Underrepresentation of racial and ethnic minority groups in gynecologic oncology: An analysis of over 250 trials.

OBJECTIVE: To describe the participation of racial and ethnic minority groups (REMGs) in gynecologic oncology trials. METHODS: Gynecologic oncology studies registered on ClinicalTrials.gov between 2007 and 2020 were identified. Trials with published results were analyzed based on reporting of race/ethnicity in relation to disease site and trial characteristics. Expected enrollment by race/ethnicity was calculated and compared to actual enrollment, adjusted for 2010 US Census population data. RESULTS: 2146 gynecologic oncology trials were identified. Of published trials (n = 252), 99 (39.3%) reported race/ethnicity data. Recent trials were more likely to report these data (36% from 2007 to 2009; 51% 2013-2015; and 53% from 2016 to 2018, p = 0.01). Of all trials, ovarian cancer trials were least likely to report race/ethnicity data (32.1% vs 39.3%, p = 0.011). Population-adjusted under-enrollment for Blacks was 7-fold in ovarian cancer, Latinx 10-fold for ovarian and 6-fold in uterine cancer trials, Asians 2.5-fold in uterine cancer trials, and American Indian and Alaska Native individuals 6-fold in ovarian trials. Trials for most disease sites have enrolled more REMGs in recent years - REMGs made up 19.6% of trial participants in 2007-2009 compared to 38.1% in 2016-2018 (p < 0.0001). CONCLUSION: Less than half of trials that published results reported race/ethnicity data. Available data reveals that enrollment of REMGs is significantly below expected rates based on national census data. These disparities persisted even after additionally adjusting for population size. Despite improvement in recent years, additional recruitment of REMGs is needed to achieve more representative and equitable participation in gynecologic cancer clinical trials.

Obstetric Clinical Trial Diversity: Analysis of Trial Focus and Representation From 2007 to 2020.

Inclusive clinical trials are necessary to improve maternal health equity. We aimed to analyze the current state of race and ethnicity reporting and representation in obstetric trials and the association with trial focus for all U.S.-based obstetric trials between 2007 and 2020. In this cross-sectional, multivariable regression analysis, the exposure variable was clinical trial focus (eg, prematurity), and the outcomes were race and ethnicity reporting and representation of diverse cohorts. Obstetric anesthesia trials reported race and ethnicity the least frequently of all trial foci (adjusted odds ratio 0.2, 95% CI 0.08-0.48). Hypertension and obstetric anesthesia trials enrolled the lowest proportion of Black participants, and prematurity trials enrolled the lowest proportion of Latinx and Asian participants. All researchers should strive to improve measurement and reporting of demographic data as well participation of diverse cohorts.

Orlistat exerts anti-obesity and anti-tumorigenic effects in a transgenic mouse model of endometrial cancer.

Introduction: Among all cancers, endometrial cancer is most strongly associated with obesity, with more than 65% of endometrial cancers attributable to obesity and being overweight. Fatty acid synthase (FAS), a key lipogenic enzyme, is expressed in endometrial cancer tumors and is associated with a worse prognosis for this disease. Orlistat, an FAS inhibitor, is an FDA-approved weight loss medication that has demonstrated anti-tumor activity in a variety of preclinical cancer models. Methods: In this study, the Lkb1fl/flp53fl/fl mouse model of endometroid endometrial cancer was exposed to three diet interventions, including a high fat diet (obese), a low fat diet (lean) and switch from a high fat to a low fat diet, and then exposed to orlistat or placebo. Results: The mice fed a high-fat diet had significantly increased body weight and tumor weight compared to mice fed a low-fat diet. Switching from a high-fat diet to a low fat diet led to a reduction in mouse weight and suppressed tumor growth, as compared to both the high fat diet and low fat diet groups. Orlistat effectively decreased body weight in obese mice and inhibited tumor growth in obese, lean, and the high fat diet switch to low fat diet mouse groups through induction of apoptosis. Orlistat also showed anti-proliferative activity in nine of 11 primary cultures of human endometrial cancer. Discussion: Our findings provide strong evidence that dietary intervention and orlistat have anti-tumor activity in vivo and supports further investigation of orlistat in combination with dietary interventions for the prevention and treatment of endometrial cancer.

Characterization of pre-operative anemia in patients undergoing surgery by a gynecologic oncologist and association with post-operative complications.

OBJECTIVE: Anemia is prevalent in patients with gynecologic cancers and is associated with increased peri-operative morbidity. We aimed to characterize risk factors for pre-operative anemia and describe outcomes among patients undergoing surgery by a gynecologic oncologist to identify potential areas for impactful intervention. METHODS: We analyzed major surgical cases performed by a gynecologic oncologist in the National Surgical Quality Improvement Program (NSQIP) database from 2014 to 2019. Anemia was defined as hematocrit <36%. Demographic characteristics and peri-operative variables for patients with and without anemia were compared using bivariable tests. Odds of peri-operative complications in patients stratified by pre-operative anemia were calculated using logistic regression models. RESULTS: Among 60 017 patients undergoing surgery by a gynecologic oncologist, 23.1% had pre-operative anemia. Women with ovarian cancer had the highest rate of pre-operative anemia at 39.7%. Patients with advanced-stage cancer had a higher risk of anemia than early-stage disease (42.0% vs 16.3%, p≤0.001). In a logistic regression model adjusting for potential demographic, cancer-related, and surgical confounders, patients with pre-operative anemia had increased odds of infectious complications (odds ratio (OR) 1.16, 95% CI 1.07 to 1.26), thromboembolic complications (OR 1.39, 95% CI 1.15 to 1.68), and blood transfusion (OR 5.78, 95% CI 5.34 to 6.26). CONCLUSIONS: There is a high rate of anemia in patients undergoing surgery by a gynecologic oncologist, particularly those with ovarian cancer and/or advanced malignancy. Pre-operative anemia is associated with increased odds of peri-operative complications. Interventions designed to screen for and treat anemia in this population have the potential for significant impact on surgical outcomes.

Enrollment of Racial and Ethnic Minoritized Groups in Gynecologic Oncology Clinical Trials: A Review of the Scope of the Problem, Contributing Factors, and Strategies to Improve Inclusion.

Racial inequities are well-documented across the gynecologic oncology care continuum, including the representation of racial and ethnic minoritized groups (REMGs) in gynecologic oncology clinical trials. We specifically reviewed the scope of REMG disparities, contributing factors, and strategies to improve inclusion. We found systematic and progressively worsening under-enrollment of REMGs, particularly of Black and Latinx populations. In addition, race/ethnicity data reporting is poor, yet a prerequisite for accountability to recruitment goals. Trial participation barriers are multifactorial, and successful remediation likely requires multi-level strategies. More rigorous, transparent data on trial participants and effectiveness studies on REMG recruitment strategies are needed to improve enrollment.

Race and Ethnicity Reporting and Representation in Obstetrics and Gynecology Clinical Trials and Publications From 2007-2020.

Importance: Clinical trials guide evidence-based obstetrics and gynecology (OB-GYN) but often enroll nonrepresentative participants. Objective: To characterize race and ethnicity reporting and representation in US OB-GYN clinical trials and their subsequent publications and to analyze the association of subspecialty and funding with diverse representation. Design and Setting: Cross-sectional analysis of all OB-GYN studies registered on ClinicalTrials.gov (2007-2020) and publications from PubMed and Google Scholar (2007-2021). Analyses included logistic regression controlling for year, subspecialty, phase, funding, and site number. Data from 332 417 studies were downloaded. Studies with a noninterventional design, with a registration date before October 1, 2007, without relevance to OB-GYN, with no reported results, and with no US-based study site were excluded. Exposures: OB-GYN subspecialty and funder. Main Outcomes and Measures: Reporting of race and ethnicity data and racial and ethnic representation (the proportion of enrollees of American Indian or Alaskan Native, Asian, Black, Latinx, or White identity and odds of representation above US Census estimates by race and ethnicity). Results: Among trials with ClinicalTrials.gov results (1287 trials with 591 196 participants) and publications (1147 trials with 821 111 participants), 662 (50.9%) and 856 (74.6%) reported race and ethnicity data, respectively. Among publications, gynecology studies were significantly less likely to report race and ethnicity than obstetrics (adjusted odds ratio [aOR], 0.54; 95% CI, 0.38-0.75). Reproductive endocrinology and infertility trials had the lowest odds of reporting race and ethnicity (aOR, 0.14; 95% CI, 0.07-0.27; reference category, obstetrics). Obstetrics and family planning demonstrated the most diverse clinical trial cohorts. Compared with obstetric trials, gynecologic oncology had the lowest odds of Black representation (ClinicalTrials.gov: aOR, 0.04; 95% CI, 0.02-0.09; publications: aOR, 0.06; 95% CI, 0.03-0.11) and Latinx representation (ClinicalTrials.gov: aOR, 0.05; 95% CI, 0.02-0.14; publications: aOR, 0.23; 95% CI, 0.10-0.48), followed by urogynecology and reproductive endocrinology and infertility. Urogynecology (ClinicalTrials.gov: aOR, 0.15; 95% CI, 0.05-0.39; publications: aOR, 0.24; 95% CI, 0.09-0.58) had the lowest odds of Asian representation. Conclusions and Relevance: Race and ethnicity reporting and representation in OB-GYN trials are suboptimal. Obstetrics and family planning trials demonstrate improved representation is achievable. Nonetheless, all subspecialties should strive for more equitably representative research.

Analysis of endometrial carcinoma TCGA reveals differences in DNA methylation in tumors from Black and White women.

OBJECTIVE: Racial disparities exist in cancer patients both in incidence and death rates. In endometrial cancer, Black patients are reported to have higher incidence of aggressive endometrial cancer subtypes and higher death rates than White women. To date, diagnostic and prognostic biomarkers associated with race-specific methylation driven genes have yet to be identified. The objective of this study was to explore DNA methylation patterns in endometrial tumor samples from White and Black women. METHODS: Differentially methylated CpGs (DMCs) and differentially methylated regions (DMRs) were identified in White tumor samples compared to Black tumor samples using Endometrial Carcinoma (EC) methylation and clinical data from The Cancer Genome Atlas (TCGA). Survival analysis was performed using survival R package and results were visualized using Kaplan-Meier plots. To access the correlation between changes in methylation and gene expression, we downloaded raw RNA-sequencing by Expectation-Maximization (RSEM) counts data from The Cancer Genome Atlas (TCGA) using TCGABiolinks package (v2.18.0). RESULTS: Our analysis revealed 704 differentially methylated CpGs in tumors from Black and White women. These differentially methylated genes showed strong negative correlation with gene expression and statistically significant enrichment in regulatory regions such as DNase I hypersensitivity sites (DHSs) and transcription factor binding sites (TFBSs). Increased variability in methylation occurred in genes such as the insulin signaling pathway in Black tumor samples. CONCLUSION: By using two independent statistical method based on means (DMR, DMCs) and variances (DVCs) on the endometrial carcinoma TCGA data, we showed that endometrial tumors from Black women are hypomethylated and more hypervariable than tumors from White women. In-depth investigation of these methylation driven markers can aid in successful management of endometrial cancer disparities and improved overall survival in Black and White populations.

Disparities in gynecologic cancer incidence, treatment, and survival: a narrative review of outcomes among black and white women in the United States.

For patients diagnosed with ovarian, uterine, or cervical cancer, race impacts expected outcome, with black women suffering worse survival than white women for all three malignancies. Moreover, outcomes for black women have largely worsened since the 1970s. In this narrative review, we first provide an updated summary of the incidence and survival of ovarian, uterine, and cervical cancer, with attention paid to differences between white and black patients. We then offer a theoretical framework detailing how racial disparities in outcomes for each of the gynecologic malignancies can be explained as the sum result of smaller white-black differences in experience of preventive strategies, implementation of screening efforts, early detection of symptomatic disease, and appropriate treatment. Much research has been published regarding racial disparities in each of these domains, and with this review, we seek to curate the relevant literature and present an updated understanding of disparities between black and white women with gynecologic malignancies.

Feasibility and Prediction of Adverse Events in a Postoperative Monitoring Program of Patient-Reported Outcomes and a Wearable Device Among Gynecologic Oncology Patients.

PURPOSE: The objective of this study was to test the feasibility of implementing a postoperative monitoring program for women with gynecologic cancers composed of patient-reported outcomes (PROs) and a wearable activity monitor. METHODS: We prospectively enrolled patients undergoing gynecologic cancer surgery to this single-arm study. Enrolled patients completed PROs (Patient-Reported Outcomes Measurement Information System physical function, sleep disturbance, anxiety, fatigue, and pain intensity) at baseline and one-week intervals for 4 weeks. They also wore a wearable accelerometer device that measured steps, heart rate, and intensity of physical activity. The primary outcome was feasibility. The secondary outcome was prediction of unscheduled contacts with the health care system on a given postoperative day. RESULTS: We enrolled 34 women. Three patients were unevaluable. The mean age was 58 years. The mean body mass index was 31 kg/m2; 17 patients were White (54.8%), 12 patients were Black (38.7%), and two patients (6.5%) were Asian. The overall wear time was 83.8%, and patients responded to 80.4% of the PRO instruments. Twenty-two patients (71%) had an unscheduled contact with the health care system postoperatively (median 1.5, 0.0-8.0). The day of an unscheduled health care utilization event was predicted with acceptable discrimination (area under the receiver operating characteristic curve 0.75; 95% CI, 0.67 to 0.81). PROs of fatigue and physical function were most predictive followed by wearable device outputs of lightly active minutes and average daily heart rate. CONCLUSION: Implementation of a postoperative monitoring program of patient-reported outcomes and a wearable device was feasible. The specific day of an unscheduled contact with the health care system was predicted with acceptable discrimination.

The Effects of NT-1044, a Novel AMPK Activator, on Endometrial Cancer Cell Proliferation, Apoptosis, Cell Stress and In Vivo Tumor Growth.

OBJECTIVES: Anti-diabetic biguanide drugs such as metformin may have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Metformin requires organic cation transporters (OCTs) for entry into cells, and NT-1044 is an AMPK activator designed to have greater affinity for two of these transporters, OCT1 and OCT3. We sought to compare the effects of NT-1044 on cell proliferation in human endometrial cancer (EC) cell lines and on tumor growth in an endometrioid EC mouse model. METHODS: Cell proliferation was assessed in two EC cell lines, ECC-1 and Ishikawa, by MTT assay after exposure to NT-1044 for 72 hours of treatment. Apoptosis was analyzed by Annexin V-FITC and cleaved caspase 3 assays. Cell cycle progression was evaluated by Cellometer. Reactive oxygen species (ROS) were measured using DCFH-DA and JC-1 assays. For the in vivo studies, we utilized the LKB1fl/flp53fl/fl mouse model of endometrioid endometrial cancer. The mice were treated with placebo or NT-1044 or metformin following tumor onset for 4 weeks. RESULTS: NT-1044 and metformin significantly inhibited cell proliferation in a dose-dependent manner in both EC cell lines after 72 hours of exposure (IC50 218 µM for Ishikawa; 87 µM for ECC-1 cells). Treatment with NT-1044 resulted in G1 cell cycle arrest, induced apoptosis and increased ROS production in both cell lines. NT-1044 increased phosphorylation of AMPK and decreased phosphorylation of S6, a key downstream target of the mTOR pathway. Expression of the cell cycle proteins CDK4, CDK6 and cyclin D1 decreased in a dose-dependent fashion while cellular stress protein expression was induced in both cell lines. As compared to placebo, NT-1044 and metformin inhibited endometrial tumor growth in obese and lean LKB1fl/flp53fl/fl mice. CONCLUSIONS: NT-1044 suppressed EC cell growth through G1 cell cycle arrest, induction of apoptosis and cellular stress, activation of AMPK and inhibition of the mTOR pathway. In addition, NT-1044 inhibited EC tumor growth in vivo under obese and lean conditions. More work is needed to determine if this novel biguanide will be beneficial in the treatment of women with EC, a disease strongly impacted by obesity and diabetes.

Adding bevacizumab to single agent chemotherapy for the treatment of platinum-resistant recurrent ovarian cancer: A cost effectiveness analysis of the AURELIA trial.

OBJECTIVE: AURELIA, a randomized phase III trial of adding bevacizumab (B) to single agent chemotherapy (CT) for the treatment of platinum-resistant recurrent ovarian cancer, demonstrated improved progression free survival (PFS) in the B+CT arm compared to CT alone. We aimed to evaluate the cost effectiveness of adding B to CT in the treatment of platinum-resistant recurrent ovarian cancer. METHODS: A decision tree model was constructed to evaluate the cost effectiveness of adding bevacizumab (B) to single agent chemotherapy (CT) based on the arms of the AURELIA trial. Costs, quality-adjusted life years (QALYs), and progression free survival (PFS) were modeled over fifteen months. Model inputs were extracted from published literature and public sources. Incremental cost effectiveness ratios (ICERs) per QALY gained and ICERs per progression free life year saved (PF-LYS) were calculated. One-way sensitivity analyses were performed to evaluate the robustness of results. RESULTS: The ICER associated with B+CT is $410,455 per QALY gained and $217,080 per PF-LYS. At a willingness to pay (WTP) threshold of $50,000/QALY, adding B to single agent CT is not cost effective for this patient population. Even at a WTP threshold of $100,000/QALY, B+CT is not cost effective. These findings are robust to sensitivity analyses. CONCLUSIONS: Despite gains in QALY and PFS, the addition of B to single agent CT for treatment of platinum-resistant recurrent ovarian cancer is not cost effective. Benefits, risks, and costs associated with treatment should be taken into consideration when prescribing chemotherapy for this patient population.

Association between differential gene expression and body mass index among endometrial cancers from The Cancer Genome Atlas Project.

OBJECTIVE: The Cancer Genome Atlas (TCGA) identified four integrated clusters for endometrial cancer (EC): POLE, MSI, CNL and CNH. We evaluated differences in gene expression profiles of obese and non-obese women with EC and examined the association of body mass index (BMI) within the clusters identified in TCGA. METHODS: TCGA RNAseq data was used to identify genes related to increasing BMI among ECs. The POLE, MSI and CNL clusters were composed mostly of endometrioid EC. Patient BMI was compared between these three clusters with one-way ANOVA. Association between gene expression and BMI was also assessed while adjusting for confounding effects of potential confounding factors. p-Values testing the association between gene expression and BMI were adjusted for multiple hypothesis testing over the 20,531 genes considered. RESULTS: Mean BMI was statistically different between the ECs in the CNL (35.8) versus POLE (29.8) cluster (p=0.006) and approached significance for the MSI (33.0) versus CNL (35.8) cluster (p=0.05). 181 genes were significantly up- or down-regulated with increasing BMI in endometrioid EC (q-value<0.01), including LPL, IRS-1, IGFBP4, IGFBP7 and the progesterone receptor. DAVID functional annotation analysis revealed significant enrichment in "cell cycle" (adjusted p-value=1.5E-5) and "DNA metabolic processes" (adjusted p-value=1E-3) for the identified genes. CONCLUSIONS: Obesity related genes were found to be upregulated with increasing BMI among endometrioid ECs. Patients with POLE tumors have the lowest median BMI when compared to MSI and CNL. Given the heterogeneity among endometrioid EC, consideration should be given to abandoning the Type I and II classification of EC tumors.

Effects of Fatty Acid Synthase Inhibition by Orlistat on Proliferation of Endometrial Cancer Cell Lines.

OBJECTIVE: Fatty acid synthase (FAS) is a key lipogenic enzyme that is highly expressed in endometrial cancer. Orlistat is a weight loss medication that has been shown to be a potent inhibitor of FAS. The goal of this study was to evaluate the anti-tumorigenic potential of orlistat in endometrial cancer cell lines. METHODS: The endometrial cancer cell lines ECC-1 and KLE were used. Cell proliferation was assessed by MTT assay after treatment with orlistat. Cell cycle progression was evaluated by Cellometer and apoptosis was assessed using the Annexin V assay. Reactive oxygen species (ROS) was measured using the DCFH-DA assay. Western immunoblotting was performed to determine changes in FAS, cellular stress, cell cycle progression, and the AMPK/mTOR pathways. RESULTS: Orlistat inhibited cell proliferation by 61 % in ECC-1 cells and 57 % in KLE cells at a dose of 500 µM. Treatment with orlistat at this concentration resulted in G1 arrest (p < 0.05) but did not affect apoptosis. Orlistat increased ROS and induced the expression of BIP (1.28-fold in ECC-1 compared to control, p < 0.05; 1.92-fold in KLE, p < 0.05) and PERK (2.25-fold in ECC-1, 1.4-fold in KLE, p < 0.05). Western immunoblot analysis demonstrated that orlistat decreased expression of important proteins in fatty acid metabolism including FAS (67 % in ECC-1, 15 % in KLE), acetyl-CoA carboxylase (40 % in ECC-1, 35 % in KLE), and carnitine palmitoyltransferase 1A (CPT1A) (65 % in ECC-1, 25 % in KLE) in a dose-dependent manner. In addition, orlistat at a dose of 500 µM increased expression of phosphorylated-AMPK (1.9-fold in ECC-1, p < 0.01; 1.5-fold in KLE, p < 0.05) and decreased expression of phosphorylated-Akt (25 % in ECC-1, p < 0.05; 37 % in KLE, p < 0.05) and phosphorylated-S6 (68 % in ECC-1, 56 % in KLE). CONCLUSIONS: Orlistat inhibits cell growth in endometrial cancer cell lines through inhibition of fatty acid metabolism, induction of cell cycle G1 arrest, activation of AMPK and inhibition of the mTOR pathway. Given that patients with endometrial cancer have high rates of obesity, orlistat should be further investigated as a novel strategy for endometrial cancer treatment.

Gemcitabine and Docetaxel Compared With Observation, Radiation, or Other Chemotherapy Regimens as Adjuvant Treatment for Stage I-to-IV Uterine Leiomyosarcoma.

OBJECTIVES: We aimed to compare progression-free survival (PFS) and overall survival (OS) among patients with stage I-to-IV uterine leiomyosarcoma (uLMS) who received adjuvant gemcitabine-docetaxel, were observed, received radiation only, or were treated with a chemotherapy regimen other than gemcitabine-docetaxel. METHODS/MATERIALS: This is a retrospective cohort study of 128 women with uLMS. Data included age, body mass index, race, stage, mitotic count, residual disease, adjuvant treatment, PFS, and OS. Variables were compared by Fisher exact or Wilcoxon rank-sum tests. Time to progression or death was plotted using Kaplan-Meier curves. Cox proportional hazards regression was used to estimate hazard ratios for progression or death by patient and tumor characteristics. RESULTS: Fifty-six (44%) women received adjuvant chemotherapy, 41 (32%) received adjuvant radiation, and 31 (24%) were observed. Of those receiving chemotherapy, 30 received gemcitabine-docetaxel, and 26 received other chemotherapy. Disease stage for the chemotherapy groups was evenly distributed. In the radiation group, 80% of patients had early-stage disease. Age, body mass index, and residual disease were similar between the groups. Mitotic count was uniformly 10 or greater only in the gemcitabine-docetaxel group. Age, stage, and residual disease were associated with worst PFS and OS. After adjusting for these variables, there was no difference in PFS or OS between gemcitabine-docetaxel and the other treatment groups. CONCLUSIONS: There was no difference in PFS or OS in women with uLMS treated with adjuvant gemcitabine-docetaxel versus those who were observed or received radiation only or a chemotherapy regimen other than gemcitabine-docetaxel. There is a need to identify novel therapies to treat this aggressive disease.

Knockdown of hTERT and Treatment with BIBR1532 Inhibit Cell Proliferation and Invasion in Endometrial Cancer Cells.

Telomerase activity and expression of the catalytic protein hTERT are associated with cell proliferation and advanced stage in endometrial cancer. Our objective was to evaluate the effect of inhibition of hTERT by siRNA and BIBR1532 on cell growth, apoptosis and invasion in endometrial cancer cells. Knockdown of hTERT or treatment of the cells with BIBR1532 decreased telomerase activity, inhibited cell proliferation, induced apoptosis, and reduced cell invasion in Ishikawa and ECC-1 cells. Either hTERT siRNA or BIBR1532 in combination with paclitaxel promoted a synergistic inhibitory effect on cell growth through induction of Annexin V expression and a remarkable reduction in cell invasion through reduction of protein expression of MMP9, MMP2, and MMP3. Increased telomerase activity and hTERT protein expression by transfections enhanced the protein expression of MMPs and increased the cell invasion ability. BIBR1532 significantly antagonized cell invasion induced by increased hTERT expression. These findings suggest that telomerase and hTERT facilitate cell invasion via MMP family in human endometrial cancer cells.

Lumbee Native American ancestry and the incidence of aggressive histologic subtypes of endometrial cancer.

OBJECTIVE: The Lumbee Indian tribe is the largest Native American tribe in North Carolina, with about 55,000 enrolled members who mostly reside in southeastern counties. We evaluated whether Lumbee heritage is associated with high-risk histologic subtypes of endometrial cancer. METHODS: We retrospectively analyzed the available records from IRB-approved endometrial cancer databases at two institutions of patients of Lumbee descent (year of diagnosis range 1980-2014). Each Lumbee case was matched by age, year of diagnosis, and BMI to two non-Lumbee controls. Chi-square test was used to compare categorical associations. Kaplan-Meier methods and log-rank test were used to display and compare disease-free survival (DFS) and overall survival (OS). Multivariate Cox proportional hazards regression was used to adjust for age and BMI while testing cohort as a predictor of DFS and OS. RESULTS: Among 108 subjects, 10/35 (29%) Lumbee and 19/72 (26%) non-Lumbee subjects had high-risk (serous/clear cell/carcinosarcoma) histologic types (p = 0.8). 12/35 (34%) Lumbee and 24/72 (33%) non-Lumbee subjects had grade 3 tumors (p = 0.9). 5/33 (15%) Lumbee and 13/72 (18%) non-Lumbee had advanced stage endometrial cancer at diagnosis (p = 0.7). Lumbee ancestry was not associated with worse survival outcomes. OS (p = 0.054) and DFS (p = 0.01) were both worse in Blacks compared to Lumbee and White subjects. CONCLUSION: In this retrospective cohort analysis, Lumbee Native American ancestry was not a significant independent predictor of rates of high-risk histological subtypes of endometrial cancer or poor survival outcomes.

Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling.

OBJECTIVES: Obesity and diabetes are well-known risk factors for the development of endometrial cancer. A high rate of aerobic glycolysis represents a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. This study aimed to investigate the effect of various concentrations of glucose on cell proliferation in endometrial cancer. METHODS: ECC-1 and Ishikawa cells were treated with low glucose (1mM), normal glucose (5mM) and high glucose (25mM), and cytotoxicity, apoptosis, cell cycle, adhesion/invasion, and changes of AMPK/mTOR/S6 and MAPK pathways were evaluated. RESULTS: Our results revealed that high glucose increased cell growth and clonogenicity in two endometrial cancer cell lines in a dose dependent manner. Low glucose induced the activity of cleaved caspase 3 and caused cell cycle G1 arrest. High glucose increased the ability of adhesion and invasion by decreasing E-cadherin and increasing Snail expression. In addition, high glucose increased glucose uptake and glycolytic activity through modulating the AMPK/mTOR/S6 and MAPK pathways. CONCLUSIONS: Our findings suggest that glucose stimulated cell proliferation through multiple complex signaling pathways. Targeting glucose metabolism may be a promising therapeutic strategy in the treatment of endometrial cancer.