Late-week surgical treatment of endometrial cancer is associated with worse long-term outcome: Results from a prospective, multicenter study.

Surgery is the cornerstone in primary endometrial cancer treatment, and with curative intent it constitutes total hysterectomy and bilateral salpingo-oopherectomy. In addition, lymphadenectomy is performed in selected patients dependent on a preoperative risk assessment. Recent reports from the surgical approach to esophageal cancer reveal worse outcome when esophagectomy is performed later in the week. On this basis, we set out to explore weekday of surgery in relation to long-term outcome in 1302 endometrial cancer patients prospectively included in the MoMaTEC multicenter study. Day of surgery was dichotomized as early-week (Monday-Tuesday) or late-week (Wednesday-Friday), and evaluated as a discrete variable. Adjusted for patient age, Body Mass Index (BMI), FIGO stage, and histology, surgery performed later in the week was associated with 50.9% increased risk of all-cause death (p = 0.029). Among high-stage patients (FIGO stage III and IV), 5-year disease-specific survival proportions were 53.0% for early-week operated vs. 40.2% for late-week operated (p = 0.005 for difference). In multivariate survival analysis of high-stage patients, late-week surgery correlated with an increased risk of disease-specific death by 88.7% and all-cause death by 76.4% (p<0.017). Evaluating only patients who underwent lymphadenectomy, the adverse prognostic effect of being operated late-week remained for both disease-specific and all-cause death (HR 2.151 and HR 1.912, p = 0.004). Whether surgery was performed early- or late-week was not influenced by patient age, BMI, preoperative histology risk classification, FIGO stage or postoperative histology (all p>0.05). In conclusion, endometrial cancer surgery conducted late-week is associated with worse long-term outcome. Our findings are most evident among patients with higher FIGO stages, and patients who underwent more extensive surgical procedure (lymphadenectomy). With support from other studies, our results suggest that high-risk patients may benefit from surgery earlier in the week.

Changes in Chromatin Structure in Curettage Specimens Identifies High-Risk Patients in Endometrial Cancer.

BACKGROUND: Most endometrial carcinoma patients are diagnosed at an early stage with a good prognosis. However, a relatively low fraction with lethal disease constitutes a substantial number of patients due to the high incidence rate. Preoperative identification of patients with high risk and low risk for poor outcome is necessary to tailor treatment. Nucleotyping refers to characterization of cell nuclei by image cytometry, including the assessment of chromatin structure by nuclear texture analysis. This method is a strong prognostic marker in many cancers but has not been evaluated in preoperative curettage specimens from endometrial carcinoma. METHODS: The prognostic impact of changes in chromatin structure quantified with Nucleotyping was evaluated in preoperative curettage specimens from 791 endometrial carcinoma patients prospectively included in the MoMaTEC multicenter trial. RESULTS: Nucleotyping was an independent prognostic marker of disease-specific survival in preoperative curettage specimens among patients with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I-II disease (HR=2.9; 95% CI, 1.2-6.5; P = 0.013) and significantly associated with age, FIGO stage, histologic type, histologic grade, myometrial infiltration, lymph node status, curettage histology type, and DNA ploidy. CONCLUSIONS: Nucleotyping in preoperative curettage specimens is an independent prognostic marker for disease-specific survival, with potential to supplement existing parameters for risk stratification to tailor treatment. IMPACT: This is the first study to evaluate the prognostic impact of Nucleotyping in curettage specimens from endometrial carcinoma and shows that this may be a clinically useful prognostic marker in endometrial cancer. External validation is warranted. Cancer Epidemiol Biomarkers Prev; 26(1); 61-67. ©2016 AACR.

Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer.

BACKGROUND: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. METHODS: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. RESULTS: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10-4). There was evidence of directional pleiotropy (P = 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. CONCLUSIONS: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. IMPACT: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR.

Five endometrial cancer risk loci identified through genome-wide association analysis.

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer.

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.

Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer.

Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.

Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.

Preoperative anemia, leukocytosis and thrombocytosis identify aggressive endometrial carcinomas.

OBJECTIVES: The objective of this study is to investigate preoperative hematological parameters for anemia, leukocytosis and thrombocytosis in relation to established prognostic factors and survival in endometrial cancer. METHODS: 557 patients treated for endometrial carcinoma were prospectively included in a study focusing on the relationship between preoperative hemoglobin, leukocyte and platelet counts, and a panel of clinicopathological characteristics and outcome. RESULTS: Preoperative anemia was present in 15.8%, leukocytosis in 11.2% and thrombocytosis in 12.1%. Among patients with localized disease (FIGO stage I/II), 18.1% had anemia and/or thrombocytosis at diagnosis. Patients with advanced disease (high FIGO stage and lymph-node metastasis) had significantly lower hemoglobin count, higher leukocyte count and higher platelet count (all p<0.008). Patients with anemia, leukocytosis and thrombocytosis had significantly shorter 5-year disease-specific survival of 61.3%, 66.0% and 61.0% respectively, compared to 87.7%, 86.3% and 87.3% for patients with normal counts (all p<0.001). In multivariate Cox regression analysis, lower hemoglobin counts and higher platelet counts were independently associated with poor outcome adjusted for the standardly applied prognostic markers (p<0.033). CONCLUSION: Preoperative anemia, leukocytosis or thrombocytosis in women with endometrial carcinoma is associated with advanced disease and poor disease-specific survival.

Hormone receptor loss in endometrial carcinoma curettage predicts lymph node metastasis and poor outcome in prospective multicentre trial.

BACKGROUND: Preoperative histologic examination of tumour tissue is essential when deciding if endometrial cancer surgery should include lymph node sampling. We wanted to investigate if biomarkers could improve prediction of lymph node metastasis and outcome. PATIENTS AND METHODS: Curettage specimens from 832 endometrial carcinoma patients prospectively recruited from 10 centres in the MoMaTEC trial (Molecular Markers in Treatment of Endometrial Cancer) were investigated for hormone receptor and p53 status. RESULTS: Eighteen per cent of tumours were double negative for oestrogen- and progesterone receptors (ER/PR loss), 24% overexpressed p53. Pathologic expression of all markers correlated with nodal metastases, high FIGO (Federation International of Gynecology and Obstetrics) stage, non-endometrioid histology, high grade and poor prognosis (all P<0.001). ER/PR loss independently predicted lymph node metastasis (odds ratios (OR) 2.0, 95% confidence interval (CI) 1.1-3.7) adjusted for preoperative curettage histology and predicted poor disease-specific survival adjusted for age, FIGO stage, histologic type, grade and myometrial infiltration (hazard ratio (HR) 2.3, 95% CI 1.4-3.9). For lymph node negative endometrioid tumours, ER/PR loss influenced survival independent of grade. CONCLUSION: 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.

Genome-wide association study identifies a common variant associated with risk of endometrial cancer.

Endometrial cancer is the most common malignancy of the female genital tract in developed countries. To identify genetic variants associated with endometrial cancer risk, we performed a genome-wide association study involving 1,265 individuals with endometrial cancer (cases) from Australia and the UK and 5,190 controls from the Wellcome Trust Case Control Consortium. We compared genotype frequencies in cases and controls for 519,655 SNPs. Forty seven SNPs that showed evidence of association with endometrial cancer in stage 1 were genotyped in 3,957 additional cases and 6,886 controls. We identified an endometrial cancer susceptibility locus close to HNF1B at 17q12 (rs4430796, P = 7.1 × 10(-10)) that is also associated with risk of prostate cancer and is inversely associated with risk of type 2 diabetes.

Stathmin overexpression identifies high-risk patients and lymph node metastasis in endometrial cancer.

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 = 763) were subjected to lymph node sampling, of which 12% had metastatic nodes (n = 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.