High-grade Endometrioid Endometrial Cancer Research Articles

Differences in single gene expression patterns and signaling pathways between Black and White patients in high grade endometrioid endometrial cancer independent of BMI

ObjectiveEndometrial cancer (EC) incidence and mortality are increasing with striking racial disparities. Race and obesity are known risk factors for EC, however, their relationship and impact on tumor biology in higher grade endometrioid EC are unclear. The objective of this pilot study was to identify gene- and pathway-level changes in tumors from Black patients compared to White, both in general and in the context of dichotomized BMI. MethodsA single institution retrospective convenience sample was obtained for grade 2 or 3 endometrioid EC, equally distributed amongst Black and White patients. Tumor samples were analyzed with the Tempus Laboratories xT NGS-based genome profiling test. DESeq2 was applied to identify differentially expressed genes, and then subjected to ingenuity pathway analysis (IPA). Continuous variables were analyzed using unpaired t-tests, and categorical using Chi-squared and Fisher exact tests. Results39 representative cases were identified and analyzed from 2006 to 2021. Baseline clinicopathologic characteristics were similar. 157 genes were differentially expressed in tumors from Black patients compared to White regardless of BMI. IPA identified 81 significantly different pathways between Black and White patients with a BMI < 40 kg/m2, and 117 with a BMI ≥ 40 kg/m2. Of these, eleven pathways were consistently and significantly activated or deactivated regardless of BMI. ConclusionDifferences in gene expression and pathway activation in EC exist between race and BMI, which highlights the need for further research to better understand the implications of these differences on endometrioid EC progression, outcomes, and treatment in this historically underserved patient population.

Multiple differences in signaling pathways and single gene expression patterns exist in high grade endometrioid endometrial cancer in Black and White patients after accounting for BMI: A single-site pilot study (2258)

Multiple differences in signaling pathways and single gene expression patterns exist in high grade endometrioid endometrial cancer in Black and White patients after accounting for BMI: A single-site pilot study (2258)

The Prognostic Characteristics and Recurrence Patterns of High Grade Endometrioid Endometrial Cancer: A Large Retrospective Analysis of a Tertiary Center.

High grade endometrioid endometrial cancer (HGEEC) is a heterogeneous group of tumors with unclear prognostic features. The aim of the present study is to evaluate the independent risk factors for recurrence and mortality and to describe the recurrence patterns of HGEEC. Ninety-six consecutive cases of HGEEC treated with primary surgery in a single Tertiary Center were retrospectively reviewed. Clinicopathological and treatment details were recorded, and all patients were closely followed up. Disease-free, overall and cancer-specific survival rates were 83.8%, 77.8% and 83.6%, respectively. Cervical stromal involvement was independently related to recurrence (HR = 25.67; 95%CI 2.95-223.30; p = 0.003) and cancer-related death (HR = 15.39; 95%CI 1.29-183.43; p = 0.031) after adjusting for other pathological and treatment variables. Recurrence rate was 16%, with 60% of these cases having lung metastases and only one case with single vaginal vault recurrence. 81.81% of the recurrences presented with symptoms and not a single recurrence was diagnosed in routine follow-up clinical examination. In conclusion, the recurrence pattern may suggest that patient-initiated follow-up (PIFU) could be considered a potential alternative to clinical-based follow-up for HGEEC survivors, especially for patients without cervical involvement and after two years from treatment. Additional caution is needed in patients with cervical stromal involvement.

HER2+ endometrioid endometrial cancer possesses distinct molecular and immunologic features associated with a more active immune microenvironment and worse prognosis

ObjectiveHER2 status is not routinely evaluated in endometrioid endometrial cancer (E-EMCA), though it is frequently overexpressed or amplified in high grade E-EMCA and uterine serous carcinoma. Defining characteristics and survival outcomes of HER2+ E-EMCA could reveal subsets of patients who may benefit from targeted therapies. Methods2927 E-EMCA tumors from the Caris Life Sciences database were analyzed by next-generation sequencing and whole exome sequencing, whole transcriptome sequencing, and immunohistochemistry for molecular and genomic features in a CLIA/CAP-certified laboratory (Caris Life Sciences, Phoenix, AZ). HER2 status was determined by transcriptomic cutoff extrapolated from uterine serous carcinoma. The relationship between HER2 status and patient outcomes was determined by Kaplan-Meier analysis. ResultsHER2 positivity was detected in 5.47% of E-EMCA. Differences in molecular alterations based on HER2 status were most apparent in microsatellite stable (MSS) tumors, which displayed increased TP53 mutations and loss of heterozygosity (LOH) and decreased PTEN and CTNNB1 mutations. HER2+ tumors had increased immune checkpoint gene expression and immune cell infiltration, particularly among MSS tumors. All HER2+ tumors displayed increased MAPK pathway activation scores (MPAS) and patients with HER2+ tumors experienced worse overall survival. ConclusionsHER2 positivity in E-EMCA corresponds with a unique molecular landscape, particularly in MSS tumors. HER2+ tumors are also associated with increased MAPK pathway activation and exhibit features of a more active immune microenvironment. These findings suggest a potential benefit of HER2 and MAPK targeted therapies as well as immunotherapies in this patient population.

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.

BRCA1/2 mutations and survival of high-grade endometrioid endometrial cancer

BackgroundBRCA1/2 mutations have been shown to be associated with the development of many solid tumors including endometrial cancer (EC). The objectives of this study are to analyze the association between BRCA1/2 mutational status and clinicopathological characteristics as well as outcomes in EC patients. Methods510 eligible EC patients from the Cancer Genome Atlas database were included in the study. The association between clinicopathological characteristics and different BRCA1/2 mutational status was compared and analyzed. Analyses of the impact of BRCA mutations on survival in EC patients was conducted using Kaplan-Meier survival analyses and Cox regressions. In order to control confounding bias between groups, propensity score matching method was used. ResultsAmong the eligible patients, 11 (2.2%) harbored BRCA1 mutation, 43 (8.4%) harbored BRCA2 mutation, and 36 (7.1%) harbored both. Body mass index, rates of hypertension history, proportion of non-endometrioid histology and rates of positive peritoneal cytology were lower in patients with BRCA1/2 mutations compared with the group of wild-type counterpart (p = 0.020, 0.048, 0.001 and 0.012, respectively). Patients with BRCA1/2 mutations showed longer overall (OS) and recurrence-free survival (RFS) (in Kaplan-Meier analyses, p < 0.001 and p = 0.004, respectively; in Cox regressions, p = 0.001 and 0.007, respectively). Further analyses showed that the impact of BRCA mutations on survival was significant only in patients with high-grade endometrioid EC. Based on the cohorts generated after propensity score matching, in high-grade endometrioid EC patients, the influence of BRCA1/2 mutations remained significant on OS, but not on RFS (p = 0.003 and 0.057 in Kaplan-Meier analyses, p = 0.020 and 0.071 in Cox regressions). ConclusionBRCA1/2 mutations are associated with better survival in patients with high grade endometrioid EC, indicating the value of BRCA testing in EC clinical management.

Obesity and visceral fat: Survival impact in high-grade endometrial cancer

BackgroundObesity is an important risk factor for the development of endometrial cancer (EC). Recent data showed that body fat distribution might be more relevant than Body Mass Index (BMI). High visceral fat percentage was shown to be an independent predictor for survival in EC, but mainly included grade 1-2 EC. ObjectiveTo evaluate body fat distribution and its relation to outcome in high-grade endometrial cancer. MethodsRetrospective study in women diagnosed with high-grade EC between February 2006 and August 2017 at the Royal Cornwall Hospital who had abdominal CT-scan as part of routine diagnostic work-up. Subcutaneous abdominal fat volumes and visceral abdominal fat volumes were quantified based on CT-scan measurements, and visceral fat percentage calculated. ResultsA total of 176 patients with high-grade EC were included. The median age was 70 years and median BMI was 29.4 kg/m2. The majority of patients had non-endometrioid endometrial cancer (NEEC; 62 %). High visceral fat percentage was associated with poor overall- and disease-specific survival (p = 0.006 and p = 0.026 respectively) in NEEC patients, but not in high-grade endometrioid EC (EEC). The most frequent obesity comorbidities hypertension and diabetes mellitus were significantly associated with high BMI and high visceral fat percentage. ConclusionIn high-grade EC, high visceral fat percentage was an independent predictor of poor survival only in NEEC. The strong correlation between high visceral fat and obesity-related comorbidities might be reflective of an unhealthy macroenvironment.

High-grade endometrial cancer survival (endometrioid to non-endometrioid histology comparison)

Purpose of Investigation: To analyze overall survival (OS) and disease-free survival (DFS) in a retrospective series of 125 patients with serous, clear cell, and high-grade endometrioid carcinoma having undergone complete treatment (primary surgery, oncology treatments, and follow up) at the present institution. Materials and Methods: All women with high-grade endometrial cancer having undergone surgery (1998-2012) and postoperatively treated and monitored at Split University Hospital Center, whose tissue samples were stored at Department of Pathology, Split University Hospital Center, were included in the study. Survival time was analyzed with Kaplan-Meier method and the log-rank test was used to assess between-group differences. Cox proportional hazard regression model was used on multivariate survival analysis. Patients were followed from the time of primary surgery until death or last follow up in December 2015. Results: Women with serous and clear cell endometrial cancer had similar survival compared to those with high-grade endometrioid endometrial cancer. On multivariate analysis, only earlier stage was an independent predictor of improved survival. Conclusions: The present findings suggest that serous and clear cell endometrial carcinomas have a similar prognosis compared to high-grade endometrioid carcinoma of the uterus.

Contribution of cervical cytology in the diagnostic work-up of patients with endometrial cancer.

Abnormal cervical cytology in patients with endometrial cancer (EC) has been associated with poor outcome. The aim of this study was to evaluate whether cervical cytology could contribute to an improved preoperative identification of high-grade EC (serous, clear cell, carcinosarcoma, high-grade endometrioid EC) in final histology. A retrospective cohort study was performed in five hospitals in the Netherlands. A total of 554 patients with EC that underwent primary surgical treatment between 2002 and 2010 were included. Primary outcome was defined as the contribution of abnormal cervical cytology in the preoperative identification of high-grade EC. As secondary outcome, recurrence-free survival (RFS) and disease-specific survival were determined based on preoperative cervical cytology, and compared to the currently established risk factors: myometrial invasion, high-grade and lymph vascular space invasion. Abnormal cervical cytology was present in 45.1%. For patients with preoperative inconclusive and high-grade histology, the presence of abnormal cervical cytology contributed to an improved identification of high-grade EC in final histology (odds ratio [OR] 6.40 [95% confidence interval {CI}: 1.92-21.26]; OR 2.86 [95% CI: 1.14-7.14]), respectively. Patients with abnormal cervical cytology had a significant worse 5-year median RFS. Abnormal cervical cytology was independently related to RFS (hazard ratio 1.67 [95% CI: 1.04-2.68]) and disease-specific survival (hazard ratio 3.15 [95% CI: 1.74-5.71]). Abnormal cytology contributes to the preoperative identification of patients with high-grade EC, and is associated with compromised outcome. Future studies are warranted to determine whether cervical cytology could be incorporated into preoperative prediction models for lymph node metastasis.

Development and validation of a targeted next generation DNA sequencing panel outperforming whole exome sequencing for the identification of clinically relevant genetic variants.

Next generation sequencing (NGS) technologies have revolutionized our approach to genomic research. The use of whole genome sequencing (WGS), whole exome sequencing (WES), transcriptome profiling, and targeted DNA sequencing has exponentially improved our understanding of the human genome and the genetic complexities underlying malignancy. Yet, WGS and WES clinical applications remain limited due to high costs and the large volume of data generated. When utilized to address biological questions in basic science studies, targeted sequencing panels have proven extremely valuable due to reduced costs and higher sequencing depth. However, the routine application of targeted sequencing to the clinical setting is limited to a few cancer subtypes. Some highly aggressive tumor types, like type 2 endometrial cancer (EC), could greatly benefit from routine genomic analysis using targeted sequencing. To explore the potential utility of a mid size panel (~150 genes) in the clinical setting, we developed and validated a custom panel against WGS, WES, and another commercially available targeted panel. Our results indicate that a mid size custom designed panel is as efficient as WGS and WES in mapping variants of biological and clinical relevance, rendering higher coverage, at a lower cost, with fewer variants of uncertain significance. Because of the much higher sequencing depth that could be achieved, our results demonstrate that targeted sequencing outperformed WGS and WES in the mapping of pathogenic variants in a breast cancer case, as well as a case of mixed serous and high-grade endometrioid EC, the most aggressive EC subtype.

Mismatch repair deficiency: a step forward personalized medicine in endometrial cancer?

Endometrial cancer (EC) is the most common female malignancy in the world, it has traditionally been classified into two subgroups based on histopathological features, however this dualistic classification does not take into consideration subtypes such as high-grade endometrioid EC. Recently, work performed as part of The Cancer Genome Atlas study has focused on molecular genomic classification of EC, with four distinct molecular subtypes described: 1. POLE ultramutated, associated with a good prognosis; 2. Microsatellite instability (MSI) hypermutated; 3. Copy number low and microsatellite stable; 4. Copy number high, serous like, associated with a poor prognosis. The subgroup of patients with MSI is of particular interest for a number of reasons, including the use of tumour screening to identify patients with Lynch syndrome, the prognostic significance of MSI, and the potential therapeutic implications. This review will focus on the current knowledge in these areas and potential future directions.

Prognostic Significance of POLE Exonuclease Domain Mutations in High-Grade Endometrioid Endometrial Cancer on Survival and Recurrence: A Subanalysis.

POLE mutations in high-grade endometrioid endometrial cancer (EEC) have been associated with improved survival. We sought to investigate the prevalence of POLE tumor mutation and its prognostic significance on outcomes and clinical applications in a subanalysis of women with high-grade EEC from a previously described cohort of 544 EEC patients in which POLE mutation status and survival outcomes were assessed. Polymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 72 tumors. Associations between POLE mutation, demographic and clinicopathologic features, and survival were investigated with Cox proportional hazard models. POLE mutations were identified in 7 (9.7%) of 72 grade 3 EECs. No significant differences in the clinicopathologic features between those with POLE mutations and those without were identified. Adjusted for age, a decreased risk of recurrence was suggested in patients with a POLE mutation (adjusted hazard ratio, 0.37; 95% confidence interval, 0.09-1.55), as well as decreased risk of death (adjusted hazard ratio, 0.19; 95% confidence interval, 0.03-1.42). POLE mutations in tumors of women with grade 3 EEC are associated with a lower risk of recurrence and death, although not statistically significant because of high variability in these estimates. These findings, consistent with recently published combined analyses, support POLE mutation status as a noteworthy prognostic marker and may favor a change in the treatment of women with grade 3 EECs, particularly in those with early-stage disease, in which omission of adjuvant therapy and decreased surveillance could possibly be appropriate.

Abstract 2: Prognostic significance of POLE exonuclease domain mutations in high grade endometrioid endometrial cancer on survival and recurrence

Objectives: POLE exonuclease domain mutations have previously been described to occur in the tumors of endometrial cancer (EC) patients, and result in the inability to repair mismatched bases during DNA replication. The prognostic impact of these mutations is controversial. We sought to investigate the prevalence of POLE mutation tumor status and its prognostic significance on survival and recurrence outcomes in women with high grade endometrioid EC.

Loss of LKB1 in high-grade endometrial carcinoma: LKB1 is a novel transcriptional target of p53.

Liver kinase B1 (LKB1) is a serine/threonine kinase that functions as a tumor suppressor and regulates cell polarity, proliferation, and metabolism. Mutations in LKB1 are associated with Peutz-Jeghers syndrome as well as sporadic cervical and lung cancers. Although LKB1-null mice develop invasive endometrial cancers, the role and regulation of LKB1 in the pathogenesis of human endometrial cancer are not well defined and are the focus of these studies. LKB1 protein and messenger RNA (mRNA) expression levels were evaluated in high-grade and low-grade endometrioid endometrial cancer (EEC) and cell lines by reverse transcriptase-polymerase chain reaction analysis, Western blot analysis, and immunohistochemistry. Mutational and promoter analyses of the LKB1 gene (serine/threonine kinase 11 [STK11]) were performed to identify the mechanisms that contribute to the loss of LKB1 in high-grade EEC. Analysis of the LKB1 gene in low-grade and high-grade EECs revealed no genetic mutations, suggesting that alterations in LKB1 transcription may be responsible for LKB1 protein loss in high-grade EEC. Analysis of the LKB1 promoter revealed 4 putative tumor protein 53 (p53) binding sites. Quantitative chromatin immunoprecipitation demonstrated that p53 bound directly to 1 of these sites and increased LKB1 promoter activity 140-fold. LKB1 promoter activity, mRNA, and protein levels were suppressed after silencing of p53 with small interfering RNA and were elevated in cells that overexpressed p53. Levels of p53 mRNA and protein expression were decreased in high-grade EEC and were positively correlated with LKB1 protein levels (Spearman correlation, r=0.601; P<.001). LKB1 is a direct transcriptional target of p53. The loss of wild-type p53 in high-grade EEC may contribute to the LKB1 loss observed in these more aggressive tumors.

Abstract 2209: Downregulation of LKB1 in high-grade endometrial carcinoma

Abstract Objective: LKB1/STK11 encodes a serine/threonine kinase that regulates cell polarity, proliferation and energy metabolism via the AMPK signaling pathway. Germline mutations of LKB1 are responsible for Peutz-Jeghers syndrome, which is characterized by hamartomatous polyps and increased incidence of several cancers. It has been demonstrated that LKB1 null mice develop invasive endometrial cancer. Our lab has previously shown that 5 of 26 (19%) of human endometrial cancers exhibited loss of LKB1 protein by Western blot analysis. The purpose of this study was to examine the expression of LKB1 in a larger set of endometrial cancers and to determine if mutations in LKB1 occur in these tumors. Methods: LKB1 protein levels were evaluated in 20 normal endometrial tissues, 17 Grade 1, 24 Grade 2, and 28 Grade 3 endometrioid endometrial adenocarcinomas by immunohistochemical staining. Laser-capture microdissection (LCM) was used to isolate RNA from 22 Grade 1, 21 Grade 2 and 23 Grade 3 fresh frozen endometrioid endometrial tissues; and LKB1 mRNA expression levels in microdissected tumor samples were quantified by TaqMan quantitative PCR. Direct genomic DNA sequencing of LKB1 coding exons were performed on 20 microdissected high-grade tumors. Results: While no significant difference in LKB1 expression was observed between normal endometrium, Grade 1 and 2 endometrial tumors, LKB1 staining was significantly lower in Grade 3 tumors when compared with normal endometrium (P&amp;lt;0.0001), Grade 1 (P&amp;lt;0.0001) and Grade 2 (P=0.016) tumors. Downregulation of LKB1 mRNA level was also demonstrated in microdissected Grade 3 endometrial tumor samples. Direct genomic DNA sequencing of LKB1 coding exons revealed a single amino acid change (L201Q) in only 1 of 20 Grade 3 endometrial tumors, suggesting that DNA mutation is not the major mechanism leading to the loss of LKB1. Conclusion: Our findings of decreased expression of LKB1 in high-grade endometrial cancers supports the hypothesis that loss of LKB1 may contribute to the development of high-grade endometrioid endometrial cancer. We are currently evaluating the mechanisms by which LKB1 levels are regulated in endometrial cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2209. doi:10.1158/1538-7445.AM2011-2209

Correlation of cyclin D1 and cyclin D3 overexpression with the loss of PTEN expression in endometrial carcinoma

Cyclins D1 and D3 play key roles in cell cycle progression. The downregulation of cyclin D3 was associated with phosphatase and tensin homolog deleted on chromosome ten-(PTEN)-induced cell cycle arrest. We attempted to determine whether cyclin D1 and D3 overexpression is correlated with PTEN inactivation in endometrioid endometrial cancer (EEC). The expression of PTEN, cyclin D1, and cyclin D3 were determined by immunohistochemical analysis in 105 EEC specimens. Forty-three percent of the EEC demonstrated loss of PTEN expression. Cyclin D3 was overexpressed in only 18% of the EEC specimens and was not associated with tumor grade. Cyclin D1 was overexpressed in 64% of the specimens and was more common in moderate or high-grade tumors (P = 0.002 and P = 0.02, respectively). The overexpression of cyclin D3 was not correlated with loss of PTEN in the EEC. The overexpression of cyclin D1 was much higher in grade 1 tumors with negative PTEN than tumors with positive PTEN expression (67% vs 26%). The overexpression of cyclin D3 was neither frequent nor correlated with the loss of PTEN expression. The overexpression of cyclin D1 was higher in the low-grade tumors with negative PTEN expression than tumors with positive PTEN expression. Overexpression of cyclin D1 is frequent in moderate or high-grade EECs and likely results from multiple mechanisms.