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Lynch syndrome (LS) predisposes to endometrial cancer (EC), colorectal cancer, and other cancers through inherited pathogenic variants affecting mismatch-repair (MMR) genes. Diagnosing LS in women with EC can reduce subsequent cancer mortality through colonoscopic surveillance and aspirin chemoprevention; it also enables cascade testing of relatives. A growing consensus supports LS screening in EC; however, the expected proportion of test positives, and optimal testing strategy is uncertain. Previous studies from insurance-based healthcare systems were limited by narrow selection criteria, failure to apply reference standard tests consistently, and poor conversion to definitive testing. The aim of this study was to establish the prevalence of LS and the diagnostic accuracy of LS testing strategies in an unselected EC population. This was a prospective cross-sectional study carried out at a large United Kingdom gynaecological cancer centre between October 2015 and January 2017. Women diagnosed with EC or atypical hyperplasia (AH) were offered LS testing. Tumours underwent MMR immunohistochemistry (IHC), microsatellite instability (MSI), and targeted MLH1-methylation testing. Women <50 years, with strong family histories and/or indicative tumour molecular features, underwent MMR germline sequencing. Somatic MMR sequencing was performed when indicative molecular features were unexplained by LS or MLH1-hypermethylation. The main outcome measures were the prevalence of LS in an unselected EC population and the diagnostic accuracy of clinical and tumour testing strategies for risk stratifying women with EC for MMR germline sequencing. In total, 500 women participated in the study; only 2 (<1%) declined. Germline sequencing was indicated and conducted for 136 and 135 women, respectively. A total of 16/500 women (3.2%, 95% CI 1.8% to 5.1%) had LS, and 11 more (2.2%) had MMR variants of uncertain significance. Restricting testing to age <50 years, indicative family history (revised Bethesda guidelines or Amsterdam II criteria) or endometrioid histology alone would have missed 9/16 (56%), 8/13 (62%) or 9/13 (69%), and 5/16 (31%) cases of LS, respectively. In total 132/500 tumours were MMR deficient by IHC of which 83/132 (63%) had MLH1-hypermethylation, and 16/49 (33%) of the remaining patients had LS (16/132 with MMR deficiency, 12%). MMR-IHC with targeted MLH1-methylation testing was more discriminatory for LS than MSI with targeted methylation testing, with 100% versus 56.3% (16/16 versus 9/16) sensitivity (p = 0.016) and equal 97.5% (468/484) specificity; 64% MSI-H and 73% MMR deficient tumours unexplained by LS or MLH1-hypermethylation had somatic MMR mutations. The main limitation of the study was failure to conduct MMR germline sequencing for the whole study population, which means that the sensitivity and specificity of tumour triage strategies for LS detection may be overestimated, although the risk of LS in women with no clinical or tumour predictors is expected to be extremely low. In this study, we observed that age, family history, and histology are imprecise clinical correlates of LS-EC. IHC outperformed MSI for tumour triage and reliably identified both germline and somatic MMR mutations. The 3.2% proportion of LS-EC is similar to colorectal cancer, supporting unselected screening of EC for LS.

Endometrial cancer is the most common gynaecological cancer in high income countries and its incidence is rising globally. Although an ageing population and fewer benign hysterectomies have contributed to this trend, the growing prevalence of obesity is the major underlying cause. Obesity poses challenges for diagnosis and treatment and more research is needed to offer primary prevention to high-risk women and to optimise endometrial cancer survivorship. Early presentation with postmenopausal bleeding ensures most endometrial cancers are cured by hysterectomy but those with advanced disease have a poor prognosis. Minimally invasive surgical staging and sentinel-lymph-node biopsy provides a low morbidity alternative to historical surgical management without compromising oncological outcomes. Adjuvant radiotherapy reduces loco-regional recurrence in intermediate-risk and high-risk cases. Advances in our understanding of the molecular biology of endometrial cancer have paved the way for targeted chemotherapeutic strategies, and clinical trials will establish their benefit in adjuvant, advanced, and recurrent disease settings in the coming years.

Endometrial cancer is the sixth commonest cancer in women worldwide, with over 417,000 diagnoses in 2020. The disease incidence has increased by 132% over the last 30 years and is set to continue to rise in response to an ageing population and increasing global rates of obesity and diabetes. A greater understanding of the mechanisms driving endometrial carcinogenesis has led to the identification of potential strategies for primary disease prevention, although prospective evaluation of their efficacy within clinical trials is still awaited. The early diagnosis of endometrial cancer is associated with improved survival, but has historically relied on invasive endometrial sampling. New, minimally invasive tests using protein and DNA biomarkers and cytology have the potential to transform diagnostic pathways and to allow for the surveillance of high-risk populations. The molecular classification of endometrial cancers has been shown to not only have a prognostic impact, but also to have therapeutic value and is increasingly used to guide adjuvant treatment decisions. Advanced and recurrent disease management has also been revolutionised by increasing the use of debulking surgery and targeted treatments, particularly immunotherapy. This review summarises the recent advances in the prevention, diagnosis and treatment of endometrial cancer and seeks to identify areas for future research.

Background Endometrial cancer (EC) is a major health concern due to its rising incidence. Whilst early stage disease is generally cured by surgery, advanced EC has a poor prognosis with limited treatment options. Altered energy metabolism is a hallmark of malignancy. Cancer cells drive tumour growth through aerobic glycolysis and must export lactate to maintain intracellular pH. The aim of this study was to evaluate the expression of the lactate/proton monocarboxylate transporters MCT1 and MCT4 and their chaperone CD147 in EC, with the ultimate aim of directing future drug development. Methods MCT1, MCT4 and CD147 expression was examined using immunohistochemical analysis in 90 endometrial tumours and correlated with clinico-pathological characteristics and survival outcomes. Results MCT1 and MCT4 expression was observed in the cytoplasm, the plasma membrane or both locations. CD147 was detected in the plasma membrane and associated with MCT1 ( p  = 0.003) but not with MCT4 ( p  = 0.207) expression. High MCT1 expression was associated with reduced overall survival ( p  = 0.029) and remained statistically significant after adjustment for survival covariates ( p  = 0.017). Conclusion Our data suggest that MCT1 expression is an important marker of poor prognosis in EC. MCT1 inhibition may have potential as a treatment for advanced or recurrent EC.

Purpose There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients. Methods Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice. Results Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer. Conclusion This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.

Introduction/BackgroundAddressing quality of life (QoL) in the growing population of endometrial cancer survivors is crucial. Cardiovascular risk factors play a pivotal role in survivorship, influencing QoL and long-term outcomes. This study aimed to identify determinants of QoL, barriers to implementing lifestyle changes, and assess the impact of optimising cardiovascular risk factors.MethodologyA prospective cohort study integrated cardiovascular risk assessments into routine follow-up over 12 months. These informed the tailored lifestyle and pharmacotherapy advice women received. QoL was measured using SF-36 and QLACS. Predictor variables were identified using Kruskal-Wallis tests with Dunn-Bonferroni correction. Regression analyses examined the relationships. Changes in QoL were evaluated using paired t-tests and Wilcoxon-signed-ranks-tests. Semi-structured interviews were conducted to identify barriers to change.ResultsAt baseline, 70 women completed QoL questionnaires. Age and BMI negatively impacted physical functioning (median (IQR) score <50 years: 87.5 (40.0–100.0)%, vs. ≥70 years: 50.0 (30–72.5)%, p=0.03; BMI 18.5–24.9kg/m2: 95.0 (80.0–100.0)%, vs. ≥30.0kg/m2: 60.0 (35.0–85.0)%, p=0.001). Socioeconomic deprivation and ethnicity influenced QoL; Asian women had significantly poorer physical and social functioning and lower QoL compared to White women (χ2=6.18, p=0.01). Age, BMI, ethnicity and socioeconomic status were independent predictors of physical functioning (R2 0.46, p<0.0001). Optimising cardiovascular risk factors resulted in weight loss (-5.4kg, p<0.0001), improvement in QRISK3 score (-2.3%, p=0.03), a significant improvement in general QoL (mean (SD) SF-36 general health score baseline: 58.8 (17.7)%, vs. 12-month: 66.8 (14.7)%, p<0.05) and physical functioning (median (IQR) score, baseline: 75.0 (40.0–90.0)%, vs. 12-month: 85.0 (65.0–100.0)%; p=0.02). Barriers to lifestyle changes included time, cost, and lack of individualised dietary advice.ConclusionEthnicity and socioeconomic deprivation are important determinants of QoL in endometrial cancer survivors. Targeting risk factors during survivorship positively influences QoL and cardiovascular health. Addressing barriers to lifestyle changes, with consideration of diverse backgrounds and socioeconomic contexts, is a crucial step toward equality in survivorship.DisclosuresHJANoneSJKNoneLS: NoneDB: NoneMKREli Lilly, GSKEJCNone

Advanced endometrial cancer continues to have a poor prognosis, due to limited treatment options, which may be further adversely impacted by obesity. Endometrial cancer stem cells have been reported to drive metastasis, chemotherapy resistance and disease relapse, but have yet to be fully characterised and no specific targeted therapies have been identified. Here, we describe the phenotype and genotype of aldehyde dehydrogenase high (ALDHhigh) and CD133+ve endometrial cancer stem cells and how adipocyte secreted mediators block the inhibitory effect of metformin on endometrial cancer stem cell activity. Ishikawa and Hec-1a cell lines were used to characterise ALDHhigh and CD133+ve endometrial cancer cells using flow cytometry, functional sphere assays and quantitative-Polymerase Chain Reaction. The comparative effect of metformin on endometrial cancer stem cell activity and bulk tumour cell proliferation was determined using an Aldefluor and cytotoxicity assay. The impact of adipocyte secreted mediators on metformin response was established using patient-derived conditioned media. ALDHhigh cells demonstrated greater endometrial cancer stem cell activity than CD133+ve cells and had increased expression of stem cell and epithelial-mesenchymal transition genes. Treatment with 0.5–1 mM metformin reduced the proportion and activity of both endometrial cancer stem cell populations (p ≤ 0.05), without affecting cell viability. This effect was, however, inhibited by exposure to patient-derived adipocyte conditioned media. These results indicate a selective and specific effect of metformin on endometrial cancer stem cell activity, which is blocked by adipocyte secreted mediators. Future studies of metformin as an adjuvant therapy in endometrial cancer should be adequately powered to investigate the influence of body mass on treatment response.

Endometrial cancer is the most common malignancy of the female genital tract and a major cause of morbidity and mortality in women. Early detection is key to ensuring good outcomes but a lack of minimally invasive screening tools is a significant barrier. Most endometrial cancers are obesity-driven and develop in the context of severe metabolomic dysfunction. Blood-derived metabolites may therefore provide clinically relevant biomarkers for endometrial cancer detection. In this study, we analysed plasma samples of women with body mass index (BMI) ≥ 30 kg/m2 and endometrioid endometrial cancer (cases, n = 67) or histologically normal endometrium (controls, n = 69), using a mass spectrometry-based metabolomics approach. Eighty percent of the samples were randomly selected to serve as a training set and the remaining 20% were used to qualify test performance. Robust predictive models (AUC > 0.9) for endometrial cancer detection based on artificial intelligence algorithms were developed and validated. Phospholipids were of significance as biomarkers of endometrial cancer, with sphingolipids (sphingomyelins) discriminatory in post-menopausal women. An algorithm combining the top ten performing metabolites showed 92.6% prediction accuracy (AUC of 0.95) for endometrial cancer detection. These results suggest that a simple blood test could enable the early detection of endometrial cancer and provide the basis for a minimally invasive screening tool for women with a BMI ≥ 30 kg/m2.

Endometrial cancer is the sixth most common cancer in women, with a rising incidence worldwide. Current approaches for the diagnosis and screening of endometrial cancer are invasive, expensive or of moderate diagnostic accuracy, limiting their clinical utility. There is a need for cost-effective and minimally invasive approaches to facilitate the early detection and timely management of endometrial cancer. We analysed blood plasma samples in a cross-sectional diagnostic accuracy study of women with endometrial cancer (n = 342), its precursor lesion atypical hyperplasia (n = 68) and healthy controls (n = 242, total n = 652) using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy and machine learning algorithms. We show that blood-based infrared spectroscopy has the potential to detect endometrial cancer with 87% sensitivity and 78% specificity. Its accuracy is highest for Type I endometrial cancer, the most common subtype, and for atypical hyperplasia, with sensitivities of 91% and 100%, and specificities of 81% and 88%, respectively. Our large-cohort study shows that a simple blood test could enable the early detection of endometrial cancer of all stages in symptomatic women and provide the basis of a screening tool in high-risk groups. Such a test has the potential not only to differentially diagnose endometrial cancer but also to detect its precursor lesion atypical hyperplasia—the early recognition of which may allow fertility sparing management and cancer prevention.

Background: Endometrial cancer incidence and mortality is increasing due to rising obesity rates, an ageing population and a preponderance of cardiovascular deaths. Novel treatments are required for women who are unfit for or who decline surgery, to reduce the risk of disease recurrence and improve survival. Laboratory work and small uncontrolled window studies suggest that metformin reduces endometrial cancer proliferation through inhibition of the PI3K-Akt-mTOR pathway and selectively targets cancer stem cells responsible for metastasis and disease recurrence in breast and ovarian cancer. Methods: i) The clinical efficacy of metformin was tested in a double-blind, placebo-controlled, randomised trial. Expression of Ki-67 and markers of the PI3K-Akt-mTOR and insulin signalling pathway were compared prior to and following treatment. ii) Cell lines were used to characterise endometrial cancer stem cells and to investigate the effect of metformin on these cells in the context of a model of obesity associated endometrial cancer. iii) The true prevalence of cardiovascular risk factors in women with endometrial cancer was compared with the general population and the impact of universal screening and treatment of modifiable risk factors on 10-year cardiovascular disease risk determined. Results: Standard diabetic doses of metformin for 1-5 weeks prior to surgery did not result in an overall reduction in endometrial cancer proliferation when tested in a methodologically robust randomised controlled trial. BMI significantly influenced response to treatment (p=0.05); non-obese women had a non-significant decrease in Ki-67 expression of 8.3% (95%CI -18.70 to +2.09) following metformin exposure, whilst no effect was seen in obese women (mean difference in post-treatment Ki-67 +5.50%, 95%CI -8.31 to +13.81). This difference was unrelated to serum drug levels. Metformin had no effect on the PI3K-Akt-mTOR pathway and insulin signalling when pre- and post-treatment endometrial biopsies were directly compared. Metformin reduced the number and activity of endometrial cancer stem cells, characterised by high ALDH activity and CD133 positivity, and decreased the expression of cancer stem cell genes at a lower concentration than that required to affect overall cell proliferation in vitro. This effect was, however, abolished in the presence of adipocyte-conditioned media. Women with newly diagnosed endometrial cancer had a 1.4-fold increased 10-year cardiovascular disease risk, as measured by QRISK2 score, compared with the general population due to higher levels of unrecognised and undertreated risk factors. Screening and treatment of these risk factors could reduce an individual's absolute risk by 1.82%, requiring 55 women with endometrial cancer to be treated to prevent one cardiovascular event compared with 145 women in the general population. Conclusions: Obese women appear to be resistant to the anti-tumour effects of metformin as a consequence of adipocyte secreted mediators. Metformin has a specific and selective effect on endometrial cancer stem cells in a cell line model; its effect on these cells in vivo should be examined. The increased risk of cardiovascular disease in women with a history of endometrial cancer may be improved by metformin treatment; the effect of long term therapy on overall and cardiovascular specific survival should be examined in a randomised controlled trial.