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Background: Racial disparities in outcomes exist in endometrial cancer (EC). The contribution of ancestry‐based variations in germline pathogenic variants (gPVs) is unknown. Methods: Germline assessment of ≥76 cancer predisposition genes was performed in patients with EC undergoing tumor‐normal Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets sequencing from January 1, 2015 through June 30, 2021. Self‐reported race/ethnicity and Ashkenazi Jewish ancestry data classified patients into groups. Genetic ancestry was inferred from Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets. Rates of gPV and genetic counseling were compared by ancestry. Results: Among 1625 patients with EC, 216 (13%) had gPVs; 15 had >1 gPV. Rates of gPV varied by self‐reported ancestry (Ashkenazi Jewish, 40/202 [20%]; Asian, 15/124 [12%]; Black/African American (AA), 12/171 [7.0%]; Hispanic, 15/124 [12%]; non‐Hispanic (NH) White, 129/927 [14%]; missing, 5/77 [6.5%]; p =.009], with similar findings by genetic ancestry (p <.001). We observed a lower likelihood of gPVs in patients of Black/AA (odds ratio [OR], 0.44; 95% CI, 0.22–0.81) and African (AFR) ancestry (OR, 0.42; 95% CI, 0.18–0.85) and a higher likelihood in patients of Ashkenazi Jewish genetic ancestry (OR, 1.62; 95% CI; 1.11–2.34) compared with patients of non‐Hispanic White/European ancestry, even after adjustment for age and molecular subtype. Somatic landscape influenced gPVs with lower rates of microsatellite instability‐high tumors in patients of Black/AA and AFR ancestry. Among those with newly identified gPVs (n = 114), 102 (89%) were seen for genetic counseling, with lowest rates among Black/AA (75%) and AFR patients (67%). Conclusions: In those with EC, gPV and genetic counseling varied by ancestry, with lowest rates among Black/AA and AFR patients, potentially contributing to disparities in outcomes given implications for treatment and cancer prevention. Plain Language Summary: Black women with endometrial cancer do worse than White women, and there are many reasons for this disparity.Certain genetic changes from birth (mutations) can increase the risk of cancer, and it is unknown if rates of these changes are different between different ancestry groups.Genetic mutations in 1625 diverse women with endometrial cancer were studied and the lowest rates of mutations and genetic counseling were found in Black and African ancestry women. This could affect their treatment options as well as their families and may make disparities worse. Among 1625 patients with endometrial cancer, 216 (13%) had germline pathogenic variants, and rates of germline pathogenic variants and subsequent genetic counseling varied by both self‐reported and inferred genetic ancestry, with lowest rates among Black/African American and African patients. These differences could potentially contribute to disparities in outcomes given implications for treatment and cancer prevention and should be further investigated. [ABSTRACT FROM AUTHOR]

Background: A complex relationship between adipose tissue and malignancy, involving an inflammatory response, has been reported. The goal of this work was to assess the prevalence of white adipose tissue (WAT) inflammation in patients with endometrial cancer (EC), and the association with circulating inflammation markers. Furthermore, the aim was to characterize the pathways activated in and the cell type composition of adipose tissue in patients with EC.Methods: Adipose tissue and blood samples were prospectively collected from 101 patients with EC at initial surgery. WAT inflammation was determined based on adipocytes surrounded by macrophages forming crown-like structures. Circulating levels of metabolic syndrome-associated and inflammatory markers were quantified. RNA-sequencing was performed on adipose samples (n = 55); differential gene expression, pathway, and cellular decomposition analyses were performed using state-of-the-art bioinformatics methods.Results: WAT inflammation was identified in 46 (45.5%) of 101 EC patients. Dyslipidemia, hypertension, and diabetes mellitus were significantly associated with WAT inflammation (p < .05). WAT inflammation was associated with greater body mass index (p < .001) and higher circulating levels of leptin, high-sensitivity C-reactive protein, and interleukin-6, as well as lower levels of adiponectin and sex hormone-binding globulin (p < .05). Transcriptomic analysis demonstrated increased levels of proinflammatory and pro-neoplastic-related gene expression in inflamed omental adipose tissue.Conclusions: WAT inflammation is associated with metabolic syndrome, obesity, and inflammatory markers, as well as increased expression of proinflammatory and proneoplastic genes. [ABSTRACT FROM AUTHOR]

Background: PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway.Methods: We conducted a single-arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1-4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss-of-function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1.Results: Twenty-eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1-3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy-evaluable patients, the ORR was 16% (90% CI, 7%-100%), and the clinical benefit rate was 28% (90% CI, 16%-100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression-free survival and overall survival were 2.5 months (95% CI, 1.2-3.0) and 9.2 months (95% CI, 5.0-15.9), respectively. The most common all-grade treatment-related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed.Conclusion: In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single-agent activity and a manageable safety profile. [ABSTRACT FROM AUTHOR]

We propose a new staging system for stage I endometrial cancer and compare its performance to the 1988 and 2009 International Federation of Gynecology and Obstetrics (FIGO) systems.We analyzed patients with 1988 FIGO stage I endometrial cancer from January 1993 to August 2011. Low-grade carcinoma consisted of endometrioid grade 1 to grade 2 lesions. High-grade carcinoma consisted of endometrioid grade 3 or nonendometrioid carcinomas (serous, clear cell, and carcinosarcoma). The proposed system is as follows:IA. Low-grade carcinoma with less than half myometrial invasion IA1: Negative nodes IA2: No nodes removed IB. High-grade carcinoma with no myometrial invasion IB1: Negative nodes IB2: No nodes removed IC. Low-grade carcinoma with half or greater myometrial invasion IC1: Negative nodes IC2: No nodes removed ID. High-grade carcinoma with any myometrial invasion ID1: Negative nodes ID2: No nodes removed Data from 1843 patients were analyzed. When patients were restaged with our proposed system, the 5-year overall survival significantly differed (P < 0.001): IA1, 96.7%; IA2, 92.2%; IB1, 92.2%; IB2, 76.4%; IC1, 83.9%; IC2, 78.6%; ID1, 81.1%; and ID2, 68.8%. The bootstrap-corrected concordance probability estimate for the proposed system was 0.627 (95% confidence interval, 0.590-0.664) and was superior to the concordance probability estimate of 0.530 (95% confidence interval, 0.516-0.544) for the 2009 FIGO system.By incorporating histological subtype, grade, myometrial invasion, and whether lymph nodes were removed, our proposed system for stage I endometrial cancer has a superior predictive ability over the 2009 FIGO staging system and provides a novel binary grading system (low-grade including endometrioid grade 1-2 lesions; high-grade carcinoma consisting of endometrioid grade 3 carcinomas and nonendometrioid carcinomas). [ABSTRACT FROM AUTHOR]

Gemcitabine is active in several gynecologic malignancies including ovarian cancer, cervical cancer, and uterine leiomyosarcoma. It has been used in an off-label setting for the treatment of advanced endometrial cancer, despite lack of published data showing efficacy. We performed a retrospective study to determine the progression-free survival and response rate of endometrial cancer patients treated with gemcitabine at Memorial Sloan-Kettering Cancer Center.Eligible patients had histologically confirmed advanced (stage IV or recurrent) endometrial cancer that was treated with single-agent gemcitabine at Memorial Sloan-Kettering Cancer Center between 1999 and 2009. Response to therapy was determined by review of computed tomography imaging by Response Evaluation Criteria in Solid Tumors 1.1 criteria.Forty-six patients were included in the analysis. Median age was 66 years (range, 52-87 years). All patients were previously treated with chemotherapy. The median number of prior lines of chemotherapy was 2 (range, 1-8). Median dose of gemcitabine administered was 800 mg/m2 infused on days 1 and 8 of a 21-day cycle. Predominant histology was endometrioid (48%, n = 22) followed by serous (35%, n = 16), clear cell (15%, n = 7), and undifferentiated (2%, n = 1). Overall response rate was 10.9% (95% confidence interval, 1.9%-19.9%); 5 patients (11%) achieved a partial response. Thirteen patients (28%) displayed stable disease lasting at least 3 months. Of note, 5 (71%) of the 7 patients with clear cell histology displayed stable disease or partial response (n = 5). The median progression-free survival was 3.0 months (95% confidence interval, 2.1-3.3 months). Nonhematologic grades 3 and 4 toxicities were rare. Ten patients (22%) were treated with granulocyte colony-stimulating factor during treatment. Grade 3 thrombocytopenia was seen in 4 patients (9%). There were no cases of grade 4 thrombocytopenia.In a mixed population of patients with previously treated advanced endometrial cancer, gemcitabine was well tolerated and showed modest activity. Patients with clear cell histology appeared to have greater likelihood of benefit. [ABSTRACT FROM AUTHOR]

The revised 2009 International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer included many changes over the 1988 system, particularly for stage I subgroups. We sought to describe the overall survival (OS) of women with stage I endometrial cancer and examine how the estimated stage-specific OS is altered in the 2009 system.A prospectively maintained institutional endometrial database was analyzed. All patients underwent primary surgery between January 1993 and June 2009.Data from 1658 women were analyzed, including 1307 patients with FIGO 1988 stage I disease. The 5-year OS for the 1988 stages IA (92.4%), IB (87.3%), and IC (75.7%) significantly differed (P < 0.001). When patients were restaged using the 2009 system, we identified 1411 stage I patients with 5-year OS for 2009 stage IA of 89.2%, versus OS of 75.1% for IB (P = 0.001). The adjusted concordance probabilities for the 1988 stage I group and 2009 stage I group were 0.612 (SD, 0.0014) and 0.536 (SD, 0.0111), respectively.The 1988 FIGO classification of stage I endometrial cancer correctly identified 3 subgroups of patients who had significantly different OS. Specifically, 1988 FIGO stages IA and IB had distinct oncologic outcomes. The revised 2009 system eliminates the most favorable group from the new classification system, and estimates of stage-specific OS for stage IB are substantially altered by the changes made in 2009. The revised system for stage I did not improve its predictive ability over the 1988 system. These data highlight the importance of developing individualized risk-prediction models and nomograms in endometrial cancer. [ABSTRACT FROM AUTHOR]

HER2 overexpression is associated with decreased overall survival in metastatic endometrial cancer. Trastuzumab with chemotherapy has demonstrated efficacy for first-line management of advanced HER2+ endometrial carcinoma, but HER2-directed therapy in the recurrent setting is limited. Zanidatamab (ZW25), a humanized, bispecific antibody that simultaneously binds the 2 distinct HER2 epitopes bound by trastuzumab and pertuzumab, has demonstrated safety and activity in HER2+ tumors. Here, we report the results of a phase 2, open-label study evaluating the efficacy and safety of zanidatamab in patients with HER2+ metastatic endometrial carcinoma/carcinosarcoma who received prior treatment. We enrolled 16 patients with HER2+ endometrial carcinoma/carcinosarcoma after progression on ≤2 lines of therapy on a single-arm phase 2 study of zanidatamab. The primary endpoint was overall response rate (ORR; complete or partial response) by Response Evaluation Criteria in Solid Tumors version 1.1. HER2 immunohistochemistry and fluorescence in situ hybridization (FISH) were performed on pretreatment samples. Intratumor HER2 genetic heterogeneity was assessed. This study did not meet its primary efficacy endpoint. Although a clinical benefit rate of 37.5% was observed by 24 weeks, only 1 patient achieved a partial response (ORR, 6.2%). Eight patients had HER2 intratumor heterogeneity or lacked HER2 amplification by FISH. Decreased HER2 expression on repeat pretreatment samples was observed in 3 (75%) of 4 patients evaluated. We observed a low response rate to zanidatamab in recurrent HER2+ endometrial carcinoma/carcinosarcoma, which may be driven by downregulation of HER2 expression. Repeat HER2 testing should be considered prior to second-line HER2-directed therapy. ClinicalTrials.gov identifier : NCT04513665 • HER2 overexpression associated with decreased survival in advanced endometrial cancer (EC). • Zanidatamab in HER2+ metastatic EC/carcinosarcoma did not meet its primary endpoint. • Intratumor heterogeneity/lack of HER2 amplification could have attributed to poor efficacy. [ABSTRACT FROM AUTHOR]

To assess the clinicopathologic, molecular profiles, and survival outcomes of patients with endometrial carcinomas (ECs) harboring telomerase reverse transcriptase (TERT) hotspot mutations or gene amplification. ECs harboring somatic TERT promoter hotspot mutations or gene amplification (TERT -altered) were identified from 1944 ECs that underwent clinical tumor-normal sequencing from 08/2016–12/2021. Clinicopathologic variables, somatic mutation profiles, and survival outcomes of TERT -alt and TERT -wild-type EC were assessed. We identified 66 TERT -altered ECs (43 TERT -mutated and 23 TERT -amplified), representing 3% of the unselected ECs across histologic subtypes. Most TERT -altered ECs were of copy number (CN)-high/TP53abn molecular subtype (n = 40, 60%), followed by microsatellite-unstable (MSI-H) or CN-low/no specific molecular profile (NSMP)(n = 13, 20% each). TERT- amplified and TERT- mutated ECs were molecularly distinct, with TERT- amplified ECs being more genomically instable and more frequently harboring TP53 and PPP2R1A alterations (q < 0.1). Compared to TERT -wild-type ECs, TERT -altered ECs were more commonly of CN-H/TP53abn molecular subtype (31% vs 57%, p = 0.001), serous histology (10% vs 26%, p = 0.004), and were significantly enriched for TP53 , CDKN2A/B, and DROSHA somatic genetic alterations (q < 0.1). Median progression-free survival was 18.7 months (95% CI 11.8–not estimable [NE]) for patients with TERT -altered EC and 80.9 months (65.8-NE) for patients with TERT- wild-type EC (HR 0.33, 95% CI 0.21–0.51, p < 0.001). Similarly, median overall survival was 46.7 months (95% CI 30-NE) for TERT- altered EC patients and not reached for TERT- wild-type EC patients (HR 0.24, 95% CI 0.13–0.44, p < 0.001). TERT -altered ECs, although rare, are enriched for CN-high/TP53abn tumors, TP53 , CDKN2A/B and DROSHA somatic mutations, and independently predict worse survival outcomes. • TERT promoter hotspot mutations and gene amplification in endometrial cancer (EC) are rare. • TERT alterations are enriched in high-risk ECs. • Patients with TERT -altered EC have inferior survival outcomes compared to those with TERT -wild-type EC. • TERT alteration stratifies survival outcomes of CN-H/TP53abn molecular subtype ECs. • Within TERT- altered ECs, TERT- amplified ECs are enriched for TP53 and PPP2R1A mutations compared to TERT- mutated ECs. [ABSTRACT FROM AUTHOR]

To evaluate adverse events (AEs) of combination lenvatinib plus pembrolizumab for the treatment of recurrent endometrial cancer (EC) and to assess outcomes by lenvatinib starting dose. We retrospectively reviewed patients with recurrent EC treated with lenvatinib plus pembrolizumab at our institution between 10/1/2019–11/30/2021. Starting dose of lenvatinib was defined as standard (20 mg) or reduced (10 mg/14 mg). AEs were manually extracted through chart review and graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. PFS, overall survival (OS), and duration of response (DOR) were analyzed. Forty-three patients were identified; median age was 67 years (range, 54–85). The most common histologies were serous (35%), endometrioid (23%), and carcinosarcoma (21%). Starting lenvatinib doses were 10 mg (n = 10), 14 mg (n = 10), and 20 mg (n = 23). Median number of cycles received was 8 (range, 1–42). Twenty-four patients (56%) required ≥1 lenvatinib dose reduction; 3 (7%) discontinued lenvatinib, and 1 (2%) discontinued pembrolizumab for intolerance or AE. Thirty-six patients (84%) experienced grade ≥ 3 AEs; hypertension, weight loss, anemia, fatigue, and thrombocytopenia were most common. The standard dose group experienced significantly shorter observed PFS vs the reduced dose group (P =.02). There was no difference in DOR (P =.09) or OS (P =.27) between the groups. In clinical practice, AEs associated with combination lenvatinib plus pembrolizumab were common and comparable to Study 309/KEYNOTE-775 findings. AEs were similar regardless of starting lenvatinib dose. Further dose optimization studies of lenvatinib plus pembrolizumab may be indicated in recurrent EC. Clinical trial data remain the gold standard to guide starting lenvatinib dosing. • Adverse events associated with combination lenvatinib plus pembrolizumab for recurrent endometrial cancer are common • Adverse events with lenvatinib plus pembrolizumab observed in this study were similar to those in Study 309/KEYNOTE-775 • The most common grade ≥ 3 adverse events were hypertension, anemia, weight loss, fatigue, and thrombocytopenia • Overall survival was similar between patients treated with the standard starting lenvatinib dose compared to a reduced dose [ABSTRACT FROM AUTHOR]

Using next generation sequencing (NGS), The Cancer Genome Atlas (TCGA) found that endometrial carcinomas (ECs) fall under one of four molecular subtypes, and a POLE mutation status, mismatch repair (MMR) and p53 immunohistochemistry (IHC)-based surrogate has been developed. We sought to retrospectively classify and characterize a large series of unselected ECs that were prospectively subjected to clinical sequencing by utilizing clinical molecular and IHC data. All patients with EC with clinical tumor-normal MSK-IMPACT NGS from 2014 to 2020 (n = 2115) were classified by integrating molecular data (i.e., POLE mutation, TP53 mutation, MSIsensor score) and MMR and p53 IHC results. Survival analysis was performed for primary EC patients with upfront surgery at our institution. Utilizing our integrated approach, significantly more ECs were molecularly classified (1834/2115, 87%) as compared to the surrogate (1387/2115, 66%, p < 0.001), with an almost perfect agreement for classifiable cases (Kappa 0.962, 95% CI 0.949–0.975). Discrepancies were primarily due to TP53 mutations in p53-IHC-normal ECs. Of the 1834 ECs, most were of copy number (CN)-high molecular subtype (40%), followed by CN-low (32%), MSI-high (23%) and POLE (5%). Histologic and genomic variability was present amongst all molecular subtypes. Molecular classification was prognostic in early- and advanced-stage disease, including early-stage endometrioid EC. The integration of clinical NGS and IHC data allows for an algorithmic approach to molecularly classifying newly diagnosed EC, while overcoming issues of IHC-based genetic alteration detection. Such integrated approach will be important moving forward given the prognostic and potentially predictive information afforded by this classification. • Clinical sequencing and immunohistochemistry data integration allows for endometrial cancer (EC) molecular classification • Integrated classification is highly concordant with existing surrogates while allowing more ECs to be classified • Integrated classification overcomes issues of immunohistochemistry-based detection of genetic alterations • Integrated molecular classification has prognostic value across all stages and histologic types of EC [ABSTRACT FROM AUTHOR]

Increased numbers of tumor infiltrating lymphocytes (TIL) in endometrial cancer (EC) are associated with improved survival, but it is unclear how this prognostic significance relates to the underlying EC molecular subtype. In this explorative hypothesis-generating study, we sought to define the immune signatures associated with the molecular subtypes of EC (i.e., POLE -mutated, microsatellite unstable (MSI-high), copy number (CN)-low, and CN-high) and to determine their correlation with patient outcomes. RNA-sequencing and molecular subtype data of 232 primary ECs were obtained from The Cancer Genome Atlas. Deconvolution of bulk gene expression data was performed using s ingle s ample G ene S et E nrichment A nalysis (ssGSEA) and C ell type I dentification B y E stimating R elative S ubsets O f known R NA T ranscripts (CIBERSORT). The association of the resultant immune signatures with overall survival was determined across molecular subtypes. Statistically significant differences in enrichment were identified in 16/30 and 6/23 immune gene sets by ssGSEA and CIBERSORT, respectively. Signature of CD8+ cells in ECs of CN-high molecular subtype was associated with improved overall survival by ssGSEA (p = 0.0108), while CD8 signatures did not appear to be prognostic in MSI-high (p = 0.74) or CN-low EC molecular subtypes (p = 0.793). Of all molecular subtypes, CN-high ECs exhibited the lowest levels of CD8+ T cell infiltration. Consistent with antigen-induced T cell activation and exhaustion, enrichment for immunomodulatory receptors was predominantly observed in ECs of MSI-high and POLE- mutated molecular subtypes. Deconvolution of bulk gene expression data can be used to identify populations of immune infiltrated endometrial cancers with improved survival. These data support the existence of unique mechanisms of immune resistance within molecular subgroups of the disease. • Distinct molecular subtypes of endometrial cancer (EC) exhibit divergent immune infiltration signatures. • Copy number (CN)-high ECs exhibit the lowest levels of CD8+ T cell infiltration of all molecular subtypes. • CD8 T cell infiltration transcriptional signatures are prognostic in CN-high ECs. [ABSTRACT FROM AUTHOR]

Our understanding of the biologic heterogeneity of endometrial cancer has improved, but which patients benefit from single-agent versus combination immune checkpoint blockade remains unclear. We conducted a single-center, randomized, open-label, phase 2 study of durvalumab 1500 mg (Arm 1) versus durvalumab 1500 mg plus tremelimumab 75 mg every 4 weeks (Arm 2) in patients with endometrial carcinoma. The primary endpoints were overall response rate (ORR) and progression-free survival (PFS) at 24 weeks. Patients were stratified by mismatch repair (MMR) status and carcinosarcoma histology. Using a Simon two-stage minimax design, we determined 40 patients per arm would provide 90% power and Type 1 error of 10%. Eighty-two patients were enrolled; 77 were evaluable for toxicity (Arm 1: 38, Arm 2: 39) and 75 evaluable for efficacy (Arm 1: 37, Arm 2: 38). Patient were stratified by MMR status (Arm 1: 5, Arm 2: 4 were MMR-deficient). The ORR in Arm 1 was 10.8% (one-sided 90% CI: 4.8–100%); the ORR in Arm 2 was 5.3% (one-sided 90% CI: 1.4–100%). Since the primary endpoint of ORR was not met, 24-week PFS was not compared to historical controls per protocol specification. No new safety signals were identified. In these patients with predominantly MMR-proficient endometrial cancer, there was limited response with single-agent and combined immune checkpoint blockade. The pre-specified efficacy thresholds were not met for further evaluation. A deeper understanding of potential mechanisms of resistance to immunotherapy in MMR-proficient endometrial cancer is needed for the development of novel therapeutic approaches. • Durvalumab has limited efficacy in all-comers but predominately mismatch repair-proficient (pMMR) endometrial cancer. • Combination durvalumab and tremelimumab similarly has limited efficacy in this predominately pMMR population. • Further molecular integration is needed to identify patients who may benefit from combination targeted/immunotherapies. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study was to evaluate whether surgical removal of regional lymph nodes influences the overall survival of women with endometrial carcinoma. Study Design: All patients with endometrioid-type endometrial cancer treated at our institution between January 1993 and December 2004 were reviewed. The Classification and Regression Tree (CART) method, a form of recursive partitioning, was used. Results: In all, 1035 patients were evaluated. International Federal of Gynecology and Obstetrics stage included the following: stage I, 824; stage II, 65; stage III, 109; and stage IV, 37. Lymph nodes were removed in 524 patients (51%). The median number of nodes removed was 16. Using the CART hierarchically, stage, age, adjuvant therapy, and the removal of 10 lymph nodes or more emerged as predictors of overall survival. Conclusion: This study emphasizes the importance of lymph node dissection in endometrial cancer. Lymph node dissection is essential for accurate surgical staging, which remains the most important prognostic factor. In addition to well-known clinicopathologic risk factors for survival, the removal of 10 or more regional lymph nodes was associated with improved overall survival in lower-stage, older patients who received no adjuvant therapy or brachytherapy only. [Copyright &y& Elsevier]

Abstract: Objective. : YKL-40 is a secreted glycoprotein of the chitinase family that has been previously described as a diagnostic and prognostic marker for a number of cancers, including epithelial ovarian cancer. In this study, we examined the frequency of serum elevation as well as the diagnostic and prognostic significance of this serum marker in endometrial cancer. Materials and methods. : Preoperative serum levels of YKL-40 and CA125 were evaluated by enzyme-linked immunosorbent assay (ELISA) for all endometrial cancer patient samples (34) available in the Memorial Sloan-Kettering Cancer Center Gynecology Service Tissue Bank between the years 1987 and 2002, and compared to a cohort of normal individuals. A YKL-40 value of 61 ng/mL has previously been determined to represent the upper limit of normal. YKL-40 values were correlated with clinical characteristics, including patient age, tumor grade, histology, clinical stage, and clinical outcome (progression-free survival [PFS] and overall survival [OS]). Results. : YKL-40 was elevated (>61 ng/mL) in 26 (76%) of 34 endometrial cancer patients compared with elevations of CA125 in 21 (62%) of 34 patients (P =0.09). Twenty-eight (82%) of all 34 patients had elevations of either CA125 or YKL-40 or both; 16 (89%) of 18 advanced-stage endometrial cancer patients had elevation of at least one of these two markers. Median preoperative YKL-40 value was 137 ng/mL (range, 22–1738 ng/mL) for endometrial cancer patients compared with 28 ng/mL (range, 15–72 ng/mL) for normal healthy subjects (P <0.0001). There was no statistically significant association of YKL-40 with patient age, tumor grade, histology, or stage. Elevation of YKL-40 (>80 ng/mL) was correlated with poor clinical outcome in univariate analysis, but was not demonstrated in multivariate analysis. At 5 years'' follow-up, the PFS rate was 80% for patients with YKL-40 <80 ng/mL compared with 43% for patients with YKL-40 >80 ng/mL (P =0.004). The 5-year OS rate for patients with YKL-40 <80 ng/mL was 79% compared with 48% for patients with YKL-40 >80 ng/mL (P =0.047). Conclusion. : Preoperative serum YKL-40 is frequently elevated and may represent a novel marker for the detection of endometrial cancer and the identification of high-risk subsets of patients with worse clinical outcome. Further investigation of this promising endometrial cancer marker in larger studies is warranted. [Copyright &y& Elsevier]

Abstract: Objectives. : To describe the incidence of symptomatic postoperative lower-extremity lymphedema in women treated for uterine corpus cancer, and to evaluate its relationship to regional lymph node removal and postoperative therapy. Methods. : A retrospective chart review of all patients with uterine corpus cancer managed over a 12-year period (1/93–12/04). All patients had a hysterectomy as part of their therapy. We identified patients with leg lymphedema – as described by the physician or reported by the patient – through medical records. We excluded cases of leg edema that developed secondary to medical conditions such as cardiovascular and renal disease, venous thrombosis, and end-stage recurrent malignancy. Lymphedema dermal changes and related fibrosis were graded using the common terminology criteria for adverse events. Results. : In all, 1289 patients with uterine corpus malignancy were evaluated. We excluded other chronic lower-extremity edema that was related to a variety of medical conditions in 74 patients (5.7%). With a median follow-up of 3 years (interquartile range, 1.1–5.4 years), new symptomatic post-treatment lower-extremity lymphedema was noted in 16 patients. Patients who had lymph nodes removed at initial surgery had a higher rate of developing lymphedema (16/670, 2.4%) than those who did not (0/619, 0%) (P = 0.0001). Furthermore, symptomatic lymphedema was limited to patients who had 10 or more regional lymph nodes removed 16/469 (3.4%). Lymphedema was noted at a median of 5.3 months after surgery (range, 1–32 months). Lymphedema was unilateral in 11 patients (69%) and bilateral in 5 (31%); moreover, it was considered grade 1 in 12 patients (75%) and grade 2 in 4 (25%). Age, weight, stage, type of hysterectomy, and type of postoperative adjuvant therapy were not associated with lymphedema. Conclusions. : To date, this is the largest series evaluating symptomatic lower-extremity lymphedema in women with uterine corpus cancer. Patients who had 10 or more regional lymph nodes removed at initial surgery appeared to be at higher risk for developing new symptomatic leg lymphedema. Patients undergoing surgery with lymphadenectomy for uterine corpus malignancy should be informed about the possibility of postoperative new symptomatic leg lymphedema. A prospective evaluation of leg lymphedema is needed to accurately determine the incidence, severity, and risk factors of this complication. [Copyright &y& Elsevier]

To examine the role of non-exenterative secondary cytoreductive surgery (SCS) compared with non-surgical treatments and identify predictors of improved survival for patients with recurrent endometrial cancer (EC). All patients undergoing primary surgical management for EC 1/1/2009–12/31/2017 who subsequently developed recurrence were retrospectively identified. Survival was determined from date of diagnosis of first recurrence to last follow-up and estimated using Kaplan-Meier method. Differences in survival were analyzed using Log-rank and Wald tests, based on Cox Proportional Hazards model. Among 376 patients with recurrent EC, median time to recurrence was 14.3 months (range, 0.2–102.2), post-recurrence median survival 29 months, median follow-up 29.2 months (range, 0–116). Sixty-one patients (16.2%) received SCS, 257 (68.4%) medical management (MM) (chemotherapy and/or radiation therapy), 32 (8.5%) hormonal therapy, 26 (6.9%) no further therapy. Patients selected for SCS were younger, had more endometrioid histology, more stage I disease at initial diagnosis, no residual disease after primary surgery, longer interval to first recurrence or progression, and the longest OS (57.6 months) (95% CI, 33.3–not reached). On multivariate analysis SCS was an independent predictor of improved survival. Among the 61 SCS patients, age < 70 at time of initial diagnosis, and endometrioid histology, were associated with improved post-relapse survival univariately (p = 0.008, 0.03, respectively). While MM was the most common treatment for first recurrence of EC, patients selected for surgery demonstrated the greatest survival benefit even after controlling for tumor size, site, histology, stage, time to recurrence. Careful patient selection and favorable tumor factors likely play a major role in improved outcomes. Surgical management should be considered whenever feasible in medically eligible patients, with additional consideration given to our suggested criteria. • In recurrent endometrial cancer, secondary cytoreductive surgery (SCS) confers better survival than other treatments. • Age <70 at initial diagnosis, and endometrioid histology, were associated with improved survival in SCS. • In well-selected, medically eligible patients, surgical management should be considered whenever technically feasible. [ABSTRACT FROM AUTHOR]

Prospective data have demonstrated the efficacy of bevacizumab monotherapy in the treatment of advanced endometrial cancer. Bevacizumab is used off-label, and real-world data regarding the role of bevacizumab in endometrial cancer treatment are scant. In this largest single-institution retrospective study of its kind, we report our experience with bevacizumab monotherapy in the treatment of advanced/recurrent endometrial cancer. All eligible patients (n = 101) had histologically confirmed endometrial cancer and were treated with bevacizumab at our institution from 2004 to 2017. Demographic data and tumor characteristics were obtained through chart review. Primary objective was response to therapy determined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Analysis included 13 grade 1/2 endometrioid, 15 grade 3 endometrioid, 44 serous, 8 carcinosarcoma, and 21 other/mixed histologies. No patients achieved complete (CR) or partial (PR) responses; 19 achieved stable disease (SD). The clinical benefit rate (CBR; CR + PR + SD) was 19% (95% CI: 12–28%). The CBRs were 7%, 17%, 21%, and 23% for patients with 1, 2, 3, and ≥ 4 prior treatment lines. Median PFS ranged from 2.6 months (2 lines) to 4.9 months (≥4 lines). The 3-year OS rate was 58% (95% CI: 47–67%). The median OS was 3.4 years (95% CI: 2.9–4.2), ranging from 2.5 years (2 lines) to 4.5 years (≥4 lines). The most common treatment-related adverse event was hypertension; 35 (78%) of 45 were grade 1 or 2. In heavily pretreated advanced endometrial cancer, bevacizumab was associated with modest clinical efficacy and remains a viable palliative option in this setting. • Bevacizumab had a clinical benefit rate of 19% in pretreated advanced endometrial cancer patients. • Bevacizumab is well tolerated in heavily treated endometrial cancer and should be considered as a palliative therapy. • Future trials with bevacizumab should incorporate the molecular classification of endometrial cancer. • Bevacizumab should be considered in novel combinations with immunotherapy/PARP inhibitors to potentially improve outcomes. [ABSTRACT FROM AUTHOR]

Selinexor, a selective inhibitor of nuclear export, monotherapy causes nuclear accumulation of tumor-suppressor proteins and has anti-tumor activity in ovarian and endometrial cancers. The safety and tolerability of oral selinexor plus intravenous carboplatin and paclitaxel chemotherapy (selinexor + CP) was evaluated in this population. This phase I, 3 + 3 dose-escalation study assessed 4 selinexor + CP regimens. Patients in cohorts of 3, regardless of disease type, were administered 1 of 4 alternating regimens (selinexor at 30 mg/m2 or 60 mg plus CP at AUC 5 and 175 mg/m2 or 80 mg/m2, respectively) for 6–10 cycles (1 cycle = 21 days), followed by selinexor maintenance. Enrolled patients with ovarian cancer had received 1 prior platinum-based therapy. Patients with endometrial cancer were chemotherapy-naive or had received 1 prior platinum-based therapy. Response was evaluated every 9 weeks. Twenty-three patients were treated (5 serous ovarian cancer; 18 endometrial cancer, including 6 carcinosarcomas). The most common treatment-related adverse events (TRAEs) were thrombocytopenia (100%), leukopenia (91%), and hyperglycemia (87%). The most common grade 3/4 TRAEs were leukopenia (70%), neutropenia (70%), lymphopenia (61%), anemia (57%), and alanine transaminase increase (43%). One treatment-related dose-limiting toxicity (grade 3 syncope) occurred. Twelve patients achieved a partial response and 1 achieved a complete response. Responses to all four regimens were observed in ovarian and endometrial cancers. Combination selinexor + CP was safe and tolerated in advanced ovarian and endometrial cancers. • Exportin 1 (XPO1/CRM1), a primary karyopherin, facilitates nuclear export of nearly all known tumor suppressor proteins. • Selinexor blocks XPO1 and has demonstrated anti-tumor activity as a monotherapy in advanced gynecological malignancies. • We evaluated the safety of selinexor with carboplatin and paclitaxel (CP) in advanced ovarian and endometrial cancers. • The recommended phase II dose of selinexor was established as a 60 mg flat dose weekly in combination with CP. • Preliminary efficacy was seen in all evaluated regimens and in both ovarian and endometrial cancer patients. [ABSTRACT FROM AUTHOR]

To compare the prevalence of patient-reported lower-extremity lymphedema (LEL) with sentinel lymph node (SLN) mapping versus comprehensive lymph node dissection (LND) for the surgical management of newly diagnosed endometrial carcinoma. Patients who underwent primary surgery for endometrial cancer from 01/2006-12/2012 were mailed a survey that included a validated 13-item LEL screening questionnaire in 08/2016. Patients diagnosed with LEL prior to surgery and those who answered ≤6 survey items were excluded. Of 1275 potential participants, 623 (49%) responded to the survey and 599 were evaluable (180 SLN, 352 LND, 67 hysterectomy alone). Median BMI was similar among cohorts (P = 0.99). External-beam radiation therapy (EBRT) was used in 10/180 (5.5%) SLN and 35/352 (10%) LND patients (P = 0.1). Self-reported LEL prevalence was 27% (49/180) and 41% (144/352), respectively (OR, 1.85; 95% CI, 1.25–2.74; P = 0.002). LEL prevalence was 51% (23/45) in patients who received EBRT and 35% (170/487) in those who did not (OR, 1.95; 95% CI, 1.06–3.6; P = 0.03). High BMI was associated with increased prevalence of LEL (OR, 1.04; 95% CI, 1.02–1.06; P = 0.001). After controlling for EBRT and BMI, LND retained independent association with an increased prevalence of LEL over SLN (OR, 1.8; 95% CI, 1.22–2.69; P = 0.003). Patients with self-reported LEL had significantly worse QOL compared to those without self-reported LEL. This is the first study to assess patient-reported LEL after SLN mapping for endometrial cancer. SLN mapping was independently associated with a significantly lower prevalence of patient-reported LEL. High BMI and adjuvant EBRT were associated with an increased prevalence of patient-reported LEL. • SLN mapping was independently associated with significantly lower rate of patient-reported lower extremity lymphedema (LEL). • Increasing BMI and use of adjuvant EBRT were associated with an increased prevalence of patient-reported LEL. • SLN mapping in the surgical management of newly diagnosed endometrial cancer may spare these patients from LEL. • Survival outcomes were similar between SLN mapping and comprehensive lymphadenectomy after endometrial cancer surgery. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The objectives of the study are to evaluate which clinicopathologic factors influenced overall survival (OS) in endometrial carcinoma and to determine if the surgical effort to assess para-aortic (PA) lymph nodes (LNs) at initial staging surgery impacts OS. Methods: All patients diagnosed with endometrial cancer from 1/1993–12/2011 who had LNs excised were included. PALN assessment was defined by the identification of one or more PALNs on final pathology. A multivariate analysis was performed to assess the effect of PALNs on OS. A form of recursive partitioning called classification and regression tree (CART) analysis was implemented. Variables included: age, stage, tumor subtype, grade, myometrial invasion, total LNs removed, evaluation of PALNs, and adjuvant chemotherapy. Results: The cohort included 1920 patients, with a median age of 62years. The median number of LNs removed was 16 (range, 1–99). The removal of PALNs was not associated with OS (P =0.450). Using the CART hierarchically, stage I vs. stages II–IV and grades 1–2 vs. grade 3 emerged as predictors of OS. If the tree was allowed to grow, further branching was based on age and myometrial invasion. Total number of LNs removed and assessment of PALNs as defined in this study were not predictive of OS. Conclusion: This innovative CART analysis emphasized the importance of proper stage assignment and a binary grading system in impacting OS. Notably, the total number of LNs removed and specific evaluation of PALNs as defined in this study were not important predictors of OS. [Copyright &y& Elsevier]

Abstract: Objectives: Nomograms are predictive models that provide the overall probability of a specific outcome. Nomograms have shown better individual discrimination than currently used staging systems in numerous tumor entities. Recently, a nomogram for predicting overall survival (OS) in women with endometrial cancer was introduced by Memorial Sloan–Kettering Cancer Center (MSKCC). The aim of this study was to test the validity of the MSKCC endometrial cancer nomogram using an independent, external patient cohort. Methods: The MSKCC nomogram is based on five readily available clinical characteristics. A multi-institutional endometrial cancer database was used to test the nomogram''s validity. All consecutive patients treated for endometrial cancer between December 1995 and May 2011 and who had all nomogram variables documented were identified for analysis. Results: Seven hundred sixty-five eligible patients were identified and used for external validation analysis. In the Austrian patient cohort, median OS was 134months, and 3-year and 5-year OS rates were 83.8% (95% CI, 80.6–86.5%) and 77.2% (95% CI, 43.5–80.5%), respectively. The nomogram concordance index was 0.71 (SE=0.017; 95% CI, 0.68–0.74). The correspondence between the actual OS and the nomogram predictions suggests a good calibration of the nomogram in the validation cohort. Conclusion: The MSKCC endometrial cancer nomogram was externally validated and was shown to be generalizable to a new and independent patient population. The nomogram provides a more individualized and accurate estimation of OS for patients diagnosed with endometrial cancer following primary therapy. The nomogram can be used for counseling patients more accurately and for better stratifying patients for clinical trials. [Copyright &y& Elsevier]