Efectividad y seguridad de palbociclib en mujeres con cáncer de mama metastásico con receptores hormonales positivos: resultados en vida real / Effectiveness and safety of palbociclib in women with hormone receptor-positive metastatic breast cancer: real-life results

Objetivos: El objetivo del estudio es evaluar la efectividad y seguridad de palbociclib como tratamiento de primera línea en mujeres con cáncer de mama metastásico con receptores hormonales positivos y receptor del factor de crecimiento epidérmico humano 2 negativo en estado postmenopáusico, y como tratamiento de segunda línea en mujeres en estado post-, pre- y perimenopáusicas.Materiales y métodos: Estudio descriptivo retrospectivo que incluyó a mujeres en tratamiento con palbociclib entre enero del 2017 y julio del 2020. Se incluyeron a los pacientes según si cumplía los criterios del informe de posicionamiento terapéutico para los inhibidores CDK4/6 publicado en 2018, ampliándose su uso tras la posterior actualización. La efectividad se evaluó midiendo la supervivencia libre de progresión y supervivencia global a partir del método Kaplan-Meier. La seguridad se evaluó mediante el número de reacciones adversas y su grado según “Common Terminology Criteria for Adverse Events” version 5.0.Resultados: Se incluyeron 60 pacientes en el estudio. La mediana de edad fue de 58,7 años, con un 35% de las pacientes pre-/perimenopáusicas. La mediana de SLP para las pacientes en primera línea en estado postmenopáusicas y segunda línea en estado post-, pre- y perimenopáusicas fue de 21,18 meses (IC95%; NA-NA) y 17,79 meses (IC95%; 7,18-28,39) respectivamente y no se alcanzó la mediana para la SG en ninguno de los dos casos. El efecto adverso más frecuente grado ≥3 fue la neutropenia. Conclusiones: Palbociclib ha mostrado un beneficio a nivel de efectividad con un perfil de seguridad tolerable en mujer con cáncer de mama metastásico. (AU)

Objectives: The aim of this study is to evaluate the effectiveness and safety of palbociclib in women with metastatic breast cancer with positive hormone receptors and human epidermal growth factor receptor 2-negative.Materials and methods: A retrospective descriptive study including women receiving palbociclib from January 2017 until July 2020. Patients were included depending on whether it met the criteria of the therapeutic positioning report for CDK4/6 inhibitors published in 2018, expanding their use after further updating. Effectiveness was assessed by measuring progression-free survival and overall survival from the Kaplan-Meier method. Safety was assessed by the number of adverse reactions and their degree according to «Common Terminology Criteria for Adverse Events» version 5.0.Results: A total of 60 patients were included in the study. The median age was 58.7 years, with 35% of pre-/perimenopausal patients. Median progression-free survival for first-line post-menopausal and second-line post-, pre- and perimenopausal patients was 21.18 months (IC95%; NR-NR) and 17.79 months (IC95%; 7.18-28.39) respectively and the median for overall survival was not reached in either case. The most common side effect of ≥3 was neutropenia. Conclusions: Palbociclib has shown an effectiveness benefit with a tolerable safety profile in women with metastatic breast cancer. (AU)

Uso de inhibidores de la aromatasa en el tratamiento del dolor pélvico asociado a endometriosis: revisión sistemática / Aromatase inhibitors in the treatment of endometriosis-associated pelvic pain: A systematic review

ObjetivoConocer el efecto del uso de los inhibidores de la aromatasa (IA) en el tratamiento del dolor pélvico asociado a endometriosis (DPAE).Material y métodosRevisión sistemática de la literatura.ResultadosSe identificaron 173 artículos de los que resultaron válidos para la revisión 25, de los cuales 4 resultaron ser ensayos clínicos aleatorizados, 3 ensayos clínicos no aleatorizados, 10 estudios prospectivos no comparativos y 8 reportes de casos clínicos. En la mayoría de los estudios y/o casos clínicos (24 de 27) el uso de los IA se asoció a una mejoría en el DPAE. Se identificaron importantes sesgos que pueden influir en el análisis de la eficacia, fundamentalmente el uso combinado de IA con otros fármacos ampliamente utilizados en el tratamiento de la endometriosis.ConclusionesA pesar de la existencia de numerosos artículos que presentan y/o analizan el efecto de los IA en el control del DPAE, los sesgos de interpretación de sus resultados, junto con el perfil de efectos secundarios de este grupo de fármacos, hacen que su uso no se haya extendido y siga siendo considerado como un tratamiento experimental de la endometriosis. A día de hoy no existen evidencias de suficiente calidad para poder recomendar el uso de los IA en el tratamiento del DPAE en la práctica clínica habitual.

ObjectiveTo know the effect of the use of aromatase inhibitors (AI) in the treatment of endometriosis-associated pelvic pain (EAPP).Material and methodsSystematic review of the literature.Results173 articles were identified of which 25 were valid for the review, of which 4 were randomized clinical trials, 3 were non-randomized clinical trials, 10 were prospective non-comparative studies and 8 were clinical case reports. In most of the studies and/or case reports (24 of 27) the use of AI was associated with an improvement in EAPP. Important biases were identified that may influence the efficacy analysis, primarily the combined use of AI with other drugs widely used in the treatment of endometriosis.ConclusionsDespite the existence of numerous articles presenting and/or analysing the effect of AIs in the control of EEAP, the biases in the interpretation of their results, together with the side effect profile of this group of drugs, mean that their use has not become widespread, and they continue to be considered an experimental treatment for endometriosis. To date, there is insufficient evidence of sufficient quality to recommend the use of AI in the treatment of EEAP in routine clinical practice.

Investigation of teratogenic effects of letrozole on fetal bone development / Investigación de los efectos teratogénicos de letrozol en el desarrollo óseo fetal

SUMMARY: Letrozole is mainly used for the treatment of unexplained infertility, breast cancer and polycystic ovarian syndrome, with secondary use in ovarian stimulation. In cases of unexpected or unknown pregnancy during the use of letrozole, letrozole may cause a teratogenic effect on the fetus. In this reason, in this study, we aimed to determine the effect of letrozole on fetal bone development. In this study, 32 pregnant Wistar albino rats were used. The rats were divided into four groups: Control (saline) and high; 0.3 mg/kg, medium; 0.03 mg/kg, low; 0.003 mg/ kg letrozole. Saline and letrozole were administered in 100 mL solutions by intraperitonaly from day 11 to day 15 of pregnancy. The skeletal system development of fetuses was examined with double skeletal staining, immunohistochemical staining methods and mineral density scanning electron microscopy. A total of 100 fetuses from female rats, 25 in each group, were included in the study. As a result of that, ossification rates were observed to decrease depending on the dose of letrozole in the forelimb limb (scapula, humerus, radius, ulna) and hindlimb (femur, tibia, fibula) limb bones. As a result of the statistical analysis, a statistically significant decrease was found in the ossification rates of all bones between the control group and low, medium, high letrozole groups (p<0.001). Exposure to letrozole during pregnancy adversely affected ossification and bone growth. However, the teratogenic effects of letrozole are unclear. Therefore, it needs to be investigated more extensively.

RESUMEN: Letrozol se usa principalmente para el tratamiento de la infertilidad inexplicable, el cáncer de mama y el síndrome de ovario poliquístico, con estimulación ovárica de uso secundario. En casos de embarazo inesperado o desconocido durante el uso de letrozol, puede causar un efecto teratogénico en el feto. Por esta razón, en este estudio, nuestro objetivo fue determinar el efecto de letrozol en el desarrollo óseo fetal. Se utilizaron 32 ratas albinas Wistar preñadas las cuales se distribuyeron en cuatro grupos: Control (solución salina) y alta; 0,3 mg/kg, medio; 0,03 mg/kg, bajo; 0,003 mg/kg de letrozol. Se administró solución salina y letrozol en soluciones de 100 mL por vía intraperitoneal desde el día 11 hasta el día 15 de la preñez. El desarrollo del sistema esquelético de los fetos se examinó con tinción esquelética doble, métodos de tinción inmunohistoquímica y microscopía electrónica de barrido de densidad mineral. Se incluyeron en el estudio un total de 100 fetos de ratas hembra, 25 en cada grupo. Como resultado, se observó que las tasas de osificación disminuían dependiendo de la dosis de letrozol en los huesos de los miembros torácicos (escápula, húmero, radio, ulna) y de las miembros pélvicos (fémur, tibia, fíbula). Se encontró una disminución estadísticamente significativa en las tasas de osificación de todos los huesos entre el grupo control y los grupos de letrozol bajo, medio y alto (p<0,001). La exposición a letrozol durante la preñez afectó negativamente la osificación y el crecimiento óseo. Sin embargo, los efectos teratogénicos del letrozol no están claros por lo que debe ser investigado más extensamente.

Efeitos do citrato de clomifeno, letrozol e estradiol sobre apoptose em células do cumulus oophorus humano / Effects of clomiphene citrate, letrozole and estradiol on apoptosis in human cumulus oophorus cells

Citrato de clomifeno (CC) e letrozol (LE) são indutores de ovulação que, apesar das altas taxas de ovulação confirmada, atingem baixas taxas de gravidez. Este estudo teve como objetivo investigar os efeitos de CC e LE in vitro, isoladamente ou em combinação com estradiol (E), na apoptose de células do cumulus oophorus humano. Realizamos um estudo prospectivo controlado utilizando culturas primárias de células do cumulus de pacientes submetidas à fertilização in vitro (n=22). A coloração com Giemsa e a imunocitoquímica para alfa-inibina foram utilizadas para avaliar a pureza e a morfologia da cultura celular. A viabilidade celular foi avaliada pelo ensaio MTT, o ciclo celular por citometria de fluxo e a expressão gênica de Caspase-3, Bax e Superóxido dismutase 2 (SOD-2) e S26 por reação em cadeia de polimerase (PCR) em tempo real. As células foram tratadas por 24 horas em 5 grupos de tratamento: CC, CC + E, LE, LE + E e controle. Nenhum dos tratamentos afetou a viabilidade celular, mas o LE reduziu a porcentagem média de células na fase S em relação ao controle (24,79 versus 21,70, p=0,0014). O tratamento com CC aumentou a expressão gênica de Bax (4 vezes) e SOD-2 (2 vezes), que foi revertida quando adicionado E à cultura. A expressão de SOD-2 aumentou em células tratadas com LE quando comparado ao controle (4 vezes), que foi também revertida por adição de E. Estes achados sugerem que CC e LE não afetam significativamente a viabilidade das células do cumulus humana. Porém, houve modulação na expressão de genes envolvidos na apoptose por essas drogas isoladamente e em associação com E, sugerindo que CC e LE podem ter efeitos diretos nas células do cumulus além de seus mecanismos de ação conhecidos.

Clomiphene citrate (CC) and letrozole (LE) are ovulatory stimulants that, despite high ovulation rates, achieve low pregnancy rates. This study aimed to investigate the in vitro effects of CC and LE, alone or in combination with estradiol (E), on apoptosis in human cumulus cells. We performed a controlled prospective study using primary cumulus cell cultures from patients undergoing in vitro fertilization (n=22). Giemsa stain and alpha-inhibin immunocytochemistry was used to assess cell culture purity and morphology. Cell viability was evaluated by MTT assay, cell cycle status by flow cytometry, and Caspase-3, Bax and superoxide dismutase 2 (SOD-2), and S26 gene expression by real-time polymerase chain reaction (qPCR). Cells were treated for 24 hours in 5 conditioned media: CC, CC + E, LE, LE + E and control. None of the treatments affected cell viability, but LE reduced the mean percentage of cells in the S phase compared to control (24.79 versus 21.70, p=0.0014). CC treatment increased mRNA expression of Bax (4 fold) and SOD-2 (2 fold), which was reversed by co-treatment with E. SOD-2 expression increased in cells treated with LE compared to control (4 fold), which was also reversed by E. These findings suggest that CC and LE do not significantly affect the viability of human cumulus cells. Still, the expression of genes involved in apoptosis was modulated by these drugs alone and in association with E, suggesting that CC and LE may have direct effects on cumulus cells beyond their known mechanisms of action.

Lipid Changes During Endocrine Therapy in Breast Cancer Patients: The Results of a 5-Year Real-World Retrospective Analysis.

BACKGROUND: The aim of this study was to investigate the status of serum lipids during endocrine therapy. METHODS: We retrospectively analysed lipid profiles during the 5-year treatment of 1487 consecutive postoperative BC patients. Lipid parameters included triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C). Those biomarkers were measured at baseline and 1, 2, 3, 4 and 5 years following the initiation of endocrine therapy. RESULTS: For premenopausal BC patients, LDL levels rapidly decreased at 1 year in the tamoxifen (TAM) group compared with baseline levels (p<0.05), and this decline remained for the following 4 years. Additionally, LDL levels were significantly lower in the TAM group than in the nonendocrine group at all assessment time points (p<0.05). Similarly, TC levels also decreased in the TAM group compared with baseline levels at all assessment time points (p<0.05), and compared with the levels in the nonendocrine group, TC levels were also lower for the first 4 years. For postmenopausal BC patients, there was no significant difference in the lipid profiles (TG, TC, LDL and HDL) in the letrozole (LET), anastrozole (ANA) or exemestane (EXE) groups compared with the nonendocrine group. For patients who received TAM, compared with the nonendocrine group, TC levels decreased at 1 year, and LDL levels decreased at 1 and 2 years. CONCLUSIONS: TAM may improve LDL and TC levels in premenopausal BC patients. In postmenopausal BC patients, aromatase inhibitors (AIs) may have no adverse effects on lipid profiles, and TAM may have limited beneficial effects on serum lipids.

Atualizações na terapêutica farmacológica para infertilidade na mulher diagnosticada com síndrome de ovários policísticos: revisão de literatura / Updates on pharmacological treatments for infertility in women diagnosed with polycystic ovary syndrome: a literature review

Objetivo: Abordar atualizações referentes à terapia medicamentosa para indução da ovulação nas mulheres diagnosticadas com síndrome dos ovários policísticos (SOP). Métodos: Revisão de literatura por meio de levantamento bibliográfico do período de 1975 a 2021, nas bases eletrônicas PubMed, SciELO e MedLine, complementado pela Diretriz Internacional Baseada em Evidências para a Avaliação e Manejo da SOP de 2018 e pelo manual da Febrasgo para SOP. Sete descritores que atendessem à finalidade da pesquisa foram utilizados. Resultados: A literatura aponta atualmente algumas drogas como opção na terapêutica para a indução de ovulação, como metformina, letrozol e citrato de clomifeno, evidenciando que o uso de letrozol isolado e em associação com a metformina apresentaram melhores taxas de ovulação, 71,5% e 75,4%, respectivamente. Conclusão: O uso do letrozol isolado ou combinado com a metformina apresentou os melhores resultados nas taxas de gravidez e ovulação, todavia o tratamento para indução ovulatória deve ser individualizado.(AU)

Objective: To address updates of medicinal therapy for ovulation induction in women diagnosed with polycystic ovary syndrome (PCOS). Methods: Reviewing Literature through a bibliographic survey from 1975 to 2021, on the electronic databases PubMed, SciELO and MedLine, complemented by the International Evidence-Based Guideline for the Evaluation and Management of PCOS 2018 and the Febrasgo guide for PCOS. Seven descriptors that matched to the purpose of the research were applied. Results: Some drugs are currently indicated in the literature as an option for ovulation induction therapy, such as: metformin, letrozole and clomiphene citrate, showing that the use of letrozole alone and in association with metformin had better ovulation rates, 71.5% and 75.4%, respectively. Conclusion: The use of letrozole alone or combined with metformin showed the best results in pregnancy and ovulation rates, however, treatment for ovulatory induction must be individualized.(AU)

Changes of tyrosine phosphorylation in liver and kidney of polycystic ovarian rats induced by letrozole / Cambios de fosforilación de tirosina en hígado y riñón de ratas ováricas poliquísticas inducidas por letrozol

Letrozole (Letro) is a drug commonly used for breast cancer treatment since it can decrease estrogen level. In experimental animal, the Letro has been used to induce the polycystic ovarian syndrome (PCOS) model. Tyrosine phosphorylation (TyrPho) is an essential process in various biological functions both normal and abnormal conditions especially reproduction. Although some side effects of Letro are reported, the alterations of TyrPho responsible for liver and kidney functions have never been demonstrated. In this study, the blood serum, liver, and kidney of control and PCOS rats induced with Letro (orally, 1 mg/ KgBW) for consecutive 21 days were used to determine the serum biochemical components and to investigate the TyrPho expression using western blot analysis. Histopathology of such tissues was observed by Masson's trichrome staining. The results showed that Letro did not affect histological structures but significantly increased the serum levels of urea nitrogen, cholesterol, triglyceride, HDL, LDL, ALT, AST, and alkaline phosphatase. Additionally, the TyrPho protein expressions of 32 and 27 kDas in liver and of 55 and 43 kDas in kidney were increased while of a kidney 26 kDa was decreased as compared to those of control. In conclusion, this recent study indicated that the changes of TyrPho proteins in liver and kidney induced with Letro associated with their functions by alteration of serum biochemical levels.

El letrozol (Letro) es un medicamento utilizado comúnmente para el tratamiento del cáncer de mama, debido a que puede disminuir el nivel de estrógeno. En animales de experimentación, el Letro se ha utilizado para inducir el modelo de síndrome de ovario poliquístico (PCOS). La fosforilación de tirosina (TyrPho) es un proceso esencial en diversas funciones biológicas, tanto en condiciones normales como anormales, especialmente en la reproducción. A pesar de informes que indican algunos efectos secundarios de Letro, no se han demostrado las alteraciones de TyrPho responsables de las funciones hepáticas y renales. En este estudio, el suero sanguíneo, el hígado y el riñón control y las ratas PCOS inducidas con Letro (por vía oral, 1 mg / KgBW) durante 21 días consecutivos se usaron para determinar los componentes bioquímicos del suero y para investigar la expresión de TyrPho usando análisis de transferencia Western. La histopatología de los tejidos se observó mediante la tinción tricrómica de Masson. Los resultados mostraron que Letro no afectó las estructuras histológicas, pero aumentó significativamente los niveles séricos de urea, colesterol, triglicéridos, HDL, LDL, ALT, AST y fosfatasa alcalina. Además, las expresiones de la proteína TyrPho de 32 y 27 kDas en el hígado y de 55 y 43 kDas en el riñón aumentaron mientras que en un riñón disminuyeron 26 kDa en comparación con el control. En conclusión, este estudio indicó que los cambios de las proteínas TyrPho en el hígado y los riñones inducidos con Letro se asociaron con sus funciones mediante la alteración de los niveles bioquímicos en suero.

A descrição teórica da detecção eletroanalítica do letrozol, assistida pelo compósito VO(OH)-polipirrol, obtido catodicamente / Theoretical description for the letrozol electroanalytical determination, assisted by the cathodically obtained composite VO(OH)-polypyrrole

RESUMO O processo da determinação eletroanalítica do fármaco letrozol, assistida pelo compósito VO(OH)-polipirrol, obtido mediante um processo catódico, foi descrito teoricamente. Tanto para a síntese do compósito, como para o processo eletroana-lítico foi sugerido e analisado, mediante a teoria de estabilidade linear e análise de bifurcações, um modelo matemático. Foi mostrado que, ao contrário da eletrossín-tese de polipirrol catódica, iniciada por um composto na solução, o polipirrol resultante tem uma morfologia mais "centrada" aos centros ativos da matriz, dopados pelos cátions VO2+. No entretanto, tanto a síntese do compósito, como o seu desempenho eletroanalítico com o letrozol podem ser considerados eficientes.

SUMMARY The process of the electroanalytical determination of letrozol drug, assisted by the cathodically obtained VO(OH)-Polypyrrole, has been theoretically described. For both the composite synthesis and electroanalytical function a mathematical model has been suggested and analyzed by means of linear stability theory and bifurcation analysis. It was shown that, contrarily to the cathodic polypyrrole electrosynthesis, initiated by a compound in a solution, the resulting cathodic polypyrrole has more "centred" morphology, in the relation to the matrix active centers, doped by VO2+ cations. Nevertheless, either the synthesis of the composite, or its electroanalytical function with letrozole may be considered efficient.

Letrozole may be a valuable maintenance treatment in high-grade serous ovarian cancer patients.

OBJECTIVES: Endocrine therapy is used as maintenance in estrogen receptor (ER) positive breast cancers and has been proposed in low-grade serous ovarian cancers (LGSOC). Here we examine a rationale for its use as maintenance in high-grade serous ovarian cancers (HGSOC). METHODS: We accessed the TCGA PANCAN dataset to evaluate the expression of ESR1. ESR1 expression data on all cancers (n=8901) and HGSOC (n=527) were followed by investigation of ER expression via immunohistochemistry (IHC) (n=4071). The same was performed in an independent cohort for matched primary and recurrent HGSOC (n=80). Finally, newly diagnosed ER+ HGSOC patients were offered a maintenance therapy with Letrozole. RESULTS: ESR1 was strongly expressed in similar levels in HGSOC as in breast cancer. We found a strong ER expression via IHC in both the primary and matched recurrent HGSOC, particularly in the Platinum-resistant subgroup. The additional use of Letrozole as maintenance treatment was associated with a significantly prolonged recurrence free interval (after 24months 60% when taking Letrozole versus 38.5% in the control group; p=0.035; RFS: IC50 reached by one subject versus 13.2months). This effect was also present in patients treated additionally with Bevacizumab; 20.8% of patients had no recurrence after 12months compared to 87.5% when taking Letrozole in addition to Bevacizumab (p=0.026). CONCLUSIONS: Primary HGSOC have a slightly higher ESR1 than and a similar ER expression breast cancer where aromatase inhibitor maintenance is routine for decades. Here we demonstrate evidence for the usefulness of Letrozole in HGSOC, particularly in patients with chemotherapy resistance or residual disease.

Hormone Therapy in Breast Cancer.

Hormonal therapy is mandatory for all patients with hormonereceptor- positive breast neoplasms. It is active both in adjuvant and metastatic disease. The only active adjuvant hormonal therapy in pre- and postmenopause is Tamoxifen. The adjuvant treatment duration influences disease-free survival, the risk of a contralateral breast cancer apparition and overall survival. The aromatase inhibitors: Anastrozol, Letrozol, Exemestan are only used in postmenopause. Fulvestrant is used in recurrent disease after or during treatment with Tamoxifen. LHRH analogues are used in premenopausal patients in adjuvantcy and sometimes in case of recurrences. Around 50% of hormonereceptor- positive breast neoplasms are or become resistant to hormone therapy. Some molecules involved in some tumour cellular growth pathways reverse the resistance to hormone therapy (Palbociclib, Everolimus).

Trombocitopenia inducida por tamoxifeno y letrozol / Thrombocytopenia induced by tamoxifen and letrozole

El tamoxifeno y el letrozol son fármacos muy utilizados en el tratamiento del cáncer de mama. Está descrito que la trombocitopenia (recuento plaquetario inferior a 100.000/mm3) es un efecto secundario raro tras el tratamiento con tamoxifeno. Sin embargo, no es un efecto adverso conocido del letrozol. Presentamos dos casos clínicos en los que tras tratamientos prolongados con estos fármacos nos encontramos con que las pacientes desarrollan trombocitopenia. En ambos casos, este efecto adverso desaparece en pocas semanas tras la retirada del fármaco.

Letrozole and tamoxifen are drugs used in the treatment of breast cancer. It is reported that thrombocytopenia (less than 100,000 / mm3 platelet count) is a rare side effect of tamoxifen. However, it is not a known side effect of letrozole. We present two cases in which after prolonged treatment with these drugs we found that the patients develop thrombocytopenia. In both cases, this adverse effect disappears a few weeks after drugs were stopped.

Comparing the effect of aromatase inhibitor (letrozole) + cabergoline (Dostinex) and letrozole alone on uterine myoma regression,a randomized clinical trial.

OBJECTIVE: To evaluate the effect of letrozole in combination with cabergoline and letrozole alone on regression of symptomatic uterine myomas in women of reproductive age. DESIGN: Randomized controlled clinical trial. SETTING: University hospital. PATIENTS: Ninety-one women of reproductive age were enrolled in the study and 88 women were eligible. Eight participants were excluded from the study. INTERVENTIONS: Eighty women of reproductive age with symptomatic myomas >4cm were evaluated in two groups. Participants in Group 1 received 2.5mg letrozole once daily and cabergoline 0.5mg/week from the first day of the menstrual cycle for 12 weeks, and participants in Group 2 received letrozole alone. MAIN OUTCOME MEASURES: Changes in uterine size and volume; myoma size, volume and number; and side effects of treatment. RESULTS: Overall, 76 patients completed the study. Compared with baseline values, mean uterine volume was reduced significantly in both groups (p=0.01), and there was no significant difference between groups (p=0.99). The mean number of dominant myomas was reduced significantly in both groups (p=0.03), with no significant difference between groups (p=0.6). The mean volume of myomas was reduced significantly in both groups (p=0.01), with no significant difference between groups (p=0.45). Although a significant decrease in number and volume of myomas was documented in each group (p<0.05), the intergroup analyses did not reveal significant differences between the two groups in terms of the change in number (p=0.28) and volume (p=0.96) of myomas. Headache was significantly more common in the letrozole+cabergoline group (nine vs two cases, p=0.02), but the two groups were comparable for the remaining minor side effects. CONCLUSION: This study showed that 12 weeks of treatment with letrozole with and without cabergoline improved the size and volume of the uterus and myomas, led to symptom improvement, and could be used for short-term treatment prior to surgery or fertility programmes. CONDENSATION: Condensation letrozole in combination with cabergoline in the management of uterine fibroids.

Experiencia institucional con Palbociclib. Estudio Prospectivo / Institutional experience with Palbociclib. Prospective Study

La ANMAT aprobó en diciembre de 2015 el uso de palbociclib en combinación con letrozol para el tratamiento de primera línea del cáncer de mama metastásico con receptores hormonales positivos y HER2 negativo, y en agosto de 2016 la combinación de palbociclib con fulvestrant para pacientes progresadas a terapia endocrina previa. El propósito del presente estudio fue realizar una evaluación prospectiva de la seguridad y eficacia del tratamiento con palbociclib en el Instituto de Oncología Ángel Roffo. Se evaluaron en forma prospectiva 71 pacientes con cáncer de mama metastásico que calificaron para tratamiento con palbociclib desde marzo de 2016 hasta junio de 2017 inclusive. Las participantes fueron tratadas con palbociclib/letrozol (n = 49) o palbociclib/fulvestrant (n = 22). La mediana de tratamiento con palbociclib/ letrozol fue de 5 meses; 3 pacientes presentaron progresión de la enfermedad, y 36 se encuentran en respuesta parcial. La mediana de tratamiento con palbociclib/fulvestrant fue de 2.6 meses; 3 experimentaron progresión de la enfermedad, mientras que el resto de las participantes de este grupo se encuentran con respuesta parcial. En total, 26 tratadas con palbociclib presentaron toxicidades hematológicas, destacándose la neutropenia de grados I a III, anemia de grados I a II, y plaquetopenia grado III. No se registraron toxicidades de grado IV. A pesar del breve período de seguimiento (16 meses), nuestras pacientes evolucionaron con escasa cantidad de progresiones (8.4%), de acuerdo con lo descrito en la literatura, y con menor toxicidad que la comunicada (36.7%) (AU)

In December 2015, ANMAT approved the use of palbociclib in combination with letrozole for the first-line treatment of hormone-receptor-positive and HER2-negative metastatic breast cancer. Subsequently, the combination of palbociclib with fulvestrant was approved in August 2016 for patients progressing from previous endocrine therapy. The purpose of the present study was to conduct a prospective evaluation of safety and efficacy of palbociclib treatment at Instituto de Oncología Ángel H. Roffo. Seventy one patients with metastatic breast cancer who qualified for treatment with palbociclib from March 2016 to June 2017, were evaluated prospectively. Participants were treated with palbociclib/letrozole (n = 49) or palbociclib/ fulvestrant (n = 22). Median of treatment with palbociclib/letrozole was 5 months; 3 patients showed progression of the disease, and 36 are in partial response. Median of treatment with palbociclib/fulvestrant was 2.6 months; 3 patients experienced disease progression, while the rest of the participants in this group were in partial response. In total, 26 treated with palbociclib presented haematological toxicities, including neutropenia grades I to III, anaemia in grades I to II, and thrombocytopenia grade III. No grade IV toxicities were recorded. Despite the brief follow-up period (16 months), our patients experienced a low number of progression (8.4%), as described in the literature, and with less toxicity than reported (36.7%) (AU)

Clinical Observation ofTongYuanNeedling Method plus Letrozol and HCG for Refractory Sterility Caused by Polycystic Ovary Syndrome / 上海针灸杂志

Objective To observe the clinical efficacy ofTong Yuan(short forTong Du Tiao Shen,Yin Qi Gui Yuan, referring to unblocking the Governor Vessel, regulating mind, and guiding qi back to the origin) needling method plus Letrozol and human chorionic gonadotropin (HCG) in treating refractory sterility caused by polycystic ovary syndrome (PCOS).Method Sixty clomiphene citrate-resistant PCOS-induced sterility patients were recruited and randomized into two groups. The treatment group was intervened byTong Yuanneedling plus Letrozol and HCG, while the control group was intervened only by Letrozol and HCG, both for 3 months. Prior to and after the treatment,the levels of estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) were detected; the endometrium, ovulation and pregnancy rates were also observed.Result After 3 menstrual cycles, the level of FSH increasedsignificantly (P<0.05), LH decreased significantly (P<0.05), LH/FSH declined significantly (P<0.05), and the level of T also dropped significantly (P<0.05) in both treatment group and control group; the level of E2also dropped significantly after the treatment in both groups (P<0.05), and the decrease in the treatment group was more significantly than that in the control group (P<0.05). The ovulation and pregnancy rates in the treatment group were significantly higher than those in the control group (P<0.05).Conclusion Tong Yuanneedling plus Letrozol and HCG can significantly down-regulate the levels of LH, E2and T, up-regulate the level of FSH, effectively improve the internal reproductive environment of refractory PCOS patients, and enhance the ovulation and pregnancy rates.

Ovarian stimulation in patients with breast cancer.

Breast cancer is the most prevalent malignancy among women under 50. Improvements in diagnosis and treatment have yielded an important decrease in mortality in the last 20 years. In many cases, chemotherapy and radiotherapy develop side effects on the reproductive function. Therefore, before the anti-cancer treatment impairs fertility, clinicians should offer some techniques for fertility preservation for women planning motherhood in the future. In order to obtain more available oocytes for IVF, the ovary must be stimulated. New protocols which prevent exposure to increased estrogen during gonadotropin stimulation, measurements to avoid the delay in starting anti-cancer treatment or the outcome of ovarian stimulation have been addressed in this review. There is no evidence of association between ovarian stimulation and breast cancer. It seems that there are more relevant other confluent factors than ovarian stimulation. Factors that can modify the risk of breast cancer include: parity, age at full-term birth, age of menarche, and family history. There is an association between breast cancer and exogenous estrogen. Therefore, specific protocols to stimulate patients with breast cancer include anti-estrogen agents such as letrozole. By using letrozole plus recombinant follicular stimulating hormone, patients develop a multifollicular growth with only a mild increase in estradiol serum levels. Controlled ovarian stimulation (COS) takes around 10 days, and we discuss new strategies to start COS as soon as possible. Protocols starting during the luteal phase or after inducing the menses currently prevent a delay in starting ovarian stimulation. Patients with breast cancer have a poorer response to COS compared with patients without cancer who are stimulated with conventional protocols of gonadotropins. Although many centres offer fertility preservation and many patients undergo ovarian stimulation, there are not enough studies to evaluate the recurrence, breast cancer-free interval or mortality rates in these women.

A Case of Complete Response to Letrozol Treatment in a Postmenopausal Woman With Breast Cancer Who has Progressed After Multiple Lines of Chemotherapy.

Approximately 60% of all breast cancers are endocrine dependent. Postmenopausal patients who have positive hormone receptor status are eligible for aromatase inhibitor treatment. Letrozole is a potent, selective, non-steroidal, third-generation aromatase inhibitor which reduces oestrogen biosynthesis approximately 99% at the dose of 2.5 mg/day. We report a 54-years-old female patient diagnosed with grade 2 invasive ductal carcinoma of the breast. She received adjuvant chemotherapy, followed by 5 years of tamoxifen. After 8 years, recurrence appeared in lung, supraclavicular lymph nodes and brain. She had many cycles of cytotoxic chemotherapeutic agents, trastuzumab and lapatinib previously. After the progression (lung and brain), palliative therapy was thought due to very poor performance status of the patient. (ECOG: 3) Letrozole was added in the treatment and we obtained near-complete remission from her lung and brain metastasis with 2.5 mg/day dose of letrozole. This study might support successfully use of aromatase inhibitors in patients who has been previously treated with multiple lines of chemotherapy and had still progressive disease.

Development and in vitro evaluation of Letrozole loaded biodegradable nanoparticles for breast cancer therapy / Desenvolvimento e avaliação in vitro de Letrozole carregado nanopartículas biodegradáveis para o tratamento do câncer de mama

The objectives of our study were to prepare and evaluate a biodegradable nanoparticulate system of Letrozole (LTZ) intended for breast cancer therapy. LTZ loaded poly(lactide-co-glycolide) nanoparticles (LTZ-PLGA-NPs) were prepared by emulsion-solvent evaporation method using methylene chloride and polyvinyl alcohol. Percentage of drug (with respect to polymer) was selected as formulation variable. LTZ-PLGA-NPs were characterized by particle size, zeta potential, infrared spectra, drug entrapment efficiency and in vitro release. Sonication was done with an ultrasound pulse sonicator at 70 W, 30 kHz for 90 sec to produce stable NPs of mean size range from 64 nm to 255 nm with high entrapment efficiency (68 percent to 82 percent). Percentage of drug significantly influenced particle size, entrapment efficiency and release (p <0.05). The system sustained release of LTZ significantly and further investigation could exhibit its potential usefulness in breast cancer therapy.

Os objetivos de nosso estudo foram preparar e avaliar o sistema de nanopartícula biodegradável de letrozol na terapia de câncer mamário. Nanopartículas de poli(lactídeo-co-glicolídeo) carregadas com LTZ (LTZ-PLGA-NPs) foram preparadas pelo método de emulsão-evaporação de solvente, utilizando dicloro metano e álcool polivinílico. A porcentagem do fármaco (com relação ao polímero) foi selecionada como variável da formulação. LTZ-PLGA-NPs foram caracterizadas pelo tamanho da partícula, potencial zeta, espectros no infravermelho, eficiência de inclusão e liberação in vitro. A sonicação foi realizada com sonicador de ultrassom, de pulso a 70W e 30 kHz por 90 segundos para produzir NPs estáveis, de faixa de tamanho médio de 64 nm a 266 nm, com alta eficiência de inclusão (68 por cento a 82 por cento). A porcentagem do fármaco foi significativamente influenciada pelo tamanho da partícula, eficiência de inclusão e liberação (p<0,05). O sistema controlou significativamente a liberação de LTZ e estudos posteriores poderiam mostrar sua utilidade potencial na terapia de câncer de mama.

A Case of Radiation Recall Dermatitis after Hormonal Therapy of Letrozol (Femara(R)) / 대한피부과학회지

Radiation recall dermatitis gap (RRD) is the development of an inflammatory reaction throughout a previously irradiated area, precipitated by the administration of certain drugs. Usually chemotherapeutic agents have been associated with RRD, but other drugs reported include tamoxifen, interferon alfa-2b, simvastatin, and antituberculous drugs. We present a case of RRD after chemotherapy with letrozol (Femara(R)). Letrozol is a third generation aromatase inhibitor, which acts as an anti-estrogen agent. This is the first reported case of RRD triggered by letrozol.