Non-endometrioid Endometrial Cancer Research Articles

Unravelling the molecular landscape of endometrial cancer subtypes: insights from multi-omics analysis.

Endometrial cancer (EC) as one of the most common gynecologic malignancies is increasing in incidence during the past 10 years. Genome-Wide Association Studies (GWAS) extended to metabolic and protein phenotypes inspired us to employ multi-omics methods to analyze the causal relationships of plasma metabolites and proteins with EC to advance our understanding of EC biology and pave the way for more targeted approaches to its diagnosis and treatment by comparing the molecular profiles of different EC subtypes. Two-sample Mendelian randomization (MR) was performed to investigate the effects of plasma metabolites and proteins on risks of different subtypes of EC (endometrioid and non-endometrioid). Pathway analysis, transcriptomic analysis, and network analysis were further employed to illustrate gene-protein-metabolites interactions underlying the pathogenesis of distinct EC histological types. We identified 66 causal relationships between plasma metabolites and endometrioid EC, and 132 causal relationships between plasma proteins and endometrioid EC. Additionally, 40 causal relationships between plasma metabolites and non-endometrioid EC, and 125 causal relationships between plasma proteins and non-endometrioid EC were observed. Substantial differences were observed between endometrioid and non-endometrioid histological types of EC at both the metabolite and protein levels. We identified 7 overlapping proteins (RGMA, NRXN2, EVA1C, SLC14A1, SLC6A14, SCUBE1, FGF8) in endometrioid subtype and 6 overlapping proteins (IL32, GRB7, L1CAM, CCL25, GGT2, PSG5) in non-endometrioid subtype and network analysis of above proteins and metabolites to identify coregulated nodes. Our findings observed substantial differences between endometrioid and non-endometrioid EC at the metabolite and protein levels, providing novel insights into gene-protein-metabolites interactions that could influence future EC treatments.

Endometrial Cancer Survival in Populations of African Descent.

To examine whether the endometrial cancer (EC) survival disadvantage among Black populations is US-specific, a comparison between African descent populations from different countries with a high development index is warranted. We analyzed 28,213 EC cases from cancer registries in Florida (2005-2018) and Martinique (2005-2018)/Guadeloupe (2008-2018), French Caribbean islands. Kaplan-Meier and all-cause Cox proportional hazards models were used to compare survival. Models were stratified by EC histology type and the main predictor examined was race/ethnicity [non-Hispanic White (NHW) and Black (NHB) women in the US versus Black women residing in the Caribbean]. For endometrioid and non-endometrioid EC, after adjusting for age, histology, stage at diagnosis, receipt of surgery, period of diagnosis, and poverty level, US NHB women and Caribbean Blacks had a higher risk of death relative to US NHWs. There was no difference between US NHBs and Caribbean Blacks (HR 1.07, 95% CI: 0.88-1.30) with endometrioid EC. However, Caribbean Black women with non-endometrioid carcinomas had a 40% (HR 1.40, 95% CI: 1.13-1.74) higher risk of death than US NHBs. The low EC survival among US Black women extends to foreign populations of African descent. For the aggressive non-endometrioid ECs, survival in Caribbean Blacks outside of the US is considerably worse.

Predicting the Risk of nOdal disease with histological and Molecular features in Endometrial cancer: the prospective PROME trial.

To assess the role of histopathological and molecular features in predicting the risk of nodal metastases in apparent early-stage endometrial cancer patients undergoing sentinel node mapping. This is a prospective trial. Consecutive patients with apparent early-stage endometrial cancer, undergoing laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and sentinel node mapping, were enrolled. Histological and molecular features were used to predict the node positivity. Charts of 223 apparent early-stage endometrial cancer patients were included in this study. Four (1.8%) patients were excluded from this study due to the lack of data about molecular features. Additionally, nine (4%) patients did not meet the inclusion criteria (due to the presence of peritoneal carcinomatosis or bulky nodes (the presence of p53 abnormality correlated with the presence of advanced stage disease (p<0.001)). The study population included 178 (84.8%) and 32 (15.2%) patients with endometrioid and non-endometrioid endometrial cancer, respectively. According to pathological uterine risk factors, 93 (44.3%), 45 (21.4%), 40 (19.1%), and 32 (15.2%) were classified as low, intermediate, intermediate-high, and high-risk, respectively. Using the surrogate molecular classification, 10 (4.8%), 42 (20%), 57 (27.1%), and 101 (48.1%) were included in the POLE mutated, p53 abnormal, MMRd/MSI-H, and NSMP, respectively. Overall, 41 (19.5%) patients were detected with positive nodes. Molecular features were not associated with the risk of having nodal metastases (OR 1.03, 95% CI 0.21 to 5.05, p=0.969 for POLE mutated; OR 0.788, 95% CI 0.32 to 1.98, p=0.602 for p53 abnormal; OR 1.14, 95% CI 0.53 to 2.42, p=0.733 for MMRd/MSI-H). At multivariable analysis, only deep myometrial invasion (OR 3.318, 95% CI 1.357 to 8.150, p=0.009) and lymphovascular space invasion (OR 6.584, 95% CI 2.663 to 16.279, p<0.001) correlated with the increased risk of positive nodes. Our data suggest that molecular classification does not seem useful to tailor the need of nodal dissection in apparent early-stage endometrial cancer. p53 abnormality predicts the risk of having advanced disease at presentation. Further external validation is needed. NCT05793333.

Development and external validation of a nomogram for predicting overall survival of patients with non-endometrioid endometrial cancer: A population-based analysis

ObjectivesThe main objective of this study was to identify the key predictors and construct a nomogram that can be used to predict the overall survival of individuals with non-endometrioid endometrial cancer. MethodsA total of 2686 non-endometrioid endometrial cancer patients confirmed between 1988 and 2018 were selected from the Surveillance, Epidemiology, and End Results database. They were divided into a training cohort and an internal validation cohort. Independent risk factors were chosen by Cox regression analyses. A predictive nomogram model for overall survival was constructed based on above factors. A Chinese cohort of 41 patients was collected to be an external validation cohort. ResultsEight variables were estimated as independent predictors for overall survival. A nomogram was established using these factors. The C-index for predicting the overall survival of patients with non-endometrioid endometrial cancer from the nomogram was 0.734, 0.700, and 0.767 in training, internal, and external validation cohort, respectively. Calibration plots and decision curve analysis showed that the nomogram was valuable for further clinical application. ConclusionWe constructed a nomogram which can be used as an effective tool to predict the 3- and 5-year overall survival of Non-endometrioid endometrial cancer patients.

Determination of p53abn endometrial cancer: a multitask analysis using radiological-clinical nomogram on MRI.

We aimed to differentiate endometrial cancer (EC) between TP53mutation (P53abn) and Non-P53abn subtypes using radiological-clinical nomogram on EC body volume MRI. We retrospectively recruited 227 patients with pathologically proven EC from our institution. All these patients have undergone molecular pathology diagnosis based on the Cancer Genome Atlas. Clinical characteristics and histological diagnosis were recorded from the hospital information system. Radiomics features were extracted from online Pyradiomics processors. The diagnostic performance across different acquisition protocols was calculated and compared. The radiological-clinical nomogram was established to determine the nonendometrioid, high-risk, and P53abn EC group. The best MRI sequence for differentiation P53abn from the non-P53abn group was contrast-enhanced T1WI (test AUC: 0.8). The best MRI sequence both for differentiation endometrioid cancer from nonendometrioid cancer and high-risk from low- and intermediate-risk groups was apparent diffusion coefficient map (test AUC: 0.665 and 0.690). For all 3 tasks, the combined model incorporating all the best discriminative features from each sequence yielded the best performance. The combined model achieved an AUC of 0.845 in the testing cohorts for P53abn cancer identification. The MR-based radiomics diagnostic model performed better than the clinical-based model in determining P53abn EC (AUC: 0.834 vs 0.682). In the present study, the diagnostic model based on the combination of both radiomics and clinical features yielded a higher performance in differentiating nonendometrioid and P53abn cancer from other EC molecular subgroups, which might help design a tailed treatment, especially for patients with high-risk EC. (1) The contrast-enhanced T1WI was the best MRI sequence for differentiation P53abn from the non-P53abn group (test AUC: 0.8). (2) The radiomics-based diagnostic model performed better than the clinical-based model in determining P53abn EC (AUC: 0.834 vs 0.682). (3) The proposed model derived from multi-parametric MRI images achieved a higher accuracy in P53abn EC identification (AUC: 0.845).

Risk factors for pelvic and para-aortic lymph node metastasis in non-endometrioid endometrial cancer

PurposeThe aim of this study was to evaluate the risk factors for pelvic lymph node metastasis (LNM) and para-aortic LNM in non-endometrioid endometrial cancer (non-EEC). MethodsA total of 283 patients with non-EEC hospitalized in the First Affiliated Hospital of Zhengzhou University from January 2012 to December 2020 were included. Various characteristics were retrospectively analyzed in relation to LNM. ResultsUnivariable and multivariable logistic regression analysis revealed cervical stromal invasion (OR = 3.441, 95% CI = 1.558–7.6, p = 0.002), myometrial invasion ≥1/2 (OR = 2.661, 95% CI = 1.327–5.337, p < 0.006), lymphovascular space involvement (LVSI) (OR = 4.118, 95% CI = 1.919–8.837, p < 0.001), positive peritoneal cytology (OR = 2.962, 95% CI = 1.344–6.530, p = 0.007), CA125 (OR = 1.002, 95% CI = 1–1.004, p = 0.026) were the independent risk factors for pelvic LNM. And myometrial invasion ≥1/2 (OR = 5.881, 95% CI = 2.056–16.427, p = 0.001), LVSI (OR = 4.962, 95% CI = 1.933–12.740, p = 0.001), adnexal (OR = 5.921, 95% CI = 2.003–17.502, p = 0.001) were the independent risk factors for para-aortic LNM. With the increase of independent risk factors, the rates of LNM were increased significantly. ConclusionsCervical stromal invasion, myometrial invasion ≥1/2, LVSI, positive peritoneal cytology, and CA125 were risk factors for pelvic LNM. Myometrial invasion ≥1/2, LVSI and involvement of the adnexa were risk factors for para-aortic LNM which could provide a good basis to help predict which non-EEC patients are at higher risk for LNM.

Prognostic evaluation of lymph-vascular space invasion in patients with endometrioid and non-endometrioid endometrial cancer: A multicenter study

IntroductionThe prognostic value of lymph-vascular space invasion (LVSI) on endometrial cancer (EC) remains controversial. This study aimed to explore the impact of LVSI on patients with endometrioid and non-endometrioid EC in China. Materials and methodsWe analyzed EC patients who underwent surgery from 2010 to 2019 in seven Chinese hospitals retrospectively and stratified patients based on histopathologic types and LVSI status. Endpoints were disease-free survival (DFS) and overall survival (OS). Propensity score matching (PSM) algorithm was used to balance the confounding factors. The survival was examined using Kaplan-Meier analysis. Cox proportional hazards regression analyses were used to find prognostic independent risk factors. ResultsAmong 3715 EC patients, LVSI positive rate was 9.31% (346/3715). After matching, LVSI present group had shorter DFS (P = 0.005), and similar OS (P = 0.656) than LVSI absent group for endometrioid EC patients. For non-endometrioid EC patients, there was no statistical difference in either DFS (P = 0.536) or OS (P = 0.512) after matching. The multivariate Cox analysis showed that LVSI was an independent risk factor of DFS [hazard ratio (HR) 2.62, 95% confidence intervals (CI) 1.35–5.10, P = 0.005] and not OS (HR 1.24, 95%CI 0.49–3.13, P = 0.656) for endometrioid EC patients. It was not a prognostic factor of either DFS (HR 1.28, 95%CI 0.58–2.81, P = 0.539) or OS (HR 1.33, 95%CI 0.55–3.13, P = 0.515) for non-endometrioid EC patients. ConclusionLVSI is an adverse prognostic factor for endometrioid EC patients and has no impact on non-endometrioid EC patients. Necessity of postoperative adjuvant therapy based on LVSI needs to be carefully considered for non-endometrioid EC patients.

The causal effects of genetically predicted alcohol consumption on endometrial cancer risk from a Mendelian randomization study

Endometrial cancer (EC) is a common gynecological tumor in females with an increasing incidence over the past few decades. Alcohol consumption has been linked to the occurrence of various cancers; However, epidemiological studies have shown inconsistent associations between alcohol consumption and EC risk. In order to avoid the influence of potential confounding factors and reverse causality in traditional epidemiological studies, we used a method based on genetic principles-Mendelian randomization (MR) analysis to test whether there is a causal relationship between alcohol consumption and EC. MR analysis was conducted using publicly available summary-level data from genome-wide association studies (GWAS). Fifty-seven single nucleotide polymorphisms (SNPs) were extracted as instrumental variables for alcohol exposure from the GWAS and Sequencing Consortium of Alcohol and Nicotine GWAS summary data involving 941,287 participants of European ancestry. SNPs for EC were obtained from the Endometrial Cancer Association Consortium, the Endometrial Cancer Epidemiology Consortium, and the UK Biobank, involving 121,885 European participants. The inverse variance weighted (IVW) method was used as the primary method to estimate the causal effect, and the MR-Egger regression and weighted median method were used as supplementary methods. Sensitivity analyses were conducted using the Mendelian Randomization Pleiotropy RESidual Sum and Outlier global test, MR-Egger intercept test, and leave-one-out analysis to evaluate the impact of pleiotropy on causal estimates. An increase of 1 standard deviation of genetically predicted log-transformed alcoholic drinks per day was associated with a 43% reduction in EC risk [odds ratio (OR) = 0.57, 95% confidence interval (CI) 0.41–0.79, P < 0.001]. Subgroup analysis of EC revealed that alcohol consumption was a protective factor for endometrioid endometrial cancer (EEC) (OR = 0.56, 95% CI 0.38–0.83, P = 0.004) but not for non-endometrioid endometrial cancer (NEC) (OR = 1.36, 95% CI 0.40–4.66, P = 0.626). The MR-Egger regression and weighted median method yielded consistent causal effects with the IVW method. The consistent results of sensitivity analyses indicated the reliability of our causal estimates. Additionally, alcohol consumption was associated with decreased human chorionic gonadotropin (HCG) and insulin-like growth factor 1 (IGF1) levels. This MR study suggests that genetically predicted alcohol consumption is a protective factor for EC, particularly for EEC, and this protective effect may be mediated through the reduction of HCG and IGF1.

The Impact of Waiting Time-to-Surgery on Survival in Endometrial Cancer Patients.

Endometrial cancer (EC) is the most common gynecological cancer in developed countries and a standard treatment of surgery should be performed as expediently as possible. Delay time to surgery and survival was debated. The aim of this investigation was to evaluate the effect of time-interval between diagnosis and surgery (TDS) in EC patients with regards to prognosis and mortality rates. This retrospective study was conducted between January 2009 and May 2021 at Bhumibol Adulyadej Hospital, Thailand. Subjects were EC cases who underwent primary surgery during the study period. Cases with partial treatment were disqualified from the study. Subjects who underwent surgery before and after 6 weeks were classified as early and delayed surgery groups. Baseline and clinical characteristics were collected and analyzed. During the study period, 419 EC cases were recruited. The mean age of participants was 56.8 years. Two-thirds (338/491) of subjects were menopausal. Endometrioid histology (406/491) was the most common histology subtype. Five years disease free survival (DFS) of early and delayed surgery groups were comparable at a percentage of 82.5 and 83.0, respectively. Among advanced stage and non-endometrioid EC cases, the delayed surgery group had significantly shorter DFS than the early group. Advanced stage, high grade and positive lympho-vascular space invasion (LVSI) were independent factors for poor DFS. Predictive factors for mortality were advanced stage and tumor recurrence. The TDS was not a prognostic factor for disease recurrence or overall mortality. Time to surgery equal to or more than 6 weeks gave worse prognosis for DFS among advanced stage or non-endometrioid histology EC.

Impact of COVID-19 Pandemic on the Diagnostic and Therapeutic Management of Endometrial Cancer: A Monocentric Retrospective Comparative Study.

Endometrial cancer represents an ideal target to evaluate the impact of COVID-19 being the most frequent gynecological malignancy in Italy, generally detected at early stages and correlated with favorable oncological outcomes. The present comparative retrospective study carried out at Campus Bio-medico University Foundation in Rome aims to evaluate the impact of the COVID-19 pandemic on the presentation, diagnosis and treatment of EC. All women with a histological diagnosis of non-endometrioid and endometrioid endometrial cancer between 1 March 2018 and 31 October 2022 were included. The number of cases was higher in period 2 (95 vs. 64 cases). Time to diagnosis did not show statistically significant differences but in period 2, 92.06% of the diagnoses were made following abnormal uterine bleeding, while in period 1, only 67.02% were. The waiting time for the intervention was significantly shorter in period 2. Definitive histology, FIGO staging, surgical technique and adjuvant therapy did not show significant differences between the two periods. The study demonstrates that the impact of the COVID-19 pandemic did not have a direct effect on the diagnostic delay, tumor staging and type of therapy but rather on the presentation pattern of endometrial cancer.

Prognostic significance of omental disease and the role of omentectomy in non-endometrioid endometrial cancer.

Non-endometrioid endometrial cancers (non-EEC) have different management from endometrioid endometrial cancers. The purpose of this study was to investigate the prognostic significance of omental disease and the role of omentectomy in non-endometrioid endometrial cancer and discuss the current literature with the findings. The study included two hundred-three patients with non-EEC who underwent surgical treatment and follow-up between January 1996 and December 2018 in a University Hospital Gynecologic Oncology Center. The patients were divided into three groups according to whether omentectomy was performed and the presence of omental metastasis. The patient's demographics, clinical characteristics such as stage, grade, histopathologic type, lymphovascular space invasion (LVSI), myometrial invasion, lymph node involvement, and survival outcomes were compared between the groups. The study included 203 patients. Twenty-five patients (12%) had omental metastases. LVSI was reported in 57.3%, 88.0%, and 43.2% of the non-omentectomy, no-omental metastasis, and omental metastatic groups, respectively (p = 0.001). The 5-year disease-free survival (DFS) and overall survival (OS) rates according to the tumor grade, peritoneal cytology, and lymphadenectomy were also compared and were found to be statistically similar. The five-year OS rates were 70.6% for the group without omental metastases and 16.2% for the group with omental metastases, respectively (p = 0.001). In the group of omentectomy, the five-year DFS rates were 62.2% in cases without omental metastasis and 13.0% in cases with omental metastasis (p = 0.001). The five-year OS rates of 86.3% and DFS rates of 80.0% in the group without omentectomy. In non-endometrioid tumors, the survival rate was better in the group that did not undergo omentectomy. Based on these results, we can say that omentectomy may not be necessary for non-endometrioid tumors whose omentum is found to be normal in intraoperative visual examination.

Prognosis and adjuvant chemotherapy for patients with malignant peritoneal cytology in early-stage non-endometrioid endometrial cancer

ObjectiveTo investigate the influence of malignant peritoneal cytology (MPC) on the prognosis of early-stage patients with endometrial clear cell carcinoma(CCC) and serous carcinoma(SC), and the value of chemotherapy in their treatment. MethodsA retrospective observational cohort study was conducted by querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2010 to 2019. Women with early-stage CCC and SC with available peritoneal cytology results were enrolled. Propensity score matching(PSM) and propensity score inverse probability of treatment weighting (IPTW) was used to balance the measured covariates in each sub-cohort. ResultsA total of 3,616 eligible patients were included, and 368 patients had MPC (10.2%). Women with MPC were more likely to receive postoperative chemotherapy (OR 2.033; 95%CI 1.589–2.602). In PSM model, MPC had worse overall survival(OS) and cancer-specific survival (CSS) (All,p < 0.001). The 5-year OS rates were 56.5% for women with MPC and 74.4% for those with negative peritoneal cytology, and the 5-year CSS rates were 60.8% versus 80.0%(All, p < 0.0001). In the subgroup analyses, MPC was associated with decreased OS and CSS in serous, clear cell histology group, and stage IA cases(All,p < 0.001), but not for stage IB or stage II disease. In multivariate analysis, chemotherapy improved the prognosis of patients with MPC(OS:p = 0.005; CSS:p = 0.010). Additionally, in stage IA subgroup, chemotherapy improved survival outcomes in patients with MPC(OS:P = 0.025; CSS:P = 0.038), in NPC patients, however, chemotherapy was a good prognostic factor for OS (P = 0.001) but not for CSS(P = 0.300). ConclusionMPC was a prognostic factor for decreased survival in early-stage endometrial CCC and SC, and those with MPC could further benefit from chemotherapy.

Dopamine receptors D1 and D2 show prognostic significance and potential therapeutic applications for endometrial cancer patients

ObjectiveCatecholaminergic signaling has been a target for therapy in different type of cancers. In this work, we characterized the ADRβ2, DRD1 and DRD2 expression in healthy tissue and endometrial tumors to evaluate their prognostic significance in endometrial cancer (EC), unraveling their possible application as an antitumor therapy. Methods109 EC patients were included. The expression of the ADRβ2, DRD1 and DRD2 proteins was evaluated by immunohistochemistry and univariate and multivariate analysis to assess their association with clinic-pathological and outcome variables. Finally, HEC1A and AN3CA EC cell lines were exposed to different concentrations of selective dopaminergic agents alone or in combination to study their effects on cellular viability. ResultsADRβ2 protein expression was not associated with clinico-pathological parameters or prognosis. DRD1 protein expression was reduced in tumors samples but showed a significant inverse association with tumor size and stage. DRD2 protein expression was significantly associated with non-endometrioid EC, high grade tumors, tumor size, worse disease-free survival (HR = 3.47 (95%CI:1.35–8.88)) and overall survival (HR = 2.98 (95%CI:1.40–6.34)). The DRD1 agonist fenoldopam showed a reduction of cellular viability in HEC1A and AN3CA cells. The exposure to domperidone, a DRD2 antagonist, significantly reduced cell viability compared to the control. Finally, DRD1 agonism and DRD2 antagonism combination induced a significant reduction in cell viability of the AN3CA cells compared to monotherapy, close to being an additive response than a synergistic effect (CI of 1.1 at 0.5% Fa). ConclusionDRD1 and DRD2 expression levels showed a significant association with clinico-pathological parameters. Both the combined activation of DRD1 and blockage of DRD2 may form an innovative strategy to inhibit tumor growth in EC.

Endometrial cancer risk and trends among distinct African descent populations.

Endometrial cancer (EC) is the fourth most common cancer among Black women in the United States, a population disproportionately affected by aggressive nonendometrioid subtypes (e.g., serous, carcinosarcoma). To examine EC vulnerability among a wider spectrum of African descent populations, a comparison between Black women residing in different countries, rather than in the United States alone, is needed. The authors analyzed 34,789 EC cases from Florida (FL) (2005-2018), Martinique (2005-2018), and Guadeloupe (2008-2018) based on cancer registry data. Age-adjusted incidence rates, incidence rate ratios (IRRs), and annual percent changes (APC) in trends were estimated for Black populations residing in the United States (non-Hispanic Blacks [NHB]) and Caribbean. The US non-Hispanic White (NHW) population was used as a reference. Caribbean Black women had the lowest rates for endometrioid and nonendometrioid subtypes. Nonendometrioid types were most common among US (FL) NHBs (9.2 per 100,000), 2.6 times greater than NHWs (IRR, 2.60; 95% confidence interval [CI], 2.44-2.76). For endometrioid EC, rates increased 1.8% (95% CI, 0.1-3.5) yearly from 2005 to 2018 for US (FL) NHBs and 1.2% (95% CI, 0.9-1.6) for US (FL) NHWs whereas no change was observed for Caribbean Blacks. For nonendometroid carcinomas, rates increased 5.6% (95% CI, 4.0-7.2) among US (FL) NHB, 4.4% (95% CI, 0.3-8.6) for Caribbean Black, and 3.9% for US (FL) NHW women (95% CI, 2.4-5.5). Lower rates of nonendometrioid EC among Caribbean Black women suggest that vulnerability for these aggressive tumor subtypes may not currently be an overarching African ancestry disparity. Most importantly, there is an alarmingly increasing trend in nonendometrioid across all populations studied, which warrants further surveillance and etiological research for this particular subtype. We analyze population-based incidence rates and trends of endometrial cancer (EC) for African descent populations residing in different countries (i.e., United States, Martinique, Guadeloupe) to examine whether EC vulnerability among Black women is socio-environmental or more ancestry-specific in nature. The increased EC risk was not uniform across all Black women since the Caribbean had the lowest rates (for endometrioid and nonendometrioid histology subtypes). Regardless, from 2005 to 2018, there was an increasing trajectory of nonendometrioid EC for all groups, regardless of race.

Non-endometrioid endometrial cancer: analysis of recurrence pattern and identification of prognostic and treatment factors affecting recurrence and survival.

We investigated the characteristics of recurrence pattern and survival of patients with non-endometrioid endometrial cancer (NEEC) and attempted to identify prognostic and treatment factors affecting disease-free survival (DFS) and overall survival (OS) of these patients. Fifty-seven patients with histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stage IA-IVA NEEC from February 2003 to December 2021 were retrospectively analyzed. The 5‑year DFS and OS rates of the total cohort were 50.6% and 56.1%, respectively. Recurrence occurred in 28patients (49.1%) during follow-up, and the most common recurrence pattern was distant metastasis (DM; 78.6% of total recurrences). The occurrence of relapse significantly reduced 5‑year OS (recurrence group vs. non-recurrence group: 12.5% vs. 100%; p < 0.001). In univariate analysis, adjuvant radiotherapy (RT) group showed significantly higher 5‑year DFS (56.7% vs. 37.9%; p = 0.04), local recurrence-free survival (91.6% vs. 50.5%; p = 0.01), and regional recurrence-free survival (88.2% vs. 56.5%; p < 0.01) than the non-RT group. In multivariate analysis, advanced FIGO stage was identified as anegative prognostic factor for DFS and OS. Lymphovascular space invasion (LVSI) and adjuvant RT were independent prognostic factors for DFS. The most common recurrence pattern observed in patients with NEEC was DM. FIGO stage and LVSI were identified as prognostic factors for survival, and RT was identified as atherapeutic modality that could increase DFS. To improve the OS of patients with NEEC, the addition of effective chemotherapy that can reduce DM may be important.

Evolving treatment landscape of advanced endometrial cancer – A current perspective from a German tertiary referral center for gynecological oncology

Endometrial cancer (EC) represents the most prevalent cancer of the female genital tract worldwide. Although EC has an overall good prognosis compared to other gynecological malignancies, a recent report from the American Cancer Society indicated that the cancer-specific survival of patients with EC has decreased since the 1970s, while the incidence has remained stable ( [1] Siegel R.L. Miller K.D. Fuchs H.E. Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan; 72: 7-33 Google Scholar ). The increasing EC-specific mortality is particularly attributable to EC with non-endometrioid histology. Although non-endometrioid histology represents only about 20% of all EC, non-endometrioid EC account for more than half of EC-related deaths ( 2 Clarke M.A. Devesa S.S. Harvey S.V. Wentzensen N. Hysterectomy-Corrected Uterine Corpus Cancer Incidence Trends and Differences in Relative Survival Reveal Racial Disparities and Rising Rates of Nonendometrioid Cancers. J Clin Oncol Off J Am Soc Clin Oncol. 2019 Aug 1; 37: 1895-1908 Google Scholar , 3 McGunigal M. Liu J. Kalir T. Chadha M. Gupta V. Survival Differences Among Uterine Papillary Serous, Clear Cell and Grade 3 Endometrioid Adenocarcinoma Endometrial Cancers: A National Cancer Database Analysis. Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2017 Jan; 27: 85-92 Google Scholar ). The determinants underlying the increase in non-endometrioid EC remain elusive. Overall, EC contrasts to the majority of other malignancies, whose cancer-specific survival has improved in recent years ( [1] Siegel R.L. Miller K.D. Fuchs H.E. Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan; 72: 7-33 Google Scholar ). Hence, it is crucial to reconsider and optimize existing therapy strategies and, to incorporate novel scientific findings into therapy algorithms. Here, we compile existing therapeutic concepts for advanced EC and propose a treatment algorithm based on current clinical and translational research findings.

Lymph-vascular Space Involvement and/or p53 Overexpression Correlated With the Clinical Outcome of Early-stage Endometrial Cancer Patients Treated With Adjuvant Vaginal Brachytherapy.

The majority of patients with endometrial cancer (EC) are diagnosed at an early stage and undergo primary surgery, followed by observation or adjuvant therapy according to risk factors on surgical samples. The objective of this study was to assess the correlation between a risk profile represented by the presence of substantial lymph-vascular space involvement (LVSI) and/or p53 overexpression and the clinical outcome of patients with early-stage endometrial cancer (EC) who received adjuvant vaginal brachytherapy (BT). This investigation assessed 79 patients who underwent hysterectomy, bilateral salpingo-oophorectomy, and pelvic and/o aortic lymphadenectomy or sentinel lymph node biopsy followed by hypofractionated (HDR)-vaginal BT, using 192Ir source, for stage I-II endometrioid (n=70) or non-endometrioid (n=9) EC. Thirty-four patients (43.0%) were considered to have an unfavorable risk profile defined by the presence of substantial LVSI and /or p53 overexpression. Five-year disease-free survival (DFS) and five-year overall survival (OS) were 93.7% and 95%, respectively. There was a significant correlation between unfavorable risk-profile and pelvic recurrence rate (p=0.002) and distant recurrence rate (p=0.017). Patients with abnormal p53 had a higher risk of local relapse (p=0.041). Substantial LVSI was strongly associated with pelvic recurrence (p=0.001) and distant metastasis (p<0.001). The presence of substantial LVSI and/or p53 overexpression strictly correlated with poor outcome of patients with early-stage EC and should be taken into consideration for better planning adjuvant treatment in this clinical setting.

Child and adult adiposity and subtype-specific endometrial cancer risk: a multivariable Mendelian randomisation study

Increased adiposity is a known risk factor for endometrial cancer (EC). This study aimed to disentangle the separate causal roles of child and adult adiposity on EC risk in adults, including endometrioid and non-endometrioid histological subtypes using multivariable Mendelian randomisation. These analyses employed genetic associations derived from UK Biobank as proxies for child and adult body size in 12,906 cases and 108,979 controls that participated in the Endometrial Cancer Association Consortium. In multivariable analyses, adult body size increased overall EC (OR 2.30, 95% CI 1.73–3.06) and endometrioid EC risk (OR 2.28, 95% CI 1.65–3.16), while child body size had minimal effect. In contrast, child body size (OR 2.26, 95% CI 1.03–4.99) but not adult body size increased non-endometrioid EC risk. As such, child adiposity has an indirect effect on endometrioid EC risk that is mediated by adult adiposity but has a direct effect on non-endometrioid EC risk that is independent of adult adiposity. These novel findings indicate that interventions targeting adiposity during distinct periods in life have a critical role in preventing subtype-specific EC.

7428 Oncologic Safety of Minimally Invasive Surgery in Non-Endometrioid Endometrial Cancer

<h3>Study Objective</h3> This study was aimed to compare the oncologic outcomes of patients with non-endometrioid endometrial cancer who underwent minimally invasive surgery with the outcomes of patients who underwent open surgery. <h3>Design</h3> retrospective study. <h3>Setting</h3> multi-institutional study. <h3>Patients or Participants</h3> patients with non-endometrioid endometrial cancer who were surgically staged by either minimally invasive surgery or open surgery. <h3>Interventions</h3> Oncologic outcomes of the patients were compared according to surgical approach. <h3>Measurements and Main Results</h3> 113 patients met the inclusion and exclusion criteria. 57 underwent minimally invasive surgery and 56 underwent open surgery. Patients who underwent minimally invasive surgery had smaller tumors (median size, 3.3 vs. 5.2%, <i>p</i>=0.0001) and a lower lymphovascular space invasion rate (29.8% vs. 48.2%, <i>p</i>=0.045). In the overall population, the numbers and rate of recurrence were significantly higher in the open surgery group (<i>p</i> = 0.016). In multivariate analysis, disease stage and tumor size were associated with DFS in contrast to surgical procedure. <h3>Conclusion</h3> Minimally invasive surgery showed similar survival outcomes when compared to open surgery in non-endometrioid endometrial cancer patients, irrespective of disease stage. When minimally invasive surgery is managed by expert surgeons, non-endometrioid histological subtypes should not be considered a contraindication for minimally invasive surgery.

The role of fat distribution and inflammation in the origin of endometrial cancer, study protocol of the ENDOCRINE study.

Obesity is a growing problem worldwide, especially in countries with improved socioeconomic circumstances. Also, in the Netherlands the incidence of overweight and obesity is rising. There is increasing evidence on the association between obesity and tumorigenesis. Of all cancer types, endometrial cancer (EC) has the strongest positive correlation with obesity. Obesity is generally defined as a body mass index (BMI) >30, yet does not cover the differences in fat distribution in visceral and subcutaneous compartments. Visceral fat is assumed to be relatively more metabolically active and likely negative prognostic biomarker in non-endometrioid EC. Whereas subcutaneous fat is mainly responsible for oestrogen production through increased aromatase activity. The aim of this study is to compare hormone levels and inflammatory markers after bilateral salpingo-oophorectomy (BSO) in obese and non-obese patients. Secondary objectives are to compare the effect of fat distribution and diagnosis (benign vs. EC) on the observed changes in hormone levels and inflammatory markers, and to compare the effect of BSO on menopausal complaints. Prospective multicentre observational cohort study. A total of 160 patients will be included, of which 80 patients with a normal BMI (18-25 kg/m2) and 80 patients with an obese BMI >32-35 kg/m2. Preoperative abdominal CT will be performed and fasting venous blood samples are obtained for hormone levels and inflammation markers analysis. During surgery, adipose tissue biopsies of subcutaneous and visceral (omental and intestinal epiploic fat) compartments will be collected and stored fresh frozen. In addition a fasting blood draw six weeks after surgery will be obtained. All subjects will fill in two questionnaires before surgery and one after surgery. We hypothesize that BMI, the type of fat distribution, and possibly the underlying pathology significantly influence in hormone levels, and systemic inflammation changes after BSO. Previous studies have found several clues for a relationship between obesity and endometrial cancer. We expect that our study will contribute to pinpoint the exact differences between 'healthy obesity' and 'unhealthy obesity' and will help to identify patients that are more at risk of developing cancer (or possibly suffer from other related problems such as cardiovascular problems e.g.).