulvestrant (17.2 months) groups were comparable to that observed in clinical trials. As expected, age at start of the treatment and menopausal status influenced endocrine therapy utilization but were not associated with PFS. Patients with recurrent disease had shorter PFS (P = .0024) than those presenting with de novo metastasis. The presence of visceral metastasis trended toward shorter PFS (P = .051). Similarly, prior endocrine therapy (P = .003) or chemotherapy (P = .036) was associated with shorter PFS. Body mass index was not associated with PFS or with dose interruption and/or modification. While the number of minorities in this analysis is limited (n = 26), these patients as a group had statistically shorter PFS on treatment (P = .002). CONCLUSIONS: The real-world progression-free survival with CDK4/6 inhibitors mimics that observed in the clinical trial. A number of clinical and demographic features were associated with PFS on CDK4/6 inhibitor-based therapy. Further studies are ongoing to validate these findings incorporating additional cancer centers.

Comparative study of estrogenic activities of phytoestrogens using OECD in vitro and in vivo testing methods.

With growing scientific interest in phytoestrogens, a number of studies have investigated the estrogenic potential of phytoestrogens in a wide variety of assay systems. However, evaluations of individual phytoestrogens with different assay systems make it difficult for predicting their relative estrogenic potency. The objective of this study was to compare estrogenic properties of fifteen known phytoestrogens using an estrogen receptor-α (ER-α) dimerization assay and Organization for Economic Cooperation and Development (OECD) standardized methods including in vitro estrogen receptor (ER) transactivation assay using VM7Luc4E2 cells and in vivo uterotrophic assay using an immature rat model. Human ER-α dimerization assay showed positive responses of eight test compounds and negative responses of seven compounds. These results were consistently found in luciferase reporter assay results for evaluating ER transactivation ability. Seven test compounds exhibiting relatively higher in vitro estrogenic activities were subjected to uterotrophic bioassays. Significant increases in uterine weights were only found after treatments with biochanin A, 8-prenylnaringenin, and coumestrol. Importantly, their uterotrophic effects were lost when animals were co-treated with antagonist of ER, indicating their ER-dependent effects in the uterus. In addition, analysis of estrogen responsive genes revealed that these phytoestrogens regulated uterine gene expressions differently compared to estrogens. Test methods used in this study provided a high consistency between in vitro and in vivo results. Thus, they could be used as effective screening tools for phytoestrogens, particularly focusing on their interactions with ER-α.

Eficacia y seguridad de fulvestrant en pacientes postmenopáusicas con cáncer de mama metastásico, receptores hormonales positivos, HER2 negativo, no tributario de quimioterapia ni radioterapia, sin enfermedad visceral y sin tratamiento endocrino previo / Efficacy and safety of fulvestrant in postmenopausal patients with metastatic breast cancer, hormone receptor positive, HER2 negative, not eligible for chemotherapy or radiotherapy, without visceral disease and without previous endocrine treatment

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de fulvestrant en pacientes adultos con cáncer de mama metastásico, RH positivos, HER2 negativo, no tributario de quimioterapia y radioterapia por toxicidad, sin enfermedad visceral y sin tratamiento endocrino previo. El subtipo de cáncer de mama más frecuente es aquel que expresa receptores hormonales (RH), y no expresa el oncogen receptor 2 del factor de crecimiento epidérmico humano (HER2, por sus siglas en inglés). En Perú, dos estudios (uno realizado en Lima entre el 2015 y el 2017 y otro en Arequipa entre el 2009 y el 2012) reportaron prevalencias del 40.2 % y 37.5 % de este subtipo de cáncer. El cáncer de mama metastásico sigue considerándose como una enfermedad incurable; sin embargo, se han desarrollado tratamientos que permiten mejorar la sobrevida del paciente, aliviar los síntomas y mejorar o mantener la calidad de vida, como la terapia endocrina. Las terapias endocrinas pueden actuar reduciendo el estrógeno, como la terapia con anastrozol o exemestano, o afectando directamente al receptor de estrógeno, como la terapia con fulvestrant. En EsSalud se cuenta con alternativas de terapia endocrina, como anastrozol y exemestano, para el tratamiento de pacientes postmenopáusicas con cáncer de mama RH positivo. No obstante, algunos especialistas consideran que fulvestrant podría ser de mayor beneficio para los pacientes. Así, el objetivo del presente dictamen preliminar es evaluar la eficacia y seguridad de fulvestrant en pacientes postmenopáusicas con cáncer de mama metastásico, RH positivo, HER2 negativo, sin enfermedad visceral, sin tratamiento endocrino previo y no tributario de quimioterapia y radioterapia, por toxicidad. METODOLOGÍA: La búsqueda de la literatura se realizó con el objetivo de identificar evidencia sobre la eficacia y seguridad de fulvestrant en pacientes postmenopáusicas con cáncer de mama metastásico, RH positivos, HER2 negativo, no tributario de quimioterapia y radioterapia por toxicidad, sin enfermedad visceral y sin tratamiento endocrino previo. Para ello se revisaron las siguientes bases de datos bibliográficas: PubMed, LILACS y The Cochrane Library. Adicionalmente, se revisó la evidencia generada por grupos internacionales que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica, tales como The National Institute for Health and Care Excellence (NICE), The National Comprehensive Cancer Network (NCCN), The European Society for Medical Oncology (ESMO), The American Society of Clinical Oncology (ASCO), pan-Canadian Oncology Drug Review (pCODR), The Canadian Agency for Drugs and Technologies in Health (CADTH), Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Quality and Efficiency in Health Care (IQWiG), Scottish Medicines Consortium (SMC), Haute Autorité de Santé (HAS), Institute for Clinical and Economic Review (ICER), y National Committee for Health Technology Incorporation (CONITEC por sus siglas en portugués). También se realizó una búsqueda manual en las bases The Guidelines International Network (G-I-N), el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), y el repositorio institucional de la Dirección General de Medicamentos, Insumos y Drogas (DIGEMID). Asimismo, se colectó información sobre el medicamento de interés del presente dictamen en las páginas web de la EMA, y FDA. Finalmente, se realizó una búsqueda manual en el portal ClinicalTrials.gov del National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o que aún no hayan sido publicados. RESULTADOS: se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: En el presente documento, se evaluó la mejor evidencia científica disponible sobre la eficacia y seguridad de fulvestrant en pacientes postmenopáusicas con cáncer de mama metastásico, RH positivos, HER2 negativo, no tributario de quimioterapia y radioterapia por toxicidad, sin enfermedad visceral y sin tratamiento endocrino previo.  En la búsqueda de la literatura científica se identificaron dos GPC (NCCN 2021; Burstein et al. 2021), dos ETS (CADTH 2018; NICE 2018) y el ECA FALCON de fase III que representa el estudio pivotal de fulvestrant (J. F. R. Robertson et al. 2016).  Las GPC de ASCO y de la NCCN difirieron en sus recomendaciones sobre el uso de fulvestrant; pero coinciden en recomendar el uso de anastrozol o exemestano. La NCCN recomendó el uso de fulvestrant, así como de anastrozol o exemestano, en pacientes postmenopáusicas con cáncer de mama metastásico, RH positivos, HER2 negativo, sin crisis visceral y sin terapia endocrina previa. En cambio, ASCO recomendó únicamente el uso de anastrozol o exemestano, sin mencionar a fulvestrant como una opción de tratamiento, en mujeres postmenopáusicas con cáncer de mama metastásico RH positivo. Las ETS de CADTH y NICE brindaron recomendaciones diferentes sobre el uso de fulvestrant; pero coincidieron en señalar que la terapia con fulvestrant no sería costo-efectiva porque existe incertidumbre sobre su efecto en la SG del paciente. CADTH aprobó el uso de fulvestrant condicionado a un descuento confidencial en el precio de este medicamento, mientras que la ETS de NICE decidió no recomendar el uso de fulvestrant en mujeres postmenopáusicas con cáncer de mama metastásicos o localmente avanzado RH positivos, HER2 negativo, y sin tratamiento endocrino previo. El ECA FALCON comparó el uso de fulvestrant versus anastrozol en mujeres postmenopáusicas con cáncer de mama metastásico o localmente avanzado, RH positivo, HER2 negativo, y sin tratamiento endocrino previo; considerando pacientes sin crisis visceral (40 %) y pacientes que no habían recibido ni quimioterapia ni radioterapia (cerca del 80 %). Este estudio no reportó diferencias en la calidad de vida, la SG o la incidencia de EAS entre los grupos de estudio. Dentro del Petitorio Farmacológico de EsSalud se cuenta con opciones de tratamiento, como anastrozol y exemestano, para el manejo de pacientes con cáncer de mama metastásico, que también son recomendadas por las GPC internacionales para el tratamiento de mujeres postmenopáusicas con cáncer de mama metastásicos o localmente avanzado RH positivos, HER2 negativo, y sin tratamiento endocrino previo. Por lo expuesto, el IETSI no aprueba el uso de fulvestrant en pacientes post menopáusicas con cáncer de mama metastásico, RH positivos, HER2 negativo, no tributario de quimioterapia y radioterapia por toxicidad, sin enfermedad visceral y sin tratamiento endocrino previo.

Eficacia y seguridad de fulvestrant en mujeres posmenopáusicas con cáncer de mama metastásico, rh positivo, HER2 negativo y progresión de la enfermedad después del uso de un inhibidor de aromatasa / Efficacy and safety of fulvestrant in postmenopausal women with metastatic, rh-positive, HER2-negative breast cancer and disease progression after use of an aromatase inhibitor

INTRODUCCIÓN: El presente dictamen preliminar expone la evaluación de la eficacia y seguridad de fulvestrant (monoterapia) en comparación con anastrazol o exemestano en pacientes posmenopáusicas con CMM, RH positivo, HER2 negativo, y progresión de la enfermedad después del uso de un IA. El cáncer de mama es la primera causa de muerte por neoplasia maligna en mujeres en el mundo. En el 2019, en Perú se detectaron 4,743 casos nuevos de cáncer de mama en mujeres; causando cerca de 1,840 muertes en el mismo año. El cáncer de mama metastásico (CMM) es una condición incurable. Se estima que la mediana de sobrevida global (SG) en pacientes con CMM es de aproximadamente tres años y que la tasa de SG hasta los 5 años es de aproximadamente 27 %.  En EsSalud, las pacientes posmenopáusicas con CMM, receptor hormonal (RH) positivo, receptor 2 del factor de crecimiento epidérmico humano (HER2) negativo y cuya enfermedad progresa después del uso de terapia endocrina con un inhibidor de aromatasa (IA) son generalmente tratadas con otro IA. Sin embargo, algunos especialistas han señalado que el uso de fulvestrant ofrece un mejor perfil de eficacia y seguridad. Por este motivo, el IETSI recibió una solicitud de evaluación de fulvestrant como una alternativa de tratamiento al uso de un IA. METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de fulvestrant (monoterapia) en comparación con anastrazol o exemestano en pacientes posmenopáusicas con CMM, RH positivo, HER2 negativo, y progresión de la enfermedad después del uso de un IA. Se utilizaron las bases de datos PubMed, Cochrane Library y LILACS. Asimismo, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan ETS y GPC, incluyendo el Healthcare Improvement Scotland, el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), además de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en el manejo del cáncer de mama como National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO) y American Society of Clinical Oncology (ASCO). Se hizo una búsqueda adicional en la página web del registro de ensayos clínicos administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.gov/) e International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para poder identificar ensayos clínicos en curso o cuyos resultados no hayan sido publicados para, de este modo, disminuir el riesgo de sesgo de publicación. RESULTADOS: Se describe la evidencia disponible según el orden jerárquico del nivel de evidencia o pirámide de Haynes 6S3 , siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: El objetivo del presente dictamen preliminar fue evaluar la mejor evidencia científica sobre la eficacia y seguridad de fulvestrant 500 mg (monoterapia) en comparación con anastrazol o exemestano en pacientes posmenopáusicas con CMM, RH positivo, HER2 negativo, y progresión de la enfermedad después del uso de un IA. En el contexto de primera línea para la enfermedad avanzada, la GPC de ESMO recomendó indistintamente el uso de monoterapia con fulvestrant o los IA; mientras que NCCN realizó una recomendación más fuerte para el tratamiento con monoterapia con fulvestrant respecto a los IA. En el contexto de segunda línea para la enfermedad avanzada, las GPC de ESMO y NCCN recomendaron el uso de fulvestrant o IA, sin preferencias entre uno u otro. No hubo recomendaciones específicas para la población con progresión a un IA. La evidencia disponible respecto a la pregunta PICO del presente dictamen no permite determinar un beneficio adicional con fulvestrant 500 mg en comparación con los IA. Los resultados de dos meta-análisis en red que compararon fulvestrant 500 mg versus los IA en mujeres posmenopáusicas, con CMM, RH positivo y tratamiento endocrino previo mostraron ausencia de diferencias estadísticamente significativas en la SLP, la SG, los EA de grado 3 o 4 y la discontinuación debido a EA; sin embargo, la heterogeneidad de las poblaciones de los estudios incluidos afecta la validez de estos resultados. Aunque un estudio observacional reportó una mejor SLP con fulvestrant 500 mg (respecto a exemestano) en pacientes posmenopáusicas, con CMM, RH positivo, HER2 negativo, que progresaron durante la terapia adyuvante con IA no esteroideos, la calidad de la evidencia fue baja y los efectos reportados en la SLP no fueron clínicamente relevantes en términos de capacidad predictiva sobre la SG. Dado que la evidencia disponible no ha mostrado que la relación riesgo-beneficio sea favorable a fulvestrant 500 mg, en comparación con anastrozol o exemestano, la aprobación de uso de fulvestrant en EsSalud no sería una decisión costo-oportuna; considerando la disponibilidad de tratamientos eficaces, con perfiles de seguridad aceptables y menos costosos en la institución (i.e. anastrozol y exemestano). Estos medicamentos se recomiendan en las GPC internacionales más recientes para la población de interés del presente dictamen. Por lo expuesto, el IETSI no aprueba el uso de fulvestrant en mujeres posmenopáusicas con CMM, RH positivo, HER2 negativo, y progresión de la enfermedad después del uso de un IA.

Effects and mechanism of Pigeonpea (Cajanus cajan (L.) Millsp.) leaves on proliferation, migration, and tube formation of hypoxic human umbilical vein endothelial cells in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Pigeonpea (Cajanus cajan (L.) Millsp) leaves (PL) are widely used for treating avascular necrosis of the femoral head. PL has an ideal effect on bone angiogenesis in patients with hormone-induced avascular necrosis of the femoral head and could promote the repair of blood vessels in the necrotic femoral head. Angiogenesis is beneficial to the treatment of myocardial ischemia. PL can be used to treat ischemic heart disease; however, no studies have examined whether it could protect the myocardium against ischemia injury via promoting angiogenesis. AIM: The present study aimed to investigate whether PL could encourage angiogenesis on hypoxic human umbilical vein endothelial cells (HUVECs) and whether estrogen receptor (ER-α), protein kinase B (Akt), and vascular endothelial growth factor (VEGF) (the ischemia injury salvage kinase pathway, phosphoinositide-3 kinase (PI3K)) are involved in this effect. METHODS: A hypoxic HUVEC model was established by culture in the hypoxia incubator. The proliferation ability of HUVECs was determined by the 2,3-Bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) method, the migration rate of HUVECs was inspected by the Transwell method, the tube formation was evaluated by the Matrigel method, and the expression of PI3K, phosphorylated Akt (p-Akt), and VEGF was detected by Western blotting. RESULTS: The proliferation, migration, and tube formation were promoted by the PL extract on hypoxic HUVECs, and the hypoxia-induced downstream signaling was counteracted, leading to increased expression of PI3K, p-Akt, and VEGF in HUVECs. CONCLUSIONS: The current findings showed that the PL extracts encourage angiogenesis. In addition, the above effects could be mediated via ER-α and PI3K/Akt/VEGF pathways.

Eficacia y seguridad de ribociclib más fulvestrant en mujeres posmenopáusicas con cáncer de mama metastásico RH-Positivo YyHER2-Negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica / Efficacy and safety of ribociclib plus fulvestrant in postmenopausal women with HR-positive and HER2-negative metastatic breast cancer, treatment-naïve or on a prior line of endocrine therapy for metastatic disease

INTRODUCCIÓN: El presente dictamen preliminar expone la evaluación de la eficacia y seguridad de ribociclib más fulvestrant, en comparación con exemestano o anastrozol, en mujeres posmenopáusicas con cáncer de mama metastásico, RH-positivo y HER2-negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica. El cáncer de mama es la primera causa de muerte por neoplasia maligna en mujeres en el mundo. En el 2019, en Perú se detectaron 4,743 casos nuevos de cáncer de mama en mujeres; causando cerca de 1,840 muertes en el mismo año. El cáncer de mama metastásico (CMM) es una condición incurable. Se estima que la mediana de sobrevida global en pacientes con CMM es de aproximadamente tres años y que la tasa de sobrevida global hasta los 5 años es de aproximadamente 27%. Los tipos de medicamentos que se usan para el CMM dependen del estado menopáusico de la paciente, del estado del receptor hormonal (RH) y del receptor 2 del factor de crecimiento epidérmico humano (HER2) del cáncer. En el contexto de EsSalud, las mujeres posmenopáusicas con CMM, RH-positivo, HER2-negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica, a menudo se tratan con un inhibidor de la aromatasa (anastrozol o exemestano). El IETSI-EsSalud recibió una solicitud de evaluación de ribociclib más fulvestrant como una alternativa terapéutica al uso de inhibidores de la aromatasa, argumentándose una potencial prolongación de la sobrevida global de los pacientes, junto con un perfil de seguridad aceptable. Al respecto, el IETSI-EsSalud consideró que existe la necesidad de terapias nuevas y efectivas para los pacientes con CMM que proporcionen mejoras en la sobrevida global del paciente, tengan perfiles de toxicidad más favorables y mejoren la calidad de vida. METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de ribociclib más fulvestrant, en comparación con exemestano o anastrozol, en mujeres posmenopáusicas con CMM, RH-positivo y HER2-negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica. Se utilizaron las bases de datos PubMed, Cochrane Library y LILACS, priorizándose la evidencia proveniente de ensayos clínicos controlados aleatorizados. Asimismo, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan ETS y GPC, incluyendo el Healthcare Improvement Scotland, el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), además de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en el manejo del cáncer de mama como National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO) y American Society of Clinical Oncology (ASCO). Se hizo una búsqueda adicional en la página web del registro de ensayos clínicos administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.gov/) e International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para poder identificar ensayos clínicos en curso o cuyos resultados no hayan sido publicados para, de este modo, disminuir el riesgo de sesgo de publicación. RESULTADOS: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de ribociclib más fulvestrant, en comparación con exemestano o anastrozol, en mujeres posmenopáusicas con CMM, RH-positivo y HER2-negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica. CONCLUSIONES: El presente dictamen preliminar tuvo como objetivo evaluar la mejor evidencia sobre la eficacia y seguridad sobre la eficacia y seguridad de ribociclib más fulvestrant, en comparación con anastrozol y exemestano, en mujeres posmenopáusicas con CMM, RH-positivo y HER2-negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica. La evidencia clave para evaluar el uso de ribociclib en combinación con fulvestrant en la población de interés proviene de MONALEESA-3, un ECA de fase III, doble ciego, controlado con placebo, de grupos paralelos. El estudio MONALEESA-3 tuvo la limitación de no responder directamente a la pregunta PICO de interés, ya que evaluó el uso de ribociclib más fulvestrant en comparación con fulvestrant solo, y no versus el comparador de interés del presente dictamen (anastrozol o exemestano). Cabe señalar que el uso de fulvestrant como monoterapia no está aprobado en EsSalud porque no se ha demostrado que sea diferente del exemestano, en términos de calidad de vida y eventos adversos en pacientes posmenopáusicas con CMM, RH-positivo y tratamiento endocrino previo, y no hay evidencia que permita generar conclusiones definitivas respecto a la sobrevida global (Dictamen Preliminar de Evaluación de Tecnología Sanitaria N.° 050-SDEPFyOTS-DETS-IETSI-2016). Los resultados de MONALESSA-3 no permiten determinar un beneficio neto con ribociclib más fulvestrant en comparación con fulvestrant más placebo por las siguientes razones: i) los resultados disponibles de SG son aún preliminares (corresponden a análisis interinos) y requieren de un mayor seguimiento (resultados del análisis final de SG) para determinar si realmente existe un beneficio en la prolongación de la vida de los pacientes, más aun en vista de una modesta reducción en el riesgo de mortalidad y una gran incertidumbre en las estimaciones reportadas (amplio intervalo de confianza, con valores cercanos al valor de la no diferencia), ii) los resultados muestran que ribociclib más fulvestrant no mejora la calidad de vida de los pacientes y, iii) los resultados muestran que ribociclib más fulvestrant aumenta significativamente el riesgo de EA serios y discontinuación debido a EA asociados a la medicación. Debido a la incertidumbre en la relación de riesgo-beneficio con ribociclib más fulvestrant, en comparación con anastrozol y/o exemestano, dada principalmente por la ausencia de evidencia que responda directamente a la pregunta PICO establecida en el presente dictamen, la aprobación de uso de ribociclib más fulvestrant no sería una decisión costo-oportuna; dada la disponibilidad de tratamientos efectivos, con perfiles de seguridad aceptables y menos costosos en la institución (anastrozol y exemestano), los cuales son recomendados en las GPC internacionales más recientes para la población de interés del presente dictamen. Por lo expuesto, el IETSI no aprueba el uso de ribociclib más fulvestrant en mujeres posmenopáusicas con CMM, RH-positivo y HER2-negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica.

Non-genomic actions of sex hormones on pregnant uterine contractility in rats: An in vitro study at term.

AIMS: The non-genomic (prompt) actions of sex steroids on pregnant uterine contractility are not fully explored yet, the aim of our study was to clarify such effects of 17-ß estradiol (E2), progesterone (P4) and testosterone (T) on late (22-day) pregnant uterine contractions together with the signaling pathways in rats in vitro. METHODS: The uterine effects of sex steroids on KCl-stimulated contractions were examined in the presence of genomic pathway blocker actinomycin D and cycloheximide, sex hormone receptor antagonists (flutamide, fulvestrant, mifepristone) and also after removing the endometrium. The modifications in uterine G-protein activation and cAMP levels were also detected. RESULTS: T and E2 both relaxed the uterine contractions in the concentration range of 10-8-10-3 M with an increase in the activated G-protein and cAMP levels of the uterus, while P4 was ineffective. Cycloheximide, actinomycin D, antagonist for T and E2 were not able to modify the responses along with the endothelium removal. Mifepristone blocked the relaxing effects of T and E2 and reduced the activation of G-protein and the formation of cAMP. SIGNIFICANCE: T and E2 can inhibit KCl-stimulated contractions in the late pregnant uterus in high concentrations and in a non-genomic manner. Their actions are mediated by a G-protein coupled receptor that can be blocked by mifepristone. A single and high dose of T or E2 might be considered in premature contractions, however, further preclinical and clinical studies are required for the approval of such a therapeutic intervention.

Fasting-mimicking diet and hormone therapy induce breast cancer regression.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.

Antrodia cinnamomea is a potentially effective complementary medicine for adjuvant therapy against breast cancer with bone metastasis: A case report.

RATIONALE: Palbociclib (PAL) is a first-in-class selective inhibitor of the cyclin-dependent kinases 4 (CDK4) and CDK6 and is indicated for the treatment of hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in combination with fulvestrant (FUL) in postmenopausal women. Antrodia cinnamomea (AC), a well-known Chinese folk medicine in Taiwan, possesses numerous biological capabilities, most notably an anti-tumor effect. However, the clinical use of AC as complementary medicine combined with adjuvant therapy is unexplored. In this case report, we evaluated AC combined with PAL plus FUL to reduce the tumor burden in an MBC patient. PATIENT CONCERNS: A Slovenian woman diagnosed with relapsed bone metastases of breast cancer (BC) was unable to undergo surgery and refused radiation therapy due to fear of side effects; she also feared the side effects of adjuvants. However, she was eager to live with a high quality of life. DIAGNOSIS: Stage IV, HR-positive/HER2-negative BC with relapse of bone metastases. INTERVENTIONS: After diagnosis of relapse of bone metastases, she received adjuvant with PAL plus FUL. Additionally, she chose to take AC orally (10 g/d). OUTCOMES: The pain was mostly relieved, and the side effects of adjuvant therapy reduced. Magnetic resonance imaging revealed reduction of tumor size at the fifth month of adjuvant therapy plus AC. After 14 months of adjuvant therapy plus AC, the tumors at the thoracic vertebrae T1 and T3 were found to have shrunk from 35.2 and 12.0 mm to 28.1 and 9.9 mm, respectively. Remarkably, no further metastases were observed. LESSONS: According to the circulating tumor cells (CTCs) test data, AC had better anti-tumor efficacy on active tumor cells than PAL plus FUL. Thus, AC could be an effective complementary medicine for adjuvant therapy in patients with HR-positive/HER2-negative MBC. Interestingly, continued elevation of carcinoma antigen 15-3 and lactate dehydrogenase levels but decreasing levels of alkaline phosphatase were observed, which may be indicative of the potent efficacy of treatment resulting in massive tumor cell death. The CTCs test may be a sensitive approach to monitor the progression of BC and subsequently evaluate the efficiency of therapy.

Targeting ERα degradation by L-Tetrahydropalmatine provides a novel strategy for breast cancer treatment.

The incidence and mortality of breast cancer (BCa) are the highest among female cancers. There are approximate 70% BCa that are classified as estrogen receptor alpha (ERα) positive. Therefore, targeting ERα is the most significantly therapeutic schedule. However, patients with breast cancer develop resistance to ERα or estrogen (E2) antagonists such as fulvestrant and tamoxifen. In the present study, we found that L-Tetrahydropalmatine (L-THP) significantly suppressed cell proliferation in ERα+ BCa cells via inducing cell cycle arrest rather than apoptosis. Additionally, L-THP enhanced the sensitivity of ERα+ BCa cells to tamoxifen and fulvestrant. Mechanically, the application of L-THP promotes ERα degradation through accumulating ubiquitin chains on ERα. Overexpressing ERα abrogates L-THP induced-antiproliferation in ERα+ BCa cells. Collectively, our work indicates that L-THP may represent a potentially novel therapeutic medicine for ERα+ breast cancer patient.

Danshen (Salvia miltiorhiza) inhibits Leu27 IGF-II-induced hypertrophy in H9c2 cells.

In this study, we used ICI 182 780 (ICI), an estrogen receptor (ER) antagonist, to investigate the estrogenic activity of Danshen, and to further explored whether Danshen extract can block Leu27IGF-II-induced hypertrophy in H9c2 cardiomyoblast cells. We first used an IGF-II analog Leu27IGF-II, which specifically activates IGF2R signaling cascades and induces H9c2 cardiomyoblast cell hypertrophy. However, Danshen extract completely inhibited Leu27IGF-II-induced cell size increase, ANP and BNP hypertrophic marker expression, and IGF2R induction. We also observed that Danshen extract inhibited calcineurin protein expression and NFAT3 nuclear translocation, leading to suppression of Leu27IGF-II-induced cardiac hypertrophy. Moreover, the anti-Leu27IGF-II-IGF2R signaling effect of Danshen was totally reversed by ICI, which suggest the cardio protective effect of Danshen is mediated through estrogen receptors. Our study suggests that, Danshen exerts estrogenic activity, and thus, it could be used as a selective ER modulator in IGFIIR induced hypertrophy model.

Neratinib: an option for HER2-positive metastatic breast cancer.

Metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer is currently incurable. The primary goals of treatment are to prolong survival while optimizing quality of life. Several agents are now available in this setting, including neratinib, tucatinib, ado-trastuzumab emtansine, and trastuzumab deruxtecan. Neratinib in combination with capecitabine was recently approved for the treatment of adult patients with advanced or metastatic breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting. Neratinib is an oral pan-HER inhibitor that binds covalently to the kinase site, providing irreversible binding. Phase 3 data showed that the combination of neratinib plus capecitabine improved progression-free survival vs lapatinib plus capecitabine. The duration of response was longer among patients in the neratinib arm. Neratinib plus capecitabine was also active against brain metastases associated with refractory, HER2-positive breast cancer, and this combination is listed in guidelines from the National Comprehensive Cancer Network for this indication. When combined with fulvestrant, neratinib demonstrated efficacy in patients with HER2-positive breast cancer, regardless of their hormone receptor status. Ongoing trials are evaluating the ability of neratinib to treat brain metastases, as well as the efficacy and safety of the triplet combination of neratinib, fulvestrant, and trastuzumab in this setting.

The protective role of estrogen and its receptors in gentamicin-induced acute kidney injury in rats.

AIM: Investigating the impact of 17ß-Estradiol/estrogen receptors in gentamicin-induced nephrotoxicity. MAIN METHODS: Three weeks post-ovariectomy or sham surgery for the Wistar albino female rats, thirty sham rats were randomly grouped (n = 6), received either vehicle or gentamicin; the estrogen receptors down regulator (fulvestrant); gentamicin plus fulvestrant; gentamicin plus the phytoestrogen (genistein). Forty-eight ovariectomized rats were randomly grouped (n = 6), treated with either vehicle or gentamicin; fulvestrant; gentamicin plus fulvestrant; genistein; gentamicin plus genistein; estradiol benzoate; gentamicin plus estradiol benzoate. Just post-treatment termination, the traditional kidney injury biomarkers (serum creatinine and blood urea nitrogen) and novel biomarkers (serum Kidney injury molecule -1, cystatin C, lactate dehydrogenase and, gamma-glutamyl transferase) were determined. Bovine serum albumin labeled with fluorescence isothiocyanate assessed megalin expression/endocytic functionality in the proximal tubules epithelial cells (PTECs). The immunohistochemical investigation for the same-sectioned slides of PTECs assessed the correlation between estrogen receptors α and megalin receptors expression. Histopathological examination of PTECs and subjective scoring system graded the damage markers. KEY FINDINGS: Estrogen receptor α expression was markedly dimensioned post-ovariectomy, co-localized and inversely correlated to megalin expression. Serum levels of the novel biomarkers were directly proportional to megalin expression in the PTECs and inversely correlated with estrogen receptor α expression. The injury was exaggerated in ovariectomized and intact rats received fulvestrant. Supplementation with estrogen or genistein ameliorated this injury. SIGNIFICANCE: Estrogen/estrogen receptors have a protective impact on gentamicin-induced acute kidney injury. Estrogen receptors antagonist exacerbate the injury, and oppositely, estrogens or phytoestrogens improve it.

Monitoring the Early Response of Fulvestrant Plus Tanshinone IIA Combination Therapy to Estrogen Receptor-Positive Breast Cancer by Longitudinal 18F-FES PET/CT.

Endocrine monotherapy of breast cancers is generally hampered by the primary/acquired resistance and adverse sides in clinical settings. Herein, advantaging the multitargeting antitumor effects and normal organ-protecting roles of Chinese herbal medicine, the aim of this study was to investigate the enhanced synergistic efficacy of fulvestrant plus Tan IIA combination therapy in ER-positive breast cancers and to monitor the early response by longitudinal 18F-FES PET/CT imaging. The experimental results showed FUL + Tan IIA combination therapy significantly inhibited tumor growth of ER-positive ZR-75-1 tumor xenografts and exhibited distinct antitumor effects at an earlier time point after treatment than did the monotherapy of FUL or Tan IIA. Moreover, 18F-FES PET/CT imaging competently monitored the early response of FUL + Tan IIA combination therapy. The quantitative 18F-FES %ID/gmax in vivo was further confirmed by and correlated well with ERα expression ex vivo. In conclusion, the synergic effect of FUL + Tan IIA combination therapy to ER-positive breast cancers was verified in the preclinical tumor models and the early treatment response could be monitored by 18F-FES PET/CT.

Dehydroepiandrosterone Prevents H2O2-Induced BRL-3A Cell Oxidative Damage through Activation of PI3K/Akt Pathways rather than MAPK Pathways.

Dehydroepiandrosterone (DHEA) is a popular dietary supplement that has well-known benefits in animals and humans, but there is not enough information about the mechanisms underlying its effects. The present study aimed at investigating these mechanisms through in vitro experiments on the effects of DHEA on rat liver BRL-3A cells exposed to oxidative stress through H2O2. The findings showed that DHEA increased the antioxidant enzyme activity, decreased ROS generation, and inhibited apoptosis in H2O2-treated cells. These effects of DHEA were not observed when the cells were pretreated with known antagonists of sex hormones (Trilostane, Flutamide, or Fulvestrant). Furthermore, treatment with estradiol and testosterone did not have the same protective effects as DHEA. Thus, the beneficial effects of DHEA were associated with mechanisms that were independent of steroid hormone pathways. With regard to the mechanism underlying the antiapoptotic effect of DHEA, pretreatment with DHEA was found to induce a significant decrease in the protein expression of Bax and caspase-3 and a significant increase in the protein expression of PI3K and p-Akt in H2O2-treated BRL-3A cells. These effects of DHEA were abolished when the cells were pretreated with the PI3K inhibitor LY294002. No changes were observed on the p-ERK1/2, p-p38, and p-JNK protein levels in H2O2-induced BRL-3A cells pretreated with DHEA. In conclusion, our data demonstrate that DHEA protects BRL-3A cells against H2O2-induced oxidative stress and apoptosis through mechanisms that do not involve its biotransformation into steroid hormones or the activation of sex hormone receptors. Importantly, the protective effect of DHEA on BRL-3A cells was mainly associated with PI3K/Akt signaling pathways, rather than MAPK signaling pathways.

Saikosaponin­D improves fear memory deficits in ovariectomized rats via the action of estrogen receptor­α in the hippocampus.

Saikosaponin­D (SSD), which is the main bioactive component in the traditional Chinese medicine Chai Hu (Bupleurum falcatum L), possesses estrogen­like properties and is widely used in treating estrogen­related neurological disorders. The current study aimed to investigate the protective effects of SSD on the fear memory deficit in ovariectomized (OVX) rats and the potential underlying mechanism. SSD treatment significantly prolonged freezing time in OVX rats in a manner similar to that of estradiol (E2), whereas this effect was markedly suppressed by co­administration of ICI182780, a non­selective estrogen receptor (ER) inhibitor. The expression of ERα in the hippocampus of OVX rats was significantly elevated by SSD; however, Erß expression and E2 synthesis were not markedly affected by SSD treatment. Collectively, this study demonstrated that SSD­mediated fear memory improvement in OVX rats may be attributed not to E2 levels or ERß activity, but to ERα activation in the hippocampus.