Endometrial Carcinoma Patients Research Articles

Impact of cachexia on disease recurrence and survival outcomes in endometrial cancer patients

ObjectiveCancer cachexia is progressive weight loss due to muscle/adipose tissue wasting and inadequate intake that occurs in response to malignancy. It is an independent predictor of disease recurrence and reduced survival in several cancers. However, cachexia’s relationship with gynecologic malignancy outcomes has only been examined in small studies with limited follow-up and inconsistent definitions of cachexia. This study investigated the impact of cachexia on disease recurrence and overall survival in high-risk endometrial carcinoma patients. MethodsThis retrospective cohort study examined data from patients with high-risk non-metastatic primary endometrial carcinoma treated at a single institution from 2015 to 2020. Treatment for all subjects included total hysterectomy, surgical staging, pelvic external beam radiotherapy with or without adjuvant chemotherapy. Radiation planning CT datasets were used to measure skeletal musculature at the L3 vertebral level. Skeletal muscle index (SMI) was defined as total L3 skeletal muscle cross sectional area (cm2)/height2 (m2), and cachexia was defined based on SMI. Results55 patients were eligible for analysis. Several SMI thresholds were used to define cachexia, and analysis was performed for each definition. Kaplan-Meier and Cox-proportional hazards regression analysis yielded no significant reduction in overall survival (OS) or progression-free survival (PFS) in patients with cachexia, regardless of threshold chosen. However, 4 of 13 definitions of cachexia showed significantly improved OS in patients without cachexia, relative to those with cachexia. There were no significant differences in disease recurrence. ConclusionsCachexia as defined in this study was not associated with poor outcomes in endometrial carcinoma patients based on OS, PFS, or disease recurrence.

The Expression and Amplification of HER2 Has a Significant Impact on the Prognosis of Endometrial Carcinoma in Korean Patients.

Objective: The purpose of this study was to analyze the protein overexpression and gene amplification of HER2 in endometrial carcinoma (EC) and to evaluate its role as a prognostic factor in Korean women. Methods: A tissue microarray (TMA) was constructed from samples from 191 patients with diverse histologic types of EC. HER2 protein expression and gene amplification status were analyzed using immunohistochemistry (IHC) and silver in situ hybridization (SISH), respectively. All patients were treated and followed up at a single tertiary medical center in Seoul, Korea, between July 2009 and October 2020. Results: In terms of histological type, among the 191 EC patients, 157 had endometrioid carcinoma, nine had uterine serous papillary carcinoma (USPC), one had clear cell carcinoma, one had squamous cell carcinoma, eight had mixed carcinoma, and 15 had uterine carcinosarcoma (UC). HER2 protein overexpression was observed in eight of the 191 (4.2%) EC patients; of these patients, five had IHC scores of 2+, and three had IHC scores of 3+. The HER2 overexpression rates of USPC, UC, and endometrioid carcinomas were 33.3%, 26.6%, and 0.6%, respectively. HER2 protein overexpression was significant in USPC and UC tissues (p < 0.000) and was associated with poor overall survival (OS) (p < 0.001). HER2 gene amplification was confirmed in seven of 184 patients (3.8%), including three patients with USPC and four patients with UC. OS was significantly shorter in patients who had HER2 amplification (p < 0.001). On multivariate analysis, HER2 expression and HER2 amplification were statistically significantly associated with worse OS (p = 0.006). However, HER2 expression without amplification was not statistically associated with OS (p = 0.993). Conclusions: HER2 protein overexpression and gene amplification are significantly correlated with shorter OS in Korean women. HER2 can be considered an important predictor of survival outcomes in EC patients.

Abstract 6204: Differential gut microbiome alpha diversity in endometrial and ovarian carcinoma patients

Abstract Background: Emerging research underscores the gut microbiome's critical role in cancer development, progression, and response to treatment. As a part of the “ASAP” study, which focuses on the implementation of comprehensive molecular profiling and deep clinical annotation of electronic health records in participants diagnosed with or at risk of developing cancer, we have established a microbiome-associated biobank and corresponding clinical dataset to systematically explore the dynamics of the gut microbiome as patients progress through cancer treatment. We describe a pilot project where we explore the baseline microbiome samples collected from ASAP participants, particularly from those with endometrial and ovarian carcinomas. Methods: Stool samples from patients were collected at the time of enrollment in the ASAP study and sampling is repeated every three months to align with the additional biosampling procedures. Microbial DNA was extracted from the baseline stool samples and subjected to sequencing of the V4 region of the 16S rRNA gene. After generating species level operational taxonomic units (OTUs), alpha diversity measures were generated in the form of the inverse Simpson index. In order to determine whether there was a difference in alpha diversity between individuals with ovarian (N = 37) and endometrial (N = 35) carcinomas, we employed a t-test with 100,000 permutations to derive an empirical p-value. Results: We present sequencing results from the initial n=297 samples. Our comparison of the alpha diversity between ASAP study participants with ovarian and endometrial carcinomas showed a significant difference between the two groups, with the ovarian cancer patients having a lower alpha diversity (empirical p-value = 0.03915). Due to the uniform sampling, biobanking, and analytical procedures, our study allows the ability to explore microbiome features amongst various cancer diagnoses while minimizing laboratory and analytical differences that plague microbiome reproducibility. Conclusions: We observed a significant difference in alpha diversity between patients with endometrial and ovarian carcinomas. Although the current results are preliminary, the wealth of information available in the ASAP protocol will allow us to continue exploring the association of the gut microbiome with cancer and the associated treatment. Citation Format: Casey T. Finnicum, Tobias Meissner, Christel Davis, Sarah Viet, Jason L. Petersen, McKenna Deaton, Benjamin Solomon, William Spanos, David Starks, Rachel Elsey, Erik A. Ehli, Casey Williams. Differential gut microbiome alpha diversity in endometrial and ovarian carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6204.

Analysis of Characteristics of Endometrial Carcinoma in Peri- and Postmenopausal Women with Abnormal Uterine Bleeding.

To analyze the menstrual characteristics of endometrial carcinoma and investigate whether abnormal uterine bleeding in the perimenopausal period differs from postmenopausal bleeding. We conducted a retrospective analysis of 928 cases of endometrial carcinoma in patients admitted from January 2016 to December 2022. We gathered fundamental clinical data and analyzed distinct clinical risk factors between the perimenopausal and postmenopausal groups. Furthermore, we computed the statistical variances in menarche, regular menstrual cycles, and the duration of abnormal uterine bleeding. Perimenopausal patients with endometrial carcinoma exhibit similar factors to postmenopausal patients, especially if they have a history of menstrual cycles lasting more than 30 years, hypertension, abnormal uterine bleeding for over 1 year, and a high risk of endometrial carcinoma. Early intervention for abnormal uterine bleeding during the perimenopausal stage can prevent up to 80% of women from developing endometrial carcinoma. Perimenopause women experiencing abnormal uterine bleeding should be mindful of the risk of endometrial carcinoma, as this awareness can substantially decrease the occurrence of the disease.

Factors Associated with Parametrial Involvement in Endometrial Carcinoma in Patients Treated with Radical Hysterectomy.

Describe factors associated with parametrial involvement, and how these factors modify the prognosis of patients with endometrial carcinoma treated with radical hysterectomy. Observational study in which categorized patients according to those with and without parametrial involvement. A descriptive analysis and comparative analysis were performed for associations between parametrial spread and clinical, surgical, and pathology variables. We analyzed 85 patients, which 18 (21%) had parametrial involvement. Pathology factors associated with parametrial involvement were the endometrioid subtype, grade 3, and variants of poor prognosis (odds ratio (OR) 3.41, 95% CI 1.09-10.64; P = 0.035), myometrial invasion of over 50% (OR 7.76, 95% CI 1.65-36.44; P = 0.009), serosal involvement (OR 17.07, 95% CI 3.87-75.35; P < 0.001), ovarian metastasis (OR 5.15, 95% CI 1.36-19.46; P = 0.016), positive peritoneal cytology (OR 3.9, 95% CI 1.04-14.77; P = 0.044), and lymph node metastasis (OR 3.4; 95% CI 1.16-9.97; P = 0.026). Five-year disease-free survival was 74% (95% CI 57.4-85.4) for the group without parametrial spread and 50.8% (95% CI 22.7-73.4) for the group with parametrial spread (P = 0.001). Similarly, 5-year overall survival was 85.2% (95% CI 67.9-93.6) for the group without parametrial spread and 47.5% (95% CI 8.1-80.2) for the group with parametrial spread (P = 0.002). Factors associated with parametrial involvement were histologies of poor prognosis, tumors affecting uterine serosa, cervix, or spread beyond the uterus. Additionally, parametrial involvement directly affects prognosis by reducing overall survival, disease-free survival and increasing odds for recurrence.

Machine learning for prediction of concurrent endometrial carcinoma in patients diagnosed with endometrial intraepithelial neoplasia

ObjectiveTo identify predictive clinico-pathologic factors for concurrent endometrial carcinoma (EC) among patients with endometrial intraepithelial neoplasia (EIN) using machine learning. Methodsa retrospective analysis of 160 patients with a biopsy proven EIN. We analyzed the performance of multiple machine learning models (n = 48) with different parameters to predict the diagnosis of postoperative EC. The prediction variables included: parity, gestations, sampling method, endometrial thickness, age, body mass index, diabetes, hypertension, serum CA-125, preoperative histology and preoperative hormonal therapy. Python ‘sklearn’ library was used to train and test the models. The model performance was evaluated by sensitivity, specificity, PPV, NPV and AUC. Five iterations of internal cross-validation were performed, and the mean values were used to compare between the models. ResultsOf the 160 women with a preoperative diagnosis of EIN, 37.5% (60) had a post-op diagnosis of EC. In univariable analysis, there were no significant predictors of EIN. For the five best machine learning models, all the models had a high specificity (71%–88%) and a low sensitivity (23%–51%). Logistic regression model had the highest specificity 88%, XG Boost had the highest sensitivity 51%, and the highest positive predictive value 62% and negative predictive value 73%. The highest area under the curve was achieved by the random forest model 0.646. ConclusionsEven using the most elaborate AI algorithms, it is not possible currently to predict concurrent EC in women with a preoperative diagnosis of EIN. As women with EIN have a high risk of concurrent EC, there may be a value of surgical staging including sentinel lymph node evaluation, to more precisely direct adjuvant treatment in the event EC is identified on final pathology.

Benchmarking mismatch repair testing for patients with cancer receiving immunotherapy.

179 Background: Mismatch repair deficiency (MMR-D) serves as a theranostic marker for directing immune checkpoint inhibitor (ICI) treatment across various cancer stages and tumor types. The College of American Pathologists endorses immunohistochemistry (IHC) as the primary approach for assessing mismatch repair (MMR) testing in colorectal (CRC) and endometrial cancer (EC) patients. An alternative method involves genetic evaluation of microsatellite instability (MSI). Previous studies have shown that resistance to immune checkpoint inhibitors (ICIs) may occur due to inaccurate MSI or MMR IHC status determination. Accurate assessment of MMR status is critical for treatment decision-making. Methods: We hypothesized that tumor-only next generation sequencing (NGS) for MMR mutation signature assessment for identification of MMR-D tumors is more sensitive than MMR IHC testing. Using a standardized, clinically validated, tumor-only NGS mutation signature pipeline in place in the Oncopanel assay at DFCI/BWH, we compared the concordance in MMR determination between NGS and IHC. We then evaluated a subset of ICI-treated patients to assess the clinical implications of these findings. Results: 1655 colorectal cancer (CRC) and endometrial carcinoma (EC) patients who had both NGS MSI (NGSd = deficient or NGSp = proficient) and MMR IHC (IHC- = absent or IHC+ = intact) assays performed were assessed. Discordant NGSd/IHC+ results were identified in 1% of CRC and 5% of EC cases that were IHC+. Importantly, patients with discordant NGSd/IHC+ (median OS: not reached [NR], 95% CI, 9.9 months-NR; median TTF: 44.4 months, 95% CI, 4.1-NR) and concordant NGSd/IHC- results, showed a similar overall survival and time to treatment failure with ICI treatment (p=non-significant) which contrasted with results for patients with concordant NGSp/IHC+ results (median OS: 14.9 months, 95% CI, 7.3-24.6, p-value 0.0025 and &lt; 0.0001; median TTF: 5.0 months, 95% CI, 3.2-7.3; p-value 0.0014 and &lt; 0.0001). Patients with EC or CRC and discordant NGSd/IHC+ results had better survival when treated with ICI-based regimens, compared to those who received non-ICI treatments (p= 0.054 and 0.017). Conclusions: In 2022, 151,030 new CRC and 65,950 new EC cases were diagnosed in the USA. Extrapolating our findings to this larger population, use of NGS mutational signature analysis instead of IHC would amount to about 1510 additional MMR-D CRC cases and 3297 additional MMR-D endometrial cases identified each year for whom first-line ICI therapy is preferred. Our findings support revisiting guideline recommendations for diagnostic testing of MMR to incorporate both IHC and targeted NGS tumor panel testing using sensitive and specific mutation signature calling algorithms. Larger prospective studies are warranted to confirm these findings in patients with mCRC and mEC treated with ICIs. Evaluation of this approach in other cancer types is also warranted.

Clinical Audit of Gynecological Cancers at National Institute of Cancer Research and Hospital, Dhaka, Bangladesh

The aim of this audit was to assess the trend of the gynecological cancers for the year of 2022. This is an observational study on retrospectively collected data of gynecological cancer patients at National Institute of Cancer Research and Hospital (NICRH), Dhaka. All cases of cancer seen at the gynecology outpatient department and cases admitted in the gynecological oncology ward at NICRH, between the months of January to December 2022 were audited. The results shown that about 5.8% of all the new cases were young women aged below 25 years. The majority of gynecological cancers were among women aged between 35 and 64 years (73.17%) and only 2.6% patients were aged above 75 years. Cervical cancer (59%) was the leading gynecological cancer among all female cancers attended at NICRH. In ovarian malignancy, most of the patients(61%) had stage lll disease and no patient in stage IV diseases. Due to  improper evaluation of abnormal uterine bleeding, majority of the endometrial carcinoma patients (64%) presented with histopathology reports after hysterectomy. This study might help to get a in depth understanding of the trend of major gynecological cancers. J Bangladesh Coll Phys Surg 2024; 42: 43-48

Impacts of ovarian reserve on conservative treatment for endometrial cancer and atypical hyperplasia.

Real-world data indicated that some endometrial atypical hyperplasia (EAH) and early endometrial carcinoma (EEC) patients of fertility preservation had a normal ovarian reserve, while some had a decreased ovarian reserve (DOR). This study was designed to investigate the effect of baseline ovarian reserve on the treatment of EAH and EEC patients who ask for preservation of fertility. This was a prospective cohort study conducted at a single university-affiliated fertility center. A total of 102 EAH and EEC patients who received fertility-preserving treatment between March 2019 and August 2020 were included and divided into a DOR group (n=22) and a non-DOR group (n=80). The 32-week CR rate of the non-DOR group was significantly higher than that of the DOR group (60.3% vs. 33.3%, P =0.028). The DOR group had a longer treatment duration to achieve CR than the non-DOR group (40.07 vs. 29.71 weeks, P=0.008, HR: 0.54, 95% CI: 0.36-0.86). Multivariate logistic regression analyses demonstrated that DOR (OR: 0.35, 95% CI: 0.13-0.99, P=0.049) and BMI ≥25 kg/m2 (OR: 0.40, 95% CI: 0.17-0.92, P=0.031) were negatively associated with 32-week CR. Decreased baseline ovarian reserve is negatively correlated with the efficacy of fertility-preserving treatment in EAH and EEC patients, as this group has a lower CR rate and a longer treatment duration to achieve CR than those without DOR.

Number of Positive Lymph Nodes and Survival in Endometrial Carcinoma: A Proposal for a Modified Staging.

To construct a new clinical staging system including the number of lymph node metastases to supplement the International Federation of Gynecology and Obstetrics (FIGO) staging for the prognosis of endometrial carcinoma patients. This cohort study retrieved the data of 28,824 patients confirmed as endometrial carcinoma between 2010 and 2015 in the surveillance, epidemiology, and end results (SEER) database. COX risk proportional model was established to evaluate the association between FIGO staging with the all-cause mortality of endometrial carcinoma. The diagnostic value of FIGO staging and the new staging for the mortality of patients were evaluated by receiver operator characteristic curve (ROC). Hazard ratio (HR) and 95% confidence interval (CI) were effect size. The 5-year survival rate of all participants was 77.21%. The median follow-up time was 60.00 (60.00,60.00) months. Patients at FIGO staging IB (HR=1.75, 95% CI: 1.62-1.90), FIGO staging II (HR=2.22, 95% CI: 2.00-2.47), FIGO staging IIIA (HR=2.74, 95% CI: 2.43-3.09), FIGO staging IIIB (HR=4.07, 95% CI: 3.48-4.76), FIGO staging IIIC1 (HR=3.84, 95% CI: 3.52-4.20), FIGO staging IIIC2 (HR=4.52, 95% CI: 4.09-4.99), FIGO staging IVA (HR=5.56, 95% CI: 4.58-6.74), and FIGO staging IVB (HR=7.62, 95% CI: 6.94-8.36) were associated with increased risk of all-cause mortality of endometrial carcinoma patients. After adding positive lymph nodes as another covariate in Model 3, the effect on of FIGO staging survival was reduced when the FIGO staging was higher than stage III/IV. The C-index of the new staging 0.781 (95% CI: 0.774-0.787) was higher than FIGO staging 0.776 (95% CI: 0.770-0.783). Our new staging using the number of positive lymph nodes supplement to the FIGO staging was superior than the FIGO staging for predicting the prognosis of endometrial cancer patients, which might help more accurately identify endometrial carcinoma patients who were at high risk of mortality and offer timely treatments in these patients.

Deciphering DNA repair gene mutational landscape in uterine corpus endometrial carcinoma patients using next generation sequencing

Deciphering DNA repair gene mutational landscape in uterine corpus endometrial carcinoma patients using next generation sequencing

Moving into the modern era of molecular classification for endometrial cancer.

The molecular subtypes of endometrial carcinoma (EC) were first described by The Cancer Genome Atlas (TCGA) a decade ago. Using surrogate approaches, the molecular classification has been demonstrated to be prognostic across EC patients and to have predictive implications. Starting in 2020, the molecular classification has been incorporated into multiple guidelines as part of the risk assessment and most recently into the International Federation of Gynecology and Obstetrics (FIGO) staging. This review article discusses the implementation of the EC molecular classification into clinical practice, the therapeutic implications, and the molecular and clinical heterogeneity of the EC molecular subtypes.

Predictors of Bilateral SLN Radiocolloid Detection in Endometrial Carcinoma.

Introduction  Sentinel lymph node (SLN) mapping is an alternative method to conventional lymphadenectomy for nodal status assessment in patients with stage I/II endometrial carcinoma (EC). This study aimed to analyze the potential predictors of unsuccessful bilateral detection of SLN after the application of radiocolloid in EC. Materials and Methods  A prospective, observational, cross-sectional study was performed on 41 patients with EC in preoperative stage I, who underwent SLN mapping after cervical application of 4mCi 99m Tc-SENTI-SCINT. The demographic, clinical, and tumor-related data were obtained from the patient's medical records. Univariate analysis was used to analyze the potential factors associated with an unsuccessful bilateral SLN biopsy. Results  The bilateral SLN detection rate of planar lymphoscintigraphy, single photon emission computed tomography/computed tomography, and gamma probe was 29.26, 41.46, and 26.82%, correspondingly. None of the 16 analyzed risk factors showed statistical significance for nonconclusive bilateral SLN biopsy. Conclusion  Larger scale studies are needed to determine the exact risk factors for unsuccessful bilateral mapping of the lymphatic drainage after cervical application of the radiotracers. This will eventually lead to improvement in bilateral SLN detection in EC patients, so unilateral lymphadenectomy could be avoided.

Tumor-infiltrating immune cell score as an independent prognostic predictor for endometrial carcinoma: Insights from a comprehensive analysis of the immune landscape.

Immune cells are crucial components in the tumor microenvironment and have a significant impact on the outcomes of patients. Here, we aimed to establish a prognostic score based on different types of tumor-infiltrating immune cells for Endometrial Carcinoma (EC). We enrolled and analyzed 516 EC patients from The Cancer Genome Atlas. The relative abundance of 22 immune cells were estimated by using the CIBERSORTx algorithm. Cox regression was performed to identify potential prognostic immune cells, which were used to develop a Tumor-infiltrating Immune Cell Score (TICS). The prognostic and incremental value of TICS for overall survival were compared with traditional prognostic factors using the C-index and decision curves. Clustering analysis using all immune cells identified three immune landscape subtypes, which had weak correlation with survival. A TICS was constructed using CD8T cells, resting memory CD4 T cells, activated NK and activated DCs, and classified patients as low-, moderate- and high-risk subgroups. The low-risk subgroup had higher tumor mutation burden and activation of IL2/STAT5, IL2/STAT3 and IFN-gamma response pathways. Conversely, the high-risk subgroup was associated with DNA copy number variation, hypoxia and EMT process. The TICS subgroups significantly predicted overall survival, which was independent of patient age, tumor stage, grade and molecular classification. Moreover, we developed a nomogram incorporating TICS and clinicopathologic factors, which significantly improved the predictive accuracy compared to the clinicopathologic model alone. The TICS is an effective and independent prognostic predictor for EC patients and may serve as a useful supplement to clinicopathological factors and molecular subtyping.

Endometrial Carcinoma: A Comprehensive Analysis of Clinical Parameters, Treatment Modalities, and Prognostic Outcomes at a Tertiary Oncology Center in the UAE.

Background Endometrial carcinoma (EC) remains a pressing global health issue, with a discernible upsurge in incidence, especially in developed countries. Notably, the United Arab Emirates (UAE) has witnessed a surge in EC cases, demanding an in-depth, region-specific exploration into the disease's clinical, treatment, and prognostic facets against the backdrop of its unique socio-genetic and environmental contours. Aim This study aimed to profess a comprehensive understanding of EC by examining clinical parameters, treatment modalities, and prognostic outcomes in the UAE context, thereby seeking to delineate potential correlations between varied therapeutic combinations, patient demographics, and tumor characteristics in affecting prognostic outcomes. Materials and methods A retrospective cohort study involving 93 patients diagnosed with EC from January 2011 to March 2023 at a leading oncology center in the UAE was conducted. Data, including demographic information, clinical presentation, treatment modalities, and prognostic outcomes, were meticulously extracted and analyzed. The R software (version 4.2.2) facilitated exhaustive statistical analyses, involving descriptive statistics, correlation analyses with the polycor package, and survival analyses utilizing the Kaplan-Meier method and Cox regression analysis via the survival and survminer packages, respectively. Results Although the correlation matrix revealed a noticeable relationship between "Family history"and "Age," most parameters displayed independence, offering a robust platform for ensuing multivariate analyses. Kaplan-Meier survival curves, stratified by therapeutic modalities, exhibited no statistically significant survival differences across therapeutic cohorts (p-values: 0.44, 0.86, and 0.83). Conversely, the composite Cox regression model underscored "non-national" demographic, Diabetes Mellitus II, and stromal invasion as pivotal prognostic factors, indicating the multifactorial nature of survival in EC patients and emphasizing demographic and tumor characteristics over therapeutic modalities as influential prognostic determinants. Conclusion In conclusion, while therapy types were not directly correlated with survival, demographic and tumor traits prominently impacted prognostic outcomes, advocating for an intricate, multidimensional approach to managing EC in the UAE. This study hopes to sow seeds for subsequent research, shaping clinically and culturally apt practices and policies in the region's healthcare landscape.

Detection of Somatic Alterations in Peritoneal Lavages of Early-Stage Endometrial Carcinoma Patients

Detection of Somatic Alterations in Peritoneal Lavages of Early-Stage Endometrial Carcinoma Patients

[Comprehensive assessment of mismatch repair and microsatellite instability status in molecular classification of endometrial carcinoma].

Objective: To explore the concordance and causes of different mismatch repair (MMR) and microsatellite instability (MSI) detection results in endometrial carcinoma (EC) molecular typing. Methods: A total of 214 EC patients diagnosed from January 2021 to April 2023 were selected at the Department of Pathology, Peking University Third Hospital. The immunohistochemistry (IHC) results of MMR protein were reviewed. Tumor specific somatic mutations, MMR germline mutations, microsatellite scores and tumor mutation burden (TMB) were detected by next-generation sequencing (NGS) with multi-gene panel. Methylation-specific PCR was used to detect the methylation status of MLH1 gene promoter in cases with deficient MLH1 protein expression. In cases with discrepant results between MMR-IHC and MSI-NGS, the MSI status was detected again by PCR (MSI-PCR), and the molecular typing was determined by combining the results of TMB and MLH1 gene promoter methylation. Results: (1) In this study, there were 22 cases of POLE gene mutation subtype, 55 cases of mismatch repair deficient (MMR-d) subtype, 29 cases of p53 abnormal subtype, and 108 cases of no specific molecular profile (NSMP). The median age at diagnosis of MMR-d subtype (54 years old) and the proportion of aggressive histological types (40.0%, 22/55) were higher than those of NSMP subtype [50 years old and 12.0% (13/108) respectively; all P<0.05]. (2) Among 214 patients, MMR-IHC test showed that 153 patients were mismatch repair proficient (MMR-p), 49 patients were MMR-d, and 12 patients were difficult to evaluate directly. MSI-NGS showed that 164 patients were microsatellite stable (MSS; equal to MMR-p), 48 patients were high microsatellite instability (MSI-H; equal to MMR-d), and 2 patients had no MSI-NGS results because the effective sequencing depth did not meet the quality control. The overall concordance between MMR-IHC and MSI-NGS was 94.3% (200/212). All the 12 discrepant cases were MMR-d or subclonal loss of MMR protein by IHC, but MSS by NGS. Among them, 10 cases were loss or subclonal loss of MLH1 and (or) PMS2 protein. Three discrepant cases were classified as POLE gene mutation subtype. In the remaining 9 cases, 5 cases and 3 cases were confirmed as MSI-H and low microsatellite instability (MSI-L) respectively by MSI-PCR, 6 cases were detected as MLH1 gene promoter methylation and 7 cases demonstrated high TMB (>10 mutations/Mb). These 9 cases were classified as MMR-d EC. (3) Lynch syndrome was diagnosed in 27.3% (15/55) of all 55 MMR-d EC cases, and the TMB of EC with MSH2 and (or) MSH6 protein loss or associated with Lynch syndrome [(71.0±26.2) and (71.5±20.1) mutations/Mb respectively] were significantly higher than those of EC with MLH1 and (or) PMS2 loss or sporadic MMR-d EC [(38.2±19.1) and (41.9±24.3) mutations/Mb respectively, all P<0.01]. The top 10 most frequently mutated genes in MMR-d EC were PTEN (85.5%, 47/55), ARID1A (80.0%, 44/55), PIK3CA (69.1%, 38/55), KMT2B (60.0%, 33/55), CTCF (45.5%, 25/55), RNF43 (40.0%, 22/55), KRAS (36.4%, 20/55), CREBBP (34.5%, 19/55), LRP1B (32.7%, 18/55) and BRCA2 (32.7%, 18/55). Concurrent PTEN, ARID1A and PIK3CA gene mutations were found in 50.9% (28/55) of MMR-d EC patients. Conclusions: The concordance of MMR-IHC and MSI-NGS in EC is relatively high.The discordance in a few MMR-d EC are mostly found in cases with MLH1 and (or) PMS2 protein loss or MMR protein subclonal staining caused by MLH1 gene promoter hypermethylation. In order to provide accurate molecular typing for EC patients, MLH1 gene methylation, MSI-PCR, MMR gene germline mutation and TMB should be combined to comprehensively evaluate MMR and MSI status.

[Fertility-preserving treatment outcomes in endometrial cancer and atypical hyperplasia patients with different molecular profiles].

Objective: To investigate the impact of molecular classification and key oncogenes on the oncologic outcomes in patients with endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) receiving fertility-preserving treatment. Methods: Patients with EC and AEH undergoing progestin-based fertility-preserving treatment and receiving molecular classification as well as key oncogenes test at Obstetrics and Gynecology Hospital, Fudan University from January 2021 to March 2023 were reviewed. Hysteroscopic lesion resection and endometrial biopsy were performed before initiating hormone therapy and every 3 months during the treatment to evaluate the efficacy. The risk factors which had impact on the treatment outcomes in EC and AEH patients were further analyzed. Results: Of the 171 patients analyzed, the median age was 32 years, including 86 patients with EC and 85 patients with AEH. The distribution of molecular classification was as follows: 157 cases (91.8%) were classified as having no specific molecular profile (NSMP); 9 cases (5.3%), mismatch repair deficient (MMR-d); 3 cases (1.8%), POLE-mutated; 2 cases (1.2%), p53 abnormal. No difference was found in the cumulative 40-week complete response (CR) rate between the patients having NSMP or MMR-d (61.6% vs 60.0%; P=0.593), while the patients having MMR-d had increased risk than those having NSMP to have recurrence after CR (50.0% vs 14.4%; P=0.005). Multi-variant analysis showed PTEN gene multi-loci mutation (HR=0.413, 95%CI: 0.259-0.658; P<0.001) and PIK3CA gene mutation (HR=0.499, 95%CI: 0.310-0.804; P=0.004) were associated with a lower cumulative 40-week CR rate, and progestin-insensitivity (HR=3.825, 95%CI: 1.570-9.317; P=0.003) and MMR-d (HR=9.014, 95%CI: 1.734-46.873; P=0.009) were independent risk factors of recurrence in EC and AEH patients. Conclusions: No difference in cumulative 40-week CR rate is found in the patients having NSMP or MMR-d who received progestin-based fertility-preserving treatment, where the use of hysteroscopy during the treatment might be the reason, while those having MMR-d have a higher risk of recurrence after CR. Oncogene mutation of PTEN or PIK3CA gene might be associated with a lower response to progestin treatment. The molecular profiles help predict the fertility-preserving treatment outcomes in EC and AEH patients.

[Risk factor analysis of lymph node metastasis in endometrial carcinoma combined with molecular types].

Objective: To investigate the relationships between molecular types of the cancer genome atlas (TCGA) of patients with endometrial carcinoma (EC) and lymph node metastasis and other clinicopathological features. Methods: The clinical pathological information of 295 patients with EC who underwent initial inpatient surgical treatment and accepted the detection of the molecular types of TCGA with next-generation sequencing technology at Peking University People's Hospital were collected during April 2016 and May 2022. The TCGA molecular typing of EC was divided into four types: POLE-ultramutated (15 cases), high microsatellite instability (MSI-H; 50 cases), copy-number low (CNL; 175 cases), and copy-number high (CNH; 55 cases). The differences of clinical pathological features among different molecular types and the risk factors of lymph node metastasis were analyzed retrospectively. Results: Among 295 patients with EC, the average age was (56.9±0.6) years. (1) There was a statistically significant difference in lymph node metastasis (0, 8.0%, 10.3% and 25.5%) among the four molecular types (χ2=12.524, P=0.006). There were significant differences in age, stage, pathological type, grade (only endometrioid carcinoma), myometrium invasion, lymphatic vascular space infiltration, and estrogen receptor among the EC patients of four molecular types (all P<0.05). Among them, while in the patients with CNH type, the pathological grade was G3, the pathological type was non-endometrioid carcinoma, and the proportion of myographic infiltration depth ≥1/2 were higher (all P<0.05). (2) Univariate analysis suggested that pathological type, grade, myometrium infiltration depth, cervical interstitial infiltration, lymphatic vascular space infiltration, and progesterone receptor were all factors which significantly influence lymph node metastasis (all P<0.01); multivariate analysis suggested that the lymphatic vascular space infiltration was an independent risk factor for lymph node metastasis (OR=5.884, 95%CI: 1.633-21.211; P=0.007). (3) The factors related to lymph node metastasis were different in patients with different molecular types. In the patients with MSI-H, the non-endometrioid carcinoma of pathological type was independent risk factor for lymph node metastasis (OR=29.010, 95%CI: 2.067-407.173; P=0.012). In the patients with CNL, myometrium infiltration depth≥1/2 (OR=4.995, 95%CI: 1.225-20.376; P=0.025), lymphatic vascular space infiltration (OR=14.577, 95%CI: 3.603-58.968; P<0.001) were the independent risk factors for lymph node metastasis. While in the CNH type patients pathological type of non-endometrioid carcinoma (OR=7.451, 95%CI: 1.127-49.281; P=0.037), cervical interstitial infiltration (OR=22.938, 95%CI: 1.207-436.012; P=0.037), lymphatic vascular space infiltration (OR=9.404, 95%CI: 1.609-54.969; P=0.013), were the independent risk factors for lymph node metastasis. Conclusions: POLE-ultramutated EC patients have the lowest risk of lymph node metastasis, and CNH patients have the highest risk of lymph node metastasis. The risk factors of lymph node metastasis of different molecular types are different. According to preoperative pathological and imaging data, lymph node metastasis is more likely to occur in patients with non-endometrioid carcinoma in MSI-H and CNH type patients, and lymph node metastasis is more likely to occur in patients with myometrium infiltration depth ≥1/2 in CNL type patients.

Low-Density Lipoprotein Contributes to Endometrial Carcinoma Cell Proliferation, Migration, and Invasion by Activating the JAK-STAT Signaling Pathway.

Cholesterol-rich low-density lipoprotein (LDL) particles have been demonstrated to regulate breast cancer cell proliferation and migration, but their biological function and relevant mechanisms in endometrial carcinoma (EC) remain unclear. Serum and tissue samples were collected from EC patients (n = 50) and patients with benign endometrial hyperplasia (n = 50). Ishikawa and RL95-2 cells were stimulated with different concentrations of LDL, followed by treatment with a JAK2 inhibitor (SD-1029). LDL concentrations were determined by ELISA. The in vitro biological behavior of cells was examined using the CCK-8 assay, EdU staining, and Transwell assay. The tumorigenicity of LDL in vivo was examined using a xenograft mouse model. western blotting, immunofluorescence, and immunohistochemistry studies were performed to measure related protein expression. The LDL concentrations and levels of p-JAK2 and p-STAT3 expression were elevated in the clinical samples. Similar trends in expression were detected in EC cells after LDL stimulation. LDL treatment significantly promoted EC cell proliferation, migration, and invasion, and also upregulated p-JAK2 and p-STAT3 expression in a dose-dependent manner. Moreover, SD-1029 dramatically blocked the LDL-mediated effects on EC cells. Intravenous injection of LDLs promoted tumor growth in the xenograft nude mice, and also increased p-JAK2, p-STAT3, and Ki-67 expression, and downregulated caspase-3 expression. These findings indicate that LDLs exert an oncogenic effect in EC cells by activating the JAK/STAT signaling pathway, and also suggest the JAK/STAT pathway as a possible therapeutic target for EC.