Endometrial Cancer Outcomes Research Articles

MiR-302a-5p/367-3p-HMGA2 axis regulates malignant processes during endometrial cancer development

BackgroundMetastasis is one of the main reasons for treatment failure in endometrial cancer. Notably, high mobility group AT-hook 2 (HMGA2) has been recognized as a driving factor of tumour metastasis. microRNAs (miRNAs) are powerful posttranscriptional regulators of HMGA2.MethodsThe binding sites of miR-302a-5p and miR-367-3p on HMGA2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. The expression levels of miR-302a-5p and miR-367-3p were detected using quantitative real-time PCR and in situ hybridization. Western blotting and immunohistochemistry were used to detect the levels of HMGA2 and epithelial-mesenchymal transition pathway-related proteins. Co-immunoprecipitation was used to detect protein interactions. The roles of miR-302a-5p and miR-367-3p in the regulation of HMGA2 during the progression of endometrial cancer were investigated using both in vitro and in vivo assays.ResultsIn the present study, high HMGA2 expression was correlated with poor clinical outcomes in endometrial cancer. The binding sites of miRNAs on HMGA2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. In the endometrial cancer cell lines Ishikawa and HEC-1A, the overexpression of miR-302a-5p/367-3p significantly inhibited the expression of HMGA2 mRNA. In endometrial cancer tissues, we showed that miR-302a-5p and miR-367-3p were significantly downregulated and thus inversely correlated with HMGA2. The miR-302a-5p and miR-367-3p expression levels were closely correlated with FIGO stage and lymph node metastasis. High expression of miR-302a-5p/367-3p was correlated with high survival rates in endometrial cancer. In addition, miR-302a-5p/367-3p suppressed the malignant behaviour of endometrial carcinoma cells via the inhibition of HMGA2 expression.ConclusionOur findings indicate that miR-302a-5p/367-3p-mediated expression of HMGA2 regulates the malignant behaviour of endometrial carcinoma cells, which suggests that the miR-302a-5p/367-3p-HMGA2 axis may be a predictive biomarker of endometrial cancer metastasis and patient survival and a potential therapeutic target in metastatic endometrial cancer.

Survival in clinical stage I endometrial cancer with single vs. multiple positive pelvic nodes: results of a multi-institutional Italian study.

ObjectiveTo investigate survival outcomes in endometrioid endometrial cancer (EEC) patients with single vs. multiple positive pelvic lymph nodes.MethodsWe performed a retrospective evaluation of all consecutive patients with histologically proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1 EEC who underwent primary surgical treatment between 2004 and 2014 at seven Italian gynecologic oncology referral centers. Patients with pre- or intra-operative evidence of extra-uterine disease (including the presence of bulky nodes) and patients with stage IIIC2 disease were excluded, in order to obtain a homogeneous population.ResultsOverall 140 patients met the inclusion criteria. The presence of >1 metastatic pelvic node was significantly associated with an increased risk of recurrence and mortality, compared to only 1 metastatic node, at both univariate (recurrence: hazard ratio [HR]=2.19; 95% confidence interval [CI]=1.2–3.99; p=0.01; mortality: HR=2.8; 95% CI=1.24–6.29; p=0.01) and multivariable analysis (recurrence: HR=1.91; 95% CI=1.02–3.56; p=0.04; mortality: HR=2.62; 95% CI=1.13–6.05; p=0.02) and it was the only independent predictor of prognosis in this subset of patients. Disease-free survival (DFS) and disease-specific survival (DSS) were significantly longer in patients with only 1 metastatic node compared to those with more than 1 metastatic node (p=0.008 and 0.009, respectively).ConclusionThe presence of multiple metastatic nodes in stage IIIC1 EEC represents an independent predictor of worse survival, compared to only one positive node. Our data suggest that EEC patients may be categorized according to the number of positive nodes.

Clinical characteristics associated with racial disparities in endometrial cancer outcomes: A surveillance, epidemiology and end results analysis

ObjectivesRacial disparities exist for endometrial cancer. We examined patterns of care and factors associated with poor outcomes for Black women with endometrial cancer. MethodsWe studied 110,826 endometrial cancer patients diagnosed between 1980 and 2008 with minimum 5years follow-up in the Surveillance, Epidemiology, and End Results database. Trends over time in sociodemographics, disease characteristics and treatment factors were analyzed over four eras: 1980–1989, 1990–1999, 2000–2004, 2005–2008. Using sequential Cox proportional hazards and Fine-Gray competing risk models we determined the association between potential explanatory variables and racial disparities in all-cause mortality (ACM) and cancer-specific mortality (CSM), respectively. ResultsClinical characteristics of Black and White women were relatively constant over time. The unadjusted hazard ratio (HR) among Black women for ACM and CSM were 1.91 (95% CI 1.86–1.97) and 2.35 (95% CI 2.26–2.43), respectively. Adjustment for sociodemographics, disease presentation and surgery decreased the ACM HR to 1.29 (95% CI 1.24–1.34) and CSM HR to 1.18 (95% CI 1.11–1.26) without further decrease from controlling for radiotherapy. Black women were less likely to undergo operative management even when prescribed. Total and radical hysterectomy, and vaginal brachytherapy (VBT) were associated with improved ACM and CSM. Combination VBT and external beam radiotherapy was associated with improved ACM. ConclusionRacial disparities in endometrial cancer survival are predominantly attributable to increased advanced stage, high-grade and aggressive histologic subtype tumors and differential use of surgery in Black women. Intensified surgical and radiation treatment is associated with improved survival, raising questions about treatment adaptations that may potentially reduce survival disparities.

Unsupervised Clustering of Immunohistochemical Markers to Define High-Risk Endometrial Cancer.

Considerable heterogeneity exists in outcomes of early endometrial cancer (EC) according to the type but also the histological grading. Our goal was to describe the immunohistochemical profiles of type I EC according to grades and type II EC, to identify groups of interacting proteins using principal component analysis (PCA) and unsupervised clustering. We studied 13 immunohistochemical markers (steroid receptors, pro/anti-apoptotic proteins, metalloproteinases (MMP) and tissue inhibitor of metalloproteinase (TIMP), and CD44 isoforms known for their role in endometrial pathology. Co-expressed proteins associated with the type, grade and outcome of EC were determined by PCA and unsupervised clustering. PCA identified three functional groups of proteins from 43 tissue samples (38 type I and 5 type II EC): the first was characterized by p53 expression; the second by MMPs, bcl-2, PR B and CD44v6; and the third by ER alpha, PR A, TIMP-2 and CD44v3. Unsupervised clustering found two main clusters of proteins, with both type I grade 3 and type II EC exhibiting the same cluster profile. PCA and unsupervised clustering of immunohistochemical markers in EC contribute to a better comprehension and classification of the disease.

High visceral fat percentage is associated with poor outcome in endometrial cancer.

Despite evidence of increased endometrial cancer (EC) risk in obese women, the impact of obesity on clinical and histological phenotype is poorly understood. This study explored abdominal fat volumes and fat distribution quantified by computed tomography (CT), in relation to tumor characteristics and outcome. 227 EC patients with preoperative abdominal CT scans were included. Total abdominal fat volume (TAV), subcutaneous abdominal fat volume (SAV) and visceral abdominal fat volume (VAV) were quantified, and visceral fat percentage calculated (VAV%=[VAV/TAV]x100). Waist circumference (WC) and liver density (LD) were measured, and body mass index (BMI) calculated. Data for estrogen, progesterone and androgen receptor (ERα/PR/AR) expression by immunohistochemistry were available for 149 tumors, and global gene expression data for 105 tumors. High BMI, TAV, SAV, VAV and WC, and low LD, were associated with low grade endometrioid tumors and PR and AR positivity (all p≤0.03). High VAV% was associated with high age (p<0.001), aneuploidy (p=0.01) and independently predicted reduced disease-specific survival (HR 1.05, 95% CI 1.00-1.11, p=0.041). Tumors from patients with low VAV% showed enrichment of gene sets related to immune activation and inflammation. In conclusion, high VAV% independently predicts reduced EC survival. Tumors arising in patients with low VAV% show enrichment of immune and inflammation related gene sets, suggesting that the global metabolic setting may be important for tumor immune response.

Type of vascular invasion in association with progress of endometrial cancer.

Vascular invasion (VI) is a well-established marker for lymph node metastasis and outcome in endometrial cancer. Our study explored whether specific types of VI, defined as lymphatic (LVI) or blood vessel invasion (BVI), predict pattern of metastasis. From a prospectively collected cohort, we conducted a case-control study by selecting three groups of endometrial cancer patients (n=183): 52 with positive lymph nodes at primary surgery, 33 with negative nodes at primary surgery and later recurrence and death from disease, and 98 with negative nodes and no recurrence. All patients underwent hysterectomy with lymphadenectomy. Immunohistochemical staining with D2-40 and CD31 antibodies was used to differentiate between BVI and LVI. By immunohistochemical staining, detection of VI increased from 24.6 to 36.1% of the cases. LVSI was significantly more often seen in patients with positive lymph nodes compared with patients with negative nodes (p=0.001). BVI was significantly more often seen in node-negative patients with recurrence compared with node-negative patients without recurrence (p=0.011). In multivariable analysis, BVI, age, and tumor grade were predictors separating patients with and without recurrence. Lymph node-positive patients showed more often LVI compared with lymph node-negative patients, while BVI seems to be a predictor for recurrent disease.

Metformin use and survival outcomes in endometrial cancer: a systematic review and meta-analysis.

Previous studies have evaluated the effects of metformin use on survival outcomes in endometrial cancer, but their results are inconsistent. We conducted a systematic review and meta-analysis to provide a quantitative assessment of the drug's effects based on available evidence. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials to identify relevant studies that evaluated the association between metformin use on survival outcomes in endometrial cancer. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to evaluate the association of metformin use with overall survival and with progression-free survival using a fixed-effects model. A total of nine studies involving 2,016 patients with endometrial cancer were identified. In a meta-analysis of eight studies involving 1,594 individuals, metformin use was associated with significant improvements in overall survival (HR, 0.51; 95% CI, 0.41 to 0.64). Metformin users similarly showed improved progression-free survival in a meta-analysis of two studies involving 632 individuals (HR, 0.63; 95% CI, 0.46 to 0.87). In conclusion, endometrial cancer patients who use metformin show improved overall survival and progression-free survival. Further studies are required to confirm the full potential effects of metformin use on survival outcomes in endometrial cancer.

The positivity of G-protein-coupled receptor-30 (GPR 30), an alternative estrogen receptor is not different between type 1 and type 2 endometrial cancer.

It is well-known that the clinical outcomes are different between type 1 (estrogen dependent) and type 2 (estrogen independent) endometrial cancer. Studies have suggested that the estrogen receptor (ER) is positively correlated with endometrial cancer survival, however we previously reported that there is no difference in the positivity of ER as well as sex hormone levels between subtypes of cancer. G-protein-coupled receptor-30 (GPR 30), an alternative estrogen receptor has been suggested to be negatively correlated with clinical outcomes of endometrial cancer. In this study we investigated whether the positivity of GPR30 is different between subtypes of cancer. The immunostaining of GPR30 and ER was examined and analysed in 128 cases taking into account menopausal status. Overall, 105 (82%) cases were GPR30 positive and 118 (92%) cases were ER positive. The positivity of GPR30 in type 1 endometrial cancer (83%) was not statistically different to type 2 endometrial cancer (78%). In addition, intensity of immunostaining of GPR30 in type 1 endometrial cancer was also not different to type 2 endometrial cancer quantified by semi-quantitative analysis (p = 0.268). Menopausal status was not associated with the positivity of GPR30 in both type 1 and type 2 endometrial cancer. Furthermore, the positivity and intensity of immunostaining of GPR30 were not correlated with the positivity and intensity of immunostaining of ER in endometrial cancer (p = 0.689). Our data further confirm that type 2 endometrial cancer may not be completely estrogen independent, and suggest that type 1 and type 2 endometrial cancer may have similar pathogenesis.

Radiation-related toxicities and outcomes in endometrial cancer: are obese women at a disadvantage?

To assess the impact of body mass index (BMI) on radiotherapy toxicities in endometrial cancer patients. This was a retrospective cohort study of women diagnosed with endometrial cancer between January 2006 and December 2014 at the Royal Cornwall Hospital Trust. Women who received radiotherapy as part of their treatment, including external beam radiotherapy (EBRT) and/or vaginal brachytherapy were included. Radiation-related toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) guidelines. Toxicity outcomes were compared across BMI groups-non-obese (BMI<30kg/m2) and obese (BMI≥30kg/m2)-according to radiotherapy treatment received (EBRT, brachytherapy or a combination). Of a total of 159 women who received radiotherapy, 110 were eligible for inclusion in the study. Sixty-three women had a BMI<30kg/m2 and 47 women were obese. Obese women had poorer Eastern Cooperative Oncology Group performance status (P=0.021) and more comorbidities (P<0.001) compared to the non-obese group. Total (any) toxicity rates were 60.3, 72.7 and 52.0% for EBRT and brachytherapy (N=63), single-mode EBRT (N=22) and brachytherapy (N=25), respectively. BMI was not associated with the incidence of acute and late radiation toxicities in the different radiotherapy groups, and there were no differences in individual complications between the BMI groups. When comparing obese to non-obese women, obesity does not negatively impact the incidence of radiation toxicities in endometrial cancer. However, toxicities remain an important challenge as they are common and negatively influence the quality of life (QoL) of survivors. Future studies need to further explore the role of BMI and possible interventions to improve toxicities and QoL.

Association between hospital surgical volume and racial disparities in access to care and outcomes for endometrial cancer

Association between hospital surgical volume and racial disparities in access to care and outcomes for endometrial cancer

Influence of site of care on racial disparities and outcomes for endometrial cancer

Influence of site of care on racial disparities and outcomes for endometrial cancer

Surgical Outcomes and Patterns of Recurrence in Endometrial Cancers

Abstract Objectives: There were two objectives: (1) to assess the survival outcome of endometrial cancer based on surgical and adjuvant treatment and (2) to note patterns of and risk factors for recurrence in endometrial cancer. Design: This was a retrospective analysis of the hospital records of women diagnosed with carcinoma of the endometrium who were operated on in the Division of Gynecologic Oncology, Christian Medical College, Vellore, India, from January 2011 to December 2013. Materials and Methods: Electronic patient records of 152 women with endometrioid endometrial cancer were obtained and used to analyze their surgical outcomes. Information regarding survival and recurrences was obtained by various methods. Survival was assessed by Kaplan–Meir survival analysis. Results: The tumors were endometrioid adenocarcinomas in 94.7% of the patients. The majority of the patients were stage IA (49.3%) and stage IB (22.3%). A few patients also had occult stage II (6.6%), and 21% had advanced stage cancer. ...

Alterations in the uterine microbiome in patients with early endometrial cancer: Variations by ethnicity and obesity.

e17114 Background: Obesity and race are known to negatively impact clinical outcomes in endometrial cancer (EC). Mounting evidence suggests the gut microbiome may play an important role in the pathogenesis of both obesity and cancer, however, little is known about the microbiome of the malignant uterus. Further, there is known to be microbiome variability by ethnicity in the vagina and gut. Thus, we sought to evaluate the microbiota of ECs and to assess for variations by obesity and race. Methods: Following IRB approval, banked tumor specimens of patients undergoing hysterectomy for management of endometrioid EC were identified. Tumors were analyzed from African-American (AA) and Caucasian (CAU) patients and stratified as obese (BMI ≥ 30kg/m2) or non-obese (BMI &lt; 30kg/m2). The microbiota of the endometrial tumors were characterized by 16S rRNA high throughput sequencing. Descriptive statistics were performed. Results: We evaluated specimens from 11 AA (52%) and 10 CAU (48%). The median age was 68.9 years. Majority of women were postmenopausal (n=17, 81%) and obese (n=14, 66.7%). Tumor grade was evenly distributed with 7 grade 1 (33.3%), 6 grade 2 (28.6%), and 8 grade 3 tumors (38.1%). We found that EC microbiota richness was higher in AA than CAU (p=0.02). When analyzed by race and obesity status, we observed significant differences in EC microbiota composition. The microbiota composition differed between obese AA and obese CAU (p=0.04). In obese subjects the distribution of Proteobacteria was 55% AA vs. 30.7% CAU (p=0.02) while Actinobacteria abundance was 17.8% versus 34.4% (p=0.05) (Table 1). Among CAU, the EC microbiota profile differed between obese and non-obese (p=0.07). At the genus level, the relative abundances of Delftia, Finelgoldia, Geobacillus, Propionibacterium and Pseudomonasvaried by obesity and race. Conclusions: Bacteria exist in the malignant uterus. EC microbiota diversity was greater in tumors of AA versus CAU women, and tumor microbiota profiles were distinct between ECs of obese and lean women. Better understanding of the inter-relationship of obesity and race on the EC microbiota may provide critical insight into the disparate clinical outcomes between AA and CAU women with EC.

High stathmin expression is a marker for poor clinical outcome in endometrial cancer: An NRG oncology group/gynecologic oncology group study

ObjectiveGynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin. MethodsWe analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer. ResultsWe first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin. ConclusionsOur findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases.

Outcome of endometrial cancer after lymphadenectomy: a single center retrospective analysis with long-lasting follow-up.

Role of lymphadenectomy in endometrial cancer is unclear. Our objective is to assess the role of lymphadenectomy in endometrial cancer. The study reviewed retrospectively 829 cases of endometrial cancer from a single non-oncological center from 1981 to 2014. Multivariable Cox regression analyses were performed. Independent variables were: 2009 FIGO stage, histological type of endometrial cancer (non-endometrioid, endometrioid, grading 1, 2 and 3), radicality on parametria, lymphatic dissection (any kind) (yes/no), any kind of chemotherapy, any kind of radiotherapy, brachytherapy, patients' age. Dependent variable was death for endometrial cancer and first relapse. Time variable was the semester of follow-up. P value for significance was set <0.05. Many data about the extension of node dissection were missing. Pelvic node dissection or sampling seem the more common procedure performed. At the 10-semester of follow-up, at the 20-semester of follow-up and at the 30 semester of follow up, lymphadenectomy does not improve overall survival at a p value of less than 0.05. Lymphadenectomy reduces the risk of relapse at the 10 semester and 20-semester of follow-up. Lymphadenectomy plays a role in preventing relapses but it is not proved that non-aggressive lymphadenectomy in endometrial cancer improves overall survival at p level of 0.05. Therefore, it cannot be excluded that a very small improvement in long lasting survival in few cases of endometrial cancer could be due to node dissections.

YAP/TAZ-Mediated Upregulation of GAB2 Leads to Increased Sensitivity to Growth Factor-Induced Activation of the PI3K Pathway.

The transcription regulators YAP and TAZ function as effectors of the HIPPO signaling cascade, critical for organismal development, cell growth, and cellular reprogramming, and YAP/TAZ is commonly misregulated in human cancers. The precise mechanism by which aberrant YAP/TAZ promotes tumor growth remains unclear. The HIPPO tumor suppressor pathway phosphorylates YAP and TAZ, resulting in cytosolic sequestration with subsequent degradation. Here, we report that the PI3K/AKT pathway, which is critically involved in the pathophysiology of endometrial cancer, interacts with the HIPPO pathway at multiple levels. Strikingly, coordinate knockdown of YAP and TAZ, mimicking activation of the HIPPO pathway, markedly decreased both constitutive and growth factor-induced PI3K pathway activation by decreasing levels of the GAB2 linker molecule in endometrial cancer lines. Furthermore, targeting YAP/TAZ decreased endometrial cancer tumor growth in vivo In addition, YAP and TAZ total and phosphoprotein levels correlated with clinical characteristics and outcomes in endometrial cancer. Thus, YAP and TAZ, which are inhibited by the HIPPO tumor suppressor pathway, modify PI3K/AKT pathway signaling in endometrial cancer. The cross-talk between these key pathways identifies potential new biomarkers and therapeutic targets in endometrial cancer. Cancer Res; 77(7); 1637-48. ©2017 AACR.

Does hysteroscopy worsen prognosis in women with type II endometrial carcinoma?

BackgroundPrior studies evaluating the impact of hysteroscopy on outcomes in endometrial cancer have predominantly evaluated type I tumors. We sought to evaluate whether hysteroscopy worsens prognosis in type II endometrial cancer.MethodsA retrospective cohort analysis of 140 patients from two institutions with type II endometrial cancer was performed. Women who underwent either diagnostic hysteroscopy (HSC) or dilation and curettage (D&C) for cancer diagnosis from June 2001 until June 2010 were included. The clinical and pathologic characteristics, including peritoneal cytology results were reviewed. The primary endpoint was disease-specific survival (DSS). The exposure of interest was hysteroscopy. Survival curves were projected using the Kaplan-Meier method and compared using the log-rank test.ResultsThere was no difference in age, histology, stage, depth of myometrial invasion, adnexal involvement, or nodal metastasis between HSC and D&C patients. Positive cytology was found in 16/54 (30%) patients following HSC and in 10/86 (12%) following D&C (p = 0.008). Fourteen patients with stage I and II disease had positive peritoneal cytology, with 11/40 (27.5%) patients in the HSC group and 3/59 (5%) patients in the D&C group(p = 0.002). Median DSS was clinically different for the HSC and D&C groups, but statistical significance was not reached (53 versus 63.5 months, p = 0.34). For stage I and II patients, 18/99 (18%) were dead of EC, with a median DSS of 60 months for HSC and 71 months for D&C (p = 0.82). Overall 46 (33%) patients developed a recurrence, with 18/54 (33%) in the HSC group compared to 28/86 (32%) in the D&C group (p = 0.92). There was no difference in recurrence location between groups.ConclusionsDiagnostic hysteroscopy significantly increased the rate of positive peritoneal cytology at the time of surgical staging in this cohort of patients with type II EC. However, we were unable to detect a difference in prognosis as measured by DSS.

FGFR2 mutations are associated with poor outcomes in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study

PurposeActivating FGFR2 mutations have been identified in ~10% of endometrioid endometrial cancers (ECs). We have previously reported that mutations in FGFR2 are associated with shorter disease free survival (DFS) in stage I/II EC patients. Here we sought to validate the prognostic importance of FGFR2 mutations in a large, multi-institutional patient cohort. MethodsTumors were collected as part of the GOG 210 clinical trial “Molecular Staging of Endometrial Cancer” where samples underwent rigorous pathological review and had more than three years of detailed clinical follow-up. DNA was extracted and four exons encompassing the FGFR2 mutation hotspots were amplified and sequenced. ResultsMutations were identified in 144 of the 973 endometrioid ECs, of which 125 were classified as known activating mutations and were included in the statistical analyses. Consistent with FGFR2 having an association with more aggressive disease, FGFR2 mutations were more common in patients initially diagnosed with stage III/IV EC (29/170;17%) versus stage I/II EC (96/803; 12%; p=0.07, Chi-square test). Additionally, incidence of progression (progressed, recurred or died from disease) was significantly more prevalent (32/125, 26%) among patients with FGFR2 mutation versus wild type (120/848, 14%; p<0.001, Chi-square test). Using Cox regression analysis adjusting for known prognostic factors, patients with FGFR2 mutation had significantly (p<0.025) shorter progression-free survival (PFS; HR 1.903; 95% CI 1.177–3.076) and endometrial cancer specific survival (ECS; HR 2.013; 95% CI 1.096–3.696). ConclusionIn summary, our findings suggest that clinical trials testing the efficacy of FGFR inhibitors in the adjuvant setting to prevent recurrence and death are warranted.

Tissue and imaging biomarkers for hypoxia predict poor outcome in endometrial cancer.

Hypoxia is frequent in solid tumors and linked to aggressive phenotypes and therapy resistance. We explored expression patterns of the proposed hypoxia marker HIF-1α in endometrial cancer (EC) and investigate whether preoperative functional imaging parameters are associated with tumor hypoxia. Expression of HIF-1α was explored both in the epithelial and the stromal tumor component. We found that low epithelial HIF-1α and high stromal HIF-1α expression were significantly associated with reduced disease specific survival in EC. Only stromal HIF-1α had independent prognostic value in Cox regression analysis. High stromal HIF-1α protein expression was rare in the premalignant lesions of complex atypical hyperplasia but increased significantly to invasive cancer. High stromal HIF-1α expression was correlated with overexpression of important genes downstream from HIF-1α, i.e. VEGFA and SLC2A1 (GLUT1). Detecting hypoxic tumors with preoperative functional imaging might have therapeutic benefits. We found that high stromal HIF-1α expression associated with high total lesion glycolysis (TLG) at PET/CT. High expression of a gene signature linked to hypoxia also correlated with low tumor blood flow at DCE-MRI and increased metabolism measured by FDG-PET. PI3K pathway inhibitors were identified as potential therapeutic compounds in patients with lesions overexpressing this gene signature. In conclusion, we show that high stromal HIF-1α expression predicts reduced survival in EC and is associated with increased tumor metabolism at FDG-PET/CT. Importantly; we demonstrate a correlation between tissue and imaging biomarkers reflecting hypoxia, and also possible treatment targets for selected patients.

JQ1 suppresses tumor growth via PTEN/PI3K/AKT pathway in endometrial cancer

Overexpression of c-Myc is associated with worse outcomes in endometrial cancer, indicating that c-Myc may be a promising target for endometrial cancer therapy. A novel small molecule, JQ1, has been shown to block BRD4 resulting in inhibition of c-Myc expression and tumor growth. Thus, we investigated whether JQ1 can inhibit endometrial cancer growth in cell culture and xenograft models. In PTEN-positive endometrial cancer cells, JQ1 significantly suppressed cell proliferation via induction of G1 phase arrest and apoptosis in a dose-dependent manner, accompanied by a sharp decline in cyclin D1 and CDK4 protein expression. However, PTEN-negative endometrial cancer cells exhibited intrinsic resistance to JQ1, despite significant c-Myc inhibition. Moreover, we found that PTEN and its downstream PI3K/AKT signaling targets were modulated by JQ1, as evidenced by microarray analysis. Silencing of PTEN in PTEN-positive endometrial cancer cells resulted in resistance to JQ1, while upregulation of PTEN in PTEN-negative endometrial cancer cells increased sensitivity to JQ1. In xenografts models of PTEN-positive and PTEN-knock-in endometrial cancer, JQ1 significantly upregulated the expression of PTEN, blocked the PI3K/AKT signaling pathway and suppressed tumor growth. These effects were attenuated in PTEN-negative and PTEN-knockdown xenograft models. Thus, JQ1 resistance appears to be highly associated with the status of PTEN expression in endometrial cancer. Our findings suggest that targeting BRD4 using JQ1 might serve as a novel therapeutic strategy in PTEN-positive endometrial cancers.