2,305 results on '"Estrogen Antagonists therapeutic use"'
Search Results
2. Making Informed Choices On Incorporating Chemoprevention into carE (MiCHOICE, SWOG 1904): Design and methods of a cluster randomized controlled trial.
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Crew KD, Anderson GL, Arnold KB, Stieb AP, Amenta JN, Collins N, Law CW, Pruthi S, Sandoval-Leon A, Bertoni D, Grosse Perdekamp MT, Colonna S, Krisher S, King T, Yee LD, Ballinger TJ, Braun-Inglis C, Mangino D, Wisinski KB, DeYoung CA, Ross M, Floyd J, Kaster A, Vander Walde L, Saphner T, Zarwan C, Lo S, Graham C, Conlin A, Yost K, Agnese D, Jernigan C, Hershman DL, Neuhouser ML, Arun B, and Kukafka R
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- Adult, Female, Humans, Middle Aged, Decision Making, Decision Support Techniques, Estrogen Antagonists therapeutic use, Estrogen Antagonists administration & dosage, Health Knowledge, Attitudes, Practice, Patient Education as Topic methods, Patient Reported Outcome Measures, Research Design, Risk Reduction Behavior, Breast Neoplasms prevention & control, Chemoprevention methods
- Abstract
Introduction: Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy., Methods/design: We are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6 months, and yearly for 5 years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation., Results/discussion: With this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S., Trial Registration: NCT04496739., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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3. Impact of Anti-Estrogen Therapy on Early Cardiovascular Referrals, Tests and Medications in Premenopausal Women with Operable Breast Cancer.
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Douglas E, Levine B, Ansari A, Ansley K, Melin S, Park CJ, Richardson K, Hatcher S, D'Agostino RB Jr, Jordan JH, and Thomas A
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- Humans, Female, Adult, Middle Aged, Retrospective Studies, Estrogen Antagonists therapeutic use, Follow-Up Studies, Receptors, Estrogen metabolism, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms pathology, Premenopause, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Referral and Consultation statistics & numerical data, Cardiovascular Diseases
- Abstract
Introduction: Premenopausal women with high-risk hormone receptor (HR)-positive breast cancer often receive ovarian function suppression (OFS) and anti-estrogen therapy which induces near complete estrogen deprivation (NCED). This treatment improves recurrence-free survival but may increase cardiovascular risk. We sought to identify patterns of cardiovascular care and outcomes in premenopausal women with operable breast cancer., Methods: Premenopausal women ≤ 50 years of age with stage I-III HR-positive or triple negative breast cancer (TNBC) were identified by retrospective review. We categorized women into 3 groups based on anti-estrogen therapy approach: NCED (HR + OFS), anti-estrogen therapy without OFS (HRnoOFS), and no anti-estrogen therapy (TNBC). Baseline characteristics, post-diagnosis cardiovascular events and cardiovascular actions (tests, referrals and medications) were recorded. Categorical variables were compared among the groups using chi-square and Fisher's exact tests; continuous outcomes were compared using ANOVA., Results: 82, 83, and 52 women were identified in the HR + OFS, HRnoOFS, and TNBC groups respectively; mean follow-up was 5.0 years. Mean number of cardiovascular actions per year were highest in the HR + OFS group compared with HRnoOFS and TNBC groups (0.35 vs. 0.20 and 0.27, respectively; P = .036). The HR + OFS group had significantly more referrals and tests per year than the other groups. Cardiovascular medication initiation did not differ among groups., Conclusions: In this early follow-up period, there were meaningful numbers of cardiovascular actions, with women on NCED experiencing the most per year. Future work should seek to further understand the impact of anti-estrogen therapy on the cardiovascular health of premenopausal women and test strategies to mitigate cardiotoxicity., Competing Interests: Disclosure AT reports stock ownership: Johnson & Johnson, Gilead Sciences, Bristol Myers Squibb, Pfizer; consulting or advisory role: Genentech, AstraZeneca; Research Funding: Sanofi, Merck (both to the institution); royalties UpToDate; KA reports research funding to the institution from Roche., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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4. EB1089 Increases the Antiproliferative Response of Lapatinib in Combination with Antiestrogens in HER2-Positive Breast Cancer Cells.
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Achounna AS, Ordaz-Rosado D, García-Quiroz J, Morales-Guadarrama G, Milo-Rocha E, Larrea F, Díaz L, and García-Becerra R
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- Humans, Female, Lapatinib pharmacology, Lapatinib therapeutic use, Calcitriol pharmacology, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Estrogen Receptor Modulators pharmacology, Proto-Oncogene Proteins c-akt metabolism, Receptor, ErbB-2 metabolism, Estrogen Antagonists therapeutic use, Cell Line, Tumor, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Calcitriol analogs & derivatives
- Abstract
HER2-positive breast cancer is associated with aggressive behavior and reduced survival rates. Calcitriol restores the antiproliferative activity of antiestrogens in estrogen receptor (ER)-negative breast cancer cells by re-expressing ERα. Furthermore, calcitriol and its analog, EB1089, enhance responses to standard anti-cancer drugs. Therefore, we aimed to investigate EB1089 effects when added to the combined treatment of lapatinib and antiestrogens on the proliferation of HER2-positive breast cancer cells. BT-474 (ER-positive/HER2-positive) and SK-BR-3 (ER-negative/HER2-positive) cells were pre-treated with EB1089 to modulate ER expression. Then, cells were treated with EB1089 in the presence of lapatinib with or without the antiestrogens, and proliferation, phosphorylation array assays, and Western blot analysis were performed. The results showed that EB1089 restored the antiproliferative response to antiestrogens in SK-BR-3 cells and improved the inhibitory effects of the combination of lapatinib with antiestrogens in the two cell lines. Moreover, EB1089, alone or combined, modulated ERα protein expression and reduced Akt phosphorylation in HER2-positive cells. EB1089 significantly enhanced the cell growth inhibitory effect of lapatinib combined with antiestrogens in HER2-positive breast cancer cells by modulating ERα expression and Akt phosphorylation suppression. These results highlight the potential of this therapeutic approach as a promising strategy for managing HER2-positive breast cancer.
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- 2024
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5. The value of oral selective estrogen receptor degraders in patients with HR-positive, HER2-negative advanced breast cancer after progression on ≥ 1 line of endocrine therapy: systematic review and meta-analysis.
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Huang X, Yu Y, Luo S, Fu W, Zhang J, and Song C
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- Humans, Female, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Fulvestrant therapeutic use, Estrogen Antagonists therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms metabolism
- Abstract
Background: Currently, the value of oral selective estrogen receptor degraders (SERDs) for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (aBC) after progression on ≥ 1 line of endocrine therapy (ET) remains controversial. We conducted a meta-analysis to evaluate progression-free survival (PFS) and safety benefits in several clinical trials., Materials and Methods: Cochrane Library, Embase, PubMed, and conference proceedings (SABCS, ASCO, ESMO, and ESMO Breast) were searched systematically and comprehensively. Random effects models or fixed effects models were used to assess pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for treatment with oral SERDs versus standard of care., Results: A total of four studies involving 1,290 patients were included in our analysis. The hazard ratio (HR) of PFS showed that the oral SERD regimen was better than standard of care in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET (HR: 0.75, 95% CI: 0.62-0.91, p = 0.004). In patients with ESR1 mutations, the oral SERD regimen provided better PFS than standard of care (HR: 0.58, 95% CI: 0.47-0.71, p < 0.00001). Regarding patients with disease progression following previous use of CDK4/6 inhibitors, PFS benefit was observed in oral SERD-treatment arms compared to standard of care (HR: 0.75, 95% CI: 0.64-0.87, p = 0.0002)., Conclusions: The oral SERD regimen provides a significant PFS benefit compared to standard-of-care ET in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET. In particular, we recommend oral SERDs as a preferred choice for those patients with ESR1m, and it could be a potential replacement for fulvestrant. The oral SERD regimen is also beneficial after progression on CDK4/6 inhibitors combined with endocrine therapy., (© 2023. The Author(s).)
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- 2024
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6. Danazol's use for menstrual suppression in transgender individuals: A retrospective multi-site cohort study.
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Scatoni A, Roberts Z, Boskey ER, Staffa S, Roden RC, Redwood E, and Grimstad F
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- Humans, Female, Retrospective Studies, Adult, Male, Estrogen Antagonists therapeutic use, Estrogen Antagonists adverse effects, Cohort Studies, Amenorrhea chemically induced, Middle Aged, Young Adult, Menstruation drug effects, Danazol therapeutic use, Danazol adverse effects, Transgender Persons
- Abstract
Background: Danazol is a synthetic progestin with androgenic effects that is approved by the Food and Drug Administration for treatment of endometriosis, benign fibrocystic breast disease, and hereditary angioedema. In recent years, increasing numbers of transgender and nonbinary individuals seeking menstrual suppression have been offered danazol due to its potential to both induce amenorrhea and cause reversible androgenic side effects including pigmentation of vellus hairs and voice changes, which may be desirable in this population. There are currently no studies assessing use of danazol within the transgender population for menstrual suppression., Objective: This study's primary aim was to evaluate the use of danazol as a menstrual suppression agent in transgender patients., Design: This was a retrospective multisite cohort study of all individuals who had been on danazol at two tertiary care centers between 2000 and 2022., Methods: All patients prescribed danazol were identified using a search of the electronic medical records. For demographic purposes, comparisons were made between those who did and did not use danazol for the purpose of menstrual suppression. A detailed chart review was then performed to analyze the experiences of menstrual suppression in transgender and nonbinary patients., Results: Most transgender and nonbinary patients on danazol for menstrual suppression remained on it at their most recent follow-up visit, and many charts noted improvements in gender dysphoria, pelvic pain, dysmenorrhea, endometriosis, and heavy menstrual bleeding. Most transgender patients achieved amenorrhea., Conclusion: Danazol may be a reasonable option for menstrual suppression in transgender and nonbinary patients. Our findings show its potential to not only induce amenorrhea but cause desired androgenic symptoms and improve gender dysphoria, pelvic pain, dysmenorrhea, endometriosis, and heavy bleeding. While the androgenic effects of danazol are less desirable in cisgender populations, it is an attractive option for menstrual suppression in transgender and nonbinary patients.
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- 2024
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7. Selective Estrogen receptor degraders (SERDs) for the treatment of breast cancer: An overview.
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Bhatia N, Hazra S, and Thareja S
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- Humans, Female, Receptors, Estrogen, Estrogen Antagonists therapeutic use, Selective Estrogen Receptor Modulators pharmacology, Selective Estrogen Receptor Modulators therapeutic use, Selective Estrogen Receptor Modulators chemistry, Aromatase Inhibitors pharmacology, Aromatase Inhibitors therapeutic use, Estrogen Receptor alpha, Breast Neoplasms drug therapy
- Abstract
Discovery of SERDs has changed the direction of anticancer research, as more than 70% of breast cancer cases are estrogen receptor positive (ER+). Therapies such as selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI's) have been effective, but due to endocrine resistance, SERDs are now considered essential therapeutics for the treatment of ER+ breast cancer. The present review deliberates the pathophysiology of SERDs from the literature covering various molecules in clinical trials. Estrogen receptors active sites distinguishing characteristics and interactions with currently available FDA-approved drugs have also been discussed. Designing strategy of previously reported SERDs, their SAR analysis, in silico, and the biological efficacy have also been summarized along with appropriate examples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
- Published
- 2023
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8. Modeling the novel SERD elacestrant in cultured fulvestrant-refractory HR-positive breast circulating tumor cells.
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Dubash TD, Bardia A, Chirn B, Reeves BA, LiCausi JA, Burr R, Wittner BS, Rai S, Patel H, Bihani T, Arlt H, Bidard FC, Kaklamani VG, Aftimos P, Cortés J, Scartoni S, Fiascarelli A, Binaschi M, Habboubi N, Iafrate AJ, Toner M, Haber DA, and Maheswaran S
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- Animals, Humans, Female, Fulvestrant, Receptors, Estrogen, Estrogen Antagonists therapeutic use, Disease Models, Animal, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Neoplastic Cells, Circulating
- Abstract
Purpose: Metastatic hormone receptor-positive (HR+) breast cancer initially responds to serial courses of endocrine therapy, but ultimately becomes refractory. Elacestrant, a new generation FDA-approved oral selective estrogen receptor degrader (SERD) and antagonist, has demonstrated efficacy in a subset of women with advanced HR+breast cancer, but there are few patient-derived models to characterize its effect in advanced cancers with diverse treatment histories and acquired mutations., Methods: We analyzed clinical outcomes with elacestrant, compared with endocrine therapy, among women who had previously been treated with a fulvestrant-containing regimen from the recent phase 3 EMERALD Study. We further modeled sensitivity to elacestrant, compared with the currently approved SERD, fulvestrant in patient-derived xenograft (PDX) models and cultured circulating tumor cells (CTCs)., Results: Analysis of the subset of breast cancer patients enrolled in the EMERALD study who had previously received a fulvestrant-containing regimen indicates that they had better progression-free survival with elacestrant than with standard-of-care endocrine therapy, a finding that was independent estrogen receptor (ESR1) gene mutations. We modeled elacestrant responsiveness using patient-derived xenograft (PDX) models and in ex vivo cultured CTCs derived from patients with HR+breast cancer extensively treated with multiple endocrine therapies, including fulvestrant. Both CTCs and PDX models are refractory to fulvestrant but sensitive to elacestrant, independent of mutations in ESR1 and Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) genes., Conclusion: Elacestrant retains efficacy in breast cancer cells that have acquired resistance to currently available ER targeting therapies. Elacestrant may be an option for patients with HR+/HER2- breast cancer whose disease progressed on fulvestrant in the metastatic setting., Translational Relevance: Serial endocrine therapy is the mainstay of management for metastatic HR+breast cancer, but acquisition of drug resistance highlights the need for better therapies. Elacestrant is a recently FDA-approved novel oral selective estrogen receptor degrader (SERD), with demonstrated efficacy in the EMERALD phase 3 clinical trial of refractory HR+breast cancer. Subgroup analysis of the EMERALD clinical trial identifies clinical benefit with elacestrant in patients who had received prior fulvestrant independent of the mutational status of the ESR1 gene, supporting its potential utility in treating refractory HR+breast cancer. Here, we use pre-clinical models, including ex vivo cultures of circulating tumor cells and patient-derived xenografts, to demonstrate the efficacy of elacestrant in breast cancer cells with acquired resistance to fulvestrant., (© 2023. The Author(s).)
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- 2023
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9. Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and Challenges.
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Rej RK, Thomas JE 2nd, Acharyya RK, Rae JM, and Wang S
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- Humans, Female, Receptors, Estrogen metabolism, Estrogen Receptor alpha metabolism, Tamoxifen pharmacology, Tamoxifen therapeutic use, Aromatase Inhibitors pharmacology, Aromatase Inhibitors therapeutic use, Selective Estrogen Receptor Modulators pharmacology, Selective Estrogen Receptor Modulators therapeutic use, Estrogen Antagonists therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism
- Abstract
Estrogen receptor alpha (ERα) is a well-established therapeutic target for the treatment of ER-positive (ER+) breast cancers. Despite the tremendous successes achieved with tamoxifen, a selective ER modulator, and aromatase inhibitors (AIs), resistance to these therapies is a major clinical problem. Therefore, induced protein degradation and covalent inhibition have been pursued as new therapeutic approaches to target ERα. This Perspective summarizes recent progress in the discovery and development of oral selective ER degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), and proteolysis targeting chimera (PROTAC) ER degraders. We focus on those compounds which have been advanced into clinical development.
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- 2023
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10. [18F]FDG and [18F]FES PET/CT Imaging as a Biomarker for Therapy Effect in Patients with Metastatic ER+ Breast Cancer Undergoing Treatment with Rintodestrant.
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Iqbal R, Yaqub M, Bektas HO, Oprea-Lager DE, de Vries EGE, Glaudemans AWJM, Aftimos P, Gebhart G, Beelen AP, Schuit RC, Windhorst AD, Boellaard R, and Menke-van der Houven van Oordt CW
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- Humans, Female, Fluorodeoxyglucose F18 therapeutic use, Positron Emission Tomography Computed Tomography methods, Receptors, Estrogen genetics, Receptors, Estrogen metabolism, Estradiol therapeutic use, Estrogen Antagonists therapeutic use, Molecular Imaging, Biomarkers, Breast Neoplasms diagnostic imaging, Breast Neoplasms drug therapy, Breast Neoplasms genetics
- Abstract
Purpose: PET with 16α-[18F]-fluoro-17β-estradiol ([18F]FES) allows assessment of whole body estrogen receptor (ER) expression. The aim of this study was to investigate [18F]-fluorodeoxyglucose ([18F]FDG) and [18F]FES PET/CT imaging for response prediction and monitoring of drug activity in patients with metastatic ER-positive breast cancer undergoing treatment with the selective estrogen receptor downregulator (SERD) rintodestrant., Experimental Design: In this trial (NCT03455270), PET/CT imaging was performed at baseline ([18F]FDG and [18F]FES), during treatment and at time of progression (only [18F]FES). Visual, quantitative, and mutational analysis was performed to derive a heterogeneity score (HS) and assess tracer uptake in lesions, in relation to the mutation profile. The primary outcome was progression-free survival (PFS)., Results: The HS and PFS in the entire group did not correlate (n = 16, Spearman's rho, P = 0.06), but patients with a low HS (< 25.0%, n = 4) had a PFS of > 5 months whereas patients with no [18F]FES uptake (HS 100.0%, n = 3) had a PFS of < 2 months. [18F]FES uptake was not affected by estrogen receptor 1 (ESR1) mutations. On-treatment [18F]FES PET/CT scans showed no [18F]FES uptake in any of the baseline [18F]FES-positive lesions. At progression, [18F]FES uptake remained blocked in patients scanned ≤ 1-2 half-lives of rintodestrant whereas it restored in patients scanned ≥ 5 days after end of treatment., Conclusions: Absence of ER expression on [18F]FES PET is a predictor for no response to rintodestrant. [18F]FES uptake during treatment and at time of progression is useful to monitor the (reversible) effect of therapy and continued mode of action of SERDs. See related commentary by Linden and Mankoff, p. 2015., (©2023 American Association for Cancer Research.)
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- 2023
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11. Can Molecular Imaging Find a Path to Navigate Evolving Breast Cancer Treatments?
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Linden HM and Mankoff DA
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- Humans, Female, Positron Emission Tomography Computed Tomography, Fluorodeoxyglucose F18 therapeutic use, Receptors, Estrogen metabolism, Estradiol therapeutic use, Estrogen Antagonists therapeutic use, Molecular Imaging, Biomarkers, Breast Neoplasms diagnostic imaging, Breast Neoplasms drug therapy, Breast Neoplasms genetics
- Abstract
[18F]fluoroestradiol (FES) PET is an FDA-approved imaging biomarker. Like IHC, FES positivity predicts clinical benefit of endocrine therapy. In addition, FES measures the target activity in endocrine agent drug development. A recent study found that whole body tumor heterogeneity of expression predicts clinical benefit, and serial FES monitors estrogen receptor blockade and posttreatment release. See related article by Iqbal et al., p. 2075., (©2023 American Association for Cancer Research.)
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- 2023
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12. Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor α Degraders to Overcome Endocrine-Resistant Breast Cancer In Vitro and In Vivo .
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Xie B, Yin Z, Hu Z, Lv J, Du C, Deng X, Huang Y, Li Q, Huang J, Liang K, Zhou HB, and Dong C
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- Humans, Animals, Mice, Female, Proteolysis Targeting Chimera, MCF-7 Cells, Estrogen Antagonists pharmacology, Estrogen Antagonists therapeutic use, Tamoxifen pharmacology, Tamoxifen therapeutic use, Receptors, Estrogen metabolism, Drug Resistance, Neoplasm, Cell Proliferation, Estrogen Receptor alpha metabolism, Breast Neoplasms drug therapy, Breast Neoplasms pathology
- Abstract
The estrogen receptor (ER) is a well-established target for endocrine therapies of ER-positive breast cancer (ER
+ BC), but endocrine resistance limits the efficacy of clinical drugs. Using proteolysis targeting chimera (PROTAC) technology to degrade ERα may be an effective alternative to endocrine therapies. Herein, we disclose a novel series of potent and selective ERα PROTACs based on an oxabicycloheptane sulfonamide (OBHSA) scaffold, with no associated ERβ degradation. These PROTACs showed significant antiproliferation and ERα degradation activities against a broad spectrum of ER+ BC cells including tamoxifen-resistant and ERα mutant cell lines. Genomics analysis confirmed that these PROTACs inhibited the nascent RNA synthesis of ERα target genes and impaired genome-wide ERα binding. Compound ZD12 exhibited excellent antitumor potency and ERα degradation activity in both tamoxifen-sensitive and -resistant BC mice models, which are superior to fulvestrant. This study demonstrates the potential of these PROTACs as novel drug candidates for endocrine-resistant BC treatment.- Published
- 2023
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13. Phase 1 study of oral selective estrogen receptor degrader (SERD) amcenestrant (SAR439859), in Japanese women with ER-positive and HER2-negative advanced breast cancer (AMEERA-2).
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Tamura K, Mukohara T, Yonemori K, Kawabata Y, Nicolas X, Tanaka T, and Iwata H
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- Female, Humans, East Asian People, Maximum Tolerated Dose, Receptors, Estrogen genetics, Genes, erbB-2 genetics, Administration, Oral, Selective Estrogen Receptor Modulators administration & dosage, Selective Estrogen Receptor Modulators pharmacokinetics, Selective Estrogen Receptor Modulators therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Estrogen Antagonists administration & dosage, Estrogen Antagonists pharmacokinetics, Estrogen Antagonists therapeutic use
- Abstract
Background: This AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer., Methods: In this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed., Results: No DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported., Conclusions: Amcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer., Trial Registration: Clinical trial registration NCT03816839., (© 2023. The Author(s).)
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- 2023
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14. Spontaneous Cerebrospinal Fluid Rhinorrhea in a Patient With Breast Cancer.
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Wang M and Ye H
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- Humans, Female, Middle Aged, Sphenoid Sinus diagnostic imaging, Sphenoid Sinus pathology, Tomography, X-Ray Computed, Cerebrospinal Fluid Rhinorrhea chemically induced, Cerebrospinal Fluid Rhinorrhea diagnosis, Cerebrospinal Fluid Rhinorrhea surgery, Breast Neoplasms drug therapy, Tamoxifen adverse effects, Tamoxifen therapeutic use, Estrogen Antagonists adverse effects, Estrogen Antagonists therapeutic use, Antineoplastic Agents, Hormonal adverse effects, Antineoplastic Agents, Hormonal therapeutic use, Bone Density drug effects
- Abstract
Despite the well documented increased risk of osteopenia in patients with breast cancer during chemotherapy and endocrine therapy, spontaneous cerebrospinal fluid rhinorrhea (CSFR) is still rare. The authors present a case of spontaneous CSFR that occurred during chemotherapy and endocrine therapy for breast cancer. The patient underwent a repair using myofascia and adipose tissue and was started on mannitol. There was no recurrence at 1-year follow-up. Therefore, clinicians should pay attention to the possibility of CSFR in patients with breast cancer, to avoid misdiagnosis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)
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- 2023
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15. A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer.
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Clusan L, Ferrière F, Flouriot G, and Pakdel F
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- Female, Humans, Drug Resistance, Neoplasm genetics, Estrogen Antagonists therapeutic use, Estrogens metabolism, Phosphatidylinositol 3-Kinases metabolism, Receptors, Estrogen metabolism, Signal Transduction, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology
- Abstract
Breast cancer is the most common cancer and the deadliest among women worldwide. Estrogen signaling is closely associated with hormone-dependent breast cancer (estrogen and progesterone receptor positive), which accounts for two-thirds of tumors. Hormone therapy using antiestrogens is the gold standard, but resistance to these treatments invariably occurs through various biological mechanisms, such as changes in estrogen receptor activity, mutations in the ESR1 gene, aberrant activation of the PI3K pathway or cell cycle dysregulations. All these factors have led to the development of new therapies, such as selective estrogen receptor degraders (SERDs), or combination therapies with cyclin-dependent kinases (CDK) 4/6 or PI3K inhibitors. Therefore, understanding the estrogen pathway is essential for the treatment and new drug development of hormone-dependent cancers. This mini-review summarizes current literature on the signalization, mechanisms of action and clinical implications of estrogen receptors in breast cancer.
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- 2023
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16. SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer.
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Lu Y, Sheng X, Liu C, Liang Z, Wang X, Liu L, Wen Z, Yang Z, Du Q, and Liu W
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- Animals, Female, Humans, Mice, Cell Line, Tumor, Estrogen Antagonists therapeutic use, Immunogenic Cell Death, Reactive Oxygen Species metabolism, Thioredoxin-Disulfide Reductase metabolism, Organometallic Compounds pharmacology, Gold chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism
- Abstract
The development of selective estrogen receptor degraders (SERDs) has brought new ideas for the clinical treatment of ER-positive advanced breast cancer. The successful application of combinational therapy inspired the exploration of other targets to prevent breast cancer progression. Thioredoxin reductase (TrxR) is an important enzyme that can regulate redox balance in cells and it was considered as a potential target for anticancer treatment. In this study, we firstly combine a clinical SERD candidate--G1T48 (NCT03455270), with a TrxR inhibitor--N-heterocyclic carbene gold(I) [NHC-Au(I)] to form dual targeting complexes that can regulate both signaling pathways. The most efficacious complex 23 exhibited significant antiproliferative profile through degrading ER and inhibiting TrxR activity. Interestingly, it can induce immunogenic cell death (ICD) caused by ROS. This is the first evidence to elucidate the role of ER/TrxR-ROS-ICD axis in ER positive breast cancer and this research may inspire new drug development with novel mechanisms. The in vivo xenograft study demonstrated that complex 23 had excellent antiproliferative activity toward MCF-7 cells in mice model., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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17. Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists.
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Scott JS, Stead D, Barlaam B, Breed J, Carbajo RJ, Chiarparin E, Cureton N, Davey PRJ, Fisher DI, Gangl ET, Grebe T, Greenwood RD, Hande S, Hatoum-Mokdad H, Hughes SJ, Hunt TA, Johnson T, Kavanagh SL, Klinowska TCM, Larner CJB, Lawson M, Lister AS, Longmire D, Marden S, McGuire TM, McMillan C, McMurray L, Morrow CJ, Nissink JWM, Moss TA, O'Donovan DH, Polanski R, Stokes S, Thakur K, Trueman D, Truman C, Tucker MJ, Wang H, Whalley N, Wu D, Wu Y, Yang B, and Yang W
- Subjects
- Mice, Humans, Animals, Female, Selective Estrogen Receptor Modulators pharmacology, Estrogen Antagonists therapeutic use, Estrogen Receptor alpha metabolism, Cell Line, Receptors, Estrogen metabolism, Breast Neoplasms drug therapy
- Abstract
Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38 . This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.
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- 2023
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18. ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid.
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Meligova AK, Siakouli D, Stasinopoulou S, Xenopoulou DS, Zoumpouli M, Ganou V, Gkotsi EF, Chatziioannou A, Papadodima O, Pilalis E, Alexis MN, and Mitsiou DJ
- Subjects
- Female, Humans, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Estrogen Antagonists therapeutic use, Estrogen Receptor alpha genetics, Estrogen Receptor Modulators therapeutic use, Fulvestrant therapeutic use, Neoplasm Recurrence, Local drug therapy, Protein Isoforms, Tamoxifen therapeutic use, Tretinoin therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Drug Resistance, Neoplasm genetics, Estrogen Receptor beta genetics, Estrogen Receptor beta metabolism
- Abstract
Adjuvant endocrine therapy (AET) is the treatment of choice for early-stage estrogen receptor alpha (ERα)-positive breast cancer (BC). However, almost 40% of tamoxifen-treated cases display no response or a partial response to AET, thus increasing the need for new treatment options and strong predictors of the therapeutic response of patients at high risk of relapse. In addition to ERα, BC research has focused on ERβ1 and ERβ2 (isoforms of ERβ), the second ER isotype. At present, the impact of ERβ isoforms on ERα-positive BC prognosis and treatment remains elusive. In the present study, we established clones of MCF7 cells constitutively expressing human ERβ1 or ERβ2 and investigated their role in the response of MCF7 cells to antiestrogens [4-hydroxytamoxifen (OHΤ) and fulvestrant (ICI182,780)] and retinoids [all-trans retinoic acid (ATRA)]. We show that, compared to MCF7 cells, MCF7-ERβ1 and MCF7-ERβ2 cells were sensitized and desensitized, respectively, to the antiproliferative effect of the antiestrogens, ATRA and their combination and to the cytocidal effect of the combination of OHT and ATRA. Analysis of the global transcriptional changes upon OHT-ATRA combinatorial treatment revealed uniquely regulated genes associated with anticancer effects in MCF7-ERβ1 cells and cancer-promoting effects in MCF7-ERβ2 cells. Our data are favorable to ERβ1 being a marker of responsiveness and ERβ2 being a marker of resistance of MCF7 cells to antiestrogens alone and in combination with ATRA.
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- 2023
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19. The oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with hormone receptor-positive HER2-negative (HR + /HER2 -) advanced/metastatic breast cancer.
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Bardia A, Mayer I, Winer E, Linden HM, Ma CX, Parker BA, Bellet M, Arteaga CL, Cheeti S, Gates M, Chang CW, Fredrickson J, Spoerke JM, Moore HM, Giltnane J, Friedman LS, Chow Maneval E, Chan I, and Jhaveri K
- Subjects
- Humans, Female, Receptors, Estrogen genetics, Receptor, ErbB-2 genetics, Ligands, Postmenopause, Estrogen Antagonists therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology
- Abstract
Purpose: GDC-0810 (ARN-810) is a novel, non-steroidal, orally bioavailable, selective estrogen receptor degrader (SERD) that potentially inhibits ligand-dependent and ligand-independent estrogen receptor (ER)-mediated signaling., Methods: A phase Ia/Ib/IIa dose escalation, combination treatment with palbociclib or a luteinizing hormone-releasing hormone, and expansion study determined the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of GDC-0810 in postmenopausal women with ER + (HER2 -) locally advanced or metastatic breast cancer (MBC). Baseline plasma ctDNA samples were analyzed to determine the ESR1 mutation status., Results: Patients (N = 152) received GDC-0810 100-800 mg once daily (QD) or 300-400 mg twice daily, in dose escalation, expansion, as single agent or combination treatment. Common adverse events regardless of attribution to study drug were diarrhea, nausea, fatigue, vomiting, and constipation. There was one dose-limiting toxicity during dose escalation. The maximum tolerated dose was not reached. GDC-0810 600 mg QD taken with food was the RP2D. Pharmacokinetics were predictable. FES reduction (> 90%) highlighting pharmacodynamic engagement of ER was observed. Outcomes for the overall population and for patients with tumors harboring ESR1 mutations included partial responses (4% overall; 4% ESR1), stable disease (39% overall; 42% ESR1), non-complete response/non-progressive disease (13% overall; 12% ESR1), progressive disease (40% overall; 38% ESR1), and missing/unevaluable (5% overall; 5% ESR1). Clinical benefit (responses or SD, lasting ≥ 24 weeks) was observed in patients in dose escalation (n = 16, 39%) and expansion (n = 24, 22%)., Conclusion: GDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs. Clinical Trial and registration date April 4, 2013. NCT01823835 ., (© 2022. The Author(s).)
- Published
- 2023
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20. 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.
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Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, Mouret-Reynier MA, Sohn JH, Taylor D, Harnden KK, Khong H, Kocsis J, Dalenc F, Dillon PM, Babu S, Waters S, Deleu I, García Sáenz JA, Bria E, Cazzaniga M, Lu J, Aftimos P, Cortés J, Liu S, Tonini G, Laurent D, Habboubi N, Conlan MG, and Bardia A
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclin-Dependent Kinase 4, Estrogen Antagonists therapeutic use, Female, Humans, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Tetrahydronaphthalenes, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms metabolism
- Abstract
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 ESR1 mutations., Results: Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 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; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .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 ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.
- Published
- 2022
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21. Genome engineering for estrogen receptor mutations reveals differential responses to anti-estrogens and new prognostic gene signatures for breast cancer.
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Harrod A, Lai CF, Goldsbrough I, Simmons GM, Oppermans N, Santos DB, Győrffy B, Allsopp RC, Toghill BJ, Balachandran K, Lawson M, Morrow CJ, Surakala M, Carnevalli LS, Zhang P, Guttery DS, Shaw JA, Coombes RC, Buluwela L, and Ali S
- Subjects
- Humans, Female, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Prognosis, Estrogen Antagonists therapeutic use, Mutation, Estrogens pharmacology, Receptors, Estrogen genetics, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms metabolism
- Abstract
Mutations in the estrogen receptor (ESR1) gene are common in ER-positive breast cancer patients who progress on endocrine therapies. Most mutations localise to just three residues at, or near, the C-terminal helix 12 of the hormone binding domain, at leucine-536, tyrosine-537 and aspartate-538. To investigate these mutations, we have used CRISPR-Cas9 mediated genome engineering to generate a comprehensive set of isogenic mutant breast cancer cell lines. Our results confirm that L536R, Y537C, Y537N, Y537S and D538G mutations confer estrogen-independent growth in breast cancer cells. Growth assays show mutation-specific reductions in sensitivities to drugs representing three classes of clinical anti-estrogens. These differential mutation- and drug-selectivity profiles have implications for treatment choices following clinical emergence of ER mutations. Our results further suggest that mutant expression levels may be determinants of the degree of resistance to some anti-estrogens. Differential gene expression analysis demonstrates up-regulation of estrogen-responsive genes, as expected, but also reveals that enrichment for interferon-regulated gene expression is a common feature of all mutations. Finally, a new gene signature developed from the gene expression profiles in ER mutant cells predicts clinical response in breast cancer patients with ER mutations., (© 2022. The Author(s).)
- Published
- 2022
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22. Accelerating drug development in breast cancer: New frontiers for ER inhibition.
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Ferraro E, Walsh EM, Tao JJ, Chandarlapaty S, and Jhaveri K
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- Aromatase Inhibitors pharmacology, Aromatase Inhibitors therapeutic use, Drug Development, Estrogen Antagonists therapeutic use, Female, Humans, Selective Estrogen Receptor Modulators therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Receptors, Estrogen metabolism
- Abstract
The estrogen receptor (ER) is an important driver in the proliferation, tumorigenesis, and progression of breast cancers, and targeting ER signaling at different levels is a successful strategy in the control of hormone receptor positive (HR+) breast cancer. Endocrine therapy has been the treatment of choice for HR+ breast cancer in the early and advanced stages with multiple agents, including selective estrogen receptor modulators (SERMS), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs), which vary in their mechanisms of action and pharmacokinetics. Combination strategies also employ cyclin dependent kinase 4 and 6 and phosphatidylinositol 3-kinase to maximize the benefits of endocrine therapy. This paper reviews the clinical development of SERDs and other novel ER inhibitors, as well as combination strategies to overcome mechanisms of ER pathway escape. It also assesses the advantages of newer oral ER inhibitors with increased bioavailability, improved therapeutic index, better administration, and increased efficacy, as well as discussing future directions in the field., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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23. Combinatorial targeting of a chromatin complex comprising Dot1L, menin and the tyrosine kinase BAZ1B reveals a new therapeutic vulnerability of endocrine therapy-resistant breast cancer.
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Salvati A, Melone V, Sellitto A, Rizzo F, Tarallo R, Nyman TA, Giurato G, Nassa G, and Weisz A
- Subjects
- Cell Line, Tumor, Cell Proliferation, Chromatin genetics, Drug Resistance, Neoplasm genetics, Estrogen Antagonists therapeutic use, Estrogen Receptor Modulators pharmacology, Estrogens, Female, Gene Expression Regulation, Neoplastic, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Histone-Lysine N-Methyltransferase pharmacology, Humans, MCF-7 Cells, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Protein-Tyrosine Kinases pharmacology, Transcription Factors, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Estrogen Receptor alpha metabolism
- Abstract
Background: Targeting vulnerabilities of cancer cells by inhibiting key regulators of cell proliferation or survival represents a promising way to overcome resistance to current therapies. In breast cancer (BC), resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor alpha (ERα) signaling to the genome. Targeting components of the ERα pathway in these tumors represents, therefore, a rational way toward effective new treatments. Interaction proteomics identified several proteins associated with ERα in BC cells, including epigenetic complexes controlling gene transcription comprising the scaffold protein menin and the histone methyltransferase Dot1L., Methods: We combined chromatin immunoprecipitation, transcriptome sequencing, siRNA-mediated gene knockdown (kd), pharmacological inhibition coupled to cellular and functional assays and interaction proteomics in antiestrogen (AE)-sensitive and AE-resistant human BC cell models to: map menin and Dot1L chromatin localization, search for their common and specific target genes, measure the effects of single or combinatorial knockdown or pharmacological inhibition of these proteins on cell proliferation and survival, and characterize their nuclear interactomes., Results: Dot1L and menin associate in MCF-7 cells chromatin, where they co-localize in a significant fraction of sites, resulting in co-regulation of genes involved, among others, in estrogen, p53, HIF1α and death receptor signaling, regulation of cell cycle and epithelial-to-mesenchymal transition. Specific inhibitors of the two factors synergize with each other for inhibition of cell proliferation of AE (tamoxifen or fulvestrant)-sensitive and AE-resistant BC cells. Menin and Dot1L interactomes share a sizeable fraction of their nuclear partners, the majority being known BC fitness genes. Interestingly, these include B-WICH and WINAC complexes that share BAZ1B, a bromodomain protein comprising a tyrosine-protein kinase domain playing a central role in chromatin remodeling and transcriptional regulation. BAZ1B kd caused significant inhibition of ERα expression, proliferation and transcriptome changes resulting in inhibition of estrogen, myc, mTOR, PI3K and AKT signaling and metabolic pathways in AE-sensitive and AE-resistant BC cells., Conclusions: Identification of a functional interplay between ERα, Dot1L, menin and BAZ1B and the significant effects of their co-inhibition on cell proliferation and survival in cell models of endocrine therapy-resistant BC reveal a new therapeutic vulnerability of these aggressive diseases., (© 2022. The Author(s).)
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- 2022
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24. AMEERA-1 phase 1/2 study of amcenestrant, SAR439859, in postmenopausal women with ER-positive/HER2-negative advanced breast cancer.
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Bardia A, Chandarlapaty S, Linden HM, Ulaner GA, Gosselin A, Cartot-Cotton S, Cohen P, Doroumian S, Paux G, Celanovic M, Pelekanou V, Ming JE, Ternès N, Bouaboula M, Lee JS, Bauchet AL, and Campone M
- Subjects
- Estrogen Antagonists therapeutic use, Female, Fulvestrant, Humans, Mutation, Postmenopause, Receptor, ErbB-2 genetics, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology
- Abstract
AMEERA-1 is a Phase 1/2 open-label single-arm study evaluating once-daily (QD) amcenestrant, an orally bioavailable selective estrogen receptor (ER) degrader, in postmenopausal women with ER+/HER2- advanced breast cancer (NCT03284957), who were mostly heavily pretreated (including targeted therapies and fulvestrant). In the dose escalation phase (Part A: n = 16), patients received amcenestrant 20-600 mg QD. Based on absence of dose-limiting toxicities, paired functional
18 F-fluoroestradiol positron emission tomography, and pharmacokinetics, 400 mg QD was selected as recommended Phase 2 dose (RP2D) for the dose expansion phase (Part B: n = 49). No Grade ≥3 treatment-related adverse events or clinically significant cardiac/eye toxicities were reported. The Part B primary endpoint, confirmed objective response rate (ORR) was 3/45 at the interim analysis and 5/46 (10.9%) at the final analysis. The overall clinical benefit rate (CBR) was 13/46 (28.3%). CBRs among patients with baseline wild-type and mutated ESR1 were 9/26 (34.6%) and 4/19 (21.1%), respectively. Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations, including Y537S. In conclusion, amcenestrant at RP2D of 400 mg QD for monotherapy is well-tolerated with no dose-limiting toxicities, and demonstrates preliminary antitumor activity irrespective of baseline ESR1 mutation status., (© 2022. The Author(s).)- Published
- 2022
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25. Latest generation estrogen receptor degraders for the treatment of hormone receptor-positive breast cancer.
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Chen YC, Yu J, Metcalfe C, De Bruyn T, Gelzleichter T, Malhi V, Perez-Moreno PD, and Wang X
- Subjects
- Estrogen Antagonists pharmacology, Estrogen Antagonists therapeutic use, Female, Fulvestrant pharmacokinetics, Fulvestrant therapeutic use, Humans, Quality of Life, Selective Estrogen Receptor Modulators adverse effects, Breast Neoplasms drug therapy, Receptors, Estrogen metabolism
- Abstract
Introduction: The selective estrogen receptor degrader (SERD) and full receptor antagonist provides an important therapeutic option for hormone receptor (HR)-positive breast cancer. Endocrine therapies include tamoxifen, a selective estrogen receptor modulator (SERM), that exhibits receptor agonist and antagonist activity, and aromatase inhibitors that block estrogen biosynthesis but which demonstrate acquired resistance. Fulvestrant, the only currently approved SERD, is limited by poor drug-like properties. A key focus for improving disease management has been development of oral SERDs with optimized target occupancy and potency and superior clinical efficacy., Areas Covered: Using PubMed, clinicaltrials.gov, and congress websites, this review explored the preclinical development and clinical pharmacokinetics from early phase clinical studies (2015 or later) of novel oral SERDs, including giredestrant, amcenestrant, camizestrant, elacestrant, and rintodestrant., Expert Opinion: Numerous oral SERDs are in clinical development, aiming to form the core endocrine therapy for HR-positive breast cancer. Through property- and structure-based drug design of estrogen receptor-binding, antagonism, degradation, anti-proliferation, and pharmacokinetic properties, these SERDs have distinct profiles which impact clinical dosing, efficacy, and safety. Assuming preliminary safety and activity data are confirmed in phase 3 trials, these promising agents could further improve the management, outcomes, and quality of life in HR-positive breast cancer.
- Published
- 2022
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26. Selective estrogen receptor degraders (SERDs) and covalent antagonists (SERCAs): a patent review (2015-present).
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Scott JS and Barlaam B
- Subjects
- Estrogen Antagonists therapeutic use, Estrogen Receptor alpha, Female, Humans, Patents as Topic, Selective Estrogen Receptor Modulators pharmacology, Selective Estrogen Receptor Modulators therapeutic use, Breast Neoplasms drug therapy, Receptors, Estrogen therapeutic use
- Abstract
Introduction: The estrogen receptor (ER) is a clinically validated oncology target with a pivotal role in hormonally driven breast cancer, the most prevalent form of female cancer. Current treatments that directly modulate ER include antagonists (SERMs), such as tamoxifen, and degraders (SERDs), such as fulvestrant which is administered by intramuscular injection., Areas Covered: This review covers patent applications that claim estrogen receptor degraders (SERDs) and covalent antagonists (SERCAs) between the period January 2015 to June 2021. A total of 114 patent applications from 23 different applicants are evaluated with stratification into acidic SERDs, basic SERDs, and SERCAs., Expert Opinion: The clinical success of fulvestrant in the treatment of ER
+ breast cancer has spurred research over the last decade into the discovery and development of novel SERDs, with a particular focus on the discovery of orally bioavailable drugs. This has resulted in a diverse range of candidates entering clinical trials. Although some have faltered in development, a cohort of oral SERDs has generated encouraging efficacy and safety data that has allowed advancement into late stage clinical trials. Data from these trials is eagerly awaited, with these molecules having the potential to offer significant benefits in the treatment of ER+ breast cancer.- Published
- 2022
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27. Preliminary results using a kit to measure tamoxifen and metabolites concentrations in capillary blood samples from women with breast cancer.
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Rehnmark S, Shabo I, Randahl H, Wengström Y, Rydberg P, and Hedayati E
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms drug therapy, Capillaries, Chromatography, High Pressure Liquid, Estrogen Antagonists therapeutic use, Feasibility Studies, Female, Humans, Mass Spectrometry, Middle Aged, Pilot Projects, Predictive Value of Tests, Reproducibility of Results, Sweden, Tamoxifen blood, Tamoxifen therapeutic use, Breast Neoplasms blood, Drug Monitoring instrumentation, Estrogen Antagonists blood, Reagent Kits, Diagnostic, Tamoxifen analogs & derivatives
- Abstract
The aim of the study was to compare 3 blood sampling methods, including capillary blood sampling, for determining Tamoxifen (TAM), Z-endoxifen (END), and 4-hydroxytamoxifen (4HT) concentrations. High performance liquid chromatography-mass spectrometry was used to quantify concentrations of TAM, END, and 4HT in plasma, venous blood, and capillary blood samples of 16 participants on TAM therapy for breast cancer. The rhelise kit was used for capillary sampling. Calibration curves using
13 C-labeled analogs of TAM, END, and 4HT as internal standards were used for quantifications. A capillary sampling kit was used successfully for all participants. Mean TAM concentrations did not differ significantly in the 3 types of samples. Mean END and 4HT concentrations did differ significantly between capillary and venous blood samples, possibly related to photodegradation in the internal standards prior to use or degradation products with chromatographic retention times similar to the metabolites. TAM, END, and 4HT concentrations were relatively stable when stored for 14 days at 8 °C and 20 °C. Therapeutic drug monitoring of TAM using an innovative kit and capillary blood sampling is feasible. Preliminary data from this study will aid in developing a multicenter, randomized clinical trial of personalized TAM dose monitoring and adjustments, with the goal of enhancing the quality-of-life and outcomes of patients with breast cancer.Clinical Trial Identification: EudraCT No 2017-000641-44., (© 2022. The Author(s).)- Published
- 2022
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28. High BRCA1 gene expression increases the risk of early distant metastasis in ER + breast cancers.
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Chang HJ, Yang UC, Lai MY, Chen CH, and Fann YC
- Subjects
- Breast Neoplasms drug therapy, Breast Neoplasms pathology, Cell Proliferation, Databases, Genetic, Estrogen Antagonists therapeutic use, Female, Gene Expression Regulation, Neoplastic, Humans, Neoplasm Metastasis, Prognosis, Tamoxifen therapeutic use, Time Factors, Up-Regulation, BRCA1 Protein genetics, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Receptors, Estrogen genetics
- Abstract
Although the function of the BRCA1 gene has been extensively studied, the relationship between BRCA1 gene expression and tumor aggressiveness remains controversial in sporadic breast cancers. Because the BRCA1 protein is known to regulate estrogen signaling, we selected microarray data of ER
+ breast cancers from the GEO public repository to resolve previous conflicting findings. The BRCA1 gene expression level in highly proliferative luminal B tumors was shown to be higher than that in luminal A tumors. Survival analysis using a cure model indicated that patients of early ER+ breast cancers with high BRCA1 expression developed rapid distant metastasis. In addition, the proliferation marker genes MKI67 and PCNA, which are characteristic of aggressive tumors, were also highly expressed in patients with high BRCA1 expression. The associations among high BRCA1 expression, high proliferation marker expression, and high risk of distant metastasis emerged in independent datasets, regardless of tamoxifen treatment. Tamoxifen therapy could improve the metastasis-free fraction of high BRCA1 expression patients. Our findings link BRCA1 expression with proliferation and possibly distant metastasis via the ER signaling pathway. We propose a testable hypothesis based on these consistent results and offer an interpretation for our reported associations., (© 2022. The Author(s).)- Published
- 2022
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29. Endoxifen, an Estrogen Receptor Targeted Therapy: From Bench to Bedside.
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Jayaraman S, Reid JM, Hawse JR, and Goetz MP
- Subjects
- Animals, Bone and Bones drug effects, Bone and Bones metabolism, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Proliferation drug effects, Estrogen Antagonists pharmacology, Estrogen Antagonists therapeutic use, Female, Humans, Molecular Targeted Therapy methods, Receptors, Estrogen drug effects, Selective Estrogen Receptor Modulators pharmacology, Selective Estrogen Receptor Modulators therapeutic use, Tamoxifen pharmacology, Tamoxifen therapeutic use, Receptors, Estrogen antagonists & inhibitors, Tamoxifen analogs & derivatives
- Abstract
The selective estrogen receptor (ER) modulator, tamoxifen, is the only endocrine agent with approvals for both the prevention and treatment of premenopausal and postmenopausal estrogen-receptor positive breast cancer as well as for the treatment of male breast cancer. Endoxifen, a secondary metabolite resulting from CYP2D6-dependent biotransformation of the primary tamoxifen metabolite, N-desmethyltamoxifen (NDT), is a more potent antiestrogen than either NDT or the parent drug, tamoxifen. However, endoxifen's antitumor effects may be related to additional molecular mechanisms of action, apart from its effects on ER. In phase 1/2 clinical studies, the efficacy of Z-endoxifen, the active isomer of endoxifen, was evaluated in patients with endocrine-refractory metastatic breast cancer as well as in patients with gynecologic, desmoid, and hormone-receptor positive solid tumors, and demonstrated substantial oral bioavailability and promising antitumor activity. Apart from its potent anticancer effects, Z-endoxifen appears to result in similar or even greater bone agonistic effects while resulting in little or no endometrial proliferative effects compared with tamoxifen. In this review, we summarize the preclinical and clinical studies evaluating endoxifen in the context of breast and other solid tumors, the potential benefits of endoxifen in bone, as well as its emerging role as an antimanic agent in bipolar disorder. In total, the summarized body of literature provides compelling arguments for the ongoing development of Z-endoxifen as a novel drug for multiple indications., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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30. The Inequality of Females in Bladder Cancer.
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Hyldgaard JM and Jensen JB
- Subjects
- Estrogen Antagonists therapeutic use, Estrogen Receptor alpha physiology, Glucuronosyltransferase physiology, Gonadal Steroid Hormones physiology, Health Status Disparities, Humans, Receptors, Estrogen physiology, Urinary Bladder Neoplasms drug therapy, ERRalpha Estrogen-Related Receptor, Urinary Bladder Neoplasms etiology
- Abstract
Urinary bladder cancer is worldwide one of the most diagnosed and costly types of cancer. One puzzle in the bladder cancer diagnosis is the disproportional relationship between genders. Males are more likely to be diagnosed with bladder cancer whereas females typically are diagnosed with more adverse disease and worse prognosis, which has led to speculation of the potential role of sex hormones and their receptors in this disease. Estrogen receptors are present in the human bladder, and their role in bladder cancer oncogenesis is increasingly becoming a focus for researchers around the world. This mini-review aims to give a brief overview of the status of female bladder cancer, and to which extend the sex hormones receptors play a role in this. A literature search was performed and included all female original studies on bladder cancer and hormone receptors. Estrogen-receptor alpha seems to be anti-oncogenic whereas estrogen-receptor beta is exhibiting its function pro-oncogenic. The receptor functions may be exercised through mRNA transcriptions and enzymes. Epidemiological studies indicate a potential increase in incidence of bladder cancer for females with earlier age at menopause, and clinical trials are investigating Tamoxifen as a potential treatment in bladder cancer. Increasing evidence supports the theory of bladder cancer development and progression as being partly hormone-dependent. This can lead to a change in conceptual background of bladder cancer etiology and development in the future. Further studies are required to more precise map the use of anti-hormonal drugs in the treatment of this cancer., (© 2021 Scandinavian Societies for Medical Microbiology and Pathology.)
- Published
- 2021
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31. Balanced dual acting compounds targeting aromatase and estrogen receptor α as an emerging therapeutic opportunity to counteract estrogen responsive breast cancer.
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Caciolla J, Martini S, Spinello A, Pavlin M, Turrini E, Simonelli F, Belluti F, Rampa A, Bisi A, Fimognari C, Zaffaroni N, Gobbi S, and Magistrato A
- Subjects
- Antineoplastic Agents, Hormonal pharmacology, Aromatase Inhibitors pharmacology, Estrogen Antagonists pharmacology, Female, Humans, Antineoplastic Agents, Hormonal therapeutic use, Aromatase Inhibitors therapeutic use, Breast Neoplasms drug therapy, Estrogen Antagonists therapeutic use
- Abstract
Breast Cancer (BC) is a leading cause of death in women, currently affecting 13% of female population worldwide. First-line clinical treatments against Estrogen Receptor positive (ER+) BC rely on suppressing estrogen production, by inhibiting the aromatase (AR) enzyme, or on blocking estrogen-dependent pro-oncogenic signaling, by targeting Estrogen Receptor (ER) α with selective Modulators/Degraders (SERMs/SERDs). The development of dual acting molecules targeting AR and ERα represents a tantalizing alternative strategy to fight ER + BC, reducing the incidence of adverse effects and resistance onset that limit the effectiveness of these gold-standard therapies. Here, in silico design, synthesis, biological evaluation and an atomic-level characterization of the binding and inhibition mechanism of twelve structurally related drug-candidates enable the discovery of multiple compounds active on both AR and ERα in the sub-μM range. The best drug-candidate 3a displayed a balanced low-nanomolar IC
50 towards the two targets, SERM activity and moderate selectivity towards a BC cell line. Moreover, most of the studied compounds reduced ERα levels, suggesting a potential SERD activity. This study dissects the key structural traits needed to obtain optimal dual acting drug-candidates, showing that multitarget compounds may be a viable therapeutic option to counteract ER + BC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)- Published
- 2021
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32. Progestin or anti-estrogen treatment for endometrial cancer: choosing the best option for selected patients.
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Caretto M and Simoncini T
- Subjects
- Aromatase Inhibitors therapeutic use, Female, Fertility Preservation, Humans, Neoplasm Metastasis drug therapy, Neoplasm Recurrence, Local drug therapy, Endometrial Neoplasms drug therapy, Estrogen Antagonists therapeutic use, Progestins therapeutic use
- Published
- 2021
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33. Men Converting from Clomiphene Citrate to Natesto with a Desire to Maintain Spermatogenesis Should Be Followed Closely.
- Author
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Kavoussi PK
- Subjects
- Adult, Clomiphene pharmacology, Clomiphene therapeutic use, Estrogen Antagonists pharmacology, Estrogen Antagonists therapeutic use, Follicle Stimulating Hormone blood, Hormone Replacement Therapy, Humans, Libido drug effects, Luteinizing Hormone blood, Male, Semen Analysis, Testosterone blood, Testosterone pharmacology, Testosterone therapeutic use, Infertility, Male drug therapy, Spermatogenesis drug effects, Testosterone deficiency
- Abstract
Objective: To report a case of a testosterone deficient man desiring maintenance of spermatogenesis converting from clomiphene citrate (CC) to Natesto, who had a decrease in gonadotropins and semen parameter values after making this medication change. The data on men maintaining gonadotropins and semen parameter values after converting from CC to Natesto is also reported., Methods: A retrospective chart review was performed. Baseline hormones prior to treatment, and again on CC and Natesto, as well as semen parameters on CC and on Natesto were assessed., Results: A 32-year-old testosterone deficient man desiring to maintain future fertility potential who had a poor symptomatic response to CC despite an adequate serum testosterone response was converted to Natesto 11 mg twice daily. His gonadotropins diminished as did his semen parameter values but with dose titration of Natesto to 11 mg in the morning and 5.5 mg in the evening he had normalization of gonadotropins and a rise in semen parameter values back towards his values on CC with a continued satisfactory symptomatic response. The remainder of the 49 men to date converting from CC to Natesto revealed stability in gonadotropins and semen parameter values., Conclusion: Testosterone deficient men interested in maintaining spermatogenesis who convert from CC to Natesto seeking a more robust symptomatic response should be followed closely with repeat serum gonadotropins and semen parameters to confirm that spermatogenesis is not being suppressed. Dose titration of Natesto may be effective at optimizing gonadotropins, semen parameter values, testosterone levels, and symptomatic response to treatment., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2021
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34. Novel promising reproductive and metabolic effects of Cicer arietinum L. extract on letrozole induced polycystic ovary syndrome in rat model.
- Author
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Ali SE, El Badawy SA, Elmosalamy SH, Emam SR, Azouz AA, Galal MK, Abd-Elsalam RM, Issa MY, and Hassan BB
- Subjects
- Animals, Aromatase Inhibitors toxicity, Cholesterol Side-Chain Cleavage Enzyme genetics, Cholesterol Side-Chain Cleavage Enzyme metabolism, Clomiphene therapeutic use, Dose-Response Relationship, Drug, Estrogen Antagonists therapeutic use, Female, Gene Expression Regulation, Enzymologic drug effects, Organ Size, Ovary pathology, Plant Extracts administration & dosage, Plant Extracts chemistry, Polycystic Ovary Syndrome chemically induced, Random Allocation, Rats, Cicer chemistry, Letrozole toxicity, Phytotherapy, Plant Extracts therapeutic use, Polycystic Ovary Syndrome drug therapy
- Abstract
Ethnopharmacological Relevance: Chickpea was used in both greek and indian traditional medicine for hormonal related conditions as menstrual induction, acceleration of parturation, treatment of retained placenta and stimulation of lactation. Chickpea (Cicer arietinum) sprout isoflavone isolates exhibited reasonable estrogenic activities. Isoflavones, a subtype of phytoestrogens, are plant derivatives with moderate estrogenic activity that tend to have protective effects on hormonal and metabolic abnormalities of women with polycystic ovary syndrome (PCOS)., Aim of the Study: In this study, we investigated the effect of UPLC/ESI-MS characterized Cicer arietinum L. seeds ethanol extract (CSE) on ovarian hormones, oxidative response and ovarian histological changes on induced PCOS rat model., Materials and Methods: Thirty-five rats were divided into five groups including negative control, PCOS, and treatment groups. PCOS was induced using letrozole (1 mg/kg) daily orally for 21 days. Each treatment group was treated with one of the following for 28 days after induction of PCOS: clomiphene citrate (1 mg/kg), and CSE at 250 and 500 mg/kg. Ovaries and uteri were excised, weighed and their sections were used for quantitative real-time reverse transcriptase polymerase chain reaction, antioxidant assays and histomorphometric study of the ovaries. The antioxidant assays, histopathological examination, hormonal and metabolic profiles, and Cyp11a1(steroidogenic enzyme) mRNA expression were measured., Results: In all treatment groups, ovarian weight was significantly decreased despite having no significant effect on uterine weight. Histomorphometric study in the treatment groups revealed a significant decrease in the number and diameter of cystic follicles, a significant increase in granulosa cell thickness while, thickness of theca cells was significantly decreased when compared to PCOS. Hormone levels, metabolic profile and antioxidant status were improved in the treatment groups. Moreover, Cyp11a1 mRNA expression was significantly downregulated in the treatment groups compared to PCOS., Conclusions: In the current study, CSE enhanced the reproductive and metabolic disorders which were associated with PCOS induction. For the first time, we have highlighted the effect of CSE in treating PCOS and its associated manifestations., (Copyright © 2021 Elsevier B.V. All rights reserved.)
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- 2021
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35. Impact of hormonal biomarkers on response to hormonal therapy in advanced and recurrent endometrial cancer.
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van Weelden WJ, Lalisang RI, Bulten J, Lindemann K, van Beekhuizen HJ, Trum H, Boll D, Werner HMJ, van Lonkhuijzen LRCW, Yigit R, Forsse D, Witteveen PO, Galaal K, van Ginkel A, Bignotti E, Weinberger V, Sweegers S, Kroep JR, Cabrera S, Snijders MPLM, Inda MA, Eriksson AGZ, Krakstad C, Romano A, van de Stolpe A, and Pijnenborg JMA
- Subjects
- Aged, Aged, 80 and over, Aromatase Inhibitors therapeutic use, Carcinoma, Endometrioid drug therapy, Carcinoma, Endometrioid genetics, Carcinoma, Endometrioid pathology, Endometrial Neoplasms drug therapy, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology, Estrogen Antagonists therapeutic use, Female, Gene Expression Regulation, Neoplastic genetics, Humans, Immunohistochemistry, Middle Aged, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Progestins therapeutic use, Progression-Free Survival, RNA, Messenger metabolism, Response Evaluation Criteria in Solid Tumors, Tamoxifen therapeutic use, Antineoplastic Agents, Hormonal therapeutic use, Biomarkers, Tumor metabolism, Carcinoma, Endometrioid metabolism, Endometrial Neoplasms metabolism, Estrogen Receptor alpha metabolism, Neoplasm Recurrence, Local metabolism, Receptors, Progesterone metabolism
- Abstract
Background: Approximately 20% of women with endometrial cancer have advanced-stage disease or suffer from a recurrence. For these women, prognosis is poor, and palliative treatment options include hormonal therapy and chemotherapy. Lack of predictive biomarkers and suboptimal use of existing markers for response to hormonal therapy have resulted in overall limited efficacy., Objective: This study aimed to improve the efficacy of hormonal therapy by relating immunohistochemical expression of estrogen and progesterone receptors and estrogen receptor pathway activity scores to response to hormonal therapy., Study Design: Patients with advanced or recurrent endometrial cancer and available biopsies taken before the start of hormonal therapy were identified in 16 centers within the European Network for Individualized Treatment in Endometrial Cancer and the Dutch Gynecologic Oncology Group. Tumor tissue was analyzed for estrogen and progesterone receptor expressions and estrogen receptor pathway activity using a quantitative polymerase chain reaction-based messenger RNA model to measure the activity of estrogen receptor-related target genes in tumor RNA. The primary endpoint was response rate defined as complete and partial response using the Response Evaluation Criteria in Solid Tumors. The secondary endpoints were clinical benefit rate and progression-free survival., Results: Pretreatment biopsies with sufficient endometrial cancer tissue and complete response evaluation were available in 81 of 105 eligible cases. Here, 22 of 81 patients (27.2%) with a response had estrogen and progesterone receptor expressions of >50%, resulting in a response rate of 32.3% (95% confidence interval, 20.9-43.7) for an estrogen receptor expression of >50% and 50.0% (95% confidence interval, 35.2-64.8) for a progesterone receptor expression of >50%. Clinical benefit rate was 56.9% for an estrogen receptor expression of >50% (95% confidence interval, 44.9-68.9) and 75.0% (95% confidence interval, 62.2-87.8) for a progesterone receptor expression of >50%. The application of the estrogen receptor pathway test to cases with a progesterone receptor expression of >50% resulted in a response rate of 57.6% (95% confidence interval, 42.1-73.1). After 2 years of follow-up, 34.3% of cases (95% confidence interval, 20-48) with a progesterone receptor expression of >50% and 35.8% of cases (95% confidence interval, 20-52) with an estrogen receptor pathway activity score of >15 had not progressed., Conclusion: The prediction of response to hormonal treatment in endometrial cancer improves substantially with a 50% cutoff level for progesterone receptor immunohistochemical expression and by applying a sequential test algorithm using progesterone receptor immunohistochemical expression and estrogen receptor pathway activity scores. However, results need to be validated in the prospective Prediction of Response to Hormonal Therapy in Advanced and Recurrent Endometrial Cancer (PROMOTE) study., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2021
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36. Network-based approach to identify prognosis-related genes in tamoxifen-treated patients with estrogen receptor-positive breast cancer.
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Wang Y, Gong X, and Zhang Y
- Subjects
- Biomarkers, Tumor metabolism, Breast Neoplasms metabolism, Breast Neoplasms mortality, Cell Line, Tumor, Databases, Genetic, Drug Resistance, Neoplasm genetics, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Poly(A)-Binding Proteins genetics, Poly(A)-Binding Proteins metabolism, Receptors, Estrogen metabolism, Signal Transduction, Transcriptome, Treatment Outcome, tau Proteins genetics, tau Proteins metabolism, Biomarkers, Tumor genetics, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Estrogen Antagonists therapeutic use, Gene Regulatory Networks, Receptors, Estrogen genetics, Tamoxifen therapeutic use
- Abstract
Tamoxifen is an estrogen receptor (ER) antagonist that is most commonly used for the treatment of ER-positive breast cancer. However, tamoxifen resistance remains a major cause of cancer recurrence and progression. Here, we aimed to identify hub genes implicated in the progression and prognosis of ER-positive breast cancer following tamoxifen treatment. Microarray data (GSE9893) for 155 tamoxifen-treated primary ER-positive breast cancer samples were obtained from the Gene Expression Omnibus database. In total, 1706 differentially expressed genes (DEGs), including 859 up-regulated and 847 down-regulated genes, were identified between relapse and relapse-free samples. Weighted correlation network analysis clustered genes into 13 modules, among which the tan and blue modules were the most significantly related to prognosis. From these two modules, we further identified and validated two prognosis-related hub genes (G-rich RNA sequence binding factor 1 (GRSF1) and microtubule-associated protein τ (MAPT)) via survival analysis based on several publicly available datasets. High expression of GRSF1 predicted poor prognosis, whereas MAPT indicated favorable outcomes in ER-positive breast cancer. Using breast cancer cell lines and tissue samples, we confirmed that GRSF1 was significantly up-regulated and MAPT was down-regulated in the tamoxifen-resistant group compared with the tamoxifen-sensitive group. The prognostic value of GRSF1 and MAPT was also verified in 48 tamoxifen-treated ER-positive breast cancer patients in our hospital. Gene set enrichment analysis (GSEA) suggested that GRSF1 was potentially involved in RNA degradation and cell cycle pathways, while MAPT was strongly linked to immune-related signaling pathways. Taken together, our findings established novel prognostic biomarkers to predict tamoxifen sensitivity, which may facilitate individualized management of breast cancer., (© 2021 The Author(s).)
- Published
- 2021
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37. Transcriptomic landscape of male and female reproductive cancers: Similar pathways and molecular signatures predicting response to endocrine therapy.
- Author
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Camargo AC, Remoli B, Portela LM, Fioretto MN, Chuffa LG, Moreno CS, and Justulin LA
- Subjects
- Androgen Antagonists pharmacology, Androgen Antagonists therapeutic use, Breast Neoplasms drug therapy, Databases, Genetic, Endometrial Neoplasms drug therapy, Estrogen Antagonists pharmacology, Estrogen Antagonists therapeutic use, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Neoplasms, Germ Cell and Embryonal drug therapy, Ovarian Neoplasms drug therapy, Prostatic Neoplasms drug therapy, Survival Analysis, Testicular Neoplasms drug therapy, Uterine Neoplasms drug therapy, Breast Neoplasms genetics, Computational Biology methods, Endometrial Neoplasms genetics, Gene Regulatory Networks drug effects, MicroRNAs genetics, Neoplasms, Germ Cell and Embryonal genetics, Ovarian Neoplasms genetics, Prostatic Neoplasms genetics, Testicular Neoplasms genetics, Uterine Neoplasms genetics
- Abstract
Reproductive cancers in both genders represent serious health problems, whose incidence has significantly risen over the past decades. Although considerable differences among reproductive cancers exist, we aimed to identify similar signaling pathways and key molecular oncomarkers shared among six human reproductive cancers that can advance the current knowledge of cancer biology to propose new strategies for more effective therapies. Using a computational analysis approach, here we uncover aberrant miRNAs-mRNAs networks shared in six reproductive tumor types, and identify common molecular mechanisms strictly associated with cancer promotion and aggressiveness. Based on the fact that estrogenic and androgenic signaling pathways were most active in prostate and breast cancers, we further demonstrated that both androgen and estrogen deprivation therapy are capable of regulating the expression of the same key molecular sensors associated with endoplasmic reticulum dysfunction and cell cycle in these cancers. Overall, our data reveal a potential mechanistic framework of cellular processes that are shared among reproductive cancers, and particularly, highlight the importance of hormonal deprivation in breast and prostate cancers and potentially new biomarkers of response to these therapeutic approaches., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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38. In vitro evaluation of estrogenic, antiestrogenic and antitumor effects of amentoflavone.
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Aliyev AT, Ozcan-Sezer S, Akdemir A, and Gurer-Orhan H
- Subjects
- Female, Humans, Antineoplastic Agents therapeutic use, Biflavonoids pharmacology, Biflavonoids therapeutic use, Breast Neoplasms drug therapy, Cell Line, Tumor drug effects, Estrogen Antagonists pharmacology, Estrogen Antagonists therapeutic use
- Abstract
Apigenin, a flavonoid, is reported to act as an estrogen receptor (ER) agonist and inhibit aromatase enzyme. However, amentoflavone, a biflavonoid bearing two apigenin molecules, has not been evaluated for its endocrine modulatory effects. Besides, it is highly consumed by young people to build muscles, enhance mood and lose weight. In the present study, apigenin was used as a reference molecule and ER mediated as well as ER-independent estrogenic/antiestrogenic activity of amentoflavone was investigated. Antitumor activity of amentoflavone was also investigated in both ER positive (MCF-7 BUS) and triple-negative (MDA-MB-231) breast cancer cells and its cytotoxicity was evaluated in human breast epithelial cells (MCF-10A). Our data confirmed ER agonist, aromatase inhibitory and cytotoxic effects of apigenin in breast cancer cells, where no ER mediated estrogenic effect and physiologically irrelevant, slight, aromatase inhibition was found for amentoflavone. Although selective cytotoxicity of amentoflavone was found in MCF-7 BUS cells, it does not seem to be an alternative to the present cytotoxic drugs. Therefore, neither an adverse effect, mediated by an estrogenic/antiestrogenic effect of amentoflavone nor a therapeutical benefit would be expected from amentoflavone. Further studies could be performed to investigate its in vivo effects.
- Published
- 2021
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39. Five-Year Adjuvant Endocrine Therapy Adherence Trajectories Among Women With Breast Cancer: A Nationwide French Study Using Administrative Data.
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Lailler G, Memoli V, Le Bihan Benjamin C, Ben Diane MK, Lauzier S, Mancini J, Bousquet PJ, and Bouhnik AD
- Subjects
- Adult, Age Factors, Aged, Cancer Survivors statistics & numerical data, Chemotherapy, Adjuvant, Cohort Studies, Female, France, Humans, Mastectomy, Middle Aged, Tamoxifen therapeutic use, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms psychology, Cancer Survivors psychology, Estrogen Antagonists therapeutic use, Medication Adherence statistics & numerical data
- Abstract
Background: Adjuvant endocrine therapy (AET) improves long-term survival of breast cancer patients, yet many women are nonadherent or discontinue this treatment. In this study we aimed to describe AET adherence trajectories over 5 years after treatment initiation and to identify factors associated with these trajectories, in a nationwide French cohort of breast cancer survivors., Patients and Methods: Every woman diagnosed with a first nonmetastatic breast cancer in 2011 in France who initiated AET in the 12 months after surgery was included from the French cancer cohort. We identified all reimbursements for AET from national health administrative data sets and modeled AET adherence trajectories over 5 years, using group-based trajectory modeling on the basis of the monthly proportion of days covered by AET. Associated factors were identified using multinomial logistic regressions., Results: We included 33,260 women. A 6-trajectory model was selected: 1, immediate discontinuation (6.6%); 2, continuous suboptimal adherence (4.3%); 3, progressive nonadherence then discontinuation (6.3%); 4, early nonadherence then discontinuation (5.7%); 5, continuous optimal adherence (68.8%); and 6, late nonadherence then discontinuation (8.3%). The main factors associated with nonadherence trajectories were extreme age (younger than 50 and older than 70 years) and switching AET., Conclusion: Approximately 70% of women had optimal adherence over all 5 years. The original nationwide approach enabled us to identify the "continuous suboptimal adherence trajectory" never previously described., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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40. Morphological and molecular changes following neoadjuvant endocrine therapy of oestrogen receptor-positive breast cancer: implications for clinical practice.
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Badr NM, Spooner D, Steven J, Stevens A, and Shaaban AM
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Hormonal, Breast Neoplasms genetics, Female, Humans, Middle Aged, Receptors, Estrogen antagonists & inhibitors, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Estrogen Antagonists therapeutic use, Neoadjuvant Therapy methods, Treatment Outcome
- Abstract
Aims: Neoadjuvant endocrine therapy (NAET) is used in the management of oestrogen receptor (ER)-positive breast cancer. The optimal method for histological assessment of response and the effect of NAET on the tumour morphology, grade and molecular profile remain unclear. The aim of this study is to investigate the NAET effect on tumour type, grade and molecular profile by analysing a well-characterised cohort of breast cancer samples in a single large UK tertiary referral centre, and to provide guidance on the pathological assessment of those lesions to inform adjuvant management and prognosis., Methods and Results: A single large-institution cohort of 132 patients who received NAET over a 13-year period was identified. Comprehensive clinical, histopathological and follow-up data were collected. A detailed histological review of a subset with residual post-treatment carcinoma was undertaken. Two carcinomas (both of the lobular type) achieved complete pathological response. Central scarring was seen in 49.3% of tumours post-treatment. Significant changes in tumour type (41.6%), tumour grade (downgrading in one-third of tumours), and progesterone receptor (PR) expression (22.3%), with a switch to PR-negative status in 17.6% of cases, were observed. The last of these was associated with an absence of tumour-infiltrating lymphocytes (P = 0.005). Ten per cent of cases showed a change in HER2 expression (P = 0.002). The median patient survival was 60 months, and downgrading of tumours was associated with better overall survival (P = 0.05)., Conclusions: We propose a histological method for assessment of residual carcinoma following NAET, and recommend repeat ER/PR/HER2 testing to inform management and prognosis., (© 2021 The Authors. Histopathology published by John Wiley & Sons Ltd.)
- Published
- 2021
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41. The nephroprotective effects and mechanisms of rehmapicrogenin include ROS inhibition via an oestrogen-like pathway both in vivo and in vitro.
- Author
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Wang M, Ke Y, Li Y, Shan Z, Mi W, Cao Y, Feng W, and Zheng X
- Subjects
- Acute Kidney Injury metabolism, Acute Kidney Injury pathology, Animals, Cell Line, Cytoprotection drug effects, Cytoprotection physiology, Drugs, Chinese Herbal pharmacology, Estrogen Antagonists pharmacology, Kidney drug effects, Kidney metabolism, Kidney pathology, Male, Mice, Mice, Inbred C57BL, Rats, Reactive Oxygen Species metabolism, Signal Transduction physiology, Acute Kidney Injury prevention & control, Drugs, Chinese Herbal therapeutic use, Estrogen Antagonists therapeutic use, Estrogens metabolism, Reactive Oxygen Species antagonists & inhibitors, Signal Transduction drug effects
- Abstract
Background: The root of Rehmannia glutinosa (R. glutinosa) is commonly used in various traditional Chinese herbal formulae to ameliorate nephropathy; however, little is known about its active component(s) and mechanisms., Aim: In the present study, we examined the protective effect and potential mechanism of rehmapicrogenin, a monomeric compound extracted from R. glutinosa, against Adriamycin (ADR)-induced nephropathy (AN) in vivo and in vitro., Methods: In this study, an ADR-induced kidney injury model was employed to investigate the nephroprotective effects of rehmapicrogenin in mice. In vivo, ELISA kits, flow cytometry, haematoxylin-eosin staining, immunofluorescence techniques, and western blotting were used to evaluate the effect of rehmapicrogenin on kidney injury in mice. In vitro, the effects of rehmapicrogenin on NRK-52E cellular damage induced by ADR were determined using the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The mechanism was investigated using ELISA kits, flow cytometry and In-Cell Western™ blotting., Results: In vivo, rehmapicrogenin treatment significantly attenuated the pathological changes in the kidney induced by ADR; rescued weight, serum creatinine (Scr), blood urea nitrogen (BUN) and urine albumin (U-ALB) levels; reduced reactive oxygen species (ROS) accumulation; and decreased oxidative stress, the apoptosis rate, and cell survival in ADR-treated mice. Importantly, both in vivo and in vitro experimental results demonstrated that rehmapicrogenin regulates the Nrf2/ARE signalling pathway, the most important pathway for oxidative stress. Rehmapicrogenin attenuated ADR-induced kidney damage by reducing oxidative stress through the oestrogen receptor pathway. Moreover, after treatment with ICI 182780 (the oestrogen receptor-nonspecific antagonist Faslodex), the improvement induced by rehmapicrogenin was significantly reversed., Conclusions: In conclusion, rehmapicrogenin attenuates kidney damage by reducing inflammatory factor release through the oestrogen signalling pathway., (Copyright © 2021. Published by Elsevier Masson SAS.)
- Published
- 2021
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42. Evaluation of the effect of trans-vaginal ovarian needle punctures on women with polycystic ovary syndrome.
- Author
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Atwa KA, Farrag MM, El-Sayed MM, Taha OT, and Elprince M
- Subjects
- Adult, Aromatase Inhibitors administration & dosage, Clomiphene therapeutic use, Drug Administration Schedule, Drug Resistance, Estrogen Antagonists therapeutic use, Female, Follicle Stimulating Hormone administration & dosage, Humans, Infertility, Female blood, Infertility, Female drug therapy, Letrozole administration & dosage, Luteinizing Hormone blood, Ovarian Follicle, Polycystic Ovary Syndrome blood, Polycystic Ovary Syndrome drug therapy, Pregnancy, Pregnancy Rate, Testosterone blood, Ultrasonography, Interventional, Vagina, Young Adult, Infertility, Female therapy, Ovary surgery, Ovulation Induction methods, Polycystic Ovary Syndrome therapy, Punctures methods
- Abstract
Objective: Evaluation of the effectiveness of ultrasound-guided trans-vaginal ovarian needle punctures on improving the management of women with polycystic ovary syndrome resistant to clomiphene citrate., Methods: This was a randomized clinical trial conducted in a tertiary Hospital, from June 2016 to December 2018. We recruited twenty- seven women with resistant PCOS with either primary or secondary infertility. They were randomly assigned into two groups. Group one included patients who had a trial of induction using aromatase inhibitors (Letrozol 2.5 mg twice daily from day 2 of the cycle and for 5 days) and FSH administered with 75 IU daily from cycle day 3 and maintained for up to the 14th day of the cycle. Group two included patients who had transvaginal ovarian puncture prior to induction with AIs and gonadotropins. Folliculometery was done starting from day 9 of the cycle. When the follicle reaches a size of 18-25 mm, HCG was given to enhance ovulation., Results: There was a significant improvement in the hormonal profile (serum LH, FSH, and testosterone with a p- value of 0.0001, 0.007, and 0.0001 respectively) in the study group after one month of treatment. The overall number of ovulatory cycles was significantly higher in the study group than the control group [84 % (62/74), 62.8 % (49/78), p- value 0.006 respectively]. The cumulative pregnancy rates were significantly higher in the study group [33.3 % (9/27)]. No complications related to the procedure were reported., Conclusion: transvaginal ovarian needle puncture is a safe and effective procedure., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
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43. Bispecific Estrogen Receptor α Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening.
- Author
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Disch JS, Duffy JM, Lee ECY, Gikunju D, Chan B, Levin B, Monteiro MI, Talcott SA, Lau AC, Zhou F, Kozhushnyan A, Westlund NE, Mullins PB, Yu Y, von Rechenberg M, Zhang J, Arnautova YA, Liu Y, Zhang Y, McRiner AJ, Keefe AD, Kohlmann A, Clark MA, Cuozzo JW, Huguet C, and Arora S
- Subjects
- Animals, Breast Neoplasms drug therapy, Cell Line, Tumor, Cell Survival drug effects, Click Chemistry, DNA metabolism, Estrogen Antagonists chemistry, Estrogen Antagonists metabolism, Estrogen Antagonists pharmacology, Estrogen Antagonists therapeutic use, Estrogen Receptor alpha chemistry, Estrogen Receptor alpha genetics, Female, Half-Life, Humans, Indoles chemistry, Indoles metabolism, Kinetics, Mice, Small Molecule Libraries metabolism, Small Molecule Libraries pharmacology, Small Molecule Libraries therapeutic use, Structure-Activity Relationship, Xenograft Model Antitumor Assays, DNA chemistry, Estrogen Receptor alpha metabolism, Small Molecule Libraries chemistry
- Abstract
Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.
- Published
- 2021
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44. Lead optimization of 4-(thio)-chromenone 6- O -sulfamate analogs using QSAR, molecular docking and DFT - a combined approach as steroidal sulfatase inhibitors.
- Author
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R S and Mk K
- Subjects
- Breast Neoplasms drug therapy, Breast Neoplasms enzymology, Enzyme Inhibitors therapeutic use, Estrogen Antagonists therapeutic use, Estrogens metabolism, Female, Humans, Hydrogen Bonding drug effects, Molecular Docking Simulation, Steryl-Sulfatase antagonists & inhibitors, Steryl-Sulfatase chemistry, Steryl-Sulfatase genetics, Enzyme Inhibitors chemistry, Estrogen Antagonists chemistry, Quantitative Structure-Activity Relationship, Steryl-Sulfatase ultrastructure
- Abstract
Aromatase and steroidal sulfatase (STS) are steroidogenic enzyme that increases the concentration of estrogens in circulation, a primary factor leading to breast cancer. At molecular level, 87% of STS is expressed and an inhibitor targeting STS could decrease the level of estrogens. In an attempt to identify the chemical structural requirement targeting placental STS inhibition, 26 compounds with pIC
50 ranging from 4.61 to 9.46 were subjected to computational studies including Quantitative Structural-Activity Relationship (QSAR), MolecularDocking followed by Density Functional Theory (DFT) studies. A robust and predictable model were developed with good R2 (0.834) and cross-validated correlation coefficient value Q2 LOO (0.786) explaining the relationship quantitatively. The regression graphs suggests that the STS inhibition was greatly dependent on the electro topological state of an atom, sum of the atom type E-state (SdssC), maximum E-states for strong hydrogen bond acceptors (maxHBa) and basic group count descriptor (BCUTp-1h). Furthermore, docking results showed favorable interactions of sulfamate analogs with catalytically important amino acid residues such as LEU74, VAL101, and VAL486. The interactions of the best active compound 3j when compared with standard Irosustat show similar binding energies. DFT studies further confirm the presence of HOMO orbital centered on chromenone ring further highlighting its importance for receptor ligand hydrophobic interaction. The study reveals that substitution of thio in chromenone nucleus and introduction of adamantyl substitution at second position are favorable in inhibiting the enzyme STS.- Published
- 2021
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45. The diagnosis and treatment of hereditary angioedema patients in Japan: A patient reported outcome survey.
- Author
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Iwamoto K, Yamamoto B, Ohsawa I, Honda D, Horiuchi T, Tanaka A, Fukunaga A, Maehara J, Yamashita K, Akita T, and Hide M
- Subjects
- Adolescent, Adult, Aged, Angioedemas, Hereditary prevention & control, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Antifibrinolytic Agents therapeutic use, Child, Child, Preschool, Complement C1 Inhibitor Protein therapeutic use, Complement Inactivating Agents therapeutic use, Danazol therapeutic use, Estrogen Antagonists therapeutic use, Female, Hospitalization, Humans, Japan, Male, Middle Aged, Patient Reported Outcome Measures, Steroids therapeutic use, Surveys and Questionnaires, Tranexamic Acid therapeutic use, Treatment Outcome, Young Adult, Angioedemas, Hereditary diagnosis, Angioedemas, Hereditary drug therapy
- Abstract
Background: The rate at which patients are accurately diagnosed with hereditary angioedema (HAE), as well as diagnosed patients access to modern treatments differs greatly among countries. Moreover, the severity and burden of HAE on patients have been reported mostly on the basis of physician-reported surveys. To gain insight into the real-world conditions of patients with HAE through a patient-reported survey in Japan and identify any unmet needs., Methods: A questionnaire was distributed to 121 patients with HAE via a Japanese HAE patient organization during 2016-2017. Responses were collected from 70 patients (57.9%) and subjected to analysis., Results: The average periods from the initial appearance of symptoms (e.g. edema) to a HAE diagnosis was 15.6 years (min-max, 0-53). Patients visited an average of 4.6 different departments until receiving a definitive diagnosis. The average age at the first visit was 25.6 years (3-73) and at diagnosis 32.8 years (0-73). Patients reported an average of 15.7 (0-100) attacks per year, but only 53.1% of attacks were treated. The days of hospitalization due to severe attacks was 14.3 (0-200) before diagnosis, but these declined to 4.3 (0-50) after diagnosis. In the treatment for attacks, 82% of the patients were treated with the plasma-derived C1 inhibitor concentrate, and 69% of the patients reported experiencing a therapeutic effect., Conclusions: There is a long gap between first attack and diagnosis of HAE, and the number of non-treated attacks is high in Japan. Steps are needed to improve the diagnostic and treatment environments to address these issues., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)
- Published
- 2021
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46. Raloxifene has favorable effects on the lipid profile in women explaining its beneficial effect on cardiovascular risk: A meta-analysis of randomized controlled trials.
- Author
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Yang F, Li N, Gaman MA, and Wang N
- Subjects
- Cardiovascular Diseases blood, Cardiovascular Diseases metabolism, Cardiovascular Diseases prevention & control, Dyslipidemias blood, Dyslipidemias complications, Dyslipidemias metabolism, Estrogen Antagonists pharmacology, Heart Disease Risk Factors, Humans, Protective Factors, Raloxifene Hydrochloride pharmacology, Randomized Controlled Trials as Topic, Cardiovascular Diseases etiology, Dyslipidemias drug therapy, Estrogen Antagonists therapeutic use, Lipid Metabolism drug effects, Lipids blood, Raloxifene Hydrochloride therapeutic use
- Abstract
There is robust evidence that the appropriate treatment of dyslipidaemia substantially reduces cardiovascular disease-related morbidity and mortality. Raloxifene is a selective oestrogen receptor modulator that also interferes with the lipid metabolism and may be of aid in the management of lipid abnormalities in females. Therefore, we conducted a systematic review and meta-analysis of the available randomized clinical trials (RCTs) exploring the effect of raloxifene on the lipid profile in women. The Scopus, Web of Science, PubMed/Medline and EMBASE databases were systematically and independently searched by two assessors from inception until 20 November 2020 without time and language restrictions. The overall findings were generated from 30 eligible RCTs. As compared to controls, raloxifene resulted in a significant elevation of the high-density lipoprotein-cholesterol (HDL-C) (WMD: 2.41 mg/dL, 95% CI: 0.84-3.97, P = 0.003) and a significant reduction of the total cholesterol (TC) (WMD:-14.84 mg/dL, 95% CI: -20.37 to -9.317, P = 0.000) and of the low-density lipoprotein-cholesterol (LDL-C) (WMD: -17 mg/dL, 95% CI: -25.77, -8.22, P = 0.000). In the stratified analysis, a significant decrease of serum triglycerides (TG) (WMD: -22.06 mg/dL) was achieved in the RCTs with a duration of ≤ 26 weeks (WMD -8.70 mg/dL) and with baseline TG concentrations of ≥ 130 mg/dL (WMD: -23.02 mg/dL). In conclusion, raloxifene treatment can increase HDL-C and lower LDL-C and TC. In terms of TG, a significant decrease can be observed if the administration of raloxifene lasts ≤ 26 weeks and if the baseline TG concentrations are ≥ 130 mg/dL., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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47. Raloxifene as a treatment option for viral infections.
- Author
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Hong S, Chang J, Jeong K, and Lee W
- Subjects
- Estrogen Antagonists therapeutic use, Estrogens agonists, Humans, Molecular Docking Simulation, Osteoporosis, Postmenopausal drug therapy, Selective Estrogen Receptor Modulators therapeutic use, Antiviral Agents therapeutic use, Drug Repositioning, Raloxifene Hydrochloride therapeutic use, SARS-CoV-2 drug effects, COVID-19 Drug Treatment
- Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused corona virus disease 2019 (COVID-19) pandemic and led to mass casualty. Even though much effort has been put into development of vaccine and treatment methods to combat COVID-19, no safe and efficient cure has been discovered. Drug repurposing or drug repositioning which is a process of investigating pre-existing drug candidates for novel applications outside their original medical indication can speed up the drug development process. Raloxifene is a selective estrogen receptor modulator (SERM) that has been approved by FDA in 1997 for treatment and prevention of postmenopausal osteoporosis and cancer. Recently, raloxifene demonstrates efficacy in treating viral infections by Ebola, influenza A, and hepatitis C viruses and shows potential for drug repurposing for the treatment of SARS-CoV-2 infection. This review will provide an overview of raloxifene's mechanism of action as a SERM and present proposed mechanisms of action in treatment of viral infections.
- Published
- 2021
- Full Text
- View/download PDF
48. Negative estrogen receptors and positive progesterone receptors breast cancers.
- Author
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Delvallée J, Etienne C, Arbion F, Vildé A, Body G, and Ouldamer L
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms mortality, Breast Neoplasms pathology, Breast Neoplasms therapy, Carcinoma, Intraductal, Noninfiltrating pathology, Chemotherapy, Adjuvant, Estrogen Antagonists therapeutic use, Female, Humans, Lymphatic Metastasis, Middle Aged, Neoplasm Invasiveness, Prognosis, Receptor, ErbB-2 metabolism, Retrospective Studies, Young Adult, Breast Neoplasms metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism
- Abstract
Context: Hormone receptors (estrogen receptor ER and progesterone receptor PR) are prognostic and predictive factors of outcome for invasive breast cancer. Some tumors only express one of these hormone receptors (ER or PR). ER negative/PR positive breast cancer is a rare subtype (1-4 %) and its existence still controversial. The aim of this study was to evaluate characteristics of this group of tumors., Methods: We collected data of all consecutive patients managed in our institution for invasive breast cancer between the 1st January 2007 and 31 December 2013. The aim of the study was to compare data of patients with ER-/PR+tumors with the three other subgroups., Results: Of the 2071 patients included during the study period, 1.2 % were ER-/PR+. These patients were younger than those with the two ER+groups (p<0.0001). The ER-/PR+tumors differed from the ER+groups for several histological prognostic factors: greater histological size (p=0.0004), higher histological grade, more HER2 overexpression/amplification, more association with ductal carcinoma in situ, more lymphovascular invasion, more nodal metastasis (p<0.0001). Chemotherapy was more often used as an adjuvant treatment in addition of endocrine therapy. Survival was equivalent for patients with ER-/PR+tumors and ER+tumors and significantly higher than patients with ER-/PR- tumors (p<0.0001)., Conclusion: Women with ER-/PR+breast cancer have worse prognostic factors than women with ER+cancers but have better overall survival than women with ER-/PR- tumors. We may think that the more frequent association of chemotherapy and endocrine therapy is responsible for this better outcome., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
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- 2021
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49. Converting Men From Clomiphene Citrate to Natesto for Hypogonadism Improves Libido, Maintains Semen Parameters, and Reduces Estradiol.
- Author
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Kavoussi PK, Machen GL, Gilkey MS, Chen SH, Kavoussi KM, Esqueda A, Wininger JD, Barsky M, and Kavoussi SK
- Subjects
- Adult, Estradiol blood, Follicle Stimulating Hormone blood, Humans, Hypogonadism blood, Luteinizing Hormone blood, Male, Reference Values, Retrospective Studies, Sperm Count, Sperm Motility, Testosterone blood, Clomiphene therapeutic use, Drug Substitution, Estrogen Antagonists therapeutic use, Hypogonadism drug therapy, Libido drug effects, Semen drug effects, Testosterone therapeutic use
- Abstract
Objective: To evaluate outcomes including libido, semen parameters, testosterone, estradiol (E2), follicle stimulating hormone (FSH), and luteinizing hormone when converting men with low libido on Clomiphene Citrate (CC) to Natesto., Methods: A retrospective chart review was performed. Baseline hormones prior to treatment, and again on CC and Natesto, as well as semen parameters on CC and on Natesto were assessed., Results: In 41 men, there was no difference in serum testosterone levels on CC vs Natesto, however; there was a significantly higher E2 on CC than on Natesto. Although FSH levels were significantly lower on Natesto than at baseline, the mean FSH level on Natesto remained in the normal reference range. There was no difference in luteinizing hormone levels at baseline vs on Natesto. There was not a significant difference in semen parameter values when men were on CC vs when they were on Natesto for 3 months. At 3 months after changing to Natesto, 38 of 41 (92.7%) men reported significantly improved libido on Natesto when compared to CC., Conclusion: Men on CC and Natesto reach eugonadal testosterone levels, however; on CC the E2 level nearly doubled from baseline, and converting men from CC to Natesto returned E2 to nearly baseline levels. There was not a detrimental effect on semen parameters, and there was subjective reporting of improved libido after converting from CC to Natesto in this cohort, but further long-term studies are needed prior to Natesto being established as a definitive treatment for hypogonadism for men desiring to maintain fertility., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
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50. A Closer Look at Estrogen Receptor Mutations in Breast Cancer and Their Implications for Estrogen and Antiestrogen Responses.
- Author
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Clusan L, Le Goff P, Flouriot G, and Pakdel F
- Subjects
- Animals, Antineoplastic Agents, Hormonal pharmacology, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Disease Management, Disease Susceptibility, Estrogen Antagonists pharmacology, Estrogen Antagonists therapeutic use, Estrogen Receptor alpha antagonists & inhibitors, Estrogen Receptor alpha chemistry, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Estrogens pharmacology, Estrogens therapeutic use, Female, Humans, Molecular Targeted Therapy, Mutation, Missense, Receptors, Estrogen antagonists & inhibitors, Receptors, Estrogen chemistry, Receptors, Estrogen metabolism, Silent Mutation, Structure-Activity Relationship, Biomarkers, Tumor, Breast Neoplasms etiology, Breast Neoplasms metabolism, Mutation, Receptors, Estrogen genetics
- Abstract
Breast cancer (BC) is the most common cancer among women worldwide. More than 70% of BC cases express estrogen receptor alpha (ERα), a central transcription factor that stimulates the proliferation of breast cancer cells, usually in the presence of estrogen. While most cases of ER-positive BC initially respond to antiestrogen therapies, a high percentage of cases develop resistance to treatment over time. The recent discovery of mutated forms of ERα that result in constitutively active forms of the receptor in the metastatic-resistance stage of BC has provided a strong rationale for the development of new antiestrogens. These molecules targeting clinically relevant ERα mutants and a combination with other pharmacological inhibitors of specific pathways may constitute alternative treatments to improve clinical practice in the fight against metastatic-resistant ER-positive BC. In this review, we summarize the latest advances regarding the particular involvement of point mutations of ERα in endocrine resistance. We also discuss the involvement of synonymous ERα mutations with respect to co-translational folding of the receptor and ribosome biogenesis in breast carcinogenesis.
- Published
- 2021
- Full Text
- View/download PDF
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