Overall Survival In Endometrial Cancer Research Articles

Expression of Intracellular Galectin-8 and -9 in Endometrial Cancer.

Endometrial cancer (EC) is a common gynecological cancer worldwide. Treatment has been improved in recent years; however, in advanced stages, therapeutic options are still limited. The expression of galectins is increased in several tumor types and that they are involved in important cell processes. Large studies on endometrial cancer are still pending; Specimens of 225 patients with EC were immunohistochemically stained with antibodies for Gal-8 and Gal-9. Expression was correlated with histopathological variables. The cytosolic expression of both galectins is associated with grading and survival. Cytosolic Galectin-8 expression is a positive prognostic factor for overall survival (OS) and progression-free survival (PFS), while nuclear Gal-8 expression correlates only to OS. The cytosolic presence of Galectin-9 is correlated with a better prognosis regarding OS. Our results suggest that expression of both galectins is associated with OS and PFS in EC. Further studies are needed to understand the underlying molecular mechanisms.

Abstract B017: Disease free survival as a predictor of overall survival in patients with high-risk endometrial cancer receiving adjuvant chemotherapy

Abstract Introduction: Disease-free survival (DFS) is often evaluated as a primary endpoint in early settings for several cancers, including endometrial cancer (EC). However, the role of DFS as a potential predictor of overall survival (OS) in EC is unknown. Elucidating the association between DFS and OS in EC is critical for contextualizing findings from trials where DFS is a primary endpoint, such as KEYNOTE-B21, which assesses the effect of treatment with pembrolizumab + adjuvant chemotherapy (CTX) vs. adjuvant CTX, with or without radiotherapy in patients with EC at high risk of recurrence. This real-world study assessed the association between DFS and OS and the impact of recurrence on OS in elderly patients with EC at high risk of recurrence receiving adjuvant CTX. Methods: SEER-Medicare data (2007–2019) were used to identify patients with EC at high risk of recurrence who received adjuvant CTX with or without radiotherapy. Patients were defined as high risk of recurrence if they had either Stage I or II EC with non-endometroid histology or Stage III or IVA EC with any histology. An EC recurrence was defined as having a diagnosis with a distinct secondary cancer >90 days after end of adjuvant CTX or receipt of additional cancer treatment >90 days after end of adjuvant CTX. Kaplan-Meier (KM) analyses were used to estimate OS (time from initiation of adjuvant therapy [index date] to death) and DFS (time from index date to earliest of recurrence or death). The correlation between DFS and OS was assessed using Kendall’s τ rank correlation. Landmark analyses were used to compare OS between patients with vs. without a recurrence at 1-, 3-, and 5-years post the index date; hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using adjusted Cox models. KM analyses were used to estimate OS from a recurrence (index date) for recurrent patients and from an imputed index date (using frequency matching) for non-recurrent patients. Results: Of 794 eligible patients, 253 (31.9%) experienced a recurrence over a median follow up of 3.6 years. Median age at diagnosis was 71.9 years, 69.8% had stage I/II disease, and 86.6% had non-endometrioid carcinoma. Median OS was not reached (5-year OS: 72.5%) and median DFS was 7.9 years (5-year DFS: 58.7%). A significant positive correlation between DFS and OS was observed (Kendall’s τ =0.83; 95% CI: 0.79–0.86; p<0.001). Patients with a recurrence had significantly higher risk of death than those without, at landmark points 1- (HR: 4.4; 95% CI: 2.8–7.0; p<.001), 3- (HR: 5.2; 95% CI: 3.1–8.7; p<.001), and 5-years (HR: 5.1; 95% CI: 2.2–11.7; p<.001). Patients with a recurrence had significantly shorter median OS than those without (median OS: 1.4 years vs. not reached; p<.001). Conclusions: In elderly patients with EC at high risk of recurrence who received adjuvant CTX, DFS was strongly correlated with OS and having a recurrence was associated with significantly higher risk of death. Our findings suggest that DFS is a strong predictor of OS in this population and may be a useful surrogate endpoint. Citation Format: Kalé Kponee-Shovein, Vimalanand S. Prabhu, Yan Song, Lei Chen, Mu Cheng, Yeran Li, Yezhou Sun, Annalise Hilts, Qi Hua, Jasmine Lichfield, Linda Duska. Disease free survival as a predictor of overall survival in patients with high-risk endometrial cancer receiving adjuvant chemotherapy [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B017.

Prediction of disease-free and overall survival in endometrial cancer using linear regressions and machine learning algorithms

Prediction of disease-free and overall survival in endometrial cancer using linear regressions and machine learning algorithms

Simultaneous HER2 positivity and CCNE1 amplification is associated with Black race and worsened overall survival in endometrial cancer (185)

Simultaneous HER2 positivity and CCNE1 amplification is associated with Black race and worsened overall survival in endometrial cancer (185)

CEP55 predicts the poor prognosis and promotes tumorigenesis in endometrial cancer by regulating the Foxo1 signaling.

Endometrial cancer is a common gynecologic cancer, which is relevant to many differentially expressed genes. Centrosomal protein 55 (CEP55) was proved to be aberrantly expressed in several cancers. However, the function of CEP55 in endometrial cancer remains largely uncertain. The differentially expressed genes in endometrial cancer were analyzed by GEO datasets. CEP55 expression and its correlation to aggressive behaviors and diagnosis were analyzed by TCGA and the Human Protein Atlas databases. The association between CEP55 expression and 5-year overall survival in endometrial cancer was predicted using Kaplan-Meier Plotter database. Cell proliferation and apoptosis were determined by western blotting, EdU staining, TUNEL staining, and LDH release. CEP55-related targets were predicted by LinkedOmics and analyzed by KEGG pathway analysis using KOBAS. Foxo1 level was detected by western blotting. CEP55 expression was increased in endometrial cancer. The upregulated CEP55 was associated with tumor invasion, histologic grade, histological type and poor prognosis in endometrial cancer. CEP55 knockdown decreased PCNA and CDK2 levels and inhibited cell proliferation. Moreover, CEP55 downregulation promoted cell apoptosis, LDH release and increased cl-caspase-3/caspase-3 level. CEP55-related targets were enriched in Foxo1 signaling. CEP55 silencing increased the transcription activity of Foxo1. Inhibition of Foxo1 activity reversed the effect of CEP55 knockdown on cell proliferation and apoptosis. In conclusion, CEP55 knockdown repressed cell proliferation and facilitated apoptosis by regulating the Foxo1 signaling in endometrial cancer.

FANCD2 promotes the malignant behavior of endometrial cancer cells and its prognostic value

Defective DNA damage repair is a key mechanism affecting tumor susceptibility, treatment response, and survival outcome of endometrial cancer (EC). Fanconi anemia complementation group D2 (FANCD2) is the core component of the Fanconi anemia repair pathway. To explore the function of FANCD2 in EC, we examined the expression of FANCD2 in human specimens and databases, and discussed the possible mechanism of carcinogenesis by in vitro assays. Immunohistochemistry results showed overexpression of FANCD2 was detected in EC tissues compared to normal and atypical hyperplasia endometrium. Higher FANCD2 expression was correlated with deeper myometrial invasion (MI) and proficient mismatch repair status. The Cancer Genome Atlas (TCGA) database analysis showed FANCD2 was upregulated in EC compared with normal tissue. The high expression of FANCD2 was associated with poor overall survival in EC. Knockdown of FANCD2 expression in EC cell lines inhibited malignant proliferation and migration ability. We demonstrated that decreased FANCD2 expression results in increased DNA damage and decreased S-phase cells, leading to a decrease in proliferative capacity in EC cells. Down-regulated FANCD2 confers sensitivity of EC cells to interstrand crosslinking agents. This study provides evidence for the malignant progression and prognostic value of FANCD2 in EC.

LncRNA THOR promotes endometrial cancer progression through the AKT and ERK signaling pathways.

The long noncoding RNA (lncRNA) THOR is highly conserved and expressed in various human cancer tissues, although its potential role and underlying mechanism in endometrial cancer (EC) remain unknown. This study aims to explore THOR's biological function and molecular mechanism in EC progression. THOR expression in EC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR) and in situ hybridization (ISH). THOR expression based on The Cancer Genome Atlas (TCGA) and clinical sample analyses was significantly higher in EC tissues than normal tissues, and higher THOR levels were closely associated with poor overall survival in EC. Additionally, a positive correlation between ISH-detected THOR expression and pathological grade was observed. CCK-8, colony formation, and transwell migration and invasion assays revealed that THOR significantly enhances the proliferation, migration, and invasion abilities of EC cells. Moreover, IGF2BP1 protein expression and ERK and AKT protein phosphorylation levels in EC cells increased significantly with THOR overexpression in EC cells. In conclusion, our findings suggest that THOR promotes EC cell growth and invasion, and IGF2BP1-mediated AKT and ERK signaling pathways activation might be involved. Clinically, THOR is significantly expressed in EC, and high THOR expression correlates with poor prognosis, making it a potential prognostic marker for EC.

Construction and validation of a prognostic model based on 11 lymph node metastasis-related genes for overall survival in endometrial cancer.

Endometrial cancer (EC) is one of the most common malignant tumors in female reproductive system. The incidence of lymph node metastasis (LNM) is only about 10% in clinically suspected early-stage EC patients. Discovering prognostic models and effective biomarkers for early diagnosis is important to reduce the mortality rate. A least absolute shrinkage and selection operator (LASSO) regression was conducted to identify the characteristic dimension decrease and distinguish porgnostic LNM related genes signature. Subsequently, a novel prognosis-related nomogram wasconstructed to predict overall survival (OS). Survival analysis was carried out to explore the individual prognostic significance of the risk model and key gene was validated in vitro. In total, 89 lymph node related genes (LRGs) were identified. Based on the LASSO Cox regression, 11 genes were selected for the development of a risk evaluation model. The Kaplan-Meier curve indicated that patients in the low-risk group had considerably better OS (p=3.583e-08). The area under the ROC curve (AUC) of this model was 0.718 at 5 years of OS. Then, we developed an OS-associated nomogram that included the risk score and clinicopathological features. The concordance index of the nomogram was 0.769. The survival verification performed in three subgroups from the nomogram demonstrated the validity of the model. The AUC of the nomogram was 0.787 at 5 years OS. Proliferation and metastasis of HMGB3 were explored in EC cell line. External validation with 30 patients in our hospital showed that patients with low-risk scores had a longer OS (p-value=0.03). Finally, we revealed that the most frequently mutated genes in the low-risk and high-risk groups are PTEN and TP53, respectively. Our results suggest that LNM plays an important role in the prognosis, and HMGB3 was potential as a biomarker for EC patients.

Role of Nucleolin in Endometrial Precancerous Hyperplasia and Carcinogenesis: Ex Vivo and In Silico Study.

Endometrial cancer (EC) is the most common gynaecological malignancy. Nucleolin (NCL) is involved in rDNA transcription, cell proliferation, and apoptosis, with high expression associated with worse overall survival (OS) in other adenocarcinomas. Our aims were to assess NCL gene and protein expression and explore the differential expression of NCL-associated genes (NAGs) in endometrial carcinogenesis. Endometrial samples were obtained from 157 women to include healthy, hyperplastic (EH), EC, and metastatic groups. RT-qPCR and immunohistochemistry were employed to assess NCL gene and protein levels. In silico analysis of NAGs in TCGA and GEO datasets was performed, with the prognostic value determined via Human Protein Atlas. NCL mRNA level of EC was lower than in healthy post-menopausal endometrium (p < 0.01). EH samples had lower NCL immuno-expression scores than healthy pre-menopausal (p < 0.001), benign post-menopausal (p < 0.01), and EC (p < 0.0001) samples. Metastatic lesions demonstrated higher NCL quick scores than primary tissue (p = 0.04). Higher NCL Immuno quick scores carried a worse OS in high-grade EC (p = 0.01). Interrogating Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) and Uterine Carcinosarcoma (TCGA-UCS) cohorts revealed NCL to be the most highly upregulated gene in carcinosarcoma, with S100A11, LMNB2, RERG, E2F1 and CCNA2 representing key dysregulated NAGs in EC. Since NCL is implicated in transforming hyperplastic glands into cancer, with further involvement in metastasis, it is suggested to be a promising target for better-informed diagnosis, risk stratification, and management of EC.

DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden in a nationwide cohort.

e17634 Background: DACH1 is a novel transcriptional repressor and tumor suppressor gene. DACH1 mutations are associated with poor prognostic features and reduced overall survival in endometrial cancer, with an increased prevalence in the Appalachian region of Kentucky. Preliminary studies have suggested an association with an increase in tumor mutation burden. In this follow up study, we utilized the nationwide Oncology Research Information Exchange Network (ORIEN) to determine the frequency of DACH1 mutations in patients with endometrial cancer through a multi-institution analysis and evaluate its impact on RNA expression, clinical correlates, and outcomes. Methods: We obtained clinical and genomic data for 691 patients with endometrial cancer from nine U.S. institutions within the ORIEN collaborative. We examined the clinical attributes of the cancers with DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). Results: Appalachian women with endometrial cancer had an increased frequency of DACH1 mutations (6/41 patients, 15%) compared to the non-Appalachian endometrial cancer population (24/581 patients, 4.1%) with p-value = 0.010, with the non-Appalachian DACH1 mutation frequency mirroring the rate of DACH1 gene mutation seen in TCGA at 3.8%. DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (32.2 vs. 4.62, p-value = 0.001) though no differences in microsatellite instability between DACH1 mutated and wild-type were present (p-value = 0.350). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, MSH2, MSH6 and PMS2. Conclusions: DACH1 mutations are prevalent in Kentucky patients with endometrial cancer, particularly those from the Appalachian region. These results were again reflected in the TCGA PanCancer Atlas as well as the ORIEN multi-institution cohort. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 as a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers.

Overall survival after surgical staging by lymph node dissection versus sentinel lymph node biopsy in endometrial cancer: a national cancer database study

ObjectiveSubstituting lymphadenectomy with sentinel lymph node biopsy for staging purposes in endometrial cancer has raised concerns about incomplete nodal resection and detrimental oncological outcomes. Therefore, this study aimed to investigate...

The Coefficient of Variation of Red Blood Cell Distribution Width Combined with Cancer Antigen 125 Predicts Postoperative Overall Survival in Endometrial Cancer.

PurposeThis study assessed the prognostic value of red blood cell distribution width (RDW) and cancer antigen 125 (CA125) in predicting the prognosis of endometrial cancer (EC) patients.Patients and MethodsIn this study, we included 525 patients with EC between January 2013 and January 2019. Demographic and clinical indicators were collected, and the receiver operating characteristics curve (ROC) and cutoff values were calculated between the early and advanced stages of EC. Independent risk factors associated with EC prognosis were assessed using Cox regression analyses and the Kaplan–Meier method.ResultsCompared to women in the early stage of EC, women with advanced stage had significantly elevated RDW coefficient of variation (RDW-CV) and CA125 levels and lower mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) (both P < 0.05). Consequently, RDW-CV and CA125 were found to be independent risk factors for EC by using ROC curve and multivariate logistic regression analysis. The survival analysis curve was used to assess the diagnostic value of RDW-CV, CA125, and their combination in the prognosis of EC. The results showed that patients with high expression of RDW-CV and CA125 had worse overall survival than those with low expression. Moreover, multivariate Cox regression analysis indicated that RDW-CV+CA125=2 was an independent prognostic factor.ConclusionThese findings suggest that CA125 combined with RDW-CV has a good prognostic value for EC. Thus, the RDW-CV+CA125 score is a promising prognostic marker for the clinical decision-making process regarding EC outcomes.

The role of sarcopenic obesity in high-grade endometrial cancer.

To investigate the relationship between obesity and sarcopenia in relation to overall survival (OS) and disease-specific survival (DSS) in high-grade endometrial cancer patients. We conducted a retrospective study in women diagnosed with high-grade endometrial cancer (EC) between February 2006 and August 2017 in the Royal Cornwall Hospital who had abdominal computerized tomography (CT)-scan as part of routine staging work-up. Sarcopenia was assessed by measuring psoas-, paraspinal- and abdominal wall muscles on CT and defined by skeletal muscle index ≤41cm2 /m2 . Sarcopenic obesity was defined as sarcopenia combined with body mass index (BMI) ≥30kg/m2 . A total of 176 patients with median age of 70years and median BMI of 29.4kg/m2 were included in the study. The majority of patients (38%) had endometrioid type histology. Sarcopenia was not associated with OS (P=0.951) or DSS (P=0.545) However, in multivariate analysis, sarcopenic obesity was associated with reduced OS in endometrioid endometrial cancer (EEC) patients (P=0.048). Sarcopenic obesity is associated with OS in high-grade EEC patients, while sarcopenia without obesity is not related to OS or DSS in high-grade EC. In non-endometrioid endometrial cancer, there is no association between sarcopenic obesity and survival.

Integrated analysis of tumor mutation burden and immune infiltrates in endometrial cancer

To explore the prognostic value of tumor mutation burden (TMB) and its correlation with immune infiltrates in endometrial cancer. Transcriptome and somatic mutation profiles of Uterine Corpus Endometrial Carcinoma (UCEC) were downloaded from TCGA database. Somatic mutations were analyzed by “maftools” and visualized in waterfall plot. We calculated TMB of each patients and divided all patients into the high-TMB group and the low-TMB group by the median threshold. Survival analysis and Wilcoxon test were used to investigate the prognostic value of TMB and its association with clinical variables. Differentially expressed genes (DEGs) were identified in 2 TMN groups and functional analysis was performed to find out significant biological pathways. A TMB-related signature was conducted by multivariate analysis, receiver operating characteristic (ROC) curve was performed to predict accuracy of the model, meanwhile, a validation cohort from Fudan University Shanghai Cancer Center (FUSCC) was obtained to verify the signature. Then we estimated association between TMB and immune infiltrates by CIBERSORT algorithm and figured out prognostic immune cells of UCEC in TIMER database. Total 575 samples including 25 normal tissues and 552 tumor samples were enrolled from TCGA database. PTEN mutations accounted for the most and single nucleotide polymorphism and C>T transitions were most frequent forms of somatic mutations in UCEC. The low-TMB group possessed worse survival than the high-TMB group (P = 0.004). DEGs in 2 TMB groups were mostly enriched in adaptive immune response and immunoglobulin/immune receptor component. A TMB-related signature consisting of GFAP, EDN3, CXCR3, PLXNA4, SST presented good predictability with area under the curve (AUC) = 0.686. In FUSCC validation cohort, the high-risk group possessed worse survival outcome than the low-risk group (P = 0.015). Immune infiltrates was correlated to survival in UCEC and low TMB were associated with less immune infiltrates, which suggested poor immune response. TMB was not only related to overall survival but also immune infiltrates in UCEC. The TMB-related signature (GFAP, EDN3, CXCR3, PLXNA4, SST) had good predictability for overall survival in endometrial cancer. Our study might have some merits in elucidating potential mechanism of TMB and immune infiltrates in UCEC and providing guidance of immunotherapy for endometrial cancer.

Bioinformatic screening for candidate biomarkers and their prognostic values in endometrial cancer

BackgroundEndometrial cancer is a common gynecological cancer with annually increasing incidence worldwide. However, the biomarkers that provide prognosis and progression for this disease remain elusive.ResultsTwo eligible human endometrial cancer datasets (GSE17025 and GSE25405) were selected for the study. A total of 520 differentially expressed mRNAs and 30 differentially expressed miRNAs were identified. These mRNAs were mainly enriched in cell cycle, skeletal system development, vasculature development, oocyte maturation, and oocyte meiosis signalling pathways. A total of 160 pairs of differentially expressed miRNAs and mRNAs, including 22 differentially expressed miRNAs and 71 overlapping differentially expressed mRNAs, were validated in endometrial cancer samples using starBase v2.0 project. The prognosis analysis revealed that Cyclin E1 (CCNE1, one of the 82 hub genes, which correlated with hsa-miR-195 and hsa-miR-424) was significantly linked to a worse overall survival in endometrial cancer patients.ConclusionsThe hub genes and differentially expressed miRNAs identified in this study might be used as prognostic biomarkers for endometrial cancer and molecular targets for its treatment.

Adjuvant radiation followed by chemotherapy is associated with improved overall survival in endometrial cancer

ObjectiveAlthough multimodality therapy has been shown to improve outcomes for patients with high-risk endometrial carcinoma, optimal type and timing of adjuvant therapies is unknown. MethodsPatients with stage I-IVA endometrial carcinoma diagnosed from 2004 to 2015, and treated with surgery, chemotherapy, and radiation were identified in the National Cancer Database. Adjuvant treatment was categorized as sequential radiation followed by chemotherapy (RT-CT), concurrent chemoradiation (CCRT, RT and CT started within 7 days), or sequential chemotherapy followed by radiation (CT-RT). Analysis for propensity score matched (PSM) cohorts comparing RT-CT to CCRT and CT-RT groups was additionally performed. ResultsA total of 17,070 patients were identified, including 12,402 (72.7%) treated with RT-CT, 2,153 (12.6%) with CCRT, and 2,515 (14.7%) with CT-RT. Median follow-up was 44.3 months. Five-year overall-survival (OS) by adjuvant treatment regimen was 77.3% (95% CI 76.4%–78.2%), 74.3% (95% CI 72.0%–76.3%), and 74.4% (95% CI 72.5%–76.3%), respectively (p < .001). When unmatched cohorts were stratified by stage, adjuvant RT-CT was associated with improved OS in stage I and III patients. A similar survival advantage associated with RT-CT was observed in PSM cohorts comparing RT-CT group to CCRT/CT-RT group (5-year OS 77.4% vs 74.2%, p = .001). However, the difference in OS was significant only among stage III patients (RT-CT 73.9% compared to CCRT/CT-RT 69.7%, p =.002). ConclusionOur findings suggest survival benefit with adjuvant RT-CT compared to CT-RT or CCRT in patients undergoing trimodality therapy for endometrial cancer. This survival benefit may be limited to stage III patients.

Prognostic Biomarkers in Endometrial Cancer: A Systematic Review and Meta-Analysis

Endometrial cancer (EC) is the sixth most common cancer in women worldwide and its mortality is directly associated with the presence of poor prognostic factors driving tumor recurrence. Stratification systems are based on few molecular, and mostly clinical and pathological parameters, but these systems remain inaccurate. Therefore, identifying prognostic EC biomarkers is crucial for improving risk assessment pre- and postoperatively and to guide treatment decisions. This systematic review gathers all protein biomarkers associated with clinical prognostic factors of EC, recurrence and survival. Relevant studies were identified by searching the PubMed database from 1991 to February 2020. A total number of 398 studies matched our criteria, which compiled 255 proteins associated with the prognosis of EC. MUC16, ESR1, PGR, TP53, WFDC2, MKI67, ERBB2, L1CAM, CDH1, PTEN and MMR proteins are the most validated biomarkers. On the basis of our meta-analysis ESR1, TP53 and WFDC2 showed potential usefulness for predicting overall survival in EC. Limitations of the published studies in terms of appropriate study design, lack of high-throughput measurements, and statistical deficiencies are highlighted, and new approaches and perspectives for the identification and validation of clinically valuable EC prognostic biomarkers are discussed.

Inflammatory prognostic markers in endometrial carcinoma: Systemic immune-inflammation index and prognostic nutritional index

Objective: Systemic inflammatory response markers have prognostic significance in many cancer types. Although the prognostic values of neutrophil/lymphocyte (NLR), and platelet/lymphocyte ratios (PLR) have been shown in patients with Endometrial Cancer (EC) there is no information in the literature about systemic immune-inflammation index (SII) and prognostic nutritional index (PNI). In our study, we aimed to reveal the prognostic role of SII and PNI in EC.&#x0D; Material and Methods: Medical data for 101 patients with EC were reviewed retrospectively. NLR, PLR, SII and PNI values were dichotomized based on receiver operating characteristic (ROC) curve analysis (cut-off values: 3.3; 177; 1035.9, and 38, respectively). At the time of diagnosis concentrations of these four serum inflammatory markers were analyzed to determine their potential association with clinicopathologic characteristics and to assess their prognostic values via the Kaplan-Meier method and multivariate Cox regression analysis.&#x0D; Results: Patients with higher NLR, PLR, SII, and lower PNI values had shorter progression-free survival (PFS) and overall survival (OS) times. Higher NLR, SII, and lower PNI, were associated with FIGO stages, lymph node involvement, lymphovascular invasion, and cervical stromal invasion while additionally NLR and PNI were associated with worse ECOG performance scores (2-3) and myometrial invasion. In univariate analyses, all these four variables were prognostic for both OS and PFS, whereas in multivariate analyzes only NLR, SII and PNI were found to be independent factors for OS and PFS.&#x0D; Conclusion: For the first time in the literature SII and PNI were determined to be independent prognostic factors for both OS and PFS in EC.

LAMC1 is a prognostic factor and a potential therapeutic target in endometrial cancer.

ObjectiveWith the emerging significance of genetic profiles in the management of endometrial cancer, the identification of tumor-driving genes with prognostic value is a pressing need. The LAMC1 gene, encoding the laminin subunit gamma 1 (LAMC1) protein, has been reported to be involved in the progression of various malignant tumors. In this study, we aimed to investigate the role of LAMC1 in endometrial cancer and elucidate the underlying mechanism.MethodsWe evaluated the immunohistochemical expression of LAMC1 in atypical endometrial hyperplasia and endometrial cancer. Within the endometrial cancer cases, we analyzed the association of LAMC1 overexpression with clinicopathological factors and prognosis. Furthermore, to indentify genes influenced by LAMC1 overexpression, we transfected HEC50B and SPAC-S cells with siRNA targeting LAMC1 and conducted microarray gene expression assays.ResultsWhile none of the atypical endometrial hyperplasia specimens exhibited LAMC1 overexpression, endometrial cancer possessed a significantly higher LAMC1 overexpression rate. LAMC1 overexpression was strongly associated with histological type, lymphovascular space invasion, lymph node metastasis, advanced International Federation of Gynecology and Obstetrics stage, and poor overall survival in endometrial cancer. Gene expression microarray analysis identified 8 genes correlated with tumor progression (LZTFL1, TAPT1, SEL1L, PAQR6, NME7, TMEM109, CCDC58, and ANKRD40) that were commonly influenced in HEC50B and SPAC-S by LAMC1 silencing.ConclusionLAMC1 overexpression is a potent biomarker for identifying endometrial cancer patients needing aggressive adjuvant therapy. We elucidated 8 candidate genes that may mediate progression of LAMC1 overexpressing cancer. Further investigation of the underlying mechanism should lead to the discovery of new therapeutic targets.

Adjuvant Radiation Followed by Chemotherapy is Associated with Improved Overall Survival in Endometrial Cancer

Although multimodality therapy has been shown to improve outcomes for patients with high-risk endometrial carcinoma, little consensus has been reached on the type and timing of adjuvant therapies. We sought to determine whether sequence of adjuvant therapy is associated with overall survival in high-risk endometrial cancer. Patients with stage I-IVA endometrial carcinoma diagnosed from 2004 to 2015, and treated with surgery, chemotherapy, and radiation were identified in the National Cancer Database. Adjuvant treatment was categorized as sequential radiation followed by chemotherapy (RT-CT), concurrent chemoradiation (CCRT), or sequential chemotherapy followed by radiation (CT-RT). RT-CT was defined as CT start >7 days after RT start, CCRT was defined as CT start within 7 days of RT start, and CT-RT was defined as RT start >7 days after CT start. Analyses were repeated using 14- and 21-day cutoffs, and yielded similar results. Survival analyses were performed using Kaplan-Meier estimates, log-rank test, and Cox proportional hazards regression. A total of 17,070 patients were identified, including 12,402 (72.7%) treated with RT-CT, 2,153 (12.6%) treated with CCRT, and 2,515 (14.7%) treated with CT-RT. Median follow-up for the cohort was 44.3 months. Five-year overall survival (OS) by adjuvant treatment regimen was 77.3% (95% CI 76.4%-78.2%), 74.3% (95% CI 72.0%-76.3%), and 74.4% (95% CI 72.5%-76.3%), respectively (p < 0.001). On multivariate Cox regression, sequence of adjuvant therapy (HR 1.09, p < 0.001), higher grade, (HR 1.06, p < 0.001), higher stage (HR 1.18, p < 0.001), government insurance (HR 1.10, p < 0.001), and non-white race (HR 1.07, p = 0.007) were independently associated with worse overall survival. Higher income (HR 0.81, p < 0.001) and >9 regional nodes resected (HR 0.84, p < 0.001) were independently associated with improved overall survival. With the exception of race, these covariates remained significantly associated with OS after correcting for multiple comparisons. Of note, treatment facility type and lymphovascular invasion were not associated with OS. When stratified by stage, the benefit of adjuvant RT-CT was limited to patients with stage III disease. Patients with stage III disease who received adjuvant RT-CT had 5-year overall survival of 73.9% versus 69.6% and 69.9% with CCRT and CT-RT, respectively (p < 0.001). In contrast, there was no difference in 5-year OS (49.7% for RT-CT, 48.3% for CCRT, and 50.3% for CT-RT) among stage IVA patients (p = 0.806). Our findings suggest a survival benefit with adjuvant RT-CT compared to CT-RT or CCRT in patients undergoing trimodality therapy for endometrial cancer. This survival benefit was exclusively seen in patients with stage III disease.