Sarah Kitson

Measuring the biological effect of presurgical metformin treatment in endometrial cancer

Background:Preclinical studies in endometrial cancer (EC) show that metformin reduces cellular proliferation by PI3K-AKT-mTOR inhibition. We tested the hypothesis that short-term presurgical metformin reduces cellular proliferation in atypical endometrial hyperplasia (AEH) and endometrioid EC, and assessed the feasibility of using phosphorylated PI3K-AKT-mTOR proteins as tissue end points.Methods:Women with AEH or EC received metformin 850 mg twice a day or no drug in the presurgical window between diagnosis and hysterectomy. Before and after the window, tissue samples were obtained; serum markers of insulin resistance (e.g. homeostasis model of assessment of insulin resistance index) were determined; and anthropometrics measured (e.g. BMI). Cell proliferation (Ki-67) and PI3K-AKT-mTOR phosphostatus were assessed by immunohistochemistry and scored blinded to treatment.Results:Twenty-eight metformin-treated and 12 untreated patients, well matched for age and BMI, completed the study. Metformin treatment (median 20 days, range 7–34) was associated with a 17.2% reduction in tumour Ki-67 (95% CI −27.4, −7.0, P=0.002), in a dose-dependent manner. Tumour PI3K-AKT-mTOR protein phosphostatus varied but the effects were not significant after adjusting for changes in controls.Conclusions:Short-term metformin was associated with reduced Ki-67 expression in EC. Changes in tumour PI3K-AKT-mTOR protein phosphostatus were seen in both groups. Future studies should address the variability attributed to different sampling techniques including devascularisation of the uterus at hysterectomy.

Working together to shape the endometrial cancer research agenda: The top ten unanswered research questions

BACKGROUND Endometrial cancer (EC) is the most common gynaecological cancer in developed nations and its incidence is rising. As a direct consequence, more women are dying from EC despite advances in care and improved survivorship. There is a lack of research activity and funding, as well as public awareness about EC. We sought to engage patients, carers and healthcare professionals to identify the most important unanswered research questions in EC. METHODOLOGY The priority setting methodology was developed by the James Lind Alliance and involved four key stages: gathering research questions; checking these against existing evidence; interim prioritisation; and a final consensus meeting during which the top ten unanswered research questions were agreed using modified nominal group methodology. RESULTS Our first online survey yielded 786 individual submissions from 413 respondents, of whom 211 were EC survivors or carers, and from which 202 unique unanswered research questions were generated. 253 individuals, including 108 EC survivors and carers, completed an online interim prioritisation survey. The resulting top 30 questions were ranked in a final consensus meeting. Our top ten spanned the breadth of patient experience of this disease and included developing personalised risk scoring, refining criteria for specialist referral, understanding the underlying biology of different types of EC, developing novel personalised treatment and prevention strategies, prognostic and predictive biomarkers, increasing public awareness and interventions for psychological issues. CONCLUSION Having established the top ten unanswered research questions in EC, we hope this galvanises researchers, healthcare professionals and the public to collaborate, coordinate and invest in research to improve the lives of women affected by EC.

Identifying high risk women for endometrial cancer prevention strategies: proposal of an endometrial cancer risk prediction model

Already the fourth most common cancer in women in the developed world, the incidence of endometrial cancer is increasing rapidly, in line with the increasing prevalence of obesity. Relatively few studies have been undertaken of risk-reducing interventions aimed at limiting the impact of the disease on both individuals and the health service. Those that have been performed have demonstrated only modest results due to their application in relatively unselected populations. A validated risk prediction model is therefore urgently required to identify individuals at particularly high risk of endometrial cancer who may benefit from targeted primary prevention strategies and to guide trial eligibility. On the basis of a systematic review of the literature, the evidence for inclusion of measures of obesity, reproduction, insulin resistance, and genetic risk in such a model is discussed, and the strength of association between these risk factors and endometrial cancer is used to guide the development of a pragmatic risk prediction scoring system that could be implemented in the general population. Provisional cutoff values are described pending refinement of the model and external validation in large prospective cohorts. Potential risk-reducing interventions are suggested, highlighting the need for future studies in this area if the increasing tide of endometrial cancer is to be stemmed. Cancer Prev Res; 10(1); 1–13. ©2016 AACR.

Ki-67 in endometrial cancer: Scoring optimization and prognostic relevance for window studies

Ki-67, a marker of cellular proliferation, is increasingly being used in pre-surgical window studies in endometrial cancer as a primary outcome measure. Unlike in breast cancer, however, there are no guidelines standardizing its measurement and its clinical relevance as a response biomarker is undetermined. It is, therefore, imperative that Ki-67 scoring protocols are optimized and its association with patient survival rigorously evaluated, in order to be able to clinically interpret the results of these studies. Using the International Ki-67 in Breast Cancer Working Group guidelines as a basis, whole slide, hot spot and invasive edge scoring protocols were evaluated using endometrial biopsies and hysterectomy specimens from 179 women. Whole sections and tissue microarrays, manual and semi-automated scoring using Definiens Developer software were additionally compared. Ki-67 scores were related to clinicopathological variables and cancer-specific survival in uni- and multivariate analysis. Against criteria of time efficiency, intra- and inter-observer variability and consistency, semi-automated hot spot scoring was the preferred method. Ki-67 scores positively correlated with grade, stage and depth of myometrial invasion (P-values all <0.03). By univariate analysis, higher Ki-67 scores were associated with a significant reduction in cancer-specific survival (P≤0.05); however, this effect was substantially attenuated in the multivariate model. In conclusion, hot spot scoring of whole sections using Definiens is an optimal method to quantify Ki-67 in endometrial cancer window study specimens. Measured this way, it is a clinically relevant marker, though further work is required to determine whether reductions in Ki-67 in neoadjuvant intervention studies translate into improved patient outcome.

BGCS uterine cancer guidelines:: Recommendations for practice

The British Gynaecological Cancer Society has issued the first Endometrial (Uterine) Cancer guidelines as recommendation for practice for the UK.

The unrecognized burden of cardiovascular risk factors in women newly diagnosed with endometrial cancer: a prospective case control study

Highlights • CVD risk was measured in a prospective study of 150 EC patients and 746 controls.• EC patients had significantly more CVD risk factors than other women.• Most CVD risk factors were either unrecognized or inadequately treated.• EC patients had a significantly higher 10-year risk of CVD (QRISK2) than controls.• Identifying and treating CVD risk factors could improve outcomes for EC survivors.

Expression of NAD(P)H quinone dehydrogenase 1 (NQO1) is increased in the endometrium of women with endometrial cancer and women with Polycystic Ovary Syndrome

Women with a prior history of polycystic ovary syndrome (PCOS) have an increased risk of endometrial cancer (EC).

Hormonal and Metabolic Strategies to Overcome Insulin Resistance and Prevent Endometrial Cancer

A role for insulin and its related protein IGF-1 as drivers of endometrial carcinogenesis is now well established, with epidemiological and in vitro evidence demonstrating insulin resistance to be critical to the development of the disease. In addition to a direct effect on the endometrium, stimulating unregulated cell proliferation, insulin also closely interacts with excess adipose tissue, increasing the aromatisation of androgens to oestrogen and decreasing the secretion of the adipokine adiponectin, a major regulator of insulin sensitivity. Interventions aimed at improving the body’s response to insulin would, therefore, be expected to have a positive effect on preventing the development of endometrial cancer. Numerous lifestyle, pharmacological and surgical interventions have been shown to influence insulin resistance, either through weight loss, increased insulin secretion or modulation of signalling through the insulin receptor. This review discusses the mechanisms underpinning these strategies and, in particular, the existing data for their role in endometrial cancer prophylaxis.

High prevalence of metabolic syndrome in women newly diagnosed with endometrial cancer

Thank you for the opportunity to respond to the letter from Galazis et al. (Galazis et al., 2018). The authors correctly state that women newly diagnosed with endometrial cancer are not routinely screened for cardiovascular risk factors in the UK. This is a missed opportunity for primary prevention; our data point to a very high prevalence of unrecognized and undertreated hypercholesterolemia, hypertension and hyperglyaemia in these women (Kitson et al., 2018). This is somewhat unsurprising given that nearly two-thirds of our patients are obese (BMI > 30 kg/m), and obesity is a known aetiological driver for both endometrial cancer and cardiovascular disease. Adipose-derived estrogen unopposed by progesterone in postmenopausal women is the most accepted theory linking obesity to endometrial carcinogenesis; however, the concept of metabolically unhealthy obesity, rather than excess adiposity per se, is gaining popularity, and goes some way towards explaining why some but not all obese women develop endometrial cancer. Defining metabolically unhealthy obesity is a contentious issue that has yet to be resolved, but most published studies have utilised the closely related concept of the metabolic syndrome. This is ‘a constellation of interrelated risk factors of metabolic origin’ that collectively predispose an individual to cardiovascular disease (Grundy et al., 2005). Individuals meeting the diagnostic criteria for the metabolic syndrome are considered metabolically unhealthy. Several indices have been used to characterise the metabolic syndrome, but the National Cholesterol Education Programs Adult Treatment Panel III (NECP ATP III) is most widely adopted. Using these criteria, we metabolically phenotyped a subset of our endometrial cancer patients. We measured waist circumference and blood pressure, and checked fasting blood glucose, lipid levels and liver enzymes. Those with elevated alanine transaminase (ALT) or alkaline phosphatase levels were referred for an ultrasound scan of their liver. In total, 52% (95% confidence intervals 42.2–61.8%) met the diagnostic criteria for metabolic syndrome (Table 1), with ≥3 of 5 indicative features (Fig. 1). In addition, 14 women were found to have previously unrecognized hepatic steatosis and non-alcoholic fatty liver disease. By contrast, 23.1% of the general US population meet the diagnostic criteria for the metabolic syndrome (Ford et al., 2004). There are no comparable data for a UK population; in our age and ethnicity-matched Health Survey for England (HSE) control women, HbA1c was measured instead of fasting blood glucose, and there were insufficient data to diagnose metabolic syndrome in 15.5%. Nonetheless, just 9.2% (95% confidence intervals 7.3–11.2) of control women met the criteria for metabolic syndrome, more than five-fold fewer than our endometrial cancer patients, a comparison that was highly significant (p < .0001), and mirrors previous work (Rosato et al., 2011). Endometrial cancer patients who met the diagnostic criteria for metabolic syndrome were more likely to be obese than those who did not (82.7% vs. 37.5%, p= .0001). However, the presence of metabolic syndrome was not associated with age, grade or stage of endometrial cancer (data not shown). Whilst these findings lend strong support to cardiovascular risk factor screening and optimization in endometrial cancer survivors, they also hint at common biological mechanisms underpinning the pathogenesis of the two conditions. Further, they offer the very exciting possibility that simple, safe, non toxic drugs with proven activity against elements of the metabolic syndrome may offer women protection against both cardiovascular disease and endometrial cancer. Interventions that reduce the risk of endometrial cancer are urgently needed to limit escalating incidence rates and consequent deaths from the disease (Crosbie and Morrison, 2014). Accumulating evidence highlights the potential anti-cancer effect of aspirin (Takiuchi et al., 2018), statins (Arima et al., 2017) and metformin, an insulin sensitising drug long used in the treatment of type 2 diabetes (Sivalingam et al., 2014). Data supporting an anti-cancer activity of the beta-blocker antihypertensive drugs have been less persuasive (Sanni et al., 2017). It is tantalising to think that adequately

Urinary HPV testing may offer hope for cervical screening non-attenders

Despite the success of cervical screening, cancer of the cervix is the fourth most common cancer affecting women worldwide (CRUK 2014). Rates are particularly high in developing nations, which lack the requisite infrastructure for cytology and colposcopy-based screening, and in certain demographic groups, where uptake of screening is poor. Recent research has focussed on developing less invasive and potentially more acceptable means of identifying women at high risk of cervical intraepithelial neoplasia (CIN). Urinary HPV testing has received particular attention because of the ease of obtaining samples and the opportunity this affords to overcoming barriers to cervical screening like embarrassment and discomfort. This article is protected by copyright. All rights reserved.