Endometrioid Endometrial Cancer Research Articles

Inhibition of LIFR Blocks Adiposity-Driven Endometrioid Endometrial Cancer Growth.

Endometrial cancer (EC) is the fourth most common cancer in women, and half of the endometrioid EC (EEC) cases are attributable to obesity. However, the underlying mechanism(s) of obesity-driven EEC remain(s) unclear. In this study, we examined whether LIF signaling plays a role in the obesity-driven progression of EEC. RNA-seq analysis of EEC cells stimulated by adipose conditioned medium (ADP-CM) showed upregulation of LIF/LIFR-mediated signaling pathways including JAK/STAT and interleukin pathways. Immunohistochemistry analysis of normal and EEC tissues collected from obese patients revealed that LIF expression is upregulated in EEC tissues compared to the normal endometrium. Treatment of both primary and established EEC cells with ADP-CM increased the expression of LIF and its receptor LIFR and enhanced proliferation of EEC cells. Treatment of EEC cells with the LIFR inhibitor EC359 abolished ADP-CM induced colony formation andcell viability and decreased growth of EEC organoids. Mechanistic studies using Western blotting, RT-qPCR and reporter assays confirmed that ADP-CM activated LIF/LIFR downstream signaling, which can be effectively attenuated by the addition of EC359. In xenograft assays, co-implantation of adipocytes significantly enhanced EEC xenograft tumor growth. Further, treatment with EC359 significantly attenuated adipocyte-induced EEC progression in vivo. Collectively, our data support the premise that LIF/LIFR signaling plays an important role in obesity-driven EEC progression and the LIFR inhibitor EC359 has the potential to suppress adipocyte-driven tumor progression.

Sentinel lymph node mapping in patients with endometrial hyperplasia: A practice to preserve or abandon?

ObjectivesTo compare outcomes of patients with premalignant endometrial pathology undergoing hysterectomy with or without sentinel lymph node (SLN) removal. Outcomes of interest included surgical adverse events (AEs), cancer status on final pathology, postoperative treatment, and The Cancer Genome Atlas (TCGA) molecular risk profiles. MethodsWe retrospectively identified patients with premalignant pathology on preoperative endometrial biopsy who underwent hysterectomy with or without SLN mapping/excision at our institution from 01/01/2017–12/31/2021. Clinical, pathologic, surgical, and TCGA profiling data were abstracted. Appropriate statistical tests were used. ResultsOf 221 patients identified, 161 (73%) underwent hysterectomy with SLN excision and 60 (27%) underwent hysterectomy without SLN excision. Median age and body mass index were similar between groups. Median operative time was 130 min for those who underwent SLN mapping/excision versus 136 min for those who did not (p = 0.6). Thirty-day postoperative AE rates were 9% (n = 15/161) and 13% (n = 8/60), respectively (p = 0.9). Ninety-eight (44%) of 221 patients had grade 1–2 endometrioid endometrial cancer on final pathology (4 [4%] were stage IB or higher). Ten (10%) of 98 patients, all within the SLN group, received adjuvant treatment. Among all patients, of 33 (15%) with TCGA molecular classification data, 27 (82%) had copy number-low, 3 (9%) microsatellite instability-high, 2 (6%) POLE-ultramutated, and 1 (3%) copy number-high disease. ConclusionsSLN assessment appears safe, detects a small number of occult nodal metastases for those upstaged, and provides additional staging information that can guide adjuvant treatment. SLN mapping should be discussed in preoperative counseling and offered using a shared decision-making approach.

Peripheral Blood Lymphocyte Subsets as a Risk Predictor of Patients with Endometrioid Endometrial Cancer.

This study aimed to explore lymphocyte subsets for the personalized prediction of endometrioid endometrial cancer (EEC) risk and evaluated the correlation between immune cells and International Federation of Gynecology and Obstetrics (FIGO) staging in patients with EEC. A case-control study was conducted to analyze the clinical data of 421 patients admitted to Fujian Maternity and Child Health Hospital from October 2017 to December 2021. t-tests or Mann-Whitney U-tests were used to analyze the percentages and absolute counts of peripheral blood lymphocyte subsets in patients with EEC and patients without cancer. The independent risk factors for ECC and FIGO stage were analyzed via multivariate binary logistic regression. The receiver operating characteristic curve was calculated to evaluate the prediction efficacy of risk factors on ECC. The CD4+ T% in the 121 patients with EEC was lower than in the 300 patients without cancer (P = 0.013). The absolute counts of peripheral CD4+ T (P = 0.002) and T cells (P = 0.007) in 37 patients with EEC were lower than in 51 patients without cancer. Multivariate binary logistic regression analysis showed that CD4+ T% and natural killer cell (NK)% were independent risk factors for FIGO staging in patients with EEC. NK% was significantly higher in patients with advanced stage (FIGO III and IV) than those with early EEC (FIGO I and II) (P = 0.004). To determine the early and advance FIGO stage of EEC, the cutoff value of NK% was calculated as 19.94%. With the decrease of CD4+ T counts, the immune status of patients with EEC is impaired. NK cells may help in the evaluation of the prognosis of patients with EEC and are likely to be an independent risk factor for FIGO staging in patients with EEC.

GSOR20 Presentation Time: 12:05 PM: Vaginal Cuff Brachytherapy versus External Beam in High Risk (T1b Grade 3) Endometrioid Endometrial Cancer: An NCDB Analysis

<h3>Purpose</h3> The optimal adjuvant management of localized, resected high risk (HR) Stage I endometrioid endometrial cancer (i.e. FIGO grade 3 with > 50% myometrial invasion) remains unclear. A Cochrane meta-analysis showed a 10% overall survival (OS) benefit when EBRT (external beam radiation therapy) was given versus no radiation treatment. However, no randomized trials have compared adjuvant EBRT to VCB (vaginal cuff brachytherapy) without chemotherapy. A SEER analysis from 2012 showed reported that in women with lymph node dissection, there was no difference in OS between EBRT and VCB in patients with HR Stage I endometrial cancer. We hypothesized that adjuvant EBRT or VCB would both be equally associated with improved OS in HR Stage I endometrial cancer in a large, modern database. <h3>Materials and Methods</h3> The National Cancer Database (NCDB) was queried for women diagnosed with endometrioid endometrial cancer from 2004-2017, who had undergone total hysterectomy or greater, and lymph node dissection revealing a pathologic stage of IB (AJCC Edition 6) or IC (AJCC Edition 7), and FIGO Grade of 3. Women were grouped by receipt of multiagent chemotherapy (MCT), VCB (without EBRT), EBRT (without VCB), or EBRT+VCB. OS was measured by Kaplan-Meier estimator, and compared using log rank test. Cox proportional hazard modeling was done, using as additional covariates tumor size, lymphovascular space invasion (LVSI), margin status, age, extent of comorbidities, treatment year, and several demographic factors (race, insurance status, educational and income level of zip code, urban versus rural location). A propensity score weighted analysis was performed, using the above covariates. <h3>Results</h3> 10,357 women were analyzed. As adjuvant treatment, 22% received EBRT alone, 26% received VCB alone, 11% received EBRT+VCB, and 42% received no radiation. 30% received adjuvant chemotherapy. Median OS for the entire group was 11.0 years. For the whole group, median OS times were 12.8 years with VCB alone, 11.3 years for EBRT alone, and 11.5 years with EBRT+brachytherapy, which were not significantly different (p > 0.05). However, median OS was only 8.6 years in patients not receiving any radiation, (p <0.0001 compared to receipt of each of the radiation modalities). For patients receiving no adjuvant chemotherapy, median OS was 12.3 years for EBRT alone, 12.8 years with VCB alone, 11.9 years with EBRT+brachytherapy (p > 0.05), but was only 9.6 years in patients not receiving any radiation (p < 0.00001). On multivariate analysis, receipt of radiation (but not receipt of multiagent chemotherapy), smaller tumor size, absence of LVSI, less comorbidities, younger age, and white race were associated with improved overall survival (p <0.003). Propensity score weighted analysis confirmed the OS benefit for women who received any RT. <h3>Conclusions</h3> In this large database, VCB and EBRT had comparable effectiveness in improving OS for HR Stage I endometrial cancer. With equal effect, VCB is favored given the more convenient schedule and decreased side effects as shown in previous randomized trials. The results of this study give impetus for a randomized trial comparing EBRT and VCB without chemotherapy in women with HR endometrioid endometrial cancer. In addition, a large percentage of women with HR disease who did not receive any radiation, despite this being the standard of care with known survival advantage, which reveals likely deficiencies in health care delivery.

PO32 Presentation Time: 10:30 AM: Outcomes After Adjuvant Radiation in Patients with Early-Stage Endometrial Cancer with Mismatch Repair Defects

<h3>Purpose</h3> Although mismatch repair (MMR) deficiency is commonly identified in endometrial cancers, its significance on outcomes remains unknown. Our study aims to determine if MMR status affects clinical outcomes in early-stage endometrial cancer patients treated with adjuvant radiation therapy. <h3>Methods/Materials</h3> We identified 194 patients with FIGO 2009 stage I-II endometrioid endometrial cancer who underwent surgical resection followed by adjuvant radiation therapy at our institution with available MMR status. Locoregional recurrence (LRR) and distant metastases were analyzed using competing risk methods, and overall survival (OS) and progression free survival (PFS) were analyzed using Kaplan-Meier. <h3>Results</h3> The median age was 65 years, and the median follow-up time was 38 months. There were 73 patients (37.6%) with an MMR deficiency, and 121 (62.4%) patients with intact MMR. Eleven patients (5.7%) experienced LRR, and 14 patients (7.2%) experienced distant recurrence. The median OS and PFS of the cohort was not reached and MMR status was not associated with OS or PFS. MMR deficiency was significantly associated with the grade of the tumor (17.1% of grade 1 versus 54.4% of grade 2 and 46.9% of grade 3 patients (<i>p</i><0.01)), the depth of myometrial invasion (<i>p</i><0.01), and the presence of LVSI (<i>p</i><0.01). MMR status was not associated with the type of radiation delivered. In the entire cohort, patients who received external beam radiation therapy had significantly worse PFS than patients who underwent brachytherapy (<i>p</i>=0.03). In patients whose tumors were MMR deficient, there was also a significant difference in PFS based on the type of radiation delivered. Patients who underwent external beam radiation therapy (EBRT) had shorter PFS versus patients who underwent brachytherapy only (<i>p</i>=0.02). In patients with MMR deficient tumors, there was a significant correlation between radiation type and stage; patients with stage II disease were more likely to undergo both EBRT and brachytherapy (<i>p</i><0.01). After adjusting for stage, type of radiation delivered was trending towards significance (p=0.07). Greater depth of myometrial invasion was also associated with the use of both EBRT and brachytherapy (<i>p</i>=0.03). <h3>Conclusions</h3> Patients with stage I-II endometrial cancer have excellent oncologic outcomes with the use of adjuvant radiation therapy, regardless of MMR status.

The present status of metformin in fertility-preserving treatment in atypical endometrial hyperplasia and endometrioid endometrial cancer.

Progestin therapy is the main fertility-sparing treatment for women with endometrial cancer (EC) and atypical endometrial hyperplasia (AEH). However, still 15-25% of these women failed to achieve complete response (CR) and then lost their fertility after definitive surgery. Metformin has been demonstrated to play an anti-cancer role in multiple cancers including EC. Several studies also suggested metformin had potential benefit in improving the therapeutic outcome of fertility-preserving treatment alongside with progestin. This review has discussed existed evidence regarding the effect of metformin combined with progestin for women with AEH and EC who desire childbearing. Nevertheless, the therapeutic effect of metformin varied in different studies due to the high heterogeneity in the patient's characteristics, the inconsistency in dose and treatment duration of metformin, the combined use of hysteroscopy, the insufficient sample size and underpowered study-design. Therefore, care should be taken when interpreting the current results on this issue. Till now, there is still no strong evidence supporting the use of metformin in fertility-preserving treatment in AEH and EEC patients. Further research is needed to provide high-quality data to validate the role of metformin as adjunctive therapy alongside with progestin to preserve fertility for AEH and EEC patients.

Single-cell transcriptomic analysis highlights origin and pathological process of human endometrioid endometrial carcinoma

Endometrial cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states. Current models do not adequately reflect oncogenic origin and pathological progression in patients. Here we use single-cell RNA sequencing to profile cells from normal endometrium, atypical endometrial hyperplasia, and endometrioid endometrial cancer (EEC), which altogether represent the step-by-step development of endometrial cancer. We find that EEC originates from endometrial epithelial cells but not stromal cells, and unciliated glandular epithelium is the source of EEC. We also identify LCN2 + /SAA1/2 + cells as a featured subpopulation of endometrial tumorigenesis. Finally, the stromal niche and immune environment changes during EEC progression are described. This study elucidates the evolution of cell populations in EEC development at single-cell resolution, which would provide a direction to facilitate EEC research and diagnosis.

Atypical Macropinocytosis Contributes to Malignant Progression: A Review of Recent Evidence in Endometrioid Endometrial Cancer Cells.

Simple SummaryA novel type of macropinocytosis has been identified as a trigger for the malignant progression of endometrial cancer. Transiently reducing epithelial barrier homeostasis leads to macropinocytosis by splitting between adjacent cells in endometrioid endometrial cancer. Macropinocytosis causes morphological changes in well-differentiated to poorly differentiated cancer cells. Inhibition of macropinocytosis promotes a persistent dormant state in the intrinsic KRAS-mutated cancer cell line Sawano. This review focuses on the mechanisms of atypical macropinocytosis and its effects on cellular function, and it describes the physiological processes involved in inducing resting conditions in endometrioid endometrial cancer cells.Macropinocytosis is an essential mechanism for the non-specific uptake of extracellular fluids and solutes. In recent years, additional functions have been identified in macropinocytosis, such as the intracellular introduction pathway of drugs, bacterial and viral infection pathways, and nutritional supplement pathway of cancer cells. However, little is known about the changes in cell function after macropinocytosis. Recently, it has been reported that macropinocytosis is essential for endometrial cancer cells to initiate malignant progression in a dormant state. Macropinocytosis is formed by a temporary split of adjacent bicellular junctions of epithelial sheets, rather than from the apical surface or basal membrane, as a result of the transient reduction of tight junction homeostasis. This novel type of macropinocytosis has been suggested to be associated with the malignant pathology of endometriosis and endometrioid endometrial carcinoma. This review outlines the induction of malignant progression of endometrial cancer cells by macropinocytosis based on a new mechanism and the potential preventive mechanism of its malignant progression.

Effects of Weight Status and Related Metabolic Disorders on Fertility-Sparing Treatment Outcomes in Endometrial Atypical Hyperplasia and Endometrial Cancer: A Retrospective Study.

Simple SummaryFertility-sparing treatment for young women with endometrial atypical hyperplasia or endometrioid endometrial cancer has become an important priority. The aim of our retrospective study was to evaluate the effects of different weight statuses and related metabolic disorders on the oncological and reproductive outcomes of fertility-sparing treatment. We found that there was a parabola-shaped relationship between the cumulative complete response rate of treatment and BMI. The apex of the curve was observed at a BMI of 21–22 kg/m2. Furthermore, we demonstrated that hyperuricemia was an independent risk factor for the failure of conservative treatment, correlating with a lower cumulative 32-week CR rate and longer treatment duration. Our results indicate that a target BMI interval for weight management should be appropriately established for patients with EAH/EEC. Early active interventions for related metabolic disorders, preferably before 32 weeks of treatment, should be provided to improve treatment efficacy.Background: Although obesity was an independent risk factor for fertility-sparing treatment in endometrial atypical hyperplasia (EAH) and endometrioid endometrial cancer (EEC), the roles of other weight statuses and related metabolism were unclear. This study aimed to investigate the body mass index (BMI) interval that produced optimal treatment efficacy and the effects of related metabolic disorders in EAH/EEC patients. Methods: A total of 286 patients (including 209 EAH and 77 well-differentiated EEC) under progestin therapy were retrospectively analyzed. The cumulative complete response (CR) rate, relapse rate, and fertility outcomes were compared among different weight or metabolic statuses. Results: Underweight and overweight/obese status significantly decreased the cumulative 16-week and 32-week CR rate (p = 0.004, p = 0.022, respectively). The highest 16-week CR rate was observed at a BMI of 21–22 kg/m2 in the overall population (p = 0.033). Obesity (HR 0.37, 95%CI 0.15–0.90, p = 0.029) and PCOS (HR 0.55, 95%CI 0.31–0.99, p = 0.047) were associated with lower 16-week CR rate. Hyperuricemia (HR 0.66, 95%CI 0.45–0.99, p = 0.043) was associated with lower 32-week CR rate. The 16-week and 32-week CR rate (p = 0.036, p = 0.008, respectively) were significantly lower in patients exhibiting both obesity and hyperuricemia. Conclusions: The optimal fertility-sparing treatment efficacy was observed at a BMI of 21–22 kg/m2 in EAH/EEC. Hyperuricemia was an independent risk factor for long-term treatment outcomes.

Not all stage I and II endometrial cancers are created equal: Recurrence-free survival and cause-specific survival after observation or vaginal brachytherapy alone in all subgroups of early-stage high-intermediate and high-risk endometrial cancer

ObjectiveTo evaluate recurrence-free survival (RFS) and cause-specific survival (CSS) after observation or vaginal brachytherapy (VB) alone in all subgroups of early-stage high-intermediate (HIR) and high-risk endometrial cancer (EC). MethodsWe identified patients with stage I HIR (GOG-249 criteria) and stage II endometrioid EC, and stage I and II non-endometrioid EC who underwent surgery at Mayo Clinic and Cleveland Clinic between 1999 and 2016. Three-year RFS and CSS after observation or VB only were estimated in 16 subgroups defined by risk factors. ResultsAmong 4156 ECs, we identified 447 (10.8%) stage I endometrioid HIR, 52 (1.3%) stage II endometrioid, 350 (8.4%) stage I non-endometrioid, and 17 (0.4%) stage II non-endometrioid ECs; observation or VB alone was applied in 349 (78.1%), 24 (46.2%), 187 (53.4%), and 2 (11.8%) patients, respectively. After observation or VB, stage I HIR endometrioid EC subgroups with <2 factors among grade 3, LVSI, or stage IB had a 3-year CSS >95% (lower 95% confidence intervals limit: 89.8%), whereas subgroups with ≥2 factors had poorer outcomes. No EC-related deaths after 3 years were reported in 97 stage IA non-endometrioid ECs without myometrial invasion. Stage II ECs had poor outcomes regardless of histology. ConclusionsObservation or VB only may be sufficient in stage I endometrioid HIR ECs with <2 factors among grade 3, LVSI, or IB and in stage IA non-endometrioid ECs without myometrial invasion. Stratification of early-stage HIR and high-risk ECs into risk subgroups potentially alleviates the overtreatment and undertreatment risk and should be considered in future research.

The role of lymph node dissection in the surgical treatment of endometrial cancer patients (retrospective analysis).

Endometrial cancer in recent years has taken the lead among cancer processes of the female reproductive system. The feasibility of pelvic and para-aortic lymph node dissection in patients with endometrial cancer has always been a controversial issue. The aim of the presented paper is to evaluate the feasibility of pelvic and para-aortic lymph node dissection in patients with endometrial cancer, depending on the stage of the disease, postoperative complications, and patient survival, depending on the volume of surgical intervention. The study involved 285 patients with stages of I-IV endometrioid endometrial cancer of the Pre-graduate Department of Oncogynecology of the National Cancer Institute. The average age of patients was 55 ± 5.7years. In 74.5%, the disease was detected at stage I and uterine extirpation was performed with/without appendages. The duration of the operation varies depending on the volume of intervention-from 1h 30min ± 10min for panhysterectomy, up to 3h 20min ± 10min when performing para-aortic lymph node dissection. The average number of lymph nodes removed was-7 ± 1.1 pelvic and 12 ± 1.5 para-aortic. The basic principles of surgical treatment consist in individual choice of the scope of surgical intervention, performing adequate lymph node dissection, and preventing relapse and metastasis of the disease.

Causal effects of systemic lupus erythematosus on endometrial cancer: A univariable and multivariable Mendelian randomization study.

ObjectiveSystemic lupus erythematosus (SLE) has been observationally associated with endometrial cancer, but the causality remains unclear. Here, we investigated for the first time the causal links between SLE and endometrial cancer risk.MethodsUnivariable and multivariable Mendelian randomization (MR) analyses were conducted to disentangle the causality of SLE with endometrial cancer. Apart from the inverse-variance weighted (IVW) method as the primary MR estimate, three complementary MR techniques including weighted median, weighted mode, and MR-Egger regression in univariable MR were conducted to clarify the robustness of the causal estimate and mediation effects of the body mass index (BMI) and were investigated within multivariable MR-IVW and MR-Egger analyses.ResultsAll univariable MR analyses consistently suggested that SLE has a protective effect on the risk of overall endometrial cancer (IVW: OR = 0.956, 95% CI = 0.932-0.981, P = 0.001) and endometrioid endometrial cancer (IVW: OR = 0.965, 95% CI = 0.933-0.999, P = 0.043). More compelling, after adjustment for BMI within the multivariable MR setting, the association between SLE and decreased risk of overall endometrial cancer was significantly stronger (IVW: OR = 0.952, 95% CI = 0.931-0.973, P = 9.58E-06).ConclusionsOur findings provide evidence of a significant causal relationship between SLE and decreased endometrial cancer risk. Further understanding of the underlying mechanisms linking SLE with endometrial cancer is therefore needed.

Fertility-Sparing Approach in Patients with Endometrioid Endometrial Cancer Grade 2 Stage IA (FIGO): A Qualitative Systematic Review.

Background Endometrial cancer (EC) is one of the most common gynecologic malignancy, mostly in postmenopausal women. The gold standard treatment for EC is surgery, but in the early stages, it is possible to opt for conservative treatment. In the last decade, different clinical and pathological markers have been studied to identify women who respond to conservative treatment. A lot of immunohistochemical markers have been evaluated to predict response to progestin treatment, even if their usefulness is still unclear; the prognosis of this neoplasm depends on tumor stage, and a specific therapeutic protocol is set according to the stage of the disease. Objective (1) To provide an overview of the conservative management of Stage 1A Grade (G) 2 endometrioid EC (FIGO) and the oncological and reproductive outcomes related; (2) to describe the molecular alterations before and after progestin therapy in patients undergoing conservative treatment. Materials and Methods A systematic computerized search of the literature was performed in the main electronic databases (MEDLINE, Embase, Web of Science, PubMed, and Cochrane Library), from 2010 to September 2021, in order to evaluate the oncological and reproductive outcomes in patients with G2 stage IA EC who ask for fertility-sparing treatment. The expression of several immunohistochemical markers was evaluated in pretreatment phase and during the follow-up in relation to response to hormonal therapy. Only scientific publications in English were included. The risk of bias assessment was performed. Review authors' judgments were categorized as “low risk,” “high risk,” or “unclear risk” of bias. Results Twelve articles were included in the study: 7 observational studies and 5 case series/reports. Eighty-four patients who took progestins (megestrol acetate, medroxyprogesterone acetate, and/or levonorgestrel-releasing intrauterine devices) were analyzed. The publication bias analysis turned out to be “low.” 54/84 patients had a complete response, 23/84 patients underwent radical surgery, and 20/84 had a relapse after conservative treatment. Twenty-two patients had a pregnancy. The length of follow-up was variable, from 6 to 142 months according to the different studies analyzed. Several clinical and pathological markers have been studied to identify women who do not respond to conservative treatment: PR and ER were the most studied predictive markers, in particular PR appeared as the most promising; MMR, SPAG9, Ki67, and Nrf2-survivin pathway provided good results with a significant association with a good response to progestin therapy. However, no reliable predictive markers are currently available to be used in clinical practice. Conclusions The conservative treatment may be an option for patients with stage IA G2 EEC who desire to preserve their fertility. The immunohistochemical markers evaluation looks promising in predicting response to conservative treatment. Further large series and randomized clinical trials are needed to confirm these results.

Conservative Management of Atypical Endometrial Hyperplasia and Early Endometrial Cancer in Childbearing Age Women.

Total hysterectomy and bilateral adnexectomy is the standard treatment for atypical endometrial hyperplasia and early-stage endometrial cancer. However, the recommended surgical treatment precludes future pregnancy when these conditions are diagnosed in women in their fertile age. In these patients, fertility-sparing treatment may be feasible if the desire for childbearing is consistent and specific conditions are present. This review summarizes the available evidence on fertility-sparing management for atypical endometrial hyperplasia and early-stage endometrial cancer. Historically, oral progestins have been the mainstay of conservative management for atypical endometrial hyperplasia and stage IA endometrioid endometrial cancer with no myometrial invasion, although there is no consensus on dosage and treatment length. Intrauterine progestin therapy has proved a valid alternative option when oral progestins are not tolerated. GnRH analogs, metformin, and hysteroscopic resection in combination with progestins appear to increase the overall efficacy of the treatment. After a complete response, conception is recommended; alternatively, maintenance therapy with strict follow-up has been proposed to decrease recurrence. The risk of disease progression is not negligible, and clinicians should not overlook the risk of hereditary forms of the disease in young patients, in particular, Lynch syndrome. Hysterectomy is performed once the desire for childbearing desire has been established. The conservative management of atypical endometrial hyperplasia and early-stage endometrial cancer is feasible, provided a strong desire for childbearing and permitting clinical–pathological conditions. However, patients must be aware of the need for a strict follow-up and the risk of progression with a possible consequent worsening of the prognosis. More homogenous and well-designed studies are necessary to standardize and identify the best treatment and follow-up protocols.

The amount of preoperative endometrial tissue surface in relation to final endometrial cancer classification

ObjectiveTo evaluate whether the amount of preoperative endometrial tissue surface is related to the degree of concordance with final low- and high-grade endometrial cancer (EC). In addition, to determine whether discordance is influenced by sampling method and impacts outcome. MethodsA retrospective cohort study within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC). Surface of preoperative endometrial tissue samples was digitally calculated using ImageJ. Tumor samples were classified into low-grade (grade 1–2 endometrioid EC (EEC)) and high-grade (grade 3 EEC + non-endometroid EC). ResultsThe study cohort included 573 tumor samples. Overall concordance between pre- and postoperative diagnosis was 60.0%, and 88.8% when classified into low- and high-grade EC. Upgrading (preoperative low-grade, postoperative high-grade EC) was found in 7.8% and downgrading (preoperative high-grade, postoperative low-grade EC) in 26.7%. The median endometrial tissue surface was significantly lower in concordant diagnoses when compared to discordant diagnoses, respectively 18.7 mm2 and 23.5 mm2 (P = 0.022). Sampling method did not influence the concordance in tumor classification. Patients with preoperative high-grade and postoperative low-grade showed significant lower DSS compared to patients with concordant low-grade EC (P = 0.039). ConclusionThe amount of preoperative endometrial tissue surface was inversely related to the degree of concordance with final tumor low- and high-grade. Obtaining higher amount of preoperative endometrial tissue surface does not increase the concordance between pre- and postoperative low- and high-grade diagnosis in EC. Awareness of clinically relevant down- and upgrading is crucial to reduce subsequent over- or undertreatment with impact on outcome.

Identification of potential models for predicting progestin insensitivity in patients with endometrial atypical hyperplasia and endometrioid endometrial cancer based on ATAC-Seq and RNA-Seq integrated analysis.

Objective: The aim of this study was to establish predictive models based on the molecular profiles of endometrial lesions, which might help identify progestin-insensitive endometrial atypical hyperplasia (EAH) or endometrioid endometrial cancer (EEC) patients before progestin-based fertility-preserving treatment initiation. Methods: Endometrial lesions from progestin-sensitive (PS, n = 7) and progestin-insensitive (PIS, n = 7) patients were prospectively collected before progestin treatment and then analyzed by ATAC-Seq and RNA-Seq. Potential chromatin accessibility and expression profiles were compared between the PS and PIS groups. Candidate genes were identified by bioinformatics analyses and literature review. Then expanded samples (n = 35) were used for validating bioinformatics data and conducting model establishment. Results: ATAC-Seq and RNA-Seq data were separately analyzed and then integrated for the subsequent research. A total of 230 overlapping differentially expressed genes were acquired from ATAC-Seq and RNA-Seq integrated analysis. Further, based on GO analysis, REACTOME pathways, transcription factor prediction, motif enrichment, Cytoscape analysis and literature review, 25 candidate genes potentially associated with progestin insensitivity were identified. Finally, expanded samples were used for data verification, and based on these data, three predictive models comprising 9 genes (FOXO1, IRS2, PDGFC, DIO2, SOX9, BCL11A, APOE, FYN, and KLF4) were established with an overall predictive accuracy above 90%. Conclusion: This study provided potential predictive models that might help identify progestin-insensitive EAH and EEC patients before fertility-preserving treatment.

Fertility-sparing treatment for endometrial cancer and atypical endometrial hyperplasia in patients with Lynch Syndrome: Molecular diagnosis after immunohistochemistry of MMR proteins.

IntroductionLynch Syndrome (LS) represents the hereditary condition that is most frequently associated with endometrial cancer (EC). The aim of this study is to assess the presence of Lynch Syndrome (LS) in young women with mismatch repair (MMR)-deficient atypical endometrial hyperplasia (AEH) and non-myoinvasive FIGO G1 endometrioid EC and its possible impact on the outcome of conservative treatment.MethodsSix MMR-deficient cases identified from a previous cohort of 69 conservatively treated patients were selected to be screened for germline mutations in MMR genes. In each patient, the outcomes of conservative treatment for AEH and EEC, including response, relapse, progression, and pregnancy, were assessed.ResultsFive out of 6 patients underwent genetic test for LS. Three out of these 5 patients showed a positive genetic test. Patient 1 showed the c.942 + 2 T>A heterozygous variant of MSH2 mutation; after 12 months of complete response, she had relapse and progression of disease. Patient 4 showed the c.2459-1G>C variant of MSH2 mutation; after complete response, she failed to achieve pregnancy; she had relapse after 24 months and underwent hysterectomy. Patient 6 showed the c.803 + 1 heterozygous variant of PMS2 mutation; she had relapse of disease after 18 months from the first complete response and then underwent hysterectomy.ConclusionsIn this series, 3 out of 6 women with MMR-deficiency had LS. None of the patients achieved pregnancy, and those who responded to treatment had subsequent relapse of disease. Patients undergoing fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer should perform MMR immunohistochemical analysis in order to screen LS.

Improving Risk Assessment for Metastatic Disease in Endometrioid Endometrial Cancer Patients Using Molecular and Clinical Features: An NRG Oncology/Gynecologic Oncology Group Study.

Simple SummaryJudging the chance (risk) of cancer spread and bad outcome in endometrial cancer continues to be a challenge. Molecular and clinical factors offer the hope of improving the accuracy of judging the danger of cancer spread (metastasis) and a bad outcome (prognosis) to help guide patient care. The aim of this research was to develop a risk score for cancer spread and bad outcome for the most common type of endometrial cancer, endometrioid endometrial cancer, using molecular features and clinical factors in endometrial cancers removed during surgery. The molecular score, referred to as MS7, was more accurate at judging the chance of nodal and distant metastasis than clinical factors like grade 3 disease and myometrial invasion. MS7 score was also better than aggressive molecular subtypes or endometrial cancer-associated genes identified by other research groups. The combination of MS7 score and myometrial invasion was the best at accurately judging the chance of nodal and distant metastasis in the most common type of endometrial cancer. The MS7 score was also shown to accurately indicate bad outcome including cancer progression and death. This research hopes to help guide patient care stopping overtreatment in lower-risk and undertreatment in higher-risk endometrial cancer patients. Objectives: A risk assessment model for metastasis in endometrioid endometrial cancer (EEC) was developed using molecular and clinical features, and prognostic association was examined. Methods: Patients had stage I, IIIC, or IV EEC with tumor-derived RNA-sequencing or microarray-based data. Metastasis-associated transcripts and platform-centric diagnostic algorithms were selected and evaluated using regression modeling and receiver operating characteristic curves. Results: Seven metastasis-associated transcripts were selected from analysis in the training cohorts using 10-fold cross validation and incorporated into an MS7 classifier using platform-specific coefficients. The predictive accuracy of the MS7 classifier in Training-1 was superior to that of other clinical and molecular features, with an area under the curve (95% confidence interval) of 0.89 (0.80–0.98) for MS7 compared with 0.69 (0.59–0.80) and 0.71 (0.58–0.83) for the top evaluated clinical and molecular features, respectively. The performance of MS7 was independently validated in 245 patients using RNA sequencing and in 81 patients using microarray-based data. MS7 + MI (myometrial invasion) was preferrable to individual features and exhibited 100% sensitivity and negative predictive value. The MS7 classifier was associated with lower progression-free and overall survival (p ≤ 0.003). Conclusion: A risk assessment classifier for metastasis and prognosis in EEC patients with primary tumor derived MS7 + MI is available for further development and optimization as a companion clinical support tool.

Does para-aortic lymphadenectomy improve survival in pathologically diagnosed early-stage grade 3 endometrioid and non-endometrioid endometrial cancers? A retrospective cohort study in Korea and Taiwan

PurposeThe therapeutic effect of para-aortic lymphadenectomy in early-stage high-grade endometrial cancer remains controversial. In this study, we investigated whether combined pelvic and para-aortic lymphadenectomy has a survival benefit compared to pelvic lymphadenectomy alone in patients with pathologically diagnosed FIGO stage I-II grade 3 endometrioid and non-endometrioid endometrial cancers. MethodsWe retrospectively reviewed the medical records of 281 patients with histologically confirmed FIGO stage I-II grade 3 endometrioid and non-endometrioid endometrial cancers who underwent pelvic lymphadenectomy alone or combined pelvic and para-aortic lymphadenectomy in staging surgery at two tertiary centers in Korea and Taiwan. Prognostic factors to predict outcomes in these cases were also analyzed. ResultsAmong 281 patients, 144 underwent pelvic lymphadenectomy alone and 137 underwent combined pelvic and para-aortic lymphadenectomy. Within a median follow-up of 45 months, there was no significant difference in recurrence-free survival (RFS) and overall survival (OS) between the two groups. In multivariable analysis, age at diagnosis ≥60 years (HR = 2.20, 95% CI 1.25–3.87, p = 0.006) and positive lymph-vascular space invasion (LVSI) (HR = 2.79, 95% CI 1.60–4.85, p < 0.001) were associated with worse RFS, and only non-endometrioid histology was associated with worse OS (HR = 3.18, 95% CI 1.42–7.12, p = 0.005). In further subgroup analysis, beneficial effects of combined pelvic and para-aortic lymphadenectomy on RFS and OS were not observed. ConclusionsIn this study, combined pelvic and para-aortic lymphadenectomy could not improve survival compared to pelvic lymphadenectomy alone in patients with FIGO stage I-II grade 3 endometrioid and non-endometrioid endometrial cancers. Therefore, para-aortic lymphadenectomy may be omitted for these cases.

Molecular classification grade 3 endometrial endometrioid carcinoma using a next-generation sequencing-based gene panel.

Over the past two decades, the incidence of endometrial cancer (EC) is increasing, and there is a need for molecular biomarkers to predict prognosis and guide treatment. A recent study from The Cancer Genome Atlas suggested to implement the EC analysis by molecular profile for improving diagnosis, prognosis, and therapeutic treatment. In this study, next-generation sequencing was performed on 70 cases of G3 endometrioid ECs (EECs) using an 11-gene panel (TP53, MLH1, MSH2, MSH6, PMS2, EPCAM, PIK3CA, CTNNB1, KRAS, PTEN, and POL) for molecular classification. The molecular classification based on the 11-gene NGS panel identified four molecular subgroups: POLE-ultramutated (n = 20, 28.6%), MSI-H (n = 27, 38.6%), NSMP (n = 13, 18.6%) and TP53mut (n = 10, 14.3%). The NGS method showed 98.6% (69 of 70 cases, kappa value 98%) in concordance with the cases assessed by immunohistochemistry (IHC). Among the seven dead cases, four were MSI-H tumors, two were TP53mut/p53abn tumors, and one was NSMP tumors with an average overall survival (OS) of 14.7 months. TP53mut subgroup showed that poor OS rates and POLE group have favorable prognosis. Our work suggested that the 11-gene panel is suitable for molecular classification in G3 EECs and for guiding prognosis and treatment decisions.