Hormone Receptor Research Articles

Colombian consensus for the molecular diagnosis of endometrial cancer

Objective: The Cancer Genome Atlas research program (TCGA) developed the molecular classification for endometrial cancer with prognostic and therapeutic utility, which was replaced by the ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) classification by consensus and international guidelines due to its high cost. This article aims to present national recommendations from an expert consensus that allows unification and implementation of the molecular classification for women with endometrial cancer nationwide, with a rational use of resources and technology. Methods: Consensus of 36 experts in clinical oncology, oncological gynecology, pathology, and genetics, with clinical practice in the national territory. The leader group performed a literature review and structuring of questions rated 1 to 9 points. A modified nominal group technique was used. There was a face-to-face meeting with master presentations, deliberative dialogue, and Google Forms (Google LLC, Mountain View, CA, USA) questionnaire voting with analysis and discussion of responses. The non-consensual responses led to a second round of voting. The final manuscript was finally prepared and revised. Results: Seven recommendations were formulated integrating the panelist responses based on evidence, but adjusted to the Colombian context and reality. Recommendation 1. The molecular classification is recommended in all the endometrial cancers using the immunohistochemistry markers as subrogated results from the molecular profile initially proposed in the TCGA classification. Recommendation 2. The sequential test strategy is recommended, starting with the immunohistochemistry markers (p53, MLH1, MSH 2, MSH6, PMS2) simultaneously in all the patients, defining to request POLE (DNA polymerase epsilon) (if available) according to the risk classification based on the surgical piece. Recommendation 3. It is recommended, that the gynecologist oncologist should be the one to request the POLE (if available) according to the final pathology report. This test must be requested for all endometrial cancers stage I-II, except in low risk (stage IA low grade endometrioid histology without linfovascular invasion normal p53) and, stages III-IV without residual disease, without affecting the request of subrogated immunohistochemistry molecular markers upon histology. The consensus proposes that the POLE is requested after the immunohistochemistry and according to the categories in the risk classification established by the 2020 ESGO/ESTRO/ESP guidelines. Recommendation 4. It is recommended to perform immunohistochemistry for hormonal receptors for all women with endometrial cancer and the HER2 in patients with p53abn, simultaneously with the others immunohistochemistry markers. Recommendation 5. It is recommended to perform the immunohistochemistry markers (p53, MLH1, MSH2, MSH6 y PMS2) in an initial endometrial biopsy or curettage when the specimen is adequate and available. In case the initial immunohistochemistry is inconclusive, or there are histological discrepancies between the initial and definitive pathology, it is recommended to repeat the molecular profile in the surgical pathology. The immunohistochemistry markers must be reported in the pathology report according to the CAP (College of American Pathologists) recommendations, independently of the type of sample. Recommendation 6. It is recommended to perform MLH1 promoter methylation testing in patients who exhibit loss of expression of MLH1 in immunohistochemistry whether it is accompanied or not with loss of expression of PMS2. All the patients with deficient MMR (mismatch repair), should be sent for genetic counseling to rule out Lynch syndrome. Recommendation 7. It is recommended to consider the molecular classification in addition to the classical histopathological criteria when making adjuvant judgments, as incorporated by the classification of prognostic groups of the 2020 ESGO/ESTRO/ESP guidelines. Conclusions: It is necessary to implement the molecular classification of endometrial cancer in clinical practice in accordance to the Colombian context, due to its prognostic and probably predictive value. This will enable the characterization of the Colombian population in order to offer individualized guided treatments. This is an academic and nonregulatory document.

Controversies on chemotherapy for early HR+/HER2- breast cancer: the role of anthracyclines and dose intensification.

Use of adjuvant chemotherapy significantly reduced the risk of recurrence and improved overall survival (OS) in patients with early-stage breast cancer. However few data are available on efficacy of different adjuvant chemotherapy regimens and schedules in patients with hormone receptor positive/HER2-negative (HR+/HER2-) breast cancer. We aim to summarize the available evidence on efficacy of adjuvant anthracycline-based chemotherapy and of the dose-dense schedule in this population. Moreover, current controversies in the management of patients with early-stage HR+/HER2- breast cancer are discussed. Patient-level meta-analysis evaluating the role of the addition of anthracycline to taxane-based chemotherapy showed that recurrence rate was 14% lower [relative risk (RR) 0.86, P = 0.0004] among patients receiving anthracycline-based treatment.Patient-level meta-analysis evaluating the role of different schedules of chemotherapy administration showed that the use of adjuvant dose-dense chemotherapy is associated with significant reduction in breast cancer recurrences and breast cancer mortality. Less evidence is available in the neoadjuvant setting. For patients with high-risk HR+/HER2- breast cancer, (neo) adjuvant anthracycline and taxane-based chemotherapy, and a dose-dense regimen should still be considered the standard of care. However, in patients with intermediate-low risk breast cancer anthracycline-free regimens could be considered an option of treatment.

Endocrine disruptor-induced epimutagenesis in vitro : Insight into molecular mechanisms.

Endocrine disrupting chemicals (EDCs) such as bisphenol S (BPS) are xenobiotic compounds that can disrupt endocrine signaling following exposure due to steric similarities to endogenous hormones within the body. EDCs have been shown to induce disruptions in normal epigenetic programming (epimutations) that accompany dysregulation of normal gene expression patterns that appear to predispose disease states. Most interestingly, the prevalence of epimutations following exposure to many different EDCs often persists over multiple subsequent generations, even with no further exposure to the causative EDC. Many previous studies have described both the direct and prolonged effects of EDC exposure in animal models, but many questions remain about molecular mechanisms by which EDCs initially induce epimutations or contribute to the propagation of EDC-induced epimutations either within the exposed generation or to subsequent generations. Additional questions remain regarding the extent to which there may be differences in cell-type specific susceptibilities to various EDCs, and whether this susceptibility is correlative with expression of relevant hormone receptors and/or the location of relevant hormone response elements (HREs) in the genome. To address these questions, we exposed cultured mouse pluripotent (induced pluripotent stem [iPS]), somatic (Sertoli and granulosa), and germ (primordial germ cell like [PGCLC]) cells to BPS and measured changes in DNA methylation levels at the epigenomic level and gene expression at the transcriptomic level. We found that there was indeed a difference in cell-type specific susceptibility to EDC-induced epimutagenesis and that this susceptibility correlated with differential expression of relevant hormone receptors and, in many cases, tended to generate epimutations near relevant HREs within the genome. Additionally, however, we also found that BPS can induce epimutations in a cell type that does not express relevant receptors and in genomic regions that do not contain relevant HREs, suggesting that both canonical and non-canonical signaling mechanisms can be disrupted by BPS exposure. Most interestingly, we found that when iPS cells were exposed to BPS and then induced to differentiate into PGCLCs, the prevalence of epimutations and differentially expressed genes (DEGs) initially induced in the iPSCs was largely retained in the resulting PGCLCs, however, >90% of the specific epimutations and DEGs were not conserved but were rather replaced by novel epimutations and DEGs following the iPSC to PGCLC transition. These results are consistent with a unique concept that many EDC-induced epimutations may normally be corrected by germline and/or embryonic epigenetic reprogramming but that due to disruption of the underlying chromatin architecture induced by the EDC exposure, many novel epimutations may emerge during the reprogramming process as well. Thus, it appears that following exposure to a disruptive agent such as an EDC, a prevalence of epimutations may transcend epigenetic reprogramming even though most individual epimutations are not conserved during this process.

The coculture of in vitro produced porcine embryos and oviductal epithelial cells improves blastocyst formation and modify embryo quality

The efficiency of in vitro embryo production in mammals is influenced by variables associated with culture conditions during maturation, fertilization, and embryonic development. The embryos obtained often exhibit low quality due to suboptimal in vitro culture conditions compared to the in vivo environment. Co-culturing gametes and embryos with somatic cells has been developed to enhance in vitro culture conditions. This study aimed to assess the impact of coculturing in vitro-produced porcine embryos with porcine oviductal epithelial cells (POEC) on embryo development and quality. Firstly, a pure culture of POEC suitable for coculture systems was established. The epithelial origin of the cells was confirmed by the expression of E-cadherin and cytokeratin. The expression pattern of hormone receptors aligned with the diestrous oviduct, and POEC also secreted oviductal glycoprotein type 1 (OVGP-1). Secondly, POEC from passage 1 (POEC-1) were used to coculture with in vitro-produced porcine embryos. A successful coculture system was established without the addition of fetal bovine serum as a supplement. Coculturing POEC-1 in monolayers with in vitro-produced porcine embryos during the initial two days of culture enhanced the percentage of blastocysts and their hatching. Although the coculture did not alter the number of cells in the blastocysts or apoptosis assessed by TUNEL, it significantly reduced reactive oxygen species (ROS) levels in cleaved porcine embryos. This study represents the first report evaluating the quality of porcine embryos produced by IVF in coculture systems and assessing ROS levels in cleaved porcine embryos obtained by IVF.

Advances in the study of the role and mechanisms of endogenous hormones in the development of myopia

With the increasing prevalence of myopia among adolescents, the pathogenesis of this condition has garnered significant attention. Studies have discovered the expression of various hormone receptors in ocular tissues of both animals and humans. Additionally, changes in hormone levels accompany the development of myopia, although the exact relationships remain inconclusive. This article reviews the potential influences and mechanisms of action of endogenous hormones such as melatonin, serotonin, insulin, glucagon, sex hormones, vitamin D, and prostaglandins in ocular tissues including the retina, choroid, and sclera. It elaborates on the relationship between fluctuations in these hormone levels and the progression of myopia, aiming to provide guidance for exploring targets for myopia prevention and control.

Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial

Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12 mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24 weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and ≥10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants (n = 98) were randomly assigned to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg dose) or placebo. The mean relative change from baseline in LF at 24 weeks was −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg), −82.4% (12 mg) and +0.3% (placebo) (all P < 0.001 versus placebo). At 24 weeks, normal LF (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760.

Characterization of NR1J1 Paralog Responses of Marine Mussels: Insights from Toxins and Natural Activators.

The pregnane X receptor (PXR) is a nuclear hormone receptor that plays a pivotal role in regulating gene expression in response to various ligands, particularly xenobiotics. In this context, the aim of this study was to shed light on the ligand affinity and functions of four NR1J1 paralogs identified in the marine mussel Mytilus galloprovincialis, employing a dual-luciferase reporter assay. To achieve this, the activation patterns of these paralogs in response to various toxins, including freshwater cyanotoxins (Anatoxin-a, Cylindrospermopsin, and Microcystin-LR, -RR, and -YR) and marine algal toxins (Nodularin, Saxitoxin, and Tetrodotoxin), alongside natural compounds (Saint John's Wort, Ursolic Acid, and 8-Methoxypsoralene) and microalgal extracts (Tetraselmis, Isochrysis, LEGE 95046, and LEGE 91351 extracts), were studied. The investigation revealed nuanced differences in paralog response patterns, highlighting the remarkable sensitivity of MgaNR1J1γ and MgaNR1J1δ paralogs to several toxins. In conclusion, this study sheds light on the intricate mechanisms of xenobiotic metabolism and detoxification, particularly focusing on the role of marine mussel NR1J1 in responding to a diverse array of compounds. Furthermore, comparative analysis with human PXR revealed potential species-specific adaptations in detoxification mechanisms, suggesting evolutionary implications. These findings deepen our understanding of PXR-mediated metabolism mechanisms, offering insights into environmental monitoring and evolutionary biology research.

Nutritional supplementation of breeding hens may promote embryonic development through the growth hormone-insulin like growth factor axis

The late stage of embryo development is a crucial period of metabolic changes, with rapid organ development requiring a substantial supply of nutrients. During this phase, maternal nutritional levels play a vital role in the growth, development, and metabolism of the offspring. In this study, we added 2 doses of β-carotene (βc) (120 mg/kg and 240 mg/kg) to the daily diet of Hailan Brown laying hens to investigate the impact of maternal nutritional enrichment on embryo development. Maternal nutrition supplementation significantly increased the expression of chicken embryo liver index, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and hepatocyte growth factor (HGF) in serum. At the same time, the expression of GH/growth hormone receptor (GHR), IGF-1 mRNA, and Proliferating Cell Nuclear Antigen (PCNA) protein in the liver was upregulated, indicating that maternal nutrition intervention may promote chicken embryo liver development through the GH-IGF-1 axis. Transcriptome sequencing results showed that differential genes in liver after maternal nutritional supplementation with β-carotene were enriched in pathways related to cell proliferation and metabolism. Consequently, we postulated that maternal β-carotene supplementation might operate via the GH-IGF-1 axis to regulate the expression of genes involved in growth and development, thereby promoting liver development. These results contribute to formulating more effective poultry feeding strategies to promote offspring growth and development.

Gedatolisib shows superior potency and efficacy versus single-node PI3K/AKT/mTOR inhibitors in breast cancer models

The PI3K, AKT, and mTOR (PAM) pathway is frequently dysregulated in breast cancer (BC) to accommodate high catabolic and anabolic activities driving tumor growth. Current therapeutic options for patients with hormone receptor (HR) + / HER2- advanced BC (ABC) include PAM inhibitors that selectively inhibit only one PAM pathway node, which can lead to drug resistance as cells rapidly adapt to maintain viability. We hypothesized that gedatolisib, which potently inhibits all Class I PI3K isoforms, as well as mTORC1 and mTORC2, may be more effective in BC cells than single-node PAM inhibitors by limiting adaptive resistances. By using multiple functional assays, a panel of BC cell lines was evaluated for their sensitivity to four different PAM inhibitors: gedatolisib (pan-PI3K/mTOR inhibitor), alpelisib (PI3Kα inhibitor), capivasertib (AKT inhibitor), and everolimus (mTORC1 inhibitor). Gedatolisib exhibited more potent and efficacious anti-proliferative and cytotoxic effects regardless of the PAM pathway mutational status of the cell lines compared to the single-node PAM inhibitors. The higher efficacy of gedatolisib was confirmed in three-dimensional culture and in BC PDX models. Mechanistically, gedatolisib decreased cell survival, DNA replication, cell migration and invasion, protein synthesis, glucose consumption, lactate production, and oxygen consumption more effectively than the other PAM inhibitors tested. These results indicate that inhibition of multiple PAM pathway nodes by a pan-PI3K/mTOR inhibitor like gedatolisib may be more effective at inducing anti-tumor activity than single-node PAM inhibitors. A global Phase 3 study is currently evaluating gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2− ABC.

Dose/Exposure Relationship of Exercise and Distant Recurrence in Primary Breast Cancer.

Postdiagnosis exercise is associated with lower breast cancer (BC) mortality but its link with risk of recurrence is less clear. We investigated the impact and dose-response relationship of exercise and recurrence in patients with primary BC. Multicenter prospective cohort analysis among 10,359 patients with primary BC from 26 centers in France between 2012 and 2018 enrolled in the CANcer TOxicities study, with follow-up through October 2021. Exercise exposure was assessed using the Global Physical Activity Questionnaire-16, quantified in standardized metabolic equivalent of task-hours per week (MET-h/wk). We examined the dose/exposure response of pretreatment exercise on distant recurrence-free interval (DRFI) for all patients and stratified by clinical subtype and menopausal status using inverse probability treatment weighted multivariable Cox models to estimate hazard ratios (HRs). For the overall cohort, the relationship between exercise and DRFI was nonlinear: increasing exercise ≥ 5 MET-h/wk was associated with an inverse linear reduction in DRFI events up to approximately 25 MET-h/wk; increasing exercise over this threshold did not provide any additional DRFI benefit. Compared with <5 MET-h/wk, the adjusted HR for DRFI was 0.82 (95% CI, 0.61 to 1.00) for ≥ 5 MET-h/wk. Stratification by subtype revealed the hormone receptor-/human epidermal growth factor receptor 2- (HR-/HER2-; HR, 0.59 [95% CI, 0.38 to 0.92]) and HR-/HER2+ (HR, 0.37 [95% CI, 0.14 to 0.96]) subtypes were preferentially responsive to exercise. The benefit of exercise was observed especially in the premenopausal population. Postdiagnosis/pretreatment exercise is associated with lower risk of DRFI events in a nonlinear fashion in primary BC; exercise has different impact on DRFI as a function of subtype and menopausal status.

Differential expression of NAT1 pharmacogene in hormone receptor positive vs. negative female breast tumors may affect drug treatment.

Studies have reported overexpression of NAT1 gene for xenobiotic metabolizing arylamine N-acetyltransferase type 1 in estrogen receptor positive breast tumors, and this association has been linked to patient chemoresistance and response to tamoxifen. We probed the expression of NAT1, using quantitative reverse transcription PCR to screen clinically characterized breast cancer tissue cDNA arrays. Primers detecting all NAT1 alternative transcripts were used, and the protocol and results are reported according to consensus guidelines. The clinical information about 166 tumor samples screened is provided, including tumor stage, estrogen and progesterone receptor status and HER2 expression. NAT1 was found to be significantly (P < 0.001) upregulated in hormone receptor positive vs. negative tumors. No correlation was apparent between NAT1 and tumor stage or HER2 expression. Our findings demonstrate a strong correlation between the expression of NAT1 and steroid hormone receptors in breast tumors, supporting its possible utility as a pharmacogenetic biomarker or drug target. Of the two polymorphic NAT genes, NAT1 is the one primarily expressed in breast tissue, and is subjected to regulation by two differential promoters and more than one polyadenylation signal. Hormonal factors may enhance NAT1 gene expression at the transcriptional or epigenetic level, and tamoxifen has additionally been shown to inhibit NAT1 enzymatic activity. The outcome of tamoxifen treatment is also more favorable in patients with NAT1 overexpressing tumors. The study adds to the growing body of evidence implicating NAT1 in breast cancer and its pharmacological treatment.

Risk factors for secondary thyroid cancer in patients with breast cancer: a propensity‑matched SEER analysis

With the rapid development of imaging technology and comprehensive treatment in modern medicine, the early diagnosis rate of breast cancer is constantly improving, and the prognosis is also improving; As breast cancer patients survive longer, the risk of developing second primary cancers increases. Since both breast and thyroid are Hormone receptor sensitive organs, which are regulated by hypothalamus pituitary target gland endocrine axis, changes in body endocrine status may lead to the occurrence of these two diseases in succession or simultaneously. This study extracted clinical data and survival outcomes of breast cancer patients registered in the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2019. After matching the case and controls with propensity scores, the selected patients were randomly split into training and test datasets at a ratio of 7:3. Univariate and multivariate COX proportional regression analysis is used to determine independent risk factors for secondary thyroid cancer and construct a column chart prediction model. Age, ethnicity, whether radiotherapy, tumor primary location, N stage, M stage were identified by Cox regression as independent factors affecting secondary thyroid cancer in patients with breast cancer patients, and a risk factor nomogram was established to predict patients’ 3 and 5 year survival probabilities. The AUC values for 3 and 5 years in the training set were 0.713, 0.707, and the c-index was 0.693 (95% CI 0.67144, 0.71456), and the AUC values for 3 and 5 years in the validation set were 0.681, 0.681, and the c-index was 0.673 (95% CI 0.64164, 0.70436), respectively.

The role of retroelements of the human genome in the development of type 1 diabetes mellitus

Retroelements (retrotransposons and endogenous retroviruses) are a class of mobile genetic elements that move in the genome by inserting their own reverse transcribed transcripts. They serve as drivers of epigenetic regulation; therefore, individual characteristics of the distribution of retroelements in the genome influence the development of multifactorial diseases. Type 1 diabetes mellitus is a multifactorial disease with an immune response against pancreatic β cells. The role of heredity in the development of the disease is estimated at 88%, and the role of allelic variants of various genes is determined. There are also other specific types of diabetes mellitus, which account for more than 2% of cases of diabetes mellitus and are monogenic diseases with an autosomal dominant mode of inheritance due to germline mutations in the MODY genes, including HNF4A, GCK, HNF1A, HNF1B. Most patients with type 1 diabetes have the protein product and ribonucleic acid (RNA) of the insulin inhibitor HERV-W-Env, which is caused by abnormal expression of the human endogenous retrovirus (HERV). An assumption has been made about the role of retroelements in the development of type 1 diabetes mellitus. This is due to their involvement in the phylogenetic formation of the endocrine system, since in evolution retroelements turned out to be sources of regulatory sequences of hormone genes, nuclear hormone receptors and binding sites for them. Type 1 diabetes mellitus is associated with the integration of HERV into the HLA-DQ gene region, with allelic variants and sizes of VNTR variable tandem repeats (part of the SVA retroelements), which regulate the expression of the insulin gene and other hormones. For this reason, it is likely that the development of type 1 diabetes mellitus may be based on individual characteristics of the distribution of HERVs in the human genome and their dynamic changes in ontogenesis. HERVs also play a role in the etiopathogenesis of diabetes mellitus through the activation of an autoimmune response, the triggering factors of which are exogenous viral infections and stress. Thus, retroelements are involved in various mechanisms of the development of type 1 diabetes mellitus, which reflects their global regulatory influence on endocrine regulation.

Association of mammographic breast density measurements and hormone receptor status of breast cancer.

Breast cancer is the most frequent cancer in women, with significant mortality. Mammography is a routine investigation for breast disease. A known risk factor for breast cancer is increased breast density. Here, we tried to observe if mammographic density also affects the hormone receptor status of breast cancer, which will help in the understanding of the biological mechanisms of breast cancer development. Suspected breast cancer patients at Lok Nayak Hospital, Delhi, underwent mammography in the Department of Radiodiagnosis. The density of breast contralateral to the mass was assessed using Hologic Quantra software version 2.1.1 [Area Breast Density(ABD)]. The hormone receptor status of all the tumours was recorded on histopathology. Of these, 100 confirmed cases were included in the study. ER-positive, PR-positive, and HER2-positive tumours were seen in 41%, 33%, and 34% patients, respectively. Regarding ER receptor status, the mean ABD for positive and negative tumours was 27% and 23%, respectively, p-value = 0.01, showing significant relation between them. Mean ABD for HER2-positive and -negative tumours was 25% and 24%, respectively, p-value = 0.75. Mean ABD for PR-positive and PR-negative tumours was 23% and 25%, respectively, p-value = 0.42 (not significant). We found that ER-positive tumours were common in dense breasts, which was statistically significant. However, this was not true for PR and HER2 receptor status. Limited studies have been done to study MD using computerised software and its effect on hormone receptor status, with conflicting results. Further, large, multicentric studies can be useful in understanding the mechanism and providing better treatment for breast cancer patients.

Lead Decreases Bone Morphogenetic Protein-7 (BMP-7) Expression and Increases Renal Cell Carcinoma Growth in a Sex-Divergent Manner.

Both tissue and blood lead levels are elevated in renal cell carcinoma (RCC) patients. These studies assessed the impact of the subchronic lead challenge on the progression of RCC in vitro and in vivo. Lead challenge of Renca cells with 0.5 μM lead acetate for 10 consecutive passages decreased E-cadherin expression and cell aggregation. Proliferation, colony formation, and wound healing were increased. When lead-challenged cells were injected into mice, tumor size at day 21 was increased; interestingly, this increase was seen in male but not female mice. When mice were challenged with 32 ppm lead in drinking water for 20 weeks prior to tumor cell injection, there was an increase in tumor size in male, but not female, mice at day 21. To investigate the mechanism underlying the sex differences, the expression of sex hormone receptors in Renca cells was examined. Control Renca cells expressed estrogen receptor (ER) alpha but not ER beta or androgen receptor (AR), as assessed by qPCR, and the expression of ERα was increased in tumors in both sexes. In tumor samples harvested from lead-challenged cells, both ERα and AR were detected by qPCR, yet there was a significant decrease in AR seen in lead-challenged tumor cells from male mice only. This was paralleled by a plate-based array demonstrating the same sex difference in BMP-7 gene expression, which was also significantly decreased in tumors harvested from male but not female mice; this finding was validated by immunohistochemistry. A similar expression pattern was seen in tumors harvested from the mice challenged with lead in the drinking water. These data suggest that lead promotes RCC progression in a sex-dependent via a mechanism that may involve sex-divergent changes in BMP-7 expression.

Lipid metabolism: a central modulator of RORt-mediated Th17 cell differentiation.

Among the T helper cell subsets, Th17 cells contribute to the development of various inflammatory and autoimmune diseases, including psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Retinoid-related orphan receptor gamma t (RORγt), a nuclear hormone receptor, serves as a master transcription factor for Th17 cell differentiation. Recent findings have shown that modulating the metabolic pathway is critical for Th17 cell differentiation, particularly through the engagement of de novo lipid biosynthesis. Suppression of lipid biosynthesis, either through the pharmacological inhibition or gene deletion of related enzymes in CD4+ T cells, results in significant impairment of Th17 cell differentiation. Mechanistic studies indicate that metabolic fluxes through both the fatty acid and cholesterol biosynthetic pathways have a pivotal role in the regulation of RORγt activity through the generation of endogenous RORγt lipid ligands. This review discusses recent discoveries highlighting the importance of lipid metabolism in Th17 cell differentiation and function, as well as exploring specific molecular pathways involved in RORγt activation through cellular lipid metabolism. We further elaborate on a pioneering therapeutic approach to improve inflammatory and autoimmune disorders via the inhibition of RORγt.

Demographics and survival outcomes of stage IV male breast cancer: A retrospective analysis of SEER database.

11142 Background: Male Breast Cancer (MBC) is a rare malignancy accounting for &lt;1% of all breast cancer cases in the United States. It is often lately diagnosed due to lack of awareness leading to substantial morbidity and mortality. Previous studies revealed higher risk of death among males compared to females across all stages, but little known about the impact of Hormone Receptor (HR) and Human Epidermal growth factor Receptor 2(HER 2) statuses on prognosis and survival among MBC patients. So, we aim to study the survival outcomes of stage IV MBC patients using SEER (Surveillance, Epidemiology, and End Results) data. Methods: A retrospective analysis was conducted using a SEER database and identified stage IV MBC cases (Any T, Any N, M1) diagnosed between 2010-2015. The selection of these years is based on the reporting of HER2 status on SEER database starting from 2010 and to ensure a current period and a minimum of 5 years of follow-up. Patient demographics, tumor HR/HER 2 status and survival data were extracted and analyzed. Subgroup analyses were performed to show the correlation between HR/HER 2 status and survival. Results: The study included 144 patients. 59.7%(86/144) were above 60 years of age. Majority were Caucasians up to 68.1%(98/144) followed by African Americans 18.7% (27/144), Hispanics 6.9%(10/144) and Asians/Pacific Islanders 6.2%(9/144). Among the subtypes, the most common was HR+/HER2- consisting of 69.4%(100/144) followed by HR+/HER2+ 19.4%(28/144), HR-/HER2- 9.7%(14/144), HR-/HER2+ 1.4%(2/144). The median overall survival varied among different subtypes of breast cancer and was noted to be 31.5 months, 25 months, 4.5 months and 10 months among HR+/HER2-, HR+/HER2+, HR-/HER2- and HR-/HER2+ respectively (Table). In the comparison between HR+/HER2+ and HR-/HER2-, the risk of death differed significantly, as indicated by a hazard ratio of 0.26 (95% CI 0.12-0.56, p = 0.001), highlighting a poor survival of HR-/HER2-. Conclusions: This retrospective analysis provides valuable insights into the demographics and survival outcomes of stage IV MBC patients. Triple negative (HR-/HER2-) subtype continues to have poor outcomes in males as well, emphasizing the need to explore novel treatment strategies to improve outcomes for this unique patient population. Although, treatment regimens for MBC are extrapolated from women, the disparity in survival across all subtypes requires the need to get more men on breast cancer clinical trials when feasible. [Table: see text]

Overall survival in patients with HER2-low breast cancer at a reference hospital in Mexico.

e12578 Background: Breast cancer is the most diagnosed cancer in women. The 5-year overall survival (OS) rate in early-stage disease is 97% while in advanced disease is 36%. HER2 is a growth receptor involved in cell survival and proliferation. An overexpression of this protein leads to a more aggressive behavior; however, with targeted therapies, OS has improved. Recently, a new classification has been developed for tumors previously known as HER2-negative: HER2-low; which are those with IHC 1+ or 2+/ISH negative. It is believed that in these types of tumors, the signaling pathways of the HER2-positive subtype are also activated. There are conflicting studies on the prognostic impact of this subgroup. Currently, there is availability of anti-HER2 treatment for patients in advanced stages, as described in the DESTINY-Breast04 study, which changes the treatment paradigm for this pathology. Methods: The aim of this study is to determine overall survival in patients with HER2-low breast cancer. A retrospective, analytical, observational cohort was performed. Patients diagnosed with HER2-negative/low breast cancer, treated at the UMAE Oncology Hospital of the CMN Siglo XXI, from January 2018 to December 2022, were included. OS and disease-free survival (DFS) were calculated using Kaplan-Meier curves, and the impact of HER2-low expression on OS and DFS was assessed using log-rank analysis. The prognostic analysis of the complete model was performed using a Cox proportional hazards model. Results: We included 213 patients. The median age was 57 years. Ninety-five patients were HER2-low (44.6%), and 118 were HER2-negative (55.4%). Seventy-six percent had positive hormone receptor (HR) status. Patients with HR+/HER2-negative were 84 (52.2%), and HR+/HER2-low were 77 (47.8%). Among HR-negative status, the majority were HER2-negative (65.4%). When comparing HER2-negative and HER2-low, no statistically significant differences were found, with a 48-month overall survival of 70% for HER2-negative compared to 87.1% for HER2-low (p= 0.5700). OS analysis in the HER2-low group, comparing HR+ vs. HR-, a statistically significant difference at 48 months of 98.31% vs. 49.17% (p &lt;0.0001), respectively, was found. Regarding DFS, a comparison between HR+ against HR-, it was 79.53% vs. 37.14%, respectively (p= 0.0002). The DFS analysis revealed that, among the variables studied, lymphovascular invasion (LVI) and HR+ status showed a statistically significant association with time to recurrence. Particularly, the presence of HR positivity was associated with a significant 82.6% reduction in the risk of recurrence. Conclusions: HER2 status alone (negative or low) did not offer a clear distinction in terms of OS or DFS. Nevertheless, it was observed a difference in OS and DFS outcomes favoring the HR-positive group when examining HR status among individuals with HER2-low, though this finding requires validation in a larger population.

Expression of hormone receptors and human epidermal growth Factor2/Neu in female breast cancer patients

Overexpression of HER2/neu and estrogen receptors (ER) and/or progesterone receptors (PR) are reported to be inversely associated with breast cancer (BC). The relationship between hormone receptors and HER2/neu is attenuated by age and numerous other clinical factors. Here, we examined the link between hormone receptors and HER-2/neu in terms of an additional variable, such as the histological grades of breast tumors in women. A total of 240 breast cancer samples were obtained from the Department of Histopathology at the University of Lahore Teaching Hospital in Lahore, Punjab. Immunohistochemistry (IHC) was used to examine the expression of hormone receptors and HER-2/neu. Using the χ2 and fisher exact test, the association between hormone receptors and HER-2/neu in various age groups and histological grades was investigated. Patients that were included in this study had ages between 30 and 90 years, with a mean age of 51.89 ± 12.01 years, and were mostly having grade 1 tumors. The most prevalent type of breast cancer was invasive ductal carcinoma (95.83%). It was found that the ER, PR, and HER-2/neu were more expressive in older (above 45) and grade 1 tumors as compared to younger (≤45) and higher-grade tumor patients. HER-2 was negatively correlated with hormonal receptors in women aged >45 years old with grade-1 tumors. Hormonal receptor (ER/PR) expression is associated with HER-2/neu expression not only in older age (>45) but also in grade 1 tumors. This correlation between HER2/neu and hormone receptors that improves with age and tumor grade is useful for predicting outcomes and, likely, for guiding therapy choices.

Efficacy and safety of eribulin-based chemotherapy in patients with advanced breast cancer: A single-centre retrospective study.

e13121 Background: Eribulin, a nontaxane microtubule dynamics inhibitor, which was approved for the third-line treatment of advanced breast cancer (ABC) in China in 2019. This retrospective study aimed to assess efficacy and safety of Eribulin-based chemotherapy in ABC patients, especially for patients exhibiting HER2-0 and HER2-low status (immunohistochemistry [IHC] 1+ or IHC 2+with a negative in situ hybridization assay). Methods: This single-center retrospective study planned to include 126 ABC patients from January 2020 to December 2023. Enrolled participants received Eribulin either as monotherapy or in combination with other regiments such as anti-angiogenic therapy, PD-1 inhibitor, or alternative chemotherapy in clinical practice. The primary outcomes included progression-free survival (PFS) and safety assessments. Results: A total of 84 patients with ABC received Eribulin were enrolled. Patients' baselines were summarized as follows: The median age was 53.3 years (range 30.0–86.0 years). 53 (63.1%) patients were HER2-low while 40 (47.6%) patients were hormone receptor (HR) positive. 63.1% patients have received at least one line chemotherapy before the use of Eribulin. According to the K-M survival analysis, the median PFS was 6.0 (range 3.2-11.3) months for all patients. The median PFS was longer for patients received aromatase inhibitors (AI) for over 6 months than patients with AI naive (median 10.1 vs 6.6 months; p=0.192) in HR positive patients. Patients who received CDK4/6 therapy had longer PFS than patients (median 10.7 vs 6.6 months; p=0.38). There was a trend toward prolonged PFS in the HER2-0 group compared with HER2-low group (median 10.13 vs 6.03 months; p=0.154), although there was no significant difference. A nonsignificant improvement of PFS was observed in HR-/HER2-0 patients, compare with HR-/HER2-low patients (median 16.4 vs 4.7mo; p=0.21). Meanwhile the median PFS of HER2-0 and HER2-Low was similar in HR positive patients. The objective response rate was 35.5% in HER2-0 group and 30.2% in HER2-low group. In multivariate cox regression, Eribulin as first line treatment (HR, 4.028; 95% CI, 1.131-14.337) and HER2-0 (HR, 2.903; 95% CI, 1.257-6.702) showed prognostic values regarding PFS. Common grade 3 or 4 adverse events that were reported in more than 10% were neutropenia (41.6%) and leukopenia (26.2%). No treatment-related deaths were reported. Conclusions: This single-center study demonstrated encouraging efficacy and safety in the ABC patients treated with Eribulin. Significant PFS benefit was associated with Eribulin treatment in patients with HER2-0 compared with HER2-low. This study still needs longer follow-up to evaluate its efficacy more comprehensively.