Selective Estrogen Receptor Modulators Research Articles

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.

Abstract PO3-29-03: An Emerging Class of ER mutations Enhances ER Dimerization and Promotes ER Activity

Abstract Physiological activation of estrogen receptor alpha (ERα) requires the binding of estradiol (E2) to the ligand binding domain (LBD) of the receptor. This interaction triggers a repositioning of helix 12 (H12), facilitating the recruitment of coactivator proteins to the unoccupied coactivator binding groove. However, in the context of breast cancer, point mutations of ERα at H12 lead to its repositioning and self-activation in the absence of E2. Through MSK clinical sequencing breast cancer cohort (MSK-IMPACT), we assayed 8302 samples of ER+ breast cancer patients and identified 649 mutations within the LBD of ERα. 471 of these mutations (73%) were located at H11-H12 loops (D538, Y537, L536), while the remaining 27% were located near the dimer interface of ERα (V422, G442, F461, S463P, L469). Through in vitro biochemical and cell assays, we identified that these mutations promote dimer formation and hormone-independent transcriptional activity. Tumors expressing these mutations exhibited significantly accelerated growth compared to their wild-type controls. Unlike Y537S, cells harboring mutations at the dimer interface maintain their sensitivity to Selective Estrogen Receptor Degraders (SERDs), including Fulvestrant, recently FDA-approved Elacestrant, and Camizestrant, as well as Selective Estrogen Receptor Modulators (SERMs) including Tamoxifen and Raloxifene. By utilizing machine learning and computational structural analyses, we uncovered that these mutants, unlike Y537 repositions H12, act distinctly through conformational change across the ERα dimer interface. Further cell assays proved that the dimerization leads to increased stability of the receptor and facilitates its nuclear localization, which is required for ERα activation. Collectively, our finding unveiled a new class of ER mutations that enforce receptor dimerization and activation of the ER signaling pathway. The discovery opens up a new therapeutic interventional possibility, suggesting that targeting dimerization could emerge as a new strategy to combat these malignancies. Citation Format: Seema Irani, Wuwei Tan, Qing Li, Weiyi Toy, Catherine Jones, Mayur Gadiya, Antonio Marra, John Katzenellenbogen, Kathryn Carlson, Benita S. Katzenellenbogen, Yang Shen, Sarat Chandarlapaty. An Emerging Class of ER mutations Enhances ER Dimerization and Promotes ER Activity [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 PO3-29-03.

Abstract PO3-18-07: Therapeutic Potential of Combining Eltanexor with Tamoxifen to Treat Primary and Metastatic Estrogen Receptor Positive (ER+) Breast Cancers

Abstract Estrogen receptors are key pathway initiators in the aggressive development of more than two-thirds of all breast cancers. Tamoxifen (TAM) is a selective estrogen receptor modulator that disables the ER pathway and inhibits the progression of ER+ breast cancer. Unfortunately, 10-40% of patients with ER+ breast cancer who were treated with TAM experience recurrence and metastasis within 10 years. We have previously identified exportin 1 (XPO1) to be more highly expressed in breast cancers with acquired TAM resistance compared to TAM-sensitive counterparts and showed that a combination treatment of TAM with an XPO1 inhibitor, selinexor, is an effective method of tumor suppression in preclinical models. In this study we investigated the activity of eltanexor, an investigational second generation XPO1 inhibitor with minimal penetration of the blood-brain barrier, to inhibit cancer growth without leading to weight loss. Our results show that mice harboring MCF7-ESR1Y537Sxenograft tumors had significantly less (P &amp;lt; .05) flank tumor growth when administered a treatment regimen of TAM and eltanexor compared to control mice. In metastatic tumor models, we observed decreased metastatic burden in mice harboring MCF7-ESR1 D538G and MCF7-ESR1Y537S tumors when co-administered TAM and eltanexor. We did not observe weight changes in either model. Our findings suggest that eltanexor may be a relevant treatment for further exploration in the context of a TAM combination therapy for treatment of ER+ breast cancer. Citation Format: Vedant Jain, Myra Kamdar, Hannah McGee, Qianying Zuo, Jin Young Yoo, Yosef Landesman, Christopher Walker, Zeynep Madak-Erdogan. Therapeutic Potential of Combining Eltanexor with Tamoxifen to Treat Primary and Metastatic Estrogen Receptor Positive (ER+) Breast Cancers [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 PO3-18-07.

Abstract PO4-27-05: A phase I open-label dose escalation trial of FWD1802 as monotherapy and in combination with palbociclib in patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations

Abstract Background: Estrogen receptor (ER) signaling sits at center of the tumor biology in ER+/HER2- breast cancers. Current standard of care involves hormone therapy with agents including selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs). Unfortunately, most patients eventually develop resistance to these therapies. Mutations in estrogen receptor 1 (ESR1) are partially responsible for the acquired resistance. Mutated estrogen receptors are still sensitive to fulvestrant but with a much less sensitivity. In January 2023, elacestrant received its first approval for the treatment of postmenopausal women or adult men with breast cancer harboring ESR1 mutations in US. However, there is still great unmet medical need for this population. FWD1802 is a third-generation oral SERD for ER-positive breast cancer patients. It binds competitively to ER, with a much higher affinity than that of fulvestrant. Preclinically, FWD1802 alone and in combination with palbociclib exhibits significant anti-tumor activity in the ER+/HER2- models and in ESR1-mutated models in vitro and in vivo. This ongoing phase I study is to assess the safety, tolerability, pharmacokinetics (PK) and clinical activity of FWD1802 as monotherapy and in combination with palbociclib in ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations. Methods: This clinical study (CTR20232130) consists of three parts: monotherapy dose escalation (Part A), dose escalation in combination with palbociclib (Part B) and monotherapy dose expansion in ESR1-mutated patients (Part C). A conventional “3+3” design is used for this study. Approximately a total of 129 patients will be enrolled. FWD1802 is administered orally daily. In monotherapy dose escalation study (Part A), at each dose level, a single ascending dose (SAD) is followed by a 28-day continuous multiple ascending dose (MAD) period (defined as 1 cycle). In Part B dose, palbociclib (125 mg daily) is administered on a 28-day treatment cycle with 21-day on treatment and 7-day off treatment, along with the 28-day treatment cycle of FWD1802. The primary objectives include dose limiting toxicity (DLT), maximum tolerated dose (MTD), safety, tolerability, and the recommended phase 2 dose (RP2D) of FWD1802. Secondary objectives include pharmacokinetics characteristics of FWD1802 and its major metabolite as monotherapy and in combination with palbociclib. Preliminary anti-tumor activity including objective response rate (ORR), duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS) will also be evaluated. DLT evaluation will be conducted after the first cycle of multi-dose period, and tumor assessment will be conducted every 8 weeks by investigators according to RECIST version 1.1. Patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutation are eligible for the enrollment. Enrolled patients should have progressed disease, or failed from previous therapy, or intolerable or inaccessible to standard therapy. In addition, patients with ECOG score ≤1 and with adequate renal, cardiac, hepatic, and hematologic function are eligible for enrollment. The monotherapy dose escalation (Part A) is currently ongoing. The dose selection for Part B and Part C will be based on the data from the ongoing Part A. Clinical trial information: CTR20232130. Research Sponsor: Shenzhen Forward Pharmaceuticals Co., Ltd. (FORWARD PHARMA). Citation Format: Ling Zeng, Jin Liu, Dan Wu, Huiwen Ge, Zirui Bian, Chenggang Zhu. A phase I open-label dose escalation trial of FWD1802 as monotherapy and in combination with palbociclib in patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations [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 PO4-27-05.

Abstract PO4-27-04: GRACE-trial: A randomized active-controlled trial for vulvovaginal atrophy in breast cancer patients on endocrine therapy

Abstract Background: Breast cancer is the most common cancer type in women worldwide. Due to hormone receptor positivity in the majority of the breast cancer tumors is endocrine therapy a crucial part in the treatment landscape of breast cancer. Selective estrogen-receptor modulators or aromatase inhibitors are the used treatment options for endocrine therapy. These medicines generate a hypoestrogenic environment by reducing circulating estrogen or by altering the effect of estrogen on tissue cells by receptor blockade. As a common side effect, vulvovaginal atrophy occurs in a majority of breast cancer patients using endocrine therapy. Vulvovaginal atrophy has a significant impact on physical and psychological wellbeing due to negative influence on quality-of-life, self-esteem and sexuality. As a consequence, adherence of endocrine therapy for the standard duration of 5 to 10 years is challenging, resulting in higher rates of therapy interruption, leading to poorer prognosis with shorter distant disease free survival. The standard treatment for vulvovaginal atrophy in postmenopausal women is based on the use of local hormonal treatment. However, when a patient has a history of breast cancer, delay of treatment and undertreatment are ubiquitous. Methods &amp; design: In this first ever prospective randomized trial breast cancer patients on endocrine therapy with vulvovaginal atrophy will be treated with the available local treatment modalities with a 1:1:1:1 randomization: estrogen, dehydroepiandrosterone, moisturizers and a co-treatment of estrogen and probiotics. Patient-reported outcomes measurements will be implemented to investigate the efficacy of the implemented treatments. These outcome measures include symptom evaluation, impact on quality-of-life and sexuality. Safety of the treatments will be evaluated by assessing systemic sex hormones concentrations. Previous research indicated no increased recurrence risk, yet no randomized trials comparing the different modalities have been published. Primary objectives: Two primary objectives have been determined. Firstly, the efficacy of the different treatment modalities will be assessed. The assessment will be based on patient-reported outcome measurements (PROMs) and clinical evaluations such as vaginal pH and the vaginal maturation index, the latter a direct microscopic evaluation of the vaginal epithelium. Secondly, safety of the different groups will be assessed. Evaluation will be done be measuring sex hormone concentrations systemically, which will be a surrogate for safety evaluation. Secondary objectives: The secondary objective in this study is the identification of microbial alterations after treatment initiation. Identification of these alterations can help in further understanding of the pathophysiology of vulvovaginal atrophy and potentially create opportunities for new treatment strategies towards vulvovaginal atrophy in breast cancer patients on endocrine therapy. Registration: The current study is registered at the European Union Clinical Trials Register (EudraCT number 2021-001921-31). Trial status: Recruitment for the study was commenced in May 2022. At time of manuscript submission, patient recruitment was ongoing. Citation Format: Glenn Vergauwen, Piet Cools, Hannelore Denys, Tom Fiers, Koen van de Vijver, Liv Veldeman, Hans Verstraelen. GRACE-trial: A randomized active-controlled trial for vulvovaginal atrophy in breast cancer patients on 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 PO4-27-04.

Abstract PO1-01-12: A retrospective cohort study on the effect of adding adjuvant ovarian function suppression to endocrine therapy in premenopausal women with T1-T2 tumor hormone-positive breast cancer on survival and disease recurrence

Abstract Background: Breast cancer is the most common diagnosed cancer in women and is the leading cause of cancer death. Young women diagnosed with breast cancer are at higher rates of adverse outcomes in terms of survival and recurrence. Hormone sensitive breast cancer is the commonest subtype of breast cancer in this group. To date, the standard adjuvant treatment is endocrine therapy for both pre and post-menopausal women. Recent published studies have recommended adding ovarian function therapy to premenopausal women who are at high risk of recurrence. In this study we evaluated the impact of adding adjuvant ovarian function suppression for premenopausal women with small (T1 and T2) hormone receptor positive node negative breast cancer who did not receive any form of chemotherapy on overall survival and disease-free recurrence. Methods: We performed a retrospective study where we evaluated the electronic medical records of 4431 premenopausal women diagnosed with breast cancer in Asan Medical Center in Seoul, South Korea. All the analyzed patients were operated from the period of January 2006 till December 2019. The inclusion criteria were age of 55 and below, T1 and T2 tumors with N0 disease who received selective estrogen receptor modulators (SERM - Tamoxifen) and didn’t receive neo or adjuvant chemotherapy. We compared patients who received SERM (Tam Only) only to patients who received SERM and ovarian function suppression (Tam + OFS) medications. The primary endpoint was overall survival (OS), and the secondary endpoint was mortality and disease-free survival (DFS). We used chi-square test for categorical variables and t-test for continuous variables. The p-value was set as p&amp;lt; 0.05 as statistically significant. Kaplan Meier curve and log rank test were used to analyze the data for overall survival, disease-free survival and mortality. We performed an additional subgroup analysis adjusted to age, tumor size, Ki67%, progesterone receptor, HER2 status and type of operation. Results: There was equal distribution of cases between tamoxifen only group and tamoxifen + OFS group (2121 versus 2310 respectively). The median age in each group was 45 years of age. Tumor size of ≤0.5cm was the commonest in the tamoxifen only group whereas tamoxifen + OFS group had majority of cases with tumor size of 1 - 2cm. Both groups had a Ki-67% of 10-20%. Histologic grade of 2 and nuclear grade of 2 were most commonly representative in the comparing groups. Invasive ductal carcinoma was the most common histological subtype (93-94%) and invasive lobular carcinoma accounted for 5-6% of cases. Regarding immunohistochemistry results, 91-93% of patients were progesterone receptor positive and 68-73% were HER2 negative. The majority underwent breast conserving surgery compared to mastectomy. We have also looked at the pattern of prescribing OFS treatment in the Tamoxifen + OFS group regarding the length of treatment. Nearly 80% of patients received OFS treatment for a period of 1-2 years whereas only 5.2% received &amp;lt; 1 year and 1.8% &amp;gt;2years. After adjusting to age, tumor size, Ki67%, PR receptor and HER2 status, the result was only significant for higher risk of DFS in the TAM + OFS group in Ki67 &amp;lt; 20%. The OFS+TAM had more DFS and mortality events compared to TAM only group. However, the only significant result was the overall survival favoring tamoxifen only group with a p-value of 0.039 and HR of 1.05-7.99. Conclusion: Adding ovarian function suppression to tamoxifen in premenopausal hormone positive node negative T1-T2 tumors didn’t show any benefit in terms of disease-free interval and overall survival. Further studies are advised to assess the benefit of adding ovarian function suppression to this group of patients Table 1: baseline characteristics of Table 2: Disease Free Survival Subgroup Analysis Citation Format: Sarah Al Safi, Hee Jeong Kim, Seonok Kim, Sae Byul Lee, Jisun Kim, Tae-Kyung Yoo, Il-Yong Chung, Beom Seok Ko, Byung Ho Son. A retrospective cohort study on the effect of adding adjuvant ovarian function suppression to endocrine therapy in premenopausal women with T1-T2 tumor hormone-positive breast cancer on survival and disease recurrence [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 PO1-01-12.

Abstract PO5-03-03: Nomogram for predicting brain metastasis in early-stage breast cancer patients

Abstract Nomogram for predicting brain metastasis in early-stage breast cancer patients Background: Brain metastasis is a significant concern for patients with early-stage breast cancer, as it can have a detrimental impact on survival and quality of life. Clinical and pathological characteristics of the primary tumor may be modeled into a nomogram that can predict the risk of brain metastasis. The goal is to create a nomogram and clinical calculator to assist in selection of patients with high risk of brain metastasis to enrich patient population for accrual on clinical trials for the purpose of preventing or delaying emergence of brain metastasis, at an early stage of their disease. Methods: We reviewed all early-stage breast cancer patients (stages I to III) N=40290 from the University of Texas MD Anderson Cancer Center, Houston, TX, from 1/1/1997 to 5/8/2020. We utilized multiple predictive statistical models to identify the most relevant variables and optimal predictive criteria. Variables for the model included patient age, tumor characteristics (such as grade,hormone receptor and HER2 status) and medical treatment (such as chemotherapy and endocrine therapy). The Receiver Operating Characteristic (ROC), and its AUC (area under the curve) was used to demonstrate the performance of the multivariate model to predict the occurrence of brain metastasis at different time points (1 year, 2 years, and 5 years), distinguishing between patients who develop brain metastasis in a time-dependent manner and those who do not. Results: The results showed the following clinical variables to be statistically significant in predicting brain metastasis: younger age, high estrogen and progesterone receptor percentage, higher tumor size; use of aromatase inhibitor therapy, and use of selective estrogen receptor modulator therapy were associated with a decreased risk of brain metastasis. Higher grade, Ki-67 levels, HER2-positive status, lymphovascular invasion and the use of chemotherapy was associated with an increased risk. The AUC values for the prediction of brain metastasis at different time points are as follows: 0.85 at 1 year, 0.83 at 2 years, and 0.82 at 5 years. These values indicate that the multivariate model has good discriminative ability, with higher values indicating a better predictive performance. An AUC of 0.85 suggests that the model has a high probability of correctly distinguishing between patients who will develop brain metastasis and those who will not at 1 year. Conclusions: Our predictive tool holds promise in assisting clinicians when making informed, personalized care decisions for patients at risk of developing brain metastasis. The model will be validated using independent patient cohorts from Institut Jules Bordet, Brussel, Belgium, to assess their accuracy and reproducibility. Continued research and validation will further refine these models, increasing their reliability and their clinical/clinical research applicability. Citation Format: Akshara Singareeka Raghavendra, Nuria Kotecki, Kristofer Jennings, Ottavia Amato, Debu Tripathy, Ahmad Awada, Nuhad Ibrahim. Nomogram for predicting brain metastasis in early-stage breast cancer patients [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 PO5-03-03.

Enhanced oral bioavailability of levormeloxifene and raloxifene by nanoemulsion: simultaneous bioanalysis using liquid chromatography-tandem mass spectrometry.

Aim & objective: Levormeloxifene (L-ORM) and raloxifene (RAL) are selective estrogen receptor modulators used in the treatment of postmenopausal osteoporosis and breast cancer. Here, we developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous estimation of both drugs. Materials & methods: A quality-by-design (QbD) approach was used for the optimization of the nanoemulsion, and US FDA guidelines were followed for method validation. Results: Multiple reaction monitoring transitions were used for L-ORM (459.05→98.50), RAL (475.00→112.02) and internal standard (180.10→110.2). Analytes were resolved in a C18 column with 80:20 v/v% acetonitrile (ACN), 0.1% formic acid in triple-distilled water as a mobile phase. The developed method was linear over a concentration range of 1-600ng/ml. Pharmacokinetic results of free L-ORM-RAL and the L-ORM-RAL nanoemulsion showed Cmax of free L-ORM- 70.65±16.64, free RAL13.53±2.72, L-ORM nanoemulsion 65.07±14.0 and RAL-nanoemulsion 59.27±17.44ng/ml. Conclusion: Future findings will contribute to the treatment of postmenopausal osteoporosis and breast cancer using L-ORM and RAL.

COMPARING THE EFFECTS OF AROMATASE INHIBITORS AND SELECTIVE OESTROGEN RECEPTOR MODULATORS ON BODY COMPOSITION, EXERCISE TOLERANCE AND MARKERS OF CARDIOVASCULAR RISK IN FEMALES WITH BREAST CANCER

INTRODUCTION Adjuvant endocrine therapy (AET) blocks the action of estrogens and is commonly prescribed in hormone receptor-positive breast cancer. Given the putative cardioprotective role of estrogens in females, AET may exacerbate the negative metabolic side-effects of anthracycline chemotherapy. This study examined the early effects of combined anthracycline chemotherapy and AET on body composition, exercise tolerance and markers of cardiovascular risk in a cohort of females with breast cancer. METHODS This was a secondary analysis of the BReast cancer EXercise InTervention (BREXIT) Trial. Females with breast cancer (n=105, aged 51 ± 8 years, BMI 27.4 ± 5.1, mean ± SD) scheduled for anthracycline chemotherapy participated in this study. Aerobic exercise capacity, body composition, physical function, and blood pressure were measured before anthracycline treatment and after 4- and 12-months follow-up. Linear mixed models assessed whether aromatase inhibitors (AI) or selective estrogen receptor modulators (SERMS) affected exercise tolerance, body composition and markers of cardiovascular risk compared to non-endocrine breast cancer treatments. RESULTS Twelve months of anthracycline treatment combined with AI or SERMs decreased total body lean mass by 1.4 kg (2%; interaction p=0.01) and 1kg (1%; interaction p=0.16) respectively, when compared to non-endocrine therapies. There were trends for AET to decrease total fat (-1.5%, interaction p=0.05) and android fat (-2.3%, interaction p=0.07) mass compared to non-endocrine therapy after 12 months. AIs significantly increased both systolic (5.8mmHg, interaction p=0.05) and diastolic (4.0mmHg, interaction p=0.05) blood pressure after 12 months of treatment compared to SERMs or non-endocrine therapies. There was no effect of either AET or SERMS on VO2peak, leg press or seated row 1RM, 30 second sit to stand or handgrip strength. DISCUSSION AND CONCLUSION Short-term treatment with adjuvant endocrine therapies may accelerate muscle loss and increase blood pressure compared to non-endocrine therapies. However, these changes were not associated with worsening of physical function.

Efficacy and safety of endoxifen in bipolar disorder: A systematic review.

Endoxifen, a protein kinase C inhibitor and selective estrogen receptor modulator, primarily used in breast cancer treatment, has recently emerged as a potential therapeutic option for managing manic episodes associated with bipolar disorder (BD). This review aims to assess the existing evidence base for endoxifen in BD treatment and evaluate the strengths and limitations of current research findings. A systematic search was conducted on Medline, Embase, and Web of Science databases. We included studies published in English that used endoxifen in BD, alongside any relevant studies identified through manual searching and conference papers with full-text availability. Information pertaining to dose, duration, clinical effects, and safety profiles was extracted from the included studies. The Cochrane Risk of Bias 2 tool was used to assess the risk of bias in clinical trials. The final review included seven case reports (including two conference presentations), two clinical trials, and one prospective study. Most studies administered endoxifen 8mg and reported an improvement in manic symptoms. Several case reports included patients with comorbid substance use, and most patients received mood stabilizers concurrently. Few reports lacked any structured outcome measures. The clinical trials used divalproex 1000mg as an active comparator, which was deemed sub-therapeutic. Despite being multicentric, the first trial lacked data on center-wise recruitment, and certain methodological concerns were observed across the included trials. There were no serious adverse effects noted, except for a significant elevation in lipid profile within a 3-week period. Limited data were available regarding endoxifen efficacy and safety in mixed episodes, depressive episodes, and maintenance treatment. There is a paucity of research on the efficacy and safety of endoxifen in BD. While existing evidence suggests short-term efficacy in manic episodes, significant limitations were identified in most of the included studies. Further research is imperative to establish the efficacy and safety of endoxifen in BD before considering its recommendation as a viable treatment option.

Improving Tamoxifen Performance in Inducing Apoptosis and Hepatoprotection by Loading on a Dual Nanomagnetic Targeting System.

Although tamoxifen (TMX) belongs to selective estrogen receptor modulators (SERMs) and selectively binds to estrogen receptors, it affects other estrogen-producing tissues due to passive diffusion and non-differentiation of normal and cancerous cells and leads to side effects. The problems expressed about tamoxifen (TMX) encouraged us to design a new drug delivery system based on magnetic nanoparticles (MNPs) to simultaneously target two receptors on cancer cells through folic acid (FA) and hyaluronic acid (HA) groups. The mediator of binding of two targeting agents to MNPs is a polymer linker, including dopamine, polyethylene glycol, and terminal amine (DPN). Zeta potential, dynamic light scattering (DLS), and Field emission scanning electron microscopy (FESEM) methods confirmed that MNPs-DPN-HA-FA has a suitable size of ~105 nm and a surface charge of -41 mV, and therefore, it can be a suitable option for carrying TMX and increasing its solubility. The cytotoxic test showed that the highest concentration of MNPs-DPN-HA-FA-TMX decreased cell viability to about 11% after 72 h of exposure compared to the control. While the protective effect of modified MNPs on normal cells was evident, unlike tamoxifen, the survival rate of liver cells, even after 180 min of treatment, was not significantly different from the control group. The protective effect of MNPs was also confirmed by examining the amount of malondialdehyde, and no significant difference was observed in the amount of lipid peroxidation caused by modified MNPs compared to the control. Flow cytometry proved that TMX can induce apoptosis by targeting MNPs. Real-time PCR showed that the modified MNPs activated the intrinsic and extrinsic mitochondrial pathways of apoptosis, so the Bak1/Bclx ratio for MNPs-DPN-HA-FA-TMX and free TMX was 70.82 and 0.38, respectively. Also, the expression of the caspase-3 gene increased 430 times compared to the control. On the other hand, only TNF gene expression, which is responsible for metastasis in some tumors, was decreased by both free TMX and MNPs-DPN-HA-FA-TMX. Finally, molecular docking proved that MNPs-DPN-HA-FA-TMX could provide a very stable interaction with both CD44 and folate receptors, induce apoptosis in cancer cells, and reduce hepatotoxicity. All the results showed that MNPs-DPN-HA-FA-TMX can show good affinity to cancer cells using targeting agents and induce apoptosis in metastatic breast ductal carcinoma T-47D cell lines. Also, the protective effects of MNPs on hepatocytes are quite evident, and they can reduce the side effects of TMX.