Fulvestrant - a new treatment for postmenopausal women with hormone-sensitive advanced breast cancer

Approximately 75% of breast tumours in postmenopausal women are positive for the oestrogen receptor (ER) and/or the progesterone receptor (PgR) and are, therefore, potential candidates for endocrine treatment. Fulvestrant is a new type of ER antagonist with no agonist effects and a novel mode of action; it binds, blocks and degrades the ER, leading to a reduction in cellular ER and, consequently, in PgR levels. This novel mode of action results in a lack of cross-resistance with other commonly used endocrine treatments. In Phase III trials in postmenopausal women with advanced breast cancer progressing on prior anti-oestrogen therapy, fulvestrant was at least as effective as the third-generation aromatase inhibitor, anastrozole, in terms of time to progression and objective response, and was associated with similar overall survival. In the first-line setting, fulvestrant showed similar efficacy to tamoxifen in patients with ER-positive and/or PgR-positive disease. Efficacy in more heavily pretreated patients has also been demonstrated in the fulvestrant compassionate use programme. Fulvestrant is well tolerated, being associated with a significantly lower incidence of joint disorders compared with anastrozole, and a lower incidence of hot flushes compared with tamoxifen. Fulvestrant, therefore, provides clinicians with a useful additional treatment for hormone-sensitive advanced breast cancer in postmenopausal women. Ongoing trials will help to clarify the optimal position of fulvestrant in the endocrine treatment sequence for these patients.     

Lasofoxifene: a new type of selective estrogen receptor modulator for the treatment of osteoporosis

Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen agonists and antagonists. Thus far SERMs have proven to be a highly versatile group and are being evaluated primarily for conditions associated with aging, including hormone-responsive cancer and osteoporosis. Tamoxifen and toremifene are currently used to treat advanced breast cancer and also have beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene is the only SERM compound actually approved worldwide for the prevention and treatment of postmenopausal osteoporosis and fragility fractures. Unfortunately, although these SERMs possess many benefits, they are also responsible for some very serious side effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These contraindications represent a major concern for the type of long-term, chronic therapy that is required to prevent osteoporosis. Moreover, both preclinical and clinical reports suggest that these SERMs are considerably less potent than estrogen, probably due to their reduced bioavailability. Lasofoxifene (CP 336,156) is a naphthalene-derivative, third-generation SERM, structurally distinct from the first- and second-generation SERMs. This compound selectively binds to both estrogen receptor subtypes (estrogen receptor-alpha or -beta) with high affinity. It has a half-inhibition concentration similar to that seen with estradiol and thus at least 10-fold higher than those reported for raloxifene and tamoxifen. Moreover, due to increased resistance to intestinal wall glucuronidation, lasofoxifene has a remarkably improved oral bioavailability with respect to other SERMs. In both preclinical and short-term clinical studies lasofoxifene has shown a proven efficacy in preventing bone loss and lowering cholesterol levels. Dose modeling from phase II studies allowed the selection of lasofoxifene 0.25 mg/day as the lowest fully effective dose. The compound shows a favorable safety profile and is currently in phase III development for the prevention and treatment of osteoporosis in postmenopausal women.     

Peptides targeting estrogen receptor alpha-potential applications for breast cancer treatment

Activation of the estrogen receptor alpha (ERα) is of prime importance for the development of hormone-dependent breast cancers. Hence, drugs able to impede the emergence of an active folding of ERα have been used for a long time as a first line therapeutic strategy. Aromatase inhibitors that block estradiol synthesis and / or antiestrogens that compete with hormone binding to the receptor are routinely prescribed. Unfortunately, emergence of tumor resistance almost invariably results from currently used antihormonal approaches. One may anticipate that a "multi-target" strategy affecting key regulatory domains distinct from ligand binding pocket of ERα may help to circumvent this problem. To reach this goal, the synthesis of peptides that may specifically inhibit intra- or inter-molecular interactions has been proposed. This paper describes functional motifs potentially suitable for the design of such antagonists. Activity of available peptidic and non-peptidic mimics of these motifs is also reviewed.     

Fulvestrant: a unique antiendocrine agent for estrogen-sensitive breast cancer

Importance of the field: The role of estrogen deprivation for the treatment of breast cancer has been understood since the 1800s. Pharmacologic advances in the field in the past decades, including tamoxifen and the aromatase inhibitors, have contributed significantly to the reduced mortality of estrogen-sensitive breast cancer. However, this subtype of breast cancer still presents with relapses and, once metastatic, progression to hormone-refractory state and loss of disease control remain an expected disease course. Fulvestrant, a pure estrogen receptor downregulator, is a new addition to the antiestrogen therapeutic armamentarium since its FDA approval in 2002. Its unique mechanism of action offers potential advantages over other estrogen targeted therapies.

Areas covered in this review: Published scientific literature, including presented abstracts, on fulvestrant from 1985 to the present were reviewed with selected publications included.

What the reader will gain: This review addresses current issues and therapies for estrogen-sensitive breast cancer, highlights the role of fulvestrant in current treatment guidelines and outlines some of the ongoing investigations of this compound.

Take home message: Fulvestrant is an effective and well-tolerated drug for treatment of metastatic estrogen-sensitive breast cancer. Work is underway to enhance its clinical benefit to patients as a single agent and in combination with other therapies.     

Fulvestrant for the treatment of endometrial cancer

Introduction: About one third of patients with endometrial cancer (EC) relapse and face a limited prognosis, if surgery or radiotherapy are not feasible. The remaining therapeutic options are chemotherapy and endocrine therapy.

Areas covered: This review summarizes the development of the first selective estrogen receptor (ER) down-regulator fulvestrant. This article provides its mechanism of action, pharmacokinetics and the available preclinical and clinical data. Furthermore, this review provides an overview of the market of treatments for recurrent or metastatic EC (RMEC) while also taking into account studies of fulvestrant in metastatic breast cancer.

Expert opinion: Even if fulvestrant showed only marginal activity in two phase II trials, it shouldn’t be abandoned but instead further developed in EC. Firstly, the dose of fulvestrant used in these trials was too low from today’s point of view. Secondly, the available literature on other endocrine agents is full of limitations and does not provide a gold standard. Furthermore, given the activity of mTOR inhibitors in EC, there may also be synergistic effects, given the cross-regulation of ER and the PI3K/AKT/mTOR pathway. The authors suggest that a prospective, phase II trial in ER positive RMEC would help to further explore the efficacy and tolerability of fulvestrant together with a mTOR inhibitor.     

氨格鲁米特治疗不同雌激素受体状态的复发转移乳腺癌

氨格鲁米特治疗不同ER状态的复发转移乳腺癌29例次,口服剂量为0.25g,qid。持续用药1mo以上。结果表明对ER阳性乳腺癌的有效率为7/15(47％),ER阴性为0/14(p<0.05)。ER阳性乳腺癌中以首次复发转移的病人,骨及软组织病灶的效果相对较好。其副反应不严重,极少需要停药,多可自行消失。临床应用时应通过ER检查,提高治疗的合理性。     

不同剂量氟维司群治疗雌激素受体阳性晚期乳腺癌患者的疗效

目的评价不同剂量氟维司群治疗雌激素受体阳性晚期乳腺癌患者的效果。方法以2014年6月至2016年1月经过我院确诊的雌激素受体阳性晚期乳腺癌患者68例作为研究对象,分为高剂量组(氟维司群500 mg组,31例)和低剂量组(氟维司群250 mg组,37例)。随访观察并比较两组患者的临床疗效、无进展生存期及不良反应情况。结果高剂量组的部分缓解率为9. 7%,疾病稳定率为38. 7%;低剂量组的部分缓解率为8. 1%,疾病稳定率为35. 1%。高剂量组的客观有效率(9. 7%vs. 8. 1%,P=0. 82)和临床获益率(48. 4%vs.43. 2%,P=0. 67)均略高于低剂量组,但差异无统计学意义。高剂量组的中位PFS时间为5. 5个月,对照组的中位PFS时间为4. 9个月,两组的生存差异有统计学意义(χ~2=4. 04,P=0. 04)。两组患者注射部位疼痛、恶心、头痛、潮热及乏力等不良反应发生率比较差异无统计学意义(P> 0. 05)。结论 500 mg氟维司群可改善雌激素受体阳性晚期乳腺癌患者的生存状况,未增加不良反应的发生。     

Interleukin-1 receptor antagonist: a new therapy for type 2 diabetes mellitus

Various complex mechanisms and their multifactorial pathways decisively provoke low-grade local and systemic inflammation in β-cells of pancreatic islets and peripheral tissues to induce β-cells' dysfunction and apoptosis, insulin resistance, and ultimately, overt type 2 diabetes mellitus (T2DM). Conventional antidiabetic agents are being less popular, as they have some potential adverse effects. Currently, many anti-inflammatory therapeutic modalities are being investigated to abate the infuriating effects of inducers of T2DM and among them, interleukin-1 receptor antagonist (IL-1Ra) is the only one that has been approved by US Food and Drug Administration. We have compared IL-1Ra with other anti-inflammatory agents and conventional antidiabetic agents. Although, IL-1Ra has broad-spectrum anti-inflammatory activities, it also has some limitations due to its short half-life. To overcome the problem of short half-life of IL-1Ra, recently, we fused IL-1Ra in recombinant human serum albumin and expressed it in Pichia pastoris. Its bioactivity was also checked by IL-1-induced A375.S2 apoptotic cells. Furthermore, we have also formulated IL-1Ra with Pluronic F-127-based thermosensitive gel and investigated its in vitro characteristics to prolong its therapeutic effects. Further studies are required to investigate its therapeutic effects against diabetes and diabetes-associated complications.     

Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis

Bazedoxifene acetate (WAY-140424; TSE-424) is an oral, nonsteroidal, indole-based selective estrogen receptor modulator (SERM) being developed for the prevention and treatment of osteoporosis. Preclinical studies on bazedoxifene have demonstrated estrogen agonist effects on the skeleton and lipid metabolism but not on breast and uterine endometrium. In combination with estrogen, bazedoxifene antagonizes the stimulatory action of estrogens on proliferation of breast cancer cells and endometrium. Phase III clinical studies have shown favorable effects on the skeleton without stimulation of endometrium and breast. Bazedoxifene prevents bone loss in postmenopausal women without osteoporosis and reduces vertebral fractures in women with postmenopausal osteoporosis. In women at high risk of fracture with multiple risk factors, bazedoxifene reduces nonvertebral fracture risk in post-hoc analysis. Bazedoxifene in combination with conjugated estrogens represents a new form of therapeutic agents for the treatment of postmenopausal symptoms and prevention of postmenopausal osteoporosis. Clinical trials with bazedoxifene/conjugated estrogens have shown beneficial effects on bone mineral density and bone turnover markers with improvement in vasomotor symptoms and little or no stimulation of breast and endometrium.     

Long-acting formulation of a new muscarinic receptor antagonist for the treatment of overactive bladder

A new muscarinic receptor antagonist, 5-hydroxymethyl tolterodine (5-HMT), was successfully encapsulated into PLGA microspheres. With an increase of PLGA concentration from 15% to 40%, encapsulation efficiency of 5-HMT increased from 55.39% to 76.32%, and the particle size of microsphere increased from 34.33 to 70.48?µm. Increasing the homogenisation speed from 850 to 2300?rpm, the particle size was reduced about 65%.The in vitro and in vivo studies in beagle dogs show that the release profile of 5-HMT-loaded microspheres (5-HMT MS) prepared with 503H is characterised by a low initial burst followed by slow release that lasted for 2 weeks. A C_max of 1.617?±?0.392?ng/mL was found on the sixth day. When evaluated for inhibition of the carbachol-induced contraction of rat urinary bladder, 5-HMT MS showed a much longer and more potent effect than tolterodine tablets. The mean urination time of the rats in the 5-HMT MS group was significantly decreased (p?<?0.05 or p?<?0.01) to less than 2 weeks.     

Mitoxantrone as a first-line treatment of advanced breast cancer

Summary Forty-two women with measurable or evaluable advanced breast cancer who had received neither prior chemotherapy for advanced disease nor any anthracycline-containing regimen as adjuvant were entered in a phase II study of mitoxantrone (Novantrone^®; dihydroxyanthracenedione). Patients were aged from 36 to 80 years, performance status was from 0 to 2. All patients had normal hematological status and normal renal and liver function tests. Cardiac scintigraphy and sonography techniques were used to monitor cardiac function. Mitoxantrone was administered at a dose of 14 mg/m² in 100 ml 5% dextrose solution over 30 minutes, repeated every three weeks.The number of courses per patient ranged from 2 to 12. Of 42 eligible patients 39 were fully evaluable for response and all for drug toxicity. Responses to treatment were: complete response four patients, partial response 10 patients, stable disease 18 patients and progressive disease seven patients. The overall response rate was 36% (95% confidence limits 20–52%). Three patients showed decreased left ventricular ejection fraction but no patient developed signs of overt left ventricular failure during the treatment period. Hematological and gastrointestinal toxicities were mild. Hair loss was minimal.The data indicate that mitoxantrone is an effective agent for the treatment of advanced breast cancer with mild side-effects, especially with respect to nausea/vomiting, hair loss and cardiotoxicity.     

Update in the treatment of locally advanced breast cancer: a multidisciplinary approach

Locally advanced breast cancer represents a wide variety of neoplasms and constitutes approximately 10%-20% of the newly diagnosed breast cancers. These cancers may have widely different clinical and biological characteristics. According to the American Joint Committee on Cancer (AJCC) staging system, all of stage III disease is considered locally advanced. The clinical treatment of locally advanced breast cancer is complex and should be tailored to the individual patient. In this paper we discuss the options of management of locally advanced breast cancer, focusing on a multidisciplinary approach through a combined-modality care involving surgery, radiotherapy and systemic therapy.     

Selective estrogen receptor modulators and aromatase inhibitors for breast cancer chemoprevention

In premenopausal women, tamoxifen for 5 years reduces the risk of estrogen receptor (ER) - positive breast cancer for at least 10 years. Women < 50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist after treatment regardless of age. Raloxifene use is consistently associated with a reduction in breast cancer risk. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive breast cancer with equal efficacy, but raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in breast cancer risk from either agent translates into reduced breast cancer mortality. Overall quality of life is similar with raloxifene or tamoxifen, but the incidence of dyspareunia, weight gain, and musculoskeletal complaints is higher with raloxifene use, whereas vasomotor symptoms, bladder incontinence, gynecologic symptoms, and leg cramps were higher with tamoxifen use. Ongoing randomized, placebo-controlled trials investigating the use of third-generation aromatase inhibitors in the chemoprevention of breast cancer in postmenopausal women include the NCIC Clinical Trials Group MAP3 (ExCel) Trial (Exemestane in Preventing Cancer in Postmenopausal Women at Increased Risk of Developing Breast Cancer), and the IBIS-II trial.71 The North American MAP3 study randomized patients to exemestane or placebo in patients who refuse treatment with a SERM, and the international IBIS-II trial compares anastrozole for 5 years versus placebo for chemoprevention in patients at increased risk.     

Eplerenone: a new selective aldosterone receptor antagonist

Eplerenone is a specific aldosterone receptor antagonist that has been shown to have antihypertensive efficacy and to reduce end-organ manifestations in experimental animal models. Studies in humans have confirmed the blood pressure-lowering efficacy of this agent, as well as providing evidence of benefit in congestive heart failure. The side-effect profile indicates that the specificity of eplerenone for the mineralocorticoid receptor is responsible for the lower incidence of sex hormone- related side-effects than have been seen with other mineralocorticoid receptor blockers. Hyperkalemia is most frequently observed with eplerenone among patients with severe impairment of renal function and in diabetics with microalbuminuria, especially in combination with angiotensin-converting enzyme inhibitors. This agent appears to be a promising and effective new addition for the treatment of hypertension and heart failure with few of the side-effects that have plagued earlier drugs of this class.     

Biochemical evidence for a new benzodiazepine receptor antagonist

1-(3-Chlorophenyl)-3-diethylcarbamoyl-1 H-1,2,4-triazole (CP-32,961) inhibited [³H]diazepam binding to rat cortical membrances and [³H]flunitrazepam binding to mouse brain in vivo. Its inhibition of the binding of [³H]Ro 15-1788 (benzodiazepine receptor antagonist) to these membranes was not facilitated by added GABA; CP-32,961 exhibited a GABA ratio of 0.84 compared to 2.44 for diazepam. Cerebellar cyclic GMP content in rats was raised by CP-32,961, which also further elevated the increased cyclic GMP levels induced by isoniazid. These neurochemical actions are similar to those shown by ethyl β-carboline-3-carboxylate (β-CCE) and suggest that CP-32,961 is a benzodiazepine receptor antagonist with inverse agonist activity.     

Trastuzumab: new indication. Adjuvant breast cancer treatment for a minority

An improvement in survival time, but cardiotoxicity remains a concern.     

The safety of palbociclib for the treatment of advanced breast cancer

Introduction: Despite improvements in the diagnosis and management of early stage breast cancer, about one third of the patients still progress to metastatic disease. Most of the patients with metastatic breast cancer have a hormone receptor positive and human epidermal growth factor receptor 2 negative subtype with a median survival of more than 3 years. For these patients, endocrine therapy with its favorable toxicity profile is the current standard of care. However, patients with metastatic breast cancer have an incurable disease. Therefore, not only efficacy but also quality of life are key when selecting a therapy regimen.

Areas covered: This paper aims to discuss the efficacy and toxicity profile of the new endocrine-based therapy option palbociclib together with endocrine treatment.

Expert opinion: The addition of targeted agents like palbociclib can overcome intrinsic or acquired resistance to endocrine therapy and substantially prolong progression free survival. The combination of palbociclib plus endocrine therapy is associated with a tolerable and well manageable toxicity profile as well as maintenance of quality of life. Thus, addition of palbociclib to endocrine therapy offers a new and important treatment option for hormone receptor positive metastatic breast cancer.     

Targeting androgen receptor and trail:a novel treatment paradigm for breast cancer

OBJECTIVE TNF-related apoptosis-inducing ligand(TRAIL)is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors.However,most breast cancer cells are resistant to TRAIL-induced apoptosis.Our objectives are to investigate the underlying molecular mechanisms and to develop strategies to overcome such resistance.METHODS To identify modulators of TRAIL-induced apoptosis,we carried out a genome wide si RNA screen.To validate the screening result,we either silenced or overexpressed the identified genes in various breast cancer cells and changes in growth and TRAIL-induced cell apoptosis were determined in vitro and in an orthotopic xenograft mouse model.Finally,we investigated whether small molecules targeting the identified genes improve the effectiveness of TRAIL-therapy.RESULTS We unexpectedly identified androgen receptor(AR)to be responsible for TRAIL resistance.While AR is classically viewed as the key factor in prostate cancer progression,we found that AR expression levels were markedly elevated in human invasive breast cancer specimens including triple-negative breast cancers(TNBC)that are highly aggressive with poor prognosis.Importantly,breast cancer cell lines express different levels of AR that correlated with their TRAIL resistance.AR overexpression in MDA-MB-231 and MDA-MB-436 cells suppressed the TRAIL sensitivity whereas knockdown of AR rendered MCF-7 and MDA-MB-453 cells sensitive to TRAIL-induced apoptosis.AR overexpression also induced TRAIL resistance in breast tumors in vivo.Further,we observed an upregulation of the TRAIL receptor,death receptor 5(DR5)in breast cancer cells,following the removal or inhibition of AR by its antagonists Casodex and MDV3100.Treatment with AR antagonists also enhanced TRAIL-induced breast cancer cell apoptosis.CONCLUSION AR signaling suppresses TRAIL-induced breast cancer cell apoptosis,in part,by suppressing DR5 expression,and a combination of AR antagonists together with TRAIL may be a novel and effective therapy for TNBC.     

Valsartan: a novel angiotensin type 1 receptor antagonist

Valsartan is a highly selective, orally available antagonist of the angiotensin Type 1 (AT1) receptor. It is indicated for treatment of mild to moderate essential hypertension. Experimental studies have confirmed the abolition or attenuation of angiotensin II (AII)-related effects, such as vasoconstriction, cell growth promotion and aldosterone release. In humans, valsartan is rapidly absorbed with maximal plasma concentrations occurring 1-2 h after oral administration. The elimination half-life comes to about 7-8 h, valsartan is metabolised to a negligible extent and most of the drug is excreted via the faeces. There is no dose adjustment required for patients with a creatinine clearance > 10 ml/min. The dose should not exceed 80 mg o.d. in patients with hepatic dysfunction, valsartan is not recommended for patients with severe hepatic dysfunction and/or biliary cirrhosis. At present, no clinically relevant pharmacokinetic drug interactions have been observed. Valsartan produces persistent blood pressure reductions in patients with mild to moderate hypertension, the recommended starting dose is 80 mg o.d. If required, the dose may either be increased to 160 mg o.d. or hydrochlorothiazide may be added. In comparison to other antihypertensive drugs valsartan therapy leads to similar blood pressure reductions, while exhibiting a favourable tolerability profile. Preliminary studies suggest beneficial effects in patients with hypertensive end-organ damage such as renal disease and left ventricular hypertrophy. Furthermore, the drug is evaluated for its efficacy in heart failure and patients post-myocardial infarction.