Recommendations on the treatment of metastatic hormone-sensitive prostate cancer: Patient selection.

The standard treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is now a combination of androgen deprivation therapy plus an androgen receptor-targeted therapy (abiraterone, apalutamide, enzalutamide or darolutamide), with or without chemotherapy (docetaxel). The selection of suitable patients for each therapeutic approach has become a determining factor to ensure efficacy and minimize side effects. This article combines recent clinical evidence with the accumulated experience of experts in medical oncology, radiation oncology and urology, to provide a comprehensive view and therapeutic recommendations for mHSPC.

Incidencia, prevalencia y patrones de tratamiento del cáncer de próstata metastásico hormonosensible en España: Estudio ECHOS / Incidence, prevalence, and treatment patterns in metastatic hormone-sensitive prostate cancer in Spain: ECHOS study

Introducción y objetivo: El manejo de los pacientes con cáncer de próstata hormonosensible metastásico (CPHSm) ha cambiado en los últimos años debido a la autorización de nuevos medicamentos. El objetivo fue caracterizar la prevalencia, incidencia y patrones de tratamiento para el CPHSm en España.Pacientes y métodos: Estudio multicéntrico, observacional, longitudinal, retrospectivo en condiciones de práctica clínica habitual con pacientes con CPHSm atendidos en hospitales españoles entre 2015 y 2019 (estudio ECHOS). Las historias clínicas se extrajeron de la base de datos BIG-PAC (geográficamente representativa).Resultados: Se incluyeron los datos de 379 hombres con CPHSm. La prevalencia varió entre 12,2-14,6%. Hubo de 671 a 824 nuevos casos anualmente, con una tendencia creciente. La incidencia media en el periodo del estudio fue de 2,5%, con valores anuales en el rango 2,2-3%. Los nuevos casos anuales de pacientes de novo y recurrentes osciló en el rango 7-11 y 77-104, respectivamente, sin tendencia observada. Mayoritariamente eran pacientes recurrentes (91%) y de alto volumen tumoral (68,6%). La primera línea de tratamiento fue la combinación de docetaxel y terapia de deprivación de andrógenos (TDA) (53%), seguida por TDA sola (23,8%), combinación de TDA y abiraterona (11,1%) y radioterapia (8,6%). En los 12 meses anteriores al diagnóstico de metástasis, la mayoría se sometieron a una prostatectomía (84,9%). El resto había recibido radioterapia (12%) o no recibieron tratamiento (3,8%).Conclusiones: El estudio ECHOS proporciona datos epidemiológicos y patrones de tratamiento actuales en la práctica clínica en pacientes con CPHSm en España. Los resultados obtenidos destacan la necesidad médica de terapias dirigidas. (AU)

Introduction and objective: The management of patients with metastatic hormone-sensitive prostate cancer (mHSPC) has changed in recent years due to the approval of new drugs. The aim of this study was to evaluate the prevalence, incidence, and treatment patterns in mHSPC in Spain.Patients and methods: Multicenter, observational, longitudinal, retrospective study in routine clinical practice of patients diagnosed with mHSPC treated in Spanish hospitals between 2015 and 2019 (ECHOS study). Electronic medical records were extracted from BIG-PAC database, which contains geographically representative Spanish centers.Results: Data from 379 men with mHSPC were included. The prevalence of mHSPC ranged between 12.2-14.6% per year, representing from 671 to 824 annual cases with an increasing trend. The mean incidence along the 4-year period was 2.5%, with annual incidence ranging 2.2-3.0%. New annual cases of de novo and recurrent disease ranged between 7-11 and 77-104, respectively, with no trend being observed. These patients were mostly recurrent (91%) with high-volume disease (68.6%). The most common first-line therapy was ADT combined with docetaxel (53%), followed by ADT alone (23.8%), combination of ADT and abiraterone (11.2%), and radiotherapy (8.6%). In the last 12 months before diagnosis of metastasis, most men had been submitted to radical prostatectomy (84.9%). The remaining patients had received radiotherapy (12%) or no treatment at all (3.8%).Conclusions: The ECHOS study provides epidemiologic data and current patterns of treatment in clinical practice of patients with mHSPC in Spain. These results emphasize the medical need of targeted treatments in these clinical settings. (AU)

Incidence, prevalence, and treatment patterns in metastatic hormone-sensitive prostate cancer in Spain: ECHOS study.

INTRODUCTION AND OBJECTIVE: The management of patients with metastatic hormone-sensitive prostate cancer (mHSPC) has changed in recent years due to the approval of new drugs. The aim of this study was to evaluate the prevalence, incidence, and treatment patterns in mHSPC in Spain. PATIENTS AND METHODS: Multicenter, observational, longitudinal, retrospective study in routine clinical practice of patients diagnosed with mHSPC treated in Spanish hospitals between 2015 and 2019 (ECHOS study). Electronic medical records were extracted from BIG-PAC database, which contains geographically representative Spanish centers. RESULTS: Data from 379 men with mHSPC were included. The prevalence of mHSPC ranged between 12.2-14.6% per year, representing from 671 to 824 annual cases with an increasing trend. The mean incidence along the 4-year period was 2.5%, with annual incidence ranging 2.2-3.0%. New annual cases of de novo and recurrent disease ranged between 7-11 and 77-104, respectively, with no trend being observed. These patients were mostly recurrent (91%) with high-volume disease (68.6%). The most common first-line therapy was ADT combined with docetaxel (53%), followed by ADT alone (23.8%), combination of ADT and abiraterone (11.2%), and radiotherapy (8.6%). In the last 12 months before diagnosis of metastasis, most men had been submitted to radical prostatectomy (84.9%). The remaining patients had received radiotherapy (12%) or no treatment at all (3.8%). CONCLUSIONS: The ECHOS study provides epidemiologic data and current patterns of treatment in clinical practice of patients with mHSPC in Spain. These results emphasize the medical need of targeted treatments in these clinical settings.

Endocannabinoids Produced by White Adipose Tissue Modulate Lipolysis in Lean but Not in Obese Rodent and Human.

White adipose tissue (WAT) possesses the endocannabinoid system (ECS) machinery and produces the two major endocannabinoids (ECs), arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). Accumulating evidence indicates that WAT cannabinoid 1 receptors (CB1R) are involved in the regulation of fat storage, tissue remodeling and secretory functions but their role in controlling lipid mobilization is unclear. In the present study, we used different strategies to acutely increase ECS activity in WAT and tested the consequences on glycerol production as a marker of lipolysis. Treating lean mice or rat WAT explants with JLZ195, which inhibits ECs degrading enzymes, induced an increase in 2-AG tissue contents that was associated with a CB1R-dependent decrease in lipolysis. Direct treatment of rat WAT explants with AEA also inhibited glycerol production while mechanistic studies revealed it could result from the stimulation of Akt-signaling pathway. Interestingly, AEA treatment decreased lipolysis both in visceral and subcutaneous WAT collected on lean subjects suggesting that ECS also reduces fat store mobilization in Human. In obese mice, WAT content and secretion rate of ECs were higher than in control while glycerol production was reduced suggesting that over-produced ECs may inhibit lipolysis activating local CB1R. Strikingly, our data also reveal that acute CB1R blockade with Rimonabant did not modify lipolysis in vitro in obese mice and human explants nor in vivo in obese mice. Taken together, these data provide physiological evidence that activation of ECS in WAT, by limiting fat mobilization, may participate in the progressive tissue remodeling that could finally lead to organ dysfunction. The present findings also indicate that acute CB1R blockade is inefficient in regulating lipolysis in obese WAT and raise the possibility of an alteration of CB1R signaling in conditions of obesity.

[Advanced luminal breast cancer (hormone receptor-positive, HER2 negative): New therapeutic options in 2015]. / Tumeurs du sein luminales (récepteurs hormonaux positifs, HER2 négatives) au stade avancé: les nouvelles options thérapeutiques en 2015.

Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients.

Fasting upregulates adipose triglyceride lipase and hormone-sensitive lipase levels and phosphorylation in mouse kidney.

Circulating non-esterified fatty acids (NEFA) rise during fasting and are taken up by the kidneys, either directly from the plasma or during re-uptake of albumin from glomerular filtrate, and are stored as triacylglycerol (TAG). Subsequent utilization of stored fatty acids requires their hydrolytic release from cellular lipid droplets, but relatively little is known about renal lipolysis. We found that total [(3)H]triolein hydrolase activity of kidney lysates was significantly increased by 15% in the fasted state. Adipose triglyceride lipase (Atgl) and hormone-sensitive lipase (Hsl) mRNA expression was time-dependently increased by fasting, along with other fatty acid metabolism genes (Pparα, Cd36, and Aox). ATGL and HSL protein levels were also significantly induced (by 239 ± 7% and 322 ± 8%, respectively). Concomitant with changes in total protein levels, there was an increase in ATGL phosphorylation at the AMPK-regulated serine 406 site in the 14-3-3 binding motif, and an increase in HSL phosphorylation at serines 565 and 660 that are regulated by AMPK and PKA, respectively. Using immunofluorescence, we further demonstrate nearly ubiquitous expression of ATGL in the renal cortex with a concentration on the apical/lumenal surface of some cortical tubules. Our findings suggest a role for ATGL and HSL in kidney lipolysis.

[Metastatic hormone-sensitive prostate cancer]. / Prise en charge des cancers de la prostate métastatiques hormonosensibles (CPMHS).

The prostate cancer in its hormone-sensitive metastatic presentation is infrequent, it is either an initial presentation of the disease or an evolution after local treatment, without castration of the biological relapse. The surgical or biological castration remains the cornerstone of the treatment. The deadline of castration initiation and its modalities of administration, intermittent or continuous rest debated but consensual on the initiation is the appearance of the symptomatic disease. The chemotherapy by docetaxel in association with the castration increases significantly the survival of the patients having a high tumoral volume. The efficacy on the whole metastatic population requires additional analyses. Clinical prognostic factors as the bone localizations (axial or appendicular), the visceral involvement (liver, lung) are determining for the survival of these patients. Biological prognostic factors are in evaluation. Except the clodronate acid, which showed a survival improvement in the hormone-sensitive metastatic prostate cancer (HSMPC), the other treatments targeting the bone (zoledronic acid, rank-ligand inhibitor) demonstrated a benefit only in castrate resistant metastatic prostate cancer (MCRPC). The management of local disease lets suggest a benefit to at least symptomatic disease, but it requires to be estimated prospectively in clinical trials. The new hormonal treatments targeting the androgen receptor in CPMRC are in evaluation in CPMHS. The objective is to increase the survival and the quality of life of the CPMHS and to delay the evolution towards the castration resistant metastatic disease.