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Journal of Clinical Oncology : Official... Oct 2022Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant... (Randomized Controlled Trial)
Randomized Controlled Trial
Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial.
PURPOSE
Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies.
METHODS
This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable mutations.
RESULTS
Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; = .002) and patients with mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively).
CONCLUSION
Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclin-Dependent Kinase 4; Estrogen Antagonists; Female; Humans; Receptor, ErbB-2; Receptors, Estrogen; Tetrahydronaphthalenes
PubMed: 35584336
DOI: 10.1200/JCO.22.00338 -
American Family Physician May 2016
Topics: Breast Diseases; Cysts; Danazol; Estrogen Antagonists; Female; Humans; Menstrual Cycle; Pain Management
PubMed: 27175723
DOI: No ID Found -
Current Urology Reports Sep 2015Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology and affect the majority of men at some time... (Review)
Review
Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology and affect the majority of men at some time during their lives. The development of BPH/LUTS is associated with an increased ratio of estrogen to androgen levels, and this ratio, when mimicked in a variety of animals, induces BPH and lower urinary tract dysfunction (LUTD). While the precise molecular etiology remains unclear, estrogens have been implicated in the development and maintenance of BPH. Numerous endogenous and exogenous estrogens exist in humans. These estrogens act via multiple estrogen receptors to promote or inhibit prostatic hyperplasia and other BPH-associated processes. The prostate is an estrogen target tissue, and estrogens directly and indirectly affect growth and differentiation of prostate. The precise role of estrogen action directly affecting prostate growth and differentiation in the context of BPH is an understudied area and remains to be elucidated. Estrogens and selective estrogen receptor modulators (SERMs) have been shown to promote or inhibit prostate proliferation illustrating their potential roles in the development of BPH as therapy. More work will be required to identify estrogen signaling pathways associated with LUTD in order to develop more efficacious drugs for BPH treatment and prevention.
Topics: Animals; Estrogen Antagonists; Estrogens; Humans; Lower Urinary Tract Symptoms; Male; Prostatic Hyperplasia; Signal Transduction; Treatment Outcome
PubMed: 26156791
DOI: 10.1007/s11934-015-0534-6 -
International Journal of Molecular... Jun 2017In mammals, the effects of estrogen are mainly mediated by two different estrogen receptors, ERα and ERβ. These proteins are members of the nuclear receptor family,... (Review)
Review
In mammals, the effects of estrogen are mainly mediated by two different estrogen receptors, ERα and ERβ. These proteins are members of the nuclear receptor family, characterized by distinct structural and functional domains, and participate in the regulation of different biological processes, including cell growth, survival and differentiation. The two estrogen receptor (ER) subtypes are generated from two distinct genes and have partially distinct expression patterns. Their activities are modulated differently by a range of natural and synthetic ligands. Some of these ligands show agonistic or antagonistic effects depending on ER subtype and are described as selective ER modulators (SERMs). Accordingly, a few phytochemicals, called phytoestrogens, which are synthesized from plants and vegetables, show low estrogenic activity or anti-estrogenic activity with potentially anti-proliferative effects that offer nutraceutical or pharmacological advantages. These compounds may be used as hormonal substitutes or as complements in breast cancer treatments. In this review, we discuss and summarize the in vitro and in vivo effects of certain phytoestrogens and their potential roles in the interaction with estrogen receptors.
Topics: Animals; Epigenesis, Genetic; Estrogen Antagonists; Humans; Phytochemicals; Receptors, Estrogen; Signal Transduction; Transcription, Genetic
PubMed: 28657580
DOI: 10.3390/ijms18071381 -
Proceedings of the National Academy of... Aug 2021Efforts to improve estrogen receptor-α (ER)-targeted therapies in breast cancer have relied upon a single mechanism, with ligands having a single side chain on the...
Efforts to improve estrogen receptor-α (ER)-targeted therapies in breast cancer have relied upon a single mechanism, with ligands having a single side chain on the ligand core that extends outward to determine antagonism of breast cancer growth. Here, we describe inhibitors with two ER-targeting moieties, one of which uses an alternate structural mechanism to generate full antagonism, freeing the side chain to independently determine other critical properties of the ligands. By combining two molecular targeting approaches into a single ER ligand, we have generated antiestrogens that function through new mechanisms and structural paradigms to achieve antagonism. These dual-mechanism ER inhibitors (DMERIs) cause alternate, noncanonical structural perturbations of the receptor ligand-binding domain (LBD) to antagonize proliferation in ER-positive breast cancer cells and in allele-specific resistance models. Our structural analyses with DMERIs highlight marked differences from current standard-of-care, single-mechanism antiestrogens. These findings uncover an enhanced flexibility of the ER LBD through which it can access nonconsensus conformational modes in response to DMERI binding, broadly and effectively suppressing ER activity.
Topics: Breast Neoplasms; Crystallography, X-Ray; Estrogen Antagonists; Estrogen Receptor alpha; Female; Humans; Protein Binding; Protein Conformation; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 34452998
DOI: 10.1073/pnas.2101657118 -
Frontiers in Neuroendocrinology Oct 2020Epidemiological, clinical, and basic research over the past thirty years have described the benefits of estrogen on cognition, mood, and brain health. Less is known... (Review)
Review
Epidemiological, clinical, and basic research over the past thirty years have described the benefits of estrogen on cognition, mood, and brain health. Less is known about tamoxifen, a selective estrogen receptor modifier (SERM) commonly used in breast cancer which is able to cross the blood-brain barrier. In this article, we review the basic pharmacology of tamoxifenas well as its effects on cognition and mood. The literature reveals an overall impairing effect of tamoxifen on cognition in breast cancer patients, hinting at central antiestrogen activity. On the other hand, tamoxifen demonstrates promising effects in psychiatric disorders, like bipolar disorder, where its therapeutic action may be independent of interaction with estrogen receptors. Understanding the neuropsychiatric properties of SERMs like tamoxifen can guide future research to ameliorate unwanted side-effects and provide novel options for difficult to treat disorders.
Topics: Affect; Animals; Antineoplastic Agents, Hormonal; Cognition; Estrogen Antagonists; Humans; Tamoxifen
PubMed: 32822707
DOI: 10.1016/j.yfrne.2020.100869 -
Expert Review of Anticancer Therapy Feb 2017The estrogen receptor (ER) is expressed at high levels in many epithelial ovarian cancers (EOC) and represents a potential target for endocrine therapy. Both... (Review)
Review
The estrogen receptor (ER) is expressed at high levels in many epithelial ovarian cancers (EOC) and represents a potential target for endocrine therapy. Both anti-estrogens and aromatase inhibitors have been evaluated in phase II clinical trials. Areas covered: We present an overview of the phase II and phase III trials of anti-estrogens (tamoxifen and fulvestrant) and aromatase inhibitors (letrozole, anastrazole and exemestane) undertaken in epithelial ovarian cancer identified through a Pubmed search. We describe predictive biomarkers that are being investigated to identify responsive cancers. Expert commentary: The efficacy of endocrine therapy in epithelial ovarian cancer is likely to be confined to histological subtypes with the highest ER expression while low grade serous ovarian cancer appears to be one subgroup with good sensitivity to these agents. The low toxicity profile of these agents is favourable although their use is unlicensed and the optimal setting undefined. Prospective clinical trials of endocrine agents in the early relapse and maintenance settings are urgently required to establish their definitive role in the management of epithelial ovarian cancer.
Topics: Animals; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Estrogen Antagonists; Female; Humans; Neoplasm Recurrence, Local; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Receptors, Estrogen; Treatment Outcome
PubMed: 27967255
DOI: 10.1080/14737140.2017.1272414 -
IARC Monographs on the Evaluation of... 1996
Review
Topics: Animals; Antineoplastic Agents; Carcinogenicity Tests; Carcinogens; Estrogen Antagonists; Humans; Tamoxifen
PubMed: 9097126
DOI: No ID Found -
IARC Monographs on the Evaluation of... 1996
Review
Topics: Animals; Antineoplastic Agents, Hormonal; Carcinogenicity Tests; Carcinogens; Estrogen Antagonists; Humans; Tamoxifen
PubMed: 9097127
DOI: No ID Found -
IARC Monographs on the Evaluation of... 1996
Review
Topics: Animals; Antineoplastic Agents, Hormonal; Carcinogenicity Tests; Carcinogens; Estrogen Antagonists; Humans; Toremifene
PubMed: 9097128
DOI: No ID Found