-
Viruses Apr 2024Clofazimine 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...
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.
Topics: Humans; Antiviral Agents; Binding Sites; Clofazimine; COVID-19 Drug Treatment; Indoles; Molecular Docking Simulation; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Structure-Activity Relationship; Sulfides; Surface Plasmon Resonance; Viral Fusion Protein Inhibitors
PubMed: 38675980
DOI: 10.3390/v16040640 -
Lipids in Health and Disease Jan 2024Endocrine drugs may affect lipid metabolism in breast cancer (BC) patients. This study explores lipid changes in early-stage BC patients taking different endocrine drugs.
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 (β = 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).
Topics: Humans; Female; Breast Neoplasms; Cholesterol, LDL; Retrospective Studies; Letrozole; Toremifene; Triglycerides
PubMed: 38191454
DOI: 10.1186/s12944-024-02002-6 -
Thoracic Cancer Feb 2024Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-positive (HER2+) breast cancer exhibits considerable heterogeneity, and it is of great interest...
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.
Topics: Humans; Adult; Female; Breast Neoplasms; Trastuzumab; Follow-Up Studies; Prognosis; Toremifene; Retrospective Studies; Tamoxifen; Disease-Free Survival; Chemotherapy, Adjuvant
PubMed: 38185807
DOI: 10.1111/1759-7714.15211 -
BMC Women's Health Jan 2024It is widely recognized that cancer itself is related to increased risk of thromembolism. Venous thromboembolism is relatively common in breast cancer patients, but... (Review)
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.
Topics: Female; Humans; Middle Aged; Breast Neoplasms; Toremifene; Mesenteric Artery, Superior; Thrombosis; Venous Thrombosis
PubMed: 38172886
DOI: 10.1186/s12905-023-02855-6 -
Frontiers in Endocrinology 2023Despite the promising efficacy of the novel antibody-drug conjugate trastuzumab deruxtecan in treating Hormone Receptor (HoR)-positive/Human Epidermal Growth Factor...
OBJECTIVE
Despite the promising efficacy of the novel antibody-drug conjugate trastuzumab deruxtecan in treating Hormone Receptor (HoR)-positive/Human Epidermal Growth Factor Receptor 2 (HER2)-low metastatic breast cancer (MBC), its categorization as a distinct entity remains disputed, as does the divergence in its endocrine and chemotherapy outcomes. This study aimed to elucidate the clinical characteristics, primary/metastatic lesion HER2 expression, and treatment outcomes of HoR-positive/HER2-low patients.
METHODS
We included HoR-positive/HER2-negative MBC patients who underwent 1 and 2 line endocrine treatment from July 2010 to October 2022 at the Fudan University Shanghai Cancer Center, comparing the clinical pathological characteristics, HER2 expression in primary/metastatic lesions, treatment, and therapeutic effects of the HER2-low and HER2-zero groups.
RESULTS
Among the 458 HoR-positive/HER2-negative MBC patients, 54.37% (249/458) were HER2-low. The HER2-low group and the HER2-zero group had similar clinical pathological characteristics and similar progression-free survival (PFS) of 1 and 2 line endocrine treatment (median PFS: 8.05 months vs 10.12 months, p=0.114, HR 1.257, 95% CI 0.771 to 1.028). The PFS of the HER2-low and HER2-zero groups was also similar, treated with different endocrine drugs (including aromatase inhibitors, tamoxifen/toremifene, fulvestrant, palbociclib, and everolimus). However, the HER2-low group had significantly shorter PFS during 1 and 2 line chemotherapy compared to the HER2-zero group (median PFS: 8.64 vs 9.03 months, p=0.027, HR 0.841, 95% CI 0.721-0.980). Additionally, 41.18% (63/153) of patients exhibited a change in HER2 expression between primary and metastatic lesions. Notably, patients whose HER2 status changed from zero to low expression had significantly prolonged PFS during chemotherapy compared to those who maintained low HER2 expression (median PFS: 14.29 vs 11.27 months, p=0.048, HR 0.597, 95% CI 0.358-0.996).
CONCLUSION
In HoR-positive MBC, patients with low and zero HER2 expression have similar clinical characteristics and respond similarly to endocrine treatment, but the chemotherapy effect is worse in the HER2-low patients. Moreover, the transformation of HER2 status from primary to metastatic lesions may have potential influence on chemotherapy outcomes. Therefore, the expression and heterogeneity of HER2 should be considered in clinical decisions.
Topics: Humans; Female; Breast Neoplasms; Antineoplastic Combined Chemotherapy Protocols; China; Treatment Outcome; Progression-Free Survival
PubMed: 37881502
DOI: 10.3389/fendo.2023.1270453 -
Cancer Research and Treatment Jan 2024Tamoxifen showed individual differences in efficacy under different CYP2D6*10 genotypes. Our study evaluated the prognosis of tamoxifen or toremifene in hormone receptor...
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.
Topics: Humans; Female; Tamoxifen; Toremifene; Breast Neoplasms; Cytochrome P-450 CYP2D6; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Genotype
PubMed: 37591782
DOI: 10.4143/crt.2023.652 -
Frontiers in Medicine 2023A superficial cervical vaginal myofibroblastoma is a rare mesenchymal tumor, originating from the superficial stroma of the vagina and cervix. This study reports a...
INTRODUCTION
A superficial cervical vaginal myofibroblastoma is a rare mesenchymal tumor, originating from the superficial stroma of the vagina and cervix. This study reports a patient, who was diagnosed with endometrioid carcinoma and a concomitant benign superficial cervicovaginal myofibroblastoma.
CASE PRESENTATION
A 53-year-old female with endometrial carcinoma was admitted to the Department of Gynecology of our hospital. She had a history of breast cancer on May 23, 2010, and took toremifene citrate for 41 months. Radical resection of the endometrial carcinoma was performed at our hospital. Based on the pathological findings, she was postoperatively diagnosed with endometrial adenocarcinoma with superficial cervical vaginal myofibroblastoma. The patient continued receiving postoperative breast cancer treatment. She underwent follow-up for 23 months. No recurrence or metastasis of the endometrial cancer or superficial cervical vaginal myofibroblastoma was observed.
CONCLUSION
There were similarities between superficial cervical vaginal myofibroblastoma and other mesenchymal tumors of the female genital tract. Superficial cervical vaginal myofibroblastomas have a good prognosis, and the combination of tissue morphology and immunohistochemistry helped establish a definitive diagnosis.
PubMed: 37081843
DOI: 10.3389/fmed.2023.1160273 -
Archives of Pathology & Laboratory... Sep 2023Whether androgen receptor (AR) expression can predict prognosis in breast cancer is under debate.
CONTEXT.—
Whether androgen receptor (AR) expression can predict prognosis in breast cancer is under debate.
OBJECTIVE.—
To analyze, retrospectively, the prognostic and treatment-predictive ability of AR status in breast cancer.
DESIGN.—
A total of 5765 patients diagnosed with primary invasive breast cancer without distant metastasis in the adjuvant setting were analyzed. The propensity score-matching method was used to develop a new cohort of 3978 patients (1989 patients each) in which important prognostic factors were balanced.
RESULTS.—
Positive AR expression is an independent prognostic factor for disease-free survival and overall survival. Estrogen receptor (ER)+ and progesterone receptor (PR)+ AR+ breast cancer patients had the longest survival, whereas ER-PR-AR- breast cancer patients had the shortest survival. The ER/PR/AR combinations could not predict the treatment effects for adjuvant trastuzumab but could be used for adjuvant chemotherapy and endocrine therapy selection. The worst survival was found in ER+PR-AR- patients receiving toremifene, ER+PR-AR+ patients receiving exemestane, ER+PR+AR- patients receiving anthracycline, and ER-PR-AR+ patients receiving taxanes. ER+PR-AR-, ER-PR-AR+, and ER-PR-AR- patients were associated with the worst survival among those who received radiotherapy and anthracycline plus taxanes.
CONCLUSIONS.—
AR in combination with ER and PR could predict the prognosis and treatment effects of chemotherapy, endocrine therapy, and radiotherapy in the adjuvant setting.
Topics: Humans; Female; Breast Neoplasms; Prognosis; Receptors, Androgen; Retrospective Studies; Receptors, Estrogen; Anthracyclines; Taxoids; Receptors, Progesterone
PubMed: 36508355
DOI: 10.5858/arpa.2021-0590-OA -
Chinese Medical Journal Jul 2022This study aimed to reveal the treatment patterns and clinical outcomes of diverse palbociclib-based regimens in Han patients with estrogen receptor-positive (ER+)...
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.
Topics: Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Everolimus; Female; Fulvestrant; Humans; Letrozole; Piperazines; Pyridines; Receptor, ErbB-2; Receptors, Estrogen; Toremifene
PubMed: 35984107
DOI: 10.1097/CM9.0000000000002240 -
Journal of Medical Virology Oct 2022Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the seventh member of the coronavirus family that can infect humans. Recently, more contagious and...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the seventh member of the coronavirus family that can infect humans. Recently, more contagious and pathogenic variants of SARS-CoV-2 have been continuously emerging. Clinical candidates with high efficacy and ready availability are still in urgent need. To identify potent anti-SARS-CoV-2 repurposing drugs, we evaluated the antiviral efficacy of 18 selective estrogen receptor modulators (SERMs) against SARS-CoV-2 infection. Six SERMs exhibited excellent anti-SARS-CoV-2 effects in Vero E6 cells and three human cell lines. Clomifene citrate, tamoxifen, toremifene citrate, and bazedoxifene acetate reduced the weight loss of hamsters challenged with SARS-CoV-2, and reduced hamster pulmonary viral load and interleukin-6 expression when assayed at 4 days postinfection. In particular, bazedoxifene acetate was identified to act on the penetration stage of the postattachment step via altering cholesterol distribution and endosome acidification. And, bazedoxifene acetate inhibited pseudoviruses infection of original SARS-CoV-2, Delta variant, Omicron variant, and SARS-CoV. These results offer critical information supporting bazedoxifene acetate as a promising agent against coronaviruses.
Topics: Antiviral Agents; Humans; Indoles; SARS-CoV-2; Selective Estrogen Receptor Modulators; COVID-19 Drug Treatment
PubMed: 35733297
DOI: 10.1002/jmv.27951