Advanced Stage Endometrial Cancer Research Articles

OKN-007 is an Effective Anticancer Therapeutic Agent Targeting Inflammatory and Immune Metabolism Pathways in Endometrial Cancer.

Advanced-stage endometrial cancer patients typically receive a combination of platinum and paclitaxel chemotherapy. However, limited treatment options are available for those with recurrent disease, and there is a need to identify alternative treatment options for the advanced setting. Our goal was to evaluate the pre-clinical efficacy and mechanism of action of Oklahoma Nitrone 007 (OKN-007) alone and in combination with carboplatin and paclitaxel in endometrial cancer. The effect of OKN-007 on the metabolic viability of endometrial cancer cells in both two- and three-dimensional (2D and 3D) cultures, as well as on clonogenic growth, in vitro was assessed. We also evaluated OKN-007 in vivo using an intraperitoneal xenograft model and targeted gene expression profiling to determine the molecular mechanism and gene expression programs altered by OKN-007. Our results showed that endometrial cancer cells were generally sensitive to OKN-007 in both 2D and 3D cultures. OKN-007 displayed a reduction in 3D spheroid and clonogenic growth. Subsequent targeted gene expression profiling revealed that OKN-007 significantly downregulated the immunosuppressive and immunometabolic enzyme indolamine 2,3-dioxygenase 1 (IDO1) (-11.27-fold change) and modulated upstream inflammatory pathways that regulate IDO1 expression (interferon- (IFN-), Jak-STAT, TGF-β, and NF-kB), downstream IDO1 effector pathways (mTOR and aryl hydrocarbon receptor (AhR)) and altered T-cell co-signaling pathways. OKN-007 treatment reduced IDO1, SULF2, and TGF-β protein expression in vivo, and inhibited TGF-β, NF-kB, and AhR- receptor-mediated nuclear signaling in vitro. These findings indicate that OKN-007 surmounts pro-inflammatory, immunosuppressive, and pro-tumorigenic pathways and is a promising approach for the effective treat endometrial cancer. Significance Statement Women with advanced and recurrent endometrial cancer have limited therapeutic options. OKN-007, which has minimal toxicity and is currently being evaluated in early-phase clinical trials for the treatment of cancer, is a potential new strategy for the treatment of endometrial cancer.

Bridging the Gap from Bench to Bedside: A Call for In Vivo Preclinical Models to Advance Endometrial Cancer and Cervical Cancer Immuno-oncology Research.

Advanced-stage endometrial and cervical cancers are associated with poor outcomes despite contemporary advances in surgical techniques and therapeutics. Recent clinical trial results have led to a shift in the treatment paradigm for both malignancies, in which immunotherapy is now incorporated as the standard of care up front for most patients with advanced endometrial and cervical cancers as the standard of care. Impressive response rates have been observed, but unfortunately, a subset of patients do not benefit from immunotherapy, and survival remains poor. Continued preclinical research and clinical trial development are crucial for our understanding of resistance mechanisms to immunotherapy and maximization of therapeutic efficacy. In this setting, syngeneic models are preferred over xenograft models as they allow for the evaluation of the tumor-immune interaction in an immunocompetent host, most closely mimicking the tumor-immune interaction in patients with cancer. Unfortunately, significant disparities exist about syngeneic models in gynecologic malignancy, in which queries from multiple large bioscience companies confirm no commercial availability of endometrial or cervical cancer syngeneic cell lines. Published data exist about the recent development of several endometrial and cervical cancer syngeneic cell lines, warranting further investigation. Closing the disparity gap for preclinical models in endometrial and cervical cancers will support physician scientists, basic and translational researchers, and clinical trialists who are dedicated to improving outcomes for our patients with advanced disease and poor prognosis.

Abstract IA010: Neighborhood socioeconomic status and outcomes of patients with endometrial cancer

Abstract Cancer disparities manifest a particularly intricate interplay between incompletely understood genomic risks, biologic susceptibility, and access to quality care. Disparate access to quality cancer care is often a reflection of a complex relationship between social, historical, and environmental factors that influence a patient’s surroundings, however large observational studies rarely quantify these contextual elements beyond individual or area-level income and education. The well-established racial and socioeconomic inequities in uterine cancer outcomes remain one of the widest amongst all cancer types, with an approximate 20% difference in 5-year survival between Black and White patients, which remains unchanged over the past 15 years. Racial disparities persist even when controlling for more advanced stage at presentation, the occurrence of more aggressive tumor subtypes and quality of treatment. When controlling for age, time period of diagnosis, region of the country, urban or rural setting, treating facility type, socioeconomic status, education, insurance, comorbidity index, pathologic stage, histology, lymphadenectomy and adjuvant treatment, African American patients still have lower overall survival than White patients (HR 1.21, 95% CI 1.16-1.26). There continues to be a concerted call for further explanation of the socioeconomic factors that contribute to these racial disparities. To date, few epidemiologic studies of uterine cancer have utilized markers that are more representative of the complex interplay of various social and environmental factors that influence health outcomes. Some studies have examined area level poverty and uterine cancer treatment and outcomes, finding that living in more vulnerable neighborhoods was associated with poor survival, delays in care, and inadequate treatment. However, these studies do not take into account the interplay of neighborhood poverty and how race, or experience of racism, may affect this relationship. Given the complex and insidious nature of racism in the United States, we have further explored how neighborhood poverty may affect uterine cancer outcomes taking into account the race of patients studied. Preliminary data from New York state suggests that neighborhood socioeconomic vulnerability is associated with worse treatment and survival for patients with uterine cancer, and this was best seen in White patients living outside of major metropolitan areas. The greatest Black/White survival disparities are seen in the wealthiest neighborhoods in New York City. Black women with advanced stage endometrial cancer living in affluent areas have no significant survival advantage over those living in vulnerable neighborhoods. Citation Format: Charlotte Gamble. Neighborhood socioeconomic status and outcomes of patients with endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA010.

Role of endometrial sampling to differentiate between advanced endometrial versus ovarian malignancy: retrospective cohort study

ObjectiveDistinguishing between advanced stage endometrial and ovarian cancer at diagnosis can be challenging, especially when patients do not present with abnormal uterine bleeding. Given emerging systemic therapies specific for ovarian...

Abstract B076: Influence of residential segregation and women’s health provider density on advanced stage endometrial cancer diagnoses

Abstract Background. Endometrial cancer (EC) is the most common gynecologic malignancy in the US, with an increasing incidence. Non-Hispanic Black (NHB) women are disproportionately impacted by EC but the complex mechanisms by which this is occurring are not yet fully understood. Taking a social ecological approach to this issue, our objective was to determine if there are associations between county-level OB-GYN provider density and residential segregation as measured by the Index of Concentration at the Extremes (ICE) on late-stage EC diagnoses in Florida. Methods. All malignant EC cases were identified from 2001 to 2016 in the Florida Cancer Database System (FCDS). Using 5-year estimates from the 2013-2017 American Community Survey, five county-level ICE variables were calculated: economic (high vs low), race and/or ethnicity (non-Hispanic white (NHW) vs. NHB and NHW vs. Hispanic), and racialized economic segregation (low-income NHB vs. high-income NHW and low-income Hispanic vs. high-income NHW). County-level provider density was calculated as the number of OB-GYN providers divided by the female population of each county multiplied by 100,000. Early stage was defined as local and late stage was defined as regional/distant. Multivariable-adjusted logistic regression models were specified to estimate the association between each ICE variable and provider density separately on late-stage diagnosis of EC. Results. There were a total of 50,363 EC cases in Florida from 2001 to 2016 with 44,678 (88.7%) having stage information. Of those with stage information, the mean age at diagnosis was 64.1 years (SD: 11.9), 71.8% were NHW, 11.5% were NHB, 14.0% were Hispanic, and 2.8% were other race. The majority of individuals had government insurance (50.6%). More NHB women (27.1%) were diagnosed with aggressive EC histologies relative to NHW (16.4%) and Hispanic women (15.5%) (p<0.001). 14,366 (32.2%) were diagnosed with late-stage EC. A larger proportion of NHB women were diagnosed with later-stage EC compared to NHW women and Hispanic women (43.7% vs. 30.3% and 32.4%, respectively, p<0.001). NHB and Hispanic women had significantly greater odds of being diagnosed with later-stage EC compared to NHW women, regardless of residential segregation (OR: 1.46, 95% CI: 1.36, 1.56 and OR: 1.09, 95% CI: 1.01, 1.17, respectively). Women living in more economically disadvantaged Hispanic segregated counties had a greater odds of being diagnosed with later-stage EC compared to those living in more NHW segregated areas (OR: 1.16, 95% CI: 1.00, 1.65). Provider density was not found to be associated with later-stage diagnosis. Discussion. Advanced stage EC at diagnosis among Black and Hispanic women in Florida seems to be largely independent of provider density and residential segregation, though NHB more commonly present with metastatic disease. Biologic drivers of oncogenesis and barriers to timely care in this group require further exploration. Given the diversity and representation from Afro-Caribbeans in Florida, community-level investigations are required. Citation Format: Ashly Westrick, Zinzi Bailey, Matthew Schlumbrecht. Influence of residential segregation and women’s health provider density on advanced stage endometrial cancer diagnoses [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B076.

A Plain Language Summary of Results from the GARNET Study of Dostarlimab in Patients with Endometrial Cancer.

Dostarlimab, also known by the brand name JEMPERLI, is a medicine that can be used to treat certain types of endometrial cancer. GARNET is an ongoing phase 1 clinical study that is testing the safety and side effects of dostarlimab and the best way to administer it to patients. The results presented in this summary are from a time point in the middle of the study What were the results? The results from the GARNET study published in 2022 showed how well dostarlimab worked for people participating in the study. Dostarlimab was found to reduce the size of tumors in patients with certain types of endometrial cancer. The patients treated with dostarlimab had side effects that could be managed and few severe side effects. The results of the GARNET study led to dostarlimab being approved to treat patients with certain types of endometrial cancer. For patients with advanced-stage endometrial cancer, or endometrial cancer that has come back after chemotherapy (recurrent), there are few treatment options. The results suggest that dostarlimab may provide long-term benefits for these patients. Clinical Trial Registration: NCT02715284 (ClinicalTrials.gov).

Comparison of Minimally Invasive and Open Surgery for the Treatment of Endometrial Cancer with a High Risk of Recurrence: A Propensity Score Matching Study in Korea and Taiwan.

This study compared oncologic outcomes between minimally invasive surgery (MIS) and open surgery for the treatment of endometrial cancer with a high risk of recurrence. This study included patients with endometrial cancer who underwent primary surgery at two tertiary centers in Korea and Taiwan. Low-grade advanced-stage endometrial cancer (endometrioid grade 1 or 2) or endometrial cancer with aggressive histology (endometrioid grade 3 or non-endometrioid) at any stage was considered to have a high risk of recurrence. We conducted 1:1 propensity score matching between the MIS and open surgery groups to adjust for the baseline characteristics. Of the total of 582 patients, 284 patients were included in analysis after matching. Compared with open surgery, MIS did not show a difference in disease-free survival [hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.67-1.77, P = 0.717] or overall survival (HR 0.67; 95% CI 0.36-1.24, P = 0.198). In the multivariate analysis, non-endometrioid histology, tumor size, tumor cytology, depth of invasion, and lymphovascular space invasion were risk factors for recurrence. There was no association between the surgical approach and either recurrence or mortality in the subgroup analysis according to stage and histology. MIS did not compromise survival outcomes for patients with endometrial cancer with a high risk of recurrence when compared with open surgery.

Single Institute Experience with Neo-Adjuvant Chemotherapy and Interval Debulking Surgery in Advanced Endometrial Cancer.

Our study aims to review the role of neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) in patients with advanced endometrial cancer. Patients with advanced endometrial cancer treated with NACT followed by IDS at our institute from January 2010 to January 2020 were recruited. Data pertaining to baseline patient characteristics, surgical details, histopathology/imaging reports, treatment and follow up details including the development of recurrence and death were collected from institutional database. Disease free survival (DFS) and overall survival (OS) were calculated using Kaplan Meier survival curves. We recruited 31 patients for our study. About 83.9% patients showed partial response and 6.4% patients responded completely to NACT with none of the patients developing disease progression. Complete cytoreduction was achieved in 90.3% patients, optimal cytoreduction in 3.2% patients while 6.5% patients had suboptimal surgery. On completion of primary treatment, complete remission was achieved by 80.6% patients while 16.1% patients had progressive disease. Median follow up period was 21months (range 1- 61months). During follow up period, 51.6% patients developed recurrent disease after achieving complete remission and 61.3% patients died of disease progression/recurrence. The median DFS and median OS of the cohort was 15months and 21months respectively. The 2year DFS for the cohort was 34.1% and the 3year OS was 30.5%. NACT followed by IDS is a reasonably good option for advanced stage endometrial cancer not amenable to primary surgery. Innovative treatments are warranted in this cluster of patients.

LIM1 contributes to the malignant potential of endometrial cancer.

The incidence of endometrial cancer (EC) has been increasing worldwide. However, because there are limited chemotherapeutic options for the treatment of EC, the prognosis of advanced-stage EC is poor. Gene expression profile datasets for EC cases registered in The Cancer Genome Atlas (TCGA) was reanalyzed. Highly expressed genes in advanced-stage EC (110 cases) compared with early-stage EC (255 cases) were extracted and Gene Ontology (GO) enrichment analysis was performed. Among the enriched genes, Kaplan-Meier (KM) plotter analysis was performed. Candidate genes expression was analyzed in HEC50B cells and Ishikawa cells by RT-qPCR. In HEC50B cells, LIM homeobox1 (LIM1) was knocked down (KD) and cell proliferation, migration, and invasion ability of the cells were evaluated. Xenografts were generated using LIM1-KD cells and tumor growth was evaluated. Ingenuity Pathway Analysis (IPA) of RNA-seq data using LIM-KD cells was performed. Expression of phospho-CREB and CREB-related proteins were evaluated in LIM1-KD cells by western blotting and in xenograft tissue by immunofluorescent staining. Two different CREB inhibitors were treated in HEC50B and cell proliferation was evaluated by MTT assay. Reanalysis of TCGA followed by GO enrichment analysis revealed that homeobox genes were highly expressed in advanced-stage EC. Among the identified genes, KM plotter analysis showed that high LIM1 expression was associated with a significantly poorer prognosis in EC. Additionally, LIM1 expression was significantly higher in high-grade EC cell lines, HEC50B cells than Ishikawa cells. Knockdown of LIM1 showed reduced cell proliferation, migration and invasion in HEC50B cells. Xenograft experiments revealed that tumor growth was significantly suppressed in LIM1-KD cells. IPA of RNA-seq data using LIM-KD cells predicted that the mRNA expression of CREB signaling-related genes was suppressed. Indeed, phosphorylation of CREB was decreased in LIM1-KD cells and LIM1-KD cells derived tumors. HEC50B cells treated by CREB inhibitors showed suppression of cell proliferation. Collectively, these results suggested that high LIM1 expression contributed to tumor growth via CREB signaling in EC. Inhibition of LIM1 or its downstream molecules would be new therapeutic strategies for EC.

Mismatch repair deficiency, next-generation sequencing-based microsatellite instability, and tumor mutational burden as predictive biomarkers for immune checkpoint inhibitor effectiveness in frontline treatment of advanced stage endometrial cancer

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...

Locoregional Control Following Adjuvant Chemotherapy and Radiotherapy for Treatment of High-Risk Endometrial Cancer

<h3>Purpose/Objective(s)</h3> Patients with locally advanced stage and aggressive histology endometrial cancer are at high risk of relapse, and usually treatment includes surgery, chemotherapy and radiotherapy. The timing and coordination of chemotherapy and radiotherapy remain controversial, though historically we have delivered adjuvant radiotherapy after completion of chemotherapy. The premise being to avoid delaying chemotherapy, which confers an overall survival benefit. We decided to review oncologic outcomes and patterns of recurrence among our patients and compare them with the published literature. <h3>Materials/Methods</h3> A retrospective review was conducted to evaluate patients who underwent primary surgery for endometrial cancer between 2005 and 2017, had a final pathology demonstrating Stage I-II endometrial cancer of serous or clear cell histology, Stage III endometrial cancer of any histology or Stage IV endometrial cancer of endometrioid adenocarcinoma histology, and were considered appropriate for adjuvant chemotherapy and radiotherapy. Kaplan-Meier analysis was used to calculate progression-free survival (PFS) and overall survival (OS). <h3>Results</h3> A total of 140 patients met the eligibility criteria and were included, with a median age of 65. The distribution according to stage was as follows: 41 (29.3%) Stage I, 24 (17.1%) Stage II, 68 (48.6%) Stage III, and 7 (5.0%) Stage IV. Of these patients, 52 (37.1%) had endometrioid, 75 (53.6%) had serous, and 11 (7.9%) had clear cell histology. All patients received chemotherapy with the median start time being 49 days after initial surgery. In total, 120 (92%) completed 6 cycles of chemotherapy. The median start time for radiotherapy was 35 days after chemotherapy and 192 days after surgery, with 129 (92.1%) completing adjuvant radiotherapy. The median dose of external beam radiotherapy (EBRT) was 4500 cGy in 25 fractions and the median dose of vaginal brachytherapy, when used, was 1800 cGy in 3 fractions. In terms of EBRT technique, 54 were treated with traditional conformal fields and 74 with IMRT techniques. The median follow-up was 63.9 months and the 5-year PFS and OS rates were 69% and 66% respectively. A total of 42 patients (30.0%) developed a recurrence; of which 2 (1.4%) were local, 10 (7.1%) were locoregional (any with component of locoregional failure), 8 (5.7%) were isolated para-aortic and 27 (19.3%) were distant. Among the 129 patients receiving radiotherapy, 6 (4.6%) patients had locoregional failure. Only 7 (5.4%) of patients had an "in-field" recurrence after EBRT, with 4 (3.1%) among patients treated with conformal fields and 3 (2.3%) among those treated with IMRT. <h3>Conclusion</h3> Adjuvant radiotherapy given after completion of surgery and adjuvant chemotherapy leads to favorable outcomes with regards to PFS and OS (compared to published randomized studies), and still results in excellent locoregional control.

Bone Marrow Toxicity and Tolerance of Sandwich Therapy for Advanced-Stage Endometrial Cancer: A Single-Institution Experience

<h3>Purpose/Objective(s)</h3> Adjuvant therapy for advanced-stage endometrial cancer (EC) involve chemotherapy (CT) and/or radiation therapy (RT). Institutional practices vary regarding the sequencing of these therapies. While recent trials favored concurrent chemoradiation followed by consolidating CT, there is no randomized comparison of efficacy between ‘sandwich' (ST) versus concurrent CT. Previous studies show BM dose is predictive of hematological toxicities (HT) in concurrent chemoradiation. In this study, we sought to determine whether bone marrow dose contributes to hematological toxicity in ST for treatment of advanced-stage EC. <h3>Materials/Methods</h3> Data for patients who received ST (CT with carboplatin/paclitaxel then 45 Gy external beam radiation therapy [EBRT] with/without paraaortic [PA] fields then additional CT) at a single academic institution for EC cases was abstracted. Full ST was defined as 3 CT cycles, then RT, followed by a final 3 CT cycles. Grade 3 (G3) higher hematologic toxicities (ANC <1000, Hgb <8.0, platelet count <50,000) were recorded for each patient based at the time of infusion or radiation therapy. T-test and Chi-square test were used as appropriate to determine association. <h3>Results</h3> 98 EC patients that underwent ST were included; 66.0% were stage IIIC. 84% of patients completed full ST, and 26.3% of cases experienced ≥1 treatment delay. Among cycle delays cases, 57.7% had ≥1 G3 hematologic toxicity: 10 neutropenia, 4 anemia, and 3 thrombocytopenia. HT rate was 49.0%: 34% neutropenia, 13% anemia, 12% thrombocytopenia. Frequency of cycle delay (31.3% vs. 21.6%) or ST non-completion (13.7% vs. 18.4%) were not significantly associated with HT presence (p>0.05, all). Significantly fewer patients who had HT both pre- and post-EBRT completed post-sandwich CT compared to toxicities occurring at other time intervals (Table). While patients with ≥2 HT during their treatment received a significant larger mean bone marrow radiation dose (69.0 vs 72.5%, p=0.037), overall dosimetric data were similar regardless of HT timing during treatment. PA boost did display more frequent HT following RT (21.1% vs. 51.7%, p = 0.033) but completed ST at similar rates (63.2% vs 36.8%, p=0.441). There was a 10% mortality rate; overall survival was similar despite presence of HT occurrence, or with HT requiring a cycle delay or cycle non-completion (p>0.05, all cases). <h3>Conclusion</h3> In our study, BM dose does matter in determining HT even in ST, but does not affect overall treatment completion. The treatment completion rate is comparable to those reported historically for CT only arm. Low rates of cycle interruption and similar overall survival point to a promising safety and efficacy profile with ST.

High visceral fat to subcutaneous fat ratios portend a poor prognosis in patients with advanced endometrial cancer

ObjectivesVisceral adiposity has been established as a predictor of outcomes in various cancers. We aimed to determine the association of radiographic measurements of visceral fat with clinical outcomes in patients with endometrial cancer. MethodsA retrospective review of patients with stage III-IV endometrial cancer who underwent surgery between 2004 and 2014 was performed. Visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and total adipose tissue (TAT;VAT+SAT) were assessed on preoperative computed tomography (CT) scans. Exploratory analysis was performed to establish the optimal cut-off values for VAT, SAT, and TAT to identify patients with poor prognostic body composition. Survival rates were analyzed using Kaplan-Meier analysis, log-rank tests, and cox-regression. ResultsEighty-three patients were included. Forty-two (51%) patients had a low VAT/SAT ratio (<0.45) and 41 (49.4%) had a high VAT/SAT ratio (>0.45). There were no significant differences in demographics between the groups. The mean VAT, SAT, and TAT were 176.3 cm2, 379.3 cm2, and 555.3 cm2 respectively. Compared to patients with low VAT/SAT ratios, patients with high VAT/SAT ratios had a shorter recurrence-free survival (median 29.6 vs 32.3 months, P = 0.01) and shorter overall survival (median 56 vs 93.7 months, P = 0.03). ConclusionsVisceral fat measurements are predictive of outcomes in patients with advanced stage endometrial cancer. Specifically, VAT to SAT ratios are predictive of overall survival. Future studies should be pursued to identify potential therapeutic targets and biological mechanisms that underlie obesity's relationship with endometrial cancer.

PD-L1 Expression in Endometrial Cancer and Its Association with Clinicopathological Features: A Systematic Review and Meta-Analysis.

Simple SummaryIn women, endometrial cancer is a crucial cancer cause-death, which is still not fully explored in its pathogenesis and immune system. Early detection is essential for proper treatment and follow-up in affected patients. This systematic review and meta-analysis aim to pool the prevalence of PD-L1 in endometrial cancer and its association with clinicopathological features. The pooled prevalence of PD-L1 was 34.26% in tumour cells, and 51.39% in immune cells among endometrial cancer patients. There was significant association of PD-L1 expression in both tumour cells and immune cells with advanced stage endometrial cancer. The presence of lympho-vascular invasion and poor overall survival were also associated with PD-L1 expression in immune cells. These information enable clinicians to stratify endometrial cancer patients for anti-PD-1/PD-L1 immune therapy.Endometrial cancer (EC) is one of the most common malignancies of the female genital tract and its current treatment mainly relies on surgical removal of the tumour bulk, followed by adjuvant radiotherapy with or without chemotherapy/hormonal therapy. However, the outcomes of these approaches are often unsatisfactory and are associated with severe toxicity and a higher recurrence rate of the disease. Thus, more clinical research exploring novel medical intervention is needed. Involvement of the immune pathway in cancer has become important and the finding of a high positive expression of programmed cell death-ligand 1 (PD-L1) in EC may offer a better targeted therapeutic approach. Numerous studies on the PD-L1 role in EC have been conducted, but the results remained inconclusive. Hence, this systematic review was conducted to provide an update and robust analysis in order to determine the pooled prevalence of PD-L1 expression in EC and evaluate its association with clinicopathological features in different focuses of tumour cells (TC) and immune cells (IC). A comprehensive literature search was conducted using the PubMed, Web of Science, and Scopus databases. Twelve articles between 2016 and 2021 with 3023 EC cases met the inclusion criteria. The effect of PD-L1 expression on the outcome parameters was estimated by the odds ratios (ORs) with 95% confidence intervals (CIs) for each study. The pooled prevalence of PD-L1 was 34.26% and 51.39% in the tumour cell and immune cell, respectively, among women with EC. The PD-L1 expression was significantly associated with Stage III/IV disease (in both TC and IC) and correlated to the presence of lympho-vascular invasion in IC. However, the PD-L1 expression in TC was not associated with the age groups, histology types, myometrial invasion, and lympho-vascular invasion. In IC, PD-L1 expression was not associated with age group, histology type, and myometrial invasion. The meta-analysis survival outcomes of PD-L1 high expression had a significant association with worse OS in IC but not in TC.

Systematic review and meta-analysis of neoadjuvant chemotherapy compared to primary debulking surgery in advanced endometrial cancer (538)

Systematic review and meta-analysis of neoadjuvant chemotherapy compared to primary debulking surgery in advanced endometrial cancer (538)

A conceptual model of vulnerability to care delay among women at risk for endometrial cancer

ObjectiveCare delay may allow for cancer progression prior to treatment initiation. However, in endometrial cancer, quantitative data to support this hypothesis is mixed. Factors that cuase delay prior to clinical presentation are present among Black women, however the whether and how they present among White women, and thus how they may drive racial disparity is unknown. MethodsIn this qualitative study, from June 2019 to March 2020, we conducted in-depth semi-structured interviews among 17 White women with EC (34–73 years), living in the Northwest (11), West (2), Midwest (1), Southwest (1), and Northeast (2) U.S. regions, including six with high-risk and/or advanced stage endometrial cancer. An exploratory and descriptive content analysis was performed using iterative rounds of inductive coding, case summaries, and additional interviews to confirm emergent themes, followed by synthetic analysis of themes from a prior qualitative study conducted among Black women, which we analyzed for overlap and distinctions. ResultsThere were critical points of overlap and distinction between Black and White women in four delay factors identified: menopause and endometrial cancer knowledge, prior negative healthcare experiences, prior/concurrent reproductive conditions, and healthcare provider response. Conceptualizing the care journey as a circular path demonstrates the potential for accumulation of delay that is dependent on underlying risk. ConclusionWe have identified four areas of vulnerability that are often unrecognized and difficult to assess in quantitative investigations of overall quality and co-occurring disparities in endometrial cancer care. With the addition of epidemiologic risk, we present a unified model of vulnerability to care delay in endometrial cancer that can be applied to future quantitative studies and ongoing clinical care.

Neoadjuvant chemotherapy for advanced stage endometrial cancer: A systematic review

ObjectiveWhile primary cytoreductive surgery (PCS) is considered the standard of care for women who present with stage IV endometrial cancer, neoadjuvant chemotherapy (NACT) followed by interval cytoreductive surgery (ICS) has emerged as an alternative treatment strategy. We summarized the literature and compared outcomes of PCS compared to NACT and ICS. MethodsWe conducted a systematic search on PubMed, Embase, Web of Science, and Scopus for articles published from January 1, 1990 to December 31, 2020. Key search terms included multiple descriptors of advanced disease status in combination with “endometrial cancer” and “neoadjuvant chemotherapy”. Our review included studies that examined survival and surgical outcomes of patients with stage III or IV endometrial cancer treated with neoadjuvant chemotherapy followed by interval cytoreductive surgery versus those who received primary cytoreductive surgery. We excluded studies examining only patients with leiomyosarcomas, carcinosarcomas, and stromal sarcomas due to the biologic heterogeneity of these malignancies. ResultsThe nine included studies encompassed 5,844 patients, of which 1,317 (22.5%) received NACT and 4,527 received PCS (77.5%). With the exception of a single study, all were retrospective observational studies or case series. Use of NACT in patients with stage IV EC increased from 16.0% in 2010 to 23.9% in 2015. Five studies analyzed median overall survival and all but one reported no significant difference between NACT + ICS vs. PCS. Optimal cytoreduction (<1 cm of residual disease) rates were similar across both treatment groups in three separate analyses, however pooled data suggest improved rates of optimal cytoreduction for NACT + ICS vs. PCS patients (81.9% vs. 51.5% respectively). Patients receiving NACT experienced significantly shorter hospital admissions and lower operative times compared to PCS counterparts. ConclusionsNACT followed by ICS reduces perioperative morbidity while offering similar overall survival.

LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer

Endometrial cancer (EC) is the fourth most common cancer in women. Advanced-stage EC has limited treatment options with a poor prognosis. There is an unmet need for the identification of actionable drivers for the development of targeted therapies in EC. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major role in cancer progression, metastasis, stemness, and therapy resistance. However, little is known about the functional significance of the LIF/LIFR axis in EC progression. In this study using endometrial tumor tissue arrays, we identified that expression of LIF, LIFR is upregulated in EC. Knockout of LIFR using CRISPR/Cas9 in two different EC cells resulted in a significant reduction of their cell viability and cell survival. In vivo studies demonstrated that LIFR-KO significantly reduced EC xenograft tumor growth. Treatment of established and primary patient-derived EC cells with a novel LIFR inhibitor, EC359 resulted in the reduction of cell viability with an IC50 in the range of 20–100 nM and induction of apoptosis. Further, treatment with EC359 reduced the spheroid formation of EC cancer stem cells and reduced the levels of cancer stem cell markers SOX2, OCT4, NANOG, and Axin2. Mechanistic studies demonstrated that EC359 treatment attenuated the activation of LIF-LIFR driven pathways, including STAT3 and AKT/mTOR signaling in EC cells. Importantly, EC359 treatment resulted in a significant reduction of the growth of EC patient-derived explants ex vivo, EC cell line-derived xenografts, and patient-derived xenografts in vivo. Collectively, our work revealed the oncogenic potential of the LIF/LIFR axis in EC and support the utility of LIFR inhibitor, EC359, as a novel targeted therapy for EC via the inhibition of LIF/LIFR oncogenic signaling.

Adjuvant treatment and outcomes for patients with stage IIIA grade 1 endometrioid endometrial adenocarcinoma

<h3>Objectives:</h3> Among patients with advanced stage endometrial cancer, those with FIGO stage IIIA grade 1 endometrioid endometrial adenocarcinoma (EEC) have favorable outcomes. Adjuvant therapy to reduce the risk of recurrence is not standard and remains controversial. The aim of this study was to describe associations between adjuvant therapy use and survival among women with stage IIIA grade 1 EEC. <h3>Methods:</h3> Women who underwent primary surgical management for stage IIIA (FIGO 2009 staging, excluding cases up-staged based on positive cytology alone) grade 1 EEC between 2004-2016 were identified in the National Cancer Data Base. Demographics and receipt of adjuvant therapy were compared using t-test for continuous variables and chi2 for categorical, dichotomous variables. Kaplan-Meier curves, log-rank test, and multivariable cox proportional hazard models adjusting for age, comorbidity, academic facility, tumor size, and lymphovascular space invasion (LVSI) status (±/unknown; reported after 2009) were used to estimate overall survival (OS) based on adjuvant treatment modality. <h3>Results:</h3> A total of 1,343 patients were identified; 310 (23.1%) received no adjuvant treatment, 357 (26.6%) had chemotherapy alone (CT), 232 (17.2%) had radiation alone (RT), and 444 (33.1%) had chemotherapy and radiation (CT+RT). Those who received CT were younger than those who received RT or no adjuvant treatment (56.3 years vs 62.1 years, p<0.001). There were no significant differences in adjuvant treatment by race, ethnicity, or academic facility. Three-year OS rate was 89.9% (95% CI 87.9%-91.6%), and 5-year OS rate was 82.3% (95% CI 79.7-84.7%). There was a significant decreasing rate of no adjuvant treatment (26.8% 2004-09 vs. 20.7% 2010-16, p=0.01) and increasing rate of CT (46.3% 2004-09 vs 68.2% 2010-16, p<0.001) over time. In the multivariate Cox model, treatment with CT was associated with significantly improved OS (HR=0.50; 95% CI 0.34-0.74; p<0.001). In contrast, treatment with RT or CT+RT was not associated with improved OS. Patients with tumor exhibiting LVSI+ were at a 2.9-fold increased risk of death, and LVSI+ was a significant risk factor in the model (p<0.001). When stratifying by LVSI status, those with LVSI- who received CT had a significantly better OS compared to other treatment groups (HR=0.24; 95% CI 0.09-0.62). Those with LVSI+ (n=157/613, 25.6% of reported cases with survival data) had improved OS with CT+RT by log-rank test (5-year OS 82.9% vs 59.0% for CT or RT, p=0.001). However, after adjusting for age and comorbidity, there was no difference in OS (HR=0.31, 95% CI 0.08-1.20; p=0.09). <h3>Conclusions:</h3> The use of adjuvant CT for the treatment of stage IIIA grade 1 EEC is increasing over time. Adjuvant CT, but not RT or CT+RT, is associated with improved OS. LVSI demonstrated a prognostic association with OS, but was only reported since 2010, limiting power to assess an interactive association between adjuvant therapy and survival. Patients with LVSI+ disease may benefit from additional therapy, however, prospective trials are needed.

Timing of chemotherapy does not impact survival in advanced-stage endometrial cancer

Objectives: The optimal timing of chemotherapy for advanced stage endometrial cancers (EC) is not known. In other advanced gynecologic malignancies, delays in treatment start have been associated with adverse outcomes. We sought to assess whether timing of neo-adjuvant (NACT) and post-operative (POC) chemotherapy in Stage III and IV EC impacts survival. Methods: Patient data from the combined SEER-Medicare database from 1991-2015 was collected. The population included 826 patients with 2009 FIGO III-IV EC who received chemotherapy as first treatment. Patients were categorized by mode of treatment: chemotherapy alone (CT), or chemotherapy with subsequent surgery (CT+S). Patients were further stratified by the time from diagnosis to start of chemotherapy. Using the median time, the four quartiles identified were 0-9 days (Q1), 10-25 days (Q2), 26-45 days (Q3), and 46-301 days (Q4). In the CT+S cohort, the time to POC was assessed. Interaction between race and chemotherapy timing were assessed as well. Multivariable Cox regression models were used to identify treatment factors associated with overall survival (OS) and cause specific survival (CSS). Results: A total of 502 and 324 patients had CT and CT+S respectively. Radiation was given in 32.1% and 45.1% of the patients in the CT and CT+S cohorts respectively, and the addition of radiation was associated with improved survival (OS HR 0.66 [0.55-0.80]; CSS HR 0.64 [0.51-0.80]). The CT+S patients were significantly younger, were more likely to be stage III, of type II histology, and had an earlier time to start of chemotherapy when compared with CT. OS (HR 0.39 [0.33-0.46]) and CSS (HR 0.35 [0.28-0.44]) were significantly improved in the CT+S cohort compared to the CT cohort. In the CT+S cohort, the median time to start NACT was 21 days. When stratifying by quartiles, Q4 was associated with improved survival when compared with Q1 (CSS HR 0.41 [0.21-0.79]), and Q2-Q3 (OS HR 0.61 [0.40-0.93]; CSS HR 0.43 [0.23-0.80]). There was no significant difference found amongst the other quartiles. The median time to start of POC was 32 days. When stratifying by quartiles, timing of POC start was not associated with survival (OS p=0.942; CSS p=0.881). Similarly, in the CT cohort, median time to start NACT was 28 days. Q4 was associated with improved survival when compared with Q1 (OS HR 0.50 [0.38-0.66]; CSS HR 0.50 [0.36-0.69]) and Q2-3 (OS HR 0.62 [0.49-0.77]; CSS HR 0.62 [0.47-0.81]). There were no differences in times to treatment based on race. Conclusions: In patients with advanced stage EC who receive NACT, delays in chemotherapy start both prior to and following interval debulking surgery do not appear to impact survival. These results stand independent of race and demographic features. Interestingly, a majority of the cohort did not undergo hysterectomy and survival outcomes were worse in this group. Timing of treatment initiation did not impact survival, even in this poor prognostic group.