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Background The objective of this study was to assess the correlation between mismatch repair (MMR) status, disease recurrence patterns, and recurrence-free survival (RFS) in patients with high-intermediate-risk (HIR) endometrioid endometrial cancer (EEC). Methods A single-institution chart review for consecutive patients who were diagnosed with ECC between 2007 and 2016 was undertaken. Tumor MMR status was determined for all patients based on reported findings for mutL homolog 1 (MLH1), postmeiotic segregation (PMS2), mutS homolog 2 (MSH2), and MSH6 immunohistochemistry; and defective MMR (dMMR) status was defined as the lack of expression of at least 1 of these proteins. Patients were classified with HIR EEC according to criteria used for Gynecologic Oncology Group study 249. The factors associated with recurrence were assessed by logistic regression. RFS and associated factors were assessed by Kaplan-Meier survival analysis and Cox proportional-hazards models. Results In total, 197 patients who had HIR EEC (64 with dMMR and 133 with intact MMR [iMMR]) were identified, of whom 32 (16.2%) developed recurrent disease. The median follow-up was 54 months. The recurrence rate for women who had dMMR was 28% compared with 10.5% for those who had iMMR (P = .002), independent of the type of adjuvant therapy they received. The increase in distant recurrences among patients who had dMMR was even more pronounced (14.1% vs 3%; P = .003). The estimated 5-year RFS was 66% for women who had dMMR compared with 89% for those who had iMMR (P = .001). Excluding isolated vaginal recurrences, the difference in 5-year RFS was 73.5% versus 95%, respectively (P = .0004). Conclusions Patients who had HIR EEC with dMMR had increased rates of recurrence and decreased RFS compared with those who had HIR EEC with iMMR, despite the receipt of similar adjuvant treatment. The current findings highlight the need for alternative treatment options and the importance of MMR status as a biomarker for patients with HIR EEC.

FOXA2, a member of the forkhead family of DNA-binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations and a recurrent missense mutation have on FOXA2 transcriptional activity. Recurrent N-terminal frameshifts resulted in truncated proteins that failed to translocate to the nucleus and have no transcriptional activity using an E-cadherin/luciferase reporter assay. Protein abundance was reduced for the recurrent p.S169 W mutation, as was transcriptional activity. A C-terminal frameshift mutation had increased FOXA2 levels evidenced by both Western blot and immunofluorescence. Given that FOXA2 is a recognized activator of E-cadherin (CDH1) expression and E-cadherin's potential role in epithelial-to-mesenchymal transition in a wide range of cancer types, we tested the hypothesis that FOXA2 mutations in primary uterine cancer specimens would be associated with reduced CDH1 transcript levels. qRT-PCR revealed significantly lower levels of CDH1 expression in primary tumors with FOXA2 mutations. Our findings in vitro and in vivo suggest that reduced transcriptional activity associated with FOXA2 mutations in uterine cancers is likely to contribute to protumorigenic changes in gene expression.

BACKGROUND Synuclein-γ (SNCG) is highly expressed in advanced solid tumors, including uterine serous carcinoma (USC). The objective of the current study was to determine whether SNCG protein was associated with survival and clinical covariates using the largest existing collection of USCs from the Gynecologic Oncology Group (GOG-8023). METHODS High-density tissue microarrays (TMAs) of tumor tissues from 313 patients with USC were stained by immunohistochemistry for SNCG, p53, p16, FOLR1, pERK, pAKT, ER, PR, and HER2/neu. Associations of SNCG and other tumor markers with overall and progression-free survival were assessed using log-rank tests and Cox proportional-hazards models, which also were adjusted for age, race, and stage. RESULTS The overall survival at 5 years was 46% for women with high SNCG expression and 62% for those with low SNCG expression (log-rank P = .021; hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.91-1.9 in adjusted Cox model). The progression-free survival rate at 5 years was worse for women who had high SNCG expression, at 40%, compared with 56% for those who had low SNCG expression (log-rank P = .0081; HR, 1.36; 95% CI, 0.96-1.92 in adjusted Cox model). High levels of both p53 and p16 were significantly associated with worse overall survival (p53: HR, 4.20 [95% CI, 1.54-11.45]; p16: HR, 1.95 [95% CI, 1.01-3.75]) and progression-free survival (p53: HR, 2.16 [95% CI, 1.09-4.27]; p16: HR, 1.53 [95% CI, 0.87-2.69]) compared with low levels. CONCLUSIONS This largest collection of USCs to date demonstrates that SNCG was associated with poor survival in univariate analyses. SNCG does not predict survival outcome independent of p53 and p16 in models that jointly consider multiple markers. Cancer 2017;123:1144-1155. © 2016 American Cancer Society.

Sentinel lymph node assessment aims to determine lymphatic spread while preventing unnecessary interventions and morbidity for those who will not benefit from lymphadenectomy. All detection methods have demonstrated reasonable sensitivity with a low false negative rate and high negative predictive value; as long as the surgeon removes all enlarged lymph nodes and a site-specific lymphadenectomy is performed if there is no mapping. The significance of micrometastases and long term outcomes are yet to be determined.