Microsatellite instability and survival outcomes in endometrial cancer: a comprehensive analysis of molecular subtypes and clinical implications

Adenomyosis is a common benign gynecological condition, defined as an extension of endometrial tissue into the myometrium. Some studies suggest that adenomyosis could be a favorable prediction factor associated with survival outcomes in endometrial cancer. The aim of our systematic review was to investigate the current knowledge regarding adenomyosis and a possible molecular mechanism of carcinogenesis in adenomyotic lesions. In addition, the long-term prognosis for patients with endometrial cancer and coexisting adenomyosis (and endometriosis) was a key point of the research. The current literature was reviewed by searching PubMed, using the following phrases: “adenomyosis and endometrial cancer” and “malignant transformation of adenomyosis”. According to the literature, genetic mutations, epigenetic changes, and inactivation of specific tumor suppressor genes in adenomyosis are still poorly understood. Data regarding the influence of adenomyosis on survival outcomes in endometrial cancer seem to be contradictory and require further clinical and molecular investigation.

This study aimed to examine the immunohistochemical expression of Inositol-Requiring Enzyme 1 Alpha (IRE1) and Protein Kinase R-like ER Kinase (PERK) immunoreactivity scores (IRS) as emerging biomarkers on key clinicopathologic features and survival outcomes in endometrial cancer (EC). Immunoreactive scores (IRS) for IRE1 and PERK were assessed in tumor samples from 73 EC survivors and compared with 20 benign endometrial controls. Associations between IRS values and clinicopathological variables were analyzed. Overall survival (OS) and disease-free survival (DFS) were evaluated using univariable and multivariable Cox proportional hazards models adjusted for age, FIGO stage, and tumor grade. IRE1-IRS and PERK-IRS were significantly higher in EC survivors compared to controls (p=0.015 and p<0.001, respectively) and PERK-IRS was higher in non-endometrioid than endometrioid tumors (p=0.017). EC survivors undergoing laparotomy exhibited higher PERK-IRS than those treated laparoscopically (p=0.009). Neither IRE1-IRS nor PERK-IRS was associated with OS or DFS, except for a negative association of high vs. low IRE1-IRS score and DFS in the unadjusted model (p=0.026) but not in the adjusted one. IRE1 and PERK expression is up-regulated in endometrial cancer and correlates with selected clinicopathological features, particularly those linked to aggressive disease. However, neither marker demonstrated independent prognostic value for survival outcomes. Further studies are warranted to clarify the role of ER stress pathways in EC biology and their potential implications for risk stratification and targeted therapy.

BackgroundSystemic inflammation has long been related with adverse survival outcomes in cancer patients, and its biomarkers, such as the Neutrophil-to-Lymphocyte Ratio (NLR), are recognized as poor prognostic indicators. However, the role of eosinophils in this field has been largely overlooked. Here, we describe two new pre-treatment biomarkers, expressed as Eosinophil-to-Lymphocytes Ratio (ELR) and Eosinophil*Neutrophil-to-Lymphocytes ratio (ENLR), and we analyse their impact on prognosis of endometrial cancer (EC) patients.MethodsA total of 163 consecutive patients diagnosed with EC and treated with postoperative radiotherapy +/− chemotherapy in our institution from January 2011 to December 2015 were evaluated. The cohort was divided in two groups applying the cut-off value of 0.1 and 0.5 according to ROC curve for pre-treatment ELR and ENLR, respectively. After patients’ stratification according to the ESMO-ESGO-ESTRO modified risk assessment, subgroup analyses were conducted.ResultsHigher values of ELR and ENLR were associated with worse OS (p = 0.004 and p = 0.010, respectively). On univariate analysis, the factors associated with shorter OS were ELR ≥ 0.1 (HR = 2.9, p = 0.017), ENLR ≥ 0.5 (HR = 3.0, p = 0.015), advanced FIGO stage (HR = 3.4, p = 0.007), endometrioid histology (HR = 0.26, p = 0.003) and ESMO-ESGO-ESTRO high-risk (HR = 10.2, p = 0.023). On multivariate Cox regression, higher ELR and ENLR were independently associated with a worse outcome adjusted for the standardly applied prognostic factors.ConclusionsIncreased values of ELR and ENLR portend worse OS in EC, especially in patients classified by the ESMO-ESGO-ESTRO guidelines as a high-risk group. To our best knowledge, this is the first report describing eosinophils-related ratios as prognostic biomarkers in malignant tumours.

Menopause, through attributable estrogen level decline and the corresponding increase in circulating androgens, significantly elevates a woman's risk for cardiometabolic diseases, including metabolic syndrome (MetS), type 2 diabetes, and cardiovascular disease. Metabolic syndrome itself is a cluster of interconnected risk factors, and among them, central obesity is a well-established factor for the development of endometrial cancer (EC), the most common gynecologic malignancy. This research investigates the impact of metabolic syndrome on survival rates among patients with endometrial cancer. The goal is to assess whether having metabolic syndrome or its individual components influences disease-free survival (DFS), overall survival (OS), cancer-specific survival, and recurrence rates. Understanding this link is crucial for determining risk levels and could help tailor treatment approaches for better long-term outcomes in endometrial cancer care.

Endometrial cancer, ranking as the 6th most prevalent cancer affecting women globally, is characterized by high mortality rates, recurrence, and poor prognosis. The disease lacks comprehensive understanding and effective treatment options. This meta-analysis focuses on randomized controlled trials to investigate targeted therapies, survival outcomes, and prognostic factors in endometrial cancer. The study follows the PICOS protocol and PRISMA guidelines, utilizing Review Manager Software (Version 5.4) for meta-analyses. Predetermined outcomes relevant to the topic guide the study search, with the GRADE tool assessing the quality of evidence and Begg's formula and Kendall's Tau evaluating certainty. Results reveal oral anastrozole and vistusertib's efficacy, reducing progression-free survival (PFS) and enhancing protein detection. The meta-analysis indicates that targeted therapies do not significantly improve PFS but reduce adverse effects. Chemotherapy does not considerably improve survival rates, and interventions show no significant difference in prognostic factors. In conclusion, anastrozole and vistusertib emerge as effective targeted therapies for endometrial cancer, supported by clinical trial evidence demonstrating reduced PFS and improved protein detection. Additionally, the carboplatin-paclitaxel combination and radiotherapy in monotherapy show promising clinical outcomes. These findings contribute to a comprehensive understanding of prognostic factors, targeted therapies, and survival outcomes in endometrial cancer, emphasizing the need for further research and clinical trials for optimal disease management.

Uterine manipulator use and survival outcomes in endometrial cancer - insights from the multicenter E-PEC trial

PurposeThe Onodera’s prognostic nutritional index (PNI) and the haemoglobin, albumin, lymphocyte and platelet (HALP) score are immune-nutritional indices that correlate with survival outcomes in several adult solid malignancies. The aim of this study was to investigate whether PNI and HALP are associated with survival outcomes in endometrial cancer.Patients and methodsWomen undergoing management for endometrial cancer were recruited to a single centre prospective cohort study. Pre-treatment PNI and HALP scores were computed for study participants and analysed as continuous variables and by selecting cut-off values based on previous publications. Both parameters were analysed in relation to overall, endometrial cancer-specific and recurrence-free survival using Kaplan-Meier estimation and multivariable Cox proportional regression.ResultsA total of 439 women, with a median age of 67 years (interquartile range (IQR), 58, 74) and BMI of 31kg/m2 (IQR 26, 37) were included in the analysis. Most had low-grade (63.3%), early-stage (84.4% stage I/II) endometrial cancer of endometrioid histological subtype (72.7%). Primary treatment was surgery in 98.2% of cases. Adjusted overall mortality hazard ratios for PNI and HALP as continuous variables were 0.97(95%CI 0.94–1.00, p = 0.136) and 0.99(95%CI 0.98–1.01, p = 0.368), respectively. Women with pre-treatment PNI ≥45 had a 45% decrease in both overall (adjusted HR = 0.55, 95% CI 0.33–0.92, p = 0.022) and cancer-specific mortality risk (adjusted HR = 0.55, 95%CI 0.30–0.99, p = 0.048) compared to those with PNI <45. There was no evidence for an effect of PNI on recurrence free survival. HALP scores were associated with adverse clinico-pathologic factors, but not overall, cancer-specific or recurrence-free survival in the multivariable analysis.ConclusionPNI is an independent prognostic factor in endometrial cancer and has the potential to refine pre-operative risk assessment.

Hospital treatment volume affects survival in patients with endometrial cancer; notably, initial treatment at high-volume centers improves survival outcomes. Our study assessed the effect of hospital treatment volume on cost-effectiveness and survival outcomes in patients with endometrial cancer in Japan. A decision-analytic model was evaluated using the following variables and their impact on cost-effectiveness: 1) hospital treatment volume (low-, intermediate-, and high-volume centers) and 2) postoperative recurrent risk factors based on pathological findings (high- and intermediate-risk or low-risk). Data were obtained from the Japan Society of Obstetrics and Gynecology database, systematic literature searches, and the Japanese Diagnosis Procedure Combination database. Quality-adjusted life years (QALY) was used as a measure of effectiveness. The model was built from a public healthcare perspective and the impact of uncertainty was assessed using sensitivity analyses. A base-case analysis showed that the incremental cost-effectiveness ratio at high-volume centers was below a willingness-to-pay (WTP) threshold of ¥5,000,000 with a maximum of ¥3,777,830/4.28 QALY for the high- and intermediate-risk group, and ¥2,316,695/4.57 QALY for the low-risk group. Treatment at the high-volume centers showed better efficiency and cost-effectiveness in both strategies compared to intermediate- or low-volume centers. Sensitivity analyses showed that the model outcome was robust to changes in input values. With the WTP threshold, treatment at high-volume centers remained cost-effective in at least 73.6% and 78.2% of iterations for high- and intermediate-risk, and low-risk groups, respectively. Treatment at high-volume centers is the most cost-effective strategy for guiding treatment centralization in patients with endometrial cancer.

IntroductionInflammation predisposes patients to tumorigenesis by damaging DNA, stimulating angiogenesis, and potentiating pro-proliferative and anti-apoptotic processes. This study investigated whether pre-treatment systemic inflammatory markers (PTSIMs) are associated with survival outcomes...

Most endometrial cancers are early-stage cancers with a good prognosis, but the prognosis for recurrent endometrial cancer is poor. Accurate prognostication is essential for the management of patients with cancer. This study aimed to assess the survival outcome of endometrial cancer using machine learning. We used data from the Surveillance, Epidemiology, and End Results (SEER) database, constructing machine learning models to predict the 5-year overall survival (OS) and cancer-specific survival (CSS). The variables included patient demographics, pathological factors, and therapeutic factors. The OS rates of 71,506 patients and the CSS rates of 66,368 patients were included. For the prediction of OS, the best machine learning model achieved a class accuracy of 0.86 (95% CI=0.85-0.87) and an area under the curve (AUC) of 0.83 (95% CI=0.82-0.84) in the internal validation set (SEER dataset). In the external validation set of 149 patients, the best model achieved a class accuracy of 0.85 (95% CI=0.86-0.86) and an AUC of 0.85 (95% CI=0.85-0.86). The model predicted CSS more accurately than OS. Using machine learning, we were able to predict the prognosis of patients with endometrial cancer.

PurposeInflammation predisposes to tumorigenesis by damaging DNA, stimulating angiogenesis and potentiating pro-proliferative and anti-apoptotic processes. The aim of this study was to investigate whether pre-treatment biomarkers of systemic inflammation are associated with survival outcomes in endometrial cancer. Patients and methodsWomen with endometrial cancer were recruited to a prospective database study. Pre-treatment systemic markers of inflammation, including C-reactive protein (CRP), Glasgow Prognostic Score and lymphocyte-based ratios [neutrophil-lymphocyte ratio (NMR), monocyte-lymphocyte ratio (MLR), systemic immune-inflammation index (SII)], were analysed in relation to overall, endometrial cancer-specific and recurrence-free survival using Kaplan-Meier estimation and multivariable Cox regression. ResultsIn total, 522 women of mostly White British ethnicity, with a median age of 66 years (interquartile range (IQR), 56, 73) and BMI of 32 kg/m2 (IQR 26, 39) were included in the analysis. Most had low-grade (67.2%), early-stage (85.4% stage I/II), endometrioid (74.5%) tumors. Women with pre-treatment CRP ≥5.5 mg/L had a 68% increase in overall (adjusted HR = 1.68, 95% CI 1.00–2.81, p = 0.049) and a two-fold higher cancer-specific mortality risk than those with CRP <5.5 mg/L (adjusted HR = 2.04, 95%CI 1.03–4.02, p = 0.04). Absolute lymphocyte count, NLR, MLR and SII were associated with adverse clinico-pathologic factors, but not overall, cancer-specific or recurrence-free survival in the multivariable analysis. ConclusionIf confirmed in an independent cohort, CRP may offer a simple, low-cost test to refine pre-treatment risk assessment and guide personalised care in endometrial cancer. Our participants were mostly of White British ethnicity and further studies are needed to confirm the utility of CRP as a prognostic biomarker in other populations.

Prospective assessment of prognostic significance of malignant peritoneal cytology in endometrial cancer: An NRG Oncology / Gynecologic Oncology Group study on GOG-210 protocol.

ObjectivesThe goal of this study was to determine the impact refusal of surgery has on overall survival in patients with endometrial cancer.MethodsFrom January 2004 to December 2015, the National Cancer...

To evaluate the association between preoperative serum human epididymis protein 4 (HE4) levels and survival outcomes in endometrial cancer (EC) patients. A retrospective cohort study was conducted of EC patients who were scheduled for surgery between September 2013 and May 2014 at Rajavithi Hospital. Association between preoperative serum HE4 levels and clinicopathological characteristics were evaluated. Cox proportional-hazards model was used to compare overall survival (OS) and recurrence-free survival (RFS) between EC patients who had high serum HE4 levels and those who did not. A total of 86 EC patients were enrolled. Serum HE4 levels was significantly associated with older age (p < 0.001), postmenopausal women (p = 0.001), large tumor size (p < 0.001), presence of lymphovascular invasion (p = 0.022), deep myometrial invasion (p = 0.001), lymph node metastasis (0.017), high-risk group (p < 0.001), and death status (p = 0.002). With a median follow-up of 53months, the 3-years OS and PFS of EC patients who had high serum HE4 levels were significantly poorer than those who did not (71% vs 95.8%, and 67.7% vs 91.7%, respectively). A high serum HE4 level was a significant prognostic factor for OS and RFS from the univariate analysis. However, it was not a significant prognostic factor in the multivariate analysis. Preoperative high serum HE4 levels were significantly associated with the worse clinicopathological characteristic of EC patients and decreased OS and RFS. Although there was no strong independent prognostic factor for survival, serum HE4 levels could be used in an algorithm for stratifying high-risk EC patients with more proper management.

The conventional histomorphology-based risk classification for endometrial cancer (EC) does not consider the molecular heterogeneity that influences prognosis and treatment response. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) system uses next-generation sequencing to assess DNA polymerase epsilon (POLE) mutations, but its high cost limits its accessibility. This study evaluated the prognostic value of a novel algorithm that combined immunohistochemistry (IHC) testing with conventional risk factors. This retrospective study included 237 patients with stage I-III EC who underwent surgery. Low-risk patients were classified without IHC, while intermediate- and high-risk patients were categorized as MMR-deficient (MMRd), p53-abnormal (p53abn), or nonspecific molecular profile (NSMP) groups based on IHC. Additionally, L1CAM expression was also evaluated. Survival outcomes were analyzed using Kaplan-Meier curves and Cox regression models. Data from 233 cases were analyzed; the median follow-up duration was 63months. Among 87 low-risk patients, only 1 experienced recurrence. The intermediate- and high-risk groups were subdivided into 42 MMRd, 16 p53abn, and 88 NSMP patients. The 5-year disease-free survival (DFS) rates were 98.8% (low-risk), 94.7% (NSMP), 80.6% (MMRd), and 59.8% (p53abn), highlighting the poorer prognosis of p53abn. p53abn independently predicted recurrence (hazard ratio [HR], 10.1) and mortality (HR, 25.6). L1CAM positivity correlated with worse DFS but was not an independent prognostic factor. Conventional risk classification combined with IHC classification using p53 and MMR is a cost-effective prognostic tool that enables risk stratification and personalized treatment decisions, even when genetic testing is unavailable.