- Endometrial Cancer (EC): We applied our optimized procedures for analyzing small tissue specimens using laser capture microscopy techniques for gene expression to oligonucleotide array, liquid chromatography (nanoRPLC), and mass spectrometry proteomics analysis in collaboration with Dr Conrads at UPitt Cancer Institute (UPCI). In an analysis of 92 stage I ECs and 12 postmenopausal endometria, 132 differentially expressed molecules were identifed using both genomic and proteomic methods. We developed standardized processes for validating expression using tissue microarray (TMA) and independent data sets. The biologic role of selected differentially expressed molecules is under investigation in collaboration with Dr. Annunziata, MOB. - Racial Disparities in EC: We have continued our focus of investigation of racial disparities in outcome between AA and caucasian (C) women with EC. Our analysis of Gynecologic Oncology Group (GOG) Phase III EC clinical trials over the past decade demonstrated worse outcome for AA with EC, even when treated in prescribed clinical trial environment. These results prompted the hypothesis that there are biological etiologies that contribute to the racial disparity in outcome. We further examined differentially expressed molecules in collaboration with members of our consortium through creation and application of a TMA containing ECs from AA and C women, matched by stage and histology. Our group is also analyzing associations between 128 African specific mtDNA polymorphisms/haplogroups and clinical and pathological characteristics of EC within and between C and AA women. This will provide a method of objectively defining AA status based on known mtDNA haplotypes. Finally, we have been collaborating with investigators at UPCI to use mass-spectrometry methods to quantitiatively evaluate protein expression of PSPH found to be consistently over-expressed in AA with EC. We are examining NF-kB pathway alterations in AA and C EC clinical samples and cell lines with Dr. Annunziata, MOB. - Obesity and EC: The relationship between obesity and EC is more significant than for any other cancer type. Obese women have a 3-5 fold increased risk of developing EC and up to a 6 fold increased risk of cancer related mortality. Our data yielded global gene expression profiles that significantly differ between ECs from lean v. obese women. Several of these molecules are associated with inflammatory processes suggesting that anovulation may promote an inflammatory microenvironment conducive to carcinogenesis. Validation is underway using a larger independent sample set from Duke University collaborators. Analysis has been completed on 70 endometrioid EC using oligonucleotide array, mutational analysis of 6 genes associated with endometrial carcinogenesis, micro-RNA, and non-RNA endpoints. Dr. Linkov of UPCI has preliminary data demonstrating differences in serum inflammatory cytokines in lean v obese EC patients. Recent data has shown that bariatric surgery is associated with a decreased incidence of EC and we will examine proteomic changes associated with the transition in EC risk. A case control analysis of circulating inflammatory markers in obese and normal weight women is ongoing. Dr. Conrad at UPCI is analyzing 15 estrogen metabolites in a serum sample set from the M.D. Anderson Endometrial Cancer SPORE, according to BMI. These preliminary data will drive definitive metabolomic analysis of estrogen in tumor/urine/serum/blood correlated with gene expression analysis using tumors in the GOG 210 endometrial cancer repository. Previous work in collaboration with the CDC has shown that higher higher progestin-potency OCs may be more protective than lower progestin potency OCs among women with a larger body habitus. We have further shown in macaque models in collaboration with Dr. Cline at Wake Forest that these protective effects may be in part due to progestin-mediated induction of apoptosis and TGF-mediated pathways. Recent data from our consortium have shown that a combination of vitamin D and progestin offer a greater protective effect than progestin alone in prevention of endometrial hyperplasia in PTEN +/- mice. Current studies are underway evaluating the gene expression profiles associated with progestin and vitamin D in EC cell lines and studies evaluating the effects of combining progestin and vitamin D on the endometrial lining. - Metastasis Models for EC: Previous studies have suggested that EC patients treated by gynecologic oncologists are more likely to receive definitive lymph node dissection and surgical staging than patients managed by a general ob/gyn. Our group analyzed the Medicare database 1988-2005 to assess the influence of gynecologic oncologists on treatment and outcome of EC patients. We found patients with metastatic disease (stages III/IV) treated by gyn oncs had higher a five-year disease-specific survival rate than patients treated by other specialists (p<0.0001). Treatment by a gynecologic oncologist was an independent prognostic factor for improved survival for patients with metastatic disease on multivariate analysis. This highlights the potential beneficial impact a clinical test for metastasis detection, particularly since only 21% of EC patients receive care by a gynecologic oncologist. We performed a cost effectiveness analysis to assess the economic feasibility of a screening test for EC metastasis. A decision model was constructed to evaluate the cost effectiveness of pre-operative screening for metastasis among patients with EC. Diagnostic testing was more expensive and more effective, with an incremental cost-effectiveness ratio of $8222 per year of life saved. Results are relatively insensitive to variation in test characteristics, costs of test and treatment, and probability of adjuvant therapies. Testing remains cost effective unless the rate of referral to a gynecologic oncologist for full staging exceeds 90%. Given the current low rates of full surgical staging, a diagnostic test to detect nodal metastasis for endometrial cancer has the potential to be cost-effective. We examined molecular expression patterns predictive of metastasis in EC patients. We found several 3-biomarker combinations using the Luminex biomaker panel that correctly identified 61-65% of lymph node negative patients and 95% lymph positive patients. We transitioned to analyses of EC tissue specimens to improve accuracy of our biomarker panel. Preliminary data using two independent samples sets have indicated differences in both protein and gene expression in metastatic EC compared to cancers confined to the uterus. Prediction models developed using one of the two sample sets provided >90% accuracy in identifying EC patients with metastasis based on a gene expression profile. We are developing an optimal molecular expression prediction model using endometrioid EC from GOG-210;this will be validated using other independent sample sets. In addition, our consortia has initiated prospective collection of EC biopsies to be used to test the accuracy of the metastasis model in pre-operative identification of EC patients with metastasis. We are testing the metastasis model in a set of recurrent stage I EC samples from GOG 210. In the setting of adequate surgical staging according to GOG criteria, stage I patients with EC who recur were most likely cases of unrecognized advanced stage disease. We will develop a model to molecularly examine the hysterectomy specimen to more accurately identify [summary truncated at 7800 characters]
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