Double negative hormone receptor status in endometrial cancer curettage independently predicts lymph node metastasis and poor prognosis in a prospective multicentre setting. Implementing hormone receptor status to improve risk-stratification for selecting patients unlikely to benefit from lymphadenectomy seems justified.

Purpose: Overexpression of the oncogen Stathmin has been linked to aggressive endometrial carcinoma and a potential for PI3Kinase inhibitors in this disease. We wanted to validate the prognostic value of Stathmin expression in a large prospective multicenter setting. As lymph node sampling is part of current surgical staging, we also aimed to test if Stathmin expression in endometrial curettage specimens could predict lymph node metastasis.Experimental Design: A total of 1,076 endometrial cancer patients have been recruited from 10 centers to investigate the biological tumor marker Stathmin in relation to clinicopathologic variables, including lymph node status and survival. Stathmin immunohistochemical staining was carried out in 477 hysterectomy and 818 curettage specimens.Results: Seventy-one percent of the patients (n ¼ 763) were subjected to lymph node sampling, of which 12% had metastatic nodes (n ¼ 94). Overexpression of Stathmin was detected in 37% (302 of 818) of the curettage and in 18% (84 of 477) of the hysterectomy specimens investigated. Stathmin overexpression in curettage and hysterectomy specimens were highly correlated and significantly associated with nonendometrioid histology, high grade, and aneuploidy. Stathmin analysis in preoperative curettage samples significantly correlated with, and was an independent predictor of, lymph node metastases. High Stathmin expression was associated with poor disease-specific survival (P 0.002) both in curettage and hysterectomy specimens.Conclusions: Stathmin immunohistochemical staining identifies endometrial carcinomas with lymph node metastases and poor survival. The value, as a predictive marker for response to PI3Kinase inhibition and as a tool to stratify patients for lymph node sampling in endometrial carcinomas, remains to be determined. Clin Cancer Res; 17(10); 3368-77. Ó2011 AACR.

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BACKGROUND: To investigate the value of neoadjuvant chemotherapy (NACT), followed by interval debulking surgery (IDS), in endometrial cancer with transperitoneal spread (stage IV). METHODS: Patients with endometrial cancer with transperitoneal spread, as determined by laparoscopy ( ± pleural effusion), were treated with NACT. Efficacy was determined according to the Response Evaluation Criteria in Solid Tumors, residual tumour at IDS and histopathological assessment of tumour regression. RESULTS: A total of 30 patients (median age: 65 years; range:44 -81 years) received 3 -4 cycles of NACT (83% paclitaxel/carboplatin). Histopathological subtypes were as follows: serous (90%), clear cell (3%) and endometrioid (6%) carcinoma. Response according to RECIST was as follows: 2 (7%) complete remission, 20 (67%) partial remission, 6 (20%) stable disease and 2 (7%) progressive disease (PD). Patients with PD were not operated upon. A total of 24 patients (80%) had optimal cytoreduction (R p1 cm), of whom 22 (92%) were without residual tumour. Four patients were considered inoperable and were excluded from further analysis. The median progression-free survival and overall survival times were 13 and 23 months, respectively. Histopathological features of chemoresponse in both uterus and omentum were related to a better PFS (P ¼ 0.017, hazard ratio (HR) ¼ 0.785) and overall survival (P ¼ 0.014, HR ¼ 0.707). In particular, the absence of tumour infiltration and necrosis were associated with prognosis. CONCLUSION: The use of NACT resulted in a high rate (80%) of optimal IDS for the treatment of endometrial cancer with transperitoneal spread.

BackgroundEvery year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT).Methodology and Principal FindingsParaffin sections from patients with (n = 9) or without (n = 9) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa(IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB(IKPRB) and PRA+PRB (IKPRAB) were cultured in presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling.ConclusionIntact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveilance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype.