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OBJECTIVE: To describe trends in the use of lymphadenectomy for endometrioid adenocarcinoma of the endometrium between 1998 and 2012. METHODS: A time-trend analysis was conducted using a population-based cancer registry covering 28% of the population of the United States. To quantify differences over the study period time, the frequency of lymphadenectomy and nodal metastasis among women who underwent surgical treatment of endometrioid endometrial adenocarcinoma was compared among consecutive 3- to 4-year periods. Biannual frequency of lymphadenectomy was modeled with Joinpoint regression to identify when potential changes in trends occurred and calculate annual percentage change. RESULTS: A total of 74,365 women who underwent surgery between 1998 and 2012 were analyzed. Frequency of lymphadenectomy increased by 4.2% annually (95% confidence interval [CI] 3.7–4.6) from 1998 to 2007, after which the frequency declined by 1.6% per year (95% CI 0.9–2.2). Between 1998–2000 and 2007–2009, the frequency of lymphadenectomy rose from 48.7% to 65.5% (risk difference 16.8%, 95% CI 15.4–18.1), the proportion of women found to have nodal metastasis increased by 1.1% (95% CI 0.4–1.7), and the frequency of negative lymphadenectomy increased by 15.7% (95% CI 14.3–17.1). The decline in frequency of lymphadenectomy after 2007 was associated a 3.1% (95% CI 2.1–4.1) decline in the rate of negative lymphadenectomy, but no change in the proportion of women found to have nodal metastasis (P=.17). CONCLUSION: The frequency of lymphadenectomy in the surgical treatment of endometrioid endometrial cancer increased by 4.2% annually from 1998 to 2007 and decreased by 1.6% annually from 2007 to 2012. LEVEL OF EVIDENCE: II

To describe the incidence of thromboembolic events (venous thromboembolism) before and after the diagnosis of epithelial endometrial cancer and to evaluate the effects of these events on survival.We used the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registries linked to Medicare claim files to identify patients with epithelial endometrial cancer diagnosed between 1992 and 2009. To identify venous thromboembolism events 3 months before diagnosis and up to 24 months after diagnosis, we used International Classification of Diseases, 9th Revision, and Healthcare Common Procedure Coding System codes.A total of 23,122 patients were included; of them 1,873 (8.1%) developed a venous thromboembolism. Patients with low-grade (grades 1 and 2) endometrioid adenocarcinoma had a significantly lower rate of venous thromboembolism 3 months before and 6 months after the diagnosis of cancer (3.6%; 95% confidence interval [CI] 3.3-3.9%) compared with carcinosarcoma (9.2%; 95% CI 7.8-10.8%), clear cell (6.9%; 95% CI 4.8-9.7%), uterine serous cancer (8.1%; 95% CI 7.01-9.3%), and grade 3 endometrioid adenocarcinoma (6.1%; 95% CI 5.4-6.9%) (P.001). On multivariate analysis during the same time period, most recent time periods of diagnosis, carcinosarcoma histology compared with lower grade endometrial cancer, higher stage, African American race, marital status, chemotherapy delivery, and lymph node dissection were associated with increased risk of venous thromboembolism. The median overall survival for women who experienced a venous thromboembolism 3 months before the diagnosis of endometrial cancer was 31 months (95% CI 20-48 months); in women diagnosed with venous thromboembolism 6 months after the cancer diagnosis was 37 months (95% CI 31-44), and in women who did not experienced a venous thromboembolism was 111 months (95% CI 109-114). After adjusting for prognostic factors, there was an association between venous thromboembolism diagnosed 3 months before endometrial cancer (hazard ratio 1.69, 95% CI 1.34-2.13) or 6 months after the diagnosis (hazard ratio 1.57, 95% CI 1.44-1.71) and lower survival.Patients with uterine serous cancer, carcinosarcoma, clear cell carcinoma, and grade 3 endometrioid adenocarcinoma had a higher rate of venous thromboembolism than patients with low-grade endometrioid adenocarcinoma. A diagnosis of venous thromboembolism was associated with decreased survival in elderly patients with endometrial cancer.II.

Objective Uterine serous carcinoma (USC) represents an aggressive subtype of endometrial cancer. We sought to understand Notch pathway activity in USC and determine if pathway inhibition has anti-tumor activity. Methods Patient USC tissue blocks were obtained and used to correlate clinical outcomes with Notch1 expression. Three established USC cell lines were treated with gamma-secretase inhibitor (GSI) in vitro . Mice harboring cell line derived or patient derived USC xenografts (PDXs) were treated with vehicle, GSI, paclitaxel and carboplatin (P/C), or combination GSI and P/C. Levels of cleaved Notch1 protein and Hes1 mRNA were determined in GSI treated samples. Statistical analysis was performed using the Wilcoxon rank sum and Kaplan–Meier methods. Results High nuclear Notch1 protein expression was observed in 58% of USC samples with no correlation with overall survival. GSI induced dose-dependent reductions in cell number and decreased levels of cleaved Notch1 protein and Hes1 mRNA in vitro . Treatment of mice with GSI led to decreased Hes1 mRNA expression in USC xenografts. In addition, GSI impeded tumor growth of cell line xenografts as well as UT1 USC PDXs. When GSI and P/C were combined, synergistic anti-tumor activity was observed in UT1 xenografts. Conclusions Notch1 is expressed in a large subset of USC. GSI-mediated Notch pathway inhibition led to both reduced cell numbers in vitro and decreased tumor growth of USC some xenograft models. When combined with conventional chemotherapy, GSI augmented anti-tumor activity in one USC PDX line suggesting that targeting of the Notch signaling pathway is a potential therapeutic strategy for future investigation.

Objectives: Universal screening for Lynch syndrome (LS) using immunohistochemistry (IHC) is recommended for patients with new colon cancer. While the sentinel malignancy in women with Lynch syndrome is equally as likely to be endometrial cancer compared to colon cancer, universal screening in endometrial cancer has not been implemented on such a large scale. Our study aims to determine any associations between loss of MMR expression and tumor clinico-pathologic characteristics, as well as the number of germ line mutations identified using IHC at our institution. Methods: A retrospective review of patients who underwent hysterectomy for grade 1 or 2 endometrioid endometrial cancer between August 2012 and January 2014 was performed. Only patients who underwent IHC for deficiencies of MLH1, MSH2, MSH6, and PMS2 were included in this cohort. Patient charts were reviewed and patient demographics, tumor size, grade, invasion, and stainingwere abstracted from electronic medical records. Results: 180 patients underwent hysterectomy for low grade EEC during the study period. Of these, 102 (56.6%) had IHC to evaluate for MMR protein deficiencies. Twenty six (25.5%) tumors had MMR loss detected via IHC, with 19 (18.6%) having deficiencies in MLH1/ PMS2 and 3 (2.9%) in MSH2/MSH6. Loss of single protein expression was observed in 4 patients, with loss of MSH6 expression noted in 2 (2.0%) and loss of MLH1 and PMS2 in 1 (1%) each. MLH1 promoter methylation analysis was performed in 7 (35.0%) of the 20 tumors, showing methylation in 6 (85.7%). One patient with MSH2 and MSH6 loss by IHC was found to have a germline mutation in MSH6. Grade 2 tumors were significantly associated with MLH1 loss on multivariate analysis (OR 5.3, p = 0.012, 95% CI 1.4–19.8). Increasing age was associated with MLH1 and PMS2 loss (OR 1.2, p = 0.021, 95% CI 1.0– 1.3). Younger age was significantly associated with MSH6 loss (OR 0.79, p = 0.025, 95% CI .64–.97). Conclusions: The most common deficiency detected via IHC involves MLH1 and PMS2 loss and is significantly associated with age. Loss of MSH6 is significantly associated with younger age. Large studies with cost-effectiveness analyses must be performed to determine if implementation of a standardized screening regimen is necessary.

Inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to induce defective homologous repair in breast carcinoma leading to heightened sensitivity to poly-ADP ribose polymerase (PARP) inhibitors. Our objective was to assess the effects on DNA repair pathways following single agent and combined PI3K and PARP inhibition utilizing endometrial cancer (EnCa) patient derived xenografts (PDX) with and without identified PIK3CA mutations. Under an institutional protocol, tumors from consenting patients with endometrioid carcinoma were collected at the time of primary surgery and genotyped for common oncogenic mutations utilizing the SNaPshot® platform. NOD/SCID mice bearing xenografts derived from two primary human endometrioid endometrial tumors with and without PIK3CA gene mutations (ENCA1 & ENCA2 respectively) were divided into four arm cohorts with equivalent tumor volumes. Vehicle or NVP BKM-120 (30 mg/kg) was administered alone and in combination with veliparib (25 mg/kg) and endometrial xenograft tumor volumes were assessed. Immunoblotting was used to assess downstream PI3K pathway and DNA repair pathway alterations in post treatment samples at specific time points. While NVP BKM120 as a single agent failed to induce significant anti-tumor activity compared to vehicle in either model, decreased pAKT, RAD51 and increased γ-H2AX levels were observed in response to NVP BKM120 alone. PIK3CA mutation status did not affect these molecular alterations. Dual NVP BKM-120 and veliparib therapy significantly impeded tumor growth (p < 0.01) in the ENCA1 model, while in ENCA2, significant tumor regression was observed (p < 0.001). No changes in mouse weight or premature death were observed in the various treatment arms. Combination therapy was associated with reconstitution of baseline RAD51 and increased γ-H2AX levels. In conclusion, these results suggest that PI3K inhibition induces defects in homologous repair mediated by RAD51 and increases reliance on PARP mediated DNA repair mechanisms. Our in vivo data suggest that PI3K inhibition sensitizes endometrial tumors with and without PIK3CA mutations to a PARP inhibitor. Citation Format: Bo Rueda, Celeste Digloria, Tracilyn Hall, Rosemary Foster, Darrell Borger, Whitfield Growdon. PI3K inhibition induces homologous repair defects in endometrioid endometrial cancer patient derived xenografts leading to synergistic anti-tumor activity with PARP inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2666. doi:10.1158/1538-7445.AM2015-2666