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Mutations in the estrogen receptor α (ERα) occur in endocrine-resistant metastatic breast cancer. However, a major gap persists with the lack of genetically tractable immune competent mouse models to study disease. Hence, we developed a Cre-inducible murine model expressing a point-activated ESR1Y541S (ESR1Y537S in humans) driven by its endogenous promoter. Germline expression of mutant ESR1Y541S reveals dramatic developmental defects in the reproductive organs, mammary glands, and bones of the mice. These observations provide critical insights into the tissue-specific roles of ERα during development and highlights the potential use of our model in further developmental and cancer studies.
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Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Crescimento e Desenvolvimento/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/fisiopatologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Mutação , Caracteres SexuaisRESUMO
The binding of 17ß-oestradiol to oestrogen receptor alpha (ERα) plays a crucial role in the control of reproduction, acting through both nuclear and membrane-initiated signalling. To study the physiological role of membrane ERα in the reproductive system, we used the C451A-ERα mouse model with selective loss of function of membrane ERα. Despite C451A-ERα mice being described as sterile, daily weighing and ultrasound imaging revealed that homozygous females do become pregnant, allowing the investigation of the role of ERα during pregnancy for the first time. All neonatal deaths of the mutant offspring mice resulted from delayed parturition associated with failure in pre-term progesterone withdrawal. Moreover, pregnant C451A-ERα females exhibited partial intrauterine embryo arrest at about E9.5. The observed embryonic lethality resulted from altered expansion of Tpbpa-positive spiral artery-associated trophoblast giant cells into the utero-placental unit, which is associated with an imbalance in expression of angiogenic factors. Together, these processes control the trophoblast-mediated spiral arterial remodelling. Hence, loss of membrane ERα within maternal tissues clearly alters the activity of invasive trophoblast cells during placentogenesis. This previously unreported function of membrane ERα could open new avenues towards a better understanding of human pregnancy-associated pathologies.
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Receptor alfa de Estrogênio , Trofoblastos , Animais , Estradiol/metabolismo , Receptor alfa de Estrogênio/genética , Feminino , Fertilidade , Humanos , Camundongos , Placenta/metabolismo , Gravidez , Progesterona/metabolismo , Receptores de Estrogênio/metabolismo , Trofoblastos/metabolismoRESUMO
Disease progression is a major problem in ovarian cancer. There are very few treatment options for patients with platinum-resistant ovarian cancer (PROC), and therefore, these patients have a particularly poor prognosis. The aim of the present study was to identify markers for monitoring the response of 123 PROC patients enrolled in the Phase I/II GANNET53 clinical trial, which evaluated the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone. In total, 474 blood samples were collected, comprising baseline samples taken before the first administration of the study drugs and serial samples taken during treatment until further disease progression (PD). After microfluidic enrichment, 27 gene transcripts were analyzed using quantitative polymerase chain reaction and their utility for disease monitoring was evaluated. At baseline, ERCC1 was associated with an increased risk of PD (hazard ratio [HR] 1.75, 95% confidence interval [CI]: 1.20-2.55; p = 0.005), while baseline CDH1 and ESR1 may have a risk-reducing effect (CDH1 HR 0.66, 95% CI: 0.46-0.96; p = 0.024; ESR1 HR 0.58, 95% CI: 0.39-0.86; p = 0.002). ERCC1 was observed significantly more often (72.7% vs. 53.9%; p = 0.032) and ESR1 significantly less frequently (59.1% vs. 78.3%; p = 0.018) in blood samples taken at radiologically confirmed PD than at controlled disease. At any time during treatment, ERCC1-presence and ESR1-absence were associated with short PFS and with higher odds of PD within 6 months (odds ratio 12.77, 95% CI: 4.08-39.97; p < 0.001). Our study demonstrates the clinical relevance of ESR1 and ERCC1 and may encourage the analysis of liquid biopsy samples for the management of PROC patients.
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Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos , Endonucleases , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Endonucleases/genética , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Idoso , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor alfa de Estrogênio/genética , Adulto , Prognóstico , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Platina/uso terapêuticoRESUMO
BACKGROUND: The treatment landscape for HR(+)HER2(-) metastatic breast cancer (MBC) is evolving for patients with ESR1 mutations (mut) and PI3K/AKT pathway genomic alterations (GA). We sought to inform clinical utility for comprehensive genomic profiling (CGP) using tissue (TBx) and liquid biopsies (LBx) in HR(+)HER2(-) MBC. METHODS: Records from a de-identified breast cancer clinicogenomic database for patients who underwent TBx/LBx testing at Foundation Medicine during routine clinical care at ~ 280 US cancer clinics between 01/2011 and 09/2023 were assessed. GA prevalence [ESR1mut, PIK3CAmut, AKT1mut, PTENmut, and PTEN homozygous copy loss (PTENloss)] were calculated in TBx and LBx [stratified by ctDNA tumor fraction (TF)] during the first three lines of therapy. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared between groups by Cox models adjusted for prognostic factors. RESULTS: ~ 60% of cases harbored 1 + GA in 1st-line TBx (1266/2154) or LBx TF ≥ 1% (80/126) and 26.5% (43/162) in LBx TF < 1%. ESR1mut was found in 8.1% TBx, 17.5% LBx TF ≥ 1%, and 4.9% LBx TF < 1% in 1st line, increasing to 59% in 3rd line (LBx TF ≥ 1%). PTENloss was detected at higher rates in TBx (4.3%) than LBx (1% in TF ≥ 1%). Patients receiving 1st-line aromatase inhibitor + CDK4/6 inhibitor (n = 573) with ESR1mut had less favorable rwPFS and rwOS versus ESR1 wild-type; no differences were observed for fulvestrant + CDK4/6 inhibitor (n = 348). CONCLUSION: Our study suggests obtaining TBx for CGP at time of de novo/recurrent diagnosis, followed by LBx for detecting acquired GA in 2nd + lines. Reflex TBx should be considered when ctDNA TF < 1%.
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BACKGROUND: Estrogen receptors express in nearly 70% of breast cancers (ER-positive). Estrogen receptor alpha plays a fundamental role as a significant factor in breast cancer progression for the early selection of therapeutic approaches. Accordingly, there has been a surge of attention to non-invasive techniques, including circulating Cell-free DNA (ccfDNA) or Cell-Free DNA (cfDNA), to detect and track ESR1 genotype. Therefore, this study aimed to examine the diagnosis accuracy of ESR1 mutation detection by cell-free DNA in breast cancer patientsthrough a systematic review and comprehensive meta-analysis. METHODS: PubMed, Embase, and Web of Science databases were searched up to 6 April 2022. Diagnostic studies on ESR1 measurement by cfDNA, which was confirmed using the tumour tissue biopsy, have been included in the study. The sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were considered to analyse the data. RESULTS: Out of 649 papers, 13 papers with 15 cohorts, including 389 participants, entered the meta-analyses. The comprehensive meta-analysis indicated a high sensitivity (75.52, 95% CI 60.19-90.85), specificity (88.20, 95% CI 80.99-95.40), and high accuracy of 88.96 (95% CI 83.23-94.69) for plasma ESR1. We also found a moderate PPV of 56.94 (95% CI 41.70-72.18) but a high NPV of 88.53 (95% CI 82.61-94.44). We also found an NLR of 0.443 (95% CI 0.09-0.79) and PLR of 1.60 (95% CI 1.20-1.99). CONCLUSION: This systematic review and comprehensive meta-analysis reveal that plasma cfDNA testing exhibits high sensitivity and specificity in detecting ESR1 mutations in breast cancer patients. This suggests that the test could be a valuable diagnostic tool. It may serve as a dependable and non-invasive technique for identifying ESR1 mutations in breast cancer patients. However, more extensive research is needed to confirm its prognostic value.
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Biomarcadores Tumorais , Neoplasias da Mama , Ácidos Nucleicos Livres , Receptor alfa de Estrogênio , Mutação , Humanos , Receptor alfa de Estrogênio/genética , Neoplasias da Mama/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Sensibilidade e Especificidade , Valor Preditivo dos TestesRESUMO
BACKGROUND: ESR1 is expressed by 60-70% of breast tumours. it's a good prognosis factor and the target of hormone therapy. Optimization of ESR1 reactivation therapy is currently ongoing. Here we probe if the transcription factor CTCF plays a role in the differential expression of ESR1 in the breast cancer cell lines MCF-7 (ESR1+) and MDA-MB-231 (ESR1-). METHODS AND RESULTS: Knockdown of CTCF in MCF-7 resulted in decreased ESR1 gene expression. CTCF binds to the promoter of ESR1 in MCF-7 but not in MDA-MB-231 cells. CTCF ESR1 binding sites are unmethylated in MCF7 but methylated in MDA-MB-231 cells. CONCLUSION: ESR1 expression in MCF7 cells is dependent on CTCF expression. CTCF can bind to specific regions of the promotor of ESR1 gene in MCF-7 cells but not in MDA-MB-231 cells, this correlates with the methylation status of these regions and could be involved in the transcriptional regulation of ESR1.
Assuntos
Neoplasias da Mama , Fator de Ligação a CCCTC , Metilação de DNA , Receptor alfa de Estrogênio , Humanos , DNA , Metilação de DNA/genética , Células MCF-7 , Células MDA-MB-231 , Neoplasias da Mama/genética , Regiões Promotoras Genéticas , Fator de Ligação a CCCTC/genética , Receptor alfa de Estrogênio/genéticaRESUMO
Cardamomin has been widely studied in cancer, but its role in cancer bladder cancer has not been mentioned. In this study, we validated the anti-cancer effect of cardamom and whether its potential mechanism is related to the PI3K/AKT pathway. After treating with different doses of cardamomin, the cytotoxicity was studied by CCK8. Secondly, we analyzed the effect of cardamomin on the proliferation, apoptosis and cell movement. Next, we analyzed the regulation of ESR1 by western blot and its impact on the PI3K/AKT pathway. We also transfected ESR1 overexpression and silencing vectors, and verified the transfection efficiency through RT-qPCR. Further, the specific mechanism of the drug's inhibitory effect on bladder cancer was also determined. We constructed the subcutaneous tumor model in vivo. After cardamomin administration, we mainly analyzed the positive expression of KI67 in tumor tissues by immunohistochemistry, and the apoptotic cells in tumor tissues by TUNEL, and related proteins in PI3K/AKT pathway by western blot. In this paper, cardamomin inhibited cell proliferation and invasion ability, blocked the transition of G0/G1 phase to S phase, and increased apoptotic rate of 5637 and HT1376 cells, as well as raised ESR1 expression. Cardamomin exerted anti-tumor effect through PI3K/AKT pathway. In vivo animal experiments indicated the inhibitory effect of cardamomin on subcutaneous implanted tumor. Cardamomin inhibited the positive expression of KI67 and promoted the TUNEL-positive cells in tumor tissues. Consistent with in vitro assay, cardamomin increased the expression of ESR1 and downregulated the PI3K/AKT pathway. Cardamomin has a significant inhibitory effect on bladder cancer, and upregulate the expression of ESR1 in bladder cancer through PI3K/AKT.
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Breast cancer (BRCA) is the most common malignancies worldwide with increasing rate. Dolichol phosphate mannose synthase (DPMS) is a critical mannosyltransferase involved in the posttranslational modification of proteins. At present, there is limited knowledge regarding the function of DPMS in breast cancer. In this study, silica analysis in multiple datasets found that dolichyl-phosphate mannosyltransferase subunit 2 (DPM2) is an unfavorable prognostic marker, suggesting its oncogenic role. Cell counting kit-8 and apoptosis assays show that DPM2-silenced cancer cells exhibit decreased growth potential and enhanced cell death rate. Further, transwell and wound healing assays show reduced invasion and migration capabilities in DPM2 knockdown groups, xenograft nude mice model demonstrated smaller tumor volume in DPM2 silenced BC cells. Then, the underlying downstream mechanism of DPM2 in BC was predicted and analyzed, highlighting classical tumorigenic pathways like JAK/STAT signaling pathway and oxidative phosphorylation activated in the cancer group. Finally, ChIP-seq analysis, expression correlation analysis, inhibitor treatment, and dual luciferase assays show that DPM2 is transcriptionally activated by estrogen receptor1 (ESR1). The results show that high expression of DPM2 mRNA is significantly correlated with shorter overall survival (OS) and disease-free survival (DFS) in breast cancer patients, and in vitro knockdown of DPM2 can significantly inhibit the malignant phenotypes of cells, including proliferation, invasion, migration, and apoptosis. These results suggest that DPM2 may play an important role in breast cancer. Altogether, we first uncovered the tumorigenic and prognostic role of DPM2 in breast cancer, cellular assays, and bioinformatics analysis highlighted DPM2 as oncogene via inhibited cancer-related signaling pathways in breast cancer. Besides, DPM2 is transcriptionally activated by ESR1, the signaling axis of ESR1/DPM2 provides a new strategy for BC-targeted therapy.
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Neoplasias da Mama , MicroRNAs , Succinimidas , Camundongos , Animais , Humanos , Feminino , Neoplasias da Mama/metabolismo , Manosiltransferases/genética , Manosiltransferases/metabolismo , Camundongos Nus , Prognóstico , Estrogênios/metabolismo , Oncogenes , Proliferação de Células , Linhagem Celular Tumoral , Movimento Celular/genética , MicroRNAs/genética , Regulação Neoplásica da Expressão GênicaRESUMO
HSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (Kd = 0.13 ± 0.02 µM) without inducing heat shock response. This is likely because dip G does not interfere with the HSP90-HSF1 interaction like N-terminal inhibitors, maintaining HSF1 in a transcriptionally silent state. We found that binding of dip G to HSP90 promotes degradation of HSP90 client protein estrogen receptor α (ER), a major oncogenic driver protein in most breast cancers. Mutations in the ER ligand-binding domain (LBD) are an established mechanism of endocrine resistance and decrease the binding affinity of mainstay endocrine therapies targeting ER, reducing their ability to promote ER degradation or transcriptionally silence ER. Because dip G binds to HSP90 and does not bind to the LBD of ER, unlike endocrine therapies, it is insensitive to ER LBD mutations that drive endocrine resistance. Additionally, we determined that dip G promoted degradation of WT and mutant ER with similar efficacy, downregulated ER- and mutant ER-regulated gene expression, and inhibited WT and mutant cell proliferation. Our data suggest that dip G is not only a molecular probe to study HSP90 biology and the HSP90 conformation cycle, but also a new therapeutic avenue for various cancers, particularly endocrine-resistant breast cancer harboring ER LBD mutations.
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Antineoplásicos , Benzofuranos , Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Mutação , Antineoplásicos/farmacologia , Benzofuranos/farmacologiaRESUMO
Clear cell renal cell carcinoma (ccRCC) is the most frequent form of kidney cancer. Metastatic stages of ccRCC reduce the five-year survival rate to 15%. In this report, we analyze the ccRCC-induced remodeling of the five KEGG-constructed excretory functional pathways in a surgically removed right kidney and its metastasis in the chest wall from the perspective of the Genomic Fabric Paradigm (GFP). The GFP characterizes every single gene in each region by these independent variables: the average expression level (AVE), relative expression variability (REV), and expression correlation (COR) with each other gene. While the traditional approach is limited to only AVE analysis, the novel REV analysis identifies the genes whose correct expression level is critical for cell survival and proliferation. The COR analysis determines the real gene networks responsible for functional pathways. The analyses covered the pathways for aldosterone-regulated sodium reabsorption, collecting duct acid secretion, endocrine and other factor-regulated sodium reabsorption, proximal tubule bicarbonate reclamation, and vasopressin-regulated water reabsorption. The present study confirms the conclusion of our previously published articles on prostate and kidney cancers that even equally graded cancer nodules from the same tumor have different transcriptomic topologies. Therefore, the personalization of anti-cancer therapy should go beyond the individual, to his/her major cancer nodules.
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BACKGROUND: Oral SERDs are a novel drug class that have been developed to counteract resistance due to ESR1 mutations. Several SERDs have emerged from phase 2 and 3 trials, with the FDA limiting approval for Elacestrant to patients with ESR1mt tumours despite PFS benefit in the overall population. However, questions remain on whether patients with ESR1wt tumours stand to benefit from oral SERDs. PATIENTS AND METHODS: Manuscripts and conference presentations of Randomised Controlled Trials were extracted after a systematic search of Embase, PubMed and Cochrane from inception until January 21,2023. RCTs investigating the efficacy of oral SERDs versus endocrine therapy for ER positive, HER2 negative advanced breast cancer, and which reported the Kaplan Meier (KM) curves of PFS in the overall and ESR1 mutant (ESR1mt) population were selected. A graphical reconstructive algorithm was applied to estimate time-to-event outcomes from reported KM curves in all overall and ESR1mt cohorts. A bipartite matching algorithm, KMSubtraction, was used to derive survival data for unreported (ESR1wt) subgroups. An individual patient data (IPD) meta-analysis was then pursued, pooling data by ESR1 mutation status in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Guidelines for IPD. RESULTS: The randomized clinical trials ACELERA, AMEERA-3, EMERALD and SERENA-2 were included, totalling 1290 patients. In the pooled analysis of the overall cohort, PFS benefit was observed with oral SERDs when compared with treatment of physicians choice (TPC) (HR 0.783, 95%CI 0.681-0.900, p<0.001). In the ESR1mt subgroup, oral SERDs demonstrated improved PFS (HR 0.557, 95%CI 0.440-0.705, p<0.001) compared to TPC. In the ESR1wt subgroup, oral SERDs demonstrated no significant PFS benefit (HR 0.944, 95%CI 0.783-1.138, p=0.543) when compared to TPC. CONCLUSIONS: The results of this IPD meta-analysis suggests that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup.
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BACKGROUND: Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new treatment strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy and tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in ESR1-mutated mBC. PATIENTS AND METHODS: In the open-label, phase II, ELAINE 2 trial (NCT04432454), women with ESR1-mutated, ER+/human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day and abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and objective response rate (ORR). RESULTS: Twenty-nine women (median age 60 years) participated; all but one were previously treated with a CDK4/6i (median duration 2 years). The lasofoxifene-abemaciclib combination was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting. One patient (with no prior CDK4/6i) discontinued treatment due to grade 2 diarrhea. No deaths occurred during the study. Median PFS was 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; â¼13 months]; PFS rates at 6, 12, and 18 months were 76.1%, 56.1%, and 38.8%, respectively. CBR at 24 weeks was 65.5% (95% CI 47.3% to 80.1%). In 18 patients with measurable lesions, ORR was 55.6% (95% CI 33.7% to 75.4%). ESR1-mutant circulating tumor DNA (ctDNA) allele fraction decreased from baseline to week 4 in 21/26 (80.8%) patients. CONCLUSIONS: Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.
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Neoplasias da Mama , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Progressão da Doença , Mutação , Diarreia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (â¼5.6 months) versus 16.2 weeks (â¼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fulvestranto/efeitos adversos , Pirrolidinas/uso terapêutico , Inibidores da Aromatase , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMO
BACKGROUND: ESR1 mutations have been identified as mechanism for endocrine resistance and are also associated with a decreased overall survival. We assessed ESR1 mutations in circulating tumor DNA (ctDNA) for impact on outcome to taxane-based chemotherapy in advanced breast cancer patients. METHODS: ESR1 mutations were determined in archived plasma samples from patients treated with paclitaxel and bevacizumab (AT arm, N = 91) in the randomized phase II ATX study. Samples collected at baseline (n = 51) and at cycle 2 (n = 13, C2) were analyzed using a breast cancer next-generation sequencing panel. This study was powered to detect a benefit in progression-free survival (PFS) at six months for patients treated with paclitaxel/bevacizumab compared to historical trials with fulvestrant. PFS, overall survival (OS), and ctDNA dynamics were exploratory analyses. RESULTS: PFS at six months was 86% (18/21) in patients with an ESR1 mutation detected and 85% (23/27) in wildtype ESR1 patients. In our exploratory analysis, median progression-free survival (PFS) was 8.2 months [95% CI, 7.6-8.8] for ESR1 mutant patients versus 8.7 months [95% confidence interval (CI), 8.3-9.2] for ESR1 wildtype patients [p = 0.47]. The median overall survival (OS) was 20.7 months [95% CI, 6.6-33.7] for ESR1 mutant patients versus 28.1 months [95% confidence interval (CI), 19.3-36.9] for ESR1 wildtype patients [p = 0.27]. Patients with ≥ two ESR1 mutations had a significantly worse OS, but not PFS, compared to those who did not [p = 0.003]. Change in ctDNA level at C2 was not different between ESR1 and other mutations. CONCLUSIONS: Presence of ESR1 mutations in baseline ctDNA might not be associated with inferior PFS and OS in advanced breast cancer patients treated with paclitaxel/bevacizumab.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Paclitaxel/efeitos adversos , Bevacizumab , Fulvestranto/uso terapêutico , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Epithelial ovarian cancer (EOC) is the most common of cancer death among malignant tumors in women, its occurrence and development are strongly linked to estrogen. Having identified the phosphatase and tensin homologue (PTEN) is a potent tumor suppressor regulating cell proliferation, migration, and survival. Meanwhile, there is a correlation between PTEN protein expression and estrogen receptor expression in EOC. However, no study has amplified on the molecular regulatory mechanism and function between estrogen and PTEN in the development of EOC. In this research, we found that PTEN shows a low expression level in EOC tissues and estrogen decreased PTEN expression via the estrogen receptor 1 (ESR1) in EOC cells. Knockdown of PTEN enhanced the proliferation and migration level of EOC cells driven by estrogen. Moreover, PTEN was also phosphorylated by G protein-coupled receptor 30 (GPR30)-Protein kinase C (PKC) signaling pathway upon estrogen stimulation. Inhibiting the phosphorylation of PTEN weakened the proliferation and migration of estrogen induced-EOC cells estrogen and decreased the phosphorylation of Protein kinase B (AKT) and Mammalian target of rapamycin (mTOR). These results indicated that estrogen decreased PTEN expression level via the ESR1 genomic pathway and phosphorylated PTEN via the GPR30-PKC non-genomic pathway to activate the PI3K/AKT/mTOR signaling pathway, thereby determining the fate of EOC cells.
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Neoplasias Ovarianas , Proteínas Proto-Oncogênicas c-akt , Humanos , Feminino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Fosforilação , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Neoplasias Ovarianas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Estrogênios , Proliferação de Células/genéticaRESUMO
OBJECTIVE: Endocrine therapy is frequently administered in patients with hormone dependent (HR+) metastatic endometrial cancer. ESR1 mutations have emerged as a key mechanism of aromatase inhibitor (AI) resistance in HR + metastatic breast cancer and can be monitored using circulating tumor DNA (ctDNA). The aim of this study was to explore the incidence and clinical relevance of circulating ESR1 mutations in patients treated by AI or megestrol acetate (M) for advanced endometrial carcinoma. METHODOLOGY: This single-center retrospective study was performed at the Henri Becquerel Center (Rouen) and looked for circulating ESR1 gene mutations by droplet digital PCR (E380Q, L536R, Y537S, Y537N, Y537C, D538G, S463P) in patients with advanced HR + endometrial carcinoma treated between 2008 and 2020 for at least 30 days by AI or M. Analyses were performed before exposure and at progression/during endocrine therapy. RESULTS: Twenty-two patients were included: 13 were treated with AI, 12 of whom progressed; 9 patients were treated with M, 8 of whom progressed. 68.1% of the patients had low-grade endometrial carcinoma and 54.5% had received chemotherapy in the metastatic setting. The median duration of treatment was 152 days (min 47 - max 629) with AI and 155 days (min 91-max 1297) with M. Under AI, there was no ESR1 mutation at baseline, and one Y537C mutation at progression with a variant allele frequency (VAF) of 0.14%. Under M, one patient had a Y537C (VAF 0.2%) at baseline that disappeared during treatment. Another patient had a Y537S mutation emergence at progression after 91 days of treatment (VAF 1.83%). There was no significant difference between the circulating DNA concentration before and after hormone therapy (p = 0.16). CONCLUSION: ESR1 mutations do not seem to be involved in the mechanisms of resistance to AI or M in HR+ endometrial cancer. The clinical relevance of their detection is not demonstrated.
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Neoplasias da Mama , Neoplasias do Endométrio , Feminino , Humanos , Neoplasias da Mama/patologia , Relevância Clínica , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Receptor alfa de Estrogênio/genética , Hormônios/uso terapêutico , Mutação , Estudos RetrospectivosRESUMO
Estrogen receptor (ER) α-expressing neurons in the ventrolateral area of the ventromedial hypothalamus (VMHvl) are implicated in the control of many behaviors and physiological processes, some of which are sex-specific. Recently, three sex-differentiated ERα subpopulations have been discovered in the VMHvl marked by co-expression with tachikinin1 (Tac1), reprimo (Rprm), or prodynorphin (Pdyn), that may subserve specific functions. These markers show sex differences in adulthood: females have many more Tac1/Esr1 and Rprm/Esr1 co-expressing cells, while males have more Pdyn/Esr1 cells. In this study, we sought to understand the development of these sex differences and pinpoint the sex-differentiating signal. We examined developmental changes in the number of Esr1 cells co-expressing Tac1, Rprm or Pdyn using single-molecule in situ hybridization. We found that both sexes have similarly high numbers of Tac1/Esr1 and Rprm/Esr1 cells at birth, but newborn males have many more Pdyn/Esr1 cells than females. However, the number of cells with Tac1/Esr1 and Rprm/Esr1 co-expression markedly decreases by weaning in males, but not females, leading to sex differences in neurochemical expression. Female mice administered testosterone at birth have expression patterns akin to male mice. Thus, a substantial neurochemical reorganization of the VMHvl occurs in males between birth and weaning that likely underlies the previously reported sex differences in behavioral and physiological responses to estrogens in adulthood.
Assuntos
Receptor alfa de Estrogênio , Núcleo Hipotalâmico Ventromedial , Camundongos , Animais , Masculino , Feminino , Receptor alfa de Estrogênio/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Diferenciação Sexual , Hipotálamo/metabolismo , Receptores de Estrogênio/metabolismo , Caracteres SexuaisRESUMO
BACKGROUND: Breast cancer susceptibility is greatly influenced by single nucleotide polymorphisms (SNPs) both in penetrance and non-penetrance genes. The Estrogen Receptor Alfa (ESR1- rs2234693 and rs2046210) have been reported as risk factor of breast cancer in different ethnic groups with inconsistent results. In this study the association of ESR1 (rs2234693 and rs2046210) with breast cancer risk was investigated in patients of Khyber Pakhtunkhwa. METHODS: A total of 312 females including 162 breast cancer patients and 150 healthy controls were enrolled in this study. The polymorphism was confirmed using T-ARMS-PCR. RESULTS: Our results revealed that ESR1-rs2234693 risk allele (C) (P = 0.21, OR = 1.27, CI = 0.87 to 1.87) and containing genotypes CC (P = 0.68, OR = 1.24, CI = 0.42 to 3.68) and TC (P = 0.23, OR = 1.32, CI = 0.83 to 2.13) were not associated with the risk of breast cancer. In case of rs2046210, the risk allele A (P < 0.0001, OR = 2.42, CI = 1.74 to 3.38) and corresponding genotypes GA (P = 0.0001, OR = 2.55, CI = 1.62 to 4.03) and AA (P = 0.02, OR = 2.20, CI = 1.12 to 4.34) were significantly associated with higher risk of breast cancer. Moreover, ESR1-rs2234693 was significantly (P < 0.05) associated with family history, stages, PR status, ER status and luminal B. The ESR1-rs2046210 showed significant (P ≤ 0.05) association with menstrual status, tumor grade and TNBC. Both the SNPs showed non-significant (P > 0.05) association with nulliparity, nodal status, HER2 status, metastasis, HER2 enriched subtype and luminal A. CONCLUSION: It is concluded that ESR1-rs2234693 is not associated with breast cancer, while rs2046210 is significantly associated with the risk of breast cancer in Khyber Pakhtunkhwa population. Further, to confirm the exact situation of ESR1 polymorphism, ESR1 existing and other SNPs need to be investigated in diverse data sets.
Assuntos
Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/genética , Estudos de Casos e Controles , Receptor alfa de Estrogênio/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
ESR1 mutation (ESR1m) is a frequent cause of acquired resistance to aromatase inhibitor (AI) plus cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), which is a first-line therapy for hormone-receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Camizestrant is a next-generation oral selective estrogen receptor degrader (SERD) that in a phase II study significantly improved progression-free survival (PFS) over fulvestrant (also a SERD) in ER+/HER2- ABC. SERENA-6 (NCT04964934) is a randomized, double-blind, phase III study evaluating the efficacy and safety of switching from an AI to camizestrant, while maintaining the same CDK4/6i, upon detection of ESR1m in circulating tumor DNA before clinical disease progression on first-line therapy for HR+/HER2- ABC. The aim is to treat ESR1m clones and extend the duration of control of ER-driven tumor growth, delaying the need for chemotherapy. The primary end point is PFS; secondary end points include chemotherapy-free survival, time to second progression event (PFS2), overall survival, patient-reported outcomes and safety.
Why will we perform this study? Patients with advanced breast cancer in which the cancer cells have the receptor for the hormone estrogen and/or progesterone are typically treated with an aromatase inhibitor, a hormone therapy that decreases estrogen being made in the body, together with an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), a drug that blocks the growth of cancer cells. Although cancers usually respond to treatment initially, the cancer cells eventually change, so the drug combination no longer works. For example, mutation of the estrogen receptor (referred to as ESR1m) can stop aromatase inhibitors from working. Camizestrant is an investigational drug that blocks estrogen receptors, including mutated receptors, reducing the growth and spread of cancer. Here we describe the SERENA-6 clinical trial, which is testing camizestrant as a treatment for patients with breast cancer with ESR1m. How will we perform this research? The phase III SERENA-6 trial will use blood tests to monitor if patients with breast cancer develop ESR1m while being treated with an aromatase inhibitor and a CDK4/6 inhibitor. If ESR1m is detected, yet the disease is stable, participants will be randomly assigned to either continue with the same aromatase inhibitor or switch to camizestrant while continuing with the same CDK4/6 inhibitor. The study will assess whether switching to camizestrant prolongs the time before the cancer grows, spreads or worsens. It will also assess the length of time that participants live for versus those who continue with an aromatase inhibitor. Clinical Trial Registration: NCT04964934 (ClinicalTrials.gov).
Assuntos
Neoplasias da Mama , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Fulvestranto/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismoRESUMO
INTRODUCTION: Migraine is a neurovascular disorder and is clinically characterized by episodic attacks of mild to severe headaches. Due to the involvement of multiple environmental and genetic factors, it has become a much more complex neurological condition to understand. Apart from the environmental variables, a plethora of genes have been implicated, and one such example is ESR1. The present study was focused to find out the association of two important polymorphisms, namely, PvuII and XbaI of the ESR1 with migraine in the population of Jammu and Kashmir (UT). METHODS: The PCR-RFLP genotyping method was utilized to detect PvuII and XbaI polymorphism, and the result was confirmed by statistical analysis. RESULTS: Although we did not find a signification association of ESR-PvuII polymorphism with migraine susceptibility {OR: 1.14 at 95% CI [0.76-1.71] (p value 0.5)}, a strong association was found with the clinical subtype of migraine; migraine with aura (MA) {OR: 2.014 at 95% CI [1.069-3.792] (p value 0.028)}. Furthermore, a significant association of ESR-XbaI polymorphism was observed with migraine {OR: 1.908 at 95% CI [1.252-2.907] (p value 0.002) and its both clinical subtypes; migraine without aura (MO) {OR: 1.870 at 95% CI [1.186-2.950] (p value 0.006)} and MA {OR: 2.014 at 95% CI [1.069-3.792] (p value 0.028)}. CONCLUSION: In conclusion, ESR1-XbaI polymorphism is significantly associated with migraine risk including both subtypes (MA and MO) in the North Indian population of Jammu.