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Background: Serous endometrial carcinoma (SEC) is a high-risk subtype of endometrial cancer. The effectiveness of multiple adjuvant therapies, namely chemotherapy (CT), radiotherapy (RT), and sequential/concurrent chemotherapy with radiotherapy (CRT), have previously been investigated. However, optimal management of early-stage SEC remains unclarified. Methods: All cases of early-stage SEC (FIGO 2009 stages I–II) treated in our institution from 2002 to 2019 were identified. Patient data were documented until September 2023. Overall survival (OS) and disease-free survival (DFS) were computed using Kaplan–Meier estimates and Cox's proportional hazard model; descriptive statistical analysis was performed. Results: A total of 50 patients underwent total hysterectomy-bilateral salpingo-oophorectomy and omentectomy, displaying stage IA (60%), IB (24%), and II (16%) disease. The median follow-up was 90.9 months. Patients underwent adjuvant CRT (n = 36, 72%), CT (n = 6, 12%), or RT (n = 6, 12%). Two patients were observed and excluded from analyses. The 42 patients who received radiotherapy had pelvic external beam radiotherapy (n = 10), vaginal brachytherapy (n = 21), or both (n = 11). CRT had better OS (HR 0.14, 95%CI 0.04–0.52, p < 0.005) and DFS (HR 0.25, 95%CI 0.07–0.97, p = 0.05) than CT alone. RT displayed no OS or DFS benefits compared to CT/CRT. Recurrences were mostly distant. Acute and late G3-4 toxicities were primarily hematologic. Conclusions: Our data underline the challenge of treating SEC. CRT appears to be superior to CT alone but not to RT. Most recurrences were distant, highlighting the need for optimized systemic treatment options. [ABSTRACT FROM AUTHOR]

Background: Serous endometrial carcinoma (SEC) is a high-risk subtype of endometrial cancer. The effectiveness of multiple adjuvant therapies, namely chemotherapy (CT), radiotherapy (RT), and sequential/concurrent chemotherapy with radiotherapy (CRT), have previously been investigated. However, optimal management of early-stage SEC remains unclarified. Methods: All cases of early-stage SEC (FIGO 2009 stages I–II) treated in our institution from 2002 to 2019 were identified. Patient data were documented until September 2023. Overall survival (OS) and disease-free survival (DFS) were computed using Kaplan–Meier estimates and Cox’s proportional hazard model; descriptive statistical analysis was performed. Results: A total of 50 patients underwent total hysterectomy-bilateral salpingo-oophorectomy and omentectomy, displaying stage IA (60%), IB (24%), and II (16%) disease. The median follow-up was 90.9 months. Patients underwent adjuvant CRT (n = 36, 72%), CT (n = 6, 12%), or RT (n = 6, 12%). Two patients were observed and excluded from analyses. The 42 patients who received radiotherapy had pelvic external beam radiotherapy (n = 10), vaginal brachytherapy (n = 21), or both (n = 11). CRT had better OS (HR 0.14, 95%CI 0.04–0.52, p < 0.005) and DFS (HR 0.25, 95%CI 0.07–0.97, p = 0.05) than CT alone. RT displayed no OS or DFS benefits compared to CT/CRT. Recurrences were mostly distant. Acute and late G3-4 toxicities were primarily hematologic. Conclusions: Our data underline the challenge of treating SEC. CRT appears to be superior to CT alone but not to RT. Most recurrences were distant, highlighting the need for optimized systemic treatment options.

Background & Introduction: Serous cancers are a biologically aggressive variety of endometrial cancer (EC) with a high rate of recurrence and mortality among all the subtypes. Herein we describe our experience with serous endometrial cancer. Objective: This study was conducted to identify the clinicopathological characteristics, treatment modalities and survival outcomes in women diagnosed with serous endometrial malignancies. Methods: This was a retrospective descriptive analysis of data on patients diagnosed with serous endometrial tumours between January 2010 to September 2019 in our institute collected from electronic medical records. Descriptive statistics such as proportions, means and standard deviations and Cox regression hazards model on risk factors were performed. Survival was plotted by Kaplan-Meier curves. Results: During the study period, 32 (5.7%) patients out of 564 diagnosed cases of endometrial cancer had serous histology. The mean age at diagnosis was 62.5 years (SD 7.6) while mean BMI was 26.4 kg/m2 (SD 4.6). Staging laparotomy was done in 27(84%) of the patients. Advanced stages (III and IV) were detected in 16 patients (50%) at primary surgery.Adjuvant chemo therapy and radiation was received by 21(65.6%) patients therapy. Out of 32 patients, 13 (40%) developed recurrence while another 13 expired. Stage at diagnosis and type of adjuvant therapy were important factors in determining the outcome. Median recurrence free and overall survival was 22(95% CI 1.4–42) and 36 months (95% CI 10.1–61.8) respectively. Conclusion: Serous endometrial cancers are an intrusive subtype of EC. Comprehensive surgical staging with optimal cytoreduction should be aimed at. Adequate upfront molecular categorization of these tumors is mandated. Adjuvant therapy with chemotherapy and radiation is given in postoperative setting. Targeted therapies and immunotherapy could be considered in recurrences.

Background: Giant tumors of the abdominal cavity, as a rule, occur in elderly patients with characteristic features and represent a serious problem in terms of choosing a radical method of therapy. Of particular difficulty are cases of giant serous endometrial cancer, requiring a differential diagnosis with ovarian cancer. Clinical case description: A clinical case of giant serous endometrial cancer mimicking ovarian cancer in a 55-year-old woman is presented. The patient came to the oncology department with complaints of abdominal enlargement, difficulty breathing and bloody discharge from the genital tract. The examination revealed the following: a giant formation (4065 cm), occupying the entire pelvic and the entire abdominal cavities, ascites, lesions of the retroperitoneal lymph nodes, and the greater omentum, an umbilical hernia. A chest CT showed multiple contrast-accumulating circular shadows of 313 mm (metastases). By the decision of the council, after the preliminary chemoembolization of both the uterine and ovarian arteries, a supravaginal amputation of the uterus with appendages was performed, along with the resection of the greater omentum, removal of the umbilical hernia with positioning a plastic mesh implant and excision of an excess skin flap. The histological examination of the intraoperative material made it possible to verify the diagnosis of a serous endometrial carcinoma with subtotal tumor necrosis, the myometrium invasion of more than a half of its thickness, with the egress to the perimetrium, metastatic lesions of both ovaries, the greater omentum, anterior abdominal wall. Stage T3b (FIGO IIIB). In the postoperative period, 6 courses of Paclitaxel / Carboplatin (AUC4-5) chemotherapy were carried out with a pronounced clinical effect. The patient was discharged in a satisfactory condition. The control PET-CT scan after the 6th chemotherapy course showed no pathology in the thoracic cavity, and no process progress in the abdominal cavity. Currently, the remission of the disease is 9 months. Conclusion: An algorithm for the diagnostic measures aimed at making the correct diagnosis is presented, and the tactics of treating a patient with giant serous endometrial cancer is described.

Simple Summary: Uterine serous carcinoma is considered a rare and aggressive variant of endometrial cancer that accounts for 10% of all endometrial cancers diagnosed but is responsible for 40% of endometrial cancer-related deaths. Unfortunately, current treatments for serous endometrial carcinoma are ineffective. Therefore, there is a need to find new therapeutic targets. The aim of this study was to analyse the metabolic profile of serous cancer in order to identify new molecules and thereby define potential therapeutic targets. We observed that most of the differential metabolites are lipid species (suggesting the important role of the lipid metabolism). In addition, we found an increase in 2-Oxo-4-methylthiobutanoic acid (synthesised by the ADI1 enzyme) in serous carcinomas. Using public database analysis and immunohistochemistry, we established a correlation between elevated ADI1 levels and serous carcinoma. Furthermore, the ectopic modification of ADI1 expression in vitro revealed the ability of ADI1 to induce pathological cell migration and invasion capabilities. Metabolomic profiling analysis has the potential to highlight new molecules and cellular pathways that may serve as potential therapeutic targets for disease treatment. In this study, we used an LC-MS/MS platform to define, for the first time, the specific metabolomic signature of uterine serous carcinoma (SC), a relatively rare and aggressive variant of endometrial cancer (EC) responsible for 40% of all endometrial cancer-related deaths. A metabolomic analysis of 31 ECs (20 endometrial endometrioid carcinomas (EECs) and 11 SCs) was performed. Following multivariate statistical analysis, we identified 232 statistically different metabolites among the SC and EEC patient samples. Notably, most of the metabolites identified (89.2%) were lipid species and showed lower levels in SCs when compared to EECs. In addition to lipids, we also documented metabolites belonging to amino acids and purine nucleotides (such as 2-Oxo-4-methylthiobutanoic acid, synthesised by acireductone dioxygenase 1 (ADI1) enzyme), which showed higher levels in SCs. To further investigate the role of ADI1 in SC, we analysed the expression protein levels of ADI1 in 96 ECs (67 EECs and 29 SCs), proving that the levels of ADI1 were higher in SCs compared to EECs. We also found that ADI1 mRNA levels were higher in p53 abnormal ECs compared to p53 wild type tumours. Furthermore, elevated ADI1 mRNA levels showed a statistically significant negative correlation with overall survival and progression-free survival among EEC patients. Finally, we tested the ability of ADI1 to induce migration and invasion capabilities in EC cell lines. Altogether, these results suggest that ADI1 could be a potential therapeutic target in poor-prognosis SCs and other Ecs with abnormal p53 expression. [ABSTRACT FROM AUTHOR]

Objective: Serous endometrial cancer (USC) is a challenging malignancy associated with metastasis, recurrence and poor outcome. To identify clinically relevant prognostic biomarkers, we focused on a panel of proteins selected after a comprehensive literature review, for tumour profiling of a homogeneous cohort of USC patients. Methods: Protein levels and localization were assessed by immunohistochemistry analysis in 36 hysterectomy samples. Tissue sections were stained with the following antibodies: Aurora A, phospho (T288) Aurora A, BRCA1, CHK1, CIP2A, Cyclin B1, Cyclin E, E2F-1, phospho (S364) E2F-1, FBXW7, FOXM1, phospho (S9) GSK3Beta, PLK1, phospho (T210) PLK1, PPP2R1B, p73, RAD51. Each marker was evaluated as a continuously-scaled variable for association with disease progression and death, using Cox proportional hazards models. The sample consisted of 36 patients with USC, half with stage III or IV disease. Results: Results showed that higher CHK1 (Checkpoint kinase 1) expression was associated with a decreased risk of progression and death, after adjusting for stage. Interestingly, analysis of a TCGA data set of 109 USC patients corroborates our results showing a favourable prognostic role of CHEK1 after adjusting for stage. Higher FBXW7 (F-box and WD repeat domain containing 7) expression and higher cytoplasmic expression of PPP2R1B (Protein Phosphatase 2 A, Scaffold Subunit Abeta) were each associated with a decreased risk of progression, after adjusting for stage. Conclusions: In conclusion, results from the present study identify new clinically relevant biomarkers and potential drug targets for uterine serous endometrial cancer. [ABSTRACT FROM AUTHOR]

ONC206 (Oncoceutics) is an imipiridone with nanomolar potency and analogue of ONC201, a selective dopamine receptor D2 (DRD2) antagonist currently being investigated in phase II clinical trials for serous endometrial cancer (SEC). This study investigated the anti-proliferative efficacy of ONC206 in SEC cell lines as well as its impact on cellular stress and adhesion/invasion. ONC206 inhibited cellular proliferation in a dose-dependent manner and was more potent than ONC201 in the ARK1 (IC50 = 0.33µM vs. IC50 = 1.59uM) and SPEC-2 (IC50 = 0.24uM vs. IC50 = 0.81uM) cell lines. Treatment with ONC206 resulted in induction of ROS production and reduction of mitochondrial membrane potential, accompanied by an increase in cleaved caspase-3 and caspase-9 activity (p < 0.01). ONC206 also significantly inhibited cellular adhesion and migration in both cell lines (p < 0.01). Pretreatment with the stress inhibitor N-acetylcysteine (NAC) significantly attenuated the efficacy of ONC206 on cell proliferation, ROS production and cellular invasion. ONC206 demonstrates nanomolar potency for the inhibition of proliferation in SEC cells. Specifically, ONC206 utilizes ISR activation as a significant pathway in the propagation of its anti-proliferative and anti-metastatic effects. Thus, ONC206 may be a promising agent in future SEC clinical trials as was its predecessor ONC201.

Objective: To study the association between the preoperative value of serum HE4 marker and poor histological prognostic factors depending on the subtype of endometrial cancer (EC): endometrioid and non-endometrioid tumors. Methods: Prospective and multicenter cohort study including patients with EC in Miguel Servet University Hospital of Zaragoza (Spain) and Hospital Clínico San Carlos of Madrid (Spain) from January 2017 to March 2020. Preoperative serum levels of HE4 were analyzed by clinical and pathological characteristics. Results: Overall, 190 patients were included. Of them, 158 were subtype I of EC and 32 were subtype II tumors. In endometrioid EC, a statistically significant association was found between the preoperative HE4 value and tumor size (p < 0.001), deep myometrial invasion (p = 0.001), lymphovascular space invasion (LVSI) (p = 0.002), cervical (p = 0.001), adnexal (p = 0.023), isthmus (p < 0.001) and parametrial involvement (p = 0.012), lymph node metastasis (p = 0.025) and FIGO stage (p < 0.001). On the contrary, no histological factors showed statistical association except LVSI (p = 0.025) in the non-endometrioid subtype. Conclusions: The preoperative value of HE4 is related differently with several established prognostic factors for EC according to the histological type of tumor. These results could be relevant in order to standardize a prognostic value of HE4 in EC. [ABSTRACT FROM AUTHOR]

ONC206 (Oncoceutics) is an imipiridone with nanomolar potency and analogue of ONC201, a selective dopamine receptor D2 (DRD2) antagonist currently being investigated in phase II clinical trials for serous endometrial cancer (SEC). This study investigated the anti-proliferative efficacy of ONC206 in SEC cell lines as well as its impact on cellular stress and adhesion/invasion. ONC206 inhibited cellular proliferation in a dose-dependent manner and was more potent than ONC201 in the ARK1 (IC50 = 0.33µM vs. IC50 = 1.59uM) and SPEC-2 (IC50 = 0.24uM vs. IC50 = 0.81uM) cell lines. Treatment with ONC206 resulted in induction of ROS production and reduction of mitochondrial membrane potential, accompanied by an increase in cleaved caspase-3 and caspase-9 activity (p < 0.01). ONC206 also significantly inhibited cellular adhesion and migration in both cell lines (p < 0.01). Pretreatment with the stress inhibitor N-acetylcysteine (NAC) significantly attenuated the efficacy of ONC206 on cell proliferation, ROS production and cellular invasion. ONC206 demonstrates nanomolar potency for the inhibition of proliferation in SEC cells. Specifically, ONC206 utilizes ISR activation as a significant pathway in the propagation of its anti-proliferative and anti-metastatic effects. Thus, ONC206 may be a promising agent in future SEC clinical trials as was its predecessor ONC201. [ABSTRACT FROM AUTHOR]

An association between BRCA pathogenic variants and an increased endometrial cancer risk, specifically serous-like endometrial cancer, has been postulated but remains unproven, particularly for BRCA2 carriers. Mechanistic evidence is lacking, and any link may be related to tamoxifen exposure or testing bias. Hysterectomy during risk-reducing bilateral salpingo-oophorectomy is, therefore, of uncertain benefit. Data from a large, prospective cohort will be informative. Data on UK BRCA pathogenic variant carriers were interrogated for endometrial cancer diagnoses. Standardised incidence ratios (SIRs) were calculated in four distinct cohorts using national endometrial cancer rates; either from 1/1/1980 or age 20, prospectively from date of personal pathogenic variant report, date of family pathogenic variant report or date of risk-reducing salpingo-oophorectomy. Somatic BRCA sequencing of 15 serous endometrial cancers was performed to detect pathogenic variants. Fourteen cases of endometrial cancer were identified in 2609 women (1350 BRCA1 and 1259 BRCA2), of which two were prospectively diagnosed. No significant increase in either overall or serous-like endometrial cancer risk was identified in any of the cohorts examined (SIR = 1.70, 95% confidence interval = 0.74–3.33; no cases of serous endometrial cancer diagnosed). Results were unaffected by the BRCA gene affected, previous breast cancer or tamoxifen use. No BRCA pathogenic variants were detected in any of the serous endometrial cancers tested. Women with a BRCA pathogenic variant do not appear to have a significant increased risk of all-type or serous-like endometrial cancer compared with the general population. These data provide some reassurance that hysterectomy is unlikely to be of significant benefit if performed solely as a preventive measure. • Endometrial cancer risk was not increased in BRCA1/2 pathogenic variant carriers. • Results were unaffected by BRCA gene, previous breast cancer or tamoxifen use. • No specific increase in serous-like endometrial cancer risk was identified. • Sequencing of 15 serous endometrial tumours revealed no pathogenic BRCA1/2 variants. [ABSTRACT FROM AUTHOR]

Purpose of Investigation: To analyze overall survival (OS) and disease-free survival (DFS) in a retrospective series of 125 patients with serous, clear cell, and high-grade endometrioid carcinoma having undergone complete treatment (primary surgery, oncology treatments, and follow up) at the present institution. Materials and Methods: All women with high-grade endometrial cancer having undergone surgery (1998-2012) and postoperatively treated and monitored at Split University Hospital Center, whose tissue samples were stored at Department of Pathology, Split University Hospital Center, were included in the study. Survival time was analyzed with Kaplan-Meier method and the log-rank test was used to assess between-group differences. Cox proportional hazard regression model was used on multivariate survival analysis. Patients were followed from the time of primary surgery until death or last follow up in December 2015. Results: Women with serous and clear cell endometrial cancer had similar survival compared to those with high-grade endometrioid endometrial cancer. On multivariate analysis, only earlier stage was an independent predictor of improved survival. Conclusions: The present findings suggest that serous and clear cell endometrial carcinomas have a similar prognosis compared to high-grade endometrioid carcinoma of the uterus. [ABSTRACT FROM AUTHOR]

Objective: High grade and non-endometrioid endometrial cancers carry a poor prognosis, and the lack of randomized prospective data has led to a wide range of practice regarding adjuvant therapy. The objective of this study was to evaluate the outcomes of different treatment strategies in patients with high-risk, early-stage endometrial cancer. Methods: Patients with high-grade endometrioid, serous endometrial cancer and carcinosarcoma diagnosed between 2000 and 2012 were identified from databases in three gynecologic oncology divisions, in Toronto and in Israel. Adjuvant treatment practices differed across the centers, creating a heterogeneous cohort. A comparison of stage I patients stratified by adjuvant treatment was undertaken. Log-rank tests and Cox proportional hazards models were employed to compare recurrence and survival across treatment groups. Results: 490patients with high risk endometrial cancer were identified, among them 213 patients with stage I disease. Israeli patients received more chemotherapy (41% vs 10% in stage I disease; P<0.001) than patients in Toronto. Chemotherapy was not associated with improved disease-free, disease-specific or overall survival, nor was it associated with fewer distant recurrences (50% vs 54%). Radiation was also not associated with improved recurrence or survival, nor did it affect the pattern of recurrence. On Cox multivariable analysis, neither radiation treatment nor chemotherapy were significantly associated with outcome (HR for recurrence, 0.72 for pelvic radiation (P=0.46) and 1.99 for chemotherapy (P=0.09); HR for death, 0.67 for pelvic radiation (P=0.29) and 1.03 for chemotherapy (P=0.94)). Conclusions: In this retrospective analysis, neither adjuvant radiation nor chemotherapy were associated with improved outcome in stage I, high risk endometrial cancer. [ABSTRACT FROM AUTHOR]

To investigate the influence of malignant peritoneal cytology (MPC) on the prognosis of early-stage patients with endometrial clear cell carcinoma(CCC) and serous carcinoma(SC), and the value of chemotherapy in their treatment. A retrospective observational cohort study was conducted by querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2010 to 2019. Women with early-stage CCC and SC with available peritoneal cytology results were enrolled. Propensity score matching(PSM) and propensity score inverse probability of treatment weighting (IPTW) was used to balance the measured covariates in each sub-cohort. A total of 3,616 eligible patients were included, and 368 patients had MPC (10.2%). Women with MPC were more likely to receive postoperative chemotherapy (OR 2.033; 95%CI 1.589–2.602). In PSM model, MPC had worse overall survival(OS) and cancer-specific survival (CSS) (All,p < 0.001). The 5-year OS rates were 56.5% for women with MPC and 74.4% for those with negative peritoneal cytology, and the 5-year CSS rates were 60.8% versus 80.0%(All, p < 0.0001). In the subgroup analyses, MPC was associated with decreased OS and CSS in serous, clear cell histology group, and stage IA cases(All,p < 0.001), but not for stage IB or stage II disease. In multivariate analysis, chemotherapy improved the prognosis of patients with MPC(OS:p = 0.005; CSS:p = 0.010). Additionally, in stage IA subgroup, chemotherapy improved survival outcomes in patients with MPC(OS:P = 0.025; CSS:P = 0.038), in NPC patients, however, chemotherapy was a good prognostic factor for OS (P = 0.001) but not for CSS(P = 0.300). MPC was a prognostic factor for decreased survival in early-stage endometrial CCC and SC, and those with MPC could further benefit from chemotherapy. [ABSTRACT FROM AUTHOR]

Endometrial cancer is the most common, and second most lethal, gynecological malignancy, and its rates of incidence and death are growing. This is likely attributable to increased numbers of high-risk type II endometrial cancers which account for ~ 30% of cases but ~ 75% of deaths due to their aggressive and metastatic behaviour. Histopathological and in vitro functional studies suggest that aberrant TGFβ1 signaling may contribute to endometrial cancer development and the acquisition of invasive/metastatic characteristics. However, little is known about the cellular and molecular mechanisms of TGFβ1 in high-risk endometrial cancers. In the present study, we examined the roles and mechanisms of TGFβ1 on cell adhesion and motility in type II endometrial cancer cell lines, KLE and HEC-1B. We show that treatment with TGFβ1 increases cell adhesion to vitronectin and transwell cell migration. We also demonstrate that TGFβ1 treatment increases integrin β3 and αv mRNA and protein levels via SMAD-independent MEK-ERK1/2 signaling. Importantly, siRNA depletion or antibody-mediated blocking of integrin αvβ3 reversed the effects of TGFβ1 on cell adhesion and migration. Our results suggest that TGFβ1-MEK-ERK1/2-integrin αvβ3 signaling could contribute to the invasive behaviour of high-risk endometrial cancer by promoting cell adhesion and migration. [ABSTRACT FROM AUTHOR]

Background & Introduction: Serous cancers are a biologically aggressive variety of endometrial cancer (EC) with a high rate of recurrence and mortality among all the subtypes. Herein we describe our experience with serous endometrial cancer., Objective: This study was conducted to identify the clinicopathological characteristics, treatment modalities and survival outcomes in women diagnosed with serous endometrial malignancies., Methods: This was a retrospective descriptive analysis of data on patients diagnosed with serous endometrial tumours between January 2010 to September 2019 in our institute collected from electronic medical records. Descriptive statistics such as proportions, means and standard deviations and Cox regression hazards model on risk factors were performed. Survival was plotted by Kaplan-Meier curves., Results: During the study period, 32 (5.7%) patients out of 564 diagnosed cases of endometrial cancer had serous histology. The mean age at diagnosis was 62.5 years (SD 7.6) while mean BMI was 26.4 kg/m 2 (SD 4.6). Staging laparotomy was done in 27(84%) of the patients. Advanced stages (III and IV) were detected in 16 patients (50%) at primary surgery.Adjuvant chemo therapy and radiation was received by 21(65.6%) patients therapy. Out of 32 patients, 13 (40%) developed recurrence while another 13 expired. Stage at diagnosis and type of adjuvant therapy were important factors in determining the outcome. Median recurrence free and overall survival was 22(95% CI 1.4-42) and 36 months (95% CI 10.1-61.8) respectively., Conclusion: Serous endometrial cancers are an intrusive subtype of EC. Comprehensive surgical staging with optimal cytoreduction should be aimed at. Adequate upfront molecular categorization of these tumors is mandated. Adjuvant therapy with chemotherapy and radiation is given in postoperative setting. Targeted therapies and immunotherapy could be considered in recurrences., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Abstract: Objective: Although the epidemiology of typical endometrial carcinomas (grades 1–2 endometrioid or Type I) is well established, less is known regarding higher grade endometrioid or non-endometrioid carcinomas (Type II). Within a large Gynecologic Oncology Group trial (GOG-210), which included central pathology review, we investigated the etiologic heterogeneity of endometrial cancers by comparing risk factors for different histologic categories. Methods: Based on epidemiologic questionnaire data, risk factor associations, expressed as odds ratios (OR) with 95% confidence intervals (CI), were estimated comparing grade 3 endometrioid and Type II cancers (including histologic subtypes) to grades 1–2 endometrioid cancers. Results: Compared with 2244 grades 1–2 endometrioid cancers, women with Type II cancers (321 serous, 141 carcinosarcomas, 77 clear cell, 42 mixed epithelial with serous or clear cell components) were older; more often non-white, multiparous, current smokers; and less often obese. Risk factors for grade 3 endometrioid carcinomas (n=354) were generally similar to those identified for Type II cancers, although patients with grade 3 endometrioid tumors more often had histories of breast cancer without tamoxifen exposure while those with Type II tumors were more frequently treated with tamoxifen. Patients with serous cancers and carcinosarcomas more frequently had breast cancer histories with tamoxifen treatment compared to patients with other tumors. Conclusions: Risk factors for aggressive endometrial cancers, including grade 3 endometrioid and non-endometrioid tumors, appear to differ from lower grade endometrioid carcinomas. Our findings support etiologic differences between Type I and II endometrial cancers as well as additional heterogeneity within Type II cancers. [Copyright &y& Elsevier]

Abstract: Objective: Abdominal peritoneal implants are characteristic of uterine serous carcinoma (USC). The presumed mechanism of dissemination is retrograde transit via the fallopian tube. We assessed the impact of tubal ligation (TL) on the metastatic profile and survival of USC patients. Methods: Patient risk factors, process-of-care variables, and disease-specific parameters were annotated. Categorical variables were compared using the χ2 test. Overall survival (OS) was estimated via the Kaplan–Meier method. Results: Among 211 USC patients, fallopian tube status was documented in 142 patients; 35 had a history of TL and 107 did not. When comparing patients with and without TL, positive peritoneal cytology was present, respectively, in 18.8% vs 45.0% (P =.01) and stage IV disease in 14.3% vs 34.6% (P =.02). Using Cox models, age was the sole significant determinant of OS in stage I/II USC. By contrast, age, lymphovascular space involvement, positive cytology, and TL independently and adversely affected survival in stage III/IV USC. Adjusting for these factors in a multivariable model, the association between TL and OS among patients with advanced disease yielded a hazard ratio of 8.61 (95% CI, 3.08–24.03; P <.001). The prevalence of lymphatic metastasis and nodal tumor burden was significantly greater in patients who underwent ligation. Conclusion: Patients with TL had significantly lower rates of positive cytology and stage IV disease than patients without TL. The lymphatic system appeared to be the dominant mode of spread after TL and was associated with a paradoxic worsening of OS, perhaps reflecting a delay in diagnosis. [Copyright &y& Elsevier]

Abstract: Objective: To report a single institution experience in surgical stage I–II serous endometrial cancer using combined carboplatin/paclitaxel and intravaginal radiation (IVRT). Methods: Between 10/00 and 12/06, 25 stage I–II patients with serous endometrial cancer were treated at our institution with surgery, postoperative IVRT, and concurrent chemotherapy (CT). Results: The mean age was 67 years old (range, 53–80 years). Surgery consisted of hysterectomy (TAH/BSO, 64%, LAVH/BSO, 36%), peritoneal washing, omental biopsy, and pelvic lymph-node dissection (median 14 nodes). Para-aortic node sampling was done in 88% (median, 6). IVRT median dose was 21 Gy (range, 18–21 Gy, in 3 fractions) and concurrent CT consisted of carboplatin to AUC=5 and taxol to 175 mg/m2 given every 3 weeks for 6 cycles. CT was well tolerated with 22/25 (88%) receiving 6 cycles. Three patients received ≤5 cycles; 2 owing to physician preference (3 and 4 cycles) and 1 owing to toxicity (5 cycles). Only 1 patient (4%) had grade 3 toxicity (abscess). Grade 2 neurotoxicity was seen in 5 patients (20%). All patients finished their IVRT as scheduled, and there was no grade 3 toxicity. With a median follow-up of 30 months, the 5-year progression-free and overall survival rate was 88%. None of the patients developed vaginal recurrence. Conclusions: Based on this study, surgical staging followed by IVRT and carboplatin/paclitaxel is well tolerated and effective in stage I–II serous endometrial cancer. Confirmation of these results on a larger number of patients with longer follow-up is still needed. [Copyright &y& Elsevier]

Abstract: Background : Endometrial cancers with a component of serous histology generally occur in postmenopausal women and can present with advanced disease even in the absence of a deeply myoinvasive primary malignancy. We present a case of stage IIIC endometrial cancer with serous histology in a 17-year-old. Case : A 17-year-old presented with menorrhagia requiring blood transfusion and a transvaginal ultrasound demonstrated a 31 mm endometrial stripe within a bulky uterus. Endometrial curettage revealed a grade 2 endometrioid adenocarcinoma. The patient desired definitive surgical management for her disease; a stage IIIC endometrial cancer with focal low-grade serous carcinoma among a grade 2 endometrioid carcinoma was noted to be superficially myoinvasive. Multiple pelvic lymph nodes had evidence of metastatic serous adenocarcinoma. Platinum-based chemotherapy was administered, and the patient is without disease 24 months following therapy. Conclusion : Advanced endometrial cancer with metastasis of serous carcinoma to the retroperitoneal lymph nodes can occur, albeit extraordinarily rarely, in very young women. This information is critically important when counseling a woman regarding conservative management of endometrial adenocarcinoma with the interest of preservation of her fertility. [Copyright &y& Elsevier]

Vaidya AP, Littell R, Krasner C, Duska LR. Treatment of uterine papillary serous carcinoma with platinum-based chemotherapy and paclitaxel. Int J Gynecol Cancer 2006; 16(Suppl. 1):267–272. Uterine papillary serous carcinoma (UPSC) is more aggressive than endometrioid endometrial cancer, as it often presents with advanced disease and follows a pattern of spread that resemblesthe serous carcinoma of the ovary. There exists little data on evaluating the combination of carboplatin and paclitaxel in UPSC. Institutional Review Board permission was obtained for a retrospective review. Tumor registry search was used to identify all patients with UPSC from 1990 to 2003. Charts were retrospectively evaluated from patients who had received at least three cycles of carboplatin and paclitaxel as first-line chemotherapy. Only patients with histologically confirmed UPSC who were treated first line with carboplatin/paclitaxel chemotherapy were included. Nineteen patients with UPSC were identified, who were treated with carboplatin and paclitaxel in the first-line adjuvant setting after initial surgical cytoreduction. All patients received at least three cycles, with 12 of the 19 patients receiving six cycles. Five patients were treated with consolidation radiotherapy following first-line chemotherapy. Mean age was 69 years (range 55–88). The majority of patients had stage III disease ( n= 11). Mean follow-up for the group was 29.5 months (7–76 months). A median progression-free interval of 12 months was seen across the entire cohort. Fourteen patients achieved a complete response following chemotherapy. The results of Gynecologic Oncology Group protocol 122 suggest that patients with advanced endometrial cancer have an improved progression-free survival when treated primarily with chemotherapy rather than radiation therapy. The results of our study show a high response rate to paclitaxel/carboplatin outpatient chemotherapy in a group of patients historically believed to have chemoresistant disease. Further prospective study of this regimen is planned. [ABSTRACT FROM AUTHOR]

Simple Summary: Serous endometrial cancer is an unusual and aggressive endometrial cancer subtype, conferring the highest mortality of all endometrial cancers. In many ways, it resembles the more common tumor entity high-grade serous ovarian cancer. Thus, there is an urgent need for better treatment options for serous endometrial cancer patients. It is crucial for all dividing cells that the DNA repair is functioning correctly. Our aim was to investigate deficiencies in DNA repair in serous endometrial cancer, in particular the presence of homologous recombination repair deficiency. This kind of DNA repair defect may indicate that a specific targeted therapy, so-called PARP inhibitors, which are already in use for the treatment of ovarian cancer, may be useful also in serous endometrial cancer. This study contributes to the largely unexplored field of DNA repair deficiencies in serous endometrial cancer, and may hence contribute to future improved prognosis for these patients. Serous endometrial cancer (SEC) resembles high-grade serous ovarian cancer (HGSOC) genetically and clinically, with recurrent copy number alterations, TP53 mutations and a poor prognosis. Thus, SEC patients may benefit from targeted treatments used in HGSOC, e.g., PARP inhibitors. However, the preclinical and clinical knowledge about SEC is scarce, and the exact role of defective DNA repair in this tumor subgroup is largely unknown. We aimed to outline the prevalence of homologous recombination repair deficiency (HRD), copy-number alterations, and somatic mutations in SEC. OncoScan SNP arrays were applied to 19 tumors in a consecutive SEC series to calculate HRD scores and explore global copy-number profiles and genomic aberrations. Copy-number signatures were established and targeted sequencing of 27 HRD-associated genes was performed. All factors were examined in relation to HRD scores to investigate potential drivers of the HRD phenotype. Ten of the 19 SEC tumors (53%) had an HRD score > 42, considered to reflect an HRD phenotype. Higher HRD score was associated with loss of heterozygosity in key HRD genes, and copy-number signatures associated with non-BRCA1/2 dependent HRD in HGSOC. A high number of SECs display an HRD phenotype. It remains to be elucidated whether this also confers PARP inhibitor sensitivity. [ABSTRACT FROM AUTHOR]

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets. • Proteogenomics provides new insights into oncogenic signaling in endometrial carcinoma • Global acetylome and phosphoproteome surveys identify new regulatory mechanisms • QKI, circRNAs, and miRNAs form a potential feedback loop to promote EMT • Antigen presentation defects may render MSI tumors resistant to checkpoint blockade Proteogenomic analyses of prospectively collected endometrial carcinomas provide insights into the role of underlying molecular pathways and the immune landscape that drive disease. [ABSTRACT FROM AUTHOR]

High-risk type II endometrial cancers account for ~30% of cases but ~75% of deaths due, in part, to their tendency to metastasize. Histopathological studies of type II endometrial cancers (non-endometrioid, mostly serous) suggest overproduction of activin B and down-regulation of E-cadherin, both of which are associated with reduced survival. Our previous studies have shown that activin B increases the migration of type II endometrial cancer cell lines. However, little is known about the relationship between activin B signaling and E-cadherin in endometrial cancer. We now demonstrate that activin B treatment significantly decreases E-cadherin expression in both a time- and concentration-dependent manner in KLE and HEC-50 cell lines. Interestingly, these effects were not inhibited by knockdown of SMAD2, SMAD3 or SMAD4. Rather, the suppressive effects of activin B on E-cadherin were mediated by MEK-ERK1/2-induced production of the transcription factor SNAIL. Importantly, activin B-induced cell migration was inhibited by forced-expression of E-cadherin or pre-treatment with the activin/TGF-β type I receptor inhibitor SB431542 or the MEK inhibitor U0126. We have identified a novel SMAD-independent pathway linking enhanced activin B signaling to reduced E-cadherin expression and increased migration in type II endometrial cancer., Competing Interests: The authors have nothing to disclose

Endometrial cancer is the fourth most common female cancer and the most common gynecological malignancy. Although it comprises only ~10% of all endometrial cancers, the serous histological subtype accounts for ~40% of deaths due to its aggressive behavior and propensity to metastasize. Histopathological studies suggest that elevated expression of activin/inhibin βB subunit is associated with reduced survival in non-endometrioid endometrial cancers (type II, mostly serous). However, little is known about the specific roles and mechanisms of activin B (βB dimer) in serous endometrial cancer growth and progression. In the present study, we examined the biological functions of activin B in type II endometrial cancer cell lines, HEC-1B and KLE. Our results demonstrate that treatment with activin B increases cell migration, invasion and adhesion to vitronectin, but does not affect cell viability. Moreover, we show that activin B treatment increases integrin β3 mRNA and protein levels via SMAD2/3-SMAD4 signaling. Importantly, siRNA knockdown studies revealed that integrin β3 is required for basal and activin B-induced cell migration, invasion and adhesion. Our results suggest that activin B-SMAD2/3-integrin β3 signaling could contribute to poor patient survival by promoting the invasion and/or metastasis of type II endometrial cancers.