Megestrol acetate drives endometrial carcinoma cell senescence via interacting with progesterone receptor B/FOXO1 axis.

Megestrol acetate is a common and efficient anticancer progesterone. To explore the activity and the therapeutic mechanisms of megestrol acetate in endometrial cancer, human endometrial cancer cell lines Ishikawa and HHUA overexpressing progesterone receptor A (PR-A) and progesterone receptor B (PR-B) were treated with megestrol acetate. Cell viability, apoptosis, cycle arrest, and senescence, as well as the expressions of p21 and p16, two hallmarks of cellular senescence, were evaluated. Compared with the control, >10 nmol/L megestrol acetate treatment could significantly reduce endometrial cancer cell growth, and induce the irreversible G1 arrest and cell senescence. The expression of cyclin D1 in megestrol acetate treated cells was downregulated, while the expressions of p21 and p16 were upregulated via PR-B isoform. FOXO1 inhibitor AS1842856 could significantly abrogate megestrol acetate-induced cell senescence, suggesting that FOXO1 was involved in megestrol acetate/PR-B axis. These findings may provide a new understanding for the treatment of human endometrial cancer.

Estradiol/nomegestrol acetate as a first-line and rescue therapy for the treatment of ovarian and deep infiltrating endometriosis.

PURPOSE: Estradiol valerate/nomegestrol acetate (E2V/NOMAC) is a new combined oral contraceptive with a good tolerability profile and low drop-out rates, which was shown to improve menstrual-related symptoms. This study aims to evaluate its effectiveness in the control of symptoms and progression of disease in women with ovarian endomestriomas and deep infiltrating endometriosis (DIE). METHODS: This was a retrospective cohort study on 39 women with pelvic endometriosis treated with E2V/NOMAC. We assessed for each patient, at the beginning of treatment and after 6 months, the painful symptoms, through a global VAS (Visual Analogue Scale) index and the size of the greatest ovarian and/or deep infiltrating endometriotic lesions. RESULTS: After 6 months of treatment, a significant reduction was observed for the global VAS score for pain symptoms and for the mean size of ovarian endometriomas, whereas DIE lesions did not present significant changes in mean size. CONCLUSIONS: E2/NOMAC was effective in reducing pain symptoms associated with pelvic endometriosis and the size of ovarian endometriomas, whereas DIE lesions remained stable. This therapy could provide good results in the control of symptoms and disease progression in women with pelvic endometriosis.

Sustained growth of intraosseous hormone-associated meningiomas after cessation of progestin therapy.

Hormone-associated meningiomas tend to stop growing or decrease in size after cessation of certain progestins, mainly cyproterone acetate. We report three observations on the natural history of hormone-associated intraosseous meningiomas, showing in a first patient that those tumors may grow rapidly under nomegestrol. We then demonstrate the sustained growth of intraosseous hormone-associated meningiomas after cessation of promesgestone and nomegestrol, independently of the intracranial portion, which concurrently decreased in size in the second case or was resected at the time of nomegestrol withdrawal in the third case, thus giving new insights into the tumorigenesis mechanisms of hormone-associated intraosseous meningiomas.

Spontaneous regression of hepatocellular carcinoma: myth or reality?

We present a case of a 68-year-old man with chronic hepatitis C infection, with no evidence of chronic liver disease during the first years of follow-up, diagnosed with a hepatocellular carcinoma (HCC) with 40 mm (α-fetoprotein (AFP) 205 ng/mL). He underwent segmental liver resection and pathology analysis was consistent with HCC and cirrhosis in the adjacent liver. Four months after surgery, AFP raised up to 126 661 ng/mL and abdominal MRI revealed a multinodular HCC. Patient rejected treatment with sorafenib and started megestrol and an herbal medicine, soursop (Annona muricata). Six months later, AFP markedly decreased (28 ng/mL) and abdominal MRI showed decreasing size and number of lesions. At 5 years of follow-up, he has no evidence of HCC. Spontaneous regression of HCC is a rare condition and the underlying mechanism is unclear. In this case there is a temporal relation between the start of megestrol and Annona muricata and HCC regression.

Nomegestrol acetate/17beta-estradiol does not negatively alter the vascular resistance of clitoral arteries: a prospective, exploratory study.

The effect of nomegestrol acetate/estradiol (NOMAC/E2) on clitoral and uterine vascularization has never been evaluated. We aimed to investigate, in women consulting for contraceptive needs, the possible changes in clitoral and uterine arteries hemodynamic parameters after 6 months treatment with NOMAC/E2 as compared with other hormonal contraceptives (HCs). In this observational, prospective pilot study, ten women were enrolled. Color Doppler ultrasound was performed on the clitoral and uterine arteries at baseline and after 6 months treatment with NOMAC/E2 (n = 5) or other HCs (n = 5). NOMAC/E2 did not exert any significant effect on clitoral vascular resistance expressed by the pulsatility index (PI); conversely, treatment with other HCs significantly increased this parameter (p = 0.04). The change in clitoral PI between the two groups retained a statistically significant difference even after adjusting for age. In the NOMAC/E2 group, at follow-up, uterine artery PI and acceleration were significantly reduced (p = 0.04), whereas no significant differences were observed in the HCs group; however, the change in uterine artery parameters did not differ significantly between the two groups. NOMAC/E2, differently from other COCs, does not negatively alter the vascular resistance of clitoral arteries and appears as a good contraceptive choice to protect both cardiovascular and sexual health.

Aproximación terapéutica al síndrome de anorexiacaquexia en pacientes con cáncer. Revisión sistemática de la literatura / Therapeutic aproach to the anorexia-cachexia syndrome in cancer patients. Systematic literature review

OBJETIVO: Realizar una revisión sistemática de la literatura sobre las aproximaciones terapéuticas al síndrome anorexia-caquexia en pacientes oncológicos avanzados. MATERIAL Y MÉTODO: Se realizó una búsqueda de artículos científicos consultando las bases de datos: PubMed, Cochrane, Elsevier, Wiley y Google Scholar, con restricción de fecha 01/01/1990-31/12/2015, en los idiomas inglés y español. Las palabras clave utilizadas fueron: "fatigue, anorexia, cachexia, cancer, treatment" y las mismas palabras traducidas al español. En la base de datos PubMed, las ecuaciones de búsqueda utilizadas fueron: "Tumoral cachexia AND treatment" y "Fatigue, anorexia, cachexia AND cancer". Se incluyeron todos los estudios que definieran el síndrome de caquexia tumoral e indicaran al menos una línea de tratamiento para el mismo. Se excluyeron aquellos en los que la caquexia era resultado de una enfermedad terminal diferente al cáncer y en los que el tratamiento había sido enfocado únicamente en la paliación del dolor oncológico. Para seleccionar los artículos se realizó una lectura del título y/o resúmenes de los mismos. En caso de duda, se procedió a la lectura completa del trabajo. Los parámetros analizados fueron: tipo de estudio, criterios de inclusión, tamaño de la muestra, tipo de cáncer, tipos de tratamiento y eficacia de los mismos. RESULTADOS: en PubMed, con la estrategia de búsqueda "tumoral cachexia AND treatment" encontramos 16 artículos de los cuales un ensayo clínico cumplía los criterios de inclusión. En la misma base de datos, mediante la estrategia de búsqueda: "fatigue, anorexia, cachexia AND cancer" encontramos 106 artículos de los cuales incluimos ocho ensayos clínicos. Como artículo relacionado con la búsqueda anterior incluimos un ensayo clínico más. Además, realizamos una búsqueda de artículos a través de diversas plataformas, e incluimos en la revisión ocho revisiones narrativas y tres ensayos clínicos. CONCLUSIONES: 1) La diversidad de estudios revisados imposibilita la realización de un metanálisis. 2) Las medidas terapéuticas de la caquexia se basan en la modulación metabólica. 3) Sigue siendo controvertida que la utilización de suplementos nutricionales mejore el pronóstico del paciente con enfermedad avanzada. 4) La literatura propone diversos tratamientos para el síndrome de caquexia tumoral, siendo en la actualidad el acetato de megestrol el tratamiento de elección. 5) Existen fármacos en desarrollo, como los miméticos de la ghrelina, que ofrecen resultados prometedores

OBJECTIVE: To review what has been published in the scientific literature about the treatment options of the anorexia- cachexia syndrome in cancer patients. METHOD: We performed a systematic review of the literature. Databases used were: PubMed, Cochrane, Elsevier, Wiley y Google Scholar, with date restriction 01/01/1990-31/12/2015. Languages were English and Spanish, Key words used were: "fatigue, anorexia, cachexia, cancer in English and Spanish. In PubMed, search strategy were: "Tumoral cachexia AND treatment" and "Fatigue, anorexia, cachexia AND cancer". Articles included had to offer information about any treatment option to the cachexia syndrome. Articles including patients suffering from other illness than cancer were excluded. Papers selection was done base on title and abstract information. In some cases the inclusion was done after reading all the content. Information selected was: type of study, inclusion criteria, simple size, type of cancer, type of treatment and results. RESULTS: In PubMed, based on the search strategy: "tumoral cachexia AND treatment" we found 16 papers but only one was included. Based on the search strategy "fatigue, anorexia, cachexia AND cancer" we found 106 papers but only 8 clinical trials were included. Other related articles were included: 4 clinical trials and 8 narrative reviews. CONCLUSION: 1) The methodological differences among the papers reviewed make impossible to develop a methaanalisis. 2) Most of the treatment lines are based on metabolic modulation. 3) It is controversial the use of nutritional supplements to improve prognosis in advanced cancer patient. 4) Among cancer cachexia treatments suggested the megestrol acetate is the election option. 5) New drugs as ghrelin have shown optimistic results

Spontaneous regression of meningiomas after interruption of nomegestrol acetate: a series of three patients.

BACKGROUND: The relationship between increased meningioma incidence and growth and long-term hormonal therapy with cyproterone acetate (CPA) in women has been recently established in literature. Following the raise in awareness from hormonal treatment, we describe a potential relationship between the progesterone agonist nomegestrol acetate (NOMAC) and meningioma growth. METHODS: After implementation of a screening protocol to detect potential interactions between hormonal exposure and occurrence of meningioma, we identified patients taking NOMAC and newly diagnosed with a meningioma. NOMAC was stopped and those patients were followed tightly both clinically and radiologically. Retrospective volumetric analysis of the tumors was performed on the imaging. RESULTS: Three patients were identified for the study. After cessation of the NOMAC, tumor shrinkage was documented for all meningiomas within the first month. Up to 70% of tumor volume reduction was observed during the first year of follow-up in one of them. None of the patients developed new symptoms. CONCLUSION: We report the first cases of meningiomas responsiveness to discontinuation of hormonal therapy with NOMAC. Similarly to cases associated with long-term CPA intake, tumor reduction, and improvement of clinical symptoms can be observed after cessation of NOMAC.

Efficacy and Safety of Appetite-Stimulating Medications in the Inpatient Setting.

BACKGROUND: Hospitalized patients are subject to acute illness and stress which may impact appetite or weight. Loss of appetite may lead to increased morbidity or mortality. Medications such as dronabinol, megestrol, and mirtazapine are used for weight gain in the outpatient setting; however, there is limited information about safety or effectiveness when initiated inpatient. OBJECTIVES: To analyze the effectiveness and safety of appetite-stimulating medications in hospitalized patients. METHODS: This was a retrospective cohort study of hospitalized patients initiated on dronabinol, megestrol, or mirtazapine for appetite. The primary outcome was change in meal intake between drug initiation and discontinuation. Secondary outcomes included documented improvement in appetite, change in weight and various laboratory parameters, and incidence of adverse effects. RESULTS: A total of 38 patients met inclusion criteria, and mirtazapine was most commonly used (42%). There was no significant difference between groups of appetite-stimulating medications with regard to mean change in meal intake, weight, albumin, or documented improvement in diet. Within groups, each agent showed numerical improvement in percentage meal intake, with a mean change from initiation to discontinuation of 17.12%. Almost half (48%) of the patients experienced improvement in diet after the start of medications. No serious adverse effects were observed. Conclusion and Relevance: In inpatients, there was no difference in change in meal intake or weight between dronabinol, megestrol, or mirtazapine, but they may show numerical improvements in meal intake. To our knowledge, this is the first study to evaluate the use of dronabinol, megestrol, and mirtazapine initiated in the inpatient setting.

Tratamiento farmacológico de la desnutrición en la EPOC / Drug therapy for malnutrition in COPD

El tratamiento farmacológico de la desnutrición en la enfermedad pulmonar obstructiva crónica (EPOC) es un campo de conocimiento controvertido y limitado por la escasa evidencia científica generada. Sus objetivos se centrarían en reducir inflamación, estrés oxidativo y pérdida progresiva de la masa muscular esquelética. Varias vías fisiopatológicas se han propuesto como dianas terapéuticas. Desde un punto de vista teórico, se ha planteado la posible eficacia de fármacos orexígenos (progestágenos, ciproheptadina y cannabinoides) esteroides anabolizantes (nandrolona), moduladores selectivos de los receptores de andrógenos, hormonas peptídicas (somatotropina -GH- y grelina), antiinflamatorios (talidomida, celecoxib y ácidos grasos omega 3, entre otros), aminoácidos y metabolitos activos (L-carnitina, creatina, leucina y β-hidroxi-β-metilbutirato), vitamina D, antioxidantes (vitaminas A, E, ácido alfa lipoico, resveratrol y N-acetil-cisteína) e inhibidores de la miostatina. Solo se han publicado datos con algunos de estos fármacos, y las guías de práctica clínica aún no reconocen su papel en esta patología

Drug therapy for malnutrition in chronic obstructive pulmonary disease (COPD) is a controversial and limited field of knowledge due to scarce generated scientific evidence. Its objectives would be reducing inflammation, oxidative stress and progressive skeletal muscle mass loss. Several pathological ways have been proposed as therapeutic target. From a theoretical point of view, the possible efficacy of different drugs has been studied. Among them: orexigenic drugs (progestagens, cyproheptadine and cannabinoids), anabolizing steroids (nandrolone), selective androgen receptor modulators, peptidic hormones (somatotropin -GH- and ghreline), anti-inflammatories (thalidomide, celecoxib and omega 3 fatty acids), amino acids and active metabolites (L-carnitine, creatin, leucin and β-hydroxy β-methylbutyrate), vitamin D, antioxidants (vitamins A, E, alpha-lipoic acid, resveratrol and N-acetyl-cysteine) and myostatin inhibitors. Studies have been published with some of these drugs, but the different clinical guidelines do not recognize their role in this entity

Nomegestrol Acetate Suppresses Human Endometrial Cancer RL95-2 Cells Proliferation In Vitro and In Vivo Possibly Related to Upregulating Expression of SUFU and Wnt7a.

Nomegestrol acetate (NOMAC) has been successfully used for the treatment of some gynecological disorders, and as a combined oral contraceptive with approval in many countries. In this study, we investigated the effects of NOMAC on human endometrial cancer cells in vitro and in vivo. The proliferation of human endometrial cancer cells (RL95-2 and KLE) were assessed using CCK-8 and EdU incorporation assays. Whole-genome cDNA microarray analysis was used to identify the effects of NOMAC on gene expression profiles in RL95-2 cells. RL95-2 xenograft nude mice were treated with NOMAC (50, 100, and 200 mg/kg) or medroxyprogesterone acetate (MPA; 100 and 200 mg/kg) for 28 consecutive days. The results showed that NOMAC significantly inhibited the growth of RL95-2 cells in a concentration-dependent manner, but not in KLE cells. Further investigation demonstrated that NOMAC produced a stronger inhibition of tumor growth (inhibition rates for 50, 100, and 200 mg/kg NOMAC were 24.74%, 47.04%, and 58.06%, respectively) than did MPA (inhibition rates for 100 and 200 mg/kg MPA were 41.06% and 27.01%, respectively) in the nude mice bearing the cell line of RL95-2. NOMAC altered the expression of several genes related to cancer cell proliferation, including SUFU and Wnt7a. The upregulation of SUFU and Wnt7a was confirmed using real-time quantitative polymerase chain reaction and Western blotting in RL95-2 cells and RL95-2 xenograft tumor tissues, but not in KLE cells. These data indicate that NOMAC can inhibit the proliferation of RL95-2 cell in vitro and suppress the growth of xenografts in the nude mice bearing the cell line of RL95-2 in vivo. This effect could be related to the upregulating expression of SUFU and Wnt7a.

Body composition and psychological improvement in healthy premenopausal women assuming the oral contraceptive containing micronized estradiol (E2) and nomegestrol acetate (NOMAC).

This observational study was conducted in healthy premenopausal women, who presented themselves for contraceptive advice at the outpatient Family Planning Clinics of the Department of Obstetrics and Gynecology of the University of Cagliari, Hospital-University of Cagliari (Italy). After a screening period of three menstrual cycles, 48 women without contraindications to estroprogestin contraceptives (OCs) were included in the study. The primary purposes of the study were to evaluate whether a 12-month-treatment with the combined OC containing micronized estradiol (1.5 mg, E2) plus nomegestrol acetate (2.5 mg, NOMAC) (E2/NOMAC) interfere on anthropometric indices (AI), body composition (BC) and psychological status (PS). In subjects with dysmenorrhea (#36), its intensity was evaluated using the visuo analogic scale (VAS), both before and during the 12-month-treatment with E2/NOMAC. E2/NOMAC did not modify neither AI nor BC in the 40 subjects who concluded the study. The PS and the VAS of dysmenorrhea were significantly (p < 0.0001) improved from the first cycle of treatment and throughout the E2/NOMAC treatment in comparison with basal values. The study suggests that E2/NOMAC is devoid of negative effects on AI and BC, with additional benefits on PS and dysmenorrhea.

Hormone therapy as a management strategy for lung metastasis after 5 years of endometrial cancer: A case report and literature review.

RATIONALE: Endometrial cancer patients with lung metastases are rare, and more rarely with long-term management of progesterone after recurrence. PATIENT CONCERNS: Informed consent of the patients and their families. DIAGNOSES: Endometrial cancer (IVB) (Refer to 2009 FIGO stag of endometrial cancer). INTERVENTIONS: the patient was treated with Megestrol Acetate Dispersible Tablets (trade name Yilizhi), 160 mg, orally, once daily, without interruption. OUTCOMES: The patient has been treated with progesterone therapy for stable conditions and her survival time is already roughly a decade (December 2006-October 2016). LESSONS: Hormone therapy may as a long-term management for hormone receptor-positive patients with recurrent endometrial cancer.

Effect on quality of life of switching to combined oral contraception based on natural estrogen: an observational, multicentre, prospective phase IV study (ZOCAL Study).

OBJECTIVES: This observational, multicentre, prospective phase IV study examined change in health-related quality of life (QOL) from baseline to 6 months in women initiating combined oral contraception (COC) based on natural estrogen. METHODS: Eligible women attending a baseline and 6-month gynaecology appointment belonged to one of three groups: group 1 used barrier contraception (condoms) and elected to continue this method; group 2 used condoms and elected to switch to COC based on natural estrogen; group 3 used COC based on ethinylestradiol and elected to switch to COC based on natural estrogen. The Spanish Society of Contraception (SEC)-QOL scale assessed health-related QOL. Secondary outcomes included symptoms of premenstrual syndrome, intermenstrual bleeding, duration and intensity of menstrual bleeding, contraception continuation rate, and tolerability. RESULTS: A total of 857 women were enrolled and 785 completed the study. Group 2 (n = 224 completed) had significantly lower SEC-QOL global and dimension scores at baseline and significantly greater increases in SEC-QOL from baseline to 6 months compared with groups 1 (n = 72) and 3 (n = 489). Group 3 reported a similar SEC-QOL score to that of group 1 at baseline but showed significantly greater improvement in SEC-QOL global and psychological scores from baseline to 6 months. Among women receiving COC based on natural estrogen, the contraception continuation rate was 713/780 (91.4%); treatment-related adverse events were reported by 13/780 (1.7%). CONCLUSIONS: Improved SEC-QOL after 6 months was found in women who were dissatisfied with their current contraception at baseline and chose to switch to COC based on natural estrogen.

Effect of oral contraceptives containing estradiol and nomegestrol acetate or ethinyl-estradiol and chlormadinone acetate on primary dysmenorrhea.

OBJECTIVE: To study the three cycles effect on primary dysmenorrhea of the monophasic 24/4 estradiol/nomegestrol acetate (E2/NOMAC) and of the 21/7 ethinyl-estradiol/chlormadinone acetate (EE/CMA) oral contraceptive. The tolerability and the effect of both preparations on metabolism and health-related quality of life were also evaluated. DESIGN: Prospective observational cohort study. SETTING: Tertiary gynecologic center for pelvic pain. PATIENTS: Subjects with primary dysmenorrhea requiring an oral contraceptive, who spontaneously selected either E2/NOMAC (n = 20) or EE/CMA (n = 20). MAIN OUTCOME MEASURES: Visual Analogue Scale (VAS) score for dysmenorrhea, Short Form-36 questionnaire for health-related quality of life, lipoproteins and days of menstrual bleeding (withdrawal bleeding during oral contraceptive). RESULTS: Mean age and body mass index (BMI) were similar between the two groups. The final analysis was performed on 34 women, 15 in E2/NOMAC and 19 in EE/CMA group. Compliance with treatment was significantly higher with EE/CMA (100%) than E2/NOMAC (75%) (p = 0.02). Both treatments significantly (p < 0.0001) reduced VAS of primary dysmenorrhea, similarly (E2/NOMAC by a mean of 74.7%, EE/CMA by a mean of 78.4%; p = 0.973). Only E2/NOMAC significantly increased SF-36 score (p = 0.001), both in physical (p = 0.001) and mental domains (p = 0.004). The mean number of days of menstrual bleeding was significantly reduced in E2/NOMAC group (from 4.86 ± 1.20 d to 2.64 ± 1.59 d, p = 0.0005 versus baseline, p = 0.007 versus EE/CMA group). BMI did not vary in either group. E2/NOMAC did not change lipoproteins and apoproteins while EE/CMA increased total cholesterol (p = 0.0114), HDL-cholesterol (p = 0.0008), triglycerides (p = 0.002), apoprotein-A1 (Apo-A1; p = 0.0006) and apopoprotein-B (Apo-B; p = 0.008), decreasing LDL/HDL ratio (p = 0.024). CONCLUSIONS: Both oral contraceptives reduced similarly primary dysmenorrhea, with E2/NOMAC also reducing withdrawal bleedings and being neutral on lipid metabolism.

Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy.

PURPOSE: The aim of this study was to test the safety, tolerability and efficacy of a novel combination of an anabolic ß2-agonist and an appetite stimulant in patients with cancer cachexia. METHODS: Thirteen patients (M/F 5:8) with advanced malignancy and involuntary weight loss received oral formoterol (80 µg/day) and megestrol acetate (480 mg/day) for up to 8 weeks. Quadriceps size (MRI), quadriceps and hand-grip strength, lower limb extensor power, physical activity and quality of life were measured at baseline and at 8 weeks. Response criteria were specified pre-trial, with a major response defined as an increase in muscle size ≥ 4 % or function ≥ 10 %. RESULTS: Six patients withdrew before 8 weeks, reflecting the frail, comorbid population. In contrast, six out of seven (86 %) patients completing the course achieved a major response for muscle size and/or function. In the six responders, mean quadriceps volume increased significantly (left 0.99 vs. 1.05 L, p=0.012; right 1.02 vs. 1.06 L, p=0.004). There was a trend towards an increase in quadriceps and handgrip strength (p>0.05). The lack of appetite symptom score declined markedly (76.2 vs. 23.8; p=0.005), indicating improvement. Adverse reactions were few, the commonest being tremor (eight reports), peripheral oedema (three), tachycardia (two) and dyspepsia (two). CONCLUSIONS: In this frail cohort with advanced cancer cachexia, an 8-week course of megestrol and formoterol in combination was safe and well tolerated. Muscle mass and/or function were improved to a clinically significant extent in most patients completing the course. This combination regimen warrants further investigation in larger, randomized trials.

The "newer" progestogens and postmenopausal hormone therapy (HRT).

After a worldwide breakdown of hormone therapy [HT] following the publications of the Women's Health Initiative trial and Million Women's Study in 2002-2003, there is now a trend to turn attention again to HT and to explore particular progestogens, which have been discredited with respect to their side effects. The progestogens to be considered should control undue proliferation of the endometrium and should not interfere negatively with the positive effects of estradiol, regarding carbohydrate and lipid metabolism as well as hemostasis. In the present review, three "newer progestogens" are scrutinized regarding their various actions, in combination with estradiol; the progestogens include dienogest, drospirenone and nomegestrol acetate. This article is part of a special issue entitled Menopause.

Current approaches to the management of Her2-negative metastatic breast cancer.

While metastatic breast cancer (MBC) remains incurable, a vast array of active therapeutic agents has provided the opportunity for long-term disease control while maintaining quality of life and physical function. Optimal management of MBC balances a multitude of factors, including a woman's performance status, social support, symptoms, disease burden, prior therapies, and surrogates for tumor biology. Choosing the most appropriate initial therapy and subsequent sequence of treatments demands flexibility as goals and patient preferences may change. Knowledge of the estrogen receptor (ER), progesterone receptor (PR), and Her2 receptor status of the metastatic tumor has become critical to determining the optimal treatment strategy in the metastatic setting as targeted therapeutic approaches are developed. Patients with ER+ or PR+ breast cancer or both have a wide array of hormonal therapy options that can forestall the use of cytotoxic therapies, although rapidly progressive phenotypes and the emergence of resistance may ultimately lead to the need for chemotherapy in this setting. So-called 'triple-negative' breast cancer - lacking ER, PR, and Her2 overexpression - remains a major challenge. These tumors have an aggressive phenotype, and clear targets for therapy have not yet been established. Chemotherapy remains the mainstay of treatment in this group, but biologically based clinical trials of new agents are critical to developing a more effective set of therapies for this patient population.

Estradiol + nomegestrol. Oral contraceptive claimed to be more natural, but presenting no obvious advantages.

No evidence of an advantage over standard oestrogen-progestin combinations, but as many serious adverse effects as with ethinylestradiol + drospirenone.