The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.

ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.

The Experience of Initiating Oral Adjuvant Treatment for Estrogen Receptor-Positive Breast Cancer.

PURPOSE/OBJECTIVES: To describe the experience of women with estrogen receptor-positive breast cancer who are initiating oral adjuvant therapy and to determine what they describe as facilitating and/or hindering this experience. 
. RESEARCH APPROACH: Qualitative inquiry. 
. SETTING: Massachusetts General Hospital Cancer Center in Boston. 
. PARTICIPANTS: 14 women aged 48-81 years. 
. METHODOLOGIC APPROACH: Qualitative, descriptive study using content analysis.
. FINDINGS: Five themes were identified. CONCLUSIONS: Each participant who was initiating oral adjuvant treatment described many unmet needs. Women who were caregivers, were older aged, had several chronic illnesses, and were on several medications reported more difficulty transitioning to oral adjuvant therapy. 
. INTERPRETATION: This study suggests that nurses need to collaborate with other members of the healthcare team to assess the needs of and provide comprehensive care to women initiating oral adjuvant therapy. This is particularly true for women who are older aged, self-reported caregivers, and on several medications, and who have chronic comorbid conditions.

Supplementation With Cell-Penetrating Peptide-Conjugated Estrogen-Related Receptor ß Improves the Formation of the Inner Cell Mass and the Development of Vitrified/Warmed Mouse Embryos.

Estrogen-related receptor ß (ESRRB), which is a member of the nuclear orphan receptor family, regulates the messenger RNA (mRNA) expression levels of the transcription factors, Oct4 and Nanog, in early embryos and germ cells, thereby maintaining the undifferentiated state and pluripotency of the relevant cells. The present study was designed to determine whether the upregulation of pluripotency-related genes by direct delivery of ESRRB protein may affect on the commitment into inner cell mass (ICM) or the development of vitrified/warmed mouse embryos. Recombinant cell-penetrating peptide (CPP) ESRRB protein was synthesized and then added into a culture medium for cryopreserved mouse embryos. Vitrified/warmed 8-cell embryos were cultured in KSOM with/without 2 µg/mL CPP-ESRRB for 48 hours and then analyzed or transferred to the uteri of foster mothers. The mRNA expression of Oct4 and Nanog was higher in CPP-ESRRB-treated blastocysts compared to the untreated controls. No difference was observed in embryonic development, but ICM:trophectoderm ratio was increased in the CPP-ESRRB-treated group compared to the untreated group, and after embryo transfer, a higher implantation rate was obtained in the CPP-ESRRB-treated group compared to the untreated group. This study shows for the first time that recombinant CPP-ESRRB can be easily integrated into vitrified/warmed mouse embryos and that it increases Oct4 expression (via a pluripotency-related gene pathway), ICM formation, and the further embryonic and full-term development of vitrified/warmed mouse embryos. This CPP-conjugated protein delivery system could therefore be a useful tool for improving assisted reproductive technology.

Tratamiento preservador del cáncer de la mama: dos años de experiencia / Conservative breast cancer treatment: two years of experience

Experiencia de nuestra institución en tratamiento preservador del cáncer de mama, analizando cirugía preservadora en términos de recidiva local, sobrevida global y libre de enfermedad. Estudio descriptivo, retrospectivo durante 2004-2005, en pacientes sometidos a tratamiento preservador: la realización de mastectomía parcial oncológica con márgenes negativos, evaluación quirúrgica de axila mediante técnica del ganglio centinela o disección axilar, el tratamiento adyuvante con radioterapia, y quimioterapia en los casos que tuviesen indicación. 132 cirugías conservadoras. Edad media 51,49 años, Tipo histológico más frecuente fue carcinoma ductal infiltrante (70,06 por ciento), (85,94 por ciento) fueron estadio I y II. La cirugía que más se realizó fue la mastectomía parcial oncológica más disección axilar (80 pacientes, 61,87 por ciento). 10,6 por ciento recibieron neoadyuvancia con quimioterapia. El promedio de ganglios obtenidos fue de 11,37, el 62,6 por ciento estado patológico axilar 0.50 por ciento expresaron receptores de estrógeno y progestágenos positivos el 13,17 por ciento sobre expresaron el Her2neu. 66,66 por ciento recibió quimioterapia adyuvante, 79,84 por ciento radioterapia adyuvante. 56,58 por ciento terapia hormonal adyuvante, seguimiento 39,89 meses promedio. 88,88 por ciento vivas libres de enfermedad, 2,22 por ciento vivas con recaída local, 5,92 por ciento viva con metástasis, 1,48 por ciento viva con recaída local y metastásica 1,07 por ciento muerta por enfermedad. El intervalo libre de enfermedad promedio fue de 25,8 meses y la sobrevida global a los 5 años de 98,24 por ciento. El tratamiento preservador es una terapia primaria efectiva en casos de cáncer de mama estadio I y II.

Presented the experience in our institution in the conservative treatment of breast cancer, we analyzed the surgery, local recurrence, and the global super life, and the disease free survival. These are a descriptive and retrospective study during 2004-2005 in patients underwent conservative treatment: realize of partial oncology mastectomy with negative margins surgical evaluation of axillaries sentinel node technique or axillaries dissection. The adjuvant treatment with radiation therapy and chemotherapy when there are indicated in the patients. We realize 132 conservative surgery, median ages of patients were 51.49 histological type more frequent was ductal infiltrante carcinoma (70.06 percent), (85.94 percent) were stage I and II. The surgical more frequent were partial oncology mastectomy with axillaries dissection (80 patients, 61.87 percent). 10.6 percent received adjuvant chemotherapy. The average of finding nodes was 11.37, the 62.6 percent pathological axillaries state were 0.50 percent expression positive estrogen and progestagen receptors 13.17 percent super expression of Her2neu. 66.66 percent received adjuvant chemotherapy, 79.84 percent adjuvant radiation therapy 56.58 percent adjuvant hormonal therapy. Average vigilance was 39.89 months. 88.88 percent alive free disease, 2.22 percent alive with local recurrence, and 5.92 percent alive with metastases. 1.48 percent alive with local and metastasis recurrence 1.07 percent dead for disease. The free interval of disease was 25.8 month and the global super life to 5 years 98.24 percent. The conservative treatment is a primary and effective in breast cancer therapy for stage I and II.

Disruption of fear memory through dual-hormone gene therapy.

BACKGROUND: The basolateral complex of the amygdala (BLA) is uniquely affected by steroid hormones. Whereas glucocorticoids (GCs)--the adrenal hormones released during stress--increase the excitability of BLA neurons, estrogen decreases it. METHODS: In this study, we used a vector designed to express a chimeric gene that contains the GC-binding domain of the GC receptor (GR) and the DNA binding domain of the estrogen receptor (ER) ("ER/GR") in infected neurons; as a result, it transduces GC signals into estrogenic ones. We microinfused ER/GR bilaterally into the BLA of rats to determine whether it would impair fear conditioning, a valuable BLA-dependent paradigm for studying the neural basis of emotional memory. RESULTS: Expression of ER/GR in the BLA caused robust expression of the transgene and a significant disruption of both auditory and contextual long-term fear memory consolidation, whereas fear learning and post-shock freezing remained intact. CONCLUSIONS: These data show that dual gene therapy with ER/GR might be a useful tool for understanding the role of steroid hormones in the storage of traumatic memories.

Endocrine therapy of metastatic breast cancer

Breast cancer growth and dissemination is regulated by estrogen and different growth factor receptor signalling pathways. The increasing knowledge of the biology of breast cancer regarding the interaction of these signalling pathways provides a tool to understand endocrine therapies response and resistance mechanisms. In patients with slowly progressive disease, no visceral involvement, and minimal symptoms, endocrine therapy could be the strategy of choice, even if the tumor has low estrogen receptor expression. Ovarian suppression and tamoxifen are recommended for premenopausal patients whether aromatase inhibitors are the option for postmenopausal ones. Chemotherapy still remains as the right alternative for hormone unresponsive or resistant patients. This is a review focused on the different strategies and combinations of endocrine therapies for metastatic breast cancer patients considering the potential strategies clinically tested to overcome resistance and the different treatments of choice available for each scenario of disseminated disease (AU)

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Leiomiomatosis intravenosa uterina. Presentación de un caso con afectación paratubárica y ovárica / Uterine intravenous leiomyomatosis. Report of a case with fallopian tube and ovarian affectation

Introducción: La leiomiomatosis intravenosa es una variante rara del leiomioma que se caracteriza por un crecimiento intraluminal de células musculares lisas en las venas o vasos linfáticos uterinos. Su histogénesis no está aclarada. A pesar de ser un tumor benigno, su comportamiento podría ser considerado como maligno debido a que puede extenderse por vía intracava e intracardíaca, aunque el pronóstico es bueno. Pacientes y métodos: Presentamos un caso en una paciente de 39 años con una masa abdominal dependiente del anejo derecho. Se realizó una histerectomía con doble anexectomía. Resultados: Macroscópicamente la masa ovárica se correspondía con una tumoración de superficie abollonada, con nódulos paratubáricos y útero deformado por la presencia de varios nódulos uterinos. Microscópicamente correspondía a un tumor constituido por células fusiformes dispuestas en haces entrecruzados y numerosos vasos en los cuales se introducía el tumor. Discusión y conclusiones: La mayoría de los casos descritos presentan afectación uterina con extensión a la vena cava e intracardíaca y eventualmente metástasis pulmonares, siendo muy rara la afectación paratubárica y ovárica que presentamos en nuestro caso. Las técnicas de inmunohistoquímica demuestran la naturaleza vascular de las luces en las cuales se introduce el tumor, y su positividad a los estrógenos y progesterona apoya la hipótesis de su origen en el músculo liso uterino, y no en la pared de los vasos (AU)

Introduction: Intravenous leiomyomatosis is a rare variant of leiomyoma characterized by the growth of smooth muscle cells inside the lumen of either uterine venous or lymphatic vessels. Its histogenesis is not clarified. In spite of being a benign tumor, its behaviour could be considered as malignant because it can extend by intracava and intracardiac way, although the prognosis is favourable. Patients and methods: A case of a 39 years old female with an abdominal mass clinically depending of right adnexa is reported. An abdominal hysterectomy with bilateral salpingo-oophorectomy was performed. Results: Grossly, an adnexal mass including a bulky surface ovarian tumor and a nodular fallopian tube wall together with a deformed uterus by the presence of multiple nodules were found. Histologically, adnexal tumor consisted of interlacing bundles of spindle-shaped cells and numerous vessels within intraluminal tumor. Discussion and conclusions: Most of the reported cases showed uterine involvement expanding to the cava and intracardiac cavities. Eventually, lung metastases were reported. Fallopian tube and ovarian involvement found in this case are quite unusual. Immunohistochemical analyses demonstrated the vascular nature of the lumina containing tumor extensions. Positivity for estrogen and progesterone receptors also supports the hypothesis about its origin from uterine smooth muscle instead of vascular walls (AU)

Estrogen receptor-alpha antisense decreases brain estrogen receptor levels and affects ventilation in male and female rats.

We hypothesized that administration of an antisense oligodeoxynucleotide (ODN) to estrogen receptor (ER)-alpha mRNA decreases the ER protein in the neonatal rat brain, alters the sex-specific ventilatory responses to aspartic acid in rats, and counteracts the effects of testosterone proportionate (TP) in females. One-day-old rat pups were injected intraventricularly with vehicle, antisense ER ODN, or scrambled ODN control. Additional groups of females received TP or vehicle and one of the three treatments. Brain ER protein levels were decreased by 65% at 6 h and 35% at 24 h after antisense ODN. Aspartic acid decreased ventilation in all groups of weanling males and females except ER ODN-treated females and TP-vehicle-treated females. Aspartic acid decreased ventilation in all groups of adult females except those given TP and in males. Weanling ER ODN-treated rats were shorter and weighed less than controls. Only adult ER ODN-treated males exhibited these traits. Thus neonatal ER affects aspartic acid modulation of breathing and body growth in a sex-specific and developmental manner.