Selective Estrogen Receptor Modulators Research Articles

Mechanistic Insights and Therapeutic Strategies in Osteoporosis: A Comprehensive Review

Osteoporosis, a metabolic bone disorder characterized by decreased bone mass per unit volume, poses a significant global health burden due to its association with heightened fracture risk and adverse impacts on patients’ quality of life. This review synthesizes the current understanding of the pathophysiological mechanisms underlying osteoporosis, with a focus on key regulatory pathways governing osteoblast and osteoclast activities. These pathways include RANK/RANKL/OPG, Wingless-int (Wnt)/β-catenin, and Jagged1/Notch1 signaling, alongside the involvement of parathyroid hormone (PTH) signaling, cytokine networks, and kynurenine in bone remodeling. Pharmacotherapeutic interventions targeting these pathways play a pivotal role in osteoporosis management. Anti-resorptive agents, such as bisphosphonates, estrogen replacement therapy/hormone replacement therapy (ERT/HRT), selective estrogen receptor modulators (SERMs), calcitonin, anti-RANKL antibodies, and cathepsin K inhibitors, aim to mitigate bone resorption. Conversely, anabolic agents, including PTH and anti-sclerostin drugs, stimulate bone formation. In addition to pharmacotherapy, nutritional supplementation with calcium, vitamin D, and vitamin K2 holds promise for osteoporosis prevention. However, despite the availability of therapeutic options, a substantial proportion of osteoporotic patients remain untreated, highlighting the need for improved clinical management strategies. This comprehensive review aims to provide clinicians and researchers with a mechanistic understanding of osteoporosis pathogenesis and the therapeutic mechanisms of existing medications. By elucidating these insights, this review seeks to inform evidence-based decision-making and optimize therapeutic outcomes for patients with osteoporosis.

Current treatment for male infertility: an umbrella review of systematic reviews and meta-analyses.

This umbrella review aimed to summarize and provide a general evaluation of the effectiveness of current treatments for male infertility and assess the quality of evidence and possible biases. An umbrella review of systematic reviews and meta-analyses available in PubMed, Web of Science, and Scopus, covering studies published up to October 2023, was conducted. Sperm concentration, morphology, and motility were used as endpoints to evaluate the effectiveness of the treatments. Of 2998 studies, 18 published meta-analyses were extracted, yielding 90 summary effects on sperm concentration (n = 36), sperm morphology (n = 26), and sperm motility (n = 28) on 28 interventions. None of the meta-analyses were classified as having low methodological quality, whereas 12 (66.7%) and 6 (33.3%) had high and moderate quality, respectively. Of the 90 summary effects, none were rated high-evidence quality, whereas 53.3% (n = 48), 25.6% (n = 23), and 21.1% (n = 19) were rated moderate, low, and very low, respectively. Significant improvements in sperm concentration, morphology, and motility were observed with pharmacological interventions (N-acetyl-cysteine, antioxidant therapy, aromatase inhibitors, selective estrogen receptor modulators, hormones, supplements, and alpha-lipoic acid) and nonpharmacological interventions (varicocele repair and redo varicocelectomy). In addition, vitamin supplementation had no significant positive effects on sperm concentration, motility, or morphology. Treatments for male infertility are increasingly diverse; however, the current evidence is poor because of the limited number of patients. Further well-designed studies on single treatment and high-quality meta-analysis of intertreatment comparisons are recommended.

PSYCHOTIC DISORDER INDUCED BY CLOMIPHENE CITRATE IN A MAN: A RARE CASE REPORT

The clomiphene citrate is one of the selective estrogen receptor modulators and its function is to indirectly induce ovulation, stimulating the secretion of pituitary gonadotropins (follicle-stimulating hormone (FSH) and luteinizing hormone (LH)), subsequently increasing testosterone circulation levels. Its main adverse effects include increased ovarian volume, vasomotor symptoms, pelvic discomfort, and hepatic dysfunction. However, some reactions to this medication may be unknown or poorly reported in the scientific literature. Hormonal effects may be responsible for the unfavorable psychotic outcomes in conjunction with the antiestrogenic activity of clomiphene. The appearance of psychotic symptoms, especially in women with a pre-existing psychiatric history, has been previously studied [1,4]. The effects were attributed to an enhanced testosterone-androgen receptor interaction in the brain, subsequently leading to alteration of emotional conditions. Proposed neurobiological targets include catecholaminergic cells in the hypothalamus and other limbic regions of the brain.). Nevertheless, the occurrence of such symptoms has not been reported in the literature in males. This letter aims to report the case of a 36-year-old male patient who presented an adverse reaction that is not clear in the literature on Clomiphene Citrate, since the majority of reported cases are in the female population with some previous psychiatric comorbidity. The patient had a previous diagnosis of fibromyalgia. Approximately 20 days after the introduction of the medication, he presented his first psychotic episode with manifest characteristics, with increased energy, hypersexualization, low need for sleep, grandiose delusions, impulsive and inappropriate behavior lasting an average of 4 days. The patient's family reported that he had never exhibited similar behavior. The second psychotic episode occurred approximately 20 days after the first. In the latter, the patient presented with persecutory delusions, risky behavior, paranoid behavior, risk of self- and hetero-aggression, and was taken to his first psychiatric hospitalization. It was reported that he used clomiphene citrate up to 15 days before psychiatric hospitalization. The use of other psychoactive substances was also ruled out (a toxicological test with a negative result) and admission and neuroimaging exams (magnetic resonance imaging of the skull) were carried out, with all results within normal limits. The patient was admitted to our service being introduced to valproic acid 1000mg/day, risperidone 2mg/day, quetiapine 100mg/day and gabapentin 900mg/day (already being used to treat chronic pain) and clomiphene was suspended. He presented rapid remission of delusions in two days with criticism present in the first week of hospitalization. Due to the absence of psychiatric history, as well as other possible causes for the appearance of symptoms, the psychotic condition described was therefore attributed to the use of clomiphene. Thus, the possibility of this medication inducing the appearance of symptoms should be considered, especially in patients experiencing their first psychotic episode [2,3].

27-Hydroxycholesterol acts on estrogen receptor α expressed by POMC neurons in the arcuate nucleus to modulate feeding behavior.

Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of POMCARH neurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMCARH neurons by inhibiting the small conductance of the calcium-activated potassium (SK) channel. Together, our findings suggest that 27HC, through its interaction with ERα and modulation of the SK channel, inhibits food intake as a negative feedback mechanism against a surge in circulating cholesterol.

Nongenomic ERα-AMPK Signaling Regulates Sex-Dependent Bcrp Transport Activity at the Blood-Brain Barrier.

The blood-brain barrier (BBB) is an extensive capillary network that protects the brain from environmental and metabolic toxins while limiting drug delivery to the central nervous system (CNS). The ATP-binding cassette transporter breast cancer resistance protein (Bcrp) reduces drug delivery across the BBB by actively transporting its clinical substrates back into peripheral circulation before their entry into the CNS compartment. 17β-Estradiol (E2)-elicited changes in Bcrp transport activity and expression have been documented previously. We report a novel signaling mechanism by which E2 decreases Bcrp transport activity in mouse brain capillaries via rapid nongenomic signaling through estrogen receptor α. We extended this finding to investigate the effects of different endocrine-disrupting compounds (EDCs) and selective estrogen receptor modulators (SERMs) on Bcrp transport function. We also demonstrate sex-dependent expression of Bcrp and E2-sensitive Bcrp transport activity at the BBB ex vivo. This work establishes an explanted tissue-based model by which to interrogate EDCs and SERMs as modulators of nongenomic estrogenic signaling with implications for sex and hormonal regulation of therapeutic delivery into the CNS.

Comparing the effects of low-level laser therapy and gaseous ozone as a preventive measure on medication-related osteonecrosis of the jaws following tooth extraction: a rat model

ObjectivesUse of numerous medications such as tyrosine kinase inhibitors (sunitinib), monoclonal antibodies (bevacizumab), fusion proteins (aflibercept), mTOR inhibitors (everolimus), radiopharmaceuticals (radium 223), selective estrogen receptor modulators (raloxifene), and immunosuppressants (methotrexate and corticosteroids) has been reported to be a risk factor for development of medication-related osteonecrosis of the jaws till date. This study aimed to evaluate the preventive effect of low-level laser therapy (LLLT) and gaseous ozone on the onset of MRONJ following tooth extraction.Materials and methodsA total of 40 male Wistar rats were randomly allocated into 4 groups of 10 rats each. The groups laser (L), ozone (O), and control (C) received weekly intraperitoneal injections of zoledronic acid (0.06 mg/kg), while group sham (S) received saline solution for 4 weeks. After the 4th injection, all subjects underwent mandibular first molar extraction and adjunctive laser or ozone was applied according to the groups. All the rats were sacrificed at 4 postoperative weeks for comparative histomorphometric evaluation of bone healing in extraction sites.ResultsLaser and ozone groups demonstrated significantly higher bone formation compared to control group (p < 0.05), while no significant difference was found between laser and ozone groups (p = 1.00). Furthermore, the greatest bone formation was observed with the sham group (p < 0.05).ConclusionsFindings of the current study support that adjunctive LLLT and ozone therapy following tooth extraction may help prevent MRONJ and improve bone healing in subjects under zoledronic acid therapy.Clinical relevanceSince the introduction in 2003, great effort has been devoted to developing a certain management protocol for MRONJ. Several publications have appeared in recent years documenting promising results of adjunctive LLLT and ozone application in treatment of MRONJ. However, experimental data are limited on this regard and the present study, for the first time, aimed to evaluate and compare the effects of LLLT and ozone in prevention of MRONJ.

Affinity for Estrogen Receptor α (ERα) in a &lt;i&gt;trans&lt;/i&gt;-Stilbene Derivative Containing a Pyridoxine Fragment

Molecular targets for a promising antitumor agent based on trans-stilbene containing a pyridoxine fragment were identified. The lead compound, (E)-6-(3,4-dimethoxystyryl)-2,2,5,8-tetramethyl-4H-[1,3] dioxino[4,5-c]pyridine, was found to selectively induce apoptosis in MCF-7 breast adenocarcinoma cells overexpressing estrogen receptor, but not in MDA-MB-231 cells negative for estrogen receptor. The mechanism by which the novel trans-stilbene derivative acts as a selective estrogen receptor modulator was analyzed, and the affinity for human estrogen receptor α (ERα) was assessed by fluorescence polarization. Unlike its structural analogs—tamoxifen and raloxifene, the lead compound showed no affinity for ERα and did not form complexes with it. Therefore, it was concluded that the selective action of the pyridoxine-containing derivative of trans-stilbene on estrogen-positive breast cancer cells occurs through an alternative mechanism. The EC 50 values for the displacement of the fluorescent ligand from the ERα active site were 22, 120, and 595 nM for estradiol, raloxifene, and tamoxifen, respectively.

A review of endocrine therapy for hormone-dependent breast cancer

Purpose of the study: to provide current data on pharmacotherapy of hormone-dependent breast cancer (hdBC) and to consider the feasibility of introducing new hormone therapy drugs for breast cancer into clinical practice. Material and Methods. We analyzed 80 publications available Pubmed, Springer, Cochrane Library, etc. concerning the study of pharmacological characteristics of various groups of drugs for the treatment of hdBC, of which 49 were included in this review. Results. Currently, there are several approaches to the treatment of hdBC. Selective estrogen receptor modulators and aromatase inhibitors are the most studied and frequently used drugs. The cyclin-dependent kinase 4/6 inhibitors can be present in both the first- and second-line therapy. Currently, close attention is paid to the development of new drugs based on genomic profiling of the tumor, which is the standard of treatment for hdBC, and contributes to the personalization of therapy. Conclusion. Further development of drugs holds great promise for increasing overall survival and more accurate prognosis, response to conventional systemic therapy, and individualization of pharmacotherapy for hdBC. However, further research and development of new drugs is required. In this regard, the introduction of oral selective estrogen receptor degraders into practice and the development of new drugs that block estrogen-dependent and independent signaling to estrogen receptors are the most promising trends.

P-367 Letrozole or Tamoxifen co-administration during fertility preservation of breast cancer patients: a retrospective cohort study

Abstract Study question How do fertility preservation (FP) outcomes differ between breast cancer patients stimulated with FSH and Tamoxifen versus FSH and Letrozole? Summary answer Letrozole and Tamoxifen co-administration yielded similar number of retrieved and cryopreserved oocytes/embryos, as well as similar oocyte maturation and fertilization and rates. What is known already Oocyte/embryo cryopreservation is recommended before initiation of chemotherapy in cancer patients. The co-administration of Tamoxifen, a selective estrogen receptor modulator, or Letrozole, an aromatase inhibitor, during ovarian stimulation with gonadotropins, are used to limit the potentially harmful effects of a supra-physiological rise in estrogen levels on hormone-sensitive cancers. However, the optimal choice between the two is still unclear and with no sound evidence. Study design, size, duration Retrospective cohort study of all FP treatments of newly diagnosed breast cancer patients in two tertiary centers between 2000-2022. Collected data included 354 FP cycles of 290 patients and compared treatment parameters and outcomes of Tamoxifen or Letrozole co-administration. Participants/materials, setting, methods Breast cancer patients who underwent FP before chemotherapy were included. Patients with a history of radiation or gonadotoxic treatment, as well as those undergoing other fertility preservation treatments, such as ovarian tissue cryopreservation were excluded. Main results and the role of chance Overall, 215 Letrozole and 139 Tamoxifen treatment cycles were compared, with no significant demographic differences. Treatments with Letrozole had higher FSH dosages (3970IU vs. 2839IU, p &amp;lt; 0.001) but shorter duration (9.7 vs. 10.5 days, p &amp;lt; 0.001). The Letrozole group achieved lower peak E2 levels and endometrial thickness (1508pmol/L, 8.1mm vs. 8760pmol/L, 9.5mm, p &amp;lt; 0.001). The mean number of retrieved oocytes was comparable between the groups (13.6 with Letrozole vs 14.7 with Tamoxifen, p = 0.06). In 122 Letrozole and 46 Tamoxifen patients that underwent strictly oocytes cryopreservation the mean number of cryopreserved oocytes was comparable (11 vs. 12.1, p = 0.21). Moreover, in embryo cryopreservation cycles of 71 patients treated with Letrozole compared to 76 patients with Tamoxifen, no difference was observed in the number of cryopreserved embryos (6.2 vs. 7.0, p = 0.12). Oocyte maturation rate among strictly oocyte preservation cycles was comparable (86% with Letrozole vs. 83% with Tamoxifen, p = 0.80), as were fertilization rates in embryo cryopreservation cycles (62% vs. 63%, p = 0.8 and 71% vs. 76%, p = 0.3 in IVF and ICSI with Letrozole and Tamoxifen, respectively). Multivariate analysis, controlling for potential confounders showed no significant correlations between Tamoxifen or Letrozole co-administration and the number of retrieved oocytes or oocyte maturation rate. Limitations, reasons for caution The primary limitation of our study is its retrospective design and the variation in treatment duration and gonadotrophin dosages among groups. Wider implications of the findings This study provides reassurance that both Tamoxifen and Letrozole are equally effective options when co-administered in FP treatments of breast cancer patients. Trial registration number not applicable

The anti-aromatase and anti-estrogenic activity of plant products in the treatment of estrogen receptor-positive breast cancer

Despite being the focal point of decades of research, female breast cancer (BC) continues to be one of the most lethal cancers in the world. Given that 80% of all diagnosed BC cases are estrogen receptor-positive (ER+) with carcinogenesis driven by estrogen-ERα signalling, current standard of care (SOC) hormone therapies are geared towards modulating the function and expression levels of estrogen and its receptors, ERα and ERβ. Currently, aromatase inhibitors (AIs), selective ER modulators (SERMs) and selective ER degraders (SERDs) are clinically prescribed for the management and treatment of ER+ BC, with the anti-aromatase activity of AIs abrogating estrogen biosynthesis, while the anti-estrogenic SERMs and SERDs antagonise and degrade the ER, respectively. The use of SOC hormone therapies is, however, significantly hampered by the onset of severe side-effects and the development of resistance. Given that numerous studies have reported on the beneficial effects of plant compounds and/or extracts and the multiple pathways through which they target ER+ breast carcinogenesis, recent research has focused on the use of dietary chemopreventive agents for BC management. When combined with SOC treatments, several of these plant components and/or extracts have demonstrated improved efficacy and/or synergistic impact. Moreover, despite a lack of in vivo investigations, plant products are generally reported to have a lower side-effect profile than SOC therapies and are therefore thought to be a safer therapeutic choice. Thus, the current review summarizes the findings from the last five years regarding the anti-aromatase and anti-estrogenic activity of plant products, as well as their synergistic anti-ER+ BC effects in combination with SOC therapies.

Fibroblast Stromal Support Model for Predicting Human Papillomavirus-Associated Cancer Drug Responses.

Human papillomavirus-related cancers (HPV + cancers) remain a significant public health concern, and specific clinical approaches are desperately needed. In translating drug response data from in vitro to in vivo , the fibroblasts of the adjacent stromal support network play a key role. Our study presents the utilization of a fibroblast 2D co-culture system to better predict translational drug assessments for HPV + cancers. We also suggest that this co-culture system should be considered for other translational approaches. Predicting even a portion of treatment paradigms that may fail in vivo with a co-culture model will yield significant time, effort, resource, and cost efficiencies.

Different dosage forms of GnRHa with endocrine therapy in premenopausal hormone Receptor-Positive breast cancer.

Despite the wide use of a three-month gonadotropin-releasing hormone agonist (3M GnRHa) for ovarian function suppression (OFS) in premenopausal breast cancer patients, it remains unclear whether it is as effective and safe as a one-month GnRHa regimen (1M GnRHa) when combined with selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs), especially in younger patients. This retrospective cohort study included 1109 premenopausal hormone receptor-positive (HR+) breast cancer patients treated with GnRHa plus SERM or AI. The estradiol (E2) inhibition rate within 1-24 months after treatment with 1M or 3M GnRHa in cohorts and different subgroups was analyzed. Following 1:1 propensity score matching, 950 patients with a mean age of 39 years and a median follow-up of 46 months were included. Both the 1M and 3M groups achieved >90% E2 inhibition within 24 months (94.53% vs 92.84%, 95% CI (-4.78%, 1.41%)), confirming the non-inferiority of 3M GnRHa. Both 1M and 3M GnRHa rapidly and consistently reduced E2 levels. 60 (6.3%) patients experienced incomplete ovarian function suppression (iOFS), with similar rates in the 1M and 3M groups (5.5% vs 7.2%). iOFS mainly occurred within the first 12 months, with age <40 years and no prior chemotherapy being the risk factors. Similar disease-free survival (DFS) and overall survival (OS) were found in the 1M and 3M groups, and in patients with complete and incomplete OFS (p > .05). The OFS with 3M GnRHa was not inferior to that with 1M GnRHa, regardless of age or combination with a SERM or an AI.

Cardiac Dysfunction Among Breast Cancer Survivors: Role of Cardiotoxic Therapy and Cardiovascular Risk Factors.

Cardiac dysfunction is the leading cause of mortality among 10-year breast cancer survivors. Limited information regarding long-term risks of cardiac dysfunction after cardiotoxic therapy (anthracyclines, trastuzumab/pertuzumab, radiation) has precluded development of surveillance guidelines for the survivors. Patients with breast cancer who completed cardiotoxic therapy underwent echocardiographic screening every 2 years. New-onset cardiac dysfunction was defined as left ventricular ejection fraction (LVEF) <50% after cardiotoxic therapy initiation and included early- and late-onset cardiac dysfunction. We evaluated 2,808 echocardiograms in 829 breast cancer survivors; the median age at breast cancer diagnosis was 54.2 years (range, 20.3-86.3); the median follow-up was 8.6 years (1.8-39.8); 39.7% received anthracyclines, 16% received trastuzumab/pertuzumab, 6.2% received both anthracyclines and trastuzumab/pertuzumab, and 38.1% received radiation alone. The cumulative incidence of cardiac dysfunction increased from 1.8% at 2 years to 15.3% at 15 years from cardiotoxic therapy initiation. Multivariable Cox regression analysis identified the following risk factors: non-Hispanic Black race (hazard ratio [HR], 2.15 [95% CI], 1.37 to 3.38), cardiotoxic therapies (anthracyclines: HR, 2.35 [95% CI, 1.25 to 4.4]; anthracyclines and trastuzumab/pertuzumab: HR, 3.92 [95% CI, 1.74 to 8.85]; reference: left breast radiation alone), selective estrogen receptor modulators (HR, 2.0 [95% CI, 1.2 to 3.33]), and precancer hypertension (HR, 3.16 [95% CI, 1.63 to 6.1]). Late-onset cardiac dysfunction was most prevalent among anthracycline- and radiation-exposed patients; early-onset cardiac dysfunction was most prevalent among patients exposed to anthracyclines and trastuzumab/pertuzumab; equal prevalence of both early- and late-onset cardiac dysfunction was observed in trastuzumab-/pertuzumab-exposed patients. Adjusted longitudinal analyses revealed an annual decline in LVEF by 0.29% (P = .009) over 20 years from breast cancer diagnosis. These findings provide evidence to support echocardiographic surveillance for several years after cardiotoxic therapy and also suggest a need to examine the efficacy of management of cardiovascular risk factors to mitigate risk.

Emerging drugs in breast cancer: a focus on antibody–drug conjugates and novel treatment options in luminal disease

SummaryRecent years have seen the introduction of several new drugs and novel treatment approaches in early and advanced-stage breast cancer, leading to relevant improvements in outcome. Still, further reduction of recurrence risk in high-risk early breast cancer is required as is further improvement of disease control in metastatic disease, preferentially with parallel improvement of tolerability. Several antibody–drug conjugates are currently under clinical development, among them drugs targeting HER2, HER3 and TROP2; in addition, bispecific HER2-directed antibodies are a promising class of drugs. In hormone receptor-positive disease, optimizing treatment options in patients progressing on prior CDK4/6-inhibitor-based therapies is a focus of clinical research and recent developments encompass small molecule growth-factor pathway inhibitors such as the AKT inhibitor capivasertib, novel PIK3Ca inhibitors such as inavolisib as well as selective oestrogen receptor degraders and modulators. This article is intended as a short review of promising novel drugs in later clinical development in the field of breast cancer.

Next generation selective estrogen receptor degraders in postmenopausal women with advanced-stage hormone receptors-positive, HER2-negative breast cancer.

Breast cancer is the most prevalent malignancy in women, and is characterized by its heterogeneity; exhibiting various subgroups identifiable through molecular biomarkers that also serve as predictive indicators. More than two thirds of breast tumors are classified as luminal with positive hormone receptors (HR), indicating that cancer cells proliferation is promoted by hormones. Endocrine therapies play a vital role in the effective treatment of breast cancer by manipulating the signaling of estrogen receptors (ER), leading to a reduction in cell proliferation and growth rate. Selective estrogen receptor modulators (SERMs), such as tamoxifen and toremifene, function by blocking estrogen's effects. Aromatase inhibitors (AI), including anastrozole, letrozole and exemestane, suppress estrogen production. On the other hand, selective estrogen receptor degraders (SERDs), like fulvestrant, act by blocking and damaging estrogen receptors. Tamoxifen and AI are widely used both in early- and advanced-stage disease, while fulvestrant is used as a single agent or in combination with other agents like the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, abemaciclib, ribociclib) or alpelisib for advanced-stage disease. Currently, SERDs are recognized as an effective therapeutic approach for the treatment of ER-positive breast cancer, showing proficiency in reducing and blocking ER signaling. This review aims to outline the ongoing development of novel oral SERDs from a practical therapeutic perspective, enhancing our understanding of the mechanisms of action underlying these compounds.

Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough.

In females, Alzheimer's disease (AD) incidences increases as compared to males due to estrogen deficiency after menopause. Estrogen therapy is the mainstay therapy for menopause and associated complications. Estrogen, a hormone with multifaceted physiological functions, has been implicated in AD pathophysiology. Estrogen plays a crucial role in amyloid precursor protein (APP) processing and overall neuronal health by regulating various factors such as brain-derived neurotrophic factor (BDNF), intracellular calcium signalling, death domain-associated protein (Daxx) translocation, glutamatergic excitotoxicity, Voltage-Dependent Anion Channel, Insulin-Like Growth Factor 1 Receptor, estrogen-metabolising enzymes and apolipoprotein E (ApoE) protein polymorphisms. All these factors impact the physiology of postmenopausal women. Estrogen replacement therapies play an important treatment strategy to prevent AD after menopause. However, use of these therapies may lead to increased risks of breast cancer, venous thromboembolism and cardiovascular disease. Various therapeutic approaches have been used to mitigate the effects of estrogen on AD. These include hormone replacement therapy, Selective Estrogen Receptor Modulators (SERMs), Estrogen Receptor Beta (ERβ)-Selective Agonists, Transdermal Estrogen Delivery, Localised Estrogen Delivery, Combination Therapies, Estrogen Metabolism Modulation and Alternative Estrogenic Compounds like genistein from soy, a notable phytoestrogen from plant sources. However, mechanism via which these approaches modulate AD in postmenopausal women has not been explained earlier thoroughly. Present review will enlighten all the molecular mechanisms of estrogen and estrogen replacement therapies in AD. Along-with this, the association between estrogen, estrogen-metabolising enzymes and ApoE protein polymorphisms will also be discussed in postmenopausal AD.

Abstract PO2-17-03: Patient reported outcomes (PROs) and survival with toremifene versus aromatase inhibitors (AI) in patients with moderate/high-risk premenopausal hormone receptor (HR)-positive breast cancer: A real-world study

Abstract Background: The selective estrogen receptor modulator (SERM) toremifene, a synthetic analogue of tamoxifen, has shown similar efficacy to tamoxifen in patients with HR-positive breast cancer and is widely used in China for the treatment of premenopausal women with breast cancer. Multiple studies have confirmed the benefit of ovarian function suppression (OFS) combined with AI and SERMs in premenopausal women with HR-positive breast cancer. However, to date, there are no data comparing the efficacy and safety of toremifene plus OFS versus AI plus OFS. In this real-world study, we compared PROs and survival with toremifene or AI combined with OFS in patients with moderate/high-risk premenopausal HR-positive breast cancer. Methods: We enrolled premenopausal female patients with HR-positive, moderate/high-risk breast cancer who received OFS combined with toremifene or AI between January 1, 2010 and December 31, 2017 at the Breast Cancer Center of Sun Yat-sen Memorial Hospital. The primary endpoint was PROs, which were collected from January 1 to March 31, 2023, including the SF-36 and five-level EuroQol five-dimensional (EQ-5D-5L) questionnaires. Disease-free-survival (DFS) and safety were secondary endpoints. Associations between treatment group and SF-36 scores were evaluated using a Student’s t test and between treatment group and EQ-5D-5L scores using nonparametric tests. DFS was assessed using the Kaplan–Meier method and Cox regression. Results: A total of 392 patients were enrolled; 171 (43.6%) received toremifene and 221 (56.4%) received AI. Mean ± standard deviation scores for the role physical and general health dimensions of SF-36 were higher in the toremifene group versus the AI group (7.44±1.21 vs 7.15±1.48, P=0.034 and 22.90±3.95 vs 21.78±4.33, P=0.009, respectively). Scores on the anxiety/depression (AD) dimension of EQ-5D-5L were significantly different between the toremifene and AI treatment groups (mean rank: 184.14 vs 206.07, P=0.038); ‘no problems’ was selected by 49.7% and 37.1% of patients in the toremifene and AI groups, respectively. There were no significant differences in the other dimensions of SF-36 and EQ-5D-5L between the toremifene and AI groups (P&amp;gt;0.05). Similar estimated 5- and 8-year DFS rates were reported for the toremifene and AI groups; 96.5% (95% CI: 93.7-99.2) and 91.9% (95% CI: 88.2-95.5), and 87.4% (95% CI: 81.1-93.8) and 87.8% (95% CI: 81.1-94.4), respectively, and the hazard ratio for DFS was 0.75 (95% CI: 0.38-1.46), P=0.39. DFS was also comparable in the two treatment groups when stratified by HER2 status, age (≤40y vs &amp;gt;40y) and estrogen receptor expression level (≤20% vs &amp;gt;20%). Adverse event rates were generally similar in the two treatment groups, except for a higher rate of endometrial thickening (17.5% vs 1.8%, p&amp;lt; 0.001) and a lower rate of morning stiffness (7.6% vs 14.5%, p&amp;lt; 0.001) in the toremifene versus the AI group. Conclusion: Patients who received toremifene plus OFS had better role physical and general health dimensions on SF-36 and AD dimensions of EQ-5D-5L than those receiving AI plus OFS. There were no significant differences in 5- or 8-year DFS between the toremifene and AI groups. Both treatments were generally well tolerated. Citation Format: Yaping Yang, Fengxia Gan, Wenqian Yang, Yuan Xia, Qiang Liu, Chang Gong. Patient reported outcomes (PROs) and survival with toremifene versus aromatase inhibitors (AI) in patients with moderate/high-risk premenopausal hormone receptor (HR)-positive breast cancer: A real-world study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-17-03.

Abstract PO3-27-09: A Multidisciplinary Telehealth Approach to Breast Cancer Prevention in a Veteran Population

Abstract INTRODUCTION An estimated 13% of women will be diagnosed with breast cancer at some point in their lifetime. There are non-modifiable and modifiable risk factors including family history, genetics, obesity, and estrogen exposure. Interventions that reduce breast cancer risk and/or mortality include screening, chemoprevention, and lifestyle modification. A recent national survey shows that there are significant gaps in providing breast cancer prevention care for female Veterans. We describe the creation of a multi-disciplinary telehealth clinic aimed at reducing breast cancer risk in a high-risk female Veteran population. METHODS The breast cancer prevention clinic (BCPC) team consists of a medical oncologist, geneticist, genetic counselor, dietician, psychologist, and nurse navigator. High risk women are identified through a combination of screening questionnaires at annual mammography and genetics or primary care provider (PCP) evaluation, then referred to the clinic. Criteria for referral include age &amp;gt;=35, Gail 5 year risk &amp;gt;= 1.7%, Tyrer-Cuzick 10 year risk &amp;gt;= 5%, or history of thoracic radiation. At the BCPC telehealth visit, the medical oncologist makes individualized recommendations about chemoprevention by discussing the risks and possible complications of therapy. Use of screening magnetic resonance imaging (MRI) is also recommended to women with lifetime Tyrer-Cuzick score &amp;gt; 20%. Within the same visit, patients meet with a dietician to discuss nutrition modification, and a psychologist to address psychosocial barriers to lifestyle change. Those who start chemoprevention attend a 3 month follow-up with a nurse navigator to discuss tolerability and side effects. Subsequently, the patient’s PCP becomes responsible for management of chemoprevention and annual breast MRI. RESULTS Between January and December 2022, 33 patients were seen in BCPC. Patients had an average age of 52 years (range 42-70), Gail 5-year score of 2.53%, Tyrer-Cuzick 10-year score of 6.65%, and Tyrer-Cuzick lifetime score of 21.5%. Thirteen patients (39.4%) started chemoprevention, the majority of which were selective estrogen receptor modulators (SERM). Nine reported starting the medication at the 3 month follow-up appointment. The most reported side effect was hot flashes in 67%, although only the majority had mild symptoms. Three reported weight gain and one reported vaginal dryness. None reported worsening arthralgia or fatigue. Despite the low incidence of severe symptoms, only 3 continued to fill the medication at the time of chart review in August 2023. Twenty (60.6%) patients did not initiate chemoprevention. Four (20%) did not qualify due to cardiovascular or thrombotic risk factors, and three (15%) did not qualify due to concurrent use of hormone replacement therapy. Two (10%) elected not to start chemoprevention because they were planning for risk reducing mastectomies. Eleven (55%) did not initiate chemoprevention due to patient preferences and concern for side effects. Twenty-eight patients were recommended to obtain breast MRI in addition to mammogram for yearly screening. At time of chart review, 15 had at least one screening breast MRI ordered by PCP after BCPC visit, with 10 MRIs performed. CONCLUSIONS The unique interdisciplinary model of our breast cancer prevention clinic allows for a comprehensive and personalized evaluation for high-risk female Veterans on interventions to reduce their breast cancer risk. However, the current model does not ensure long-term compliance with these interventions. Studies have shown that more frequent/short-term follow up may improve compliance with endocrine therapies. Future directions include clinic expansion and providing additional follow-up with the multidisciplinary team to promote continued adherence to BCPC interventions. Citation Format: Hanqing Shang, Sarah Ansari, Shweta Dhar, Mahdieh Irranejadparizi, Stacey Edwards, Jessica Honkomp, Meagan Siehr, Bethany Aiena, Mary Nikityn, Diana Bearden, Deleene Menefee, Sita Bushan. A Multidisciplinary Telehealth Approach to Breast Cancer Prevention in a Veteran Population [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-27-09.

Abstract PO3-12-06: The pilot study for a mobile-based monitoring solution to manage menopausal symptoms of premenopausal breast cancer patients with endocrine therapy

Abstract Background Endocrine therapy (ET) is the most important treatment for hormone receptor (HR)-positive breast cancer (BC) patients. Each of the endocrine medications, such as aromatase inhibitors (AIs), luteinizing hormone-releasing hormone (LHRH) analogs, and selective estrogen receptor modulators, has its own set of side effects, and these might lead to poor drug adherence and eventual discontinuation. There are few systematic monitoring systems for menopausal symptoms of patients on ET. We conducted a prospective, pilot study through the mobile platform-based monitoring solution which contains a questionnaire about menopausal symptoms to assess the feasibility of the solution. Methods We screened and collected data from HR-positive BC patients who underwent surgery at a single institution from May 2022, until recruiting a total of 20 patients. Patients scheduled for postoperative ET at age 50 or younger were included. Preoperatively confirmed metastatic BC patients were excluded. A total of 19 patients were enrolled, excluding one patient who self-discontinued medication. Menopause Rating Scale (MRS) surveys were periodically administered to the patients using a mobile platform-based solution to collect responses during first 3 months of ET. The primary endpoint of this study was the response rate of the patients, and the second endpoint was MRS scores and patient satisfaction. At the time of initial enrollment before the start of ET, MRS was collected using a paper questionnaire. The concordance rate of MRS response using a paper questionnaire and this solution was compared. We also conducted a user evaluation at the end of the third month of ET to determine satisfaction. The data collected from the solution were used by physicians to assist in patient care for clinical use. Results The median age of the cohort was 39 (range 29-47). Six patients were treated with Tamoxifen alone, Tamoxifen with LHRH analog in 12 patients, and AI with LHRH analog in 1 patient. There were 3 (15.8%) of pTis, 13 (68.4%) of pT1, and 3 (15.8%) of pT2, as well as 18 (94.7%) of pN0 and 1 (5.3%) patients of pN1. The total response rate of patients to the solution during the study period was 84.5%. Each symptom has different response rates and MRS scores, from 70.2% for sex-related symptoms to 95.4% for joint pain, and from 1.24 out of 4 for sleep disturbances to 0.45 out of 4 for vaginal dryness. The match rate between mobile and paper surveys was 90.0%. The overall satisfaction score for the solution of patients was 8.06 out of 10, with the highest score (8.79 out of 10) given in terms of using patients’ responses in outpatient appointments with the physician. Conclusion The analysis of MRS using this mobile solution in premenopausal BC patients undergoing postoperative ET is expected to be feasible for clinical use and should be analyzed in a large-scale study in the future. Citation Format: Dong Seung Shin, Jai Min Ryu, Byung Joo Chae, Jeong Eon Lee, Seok Won Kim, Seok Jin Nam, Jonghan Yu. The pilot study for a mobile-based monitoring solution to manage menopausal symptoms of premenopausal breast cancer patients with endocrine therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-12-06.

Abstract PO3-18-05: Pharmacokinetics (PK) of lasofoxifene (LAS) monotherapy and combined with abemaciclib (Abema)

Abstract Introduction: LAS is a selective estrogen receptor modulator (SERM)/tissue-selective estrogen agonist/antagonist studied in women with osteoporosis and vulvar-vaginal atrophy, and most recently, metastatic breast cancer (mBC) with ESR1 mutations. LAS data in healthy postmenopausal women and young men show linear PK and no differences by age or race (Gardner. J Clin Pharmacol 2006;46:52-58; Prakash. Drug Metab Dispos 2008;26:1218-26; Data on file). Also, no PK differences were found between Caucasian and Japanese patients (Jhee. AACR-JCA 2022, abstract A83; Fountaine. J Clin Pharmacol 2006;46:693-99). Here we report select PK data of LAS (5 mg/day) from women with mBC in the ELAINE 1 and ELAINE 2 oncology trials to indirectly investigate possible drug-drug interactions between LAS and Abema. Methods: Patients with mBC and ESR1 mutations who progressed on endocrine therapy and CDK4/6 inhibitors received LAS 5 mg/day as monotherapy (ELAINE 1) or combined with Abema (provided by Eli Lilly and Co) 150 mg BID (ELAINE 2). Blood was collected prior to daily dosing at weeks 2, 4, 8, and every 4 weeks up to the final visit in ELAINE 1, and visits during the first 8 weeks in ELAINE 2, to determine the plasma trough steady-state concentrations (Css) of LAS, Abema, and two active Abema metabolites (M2 and M20). LAS was assayed using validated high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS; detection 0.025 to 25.0 ng/mL); levels below the lower limit of quantification (LLOQ) were reported as 0 ng/mL. Abema and its M2 and M20 metabolites were measured by validated Turbo Ion Spray LC/MS/MS (detection 1.00 to 500 ng/mL); values below the LLOQ were reported as &amp;lt; LLOQ ng/mL. Mean trough Css at each visit were calculated for LAS (ELAINE 1 and 2), and Abema and its M2 and M20 metabolites (ELAINE 2). LAS levels from ELAINE 1 and 2 were compared, while Abema, M2 and M20 plasma levels in ELAINE 2 were compared with previously reported levels. Such indirect comparisons may help determine if Abema altered the metabolism of LAS, or if LAS altered that of Abema, M2, or M20. The relationships of LAS and Abema levels with progression-free survival (PFS) were also explored. Results: Across all time points for subjects who had PK samples assessed, the LAS mean trough Css was 33.6 ng/mL (CV%, 39.8) in ELAINE 1 (n=40) and 30.9 ng/mL (CV 50.5%) in ELAINE 2 (n=29); in both studies, LAS concentrations were consistent across visits. LAS levels in ELAINE 2 were similar to those in ELAINE 1 with no evidence of accumulation. Mean (CV%) Abema plasma concentrations at weeks 2, 4, 6 and 8 were 199 (102%), 107 (130%), 82 (271%), and 94.3 (223%) ng/mL, respectively. Minimum and maximums of the mean trough Css for LAS, Abema, M2, and M20 are shown in Table 1. No relationships between LAS or Abema levels and antitumor activity measured by PFS were seen (data to be presented). Conclusion: The steady-state PK of 5 mg LAS in the ELAINE 1 and 2 studies suggest that the addition of abemaciclib to LAS did not result in an obvious or significant LAS-Abema, drug-drug interaction. Abema PK data from ELAINE 2 were consistent with published data (European Medicines Agency, Verzenio). These results support the continued development of LAS alone and combined with Abema for treating ER+/HER2-, ESR1-mutated mBC that progressed on endocrine therapy and CDK4/6 inhibitors. Table. Mean trough, steady-state concentrations of lasofoxifene and abemaciclib. XX- XX aData from patients who received oral LAS (5 mg/day) plus Abema (150 mg BID). Abema, abemaciclib; LAS, lasofoxifene; M2 and M20 are Abema metabolites. Citation Format: Senthil Damodaran, Paul V. Plourde, Simon Jenkins, Phil Mayer, David J Portman, Matthew Goetz. Pharmacokinetics (PK) of lasofoxifene (LAS) monotherapy and combined with abemaciclib (Abema) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-05.