Silmitasertib (CX-4945) Disrupts ERα/HSP90 Interaction and Drives Proteolysis through the Disruption of CK2ß Function in Breast Cancer Cells.

Aberrant estrogen receptor (ERα) signaling mediates detrimental effects of tamoxifen including drug resistance and endometrial hyperplasia. ERα36, an alternative isoform of ERα, contributes to these effects. We have demonstrated that CK2 modulates ERα expression and function in breast cancer (BCa). Here, we assess if CX-4945 (CX), a clinical stage CK2 inhibitor, can disrupt ERα66 and ERα36 signaling in BCa. Using live cell imaging, we assessed the antiproliferative effects of CX in tamoxifen-sensitive and tamoxifen-resistant BCa cells in monolayer and/or spheroid cultures. CX-induced alterations in ERα66 and ERα36 mRNA and protein expression were assessed by RT-PCR and immunoblot. Co-immunoprecipitation was performed to determine the differential interaction of ERα isoforms with HSP90 and CK2 upon CX exposure. CX caused concentration-dependent decreases in proliferation in tamoxifen-sensitive MCF-7 and tamoxifen-resistant MCF-7 Tam1 cells and significantly repressed spheroid growth in 3D models. Additionally, CX caused dramatic decreases in endogenous or exogenously expressed ERα66 and ERα36 protein. Silencing of CK2ß, the regulatory subunit of CK2, resulted in destabilization and decreased proliferation, similar to CX. Co-immunoprecipitation demonstrated that ERα66/36 show CK2 dependance for interaction with molecular chaperone HSP90. Our findings show that CK2 functions regulate the protein stability of ERα66 and ERα36 through a mechanism that is dependent on CK2ß subunit and HSP90 chaperone function. CX may be a component of a novel therapeutic strategy that targets both tamoxifen-sensitive and tamoxifen-resistant BCa, providing an additional tool to treat ERα-positive BCa.

Tamoxifen metabolites treatment promotes ERα+ transition to triple negative phenotype in vitro, effects of LDL in chemoresistance.

OBJECTIVE: Estrogen receptor-positive (ER+) breast cancer represents about 80 % of cases, tamoxifen is the election neoadjuvant chemotherapy. However, a large percentage of patients develop chemoresistance, compromising recovery. Clinical evidence suggests that high plasmatic levels of low-density lipoproteins (LDL) could promote cancer progression. The present study analyzed the effect of LDL on the primary plasmatic active Tamoxifen´s metabolites resistance acquisition, 4-hydroxytamoxifen (4OH-Tam) and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen), in breast cancer ER+ cells (MCF-7). METHODS: Two resistant cellular variants, MCF-7Var-H and MCF-7Var-I, were generated by a novel strategy and their phenotype features were evaluated. Phenotypic assessment was performed by MTT assays, cytometry, immunofluorescence microscopy, zymography and protein expression analysis. RESULTS: MCF-7Var-H, generated only with tamoxifen metabolites, showed a critical down-regulation in hormone receptors, augmented migration capacity, metalloprotease 9 extracellular medium excretion, and a mesenchymal morphology in contrast with native MCF-7, suggesting the transition towards Triple-negative breast cancer (TNBC) phenotype. In contrast, MCF-7Var-I which was generated in a high LDL media, showed only a slight upregulation in ER and other less noticeable metabolic adaptations. Results suggest a potential role of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in phenotypic differences observed among variants. CONCLUSION: LDL high or low concentrations during Tamoxifen´s metabolites chemoresistance acquisition leads to different cellular mechanisms related to chemoresistance. A novel adaptative cellular response associated with Nrf2 activity could be implicated.

Citrus polymethoxyflavones degrade estrogen receptor-alpha (ERα) and combine with tamoxifen for the treatment of estrogen receptor-positive breast cancer.

Estrogen receptor-positive (ER+) breast cancer seriously endangers the women's physical and mental health worldwide and ER targeting therapy is vital. Here, we found that a citrus polymethoxyflavones (PMFs)-rich hydrolysate (C-H) and its major components (nobiletin and 3-methoxynobiletin) potently degrade ERα protein via the ubiquitin-proteasome pathway, thereby impairing the proliferation of ER+ breast cancer cells. Moreover, our study exhibited that C-H combined with tamoxifen (TAM) inhibited the cell proliferation of ER+ breast cancer in vitro. It was further confirmed that C-H decreased tumor growth of ER+ breast cancer in tumor-bearing 129 mice in vivo and improved the efficacy of tamoxifen. Our study revealed that the citrus PMFs have potential applications as pharmaceutical and healthcare products in breast cancer treatment by targeting ERα protein degradation.

Spontaneous coronary artery dissection in the context of tamoxifen; Is there any correlation?

Key Clinical Message: Clinicians should consider spontaneous coronary artery dissection in middle-aged women presenting with acute coronary syndromes and a history of tamoxifen use, to ensure timely diagnosis, and appropriate management strategies. Abstract: Spontaneous coronary artery dissection (SCAD) is characterized by a non-iatrogenic, nontraumatic separation of the coronary artery wall, contributing to acute coronary syndromes (ACS), and sudden cardiac death. SCAD predominantly affects the left anterior descending artery (LAD) and is frequently observed in middle-aged women. This condition has been associated with cancer treatment and exogenous hormones exposure. The diagnostic gold standard remains coronary angiography, management strategies include conservative measures, percutaneous coronary intervention (PCI), and coronary artery bypass graft surgery (CABG). We describe a case of a 54-year-old woman with breast cancer and a history of tamoxifen use, presenting with SCAD in the posterolateral branch (PLB) originating from the left circumflex artery (LCX), and right coronary artery (RCA) and managed conservatively.

HER4 Affects Sensitivity to Tamoxifen and Abemaciclib in Luminal Breast Cancer Cells and Restricts Tumor Growth in MCF-7-Based Humanized Tumor Mice.

The impact of the HER4 receptor on the growth and treatment of estrogen receptor-positive breast cancer is widely uncertain. Using CRISPR/Cas9 technology, we generated stable HER4 knockout variants derived from the HER4-positive MCF-7, T-47D, and ZR-75-1 breast cancer cell lines. We investigated tumor cell proliferation as well as the cellular and molecular mechanisms of tamoxifen, abemaciclib, AMG232, and NRG1 treatments as a function of HER4 in vitro. HER4 differentially affects the cellular response to tamoxifen and abemaciclib treatment. Most conspicuous is the increased sensitivity of MCF-7 in vitro upon HER4 knockout and the inhibition of cell proliferation by NRG1. Additionally, we assessed tumor growth and immunological effects as responses to tamoxifen and abemaciclib therapy in humanized tumor mice (HTM) based on MCF-7 HER4-wildtype and the corresponding HER4-knockout cells. Without any treatment, the enhanced MCF-7 tumor growth in HTM upon HER4 knockout suggests a tumor-suppressive effect of HER4 under preclinical but human-like conditions. This phenomenon is associated with an increased HER2 expression in MCF-7 in vivo. Independent of HER4, abemaciclib and tamoxifen treatment considerably inhibited tumor growth in these mice. However, abemaciclib-treated hormone receptor-positive breast cancer patients with tumor-associated mdm2 gene copy gains or pronounced HER4 expression showed a reduced event-free survival. Evidently, the presence of HER4 affects the efficacy of tamoxifen and abemaciclib treatment in different estrogen receptor-positive breast cancer cells, even to different extents, and is associated with unfavorable outcomes in abemaciclib-treated patients.

Fifteen-Centimeter Giant Tamoxifen-Associated Endometrial Polyp Presenting With Constipation: A Case Report and Review of the Literature.

Endometrial polyps are benign disorganized growth of endometrial glands and stroma in the uterine cavity. They are associated with subfertility, abnormal uterine bleeding, and tamoxifen use. While most polyps are smaller than 2 cm in size, rare giant polyps can cause concerns over malignancy. We report a case of a 15 cm giant endometrial polyp in a 58-year-old woman with a history of tamoxifen use who presented with an uncommon complaint of constipation. Additionally, a literature review of giant endometrial polyp cases is presented. This case represents the largest reported endometrial polyp to date.

Venous thromboembolism in women with hormone-dependent breast cancer. To continue or discontinue hormonal treatment? Insights from the RIETE registry.

INTRODUCTION: Hormone therapy (HT) for breast cancer is associated with an increased risk of venous thromboembolism (VTE). This study examines the effects of continuing versus discontinuing HT on VTE recurrence, major bleeding, and mortality, after an acute VTE event. METHODS: Using data in the RIETE-registry from March 2001 through September 2021, we calculated incidence rates and rate-ratios (RR) for VTE events in patients on- and off HT. Cox regression models assessed the impact of HT continuation. RESULTS: Among 479 women with breast cancer on HT who developed VTE (pulmonary embolism 279, isolated deep vein thrombosis 200), 350 (73 %) continued HT. These women were slightly older (70 ± 13 vs. 67 ± 16 years) than those discontinuing HT, with no significant differences in other baseline characteristics. Over a median follow-up of 294 days, 25 (5.2 %) developed VTE recurrences, 18 (3.7 %) had major bleeding, and 73 (15.2 %) died. Rates of VTE recurrence did not differ significantly between groups (RR: 1.28, 95 % CI 0.44-3.75), except in the first three months post-VTE, where a higher rate was observed in those continuing HT (6.02/100 patients-year vs. no events). On multivariable analysis, HT continuation showed no association with VTE recurrences after adjusting for other thromboembolic risk factors (adjusted hazard ratio [aHR] 1.49, 95 % CI 0.5-4.45). CONCLUSION: Continuing HT after a VTE event in women with breast cancer does not generally affect the long-term risk of VTE recurrences but is associated with a higher risk in the first three months. These findings highlight the need for careful monitoring during this period.

Risk of endometrial malignancy in women treated for breast cancer: the BLUSH prediction model - evidence from a comprehensive multicentric retrospective cohort study.

OBJECTIVE: This study aimed to evaluate characteristics of endometrial surveillance in women treated for breast cancer to build a clinical prediction model. DESIGN: A multicentric retrospective cohort study was conducted at two tertiary-care university hospitals from January 2020 to June 2023. Perimenopausal and postmenopausal women treated for breast cancer were categorized into two groups: patients with and without diagnosis of endometrial malignancy (endometrial carcinoma) or premalignancy (atypical endometrial hyperplasia). Characteristics of breast cancer and ultrasonographic and hysteroscopic examinations were compared. A prediction model for endometrial malignancy was built using logistic regression. Predictive accuracy was assessed using the receiver operating characteristic (ROC) curve and goodness of fit using the Hosmer-Lemeshow test. RESULTS: One hundred and thirty-two (28 with premalignancy or malignancy and 104 without malignancy) women were analyzed. A nomogram was produced for prediction model development utilizing the presence and duration in months of abnormal uterine (BL)eeding, ultrasound (US) vascular pattern and echogenicity and (H)ysteroscopic appearance of endometrium (BLUSH) as determined by logistic regression. Sensitivity and specificity were 79.17% and 95.19%, respectively, with an area under ROC curve of 0.965, indicating good accuracy. Good goodness of fit and prediction stability were indicated by the calibration curve and Hosmer-Lemeshow test (χ2 = 26.36; p = 0.999). CONCLUSIONS: Breast cancer survivors undergoing endometrial surveillance might benefit from a potentially useful prediction model based on hysteroscopic appearance, ultrasonographic uniformity of endometrium, Doppler flow and presence of abnormal uterine bleeding.

miR-770-5p-induced cellular switch to sensitize trastuzumab resistant breast cancer cells targeting HER2/EGFR/IGF1R bidirectional crosstalk.

Background/aim: Studies highlighted the bidirectional crosstalk between the HER family members in breast cancer as resistance mechanism to anti-HER agents. Cross-signaling between HER2/EGFR and ER/IGF1R could play role in the development of resistance to therapeutics hence stimulating cell growth. To overcome this resistance, combined therapies targeting both pathways simultaneously have been proposed as an effective strategy. The involvement of miRNAs in resistance of targeted therapies like trastuzumab was demonstrated in recent studies. Hence the regulation of miRNAs in resistance state could reverse the cell behaviour to drugs. Previously we found that overexpression of miR-770-5p downregulated AKT and ERK expression through HER2 signaling and potentiated the effect of trastuzumab. In this study we examined the impact of miR-770-5p on trastuzumab resistance. Materials and methods: Cells were treated with tamoxifen or trastuzumab to examine their role in bidirectional crosstalk. The molecule mechanism of miR-770-5p on HER2/EGFR/IGF1R bidirectional crosstalk was explored by western blot. The expression of miR-770-5p in trastuzumab resistant cells was examined by q-PCR. To investigate the effect of miR-770-5p on cancer cell proliferation in trastuzumab resistance state, resistant cells were analyzed by iCELLigence real-time cell analyzer. Results: miR-770-5p expression was significantly downregulated in trastuzumab-resistant BT-474 and SK-BR-3 cells. Overexpression of miR-770-5p sensitized the resistant cells to trastuzumab, as evidenced by reduced cell proliferation and increased cell viability. Additionally, in resistant cells, increased expression and activation of EGFR and IGF1R were observed. However, miR-770-5p overexpression resulted in decreased phosphorylation of AKT and ERK, indicating its suppressive role in EGFR/HER2 signaling. Furthermore, miR-770-5p downregulated the expression of IGF1R and mTOR, suggesting its involvement in regulating the escape signaling mediated by IGF1R in resistance. Conclusion: In conclusion, our findings demonstrate the critical role of miR-770-5p in regulating bidirectional crosstalk and overcoming trastuzumab resistance in breast cancer cells. These results highlight the potential of miR-770-5p as a therapeutic target to improve the efficacy of targeted therapies and address resistance mechanisms in breast cancer.

Adjuvant endocrine therapy choices in premenopausal patients with hormone receptor-positive early breast cancer: Insights from the prospective GIM23-POSTER study.

BACKGROUND: Most premenopausal patients with early breast cancer (eBC) are diagnosed with hormone receptor-positive disease and therefore candidate for adjuvant endocrine therapy (ET). PATIENTS AND METHODS: The Gruppo Italiano Mammella (GIM) 23-POSTER (GIM23) is a multicenter, prospective, observational study conducted in 26 Italian institutions, aiming to evaluate ET choices for premenopausal patients affected by hormone receptor-positive eBC in a real-world setting. Here we report also the results in terms of type of ET prescribed according to the definition of high-risk patients by monarchE and NATALEE trials. RESULTS: Between October 2019 and June 2022, 600 premenopausal patients were included, with a median age of 46 years. Almost half (271, 45.2 %) of the patients had stage I disease, while 254 (42.3 %) and 60 (10.0 %) patients had stage II and III, respectively. Overall, 149 (25.1 %) patients received tamoxifen alone, 83 (14.0 %) tamoxifen with ovarian function suppression (OFS), while 361 (60.9 %) received aromatase inhibitor (AI) with OFS. Patients treated with AI and OFS had higher number of metastatic axillary nodes, higher grade and more often received chemotherapy (all p < 0.001). According to the inclusion criteria of the monarchE and NATALEE trials, 81 patients (15.6 %) were considered high-risk for the monarchE and received AI with OFS in 88.9 % of the cases, while 231 patients (44.4 %) were considered high-risk for the NATALEE trial and received AI with OFS in 74.5 % of cases. CONCLUSIONS: AI with OFS is the most prescribed adjuvant ET among premenopausal patients, especially in the presence of high-risk features.

Inverse FASN and LDHA correlation drives metabolic resistance in breast cancer.

BACKGROUND: Breast cancer manifests as a heterogeneous pathology marked by complex metabolic reprogramming essential to satisfy its energy demands. Oncogenic signals boost the metabolism, modifying fatty acid synthesis and glucose use from the onset to progression and therapy resistant-forms. However, the exact contribution of metabolic dependencies during tumor evolution remains unclear. METHODS: In this study, we elucidate the connection between FASN and LDHA, pivotal metabolic genes, and their correlation with tumor grade and therapy response using datasets from public repositories. Subsequently, we evaluated the metabolic and proliferative functions upon FASN and LDHA inhibition in breast cancer models. Lastly, we integrated metabolomic and lipidomic analysis to define the contributions of metabolites, lipids, and precursors to the metabolic phenotypes. RESULTS: Collectively, our findings indicate metabolic shifts during breast cancer progression, unvealling two distinct functional energy phenotypes associated with aggressiveness and therapy response. Specifically, FASN exhibits reduced expression in advance-grade tumors and therapy-resistant forms, whereas LDHA demonstrates higher expression. Additionally, the biological and metabolic impact of blocking the enzymatic activity of FASN and LDHA was correlated with resistant conditions. CONCLUSIONS: These observations emphasize the intrinsic metabolic heterogeneity within breast cancer, thereby highlighting the relevance of metabolic interventions in the field of precision medicine.

Glutathione and Xanthine Metabolic Changes in Tamoxifen Resistant Breast Cancer Cell Lines are Mediated by Down-Regulation of GSS and XDH and Correlated to Poor Prognosis.

Background: Tamoxifen is commonly used in the treatment of hormonal-positive breast cancer. However, 30%-40% of tumors treated with tamoxifen develop resistance; therefore, an important step to overcome this resistance is to understand the underlying molecular and metabolic mechanisms. In the present work, we used metabolic profiling to determine potential biomarkers of tamoxifen resistance, and gene expression levels of enzymes important to these metabolites and then correlated the expression to the survival of patients receiving tamoxifen. Methods: Tamoxifen-resistant cell lines previously developed and characterized in our laboratory were metabolically profiled with nuclear magnetic resonance spectroscopy (NMR) using cryogenic probe, and the findings were correlated with the expression of genes that encode the key enzymes of the significant metabolites. Moreover, the effect of significantly altered genes on the overall survival of patients was assessed using the Kaplan-Meier plotter web tool. Results: We observed a significant increase in the levels of glutamine, taurine, glutathione, and xanthine, and a significant decrease in the branched-chain amino acids, valine, and isoleucine, as well as glutamate and cysteine in the tamoxifen-resistant cells compared to tamoxifen sensitive cells. Moreover, xanthine dehydrogenase and glutathione synthase gene expression were downregulated, whereas glucose-6-phosphate dehydrogenase was upregulated compared to control. Additionally, increased expression of xanthine dehydrogenase was associated with a better outcome for breast cancer patients. Conclusion: Overall, this study sheds light on metabolic pathways that are dysregulated in tamoxifen-resistant cell lines and the potential role of each of these pathways in the development of resistance.

Tamoxifen may contribute to preserve cardiac function in Duchenne muscular dystrophy.

Duchenne muscular dystrophy is life-limiting. Cardiomyopathy, which mostly ensues in the second decade of life, is the main cause of death. Treatment options are still limited. The TAMDMD (NCT03354039) trial assessed motor function, muscle strength and structure, laboratory biomarkers, and safety in 79 ambulant boys with genetically confirmed Duchenne muscular dystrophy, 6.5-12 years of age, receiving either daily tamoxifen 20 mg or placebo for 48 weeks. In this post-hoc analysis, available echocardiographic data of ambulant patients recruited at one study centre were retrieved and compared before and after treatment. Data from 14 patients, median 11 (interquartile range, IQR, 11-12) years of age was available. Baseline demographic characteristics were similar in participants assigned to placebo (n = 7) or tamoxifen (n = 7). Left ventricular end-diastolic diameter in the placebo group (median and IQR) was 39 (38-41) mm at baseline and 43 (38-44) mm at study end, while it was 44 (41-46) mm at baseline and 41 (37-46) mm after treatment in the tamoxifen group. Left ventricular fractional shortening in the placebo group was 35% (32-38%) before and 33% (32-36%) after treatment, while in the tamoxifen group it was 34% (33-34%) at baseline and 35% (33-35%) at study end. No safety signals were detected. CONCLUSION: This hypothesis-generating post-hoc analysis suggests that tamoxifen over 48 weeks is well tolerated and may help preserving cardiac structure and function in Duchenne muscular dystrophy. Further studies are justified. CLINICALTRIALS: gov Identifier: EudraCT 2017-004554-42, NCT03354039 What is known: • Duchenne muscular dystrophy (DMD) is life-limiting. Cardiomyopathy ensues in the second decade of life and is the main cause of death. Treatment options are still limited. • Tamoxifen reduced cardiac fibrosis in mice and improved cardiomyocyte function in human-induced pluripotent stem cell-derived cardiomyocytes. WHAT IS NEW: • In this post-hoc analysis of the TAMDMD trial among 14 boys, median 11 years of age, treated with either tamoxifen or placebo for 48 weeks, treatment was well-tolerated. • A visual trend of improved left-ventricular dimensions and better systolic function preservation generates the hypothesis of a potential beneficial effect of tamoxifen in DMD cardiomyopathy.

Tamoxifen modulates nutrition deprivation-induced ER stress through AMPK-mediated ER-phagy in breast cancer cells.

PURPOSE: Rapid proliferation and nutrition starvation in the tumor microenvironment pose significant challenges to cellular protein homeostasis. The accumulation of misfolded proteins in the endoplasmic reticulum lumen induces stress on cells and causes irreversible damage to cells if unresolved. Emerging reports emphasize the influence of the tumor microenvironment on therapeutic molecule efficacy and treatment outcomes. Hence, we aimed to understand the influence of tamoxifen on the cellular adaptation to endoplasmic reticulum stress during metabolic stress in breast cancer cells. METHODS: Nutrition deprivation induces endoplasmic reticulum stress (ER stress), and the unfolded protein response (UPR) in breast cancer cells was confirmed by a Thioflavin B assay and western blotting. Tamoxifen-indued ER-phagy was studied using an MCD assay, confocal microscopy, and western blotting. RESULTS: Nutrition deprivation induces ER stress in breast cancer cells. Interestingly, tamoxifen modulates the nutrition deprivation-induced endoplasmic reticulum stress through enhancing the selective ER-phagy, a specialized autophagy. The tamoxifen-induced ER-phagy is mediated by AMPK activation. The pharmacological inhibition of AMPK blocks tamoxifen-induced ER-phagy and tamoxifen modulatory effect on ER stress during nutrition deprivation. CONCLUSION: Tamoxifen modulates ER stress by inducing ER-phagy through AMPK, thereby, may support breast cancer cell survival during nutrition deprivation conditions.

Involvement of lysophosphatidic acid (LPA) receptor-mediated signaling in breast cancer cell functions by long-term tamoxifen treatment under hypoxic and estrogen-deprived conditions.

BACKGROUND: Tamoxifen (TAM) is a selective estrogen receptor modulator and has anti-estrogenic activity. Breast cancer cells acquire drug resistance to TAM as a consequence of long-term treatment. Lysophosphatidic acid (LPA) receptor-mediated signaling contributes to the promotion of tumor progression. This study aimed to evaluate the role of LPA receptors in the modulation of biological functions by long-term TAM treatment in breast cancer MCF-7 cells under hypoxic and estrogen-deprived conditions. METHODS: Long-term TAM treated (MCF-TAM) cells were generated from MCF-7 cells. Cells were cultured in estrogen-free medium at 1 % O2. LPA receptor expressions were measured by quantitative real-time RT-PCR analysis. Cell motile activity was investigated using Cell Culture Inserts. The CCK-8 kit was used to determine the cell proliferation rate. RESULTS: LPAR1 and LPAR3 expressions were elevated in MCF-TAM cells. MCF-TAM cell motility was enhanced by culturing at 1 % O2, compared with MCF-7 cells. When cells were cultured in estrogen-deprived medium at 1 % O2, the cell proliferation rate of MCF-TAM cells was significantly higher than that of MCF-7 cells. CONCLUSION: These results suggest that LPA receptor-mediated signaling plays an important role in the acquisition of malignant properties in long-term TAM treated MCF-7 cells under hypoxic and estrogen-deprived conditions.

Cost-effectiveness of adjuvant endocrine treatment with tamoxifen for male breast cancer.

BACKGROUND: Tamoxifen (TAM) is recommended as the first-line strategy for men with estrogen receptor (ER)-positive early breast cancer who are candidates for adjuvant endocrine therapy in ASCO guideline. Our study aims to analyze the cost-effectiveness of receiving adjuvant endocrine therapy with TAM compared to no TAM, and to assess the cost-effectiveness of using TAM with high adherence over low adherence for ER-positive early male breast cancer in the USA. METHODS: Two Markov models comprising three mutually exclusive health states were constructed: (1) the first Markov model compared the cost-effectiveness of adding TAM with not using TAM (TAM versus Not-TAM); (2) the second model compared the cost-effectiveness of receiving TAM with high adherence and low adherence (High-adherence-TAM versus Low-adherence-TAM). The simulation time horizon for both models was the lifetime of patients. The efficacy and safety data of two models were elicited from the real-world studies. Model inputs were derived from the US website and published literature. The main outcomes of two models both included the total cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: In the first model, TAM yielded an ICER of $5707.29 per QALY compared to Not-TAM, which was substantially below the WTP threshold of $50,000.00 per QALY in the USA. Probabilistic sensitivity analysis results demonstrated a 100.00% probability of cost-effectiveness for this strategy. In the second model, High-adherence-TAM was dominated absolutely compared to Low-adherence-TAM. The High-adherence-TAM was cost-effective with a 99.70% probability over Low-adherence-TAM when WTP was set as $50,000.00/QALY. All of these parameters within their plausible ranges did not reversely change the results of our models. CONCLUSIONS: Our study will offer valuable guidance for physicians or patients when making treatment decisions and provide an effective reference for decision-making to consider the appropriate allocation of funds to this special group.

Investigating the tamoxifen/high-fat diet synergy: a promising paradigm for nonalcoholic steatohepatitis induction in a rat model.

Non-alcoholic steatohepatitis (NASH) is a severe liver condition characterized by excessive fat deposition, ballooning, and lobular inflammation. This investigation was conducted to estimate the capability of concomitant tamoxifen administration (TAM) with a high fat diet (HFD) to induce a reliable NASH model that mimics human NASH features. Rats were administered TAM (25 mg/kg/day p.o.) and consumed HFD for 5 weeks. A time-course investigation was conducted to determine the optimal time for NASH development. Liver function indices, hepatic lipid profile factors, oxidative stress biomarkers, and inflammatory mediators were estimated. Additionally, macroscopic and microscopic changes were examined. Compared with the time-matched control group receiving vehicle alone, TAM/HFD significantly impaired liver function indices represented as marked elevation in ALT, AST, and ALP serum levels. TAM/HFD significantly increased lipid profile factors including high TG and TC hepatic levels. Additionally, TAM/HFD remarkably raised hepatic levels of TNF-α and IL-17 and significantly decreased IL-10. The combination also increases the oxidative status evidenced by high content of MDA as well as low activity of GPx and SOD. Accordingly, the combination of TAM and HFD for 5 weeks collaboratively promotes NASH development by initiating compromised hepatocyte functionality, elevated lipid levels, oxidative stress, and liver inflammation.

Reversal of tamoxifen resistance by artemisinin in ER+ breast cancer: bioinformatics analysis and experimental validation.

Breast cancer is the leading cause of cancer-related deaths in women worldwide, with Hormone Receptor (HR)+ being the predominant subtype. Tamoxifen (TAM) serves as the primary treatment for HR+ breast cancer. However, drug resistance often leads to recurrence, underscoring the need to develop new therapies to enhance patient quality of life and reduce recurrence rates. Artemisinin (ART) has demonstrated efficacy in inhibiting the growth of drug-resistant cells, positioning art as a viable option for counteracting endocrine resistance. This study explored the interaction between artemisinin and tamoxifen through a combined approach of bioinformatics analysis and experimental validation. Five characterized genes (ar, cdkn1a, erbb2, esr1, hsp90aa1) and seven drug-disease crossover genes (cyp2e1, rorc, mapk10, glp1r, egfr, pgr, mgll) were identified using WGCNA crossover analysis. Subsequent functional enrichment analyses were conducted. Our findings confirm a significant correlation between key cluster gene expression and immune cell infiltration in tamoxifen-resistant and -sensitized patients. scRNA-seq analysis revealed high expression of key cluster genes in epithelial cells, suggesting artemisinin's specific impact on tumor cells in estrogen receptor (ER)-positive BC tissues. Molecular target docking and in vitro experiments with artemisinin on LCC9 cells demonstrated a reversal effect in reducing migratory and drug resistance of drug-resistant cells by modulating relevant drug resistance genes. These results indicate that artemisinin could potentially reverse tamoxifen resistance in ER-positive breast cancer.

Endoxifen Concentration is Associated with Recurrence-Free Survival in Hormone-Sensitive Breast Cancer Patients.

Purpose: The metabolism of tamoxifen is influenced by various cytochrome p450 enzymes, including CYP2D6 and CYP2C19, leading to variations in the levels of endoxifen, even with the same tamoxifen dosage. However, the clinical significance of endoxifen on the prognosis of breast cancer patients remains controversial. This study aimed to elucidate the relevance of endoxifen level to recurrence-free survival censored with tamoxifen discontinuation (RFSt), representing the RFS for tamoxifen itself, of breast cancer patients and determine a suitable cutoff for prognostication. Materials and Methods: The study included 478 breast cancer patients, and tamoxifen and its metabolites, including endoxifen, were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). An optimal cutoff was determined with maximally selected rank statistics. Survival analysis and Cox regression were conducted based on this cutoff. Results: An endoxifen level of 21.00 ng/mL was the optimal cutoff for prognostication. Survival analysis revealed a statistically significant difference in RFSt between the low endoxifen group (≤ 21.00 ng/mL) and high endoxifen group (> 21.00 ng/mL) (log-rank test, p=0.032). The 10-year probability of RFSt was 83.2% (95% CI, 77.0-89.9%) and 88.3% (95% CI, 83.3-93.5%) in the low and high endoxifen groups, respectively. Multivariable Cox proportional hazards regression indicated endoxifen concentration as a significant factor affecting prognosis, which was adjusted with other clinical characteristics. Conclusion: Endoxifen could serve as a marker for appropriate tamoxifen treatment, and an endoxifen cutoff of 21.00 ng/mL could be advantageous in prognostication. Based on this cutoff, therapeutic drug monitoring would benefit patients displaying a suboptimal concentration.

Endocrine consequences of breast cancer therapy and survivorship.

Breast cancer survivorship is increasing, due to earlier diagnosis of the disease and more effective therapies. Long-term endocrine sequelae, including early menopause, bone health, fertility implications and menopausal symptoms, are important survivorship issues. Ovarian failure is common with chemotherapy and options for preserving fertility in young women include ovarian suppression during chemotherapy and oocyte or embryo cryopreservation before chemotherapy. Tamoxifen as adjunct therapy in premenopausal women leads to ovarian stimulation, sometimes ovulation and occasionally pregnancy with important teratogenic implications. Aromatase inhibitor therapy with or without gonadotrophin releasing hormone (GnRH) agonist leads to profound bone loss and anti-resorptive therapy is advised to prevent fracture. Tamoxifen acts to preserve bone in postmenopausal women but not premenopausal women. Pregnancy is not discouraged in young women with early breast cancer, even to the point of pausing adjunct therapy in order to conceive. However, menopausal hormone therapy is discouraged even years later. Non-hormonal therapy for menopausal symptoms in breast cancer survivors is available but, in some cases, estrogen-containing therapy may be worthy of consideration for quality of life in the informed patient.