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

PURPOSE: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%-20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. EXPERIMENTAL DESIGN: We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC. RESULTS: Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden (POLEmut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival P > 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the no specific molecular profile (NSMP) subtype, where immune infiltrates lacking B cells (TILB minus) had inferior outcome (disease-specific survival: HR, 4.0; 95% confidence interval, 1.1-14.7; P < 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes. CONCLUSIONS: Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study.

ObjectiveMolecular profiling is developing to inform treatment in endometrial cancer. Using real world evidence, we sought to evaluate frontline immune checkpoint inhibitor vs chemotherapy effectiveness in advanced endometrial cancer, stratified by Tumor Mutational Burden (TMB) ≥10 mut/MB and microsatellite instability (MSI).MethodsPatients with advanced endometrial cancer in the US-based de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database were included. Data originated from patients treated between January 2011- March 2022 at 280 US clinics. Next-generation sequencing assays were performed via FoundationOne or FoundationOneCDx. Longitudinal clinical data were derived from electronic health records. Immune checkpoint inhibitor treatment included pembrolizumab, dostarlimab, and nivolumab monotherapies. Time to next treatment, time to treatment discontinuation, and overall survival were assessed with the log-rank test and Cox proportional hazard models with adjusted hazard ratios (aHR) for known prognostic factors. We used the Likelihood ratio test to compare biomarker performance.ResultsA total of 343 patients received chemotherapy and 28 received immune checkpoint inhibitor monotherapy as frontline treatment. Patients who received monotherapy were more likely to be stage III at diagnosis (immune checkpoint inhibitor: 54.6% vs chemotherapy: 15.0%; p

PURPOSE: Outdoor light at night (LAN) can result in circadian disruption and hormone dysregulation and is a suspected risk factor for some cancers. Our study is the first to evaluate the association between LAN and risk of endometrial cancer, a malignancy with known relationship to circulating estrogen levels. METHODS: We linked enrollment addresses (1996) for 97,677 postmenopausal women in the prospective NIH-AARP cohort to satellite imagery of nighttime radiance to estimate LAN exposure. Multivariable Cox models estimated hazard ratios (HR) and 95% confidence intervals (95% CI) for LAN quintiles and incident endometrial cancer overall (1,669 cases) and endometrioid adenocarcinomas (991 cases) through follow-up (2011). We tested for interaction with established endometrial cancer risk factors. RESULTS: We observed no association for endometrial cancer overall (HRQ1vsQ5 0.92; 95% CI 0.78-1.08; p trend = 0.67) or endometrioid adenocarcinoma (HRQ1vsQ5 1.01; 95% CI 0.82-1.24; p trend = 0.36). Although body mass index and menopause hormone therapy were both associated with risk, there was no evidence of interaction with LAN (p interactions = 0.52 and 0.50, respectively). CONCLUSION: Our study did not find an association between outdoor LAN and endometrial cancer risk, but was limited by the inability to account for individual-level exposure determinants. Future studies should consider approaches to improve characterization of personal exposures to light.

BackgroundGermline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) cause Lynch syndrome, an autosomal dominant hereditary cancer susceptibility syndrome. The risk for endometrial cancer is significantly higher in women with MSH6 pathogenic/likely pathogenic (P/LP) variants compared with that for MLH1 or MSH2 variants.MethodsThe proband was tested via a clinical testing, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). RT-PCR was performed using patient's blood DNA and cDNA was analyzed by DNA sequencing and a cloning approach.ResultsWe report a 56-year-old female with endometrial cancer who carries a germline variant, MSH6 c.4001G > C, located at the last nucleotide of exon 9. While the pathogenicity of this variant was previously unknown, functional studies demonstrated that this variant completely abolished normal splicing and caused exon 9 skipping, which is expected to lead to a prematurely truncated or abnormal protein.ConclusionOur results indicate that this variant likely contributes to cancer predisposition through disruption of normal splicing, and is classified as likely pathogenic.

OBJECTIVE: Endometrial cancer recurrence is one of the main factors leading to increased mortality, and there is a lack of predictive models. Our study aimed to establish a nomogram predictive model to predict recurrence in endometrial cancer patients. METHOD: Screen 517 endometrial cancer patients who came to Nanjing Drum Tower Hospital from 2008 to 2018. All these data are listed as the training group, and then 70% and 60% are randomly divided into verification groups 1 and 2. Univariate, Multivariate logistic regression, stepwise regression were used to select variables for nomogram. Nomogram identification and calibration were evaluated by concordance index (c-index), area under receiver operating characteristic curve (AUC) over time and calibration plot Function. By decision curve analysis (DCA), net reclassification index (NRI), integrated discrimination improvement (IDI), we compared and quantified the net benefit of nomogram and ESMO-ESGO-ESTRO model-based prediction of tumor recurrence. RESULTS: A nomogram predictive model of endometrial cancer recurrence was established with the eight variables screened. The c-index (for the training cohort and for the validation cohort) and the time-dependent AUC showed good discriminative power of the nomogram. Calibration plots showed good agreement between nomogram predictions and actual observations in both the training and validation sets. CONCLUSIONS: We developed and validated a predictive model of endometrial cancer recurrence to assist clinicians in assessing recurrence in endometrial cancer patients.

INTRODUCTION: The expression of androgen receptor (AR) is not commonly tested or studied in uterine cancers, unlike estrogen receptor (ER) and progesterone receptor (PR) which are positive in most endometrial carcinomas. In this series, we evaluated the expression of AR and its comparison to ER and PR in different types of endometrial cancers and have reviewed the literature. MATERIALS AND METHODS: The status of AR, ER, and PR expression were evaluated in 71 cases which were categorized into endometrial endometrioid cancer (EEC), non-endometrioid endometrial cancers (NEEC), and metastatic carcinomas of endometrium. Expression of the receptors were compared to each other as well as to mismatch repair proteins (MMR), p53, and body mass index (BMI) using Fishers Exact test in the StatPlus software. RESULTS: In EECs, the positivity was 97% for all the three receptors. In NEEC, positivity rates were 68%, 48%, and 35% for AR, ER, and PR respectively. In Metastatic carcinomas, AR and ER positivity was seen in 100% while PR was positive in 75% of the cases. In all cancers, the rates were 17% (11/66) for MMR loss, 57% (30/53) for p53 aberrant expression, and 76% (54/71) for the patients with BMI of ≥ 25 (kg/m2). CONCLUSION: AR is expressed in a high percentage of endometrial cancers. Its significance is more evident in high-grade NEEC where ER and PR may not be expressed. These findings warrant further evaluation of AR expression and candidacy of this pathway as a potential therapeutic target in endometrial cancers.

PURPOSE: The status of p53 in a tumor can be inferred by next-generation sequencing (NGS) or by immunohistochemistry (IHC). We examined the association between p53 IHC and sequence and whether p53 IHC alone, or integrated with TP53 NGS, predicts the outcome. METHODS: From GOG-86P, a randomized phase II study of chemotherapy combined with either bevacizumab or temsirolimus in advanced endometrial cancer, 213 cases had p53 protein expression data measured by IHC and TP53 NGS data. An analysis was designed to integrate p53 expression by IHC with the presence or absence of a TP53 mutation. These variables were further correlated with progression-free survival (PFS) and overall survival (OS) in the chemotherapy plus bevacizumab arms versus the chemotherapy plus temsirolimus arm. RESULTS: In the analysis of p53 IHC, the most striking treatment effect favoring bevacizumab was in cases where p53 was overexpressed (PFS hazard ratio [HR]: 0.46, 95% CI, 0.26 to 0.88; OS HR: 0.31, 95% CI, 0.16 to 0.62). On integrated analysis, patients with TP53 missense mutations and p53 protein overexpression had a similar treatment effect on PFS (HR: 0.41, 95% CI, 0.22 to 0.83) and OS (HR: 0.28, 95% CI, 0.14 to 0.59) favoring bevacizumab plus chemotherapy relative to temsirolimus plus chemotherapy. Concordance between TP53 NGS and p53 IHC was 88%. Concordance was 92% when cases with TP53 mutations and POLE mutations or mismatch repair deficiency were removed. CONCLUSION: IHC for p53 alone or when integrated with sequencing for TP53 identifies a specific, high-risk tumor genotype/phenotype for which bevacizumab is particularly beneficial in improving outcomes when combined with chemotherapy.

ObjectiveAs healthcare expenditures continue to rise, identifying mechanisms to reduce unnecessary costs is critical. The objective of this study is to estimate the annual cost of wasted indocyanine green (ICG) used for sentinel lymph node mapping in patients with endometrial cancer.MethodsUsing the Surveillance, Epidemiology, and End Results program database and Premier database, we determined the annual number of cases in which sentinel lymph node mapping with ICG would be used and the median cost of ICG to institutions and patients, respectively. We assumed that gynecologic oncologists use 2-4 mL (20-40%) of the currently available ICG vial kit (25 mg per 10 mL) per case. Estimated waste was then calculated using cost as a measure of institutional waste and charge as excess cost transferred to patients or payers.ResultsAn estimated 45,864 cases of localized endometrial cancer were identified and eligible for sentinel lymph node (SLN) mapping. The mean total cost associated with ICG was 99.20 and the mean charge was $483.64. The estimated excess annual cost to hospitals was $2,729,825 to $3,639,767. Similarly, using mean charge data, the annual cost of wasted drug for patients and payers was $13,308,999 to $17,745,332.ConclusionsThe annual cost of wasted ICG due to its current manufactured vial size exceeds $2 million for hospitals and $13.3-$17.7 million for patients. We suggest ICG vials should be packaged in a 10 mg vial kit (2-4 mL sterile solution) to avoid drug waste and the financial impact to institutions and patients.

BackgroundMechanisms underlying the adiposity-cancer relationship are incompletely understood. We quantified the mediating roles of C-reactive protein (CRP), leptin, fasting insulin, and estradiol in the effect of adiposity on estrogen receptor (ER)-positive breast, endometrial, and colorectal cancer risk in postmenopausal women.MethodsWe used a case-cohort study within the Women's Health Initiative Observational Study, analyzed as a cumulative sampling case-control study. The study included 188 breast cancer cases, 98 endometrial cancer cases, 193 colorectal cancer cases, and 285 controls. Interventional indirect and direct effects on the risk ratio (RR) scale were estimated using causal mediation analysis.ResultsFor breast cancer, the total effect RR for BMI ≥30 versus ≥18.5-

IntroductionChemotherapy plus radiation (Cis-RT + CP) did not demonstrate superiority in prolonging relapse-free survival compared to chemotherapy alone in patients with stage III or IVA endometrial carcinoma. The impact of treatment on quality of life (QOL), neurotoxicity (NTX) and psychometric properties of the gastrointestinal (GI) symptoms subscale during treatment and up to 1 year are described herein.MethodsQOL assessments were scheduled at baseline, 6 weeks (post completion of RT (Cis-RT + CP) or prior to cycle 3 (CP)), then 18 weeks (end of treatment) and 70 weeks (1 year after the end of treatment) after starting treatment. QOL instruments included the FACT-En TOI, FACT/GOG-neurotoxicity (Ntx) subscale (short), and the gastrointestinal (GI) symptoms subscale.ResultsAt the end of treatment, patients receiving Cis-RT + CP reported a statistically significant decreased QOL when compared to CP. The decline in QOL was reflected in physical well-being, functional well-being, and endometrial cancer specific concerns, but the minimally important differences (MID) were not considered clinically meaningful. Patients in both groups reported increased chemotherapy-induced Ntx symptoms with the CP group having worse scores and reaching peak symptoms at the time of chemotherapy completion. Patients on Cis-RT + CP reported statistically significantly worse GI symptoms after radiation therapy compared to patients on CP, this occurred across assessment intervals, though the MID was not meaningful. Psychometric evaluations indicated that the GI symptom scale is reliable, valid, and responsive to change.ConclusionsPROs indicate that the chemoradiotherapy group experienced worse HRQoL and GI toxicity compared to patients randomized to chemotherapy alone for locally advanced endometrial cancer though based on the MID, these were not clinically meaningful differences. The GI symptom subscale was a reliable and valid scale that has value for future trials.Trial registrationNCT00942357.

Tumor-infiltrating B cells can play an important role in anti-tumor responses but their presence is not well understood. In this study, we extracted the B cell receptor repertoires from 9522 tumor and adjacent non-tumor samples across 28 tumor types in the Cancer Genome Atlas project and performed diversity and network analysis. We identified differences in diversity and network statistics across tumor types and subtypes and observed a trend towards increased clonality in primary tumors compared to adjacent non-tumor tissues. We also found significant associations between the repertoire features and mutation load, tumor stage, and age. Our V-gene usage analysis identified similar V-gene usage patterns in colorectal and endometrial cancers. Lastly, we evaluated the prognostic value of the repertoire features and identified significant associations with survival in seven tumor types. This study warrants further research into better understanding the role of tumor-infiltrating B cells across a wide range of tumor types.

BackgroundPostmenopausal pregnenolone and/or progesterone levels in relation to endometrial and ovarian cancer risks have been infrequently evaluated. To address this, we utilized a sensitive and reliable assay to quantify prediagnostic levels of seven markers related to endogenous hormone metabolism.MethodsHormones were quantified in baseline serum collected from postmenopausal women in a cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT). Women using exogenous hormones at baseline (1992-1993) were excluded. Incident endometrial (n = 65) and ovarian (n = 67) cancers were diagnosed during 12 follow-up years and compared with a subcohort of 345 women (no hysterectomy) and 413 women (no oophorectomy), respectively. Cox models with robust variance were used to estimate cancer risk.ResultsCirculating progesterone levels were not associated with endometrial [tertile (T)3 vs. T1 HR (95% confidence interval): 1.87 (0.85-4.11); P trend = 0.17] or ovarian cancer risk [1.16 (0.58-2.33); 0.73]. Increasing levels of the progesterone-to-estradiol ratio were inversely associated with endometrial cancer risk [T3 vs. T1: 0.29 (0.09-0.95); 0.03]. Increasing levels of 17-hydroxypregnenolone were inversely associated with endometrial cancer risk [0.40 (0.18-0.91); 0.03] and positively associated with ovarian cancer risk [3.11 (1.39-6.93); 0.01].ConclusionsUsing sensitive and reliable assays, this study provides novel data that endogenous progesterone levels are not strongly associated with incident endometrial or ovarian cancer risks. 17-hydroxypregnenolone was positively associated with ovarian cancer and inversely associated with endometrial cancer.ImpactWhile our results require replication in large studies, they provide further support of the hormonal etiology of endometrial and ovarian cancers.

BackgroundThe aim of this study was to determine how Stathmin-1 and Heat Shock Protein 27 (HSP27) can be used as adjunctive biomarkers to differentiate high-grade dysplasia from benign/reactive lesions in cervical tissues. In addition, we aimed to see if any of these markers can differentiate endometrial from endocervical adenocarcinomas.MethodsFifty cases including benign cervical tissue, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), adenocarcinoma in situ of the endocervix, invasive endocervical adenocarcinoma, and endometrial adenocarcinoma were selected. Stathmin-1 and HSP27 immunohistochemistry (IHC) were performed for each case and the results were compared to the previously available p16 IHC stains.Resultsp16 stained positively in 100% of HSIL, endocervical adenocarcinoma in situ, and invasive endocervical cases. Stathmin-1 stained positively in 43% of HSIL and 90% of endocervical adenocarcinoma in situ and all invasive endocervical cases. Stathmin-1 and p16 were negative in all benign cervical samples. Stathmin-1, HSP27, and p16 stained 100% of LSIL cases. HSP27 stained indiscriminately, including 100% of benign cervical tissue. 87% of the endometrial adenocarcinomas stained positively for p16, Stathmin-1, and HSP27.Conclusionp16 remains superior to both Stathmin-1 and HSP27 in differentiating dysplasia from benign, reactive changes of the cervix.

BackgroundAdherence to National Comprehensive Cancer Network guidelines have been adopted as the standard of care for various cancers and have been cited to have survival benefits. Few studies have examined the association of adherent treatment and endometrial cancer survival among various racial/ethnic groups and socioeconomic statuses.MethodsBetween January 1, 2006 and December 31, 2015, 83,673 women diagnosed with endometrial carcinomas were identified from the Surveillance, Epidemiology, and End Results database. Descriptive statistics of demographic and clinical characteristics were performed. Cox-proportional hazards models were used to examine the effect on cause-specific survival for adherence to guidelines across racial/ethnic and socioeconomic groups.ResultsWithin our sample, 59.5% were treated according to guidelines. Nonadherence to treatment guidelines was significantly associated with decreased survival compared with adherent care (adjusted hazard ratio [HR], 1.59; 95% CI, 1.52-1.67). Being of Black (adjusted HR, 1.41; 95% CI, 1.32-1.51) or Native Hawaiian/Pacific Islander (adjusted HR, 1.44; 95% CI, 1.19-1.73) race/ethnicity compared with White women was significantly associated with worse survival. Being of Asian race/ethnicity (adjusted HR, 0.86, 95% CI, 0.78-0.94) was significantly associated with improved survival compared with White women. Lower neighborhood socioeconomic status was associated with a negative effect on survival relative to women in the highest socioeconomic status category.ConclusionsFindings from this study suggest treatment adherence is an independent predictor of improved survival; however, improved survival was not observed equally among all racial/ethnic and socioeconomic status groups.Lay summaryThe National Comprehensive Cancer Network (NCCN) has developed guidelines for physicians to follow in treating various cancers. Within this study of 83,673 women with endometrial cancer, 59.5% of women were treated according to the NCCN guidelines. The findings suggest following NCCN guidelines for treatment of endometrial cancer improves survival. Black or Native Hawaiian/Pacific Islander race and lower neighborhood socioeconomic status has worse survival rates compared with other groups, indicating the importance of exploring other factors that may shape treatment across racial/ethnic and socioeconomic status groups.

ObjectiveTo evaluate the association of race-ethnicity and neighborhood socioeconomic status with adherence to National Comprehensive Cancer Network guidelines for endometrial carcinoma.MethodsData are from the SEER (Surveillance, Epidemiology, and End Results) cancer registry of women diagnosed with endometrial carcinoma for the years 2006-2015. The sample included 83,883 women after inclusion and exclusion criteria were applied. Descriptive statistics, bivariate analyses, univariate, and multivariate logistic regression models were performed to evaluate the association between race-ethnicity and neighborhood socioeconomic status with adherence to treatment guidelines.ResultsAfter controlling for demographic and clinical covariates, Black (odds ratio [OR] 0.89, P

BackgroundSuccessfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P.MethodsTP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P.ResultsMutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53.ConclusionsThis exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574.

BACKGROUND: Cardiometabolic abnormalities are a leading cause of death among women, including women with cancer. METHODS: This study examined the association between prediagnosis cardiovascular health and total and cause-specific mortality among 12,076 postmenopausal women who developed local- or regional-stage invasive cancer in the Womens Health Initiative (WHI). Cardiovascular risk factors included waist circumference, hypertension, high cholesterol, and type 2 diabetes. Obesity-related cancers included breast cancer, colorectal cancer, endometrial cancer, kidney cancer, pancreatic cancer, ovarian cancer, stomach cancer, liver cancer, and non-Hodgkin lymphoma. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for important predictors of survival. RESULTS: After a median follow-up of 10.0 years from the date of the cancer diagnosis, there were 3607 total deaths, with 1546 (43%) due to cancer. Most participants (62.9%) had 1 or 2 cardiometabolic risk factors, and 8.1% had 3 or 4. In adjusted models, women with 3 to 4 risk factors (vs none) had a higher risk of all-cause mortality (HR, 1.99; 95% CI, 1.73-2.30), death due to cardiovascular disease (CVD) (HR, 4.01; 95% CI, 2.88-5.57), cancer-specific mortality (HR, 1.37; 95% CI, 1.1-1.72), and other-cause mortality (HR, 2.14; 95% CI, 1.70-2.69). A higher waist circumference was associated with greater all-cause mortality (HR, 1.17; 95% CI, 1.06-1.30) and cancer-specific mortality (HR, 1.22; 95% CI, 1.04-1.42). CONCLUSIONS: Among postmenopausal women diagnosed with cancer in the WHI, cardiometabolic risk factors before the cancer diagnosis were associated with greater all-cause, CVD, cancer-specific, and other-cause mortality. These results raise hypotheses regarding potential clinical intervention strategies targeting cardiometabolic abnormalities that require future prospective studies for confirmation. LAY SUMMARY: This study uses information from the Womens Health Initiative (WHI) to find out whether cardiac risk factors are related to a greater risk of dying among older women with cancer. The WHI is the largest study of medical problems faced by older women in this country. The results show that women who have 3 or 4 risk factors are more likely to die of any cause, heart disease, or cancer in comparison with women with no risk factors. It is concluded that interventions to help to lower the burden of cardiac risk factors can have an important impact on survivorship among women with cancer.

BackgroundAccumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.MethodsUsing LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.ResultsGenetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (P Bonferroni < 2.4 × 10-9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.ConclusionsUsing cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.ImpactOur research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

Along with early-onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; however, the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown. We screened 71 patients with MPC of the stomach, colorectal, and endometrium, sequencing 65 cancer predisposition genes. A subset of 19 patients with early-onset MPC of stomach and colorectum were further evaluated for variants in cancer related genes using both normal and tumor whole exome sequencing. Among 71 patients with MPCs, variants classified to be pathogenic were observed in 15 (21.1%) patients and affected Lynch Syndrome (LS) genes: MLH1 (n = 10), MSH6 (n = 2), PMS2 (n = 2), and MSH2 (n = 1). All carriers had tumors with high microsatellite instability and 13 of them (86.7%) were early-onset, consistent with LS. In 19 patients with early-onset MPCs, loss of function (LoF) variants in RECQL5 were more prevalent in non-LS MPC than in matched sporadic cancer patients (OR = 31.6, 2.73-1700.6, p = 0.001). Additionally, there were high-confidence LoF variants at FANCG and CASP8 in two patients accompanied by somatic loss of heterozygosity in tumor, respectively. The results suggest that genetic screening should be considered for synchronous cancers and metachronous MPCs of the LS tumor spectrum, particularly in early-onset. Susceptibility variants in non-LS genes for MPC patients may exist, but evidence for their role is more elusive than for LS patients.

ObjectiveLynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV.Methods341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13-12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified.ResultsTwenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total).ConclusionsSince double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.

In type 1 endometrial cancer, unopposed estrogen stimulation is thought to lead to endometrial hyperplasia which precedes malignant progression. Recent data from our group and others suggest that ALDH activity mediates stemness in endometrial cancer, but while aldehyde dehydrogenase 1 (ALDH1) has been suggested as a putative cancer stem cell marker in several cancer types, its clinical and prognostic value in endometrial cancer remains debated. The aim of this study was to investigate the clinical value of ALDH1 expression in endometrial hyperplasia and to determine its ability to predict progression to endometrial cancer. Interrogation of the TCGA database revealed upregulation of several isoforms in endometrial cancer, of which the ALDH1 isoforms collectively constituted the largest group. To translate its expression, a tissue microarray was previously constructed which contained a wide sampling of benign and malignant endometrial samples. The array contained a metachronous cohort of samples from individuals who either developed or did not develop endometrial cancer. Immunohistochemical staining was used to determine the intensity and frequency of ALDH1 expression. While benign proliferative and secretory endometrium showed very low levels of ALDH1, slightly higher expression was observed within the stratum basalis. In disease progression, cytoplasmic ALDH1 expression showed a step-wise increase between endometrial hyperplasia, atypical hyperplasia, and endometrial cancer. ALDH1 was also shown to be an early predictor of EC development, suggesting that it can serve as an independent prognostic indicator of patients with endometrial hyperplasia with or without atypia who would progress to cancer (p = 0.012).

PurposeLimitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling. The Gynecologic Oncology Group studied carboplatin plus paclitaxel (TC) as a noninferior alternative to TAP.MethodsGOG0209 was a phase III, randomized, noninferiority, open-label trial. Inclusion criteria were stage III, stage IV, and recurrent endometrial cancers; performance status 0-2; and adequate renal, hepatic, and marrow function. Prior radiotherapy and/or hormonal therapy were permitted, but chemotherapy, including radiosensitization, was not. Patients were treated with doxorubicin 45 mg/m2 and cisplatin 50 mg/m2 (day 1), followed by paclitaxel 160 mg/m2 (day 2) with granulocyte colony-stimulating factor or paclitaxel 175 mg/m2 and carboplatin area under the curve 6 (day 1) every 21 days for seven cycles. The primary endpoint was overall survival (OS; modified intention to treat). Progression-free survival (PFS), health-related quality of life (HRQoL), and toxicity were secondary endpoints.ResultsFrom 2003 to 2009, 1,381 women were enrolled. Noninferiority of TC to TAP was concluded for OS (median, 37 v 41 months, respectively; hazard ratio [HR], 1.002; 90% CI, 0.9 to 1.12), and PFS (median, 13 v 14 months; HR, 1.032; 90% CI, 0.93 to 1.15). Neutropenic fever was reported in 7% of patients receiving TAP and 6% of those receiving TC. Grade > 2 sensory neuropathy was recorded in 26% of patients receiving TAP and 20% receiving TC (P = .40). More grade ≥ 3 thrombocytopenia (23% v 12%), vomiting (7% v 4%), diarrhea (6% v 2%), and metabolic (14% v 8%) toxicities were reported with TAP. Neutropenia (52% v 80%) was more common with TC. Small HRQoL differences favored TC.ConclusionWith demonstrated noninferiority to TAP, TC is the global first-line standard for advanced endometrial cancer.

PurposeHealth-related quality of life (HRQOL) is an important prognostic factor in cancer patients. To date, no other studies have assessed the association between HRQOL measured before diagnosis and survival in older women with endometrial cancer.MethodsThe Surveillance, Epidemiology, and End Results - Medicare Health Outcomes Survey linked database was used to identify 995 women who were at least 65 years old and completed a survey before diagnosis with endometrial cancer. We obtained scores for 10 HRQOL scales, as measured by Medical Outcomes Study Short Form-36 and Veterans RAND 12-Item Survey, and data on activities of daily living (ADLs) impairments and depressive symptoms. Fine and Gray competing risks regression and Cox proportional hazards were used to estimate the association of HRQOL with endometrial cancer-specific and overall survival, respectively.ResultsWomen who died had worse pre-diagnosis HRQOL than women who were still alive at the end of the study period. For every five-point increase in HRQOL score, overall survival improved by 5-9%. The strongest associations were observed for vitality (HR = 0.91, 95% CI 0.86, 0.97, p = 0.0021) and physical functioning (HR = 0.92, 95% CI 0.87, 0.97, p = 0.0010). ADL impairments were generally not predictive of survival, though depressive symptoms were significantly associated with increased hazard of death from all causes (HR = 1.34, 95% CI 1.00, 1.79, p = 0.0466).ConclusionHRQOL measured before diagnosis with endometrial cancer has prognostic value. Having measures of HRQOL available at diagnosis may facilitate timely supportive care to improve survival.

Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) constitute a mammalian STE20-like serine/threonine kinase subfamily. Recent studies provide substantial evidence for MAP4K family kinases in the Hippo pathway regulation, suggesting a broad role of MAP4Ks in human physiology and diseases. However, a comprehensive analysis of the regulators and effectors for this key kinase family has not been fully achieved. Using a proteomic approach, we define the protein-protein interaction network for human MAP4K family kinases and reveal diverse cellular signaling events involving this important kinase family. Through it, we identify a STRIPAK complex component, STRN4, as a generic binding partner for MAP4Ks and a key regulator of the Hippo pathway in endometrial cancer development. Taken together, the results of our study not only generate a rich resource for further characterizing human MAP4K family kinases in numerous biological processes but also dissect the STRIPAK-mediated regulation of MAP4Ks in the Hippo pathway.

ObjectiveTo examine outcomes in a modern treatment era for stage III uterine serous carcinoma (USC).MethodsFifty women were retrospectively identified as 2009 International Federation of Gynecology and Obstetrics stage III USC patients who received radiotherapy (RT) at our institution between 1/2003-5/2018. The patients were divided into 2 cohorts: 20 in the early era (2003-2010) and 30 in the modern era (2011-2018). Patient characteristics were compared using χ² tests for categorical variables and t-tests for continuous variables. Recurrence free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards.ResultsThe modern era differed from the early era in the increased use of volume-directed external beam RT (EBRT) as opposed to vaginal brachytherapy (VB) alone (33.3% vs 5.0%, p=0.048), minimally invasive surgery (56.7% vs. 25%, p=0.027), sentinel node sampling (26.7% vs. 0%, p=0.012), computed tomography imaging in the perioperative period (63.3% vs. 30%, p=0.044), and human epidermal growth factor receptor 2/neu testing (96.7% vs. 55%, p=0.001). Median follow-up for early and modern eras was 37.27 and 33.23 months, respectively. The early vs. modern 3-year RFS was 33% and 64% (p=0.039), respectively, while the 3-year OS was 55% and 90% (p=0.034). Regional nodal recurrence more common among the patients who received VB only (p=0.048).ConclusionModern era treatment was associated with improved RFS and OS in patients with stage III USC. Regional nodal recurrences were significantly reduced in patients who received EBRT.

BackgroundAdjuvant tamoxifen reduces the risk of breast cancer recurrence in women with oestrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer.ObjectivesTo determine the effectiveness and safety of the levonorgestrel intrauterine system (LNG-IUS) in pre- and postmenopausal women taking adjuvant tamoxifen following breast cancer for the outcomes of endometrial and uterine pathology including abnormal vaginal bleeding or spotting, and secondary breast cancer events.Search methodsWe searched the following databases on 29 June 2020; The Cochrane Gynaecology and Fertility Group specialised register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO and Cumulative Index to Nursing and Allied Health Literature. We searched the Cochrane Breast Cancer Group specialised register on 4 March 2020. We also searched two trials registers, checked references for relevant trials and contacted study authors and experts in the field to identify additional studies.Selection criteriaWe included randomised controlled trials (RCTs) of women with breast cancer on adjuvant tamoxifen that compared the effectiveness of the LNG-IUS with endometrial surveillance versus endometrial surveillance alone on the incidence of endometrial pathology.Data collection and analysisWe used standard methodological procedures recommended by Cochrane. The primary outcome measure was endometrial pathology (including polyps, endometrial hyperplasia, or endometrial cancer), diagnosed at hysteroscopy or endometrial biopsy. Secondary outcome measures included fibroids, abnormal vaginal bleeding or spotting, breast cancer recurrence, and breast cancer-related deaths. We rated the overall certainty of evidence using GRADE methods.Main resultsWe included four RCTs (543 women analysed) in this review. We judged the certainty of the evidence to be moderate for all of the outcomes, due to imprecision (i.e. limited sample sizes and low event rates). In the included studies, the active treatment arm was the 20 μg/day LNG-IUS plus endometrial surveillance; the control arm was endometrial surveillance alone. In tamoxifen users, the LNG-IUS probably reduces the incidence of endometrial polyps compared to the control group over both a 12-month period (Peto odds ratio (OR) 0.22, 95% confidence interval (CI) 0.08 to 0.64, I² = 0%; 2 RCTs, n = 212; moderate-certainty evidence) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). For long-term follow-up, this suggests that if the incidence of endometrial polyps following endometrial surveillance alone is assumed to be 23.5%, the incidence following LNG-IUS with endometrial surveillance would be between 3.8% and 10.7%.  The LNG-IUS probably slightly reduces the incidence of endometrial hyperplasia compared with controls over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). This suggests that if the chance of endometrial hyperplasia following endometrial surveillance alone is assumed to be 2.8%, the chance following LNG-IUS with endometrial surveillance would be between 0.1% and 1.9%. However, it should be noted that there were only six cases of endometrial hyperplasia. There was insufficient evidence to reach a conclusion regarding the incidence of endometrial cancer in tamoxifen users, as no studies reported cases of endometrial cancer. At 12 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting compared to the control group (Peto OR 7.26, 95% CI 3.37 to 15.66; I² = 0%; 3 RCTs, n = 376; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 1.7%, the chance following LNG-IUS with endometrial surveillance would be between 5.6% and 21.5%. By 24 months of follow-up, abnormal vaginal bleeding or spotting occurs less frequently than at 12 months of follow-up, but is still more common in the LNG-IUS group than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10; I² = 0%; 2 RCTs, n = 233; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 4.2%, the chance following LNG-IUS with endometrial surveillance would be between 4.4% and 23.9%. By 60 months of follow-up, there were no cases of abnormal vaginal bleeding or spotting in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). As a result, there is probably little or no difference in these outcomes between the LNG-IUS treatment group and the control group.  AUTHORS' CONCLUSIONS: The LNG-IUS probably slightly reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. Data were lacking on whether the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available RCTs that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events.

BackgroundIn recent years, sentinel lymph node excision and ultrastaging have been performed in endometrial carcinomas to obtain information about lymph node status, avoiding unnecessary complete pelvic and paraaortic lymphadenectomy. The purpose of this retrospective study was to provide a comprehensive evaluation of the pathological features of endometrial carcinomas and their significance in association with sentinel lymph node involvement.MethodsPatients with endometrial carcinomas, preceded by sentinel lymph node mapping, were classified into Group-I and Group-II with negative and positive involvement, respectively. The pathological features, associated with sentinel lymph node involvement, were statistically analyzed, including determination of test performance parameters.ResultsAmong 70 patients who had undergone hysterectomy and sentinel lymph node excision, 61 had carcinoma and 9 had atypical hyperplasia. There were 50 patients in Group-I and 10 in Group-II. In Group-II, the significant pathological features were: 1) lower uterine segment involvement (100%), 2) an average tumor size of ≥5 CM, 3) lymphovascular invasion (50%), 4) cervical stromal invasion (40%), and 5) depth of myometrial invasion of ≥50% (50%). The incidences of these pathological features were significantly less in Group-I. Statistical analyses singled out "lower uterine segment involvement" as the most important feature.ConclusionsWe have identified five pathological features which are associated with sentinel lymph node involvement. Since lower uterine segment involvement has occurred in all cases of the Group-II cohort, we recommend FIGO and other organizations that determine staging rules should consider whether tumors that involve the lower uterine segment should be staged as higher than "1a", if the findings in this small series are confirmed by other studies. The results of this study may guide pathologists and oncologists in the diagnostic and therapeutic approaches to management of endometrial carcinomas.

PurposeMenopausal hormone therapy (MHT) use induces alterations in circulating estrogens/estrogen metabolites, which may contribute to the altered risk of reproductive tract cancers among current users. Thus, the current study assessed associations between circulating estrogens/estrogen metabolites and ovarian and endometrial cancer risk among MHT users.MethodsWe conducted a nested case-control study among postmenopausal women using MHT at baseline in the Women's Health Initiative Observational Study (179 ovarian cancers, 396 controls; 230 endometrial cancers, 253 controls). Multivariable logistic regression was utilized to estimate odds ratios and 95% confidence intervals overall and by subtype.ResultsEstrogen/estrogen metabolite levels were not associated with overall or serous ovarian cancer risk, examined separately. However, unconjugated estradiol was positively associated with non-serous ovarian cancer risk [quintile 5 vs. quintile 1: 3.01 (1.17-7.73); p-trend = 0.03; p-het

OBJECTIVES:To assess whether comprehensive genomic profiling (CGP) in the setting of routine clinical care allows molecular classification of recurrent endometrial cancer (EC) into the four Cancer Genome Atlas (TCGA) categories: POLE ultramutated, microsatellite instable, copy-number low, and copy-number high and whether this approach can identify genomic alterations (GAs) which inform treatment decisions. METHODS:Archival tissues from 74 patients diagnosed with recurrent EC were prospectively analyzed using hybrid-capture-based genomic profiling. Tumor mutational burden and microsatellite instability were measured. Clinically relevant GAs (CRGAs) were defined as GAs associated with targeted therapies available on-label or in mechanism-driven clinical trials. RESULTS:Using POLE mutational analysis, mismatch repair status, and p53 mutational analysis as surrogate for 'copy-number' status CGP segregated all cases into four TCGA molecular subgroups. While recurrent serous ECs were predominantly copy-number high, we found no clear prevalence of a specific molecular subtype in endometrioid, clear cell or undifferentiated tumors. Every tumor sample had at least one GA and 91% (67/74) had at least one CRGA. In this series 32% (24/74) of patients received a matched therapy based on the results of CGP. Objective responses to the matched therapy were seen in 25% (6/24) of patients with an additional 37.5% (9/24) achieving stable disease leading to a clinical benefit rate of 62.5% with a median treatment duration of 14.6 months (range 4.3-69 months). CONCLUSIONS:CGP allows molecular classification of EC into four TCGA categories and allows identification of potential biomarkers for matched therapy in the setting of routine clinical care.

ObjectiveWomen with endometrial or cervical cancer at risk for recurrence receive postoperative radiation therapy (RT). A patient reported outcomes (PRO) instrument to assess bowel and urinary toxicities is the Expanded Prostate Cancer Index Composite (EPIC), which has been validated in men with prostate cancer. As this instrument specifically measures bowel toxicity and the degree to which this is a problem, it was used in NRG Oncology/RTOG 1203 to compare intensity modulated RT (IMRT) to standard RT. This paper reports on the expanded validation of EPIC for use in women receiving pelvic RT.MethodsIn addition to the EPIC bowel domain, urinary toxicity (EPIC urinary domain), patient reported bowel toxicities (PRO-CTCAE) and quality of life (Functional Assessment of Cancer Therapy (FACT)) were completed before, during and after treatment. Sensitivity, reliability and concurrent validity were assessed.ResultsMean bowel and urinary scores among 278 women enrolled were significantly worse during treatment and differed between groups. Acceptable to good reliability for bowel and urinary domain scores were obtained at all time points with the exception of one at baseline. Correlations between function and bother scores within the bowel and urinary domains were consistently stronger than those across domains. Correlations between bowel domain scores and PRO-CTCAE during treatment were stronger than those with the FACT.ConclusionCorrelations within and among the instruments indicate EPIC bowel and urinary domains are measuring conceptually discrete components of health. These EPIC domains are valid, reliable and sensitive instruments to measure PRO among women undergoing pelvic radiation.

BACKGROUND: Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence. METHODS: In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life. RESULTS: Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group. CONCLUSIONS: Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.).

ObjectivesThe ability to stratify a patient's risk of metastasis and survival permits more refined care. A proof of principle study was undertaken to investigate the relationship between single nucleotide polymorphisms (SNPs) in literature based candidate cancer genes and the risk of nodal metastasis and clinical outcome in endometrioid endometrial cancer (EEC) patients.MethodsSurgically-staged EEC patients from the Gynecologic Oncology Group or Washington University School of Medicine with germline DNA available were eligible. Fifty-four genes represented by 384 SNPs, were evaluated by Illumina Custom GoldenGate array. Association with lymph node metastases was the primary outcome. Progression-free survival (PFS) and overall survival (OS) was also evaluated.Results361 SNPs with high quality genotype data were evaluated in 337 patients with outcome data. Five SNPs in CXCR2 had an odds ratio (OR) between 0.68 and 0.70 (p-value ≤ 0.025). The A allele rs946486 in ABL had an OR of 1.5 (p-value = 0.01) for metastasis. The G allele in rs7795743 in EGFR had an OR for metastasis of 0.68 (p-value = 0.02) and hazard ratio (HR) for progression of 0.66 (p-value = 0.004). Importantly, no SNP met genome wide significance after adjusting for multiple test correcting and clinical covariates. The A allele in rs2159359 SNP in NME1 and the G allele in rs13222385 in EGFR were associated with worse OS. Both exhibited genome wide significance; rs13222385 remained significant after adjusting for prognostic clinical variables.ConclusionSNPs in cancer genes including rs2159359 SNP in NME1 and rs13222385 in EGFR may stratify risk in EEC and are prioritized for further investigation.

BackgroundObesity is a strong risk factor for endometrial cancer, but it is unclear whether metabolic syndrome (MetS) contributes to endometrial cancer risk over and above the contribution of obesity.MethodsWe examined the association of MetS and its components with risk of endometrial cancer in a sub-cohort of 24,210 women enrolled in the Women's Health Initiative cohort study. Two variants of the National Cholesterol Education Program Adult Treatment Panel III definition of the MetS were used: one including and one excluding waist circumference (WC). Cox proportional hazards models were used to estimate the association of the study exposures with disease risk.ResultsWhen WC was included in the definition, MetS showed an approximately two-fold increase in endometrial cancer risk (HR 2.20; 95% CI 1.61-3.02); however, when WC was excluded, MetS was no longer associated with risk. We also observed that women with hyperglycemia, dyslipidemia and hypertension, in combination, had almost a twofold increased risk of endometrial cancer, independent of WC (HR 1.94; 95% CI 1.09, 3.46). Glucose, and, in particular, WC and body mass index were also positively associated with risk.ConclusionsOur findings suggest that MetS may predict risk of endometrial cancer independent of obesity among women with the remaining four Mets components.

Lifestyle-related factors influence risk of endometrial and ovarian cancers, but few studies have examined their joint associations with risk of these cancers. Using multivariable Cox regression models, we assessed the association of a healthy lifestyle index (HLI-a composite score (range, 0-20) involving diet, alcohol consumption, physical activity, body mass index, and smoking; higher scores represent healthier behavior) with risk of endometrial and ovarian cancers among 108,136 postmenopausal women who were recruited in the US Women's Health Initiative study between 1993 and 1998. After a median follow-up of 17.9 years, 1,435 endometrial cancer cases and 904 ovarian cancer cases had been ascertained. Women in the highest quintile of the HLI score had a lower risk of overall, type I, well-differentiated, moderately differentiated, poorly differentiated, and localized endometrial cancer than those in the lowest quintile (for quintile 5 vs. quintile 1, hazard ratio (HR) = 0.61 (95% CI: 0.51, 0.72), HR = 0.60 (95% CI: 0.49, 0.72), HR = 0.66 (95% CI: 0.46, 0.96), HR = 0.69 (95% CI: 0.52, 0.90), HR = 0.49 (95% CI: 0.34, 0.72), and HR = 0.61 (95% CI: 0.50, 0.74), respectively). The HLI score had a weak positive association with risk of serous ovarian cancer. Our findings underscore the potential importance of a healthy lifestyle in lowering endometrial cancer risk among postmenopausal women.

In this study, we aimed to identify mutations of key genes associated with docetaxel resistance in nine endometrial cancer cell lines. Endometrial cancers are associated with several critical gene mutations, including PIK3A, PTEN, and KRAS. Different gene mutations in endometrial cancer cells have varied responses to anticancer drugs and cancer therapies. The most frequently altered gene in endometrioid endometrial carcinoma tumors is PTEN. PTEN protein has lipid phosphatase and protein phosphatase activity, as well as other functions in the nucleus. Although the tumor-suppressive function of PTEN has mainly been attributed to its lipid phosphatase activity, a role for PTEN protein phosphatase activity in cell cycle regulation has also been suggested. Various tumor type-specific PTEN mutations are well documented. Here, nine endometrioid endometrial cancer cell lines with PIK3A, PTEN, and KRAS gene mutations were treated with docetaxel and radiation. One mutation with a docetaxel drug-resistant effect was a truncated form of PTEN. Among PTEN mutations in endometrial cancer cells, the Y68 frame shift mutation of PTEN constitutes a major mechanism of resistance to docetaxel treatment. The molecular mechanism involves truncation of the 403 amino acid PTEN protein at amino acid 68 by the Y68 frame shift, leading to the loss of PTEN protein phosphatase and lipid phosphatase activities.

OBJECTIVE: To assess the rates and distribution of first recurrence in patients with FIGO stage IIIC1 endometrial cancer (EC) who did not undergo paraaortic dissection at surgical staging. METHODS: We retrospectively selected all (n = 207) stage IIIC1 patients treated at a single institution from 5/1993-1/2017. Sites of first recurrence were identified, disease-free (DFS) and overall survival (OS) calculated, multivariate logistic regression performed to identify factors associated with recurrence. RESULTS: Three-year DFS and OS were 66.5% and 85.7%, respectively. The most common histology was endometroid (64.2%). Three-year DFS was 81% (SE±3.8%) endometrioid vs. 39.5% (SE±6.6%) non-endometrioid (P

Despite advances in surgical technique and adjuvant treatment, endometrial cancer has recently seen an increase in incidence and mortality in the USA. The majority of endometrial cancers can be cured by surgery alone or in combination with adjuvant chemo- or radiotherapy; however, a subset of patients experience recurrence for reasons that remain unclear. Recurrence is associated with chemoresistance to carboplatin and paclitaxel and consequentially, high mortality. Understanding the pathways involved in endometrial cancer chemoresistance is paramount for the identification of biomarkers and novel molecular targets for this disease. Here, we generated the first matched pairs of carboplatin-sensitive/carboplatin-resistant and paclitaxel-sensitive/paclitaxel-resistant endometrial cancer cells and subjected them to bulk RNA sequencing analysis. We found that 45 genes are commonly upregulated in carboplatin- and paclitaxel-resistant cells as compared to controls. Of these, the leukemia inhibitory factor, (LIF), the protein tyrosine phosphatase type IVA, member 3 (PTP4A3), and the transforming growth factor beta 1 (TGFB1) showed a highly significant correlation between expression level and endometrial cancer overall survival (OS) and can stratify the 545 endometrial cancer patients in the TCGA cohort into a high-risk and low-risk-cohorts. Additionally, four genes within the 45 upregulated chemoresistance-associated genes are ADAMTS5, MICAL2, STAT5A, and PTP4A3 codes for proteins for which small-molecule inhibitors already exist. We identified these proteins as molecular targets for chemoresistant endometrial cancer and showed that treatment with their correspondent inhibitors effectively killed otherwise chemoresistant cells. Collectively, these findings underline the utility of matched pair of chemosensitive and chemoresistant cancer cells to identify markers for endometrial cancer risk stratification and to serve as a pharmacogenomics model for identification of alternative chemotherapy approaches for treatment of patients with recurrent disease.

Although the majority of low-grade, early-stage endometrial cancer patients have good survival with surgery alone, patients who recur tend to do poorly. Identification of patients at high risk of recurrence who would benefit from adjuvant treatment or more extensive surgical staging would help optimize individualized care of endometrial cancer patients. CTNNB1 (encodes β-catenin) mutations identify a subset of low-grade, early-stage endometrial cancer patients at high risk of recurrence. Mutation of CTNNB1 exon 3 is classically associated with translocation of the β-catenin protein from the membrane to the nucleus and activation of Wnt/β-catenin signaling. Given the clinical utility of identifying endometrial carcinomas with CTNNB1 mutation, the purpose of this study was to determine if immunohistochemistry could act as a surrogate for CTNNB1 gene sequencing. Next-generation sequencing was performed on 345 endometrial carcinomas. Immunohistochemical localization of β-catenin was determined for 53/63 CTNNB1 exon 3 mutant tumors for which tissue was available and a subset of wild-type tumors. Nuclear localization of β-catenin had 100% specificity in distinguishing CTNNB1 mutant from wild type, but sensitivity was lower (84.9%). Nearly half of CTNNB1 mutant cases had only 5-10% of tumor cells with β-catenin nuclear localization. The concordance between pathologists blinded to mutation status in assessing nuclear localization was 100%. The extent of β-catenin nuclear localization was not associated with specific CTNNB1 gene mutation, tumor grade, presence of non-endometrioid component, or specific concurrent gene mutations in the tumor. For comparison, nuclear localization of β-catenin was more diffuse in desmoid fibromatosis, a tumor also associated with CTNNB1 mutation. Thus, nuclear localization of β-catenin assessed by immunohistochemistry does not detect all endometrial cancers with CTNNB1 gene mutation. The extent of nuclear localization may be tumor type dependent. For endometrial cancer, immunohistochemistry could be an initial screen, with CTNNB1 sequencing employed when nuclear localization of β-catenin is absent.

Purpose NRG Oncology/RTOG 1203 was designed to compare patient-reported acute toxicity and health-related quality of life during treatment with standard pelvic radiation or intensity-modulated radiation therapy (IMRT) in women with cervical and endometrial cancer. Methods Patients were randomly assigned to standard four-field radiation therapy (RT) or IMRT radiation treatment. The primary end point was change in patient-reported acute GI toxicity from baseline to the end of RT, measured with the bowel domain of the Expanded Prostate Cancer Index Composite (EPIC). Secondary end points included change in patient-reported urinary toxicity, change in GI toxicity measured with the Patient-Reported Outcome Common Terminology Criteria for Adverse Events, and quality of life measured with the Trial Outcome Index. Results From 2012 to 2015, 289 patients were enrolled, of whom 278 were eligible. Between baseline and end of RT, the mean EPIC bowel score declined 23.6 points in the standard RT group and 18.6 points in the IMRT group ( P = .048), the mean EPIC urinary score declined 10.4 points in the standard RT group and 5.6 points in the IMRT group ( P = .03), and the mean Trial Outcome Index score declined 12.8 points in the standard RT group and 8.8 points in the IMRT group ( P = .06). At the end of RT, 51.9% of women who received standard RT and 33.7% who received IMRT reported frequent or almost constant diarrhea ( P = .01), and more patients who received standard RT were taking antidiarrheal medications four or more times daily (20.4% v 7.8%; P = .04). Conclusion Pelvic IMRT was associated with significantly less GI and urinary toxicity than standard RT from the patient's perspective.

OBJECTIVE: Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy. METHODS: In this randomized phase II trial, patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) endometrial cancer were randomly assigned to treatment with PC plus bevacizumab (Arm 1), PC plus temsirolimus (Arm 2) or ixabepilone and carboplatin (IC) plus bevacizumab (Arm 3). The primary endpoint was progression-free survival (PFS). Comparable patients on the PC Arm of trial GOG209 were used as historical controls. Secondary endpoints were response rate, overall survival (OS), and safety. RESULTS: Overall, 349 patients were randomized. PFS duration was not significantly increased in any experimental arm compared with historical controls (p > 0.039). Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63-1.02), 1.22 (0.96-1.55) and 0.87 (0.68-1.11), respectively. Response rates were similar across arms (60%, 55% and 53%, respectively). Relative to controls, OS duration (with censoring at 36 months), was significantly increased in Arm 1 (p

BackgroundThe newly developed Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has consistently been shown to be prognostically significant in endometrial carcinomas (EC). Recently, we and others have demonstrated L1 cell-adhesion molecule (L1CAM) to be a significant indicator of high-risk disease in EC. In the current study, it was our aim to determine the prognostic significance of aberrant L1CAM expression in ProMisE subgroups in a large, single centre, population-based EC cohort.MethodsProMisE (POLE; MMR-D; p53 wt/NSMP; p53 abn) classification results from a cohort of 452 EC were available for analysis. L1CAM expression was studied by immunohistochemistry on whole slides. Correlations between clinicopathological data and survival were calculated.ResultsExpression of L1CAM was most frequent in p53 abnormal tumours (80%). L1CAM status was predictive of worse outcome among tumours with no specific molecular profile (p53 wt/NSMP) (p

ObjectivePaclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy.MethodsIn this randomized phase II trial, patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) endometrial cancer were randomly assigned to treatment with PC plus bevacizumab (Arm 1), PC plus temsirolimus (Arm 2) or ixabepilone and carboplatin (IC) plus bevacizumab (Arm 3). The primary endpoint was progression-free survival (PFS). Comparable patients on the PC Arm of trial GOG209 were used as historical controls. Secondary endpoints were response rate, overall survival (OS), and safety.ResultsOverall, 349 patients were randomized. PFS duration was not significantly increased in any experimental arm compared with historical controls (p > 0.039). Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63-1.02), 1.22 (0.96-1.55) and 0.87 (0.68-1.11), respectively. Response rates were similar across arms (60%, 55% and 53%, respectively). Relative to controls, OS duration (with censoring at 36 months), was significantly increased in Arm 1 (p

PurposeTo evaluate the incidence of colon cancer as a second primary cancer (CCSPC) and the survival outcomes of women with and without CCSPC after the diagnosis of endometrial cancer (EC).MethodsThe standardized incidence ratio (SIR) of CCSPC and survival outcomes of EC survivors with and without CCSPC were analyzed using data from January 1 1993 to December 31 2011, obtained from the Korea Central Cancer Registry.ResultsOf 14,797 EC survivors, 147 (0.99%) developed CCSPC after an average interval of 5.5 years. The SIR of CCSPC among EC survivors was 2.56, higher than that of colon cancer in the general population. The SIR of CCSPC was highest for the ascending (3.77), followed by the transverse (3.45), descending colon (2.06), and rectum (1.99). The risk of a proximal site of CCSPC was high, especially within 5 years after the diagnosis of EC in the ascending (SIR, 4.37) and transverse (4.91) colon, and in young survivors (

OBJECTIVE:With the increasing incidence of endometrial cancer, the high survival rate, and the large number of endometrial cancer survivors, investigations of long-term genitourinary outcomes are important for the management of these outcomes among endometrial cancer survivors. METHODS:Cohorts of 2648 endometrial cancer survivors diagnosed in the state of Utah between 1997 and 2012 and 10,503 general population women were identified. All ICD-9 diagnosis codes were collected from the state's two largest healthcare systems and statewide databases. Multivariate Cox regression models were used to estimate hazard ratios at 1-5years and >5-10years after endometrial cancer diagnosis for genitourinary outcomes. RESULTS:Endometrial cancer survivors were at elevated risk for urinary system disorders between 1 and 5years (HR: 1.64, 95% CI: 1.50-1.78) and >5-10years (HR: 1.40, 95% CI: 1.26-1.56) and genital organ disorders between 1 and 5years (HR: 1.71, 95% CI: 1.58-2.03) and >5-10years (HR: 1.33, 95% CI: 1.19-1.49). Significantly elevated risk was observed among endometrial cancer survivors for renal failure, chronic kidney disease, urinary tract infections, and nonmalignant breast conditions, persisting between >5-10years. Between 1 and 5years after cancer diagnosis, those with higher stage, higher grade, older age and treated with radiation or chemotherapy were at higher risk for urinary disorders. CONCLUSIONS:Endometrial cancer survivors were at higher risk for many genitourinary outcomes compared to women from the general population. This study presents evidence suggesting the necessity of increased monitoring and counseling for genitourinary disorders for endometrial cancer patients both immediately after treatment cessation and for years afterwards.

ObjectivePatient-derived organoids (PDOs), used in multiple tumor types, have allowed evaluation of tumor characteristics from individual patients. This study aimed to assess the feasibility of applying PDO in vitro culture for endocrine-based and drug sensitivity testing in endometrial cancer.MethodsEndometrial cancer cells were enzymatically dissociated from tumors retrieved from fresh hysterectomy specimens and cultured within basement membrane extract in serum-free medium. An organoid growth assay was developed to assess the inhibitory effects of a variety of drugs including endocrine treatments. Organoid cultures were also prepared for histological and immunohistochemical comparison to the tumors of origin.ResultsFifteen endometrial cancer specimens were successfully cultured as PDOs. Small spherical structures formed within 24 hours, and many continued to grow to larger, denser organoids, providing the basis for an organoid growth assay. The STAT3 transcription factor inhibitor, BBI608 (Napabucasin), strongly inhibited growth in almost all PDO cultures, suggesting that stemness programing is involved in organoid formation and/or growth. Inhibition by different growth factor receptor tyrosine kinase inhibitors was observed in several PDO specimens. Four cultures were inhibited by fulvestrant, implying the importance of estrogen-receptor signaling in some PDO cultures. Organoids closely resembled their tumors of origin in both histomorphology and immunohistochemical expression.ConclusionsThe use of endometrial cancer PDO cultures for development of drug sensitivity testing for individual patient tumors is feasible. The potential value of the PDO model for clinical decision making will require clinical trial evaluation.

ObjectiveGynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin.MethodsWe analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer.ResultsWe first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin.ConclusionsOur findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases.

Novel treatments that improve outcomes for patients with recurrent or metastatic endometrial cancer (EC) remain an unmet need. Aberrant signaling by fibroblast growth factors (FGFs) and FGF receptors (FGFRs) has been implicated in several human cancers. Activating mutations in FGFR2 have been found in up to 16% of ECs, suggesting an opportunity for targeted therapy. This review summarizes the role of the FGF pathway in angiogenesis and EC, and provides an overview of FGFR-targeted therapies under clinical development for the treatment of EC.

BackgroundThe incidence of endometrial cancer increases with age and is associated with medical comorbidities such as obesity and diabetes. Although a few cohort studies of