Patient-reported outcome and survival in premenopausal hormone receptor-positive breast cancer patients at moderate to high risk: comparing toremifene with aromatase inhibitor in a real-world study.

Toremifene, a selective estrogen receptor modulator, is commonly used in China for premenopausal breast cancer patients. This real-world study aimed to compare patient-reported outcome (PRO) and survival between toremifene and aromatase inhibitor (AI) plus ovarian function suppression (OFS) in patients with moderate-/high-risk premenopausal hormone receptor (HR)-positive breast cancer. The primary endpoint was PROs, assessed using SF-36 and EQ-5D-5L questionnaires between January and March 2023. A total of 392 patients were included, with 171 receiving toremifene and 221 receiving AI. The toremifene group showed significantly higher scores in the role physical (p = 0.034) and mental health (p = 0.009) dimensions of SF-36 and lower anxiety/depression (AD) scores (p = 0.038) in EQ-5D-5L compared to AI group. The estimated 5- and 8-year disease-free survival (DFS) rates were similar in toremifene and AI groups: 96.5% versus 91.9%, and 87.4% versus 87.8% (p = 0.39), respectively. Adverse event rates were similar in two groups, except for a greater risk of endometrial thickening (p < 0.001) and a lower occurrence of morning stiffness (p < 0.001) in the toremifene compared to the AI group. Premenopausal HR-positive breast cancer patients receiving toremifene plus OFS had better role physical and mental health outcomes and lower AD dimensions than those receiving AI plus OFS. Both treatments had comparable DFS and favorable tolerability profiles.

Research Progress on Spike-Dependent SARS-CoV-2 Fusion Inhibitors and Small Molecules Targeting the S2 Subunit of Spike.

Since the beginning of the COVID-19 pandemic, extensive drug repurposing efforts have sought to identify small-molecule antivirals with various mechanisms of action. Here, we aim to review research progress on small-molecule viral entry and fusion inhibitors that directly bind to the SARS-CoV-2 Spike protein. Early in the pandemic, numerous small molecules were identified in drug repurposing screens and reported to be effective in in vitro SARS-CoV-2 viral entry or fusion inhibitors. However, given minimal experimental information regarding the exact location of small-molecule binding sites on Spike, it was unclear what the specific mechanism of action was or where the exact binding sites were on Spike for some inhibitor candidates. The work of countless researchers has yielded great progress, with the identification of many viral entry inhibitors that target elements on the S1 receptor-binding domain (RBD) or N-terminal domain (NTD) and disrupt the S1 receptor-binding function. In this review, we will also focus on highlighting fusion inhibitors that target inhibition of the S2 fusion function, either by disrupting the formation of the postfusion S2 conformation or alternatively by stabilizing structural elements of the prefusion S2 conformation to prevent conformational changes associated with S2 function. We highlight experimentally validated binding sites on the S1/S2 interface and on the S2 subunit. While most substitutions to the Spike protein to date in variants of concern (VOCs) have been localized to the S1 subunit, the S2 subunit sequence is more conserved, with only a few observed substitutions in proximity to S2 binding sites. Several recent small molecules targeting S2 have been shown to have robust activity over recent VOC mutant strains and/or greater broad-spectrum antiviral activity for other more distantly related coronaviruses.

The Dual-Targeted Fusion Inhibitor Clofazimine Binds to the S2 Segment of the SARS-CoV-2 Spike Protein.

Clofazimine and Arbidol have both been reported to be effective in vitro SARS-CoV-2 fusion inhibitors. Both are promising drugs that have been repurposed for the treatment of COVID-19 and have been used in several previous and ongoing clinical trials. Small-molecule bindings to expressed constructs of the trimeric S2 segment of Spike and the full-length SARS-CoV-2 Spike protein were measured using a Surface Plasmon Resonance (SPR) binding assay. We demonstrate that Clofazimine, Toremifene, Arbidol and its derivatives bind to the S2 segment of the Spike protein. Clofazimine provided the most reliable and highest-quality SPR data for binding with S2 over the conditions explored. A molecular docking approach was used to identify the most favorable binding sites on the S2 segment in the prefusion conformation, highlighting two possible small-molecule binding sites for fusion inhibitors. Results related to molecular docking and modeling of the structure-activity relationship (SAR) of a newly reported series of Clofazimine derivatives support the proposed Clofazimine binding site on the S2 segment. When the proposed Clofazimine binding site is superimposed with other experimentally determined coronavirus structures in structure-sequence alignments, the changes in sequence and structure may rationalize the broad-spectrum antiviral activity of Clofazimine in closely related coronaviruses such as SARS-CoV, MERS, hCoV-229E, and hCoV-OC43.

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).

Quantum biochemical analysis of the binding interactions between a potential inhibitory drug and the Ebola viral glycoprotein.

Ebola virus disease (EVD) causes outbreaks and epidemics in West Africa that persist until today. The envelope glycoprotein of Ebola virus (GP) consists of two subunits, GP1 and GP2, and plays a key role in anchoring or fusing the virus to the host cell in its active form on the virion surface. Toremifene (TOR) is a ligand that mainly acts as an estrogen receptor antagonist; however, a recent study showed a strong and efficient interaction with GP. In this context, we aimed to evaluate the energetic affinity features involved in the interaction between GP and toremifene by computer simulation techniques using the Molecular Fractionation Method with Conjugate Caps (MFCC) scheme and quantum-mechanical (QM) calculations, as well as missense mutations to assess protein stability. We identified ASP522, GLU100, TYR517, THR519, LEU186, LEU515 as the most attractive residues in the EBOV glycoprotein structure that form the binding pocket. We divided toremifene into three regions and evaluated that region i was more important than region iii and region ii for the formation of the TOR-GP1/GP2 complex, which might control the molecular remodeling process of TOR. The mutations that caused more destabilization were ARG134, LEU515, TYR517 and ARG559, while those that caused stabilization were GLU523 and ASP522. TYR517 is a critical residue for the binding of TOR, and is highly conserved among EBOV species. Our results may help to elucidate the mechanism of drug action on the GP protein of the Ebola virus and subsequently develop new pharmacological approaches against EVD.Communicated by Ramaswamy H. Sarma.

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.

Endometrial Adenofibroma in a Patient Receiving Toremifene: A Case Report

INTRODUCTION: Adenofibroma is a rare benign Müllerian mixed tumor composed of epithelial and mesenchymal cells. This tumor may occasionally be associated with toremifene therapy which is used as an adjuvant drug for breast cancer. CASE PRESENTATION: We describe a case of a 55-year-old woman with adenofibroma of the endometrium. This patient was receiving toremifene after surgery and neoadjuvant chemotherapy for breast cancer. She underwent a total abdominal hysterectomy and bilateral salpingectomy. There was no evidence of tumor residual or recurrence at 32 months of MRI follow-up. CONCLUSION: In conclusion, we report a rare case of endometrial adenofibroma in a patient receiving toremifene. It must be borne in mind that long-term toremifene therapy may increase the frequency of endometrial neoplasms.

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.

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.