Biomarkers For Endometrial Cancer Research Articles

Cervicovaginal metabolome and tumor characteristics for endometrial cancer detection and risk stratification.

Endometrial cancer is highly prevalent and lacking non-invasive diagnostic techniques. Diagnosis depends on histological investigation of biopsy samples. Serum biomarkers for endometrial cancer have lacked sensitivity and specificity. The objective of this study was to investigate the cervicovaginal environment to improve understanding of metabolic reprogramming related to endometrial cancer and identify potential biomarker candidates for non-invasive diagnostic and prognostic tests. Cervicovaginal lavages were collected from 192 participants with endometrial cancer (n=66) and non-malignant conditions (n=108), and global untargeted metabolomics was performed. Using the metabolite data (n=920), we completed a multivariate biomarker discovery analysis. We analyzed grade 1/2 endometrioid carcinoma (n=53) and other endometrial cancer subtypes (n=13) to identify shared and unique metabolic signatures between the subtypes. When compared to non-malignant conditions, downregulation of proline (p<0.0001), tryptophan (p<0.0001), and glutamate (p<0.0001) was found among both endometrial cancer groups, relating to key hallmarks of cancer including immune suppression and redox balance. Upregulation (q<0.05) of sphingolipids, fatty acids, and glycerophospholipids was observed in endometrial cancer in a type-specific manner. Furthermore, cervicovaginal metabolites related to tumor characteristics, including tumor size and myometrial invasion. Our findings provide insights into understanding the endometrial cancer metabolic landscape and improvement into diagnosis. The metabolic dysregulation described in this paper linked specific metabolites and pathophysiological mechanisms including cellular proliferation, energy supply, and invasion of neighbouring tissues. Furthermore, cervicovaginal metabolite levels related to tumor characteristics, which are used for risk stratification. Overall, development of non-invasive diagnostic can improve both the acceptability and accessibility of diagnosis.

Spatial distribution of tumor‐resident macrophages as predictive biomarkers in endometrial cancer

Spatial distribution of tumor‐resident macrophages as predictive biomarkers in endometrial cancer

Upregulation of ESPL1 is associated with poor prognostic outcomes in endometrial cancer

Background Extra spindle pole bodies-like 1 (ESPL1) is known to play a crucial role in the segregation of sister chromatids during mitosis. Overexpression of ESPL1 is considered to have oncogenic effects in various human cancers. However, the specific biological function of ESPL1 in endometrial cancer (EC) remains unclear. Methods The TCGA and GEO databases were utilized to assess the expression of ESPL1 in EC. Immunohistochemistry was utilized to detect separase expression in EC samples. Kaplan-Meier survival analysis and Cox regression analysis were performed to evaluate the diagnostic and prognostic significance of ESPL1 in EC. Gene Set Enrichment Analysis (GSEA) was employed to explore the potential signaling pathway of ESPL1 in EC. Cell proliferation and colony formation ability were analyzed using CCK-8 and colony formation assay. Results Our analysis revealed that ESPL1 is significantly upregulated in EC, and its overexpression is associated with advanced clinical characteristics and unfavourable prognostic outcomes. Suppression of ESPL1 attenuated proliferation of EC cell line. Conclusion The upregulation of ESPL1 is associated with advanced disease and poor prognosis in EC patients. These findings suggest that ESPL1 has the potential to serve as a diagnostic and prognostic biomarker in EC, highlighting its significance in the management of EC patients.

Abstract B019: Assessing Circulating TumOur DNA as a prognostic biomarker in endometrial cancer (The CODEC Study)

Abstract Introduction/Background: Endometrial cancer (EC) is the most common gynecological cancer in the developing world. While significant progress has been made through molecular sub-classification, the treatment of EC for many women remains contentious and better biomarkers are required to guide therapy selection. Circulating tumor DNA (ctDNA) a ‘liquid biopsy’, involves collection of tumor specific DNA via a blood test and can quantify cancer burden and detect tumor specific genomic information. The CODEC study is a prospective pilot study to assess the utility of ctDNA as a prognostic biomarker in EC with the hope that it may help predict relapse and guide selection of adjuvant therapy. Methodology: Women with Type 2 EC planned for surgery and consenting to the collection of biospecimens were enrolled prior to surgery and followed prospectively. Blood was collected perioperatively and then every three months for up to two years and at relapse. Broad sequencing of participants’ tumors was performed, the results of which guided the design of personalized droplet digital PCR (ddPCR) assays for ctDNA analysis. ctDNA was extracted from 5ml of plasma and tested in quadruplicate. PET defined metabolic tumor volume was compared to ctDNA and analysis of ctDNA and relapse free survival (RFS) performed using a Cox proportional hazards regression model. Results: Somatic mutations to guide ddPCR analysis were detected in 45 enrolled women stages 1- 4 including pathogenic variants in POLE. ctDNA results are currently available for 30 participants (remaining results awaited). 12/30 participants had detectable ctDNA preoperatively and 5/25 at Time Point 3 (2-6 weeks post-surgery). ctDNA levels varied significantly across the cohort but results to date indicate that perioperative ctDNA positivity is associated with relapse. Interestingly in those that had detectable ctDNA preoperatively, the majority had a rise in ctDNA intraoperatively. Conclusion: This proof-of-concept analysis showed that ctDNA can successfully be detected in the perioperative setting and is the first study in EC to compare ctDNA with PET findings. Although testing is still underway, the early results indicate that ctDNA maybe a useful biomarker to predict relapse and guide the selection of adjuvant therapy. Citation Format: Rachel Delahunty, Rainier Arnolda, Thuan Tzen Koh, Michael Hofman, Hayley Johnston, Patricia Wojtowicz, Caitlyn Nguyen, Nicole Brooks, Kym Reid, Julie Lamont, Thomas Jobling, Deborah Neesham, Vanessa Obers, Clair Shadbolt, Brooke Sawyer, Paul Smith, Jennifer Ellis, Geradline Goss, Mila Volcheck, Madawa Jayawardana, Sandun Silva, Chelsee Hewitt, Kate Jones, Andrew Fellowes, Orla McNally, Stephen Wong, Elizabeth Christie, Costas Yannakou. Assessing Circulating TumOur DNA as a prognostic biomarker in endometrial cancer (The CODEC Study) [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B019.

Abstract A023: Assessing the reproducibility crisis in vaginal microbiome studies for clinical applications in endometrial cancer

Abstract Recent associations between vaginal microbiota and gynecological cancer have led to high-throughput sequencing datasets identifying diagnostic biomarkers for Endometrial Cancer (EC). However, lack of bioinformatics standards results in inconsistent independent studies with poor reproducibility, making them clinically inapplicable. This study leverages publicly available amplicon sequence data to address the reproducibility of EC microbiome studies. We implemented bioinformatics pipelines from five studies to reproduce and measure the replicability of published results across cohorts using metrics such as alpha diversity, beta diversity and differentially expressed taxa. We further evaluated separability between benign and cancer patients at different taxonomic levels (phylum, class, order, family, and genus) within and across datasets using boosted tree classifiers and Area Under the Curve (AUC) as the performance metric. While we reproduced the general trend of observing higher microbial diversity in EC compared to healthy controls, we found irregularities in two cohorts. Using beta diversity distance metrics, we identified that histology alone explains less than 3% of the variance in all cohorts. Three microbiome differential abundance methods were used in the five studies. While they all agree on a decrease in the Lactobacillus genus in EC patients, there is no consensus on other taxa associated with EC. We also found that separability between benign and cancerous conditions is highest at the class level, having an AUC score of 0.86. In subsequent steps, we will perform an integrative analysis to identify an EC vaginal microbiome predictive signature that is preserved across all five cohorts, benefiting screening programs. Citation Format: Dollina D. Dodani, Aline Talhouk. Assessing the reproducibility crisis in vaginal microbiome studies for clinical applications in endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A023.

A new methodology to reveal potential nucleic acid modifications associated with the risk of endometrial cancer through dispersive solid-phase extraction coupled with UHPLC-QE-Orbitrap-MS/MS and HPLC-UV.

Nucleic acid modifications have attracted increasing attention in recent years since they have been found to be related to a number of diseases including cancer. Previous studies have shown that the early development of endometrial cancer (EC) is often accompanied by changes in methylation levels of related genes, and the expression of related proteins that regulate reactive oxygen species (ROS) shows significant differences in EC cells and tissues. However, it has not been reported whether nucleic acid modifications related to methylation or ROS can serve as biomarkers for EC. Accurate quantification of these nucleic acid modifications still has challenges because their amounts in urine are very low and the interferences in urine are complicated. In this study, a novel dispersive solid-phase extraction (DSPE) method based on chitosan-carbon nanotube-Al2O3 (CS-CNT-Al2O3) has been established for the analysis of 5-hydroxymethyluracil (5mU), 5-methyl-2'-deoxycytidine (5-mdC), 5-hydroxymethyl-2'-deoxycytidine (5-hmdC), 5-formyl-2'-deoxycytidine (5-fdC), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in EC patient urine samples coupled with UHPLC-QE-Orbitrap-MS/MS and HPLC-UV. Firstly, the synthesis of the CS-CNT-Al2O3 nanocomposite was conducted by a sono-coprecipitation method and was characterized by scanning electron microscope (SEM), energy dispersive spectrometer (EDS), and Fourier transform infrared (FTIR). Under the optimal extraction conditions of DSPE, we successfully quantified 5mU, 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG in urine samples from 37 EC patients and 39 healthy controls. The results showed that there were significant differences in the levels of 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG in EC patients compared to the healthy control group. The receiver operator characteristic (ROC) curve analysis was carried out to evaluate the potential of 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG to distinguish EC patients from healthy volunteers. The area under the curve (AUC) for 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG was 0.7412, 0.667, 0.8438, and 0.7981, respectively. It indicated that 5-mdC, 5-hmdC, 5-fdC, and 8-OHdG had certain potential in distinguishing between EC patients and healthy volunteers and they could act as potential non-invasive biomarkers for early diagnosis of EC. Moreover, the present study would stimulate investigations of the effects of nucleic acid modifications on the initiation and progression of EC.

Identification and validation of serum metabolite biomarkers for endometrial cancer diagnosis

Endometrial cancer (EC) stands as the most prevalent gynecological tumor in women worldwide. Notably, differentiation diagnosis of abnormity detected by ultrasound findings (e.g., thickened endometrium or mass in the uterine cavity) is essential and remains challenging in clinical practice. Herein, we identified a metabolic biomarker panel for differentiation diagnosis of EC using machine learning of high-performance serum metabolic fingerprints (SMFs) and validated the biological function. We first recorded the high-performance SMFs of 191 EC and 204 Non-EC subjects via particle-enhanced laser desorption/ionization mass spectrometry (PELDI-MS). Then, we achieved an area-under-the-curve (AUC) of 0.957–0.968 for EC diagnosis through machine learning of high-performance SMFs, outperforming the clinical biomarker of cancer antigen 125 (CA-125, AUC of 0.610–0.684, p < 0.05). Finally, we identified a metabolic biomarker panel of glutamine, glucose, and cholesterol linoleate with an AUC of 0.901–0.902 and validated the biological function in vitro. Therefore, our work would facilitate the development of novel diagnostic biomarkers for EC in clinics.

The value of il-1α, il-1β, il-6, il-8 and tnf-α as potential diagnostic biomarkers in endometrial cancer

The value of il-1α, il-1β, il-6, il-8 and tnf-α as potential diagnostic biomarkers in endometrial cancer

Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Endometrial Cancer: A Review on Immunohistochemistry Staining Patterns and Clinical Implications.

Among the four endometrial cancer (EC) TCGA molecular groups, the MSI/hypermutated group represents an important percentage of tumors (30%), including different histotypes, and generally confers an intermediate prognosis for affected women, also providing new immunotherapeutic strategies. Immunohistochemistry for MMR proteins (MLH1, MSH2, MSH6 and PMS2) has become the optimal diagnostic MSI surrogate worldwide. This review aims to provide state-of-the-art knowledge on MMR deficiency/MSI in EC and to clarify the pathological assessment, interpretation pitfalls and reporting of MMR status.

Integrative approach: Advancing endometrial cancer biomarkers through machine learning and network-derived RNA-Seq screening

The study aims to identify potential RNA biomarkers for progressive endometrial cancer with a machine learning-based approach. High throughput screening of RNA-Seq expression data identified Differentially Expressed Genes(DEGs) for various stages (Stage I-Stage III) of endometrial cancer. Overlapping genes among different stages of the disease were screened and compared for commonality with TCGA and the GTEx RNA Sequencing expression data. 1466 genes were found overlapping and expressed differentially in the progressive disease from healthy endometrial to Stage I to Stage II to Stage III endometrial cancer. Machine learning (ML) classifiers, namely Random Forest, Principal Component Analysis, Multinomial Naïve Bayes, and Support Vector Machine with Recursive Feature Elimination, helped select the most important ranked interacting DEGs. Overlapping important ranked DEGs, hub proteins, and significant modules from protein-protein interaction network analysis were used as candidate biomarkers for progressive endometrial cancer. In silico validations of druggable top-ranked cancer targets for their essentiality on cancer cell lines and high expression in immunohistochemistry analysis were performed. Further, their dysregulated expressions were evaluated in different cancers. The dysregulation of the proposed biomarkers, namely PKM, RAN, PHGDH, and SLC7A5, showed a decrease in the survival of the patients associated with endometrial cancer. These overlapping associations offer common cancer-specific targets among different stages of cancer which may assist, during the onset of the disease, in pointing to proliferating cancer cells. They provide significant visions in the understanding of progressive endometrial cancer.

KLRB1 is a novel prognostic biomarker in endometrial cancer and is associated with immune infiltration.

Endometrial cancer (EC) has the characteristics of high mortality and poor prognosis in the advanced stage, which seriously threatens women's health. Killer cell lectin-like receptor B1 (KLRB1) is a promising immune checkpoint of which the expression level can regulate the killing effect on tumor cells of the immune system, thereby affecting the survival and prognosis of tumor patients. However, it is still unclear whether KLRB1 is associated with survival and prognosis in patients with EC. Therefore, our study focused on the relationship between KLRB1 and immune cells to explore the role of KLRB1 on the immune microenvironment, and to further explore its feasibility as a prognostic marker in EC. In this study, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to analyze the messenger RNA (mRNA) expression level of KLRB1 in normal endometrial and EC tissues. The University of Alabama at Birmingham Cancer data analysis Portal (UALCAN) database was used to determine the correlation between KLRB1 mRNA expression and clinical features among the EC patients. KLRB1 expression levels were investigated in the Tumor IMmune Estimation Resource (TIMER) database to reveal its relationship with immune cell infiltration of EC. Finally, using the R package clusterProfiler, enrichment analysis was performed on KLRB1 to study its potential function. The results suggested that KLRB1 expression varied in different tumor tissues, and the EC group had lower mRNA expression levels than did the control group. It was also found that patients with high expression of KLRB1 had a better prognosis. According to further enrichment and immune infiltration analyses, KLRB1 expression had a closed relationship with the level of infiltration of some immune cell types, such as B cells memory, eosinophils, and Tregs, among others. KLRB1 expression is associated with the infiltration of immune cells and can be used as a prognostic biomarker in EC.

Immune signatures of the POLE mutation in endometrial carcinomas: a systematic study based on TCGA data and clinical cohort validation.

POLE is a critical biomarker for endometrial cancer (ECs) prognosis and therapeutic decision. However, the immune infiltration and immunotherapy-related gene expression in the tumor microenvironment (TME) of POLE-mutated ECs remain unresolved. The TCGA database was used to characterize the TME of POLE mutants, which primarily included immune cells and co-expression genes. We used immunohistochemistry (IHC) to determine immune cell abundance and PD-L1 expression in 104 EC tissues, including 11 POLE mutants and 93 wild-type. The bioinformatic study found significant differences in gene expression of the chemokine family, immune-cell markers, and lysozyme in POLE mutants, along with immune response activation. In POLE-mutated ECs, the abundance of CD4+T, CD8+T, M1 macrophages, and dendritic cells increased considerably. Furthermore, POLE mutations may enhance immune cell recruitment or activation and lymphocyte homing in ECs. POLE mutants also had increased expression of immune-checkpoint suppressor genes such as PD-L1, CTLA-4, TIM-3, and others. The tumor mutation burden (TMB) was higher in ECs with POLE mutation. In the validation cohort, we discovered that POLE mutations were related to the immune infiltration abundance of CD8+, CD4+, and Foxp3+ cells and PD-L1 expression by IHC. The prognosis of TCGA-ECs showed that the survival time of the CD8, CD4, PD-L1, or Foxp3 over-expression subgroup of the POLE mutants was significantly prolonged compared to the down-regulation subgroup or the POLE wild-type. The infiltration abundance of CD8+ T, CD4+ T, Foxp3+ T cells, and the expression of PD-L1 harbor crucial value for the prognosis or individualized therapy of POLE-mutated ECs.

82. Can mitochondrial DNA mutations be used as a biomarker for endometrial cancer?

82. Can mitochondrial DNA mutations be used as a biomarker for endometrial cancer?

Preoperative Serum Levels of PDGF-AB, PDGF-BB, TGF-α, EGF and ANG-2 in the Diagnosis of Endometrial Cancer.

(1) Background: It is relevant to find new diagnostic biomarkers for endometrial cancer. This study aimed to investigate whether PDGF-AB, PDGF-BB, TGF-α, EGF and ANG-2 could be considered new useful markers for diagnosis and survival of endometrial cancer. (2) Methods: A total of 93 women diagnosed with endometrial cancer (EC) and 66 patients with non-cancerous endometrial lesions (NCEL) were included in this study. (3) Results: Median serum levels of PDGF-AB, PDGF-BB, TGF-α, EGF and ANG-2 were significantly higher in the EC group compared to the NCEL group (for PDGF-AB, PDGF-BB, TGF-α and ANG-2, p = 0.0000; for EGF, p = 0.0186). The cut-off level of PDGF-AB was set at 127.69 pg/mL with a sensitivity of 87.1% and a specificity of 66.67% (AUC = 0.78, p < 0.000001). The cut-off level of PDGF-BB was set at 207.86 ng/L with a sensitivity of 82.8% and a specificity of 75.76% (AUC = 0.85, p < 0.000001). The cut-off level of TGF-α was set at 33.85 ng/L with a sensitivity of 82.8% and a specificity of 75.76% (AUC = 0.82, p < 0.000001). The cut-off level of EGF was set at 934.76 pg/mL with a sensitivity of 83.87% and a specificity of 28.79% (AUC = 0.61, p = 0.018472). The cut-off level of ANG-2 was set at 3120.68 pg/mL with a sensitivity of 72.04% and a specificity of 93.94% (AUC = 0.87, p < 0.000001). (4) Conlusion: It was concluded that all the proteins studied could be potential diagnostic markers in endometrial cancer.

Comprehensive analysis and experimental validation reveal elevated CLCN4 is a promising biomarker in endometrial cancer.

Several studies have reported the role of CLCN4 in tumor progression. However, its mechanism remains to be thoroughly studied. The objective of this study was to explore the potential pathogenic role of CLCN4 in endometrial carcinoma (UCEC) with a better understanding of the pathological mechanisms involved. The potential roles of CLCN4 in different tumors were explored based on The Cancer Genome Atlas (TCGA), the expression difference, mutation, survival, pathological stage, Immunity subtypes, Immune infiltration, tumor microenvironment (TME), tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) related to CLCN4 were analyzed. Then, the expression, prognosis, mutation, and functional enrichment of CLCN4 in UCEC were analyzed. Immunohistochemical experiment was used to verify the expression of CLCN4 in endometrial cancer tissues and normal tissues. In vitro, we knocked down of CLCN4 in HEC-1-A cells and performed CCK8, WB, RT-PCR, wound-healing, transwell assays to further validation of the molecular function. Results revealed that high expression of CLCN4 was observed in 20 cancer types of TCGA. CLCN4 expression correlates with poor survival in MESO, BLCA, THCA, especially UCEC tumors. CLCN4 expression was significantly associated with CD4+ T-cell infiltration, especially CD4+ Th1-cell. Immunohistochemical experiment reveals that CLCN4 is high expressed in endometrial tumors, in vitro experiment reveals that knockdown of CLCN4 inhibits the cells proliferation, migration and invasion. Our study is the first to offer a comprehensive understanding of the oncogenic roles of CLCN4 on different tumors. CLCN4 may become a potential biomarker in UCEC.

Four differentially expressed exosomal miRNAs as prognostic biomarkers and therapy targets in endometrial cancer: Bioinformatic analysis.

Endometrial cancer (EC) is one of the most common gynecological malignancies worldwide. Accumulated evidence has demonstrated exosomes of cancer cells carry microRNAs (miRNAs) to nonmalignant cells to induce metastasis. Our study aimed to find possible biomarkers of EC. Data for miRNA expression related with exosome from EC patients were downloaded from The Cancer Genome Atlas database, and the miRNA expression profiles associated with exosomes of EC were downloaded from the National Center for Biotechnology Information. We used different algorithms to analyze the differential miRNA expression, infer the relative proportion of immune infiltrating cells, predict chemotherapy sensitivity, and comprehensively score each gene set to evaluate the potential biological function changes of different samples. The gene ontology analysis and Kyoto encyclopedia of genome genomics pathway analysis were performed for specific genes. A total of 13 differential miRNAs were identified, of which 4 were up-regulated. The 4 miRNAs, that is hsa-miR-17-3p, hsa-miR-99b-3p, hsa-miR-193a-5p, and hsa-miR-320d, were the hub exosomal miRNAs that were all closely related to the clinic phenotypes and prognosis of patients. This study preliminarily indicates that the 4 hub exosomal miRNAs (hsa-miR-17-3p, hsa-miR-99b-3p, hsa-miR-193a-5p, and hsa-miR-320d) could be used as prognostic biomarkers or therapy targets in EC. Further studies are required to make sure of their real feasibility and values in the EC clinic and the relative research.

Assessment of Tissue Expression of PIR2/RNF144b Protein in the Different Stages of Endometrial Cancer

Background Endometrial cancer is considered as one of the most common gynaecological cancers in developed countries. Its incidence has risen about 20% over the last decade and the rate 0f death has risen &amp;gt;100% over the past two decades. Aim of the Work This retrospective cohort study will assess tissue expression of PIR2 protein in the different stages of endometrial cancer. Materials and Methods A retrospective cohort study was conducted at Ain Shams University Maternity Hospital (The Early Cancer Detection Unit), A Formalin fixed paraffin embedded tissues (FFPT) was collected from the patient's the pathology unit at Gynecology &amp; Obstetrics hospital, Ain Sham University hospitals in a period of 12 months during 2017 – 2018. The study was conducted on 60 women diagnosed as endometrial cancer; they are subdivided into 2 groups: 1st group: 30 patients with stage 1 endometrial cancer by surgical staging, 2nd group: 30 patients with other advanced stages of endometrial cancer by surgical staging. Results In this study, we show that the E3-ubiquitin ligase PIR2/RNF144B is a potential targetable biomarker in endometrial cancer. There is a high significant association between the PIR2/RNF144b and different stages of EC and higher tumor grades are associated with higher protein expression. The paraffin -embedded endometrial tissue for each patient eligible for the study was analyzed for tissue expression of PIR2 protein using Immunohistochemistry. Conclusion We suggested that PIR2/RNF144b can potentially be used as a biomarker for endometrial cancer for early diagnosis and for monitoring clinical progress of cancer status and efficacy of used treatment.

The prognostic significance of DDIT4 in endometrial cancer.

Despite extensive research on endometrial cancer and tumor hypoxic microenvironment, there are no reports exploring the role of DDIT4 in endometrial cancer. This study aimed to elucidate the significance of DDIT4, as a prognostic biomarker for endometrial cancer by immunohistochemical staining and statistical analysis. Four endometrial cancer cells were cultured under normoxia and hypoxia, and the differentially expressed genes were examined using RNA-seq. Immunohistochemical staining for DDIT4 and HIF1A was performed in 86 patients with type II endometrial cancer treated at our hospital, and their correlation with other clinicopathological factors and the prognostic role was analyzed using statistical methods. The expression analysis of hypoxia-inducible genes using four types of endometrial cancer cells revealed that DDIT4 was among the 28 genes that were upregulated in all cells. Based on our results of immunohistochemistry of DDIT4 expression in endometrial cancer tissues, univariate and multivariate analyses based on COX regression analysis showed that high DDIT4 expression significantly correlated to favorable prognosis in both progression-free survival and overall survival. Limited to recurrent cases, metastasis to only lymph nodes was significantly related to high DDIT4 expression, whereas metastasis to other parenchymal organs was significantly dominant in patients with low DDIT4 expression. The expression of DDIT4 enables to predict survival and recurrence in type II endometrial cancer.

Molecular subtypes of endometrial cancer: Implications for adjuvant treatment strategies.

When determining adjuvant treatment for endometrial cancer, the decision typically relies on factors such as cancer stage, histologic grade, subtype, and a few histopathologic markers. The Cancer Genome Atlas revealed molecular subtyping of endometrial cancer, which can provide more accurate prognostic information and guide personalized treatment plans. To summarize the expression and molecular basis of the main biomarkers of endometrial cancer. PubMed was searched from January 2000 to March 2023. Studies evaluating molecular subtypes of endometrial cancer and implications for adjuvant treatment strategies. Three authors independently performed a comprehensive literature search, collected and extracted data, and assessed the methodological quality of the included studies. We summarized the molecular subtyping of endometrial cancer, including mismatch repair deficient, high microsatellite instability, polymerase epsilon (POLE) exonuclease domain mutated, TP53 gene mutation, and non-specific molecular spectrum. We also summarized planned and ongoing clinical trials and common therapy methods in endometrial cancer. POLE mutated endometrial cancer consistently exhibits favorable patient outcomes, regardless of adjuvant therapy. Genomic similarities between p53 abnormality endometrial cancer and high-grade serous ovarian cancer suggested possible overlapping treatment strategies. High levels of immune checkpoint molecules, such as programmed cell death 1 and programmed cell death 1 ligand 1 can counterbalance mismatch repair deficient endometrial cancer immune phenotype. Hormonal treatment is an appealing option for high-risk non-specific molecular spectrum endometrial cancers, which are typically endometrioid and hormone receptor positive. Combining clinical and pathologic characteristics to guide treatment decisions for patients, including concurrent radiochemotherapy, chemotherapy, inhibitor therapy, endocrine therapy, and immunotherapy, might improve the management of endometrial cancer and provide more effective treatment options for patients. We have characterized the molecular subtypes of endometrial cancer and discuss their value in terms of a patient-tailored therapy in order to prevent significant under- or overtreatment.

Long-term follow up of selinexor maintenance in patients with TP53wt advanced or recurrent endometrial cancer: A pre-specified subgroup analysis from the phase 3 ENGOT-EN5/GOG-3055/SIENDO study.

427956 Background: Molecular characterization is important to inform treatment decisions for patients with endometrial cancer (EC). Wild type TP53 ( TP53wt) is found in ~75% of newly diagnosed EC and 50% of advanced/recurrent tumors; there are no specific targeted therapies available for patients with TP53wt EC. Selinexor is an investigational oral XPO1 inhibitor that drives nuclear retention and functional activation of wild type tumor suppressor proteins, including p53. Methods: SIENDO (NCT03555422) was a phase 3 double-blind study evaluating selinexor vs placebo as maintenance therapy in patients with advanced/recurrent EC following response to prior systemic therapy. The primary endpoint was progression-free survival (PFS), which was previously presented at the ESMO plenary in March 2022. Preliminary analysis of a pre-specified exploratory subgroup of patients with TP53wt EC showed a decrease in risk for progression or death with a median PFS of 13.7 months with selinexor as maintenance therapy vs 3.7 months with placebo at the time of primary PFS analysis. The safety and efficacy of selinexor as maintenance therapy was now further assessed with long-term follow-up in the pre-specified subgroup of patients with TP53wt EC. Results: 113 patients with TP53wt EC were randomly assigned to receive selinexor vs placebo as maintenance therapy (selinexor, n=77/placebo, n=36). As of data cutoff on Nov 30, 2022, median follow-up was 20.3 months, with 26.3% and 22.9% patients still on selinexor and placebo treatment, respectively. Median PFS for the TP53wt subgroup was 20.8 months with selinexor vs 5.2 months with placebo (HR [Stratified by chemotherapy response CR vs PR] 0.46; 95% CI (0.27, 0.79), nominal one-sided p=0.002). Efficacy was observed regardless of MSS/MSI status. The most common adverse events (AEs) of any grade (selinexor/placebo) were nausea (90%/34%), vomiting (61%/11%) and diarrhea (38%/34%); and most common grade 3+ AEs included: neutropenia (18%/0%), nausea (12%/0%), and thrombocytopenia (9%/0%). TEAEs leading to discontinuations were reported in 15%/0% of patients, respectively. Conclusions: Long-term follow-up of a pre-specified subgroup analysis showed durable PFS benefit with selinexor maintenance in TP53wt EC, which offers the potential to prolong response to prior systemic therapy. These data suggest that TP53 status is a robust prognostic biomarker for EC and selinexor may provide meaningful benefit in patients who have TP53wt tumors. A phase 3 trial is underway to further investigate the safety and efficacy of selinexor as maintenance therapy in patients with advanced or recurrent TP53wt EC (NCT05611931). Updated PFS and results in additional molecular subtypes (MSS/MSI) of the TP53wt subgroup will be included at the time of presentation. Clinical trial information: NCT03555422 .