RESUMEN
Targeted agents have significantly prolonged survival and improved response rates in first- and second-line settings of hormone receptor-positive/HER2-negative metastatic breast cancer. Optimal sequencing of the available options may prolong endocrine sensitivity, slow disease progression and delay the need for chemotherapy. However, the optimal treatment sequence remains unclear and therapeutic decisions are complex. We review the latest recommendations and supporting evidence for endocrine therapy in women with hormone receptor-positive/HER2-negative metastatic breast cancer and discuss strategies for the optimal sequential therapy in scenarios of response to endocrine therapy. Although more data are needed to define the best sequence of endocrine treatments, more personalized sequential strategies, which take into account response to previous treatments as well as disease symptoms and safety issues, will be increasingly feasible.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina/genética , Femenino , Humanos , Metástasis de la Neoplasia , Receptor ErbB-2/genética , Receptores de Estrógenos/genética , Receptores de Progesterona/genéticaRESUMEN
BACKGROUND: Ovaries are sensitive to chemotherapy, which may lead to early depletion of primordial follicle reserve. One strategy for gonadal function preservation is temporary ovarian suppression with Gonadotropin Releasing Hormone agonists (GnRHa) during chemotherapy. To date, GnRHa protective mechanism of action remains not fully elucidated. METHODS: We collected 260 immature cumulus cell-oocyte complexes (COC) from 111 women < 38 years old, with a normal ovarian reserve. The COC were randomly assigned to the following groups: a) control; culture with the addition of b) GnRHa; c) cyclophosphamide; d) cyclophosphamide plus GnRHa. After in vitro treatments, RNA and proteins were extracted from oocytes and cumulus cells (CC), separately. Potential effects of drugs were evaluated on GnRH receptors, apoptosis pathways, ceramide pathway, and glutathione synthesis by quantitative PCR and, whenever possible, by Western blot. RESULTS: Cyclophosphamide triggered activation of the extrinsic pathway of apoptosis mediated by BAX in CC. The co-administration of GnRHa inhibited the apoptosis pathway in CC. According to our model, the GnRHa does not directly act on oocytes, which do not express GnRH receptors. Moreover, glutathione synthesis was decreased after GnRHa treatment both in CC and oocytes. CONCLUSION: Our data suggest that the protective mechanisms induced by GnRHa is mediated by an anti-apoptotic effect on CC.
Asunto(s)
Apoptosis/efectos de los fármacos , Células del Cúmulo/efectos de los fármacos , Hormona Liberadora de Gonadotropina/farmacología , Receptores LHRH/genética , Proteína X Asociada a bcl-2/genética , Adulto , Apoptosis/genética , Caspasa 3/genética , Caspasa 3/metabolismo , Ceramidas/metabolismo , Células del Cúmulo/citología , Células del Cúmulo/metabolismo , Ciclofosfamida/farmacología , Femenino , Regulación de la Expresión Génica , Glutatión/metabolismo , Humanos , Oocitos/citología , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Reserva Ovárica/genética , Receptores LHRH/metabolismo , Factor 3 Asociado a Receptor de TNF/genética , Factor 3 Asociado a Receptor de TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína Destructora del Antagonista Homólogo bcl-2/genética , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Receptor fas/genética , Receptor fas/metabolismoRESUMEN
RESEARCH QUESTION: This study explored the knowledge, attitudes and practice of physicians towards fertility and pregnancy-related issues in young BRCA-mutated breast cancer patients. DESIGN: Physicians attending two international breast cancer conferences completed a 26-item questionnaire exploring fertility preservation, pregnancy during (BCP) or after breast cancer. A statistical comparison was carried out of the responses exploring the same issues in young breast cancer patients overall or specifically in those with BRCA mutations. RESULTS: The survey was completed by 273 physicians. Ovarian tissue cryopreservation (33% versus 40%; P = 0.009) and gonadotrophin-releasing hormone analogues during chemotherapy (74% versus 81%; P = 0.001) were less commonly suggested in BRCA-mutated patients than in the overall breast cancer population. 42% of respondents agreed or were neutral on the statement that ovarian stimulation should not be considered safe in BRCA-mutated breast cancer patients. 45% and 30% agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence in BRCA-mutated patients or in the overall breast cancer population, respectively (P < 0.001). 15% and 3% disagreed that transplanting the cryopreserved ovarian tissue can be considered safe in BRCA-mutated patients or in the overall breast cancer population, respectively (P < 0.001). 33.3% were against the addition of platinum agents as neoadjuvant chemotherapy in BRCA-mutated patients with BCP. CONCLUSIONS: Several misconceptions on fertility preservation and pregnancy-related issues in breast cancer patients persist even among physicians directly involved in breast cancer care. Focused research efforts to address these issues in BRCA-mutated breast cancer patients and education to improve physicians' knowledge and adherence to available guidelines are urgently needed.
