Comparison of effects of tamoxifen and Toremifene on hepatic function and serum lipids in breast cancer patients during adjuvant endocrine therapy.

To investigate the effects of tamoxifen (TAM) and toremifene (TOR) on hepatic function and serum lipid levels in breast cancer patients receiving adjuvant endocrine therapy. The clinical data of 597 early breast cancer patients treated at the First Affiliated Hospital of Nanjing Medical University between January 2016 and December 2022 were collected. All the patients received standard adjuvant endocrine therapy with TAM or TOR after chemotherapy. Hepatic function and serum lipid data of all patients before and at 6 months and 1, 2, and 3 years after the treatment were collected retrospectively and analyzed statistically. There: no negative effect on hepatic function was observed in patients treated with either TAM or TOR. The triglyceride levels in both groups increased during treatment, and the effect of TAM on improving total cholesterol levels was stronger. Total cholesterol levels were not affected by time or treatment regimen. The low-density lipoprotein cholesterol levels decreased in both groups, and the effect was similar between groups. TAM can decrease the high-density lipoprotein cholesterol levels, whereas TOR can increase the high-density lipoprotein cholesterol levels, and there was a significant difference between groups. In the postoperative adjuvant endocrine therapy, TOR and TAM will not negatively impact the hepatic function of breast cancer patients, and TOR is better than TAM in the management of serum lipids; therefore, it may be a better choice for clinical medication.

Lipid changes during endocrine therapy in early-stage breast cancer patients: A real-world study.

BACKGROUND: Endocrine drugs may affect lipid metabolism in breast cancer (BC) patients. This study explores lipid changes in early-stage BC patients taking different endocrine drugs. METHODS: The changing trend of blood lipid during endocrine therapy in 2756 BC patients from January 2013 to December 2021 was retrospectively analyzed. The changes in four lipid parameters were assessed by the Generalized Linear Mixed Model, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C), and high-density lipoprotein (HDL-C). These parameters were quantified at baseline and at 6, 12, 18, 24, 36, 48, 60, and 72 months after endocrine therapy initiation. Furthermore, a subgroup analysis according to menopausal status or medication types was conducted. RESULTS: A total of 1201 patients taking aromatase inhibitors (AIs), including anastrozole (ANA), letrozole (LET), or exemestane (EXE), and 1555 patients taking toremifene (TOR) were enrolled. TC and TG levels showed a significantly elevated trend during 5 years of treatment (P < 0.05). HDL-C levels increased from baseline in the TOR group (P < 0.05). Compared with the postmenopausal AI group, the increasing trends of TC, TG, and LDL-C in the premenopausal AI group were more evident with the extension of time (ß = 0.105, 0.027, 0.086, respectively). Within 3 years, TC, TG, and LDL-C levels in the ANA and LET groups were significantly higher than baseline (P < 0.05). Moreover, the levels of TG in the EXE group were significantly lower than that in the ANA or LET group (P < 0.05), but this significant difference disappeared after 3 years. CONCLUSIONS: AIs significantly influenced lipid profiles more than TOR. AIs had a greater effect on blood lipids in premenopausal patients. Steroidal AIs (EXE) may affect lipid levels less than nonsteroidal AIs (ANA and LET).

Thrombosis of acute superior mesenteric artery in a patient with breast cancer receiving toremifene therapy: a case report and literature review.

It is widely recognized that cancer itself is related to increased risk of thromembolism. Venous thromboembolism is relatively common in breast cancer patients, but arterial thrombosis, especially acute superior mesenteric artery thrombosis (SMAT) associated with chemotherapy or endocrinotherapy, rarely occurs in breast cancer patients. There were few reports about acute SMAT in cancer patients who underwent chemotherapy, but no reports of acute SMAT caused by endocrine-therapy. We reported a 54-year-old patient with acute SMAT during toremifene treatment after breast cancer surgery. She underwent 4 cycles chemotherapy of TC regimen, then accepted toremifen endocrinotherapy because of positive estrogen receptor. She suffered from acute SMAT after 2 months toremifen treatment. Therefore, we consider that this case of acute SMAT may be a rare adverse event of toremifen. In view of the high risk and rarity of acute SMAT caused by toremifene, we suggest that except for venous thrombosis, arterial thrombosis in special position (ATSP) should be kept in mind during use of toremifene. Once a thrombotic event occurs, toremifene should be stopped immediately.

Prognostic factors and benefit populations of ovarian function suppression in premenopausal HR+/HER2+ early-stage breast cancer patients who received trastuzumab: Evidence from a real-world study with long-term follow-up.

BACKGROUND: Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-positive (HER2+) breast cancer exhibits considerable heterogeneity, and it is of great interest whether patients with premenopausal HR+/HER2+ breast cancer treated with trastuzumab can benefit from ovarian function suppression (OFS) therapy similarly to HR+/HER2- breast cancer. Here, we conducted a real-world study in this population to identify both who would derive substantial benefits from the addition of OFS and clinicopathological factors with potential prognostic value. METHODS: Multicenter data from 253 premenopausal patients with HR+/HER2+ early-stage breast cancer who received trastuzumab from October 2009 to October 2018 were retrospectively included. The Kaplan-Meier method was used for survival analysis, while the log-rank test was used to compare the survival rates. Univariate and multifactor Cox regression analyses were performed to analyze the independent risk factors affecting invasive disease-free survival (IDFS). RESULTS: After a median follow-up of 98.50 months, compared with tamoxifen/toremifene alone, tamoxifen/toremifene/aromatase inhibitors plus OFS demonstrated significant benefits in the overall study population (HR = 0.289, 95% CI: 0.100-0.835, p = 0.022, 8-year IDFS rate: 90.78% vs. 95.54%), especially in the lymph node-positive subgroup and age ≤40 years subgroup. Age ≤40 years, histological grade >2, lymph node involvement, PR ≤50%, and tamoxifen alone were independent prognostic factors. CONCLUSIONS: For premenopausal HR+ breast cancer patients, HER2 positivity alone is an indication for the addition of OFS in adjuvant endocrine therapy. Age, histological grade, lymph node status, the expression of PR, and OFS treatment were independent prognostic factors in this population.

Toremifene, an Alternative Adjuvant Endocrine Therapy, Is Better Than Tamoxifen in Breast Cancer Patients with CYP2D6*10 Mutant Genotypes.

PURPOSE: Tamoxifen showed individual differences in efficacy under different CYP2D6*10 genotypes. Our study evaluated the prognosis of tamoxifen or toremifene in hormone receptor (HR)-positive breast cancer patients under different genotypes. MATERIALS AND METHODS: CYP2D6*10 genotypes of HR-positive breast cancer patients were determined by Sanger sequencing, and all the patients were divided into tamoxifen group or toremifene group. RESULTS: A total of 268 patients with HR-positive breast cancer were studied. The median follow-up time was 72.0 months (range, 5.0 to 88.0 months). Of these, 88 (32.9%), 114 (42.5%), and 66 (24.6%) patients had C/C, C/T, and T/T genotypes, respectively. Among patients who received tamoxifen (n=176), the 5-year disease-free survival (DFS) rate in patients with C/C and C/T genotype was better than that in patients with T/T genotype, and the difference was statistically significant (p < 0.001 and p=0.030, respectively). In patients receiving toremifene, CYP2D6*10 genotype was not significantly associated with DFS (p=0.325). Regardless of genotypes, the 5-year DFS rate was higher in patients treated with toremifene than in patients with tamoxifen (91.3% vs. 80.0%, p=0.011). Compared with tamoxifen, toremifene remained an independent prognostic marker of DFS in multivariate analysis (hazard ratio, 0.422; p=0.021). For all the 180 patients with CYP2D6*10 C/T and T/T genotypes, the 5-year DFS rate was significantly higher in the toremifene group than in the tamoxifen group (90.8% vs. 70.1%, p=0.003). CONCLUSION: Toremifene may be an alternative adjuvant endocrine therapy for patients with CYP2D6*10 mutant genotypes.

The adverse effect of anticancer drug toremifene on vascular smooth muscle cells is an important aspect of its tumor growth inhibition.

PURPOSE: Toremifene (TOR) is widely used as an antineoplastic drug and has an inhibitory effect on angiogenesis in mesenteric desmoid tumors and vascular intracranial solitary fibrous tumors. However, no study has investigated the direct effect of TOR on vascular cells. This study aimed at exploring the effect of TOR on the behaviors of vascular smooth muscle cells (VSMCs). METHODS: Human aortic umbilical vascular smooth muscle cells (HAVSMCs) were treated by TOR. Cell morphology, migration, adhesion, and proliferation assay were investigated. The cell cycle, apoptosis, mitochondrial membrane potential, and reactive oxygen species were assessed using flow cytometry. Caspase-3 and 9 activities were assayed using Caspase-3 and Caspase-9 Activity Assay kits, respectively. Immunofluorescence and Western blot assays were carried out to characterize protein expressions of PCNA, p53, and Rho/ROCK signaling pathway. RESULTS: TOR damaged cytoskeleton, inhibited VSMC proliferation, migration, and adhesion, and induced abnormal cell morphology and apoptosis. The antiproliferative activity of TOR was associated with the induction of G0/G1 phase arrest, blocking the cell cycle. TOR disrupted intracellular reactive oxygen species and mitochondrial membrane potential, and enhanced p53 expression and the activities of caspase-3 and caspase-9. Thus, TOR-induced apoptosis by the mitochondrial signaling pathway. Additionally, TOR induced decreased Rho, ROCK, MLC, and pMLC proteins. Collectively, TOR may affect multiple behaviors of VSMCs by damaging cytoskeleton through the Rho/ROCK pathway. CONCLUSION: The adverse effect of TOR on VSMCs could be considered as an important aspect of tumor growth inhibition.

[A real-world study of the effects of endocrine therapy on liver function in breast cancer].

Objective: To compare the effect of different endocrine therapy drugs on liver function in patients with early breast cancer. Methods: A retrospective cohort study was conducted to include 4 318 patients with early breast cancer who received adjuvant endocrine therapy in Department of Breast Surgery, Peking Union Medical College Hospital from January 1, 2013 to December 31, 2021. All the patients were female, aged (51.2±11.3) years (range: 20 to 87 years), including 1 182 patients in the anastrozole group, 592 patients in the letrozole group, 332 patients in the exemestane group, and 2 212 patients in the toremifene group. The mixed effect model was used to analyze and compare the liver function levels of patients at baseline, 6, 12, 18, 24, 36, 48, 60 months of medication, and 1 year after drug withdrawal among the three aromatase inhibitors (anastrozole, letrozole, exemestane) and toremifene. Results: ALT and AST of the 4 groups were significantly higher than the baseline level at 6 months (all P<0.01), and there were no significant differences in total bilirubin, direct bilirubin and AST levels among all groups one year after drug withdrawal (P: 0.538, 0.718, 0.061, respectively). There was no significant difference in the effect of all groups on AST levels (F=2.474, P=0.061), and in the effect of three aromatase inhibitors (anastrozole, letrozole, and exemestane) on ALT levels (anastrozole vs. letrozole, P=0.182; anastrozole vs. exemestane, P=0.535; letrozole vs. exemestane, P=0.862). Anastrozole and letrozole had significantly higher effects on ALT levels than toremifene (P<0.01, P=0.009). The proportion of abnormal liver function in each group increased significantly at 6 months compared with baseline, and then the proportion showed a decreasing trend over time. Conclusions: Three aromatase inhibitors (anastrozole, letrozole, and exemestane) and toremifene can significantly increase the level of ALT and AST in patients with breast cancer, and the levels can gradually recover to the baseline after 1 year of drug withdrawal. The effect of non-steroidal aromatase inhibitors (anastrozole, letrozole) on ALT levels is greater than toremifene.

A real-world study of the effects of endocrine therapy on liver function in breast cancer / 中华外科杂志

Objective: To compare the effect of different endocrine therapy drugs on liver function in patients with early breast cancer. Methods: A retrospective cohort study was conducted to include 4 318 patients with early breast cancer who received adjuvant endocrine therapy in Department of Breast Surgery, Peking Union Medical College Hospital from January 1, 2013 to December 31, 2021. All the patients were female, aged (51.2±11.3) years (range: 20 to 87 years), including 1 182 patients in the anastrozole group, 592 patients in the letrozole group, 332 patients in the exemestane group, and 2 212 patients in the toremifene group. The mixed effect model was used to analyze and compare the liver function levels of patients at baseline, 6, 12, 18, 24, 36, 48, 60 months of medication, and 1 year after drug withdrawal among the three aromatase inhibitors (anastrozole, letrozole, exemestane) and toremifene. Results: ALT and AST of the 4 groups were significantly higher than the baseline level at 6 months (all P<0.01), and there were no significant differences in total bilirubin, direct bilirubin and AST levels among all groups one year after drug withdrawal (P: 0.538, 0.718, 0.061, respectively). There was no significant difference in the effect of all groups on AST levels (F=2.474, P=0.061), and in the effect of three aromatase inhibitors (anastrozole, letrozole, and exemestane) on ALT levels (anastrozole vs. letrozole, P=0.182; anastrozole vs. exemestane, P=0.535; letrozole vs. exemestane, P=0.862). Anastrozole and letrozole had significantly higher effects on ALT levels than toremifene (P<0.01, P=0.009). The proportion of abnormal liver function in each group increased significantly at 6 months compared with baseline, and then the proportion showed a decreasing trend over time. Conclusions: Three aromatase inhibitors (anastrozole, letrozole, and exemestane) and toremifene can significantly increase the level of ALT and AST in patients with breast cancer, and the levels can gradually recover to the baseline after 1 year of drug withdrawal. The effect of non-steroidal aromatase inhibitors (anastrozole, letrozole) on ALT levels is greater than toremifene.

[Elderly Advanced Breast Cancer Effectively Treated with Locoregional Therapy-A Case Report].

We report a case of advanced breast cancer in an elderly patient effectively treated with locoregional therapy. The patient was an 81-year-old woman who presented with an increasing right breast lump. The tumor was 55 mm in diameter, accompanied by fixation to pectoral muscle. A core needle biopsy for right breast tumor led to a diagnosis of mucinous carcinoma, positive for estrogen receptor(ER)and progesterone receptor(PgR), negative for HER2/neu. The Ki-67 positive cell index was 10%. A bone scintigraphy revealed multiple bone metastases, so, we confirmed the diagnosis as T4cN2aM1, Stage Ⅳ. She initiated endocrine therapy by letrozole. By changing the endocrine therapy to toremifene followed by fulvestrant, the therapy achieved a partial response. However, the size of the primary tumor increased accompanied by bleeding, and surgical resection of the right breast was performed for local control. The locoregional surgery was effective, improving the patient's quality of life. She was administered lapatinib as anti-HER2 therapy in addition to the endocrine therapy. Two years and 6 months after surgery, there has been no worsening of bone metastasis or appearance of visceral metastasis.

Concomitant administration of warfarin and toremifene: A case report.

WHAT IS KNOWN AND OBJECTIVE: Antiestrogen agents have been reported to enhance the anticoagulant activity of warfarin. The use of tamoxifen with warfarin has been contraindicated. However, warfarin in combination with toremifene has not been reported. We report a case in which warfarin was combined with toremifene and applied warfarin dose prediction models to predict the dose of warfarin. CASE SUMMARY: We report the case of a 50-year-old woman with a history of breast cancer, who underwent long-term toremifene therapy after mastectomy. The patient was treated with warfarin after prosthetic valve replacement and had a fluctuating international normalized ratio (INR) following the concomitant administration of toremifene. We applied the warfarin dose prediction model to adjust the warfarin dose during treatment. Finally, her INR stabilized with a lower dose of warfarin, and there was no serious bleeding during the 1-year follow-up. WHAT IS NEW AND CONCLUSION: Warfarin does not have a serious interaction with toremifene in this case, but it needed about 37.5% dose reduction which was comparable to the interaction of some common antibiotics with warfarin.

Process development for the total synthesis of the novel drug metabolite Carboxy toremifene as a standard reference material along with characterization and purity assessment for the Antidoping quality Control Purposes.

Tamoxifen and toremifene are two selective estrogen receptor modulators (SERMs) commonly used to treat breast cancer in women. Toremifene is well-known as a triphenylethylene derivative. Carboxy toremifene is a common metabolite of toremifene and tamoxifen. Since 2005, the World Anti-Doping Agency (WADA) has banned the SERMs category during in and out of competition. These substances are in the S4 category in the WADA prohibited list as "agents with anti-oestrogenic activity." However, there is no commercially accessible carboxy toremifene reference material in the market. This research highlights the novel synthetic procedure, the development of a carboxy toremifene HPLC method, and validation, along with detailed characterization using advanced analytical techniques using 1 H NMR, HRMS, FT-IR-ATR and UV-visible spectroscopy. RP-HPLC-DAD method was developed and validated to assess the purity of carboxy toremifene. Developed reference material has shown 100% purity. Therefore, we recommend that this synthesized carboxy toremifene may be used as reference material to strengthen the WADA-accredited lab to maintain a clean sports mission during sports competitions.

Treatment patterns and clinical outcomes in patients with metastatic breast cancer treated with palbociclib-based therapies: real-world data in the Han population.

BACKGROUND: This study aimed to reveal the treatment patterns and clinical outcomes of diverse palbociclib-based regimens in Han patients with estrogen receptor-positive (ER+) metastatic breast cancer in routine clinical practice. METHODS: The clinical data of patients with ER+ metastatic breast cancer treated with palbociclib were collected from the National Cancer Center database. The efficacy profile of palbociclib in this Han population was evaluated, especially for various combination regimens. The efficacy of palbociclib-based therapy in patients with prior everolimus treatment was also assessed. RESULTS: A total of 186 patients from 89 cities in 18 provinces in China were enrolled. The median progression-free survival (PFS) was similar among different palbociclib-combined groups ( P  = 0.566): 10.0 months (95% confidence interval [CI] 3.8-16.1) in the +exemestane group, 9.7 months (95% CI 6.3-13.1) in the +letrozole group, 7.8 months (95% CI 5.5-10.2) in the +fulvestrant group, 7.2 months (95% CI 3.2-11.3) in the +toremifene group, and 6.1 months (95% CI 1.2-11.0) in the +anastrozole group. Thirty-four patients (18.3%) had received everolimus for their metastatic disease before the prescription of palbociclib. The disease control rate was significantly lower in patients who had received previous everolimus than in the everolimus-naïve group (50.0% vs . 82.2%, P  < 0.001). Patients pre-treated with everolimus had significantly worse PFS than those in the everolimus-naïve group (3.4 months vs . 8.8 months, P   =  0.001). After propensity score matching, patients pre-treated with everolimus had similar PFS (4.4 months, 95% CI 0.5-8.2) compared with everolimus-naïve patients (6.1 months, 95% CI 4.7-7.5, P   =  0.439). CONCLUSIONS: Various palbociclib-based regimens have promising efficacy in ER+ metastatic breast cancer in real-world settings, even in patients who had been pre-treated with everolimus.

Chinese breast cancer patients with CYP2D6*10 mutant genotypes have a better prognosis with toremifene than with tamoxifen.

PURPOSE: To evaluate the prognosis of estrogen receptor-positive breast cancer patients with CYP2D6*10 mutant genotypes under tamoxifen or toremifen therapy. METHODS: Estrogen receptor-positive breast cancer patients were selected and CYP2D6*10 genotypes (C/C, C/T, and T/T) were determined by Sanger sequencing. Patients were divided into tamoxifen, toremifene, or tamoxifen + toremifene groups according to prior therapy. The correlation between CYP2D6*10 genotype and disease-free survival was analyzed. RESULTS: In total, 293 estrogen receptor-positive breast cancer patients treated with tamoxifen or toremifene between 2008 and 2017 were studied. Median follow-up was 39 months (10-141). Of these, 107 (36.52%), 112 (38.23%), and 74 (25.26%) patients had C/C, C/T, and T/T genotypes, respectively. Genotype was significantly associated with disease-free survival in tamoxifen patients. Patients with C/T and T/T genotypes showed worse disease-free survival than patients with a C/C genotype. Genotype and disease-free survival in toremifene and tamoxifen+toremifene patients were not correlated. Of patients with a C/T genotype, toremifene or tamoxifen+toremifene groups showed better disease-free survival than tamoxifen patients. Although disease-free survival of patients with a T/T genotype in the three groups was not statistically different, tamoxifen patients showed worse disease-free survival. There was no correlation between different treatments and disease-free survival in patients with a C/C genotype. Cox proportional hazard analysis revealed toremifene patients had a better prognosis than tamoxifen patients; toremifene was an independent protective factoremifene for disease-free survival. CONCLUSIONS: Tamoxifen was less effective in patients with CYP2D6*10 C/T and T/T genotypes. Estrogen receptor-positive breast cancer patients with a CYP2D6*10 mutation genotype have a better prognosis with toremifen than tamoxifen.

Comparison of adverse drug reactions between tamoxifen and toremifene in breast cancer patients with different CYP2D6 genotypes: A propensity-score matched cohort study.

CYP2D6 gene polymorphism has a profound impact upon the effect of tamoxifen as adjuvant endocrine therapy in breast cancer. However, it had never been reported whether the adverse drug reactions vary by CYP2D6 metabolic status for patients treated with tamoxifen or toremifene. We conducted a retrospective study in breast cancer patients to investigate the impact of CYP2D6 metabolic status on liver dysfunction events, gynecological events and dyslipidemia events. According to CYP2D6*10 (100C → T) genotype, the enrolled patients were further categorized into four cohorts (extensive metabolizers taking tamoxifen [EM + TAM], extensive metabolizers taking toremifene [EM + TOR], intermediate metabolizers taking tamoxifen [IM + TAM], and intermediate metabolizers taking toremifene [IM + TOR]). A total of 192 patients were included in the study, with a median follow-up time of 26.2 months. In EM + TAM cohort, the risks of liver dysfunction events (P = .004) and gynecological events (P = .004) were significantly higher compared to EM + TOR cohort. In IM + TAM cohort, the risks of liver dysfunction events (P = .14) and gynecological events (P = .99) were not significantly different from IM + TOR cohort. A significant decrease of total cholesterol was observed in EM + TAM cohort around 1 year after taking tamoxifen (P < .001). Significant interactions between CYP2D6 metabolic status and endocrine agents were observed in terms of liver dysfunction events (P-interaction = .007) and gynecological events (P-interaction = .026). These findings suggested that CYP2D6 gene polymorphism played a significant role in predicting liver dysfunction, gynecological diseases and lipid metabolism changes among patients taking tamoxifen or toremifene.

Hormonally Regulated Myogenic miR-486 Influences Sex-specific Differences in Cancer-induced Skeletal Muscle Defects.

Cancer-induced skeletal muscle defects show sex-specific differences in severity with men performing poorly compared to women. Hormones and sex chromosomal differences are suggested to mediate these differences, but the functional skeletal muscle markers to document these differences are unknown. We show that the myogenic microRNA miR-486 is a marker of sex-specific differences in cancer-induced skeletal muscle defects. Cancer-induced loss of circulating miR-486 was more severe in men with bladder, lung, and pancreatic cancers compared to women with the same cancer types. In a syngeneic model of pancreatic cancer, circulating and skeletal muscle loss of miR-486 was more severe in male mice compared to female mice. Estradiol (E2) and the clinically used selective estrogen receptor modulator toremifene increased miR-486 in undifferentiated and differentiated myoblast cell line C2C12 and E2-inducible expression correlated with direct binding of estrogen receptor alpha (ERα) to the regulatory region of the miR-486 gene. E2 and toremifene reduced the actions of cytokines such as myostatin, transforming growth factor ß, and tumor necrosis factor α, which mediate cancer-induced skeletal muscle wasting. E2- and toremifene-treated C2C12 myoblast/myotube cells contained elevated levels of active protein kinase B (AKT) with a corresponding decrease in the levels of its negative regulator PTEN, which is a target of miR-486. We propose an ERα:E2-miR-486-AKT signaling axis, which reduces the deleterious effects of cancer-induced cytokines/chemokines on skeletal muscle mass and/or function.

Effects of Tamoxifen vs. Toremifene on fatty liver development and lipid profiles in breast Cancer.

BACKGROUND: Tamoxifen (TAM) and Toremifene (TOR), two kinds of selective estrogen receptor modulators (SERMs), have equal efficacy in breast cancer patients. However, TAM has been proved to affect serum lipid profiles and cause fatty liver disease. The study aimed to compare the effects of TAM and TOR on fatty liver development and lipid profiles. METHODS: This study performed a retrospective analysis of 308 SERMs-treated early breast cancer patients who were matched 1:1 based on propensity scores. The follow-up period was 3 years. The primary outcomes were fatty liver detected by ultrasonography or computed tomography (CT), variation in fibrosis indexes, and serum lipid profiles change. RESULTS: The cumulative incidence rate of new-onset fatty liver was higher in the TAM group than in the TOR group (113.2 vs. 67.2 per 1000 person-years, p < 0.001), and more severe fatty livers occurred in the TAM group (25.5 vs. 7.5 per 1000 person-years, p = 0.003). According to the Kaplan-Meier curves, TAM significantly increased the risk of new-onset fatty liver (25.97% vs. 17.53%, p = 0.0243) and the severe fatty liver (5.84% vs. 1.95%, p = 0.0429). TOR decreased the risk of new-onset fatty liver by 45% (hazard ratio = 0.55, p = 0.020) and showed lower fibrotic burden, independent of obesity, lipid, and liver enzyme levels. TOR increased triglycerides less than TAM, and TOR increased high-density lipoprotein cholesterol, while TAM did the opposite. No significant differences in total cholesterol and low-density lipoprotein cholesterol are observed between the two groups. CONCLUSIONS: TAM treatment is significantly associated with more severe fatty liver disease and liver fibrosis, while TOR is associated with an overall improvement in lipid profiles, which supports continuous monitoring of liver imaging and serum lipid levels during SERM treatment.

Effect of Toremifene on Endometrium and Neurocognitive Function in Patients with Breast Cancer Based on Resting-State Functional Magnetic Resonance Imaging.

In this study, the characteristics of hemodynamic changes with use of toremifene before and after neoadjuvant chemotherapy in breast cancer treatment were analyzed using resting-state functional magnetic resonance imaging. Also, the effect of toremifene on the quality of life of patients with advanced breast cancer was analyzed. The study population comprised 100 patients who received endocrine therapy after breast cancer surgery in our hospital from January 2016 to January 2019. Patients were randomly divided into an observation group and a control group, with 50 cases in each group. The observation group was treated with tamoxifen combined with toremifene treatment; the control group was treated with toremifene. Before and after chemotherapy, the same scheme was used to perform dynamic contrast-enhanced imaging of the breast using a 1.5T superconducting scanner with 3 mL/second bolus injection of adiphenine meglumine 0.2 mmol/kg. Semiquantitative blood flow measurement was completed on the workstation and before and after chemotherapy to compare results. The patient's quality of life, progesterone and estrogen levels, social function, physical function, mental function, and material function were analyzed. The mean values of the early enhancement parameters Efirst, Vfirst, Ee, and Ve before chemotherapy were greater than in the residual lesions after chemotherapy (P < 0.5). The semiquantitative study of resting brain function before and after breast cancer neoadjuvant chemotherapy showed that the hemodynamics of the residual lesions were significantly reduced, and the blood flow rate was significantly reduced. Compared with the clinical effect of tamoxifen in the treatment of breast cancer after surgery, tamoxifen combined with toremifene has more advantages in improving quality of life, improving progesterone levels, and reducing estrogen levels, and it has no detrimental effects on the endometrium.

Efficacy of everolimus combined with endocrine therapy in HR-positive/HER-2-negativeadvanced breast cancer.

PURPOSE: To explore the efficacy and safety of everolimus combined with endocrine therapy in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER-2)-negative advanced breast cancer. METHODS: The clinical information of 108 patients with HR-positive/HER-2-negative advanced breast cancer, who were admitted to and treated in our hospital from June 2014 to June 2016, was retrospectively analyzed. Of them, 54 patients were treated with everolimus combined with endocrine drugs (Everolimus group), while the other 54 patients underwent endocrine monotherapy (Control group). The clinical response rate and incidence of adverse reactions were compared between the two groups of patients, and the patients were followed up to record survival. Besides, the possible influencing factors for progression-free survival (PFS) were analyzed. RESULTS: The objective response rate (ORR) was 22.2% and 14.8%, respectively, in everolimus group and the Control group, while the clinical benefit rate (CBR) was 66.7% and 37.0%, respectively, in the two groups. There were statistically significant differences in the CBRs of the first-line and second-line therapies. The majority of adverse reactions were in grade I and II, with lower incidence rates of grade III and IV adverse reactions. The median PFS of the two groups of patients was 7.3±5.6 months and 6.7±5.1 months, respectively. The log-rank test revealed that there was a statistically significant difference in the PFS between the two groups of patients. According to the multivariate regression analysis results, progesterone receptor (PR)+, absence of visceral metastases, and sensitivity to endocrine therapy were the protective prognostic factors for PFS. CONCLUSION: Everolimus combined with endocrine therapy has significant clinical efficacy in patients with HR-positive/HER-2-negative advanced breast cancer, and can effectively improve the survival of patients with tolerable adverse reactions. PR+, absence of visceral metastases and sensitivity to endocrine therapy are the protective prognostic factors for PFS.

Repurposing of FDA-Approved Toremifene to Treat COVID-19 by Blocking the Spike Glycoprotein and NSP14 of SARS-CoV-2.

The global pandemic of Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to the death of more than 675,000 worldwide and over 150,000 in the United States alone. However, there are currently no approved effective pharmacotherapies for COVID-19. Here, we combine homology modeling, molecular docking, molecular dynamics simulation, and binding affinity calculations to determine potential targets for toremifene, a selective estrogen receptor modulator which we have previously identified as a SARS-CoV-2 inhibitor. Our results indicate the possibility of inhibition of the spike glycoprotein by toremifene, responsible for aiding in fusion of the viral membrane with the cell membrane, via a perturbation to the fusion core. An interaction between the dimethylamine end of toremifene and residues Q954 and N955 in heptad repeat 1 (HR1) perturbs the structure, causing a shift from what is normally a long, helical region to short helices connected by unstructured regions. Additionally, we found a strong interaction between toremifene and the methyltransferase nonstructural protein (NSP) 14, which could be inhibitory to viral replication via its active site. These results suggest potential structural mechanisms for toremifene by blocking the spike protein and NSP14 of SARS-CoV-2, offering a drug candidate for COVID-19.

A Virion-Based Assay for Glycoprotein Thermostability Reveals Key Determinants of Filovirus Entry and Its Inhibition.

Ebola virus (EBOV) entry into cells is mediated by its spike glycoprotein (GP). Following attachment and internalization, virions traffic to late endosomes where GP is cleaved by host cysteine proteases. Cleaved GP then binds its cellular receptor, Niemann-Pick C1. In response to an unknown cellular trigger, GP undergoes conformational rearrangements that drive fusion of viral and endosomal membranes. The temperature-dependent stability (thermostability) of the prefusion conformers of class I viral fusion glycoproteins, including those of filovirus GPs, has provided insights into their propensity to undergo fusion-related rearrangements. However, previously described assays have relied on soluble glycoprotein ectodomains. Here, we developed a simple enzyme-linked immunosorbent assay (ELISA)-based assay that uses the temperature-dependent loss of conformational epitopes to measure thermostability of GP embedded in viral membranes. The base and glycan cap subdomains of all filovirus GPs tested suffered a concerted loss of prefusion conformation at elevated temperatures but did so at different temperature ranges, indicating virus-specific differences in thermostability. Despite these differences, all of these GPs displayed reduced thermostability upon cleavage to GP conformers (GPCL). Surprisingly, acid pH enhanced, rather than decreased, GP thermostability, suggesting it could enhance viral survival in hostile endo/lysosomal compartments. Finally, we confirmed and extended previous findings that some small-molecule inhibitors of filovirus entry destabilize EBOV GP and uncovered evidence that the most potent inhibitors act through multiple mechanisms. We establish the epitope-loss ELISA as a useful tool for studies of filovirus entry, engineering of GP variants with enhanced stability for use in vaccine development, and discovery of new stability-modulating antivirals.IMPORTANCE The development of Ebola virus countermeasures is challenged by our limited understanding of cell entry, especially at the step of membrane fusion. The surface-exposed viral protein, GP, mediates membrane fusion and undergoes major structural rearrangements during this process. The stability of GP at elevated temperatures (thermostability) can provide insights into its capacity to undergo these rearrangements. Here, we describe a new assay that uses GP-specific antibodies to measure GP thermostability under a variety of conditions relevant to viral entry. We show that proteolytic cleavage and acid pH have significant effects on GP thermostability that shed light on their respective roles in viral entry. We also show that the assay can be used to study how small-molecule entry inhibitors affect GP stability. This work provides a simple and readily accessible assay to engineer stabilized GP variants for antiviral vaccines and to discover and improve drugs that act by modulating GP stability.