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Preoperative use of metformin in obese women with endometrioid endometrial cancer (EEC) reduces tumor proliferation and inhibits the mammalian target of rapamycin pathway, though is only effective in select cases. This study sought to identify a predictive and/or pharmacodynamic proteomic signature of metformin response to tailor its pharmacologic use. Matched pre‐ and post‐metformin‐treated tumor tissues from a recently completed preoperative window trial of metformin in EEC patients (ClinicalTrials.gov: NCT01911247) were analyzed by mass spectrometry (MS)‐based proteomic and immunohistochemical analyses. Jupiter microtubule‐associated homolog 1 (JPT1) was significantly elevated in metformin responders (n = 13) vs nonresponders (n = 7), and found to decrease in abundance in metformin responders following treatment; observations that were verified by immunohistochemical staining for JPT1. Metformin response and loss of JPT1 were assessed in RL95‐2 and ACI‐181 endometrial cancer (EC) cell lines. We further identified that silencing of JPT1 abundance does not alter cellular response to metformin or basal cell proliferation, but that JPT1 abundance does decrease in response to metformin treatment in RL95‐2 and ACI‐181 EC cell lines. These data suggest that JPT1 represents a predictive and pharmacodynamic biomarker of metformin response that, if validated in larger patient populations, may enable preoperative EEC patient stratification to metformin treatment and the ability to monitor patient response., We report JPT1 (Jupiter microtubule‐associated homolog 1) as a predictive and pharmacodynamic biomarker candidate of metformin response in endometrial cancers.

Objective This study was aimed to measure the effects of a high-fat diet and metformin on placental mechanistic target of rapamycin (mTOR) signaling in mice. Study Design Pregnant friend virus B (FVB)-strain mice were allocated on embryonic day (e) 0.5 to one of four groups; group 1: control diet (CD, 10% fat) + control treatment (CT), group 2: CD + metformin treatment (MT), group 3: high-fat diet (HFD, 60% fat) + CT, and group 4: HFD + MT. Metformin (2.5 mg/mL) was provided in water; CT mice received water. Fetuses and placentas were collected. Western blot measured placental p-Akt and p-S6 expression. Results 20 dams (five/group) and 192 fetuses were studied. Compared with CD-fed, HFD-fed dams had higher placental p-Akt protein expression (p Conclusion Increased placental mTOR signaling and metformin inhibition of placental mTOR signaling only occurred in the presence of an HFD exposure. These findings suggest that metformin may modulate placental mTOR signaling in the presence of metabolic exposures during pregnancy.

Objectives Evaluate association between obesity and angiogenic-related gene expression in endometrial cancer (EC). Evaluate interaction between diet and metformin on angiogenic-related gene expression. Methods We evaluated the association between 168 human angiogenic-related genes and body mass index (BMI) in the TCGA Uterine Corpus Endometrial Carcinoma cohort (endometrioid endometrial cancer (EEC) cohort n = 290, and copy number high cohort n = 55), an independent validation cohort from Gynecologic Cancer Center of Excellence (GYN-COE) (n = 62) and corresponding 185 homologous mouse genes in an LKB1fl/flp53fl/fl mouse model of EC (n = 20). Mice received 60% of calories from fat in a high-fat diet (HFD), mimicking diet-induced obesity, versus 10% of calories from fat in a low-fat diet (LFD). After tumor growth, HFD (n = 5) and LFD (n = 5) mice were treated with metformin (200 mg/kg/day) or control. Whole transcriptome analysis of mouse tumors was performed using RNA-Seq. Results At a false-discovery rate of 10%, twenty-one angiogenic-related genes were differentially expressed with respect to BMI when adjusting for grade in the TCGA EEC cohort. Evaluation of these genes in the mouse model control group revealed association between increased Edil3 expression in HFD versus LFD mice (2.5-fold change (FC); unadjusted p = 0.03). An interaction was observed for expression of Edil3 between diet and metformin treatment (unadjusted p = 0.009). Association between BMI and increased expression of EDIL3 was validated in one of four EDIL3 probesets in the GYN-COE cohort (p = 0.0011, adjusted p = 0.0342). Conclusions Obesity may promote tumor progression via differential modulation of angiogenic pathways in EEC. Our exploratory findings demonstrated that EDIL3 may be a candidate gene of interest.

OBJECTIVES: This study aimed to assess the association between hormone replacement therapy and the incidence of subsequent malignancies in patients who underwent risk-reducing salpingo-oophorectomy and had mutations predisposing them to Müllerian cancers. METHODS: This Institutional Review Board-approved retrospective study was performed at five academic institutions. Women were included if they were age 18-51 years, had one or more confirmed germline highly penetrant pathogenic variants, and underwent risk-reducing salpingo-oophorectomy. Patients with a prior malignancy were excluded. Clinicodemographic data were collected by chart review. Patients with no documented contact for one year prior to study termination were called to confirm duration of hormone use and occurrence of secondary outcomes. Hormone replacement therapy included any combination of estrogen or progesterone. RESULTS: Data were analyzed for 159 women, of which 82 received hormone replacement therapy and 77 did not. In both groups an average of 6 years since risk reduction had passed. The patients treated with hormone replacement therapy did not have a higher risk of subsequent malignancy than those not treated with hormone replacement therapy (6 out of 82 vs. 7 out of 77, P=0.68). Patients who received hormone replacement therapy were younger than those who did not receive hormone replacement therapy (39.0 vs. 43.9 years, P

Objectives: The inclusion of palliative care (PC) across the cancer continuum has been identified as a marker of high-quality cancer care. With limited PC specialists, integrated approaches may be necessary with the primary oncologist providing this care. However, recurrent ovarian cancer patients often have significant physical and/or emotional needs that may be best addressed by PC specialists. Our primary objective was to test the effect of a structured PC intervention on quality of life (QOL) for patients with recurrent ovarian cancer. Secondary objective was to assess the effect of the structured PC approach on overall survival. Methods: This was an IRB approved prospective randomized controlled trial at 2 academic institutions and was registered with clinicaltrials.gov (NCT02090582). Eligible patients included those with platinum resistant ovarian cancer or platinum sensitive cancer with a sentinel clinical event (recent bowel obstruction, liver metastases, pleural effusion or ascites). Subjects were randomized 1:1 to usual care versus a structured palliative care intervention (see Figure 1). Quality of life was assessed using the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) and Functional Assessment of Chronic Illness Therapy-Palliative Care (FACIT-PAL) at baseline and 12-week intervals. Wilcoxon tests were used to detect differences between arms. Overall survival was analyzed using Kaplan-Meyer curves. Results: A total of 54 subjects were enrolled from 5/2014-4/2016; 26 in the intervention arm and 28 in the control arm. Median follow up was 6.5 months (Range: 2-12months). Median age of subjects was 63 with an ECOG performance status of 1. The majority of patients were Caucasian (44; 81.5%) and had platinum resistant disease (37; 68.5%). Most patients had received between 1-3 prior lines of chemotherapy (34/54; 63%); 5 patients (9.2%) had received ≥6 lines of therapy. There was no difference in overall or subset QOL in patients receiving usual care compared to those in the structured PC arm (p=0.14). There were no differences in hospital admissions (p=0.96), days from last chemo to hospice admission (p=1.0), days from hospice admission to death (p=0.41), place of death (p=0.68) or number of PC appointments (p=0.30) between the two arms. Patients enrolled in the 2nd half of the cohort were more likely to die at home rather than in the hospital or inpatient hospice (p=0.01) compared to subjects enrolled early in the study period. 81% of subjects randomized to the intervention arm completed at least 1 QDACT assessment (range 1-17). Similarly, there was no overall survival difference between the 2 arms (9.3m vs 10.1m; p=0.21). Download : Download high-res image (146KB) Download : Download full-size image Conclusions: Structured integrated approaches between gynecologic oncology providers and PC specialists are feasible. The QDACT tool may be an effective, standardized measure to assess cancer symptom burden over time in this population. Further study is needed to identify interventions and collaborations that may have the greatest impact on QOL for recurrent ovarian cancer patients.

Obesity and diabetes have been associated with increased risk and worse outcomes in ovarian cancer (OC). The biguanide metformin is used in the treatment of type 2 diabetes and is also believed to have anti-tumorigenic benefits. Metformin is highly hydrophilic and requires organic cation transporters (OCTs) for entry into human cells. Phenformin, another biguanide, was taken off the market due to an increased risk of lactic acidosis over metformin. However, phenformin is not reliant on transporters for cell entry; and thus, may have increased potency as both an anti-diabetic and anti-tumorigenic agent than metformin. Thus, our goal was to evaluate the effect of phenformin on established OC cell lines, primary cultures of human OC cells and in an orthotopic mouse model of high grade serous OC. In three OC cell lines, phenformin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, caused cellular stress, inhibited adhesion and invasion, and activation of AMPK and inhibition of the mTOR pathway. Phenformin also exerted anti-proliferative effects in seven primary cell cultures of human OC. Lastly, phenformin inhibited tumor growth in an orthotopic mouse model of serous OC, coincident with decreased Ki-67 staining and phosphorylated-S6 expression and increased expression of caspase 3 and phosphorylated-AMPK. Our findings demonstrate that phenformin has anti-tumorigenic effects in OC as previously demonstrated by metformin but it is yet to be determined if it is superior to metformin for the potential treatment of this disease.

// Li Sun 1, 3, * , Yajie Yin 1, 2, 3, * , Leslie H. Clark 3 , Wenchuan Sun 3 , Stephanie A. Sullivan 3 , Arthur-Quan Tran 3 , Jianjun Han 4 , Lu Zhang 1 , Hui Guo 1 , Esther Madugu 3 , Tommy Pan 3 , Amanda L. Jackson 5 , Joshua Kilgore 6 , Hannah M. Jones 3 , Timothy P. Gilliam 3 , Chunxiao Zhou 3, 7 and Victoria L. Bae-Jump 3, 7 1 Department of Gynecologic Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China 2 School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China 3 Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 4 Department of Surgical Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China 5 Division of Gynecologic Oncology, University of Cincinnati, Cincinnati, OH, USA 6 Houston Methodist Gynecologic Oncology Associates, Houston, TX, USA 7 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA * These authors have contributed equally to this work Correspondence to: Victoria L. Bae-Jump, email: victoria_baejump@med.unc.edu Chunxiao Zhou, email: czhou@med.unc.edu Keywords: glycolysis, glutaminolysis, ovarian cancer, AMPK/mTOR Received: April 19, 2017 Accepted: June 04, 2017 Published: June 29, 2017 ABSTRACT Cancer cell metabolism is required to support the biosynthetic demands of cell growth and cell division, and to maintain reduction oxidaton (redox) homeostasis. This study was designed to test the effects of glucose and glutamine on ovarian cancer cell growth and explore the inter-relationship between glycolysis and glutaminolysis. The SKOV3, IGROV-1 and Hey ovarian cancer cell lines were assayed for glucose, pyruvate and glutamine dependence by analyzing cytotoxicity, cell cycle progression, apoptosis and ATP production. As determined by MTT assay, glucose stimulated cell growth while the combination of glucose, glutamine and pyruvate resulted in the greatest stimulation of cell proliferation. Furthermore, 2-deoxy-glucose (2-DG) and 3-bromopyruvate (3-BP) induced apoptosis, caused G1 phase cell cycle arrest and reduced glycolytic activity. Moreover, 2-DG in combination with a low dose of aminooxyacetate (AOA) synergistically increased the sensitivity to 2-DG in the inhibition of cell growth in the ovarian cancer cell lines. These studies suggest that dual inhibition of glycolysis and glutaminolysis may be a promising therapeutic strategy for the treatment of ovarian cancer.

Highlights • TP53 mutations are common in serous endometrial tumors. • Endometrial tumors with micro and macrometastasis are more likely than tumors with ITC only to have LVSI. • No patient with ITC only disease had a recurrence in the study time frame., Objectives Lymph node (LN) metastasis and genomic profiles are important prognostic factors in endometrial cancer (EMCA). However, the prognostic significance of low volume metastasis found in sentinel lymph nodes (SLN) is unknown. We sought to determine if genomic mutations were associated with metastatic volume. Methods Surgically staged women with EC who were enrolled in both a SLN clinical trial and tumor sequencing protocol were eligible. Relevant targets were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. Three specific gene mutations were evaluated, TP53, PTEN and PIK3CA in the primary tumor of patients with LN negative, LN positive and ITC disease. Results 42 patients were eligible; of these, 7 (16.7%) had ITC only and 7 (16.7%) had micrometastatic or macrometastatic (LN positive) disease. No differences were seen in TP53, PIK3CA or PTEN between groups. All ITC patients with TP53 mutations were of non-endometrioid histology (2/7). Deeper myometrial invasion and lymph vascular space invasion were more likely to occur in the LN positive group (p

Fatty acid synthase (FAS) is a key lipogenic enzyme that is highly expressed in endometrial cancer. Orlistat is a weight loss medication that has been shown to be a potent inhibitor of FAS. The goal of this study was to evaluate the anti-tumorigenic potential of orlistat in endometrial cancer cell lines. The endometrial cancer cell lines ECC-1 and KLE were used. Cell proliferation was assessed by MTT assay after treatment with orlistat. Cell cycle progression was evaluated by Cellometer and apoptosis was assessed using the Annexin V assay. Reactive oxygen species (ROS) was measured using the DCFH-DA assay. Western immunoblotting was performed to determine changes in FAS, cellular stress, cell cycle progression, and the AMPK/mTOR pathways. Orlistat inhibited cell proliferation by 61 % in ECC-1 cells and 57 % in KLE cells at a dose of 500 μM. Treatment with orlistat at this concentration resulted in G1 arrest (p

BACKGROUND: Maternal obesity and excessive gestational weight gain (GWG) are associated with delivery of a large-for-gestational-age infant. We used a high-fat diet (HFD) mouse model to separate the effect of maternal obesity from excessive GWG on fetal growth. Our objective was to identify fetal gene expression changes in an HFD and control diet (CD) mouse model with and without metformin exposure. STUDY DESIGN: Normal weight timed-pregnant (Female Friend virus B) strain mice were allocated on day e0.5 to receive HFD or CD and either plain water or metformin (2.5 mg/mL in drinking water). Dams were euthanized on day e17.5 and fetal livers harvested and frozen at −80°C. RNA was extracted and hybridized to a customized 96-gene Nanostring panel focused on angiogenesis, inflammation, and growth gene expression. Fetal liver gene expression was compared between metformin and plain water groups using analysis of variance. Significant differences in gene expression, defined by a false discovery controlled q value

OBJECTIVE To examine whether preoperative thrombocytosis or leukocytosis is associated with increased postoperative morbidity or mortality. METHODS Patients with ovarian cancer undergoing primary surgery from 2005 to 2012 were identified from the American College of Surgeons National Surgical Quality Improvement Project. Thrombocytosis was defined as platelets greater than 450,000/mm and leukocytosis as white blood cells greater than 10,000/mm. We examined 30-day postoperative complications and mortality. Descriptive statistics and adjusted multivariable logistic regression were used for analysis. RESULTS We identified 1,072 patients. The incidence of thrombocytosis was 9.6%, leukocytosis was 18.7%, and 4.9% had both. Leukocytosis was associated with major complication (16.5% compared with 10.3%, P=.01) but not postoperative death (3.0% compared with 1.3%, P=.08). Thrombocytosis was also associated with major complication (19.4% compared with 10.7%, P

Objective While some observational studies have suggested a protective effect of metformin on incident cancer, concerns about potential bias remain. We compared the incidence of endometrial cancer in metformin versus sulfonylurea initiators. Research design and methods We conducted a retrospective cohort analysis using US healthcare claims (MarketScan®), 2000–2011. We identified new users of metformin versus sulfonylureas with no prior cancer diagnoses and followed them until a diagnosis of endometrial cancer, hysterectomy, treatment change, or disenrollment. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards, using an as-treated analytic approach. Stabilized inverse probability of treatment weights were used to adjust for potential confounding at baseline. Results Of 541,128 eligible women, 456,838 (84%) initiated metformin and 84,290 (16%) initiated sulfonylurea. The treatment groups differed at baseline in terms of age and recent diagnosis codes for diabetes, polycystic ovarian syndrome, and endometrial hyperplasia. Over a median follow-up of 1.2 (IQR 0.4–2.3) years and a total of 2,030,914 person-years, 729 women developed endometrial cancer. Metformin initiation was associated with a lower risk of endometrial cancer in the unadjusted analysis (HR 0.81, 95% CI 0.67–0.97). However, after balancing baseline covariates across groups, metformin was not associated with a reduced risk of endometrial cancer (HR 1.09, 95% CI 0.88–1.35). This finding was consistent across multiple sensitivity analyses and subgroup analyses in diabetic patients and relevant age groups. Conclusions In this population-based cohort of >500,000 women, initiating metformin compared with sulfonylureas was not associated with a reduced risk of developing endometrial cancer.

Obesity has been linked with increased risk for and worse outcomes from cancer, including gynecologic cancers. Metformin (1,1-dimethylbiguanide) is a biguanide anti-hyperglycemic widely used for the treatment of type 2 diabetes. Epidemiologic studies suggest metformin both lowers cancer risk and improves cancer outcomes in diabetic patients when compared to those treated with other anti-diabetic medications. This epidemiologic evidence prompted pre-clinical investigation of the effects of metformin in cancer. In vitro and in vivo data find that metformin possesses anti-cancer effects through both indirect and direct effects on tumor growth. Indirect effects are likely due to inhibition of hepatic gluconeogenesis, resulting in reduced circulating glucose and insulin levels, which may decrease growth factor-stimulated tumor growth. Metformin may directly affect tumor growth through inhibition of mitochondrial complex 1 and activation of adenosine monophosphate-activated protein kinase (AMPK), resulting in the regulation of multiple downstream signaling pathways that control cell proliferation and metabolism, including inhibition of the mammalian target of rapamycin (mTOR) pathway as well as decreased fatty acid and lipid sythesis.

Obesity is a significant risk factor for ovarian cancer (OC) and associated with worse outcomes for this disease. We assessed the anti-tumorigenic effects of metformin in human OC cell lines and a genetically engineered mouse model of high grade serous OC under obese and lean conditions. Metformin potently inhibited growth in a dose-dependent manner in all four human OC cell lines through AMPK/mTOR pathways. Treatment with metformin resulted in G1 arrest, induction of apoptosis, reduction of invasion and decreased hTERT expression. In the K18-gT121+/-; p53fl/ fl; Brca1fl/fl (KpB) mouse model, metformin inhibited tumor growth in both lean and obese mice. However, in the obese mice, metformin decreased tumor growth by 60%, whereas tumor growth was only decreased by 32% in the lean mice (p=0.003) compared to vehicle-treated mice. The ovarian tumors from obese mice had evidence of impaired mitochondrial complex 2 function and energy supplied by omega fatty acid oxidation rather than glycolysis as compared to lean mice, as assessed by metabolomic profiling. The improved efficacy of metformin in obesity corresponded with inhibition of mitochondrial complex 1 and fatty acid oxidation, and stimulation of glycolysis in only the OCs of obese versus lean mice. In conclusion, metformin had anti-tumorigenic effects in OC cell lines and the KpB OC pre-clinical mouse model, with increased efficacy in obese versus lean mice. Detected metabolic changes may underlie why ovarian tumors in obese mice have heightened susceptibility to metformin.

We conducted a preoperative window study of metformin in endometrial cancer (EC) patients and evaluated its antiproliferative, molecular and metabolic effects. Twenty obese women with endometrioid EC were treated with metformin (850 mg) daily for up to 4 weeks prior to surgical staging. Expression of the proliferation marker Ki-67, estrogen receptor (ER), progesterone receptor (PR), adenosine monophosphate-activated protein kinase (AMPK), and downstream targets of the mammalian target of rapamycin (mTOR) pathway were measured by immunohistochemistry. Global, untargeted metabolomics analysis of serum pre- and postmetformin treatment, and matched tumor, was performed. Metformin reduced proliferation by 11.75% (P = 0.008) based on the comparison of pre- and posttreatment endometrial tumors. A total of 65% of patients responded to metformin as defined by a decrease in Ki-67 staining in their endometrial tumors post-treatment. Metformin decreased expression of phosphorylated (p)-AMPK (P = 0.00001), p-Akt (P = 0.0002), p-S6 (51.2%, P = 0.0002), p-4E-BP-1 (P = 0.001), and ER (P = 0.0002) but not PR expression. Metabolomic profiling of serum indicated that responders versus nonresponders to treatment were more sensitive to metformin's effects on induction of lipolysis, which correlated with increased fatty acid oxidation and glycogen metabolism in matched tumors. In conclusion, metformin reduced tumor proliferation in a pre-operative window study in obese EC patients, with dramatic effects on inhibition of the mTOR pathway. Metformin induced a shift in lipid and glycogen metabolism that was more pronounced in the serum and tumors of responders versus nonresponders to treatment.This study provides support for therapeutic clinical trials of metformin in obese patients with EC.

BACKGROUND The objective of the current study was to evaluate the effect of obesity on pretreatment quality of life (QoL) in gynecologic oncology patients. METHODS The authors analyzed collected data from an institution-wide cohort study of women with gynecologic cancers enrolled from August 2012 to June 2013. The Functional Assessment of Cancer Therapy-General, site-specific symptom scales, and the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) global mental and physical health tools were administered. Survey results were linked to clinical data abstracted from medical records (demographics and comorbid conditions). Bivariate tests and multivariate linear regression models were used to evaluate factors associated with QoL scores. RESULTS A total of 182 women with ovarian, uterine, cervical, and vulvar/vaginal cancers were identified; of these, 152 (84%) were assessed before surgery. Mean body mass index was 33.5 kg/m2 and race included white (120 patients [79%]), black (22 patients [15%]), and other (10 patients [6.5%]). A total of 98 patients (64.5%) were obese (body mass index ≥30). On multivariate analysis, subscales for functional (17 vs 19; P = .04), emotional (16 vs 19; P = .008), and social (22 vs 24; P = .02) well-being as well as overall Functional Assessment of Cancer Therapy-General scores (77 vs 86; P = .002) and Patient-Reported Outcomes Measurement Information System global physical health scores (45 vs 49; P = .003) were found to be significantly lower in obese versus nonobese patients. CONCLUSIONS Before cancer treatment, obese patients with gynecologic malignancies appear to have worse baseline QoL than their normal-weight counterparts. Emerging models of QoL-based cancer outcome measures may disproportionately affect populations with a high obesity burden. The potential disparate impact of cancer therapy on longitudinal QoL in the obese versus nonobese patients needs to be evaluated. Cancer 2015;121:395–402. © 2014 American Cancer Society.

We examined the distribution of obesity, diabetes, and race in Type I and Type II endometrial cancers (EC) and their associations with clinical outcomes.A multi-institutional retrospective analysis of Type I and II EC cases from January 2005 to December 2010 was conducted. Type I (endometrioid), Type II (serous and clear cell), low grade (LG) (grade 1 and 2 endometrioid), and high grade (HG) (grade 3 endometrioid, serous, clear cell) cohorts were compared. Univariate and multivariate analyses were used to determine time-to-recurrence (TTR), recurrence-free survival (RFS), and overall survival (OS).Type I EC patients were more frequently obese than Type II (66% versus 51%, p0.0001) and had similar rates of diabetes (25% versus 23%, p=0.69). African-Americans (AA) had higher median BMI than Caucasians in both Type I (p0.001) and II (p0.001) ECs, and were twice as likely to have diabetes (p0.001). In Type I EC, DM was associated with worse RFS and OS in unadjusted and adjusted models (RFS HR 1.38, 95%CI 1.01-1.89; OS HR 1.86, 95%CI 1.30-2.67), but not with TTR. BMI was associated with improved TTR in the adjusted analysis for Type I EC (HR 0.98, 95%CI 0.95-1.0), but not with RFS or OS. There was no association between DM or BMI and outcomes in Type II or HG EC. AA race was not associated with RFS or OS on adjusted analyses in any group.Obesity and diabetes are highly prevalent in Type I and II ECs, especially in AA. DM was associated with worse RFS and OS in Type I EC. Neither DM nor BMI was associated with outcomes in Type II or HG EC.

Objective Preclinical evidence suggests that metformin exhibits anti-tumorigenic effects in endometrial cancer. We sought to investigate the association of metformin on endometrial cancer outcomes. Methods A multi-institutional IRB-approved retrospective cohort analysis was conducted comparing endometrial cancer patients with diabetes mellitus who used metformin (based on medication review at the time of diagnosis) to those who did not use metformin from 2005 to 2010. Metformin use on treatment related outcomes (TTR: time to recurrence; RFS: recurrence free survival; OS: overall survival) were evaluated using univariate and multivariate modeling. Results 24% (363/1495) endometrial cancer patients were diabetic, of whom 54% used metformin. Metformin users were younger and heavier than non-users, though nearly all were postmenopausal and obese. 75% of both groups had endometrioid histology. Stage, grade, and adjuvant therapy distributions were similar. Metformin users had improved RFS and OS. Non-metformin users had 1.8 times worse RFS (95% CI: 1.1–2.9, p=0.02) and 2.3 times worse OS (95% CI: 1.3–4.2, p=0.005) after adjusting for age, stage, grade, histology and adjuvant treatment. Metformin use was not associated with TTR. Conclusion Metformin use was associated with improved RFS and OS but not TTR, most likely due to improving all-cause mortality. Its role in modifying cancer recurrence remains unclear. Prospective studies that capture metformin exposure prior to, during and post endometrial cancer treatment may help define the role of metformin upon cancer specific and overall health outcomes.

Purpose: Obesity is associated with increased risk and worse outcomes for endometrial cancer (EC). Metformin, a frontline therapy for type 2 diabetes, is thought to have both indirect and direct anti-cancer effects via decreasing circulating insulin/glucose and activating AMPK/inhibiting mTOR signaling, respectively. Due to its positive charge (pKa 12.4) and hydrophilicity (logD -6.13 at pH 7.4), metformin requires cation transporters for cellular uptake where it can then activate AMPK; and thus, variation in transporter expression may be critical for response to metformin for cancer treatment. Thus, we explored the inter-relationship of obesity, cation transporter expression and the anti-tumorigenic efficacy of metformin in a genetically engineered endometrioid EC mouse model. Methods: LKB1fl/fl p53fl/fl mice were fed a low-fat diet (10% calories from fat) vs. a high-fat diet (60% calories from fat) to mimic diet-induced obesity, starting at 3 weeks of age (n=10 mice/group). AdCre was injected at 6 weeks of age to induce EC. Mice were treated for four weeks with placebo or metformin (200 mg/kg/day, oral gavage) following tumor onset. Cell proliferation/apoptotic markers and downstream targets of AMPK/mTOR signaling were evaluated in the ECs by immunohistochemistry. Cation transporter expression was assessed in the ECs by Western blotting and RNA sequencing. Results: Obesity led to a doubling of endometrial tumor size in obese vs. lean mice (1.469g vs. 0.75g). Metformin was more potent in inhibiting tumor growth in obese vs. lean mice (78% vs. 60%) compared to the respective controls (p Conclusion: Our data suggest that metformin has greater anti-tumorigenic efficacy in obese vs. lean mice with EC. In addition, cation transporters were expressed in the endometrial tumors and were affected by metformin treatment. Studies are underway in EC patients to understand the impact of obesity and transporter expression on response rates to metformin in the clinic. Note: This abstract was not presented at the meeting. Citation Format: Aruljothi Muralidharan, Hui Guo, Jianjun Han, Lu Zhang, Wenchuan Sun, Yajie Yin, Chunxiao Zhou, Ruth S. Everett, Dhiren R. Thakker, Victoria L. Bae-Jump. Metformin treatment outcomes in relation to obesity and cation transporter expression in mouse models of endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3609.

e17031 Background: Obesity has been linked to worse outcomes in epithelial ovarian cancer (EOC), due to underlying metabolic dysfunction. Visceral fat (i.e. central obesity) compared to subcutaneous fat is more metabolically active and has been linked to higher rates of obesity-related comorbidities such as hypertension and diabetes, but less is known of the impact of increased visceral adiposity on EOC outcomes. Thus, our goal was to evaluate if visceral adiposity, as determined by computed tomography (CT) morphometric measurements, was associated with worse outcomes in EOC patients undergoing platinum and taxane-based chemotherapy. Methods: EOC patients diagnosed between 12/2004 and 5/2016 who received neoadjuvant or adjuvant treatment with platinum and taxane-based chemotherapy were included. Data on age, stage, grade, histology, BMI, comorbidities, treatment approaches and outcomes were collected. CT images closest to the time of diagnosis were retrospectively evaluated for mid-waist visceral fat volume (VFV), mid-waist subcutaneous fat volume (SFV) and the ratio of mid-waist VFV/SFV. Visceral adiposity is commonly defined as a VFV/SFV ≥ 0.4. Cox regression models were used to analyze time-to-event outcomes. Results: Two hundred fifty-eight EOC patients were evaluated. Seventy-five percent of patients were diagnosed with Stage III or IV disease, with high grade serous as the most common histology (72%). Median age at diagnosis was 62.4 years. Approximately 65% were obese; the median BMI was 26.8 (IQR 23.1 – 32.6). The median VFV/SFV ratio was 0.46 (IQR 0.32 – 0.70). Patients were categorized into those with a VFV/SFV ratio greater than 0.4 or a ratio less than 0.4. When comparing these two groups, there was no difference in progression free survival (PFS) for women with a VFV/SFV ratio greater or less than 0.4 (p = 0.22). However, a VFV/SFV ratio of greater than 0.4 was associated with worse overall survival (OS) (p = 0.01). Conclusions: We found that visceral adiposity, defined as a VFV/SFV ratio greater than 0.4, appeared to be associated with decreased OS, but not PFS. These findings suggest that body fat distribution may be an important prognostic factor for EOC and should be further explored as we expect the obesity epidemic to continue and influence EOC oncologic outcomes.

To estimate disease regression, persistence, and progression in women with complex endometrial hyperplasia and stage I endometrial carcinoma treated with a levonorgestrel-releasing-intrauterine system or oral progesterone.Records of all patients who received progestin therapy for endometrial hyperplasia or early-stage endometrioid cancer between January 1999 and July 2011 were reviewed. Demographic data (age, body mass index), presentation, treatment modality and rationale, rates of response, recurrence, and salvage surgery were collected and compared using Student's t and χ tests. Fertility outcomes when available were analyzed.One hundred eighty-six women received primary hormone therapy for endometrial hyperplasia or cancer. Of these, 153 had adequate follow-up without surgery or radiation as part of primary treatment. Average age at diagnosis was 49.6 years (range 22-92 years). The most common reasons cited for hormone therapy were medical comorbidities (46%) and fertility (21%). Patients with hyperplasia compared with cancer had significantly different complete response (66-70% compared with 6-13%), initial response with recurrence (11-23% compared with 19-30%), and no response rates (11-19% compared with 57-75%), respectively (P.001). Outcomes were not significantly different between the levonorgestrel-releasing intrauterine system and oral progesterone among patients with cancer at all time points. In patients with hyperplasia, outcomes were not significantly different except during the 9-month to 12-month assessment where those who received systemic hormones were less likely to have disease persistence or progression compared with patients who had levonorgestrel-releasing intrauterine systems. Three patients achieved pregnancy.Hormone therapy has varied response rates among women with endometrial hyperplasia or cancer who do not undergo surgery. Close patient monitoring remains paramount given the high recurrence and high percentage of patients who will not respond.

// Anuj Suri 1 , Xiugui Sheng 2, * , Kevin M. Schuler 3 , Yan Zhong 4, 5 , Xiaoyun Han 2, 4 , Hannah M. Jones 4 , Paola A. Gehrig 4, 6 , Chunxiao Zhou 4, 6 , Victoria L. Bae-Jump 4, 6 1 Houston Methodist Gynecologic Oncology Associates, Houston, TX, USA 2 Department of Gynecologic Oncology, Shandong Cancer Hospital & Institute, Jinan University, Jinan, Shandong, China 3 Good Samaritan Hospital, Division of Gynecologic Oncology, Cincinnati, OH, USA 4 Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 5 Department of Gynecologic Oncology, Linyi Cancer Hospital, Shandong, China 6 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA * This author contributed an equal amount of work as the first author Correspondence to: Victoria L. Bae-Jump, e-mail: victoria_baejump@med.unc.edu Chunxiao Zhou, e-mail: czhou@med.unc.edu Keywords: ovarian cancer, COX-2 inhibitor, celecoxib, obesity, genetically engineered mouse model Received: January 21, 2016 Accepted: March 28, 2016 Published: April 8, 2016 ABSTRACT Our objective was to evaluate the effect of the COX-2 inhibitor, celecoxib, on (1) proliferation and apoptosis in human ovarian cancer cell lines and primary cultures of ovarian cancer cells, and (2) inhibition of tumor growth in a genetically engineered mouse model of serous ovarian cancer under obese and non-obese conditions. Celecoxib inhibited cell proliferation in three ovarian cancer cell lines and five primary cultures of human ovarian cancer after 72 hours of exposure. Treatment with celecoxib resulted in G1 cell cycle arrest, induction of apoptosis, inhibition of cellular adhesion and invasion and reduction of expression of hTERT mRNA and COX-2 protein in all of the ovarian cancer cell lines. In the KpB mice fed a high fat diet (obese) and treated with celecoxib, tumor weight decreased by 66% when compared with control animals. Among KpB mice fed a low fat diet (non-obese), tumor weight decreased by 46% after treatment with celecoxib. In the ovarian tumors from obese and non-obese KpB mice, treatment with celecoxib as compared to control resulted in decreased proliferation, increased apoptosis and reduced COX-2 and MMP9 protein expression, as assessed by immunohistochemistry. Celecoxib strongly decreased the serum level of VEGF and blood vessel density in the tumors from the KpB ovarian cancer mouse model under obese and non-obese conditions. This work suggests that celecoxib may be a novel chemotherapeutic agent for ovarian cancer prevention and treatment and be potentially beneficial in both obese and non-obese women.

Objectives The aim of the study were to evaluate the gap between recommended and received adjuvant therapy in elderly patients with endometrial cancer (EC) and to determine the percent of women 70 years and older who would meet enrollment criteria for representative Gynecologic Oncology Group (GOG) trials. Methods and Materials An institutional review board approved retrospective chart review of all EC cases from a tertiary care institution from 2005 to 2010 was performed. Clinical, surgical, and pathologic data were abstracted from electronic medical records. Gynecologic Oncology Group protocols 249, 209, and 229L were selected as representative national EC trials. Patients were evaluated for eligibility by each protocol’s criteria. Results Twenty-six percent (280/1064) of patients with EC were older than 70 years. More than 60% (181/280) of elderly patients with EC were recommended to undergo adjuvant therapy. By therapy type, 64% (48/75) of elderly patients who were recommended adjuvant radiation received it, 53% (49/92) of elderly patients who were recommended combination chemotherapy and radiation received it, and 29% (4/14) of elderly patients who were recommended chemotherapy received it. In evaluating enrollment criteria for GOG 249, 30% (40/134) of pathologically eligible patients would have been eliminated for medical clearance; for GOG 209, 31% (26/86) would have been eliminated, and for GOG 229L, 9% (4/45) would have been eliminated purely for medical reasons. Conclusions More adjuvant treatment is recommended in the elderly patients because of a higher incidence of advanced disease and aggressive histopathology. Approximately half of the elderly patients who were recommended treatment actually received it. In addition, clinical trial data are limited for elderly patients because approximately one third of the women aged 70 years and older who meet pathologic enrollment criteria for trials were excluded because of complex medical disease.

The Cancer Genome Atlas (TCGA) identified four integrated clusters for endometrial cancer (EC): POLE, MSI, CNL and CNH. We evaluated differences in gene expression profiles of obese and non-obese women with EC and examined the association of body mass index (BMI) within the clusters identified in TCGA.TCGA RNAseq data was used to identify genes related to increasing BMI among ECs. The POLE, MSI and CNL clusters were composed mostly of endometrioid EC. Patient BMI was compared between these three clusters with one-way ANOVA. Association between gene expression and BMI was also assessed while adjusting for confounding effects of potential confounding factors. p-Values testing the association between gene expression and BMI were adjusted for multiple hypothesis testing over the 20,531 genes considered.Mean BMI was statistically different between the ECs in the CNL (35.8) versus POLE (29.8) cluster (p=0.006) and approached significance for the MSI (33.0) versus CNL (35.8) cluster (p=0.05). 181 genes were significantly up- or down-regulated with increasing BMI in endometrioid EC (q-value0.01), including LPL, IRS-1, IGFBP4, IGFBP7 and the progesterone receptor. DAVID functional annotation analysis revealed significant enrichment in "cell cycle" (adjusted p-value=1.5E-5) and "DNA metabolic processes" (adjusted p-value=1E-3) for the identified genes.Obesity related genes were found to be upregulated with increasing BMI among endometrioid ECs. Patients with POLE tumors have the lowest median BMI when compared to MSI and CNL. Given the heterogeneity among endometrioid EC, consideration should be given to abandoning the Type I and II classification of EC tumors.

5586Background: Lymph node (LN) metastasis and genomic profiles are important prognostic factors in endometrial cancer (EC). However, the prognostic significance of the volume of metastatic disease...

Objectives The appropriate sequencing of chemotherapy and radiation for the treatment of advanced endometrial cancer has not yet been determined. We sought to evaluate the outcome and adverse effects in patients with advanced stage endometrial cancer treated with postoperative chemotherapy and radiation to determine whether there was an advantage to a particular sequencing modality. Methods A multicenter retrospective analysis of patients with surgical stages III and IV endometrial cancer from 1993 to 2007 was conducted. Inclusion criteria were comprehensive staging procedure including hysterectomy, bilateral salpingo-oophorectomy, ±Alloccurrencesof"+/-"werechangedtoaplusminussign.Pleaseverify.-->selective pelvic/aortic lymphadenectomy, and treatment with adjuvant chemotherapy and radiation. Differences in frequencies of adverse events were tested with Pearson's chi-square test for comparing proportions. OS and PFS rates were calculated using Kaplan–Meier estimates. Hazard Ratios (HR) were estimated from multivariate Cox proportional hazards models. Results One hundred and nine patients with advanced stage endometrial cancer were identified who received postoperative adjuvant therapies; 41% ( n =45) chemotherapy followed by radiation and then further chemotherapy (CRC), 17% ( n =18) radiation followed by chemotherapy (RC), and 42% ( n =46) chemotherapy followed by radiation (CR). The median age was 62 years (range: 35–83); 48% had endometrioid tumors; and 90% underwent optimal cytoreduction. There was no difference in the frequency of adverse effects due to either chemotherapy ( p =0.35) or radiotherapy ( p =0.14); dose modifications ( p =0.055); or delays ( p =0.80) between the various sequencing modalities. There was a significant difference between adjuvant treatment groups for both OS (log rank p =0.011) and PFS (log rank p =0.025), with those receiving CRC having a superior 3-year OS (88%) and PFS (69%) compared to RC (54% and 47%) or CR (57% and 52%). After adjusting for stage, age, grade, race, histology and cytoreduction status the OS HR for therapy was 5.74 (95% CI, 1.96 to 16.77) for RC and 2.60 (95% CI, 1.01 to 6.71) for CR, compared to CRC, p =0.003. When the analysis was restricted to optimally cytoreduced patients, those who were treated with RC were at higher risk for disease progression [HR=3.53 (95% CI, 1.29 to 9.71)], p =0.024, and death [HR=7.24 (95% CI, 2.25 to 23.37)], p =0.001, than patients who received sequential CRC. Conclusions Sequential CRC was associated with improved survival in women with advanced stage disease compared to other sequencing modalities with a similar adverse effect profile. Future clinical trials are needed to prospectively evaluate appropriate sequencing and types of adjuvant chemotherapy and radiotherapy for the treatment of advanced stage endometrial cancer.

Objectives Obesity and diabetes are well-known risk factors for the development of endometrial cancer. A high rate of aerobic glycolysis represents a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. This study aimed to investigate the effect of various concentrations of glucose on cell proliferation in endometrial cancer. Methods ECC-1 and Ishikawa cells were treated with low glucose (1mM), normal glucose (5mM) and high glucose (25mM), and cytotoxicity, apoptosis, cell cycle, adhesion/invasion, and changes of AMPK/mTOR/S6 and MAPK pathways were evaluated. Results Our results revealed that high glucose increased cell growth and clonogenicity in two endometrial cancer cell lines in a dose dependent manner. Low glucose induced the activity of cleaved caspase 3 and caused cell cycle G1 arrest. High glucose increased the ability of adhesion and invasion by decreasing E-cadherin and increasing Snail expression. In addition, high glucose increased glucose uptake and glycolytic activity through modulating the AMPK/mTOR/S6 and MAPK pathways. Conclusions Our findings suggest that glucose stimulated cell proliferation through multiple complex signaling pathways. Targeting glucose metabolism may be a promising therapeutic strategy in the treatment of endometrial cancer.

High rates of aerobic glycolysis represent a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. The present study was aimed at evaluating the potential of a novel lactate dehydrogenase (LDH) inhibitor, Galloflavin, as a therapeutic agent for endometrial cancer. Our results revealed that Galloflavin effectively inhibited cell growth in endometrial cancer cell lines and primary cultures of human endometrial cancer through its involvement in multiple signaling pathways that regulate metabolism, cell cycle, apoptosis, cell stress and metastasis. Electronic supplementary material The online version of this article (doi:10.1186/s13045-014-0097-x) contains supplementary material, which is available to authorized users.

Objective . Endometrial cancer and breast cancer are two common malignancies found in women. As a result of estrogen dependency, an association is thought to exist between these entities. This study was undertaken to determine if the endometrial carcinomas, which develop in women with a history of breast cancer, were more likely to be of the endometrioid or the serous histology, which is generally considered non-estrogen-dependent. Methods . A retrospective chart review was conducted for the years 1984–2001. All women who were diagnosed at our institution with endometrial carcinoma were identified. The women who also had a prior history of breast cancer were identified and comprise the cohort for this study. Information regarding age at diagnosis, tumor stage, histologic subtype, and tamoxifen exposure were recorded and analyzed. Results . About 1,166 women were diagnosed with endometrial cancer during the study period, of whom 54 (4.6%) had a pre-existing diagnosis of breast cancer. Of the 54 women in this study, 41 had tumors of the endometrioid histology and 13 had a tumor of the serous subtype. There was no difference with regards to median age at the time of diagnosis or years of tamoxifen exposure. Women with breast cancer were more likely to develop uterine serous carcinoma (USC) as compared to one of endometrioid histology (OR 2.6; 95% CI 1.29–5.23). Conclusions . Women with breast cancer who subsequently developed endometrial cancer exhibited a 2.6-fold increased risk of developing a USC as compared to an endometrioid carcinoma. These findings suggest that there may be an underlying genetic predisposition linking breast cancer and USC.

Background: We examined the association of platinum resistance with genetic mutations in high grade serous ovarian cancer (HSOC) patients undergoing high-throughput genomic tumor sequencing. Methods: Snap-frozen and fresh frozen paraffin embedded tissue samples were collected from HSOC patients enrolled on UNCseq (NCT01457196). UNCSeq is an institutional protocol which uses next generation sequencing to detect genetic mutations in a wide array of malignancies. Illumina libraries were prepared separately from tumor and a matched normal sample from each patient. Relevant targets were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. Samples were sequenced on Illumina HiSeq machines in a variety of formats. Mutations with a quality score or < 6 months of disease free interval following completion of induction therapy, respectively. Results: Overall 39 HSOC cases met inclusion criteria; 32 tumors met criteria for platinum sensitive and 7 platinum resistant. 308 mutations were noted in at least one individual across all patients. The top observed mutations in platinum sensitive HSOC were TP53 (41%, n= 13), GucylA2 (19%, n=6), MLL2 (19%, n=6) and MTOR (16%, n=5). The top observed mutations in platinum resistant tumors were TP53 (71%, n=5), TET1 (43%, n=3), NF1 (43%, n=3) and MLL3 (43%, n=3). There was a trend toward more p53 mutations in resistant tumors (71% versus 41%, p=0.21) There was no difference in the total number of mutations per tumor in platinum sensitive and resistant patients, (3 vs. 4, p=0.516). Conclusions: We did not detect a difference in the number of genetic mutations in HSOC according to platinum sensitivity. Platinum resistant tumors had a trend toward higher frequency of TP53 mutations than platinum sensitive HSOCs. Furthermore, we identified 3 frequently mutated genes in platinum resistant HSOC: TET1, an epigenetic regulator, NF1, a tumor suppressor gene and MLL3, a histone modifier gene. Ongoing tumor sequencing of HSOCs on UNCseq will help to confirm these results. Citation Format: Tara Castellano, Leslie H. Clark, Naim Rashid, Victoria Bae-Jump. Genetic variation in platinum-sensitive and platinum-resistant high-grade serous epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 412. doi:10.1158/1538-7445.AM2017-412

Introduction: Obesity is associated with increased risk for and worse outcomes from endometrial cancer (EC). Orlistat is a weight loss medication that has been shown to be a potent inhibitor of fatty acid synthase (FAS), and FAS is known to be upregulated in ECs. Thus, we sought to investigate the anti-tumorigenic potential of orlistat in EC cell lines and a genetically engineered mouse model of endometrioid EC (LKB1fl/flp53fl/fl mouse model). Methods: Two endometrial cell lines, ECC-1 and KLE, were used. Cell proliferation was assessed by MTT assay after exposure to orlistat. Western immunoblotting was performed to evaluate the effect of orlistat on downstream targets of fatty acid metabolism. LKB1fl/flp53fl/fl mice were fed a control low fat diet (LFD; 10% calories from fat, lean group) versus a high fat diet (HFD; 60% calories derived from fat, obese group) to mimic diet-induced obesity, starting at 3 wks of age. AdCre was injected at 6 wks of age to induce invasive EC. Mice were treated with placebo or orlistat (200 mg/kg/day, IM) following tumor onset for 4 weeks (N=10 mice/group). Immunohistochemistry was performed to assess for the effect of orlistat on expression of Ki-67 (marker of cell proliferation), vascular endothelial growth factor (VEGF) and phosphorylated (p)-acetyl-CoA carboxylase (ACC). Results: Orlistat inhibited growth in a dose-dependent manner for both endometrial cell lines with a mean IC50 for ECC-1 of 88.7 uM and 145.4 uM for KLE (p Conclusions: Orlistat inhibited EC cell proliferation and endometrial tumor growth in an endometrioid EC mouse model, with increased efficacy in obese versus lean mice. Therefore, orlistat may be worthy of drug repurposing as an anti-tumorigenic agent in EC, with the potential added benefit of weight loss in this obesity-linked disease. Citation Format: Stephanie Sullivan, Arthur-Quan Tran, Weiya Wysham, Paola Gehrig, Chunxiao Zhou, Victoria Bae-Jump. Orlistat as a novel targeted therapy for obesity-driven endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 453. doi:10.1158/1538-7445.AM2017-453