The impact of obesity and bariatric surgery on the immune microenvironment of the endometrium.

BACKGROUND: The incidence of endometrial cancer is rising in parallel with the obesity epidemic. Obesity increases endometrial cancer risk and weight loss is protective, but the underlying mechanisms are incompletely understood. We hypothesise that the immune microenvironment may influence susceptibility to malignant transformation in the endometrium. The aim of this study was to measure the impact of obesity and weight loss on the immunological landscape of the endometrium. METHODS: We conducted a prospective cohort study of women with class III obesity (body mass index, BMI ≥ 40 kg/m2) undergoing bariatric surgery or medically-supervised low-calorie diet. We collected blood and endometrial samples at baseline, and two and 12 months after weight loss intervention. Serum was analysed for inflammatory markers CRP, IL-6 and TNF-α. Multiplex immunofluorescence was used to simultaneously identify cells positive for immune markers CD68, CD56, CD3, CD8, FOXP3 and PD-1 in formalin-fixed paraffin-embedded endometrial tissue sections. Kruskal-Wallis tests were used to determine whether changes in inflammatory and immune biomarkers were associated with weight loss. RESULTS: Forty-three women with matched serum and tissue samples at all three time points were included in the analysis. Their median age and BMI were 44 years and 52 kg/m2, respectively. Weight loss at 12 months was greater in women who received bariatric surgery (n = 37, median 63.3 kg) than low-calorie diet (n = 6, median 12.8 kg). There were significant reductions in serum CRP (p = 3.62 × 10-6, r = 0.570) and IL-6 (p = 0.0003, r = 0.459), but not TNF-α levels, with weight loss. Tissue immune cell densities were unchanged except for CD8+ cells, which increased significantly with weight loss (p = 0.0097, r = -0.323). Tissue CD3+ cell density correlated negatively with systemic IL-6 levels (p = 0.0376; r = -0.318). CONCLUSION: Weight loss is associated with reduced systemic inflammation and a recruitment of protective immune cell types to the endometrium, supporting the concept that immune surveillance may play a role in endometrial cancer prevention.

The impact of obesity and bariatric surgery on circulating and tissue biomarkers of endometrial cancer risk.

Obesity is the strongest risk factor for endometrial cancer (EC). To inform targeted screening and prevention strategies, we assessed the impact of obesity and subsequent bariatric surgery-induced weight loss on endometrial morphology and molecular pathways implicated in endometrial carcinogenesis. Blood and endometrial tissue were obtained from women with class III-IV obesity (body mass index ≥40 and ≥50 kg/m2 , respectively) immediately prior to gastric bypass or sleeve gastrectomy, and at two and 12 months' follow up. The endometrium underwent pathological examination and immunohistochemistry was used to quantify proliferation (Ki-67), oncogenic signaling (PTEN, pAKT, pERK) and hormone receptor (ER, PR) expression status. Circulating biomarkers of insulin resistance, reproductive function and inflammation were also measured at each time point. Seventy-two women underwent bariatric surgery. At 12 months, the mean change in total and excess body weight was -32.7 and -62.8%, respectively. Baseline endometrial biopsies revealed neoplastic change in 10 women (14%): four had EC, six had atypical hyperplasia (AH). After bariatric surgery, most cases of AH resolved (5/6) without intervention (3/6) or with intrauterine progestin (2/6). Biomarkers of endometrial proliferation (Ki-67), oncogenic signaling (pAKT) and hormone receptor status (ER, PR) were significantly reduced, with restoration of glandular PTEN expression, at 2 and 12 months. There were reductions in circulating biomarkers of insulin resistance (HbA1c, HOMA-IR) and inflammation (hsCRP, IL-6), and increases in reproductive biomarkers (LH, FSH, SHBG). We found an unexpectedly high prevalence of occult neoplastic changes in the endometrium of women undergoing bariatric surgery. Their spontaneous reversal and accompanying down-regulation of PI3K-AKT-mTOR signaling with weight loss may have implications for screening, prevention and treatment of this disease.

Prevention Strategies in Endometrial Carcinoma.

PURPOSE OF THE REVIEW: To assess the most recent high-quality evidence for endometrial cancer prevention strategies. RECENT FINDINGS: Obesity is an established risk factor for endometrial cancer. Weight cycling and weight gain in middle age are risk factors for endometrial cancer. Bariatric surgery reduces the risk of endometrial cancer by up to 81% in obese women who attain and maintain a normal weight. Combined oral contraceptives provide durable protection against endometrial cancer for 30 years or more. Ever use of the levonorgestrel intrauterine system (LNG-IUS) and inert intrauterine devices reduce endometrial cancer risk. The first oestrogen-based non-progestin HRT for non-hysterectomised women that contains estradiol and bazedoxifene has an effective protective effect on endometrium. Bisphosphonates reduce endometrial cancer risk. Weight loss and LNG-IUS would seem to be an effective strategy for preventing the development of obesity-driven endometrial cancer in the highest risk women. Future research may identify other safe and effective chemoprevention interventions, such as aspirin, bisphosphonates or metformin.

Interventions for weight reduction in obesity to improve survival in women with endometrial cancer.

BACKGROUND: Diagnoses of endometrial cancer are increasing secondary to the rising prevalence of obesity. Obesity plays an important role in promoting the development of endometrial cancer, by inducing a state of unopposed oestrogen excess, insulin resistance and inflammation. It also affects treatment, increasing the risk of surgical complications and the complexity of radiotherapy planning, and may additionally impact on subsequent survival. Weight-loss interventions have been associated with improvements in breast and colorectal cancer-specific survival as well as a reduction in the risk of cardiovascular disease, a frequent cause of death in endometrial cancer survivors. OBJECTIVES: To determine the impact of weight-loss interventions, in addition to standard management of endometrial cancer, on overall survival and the frequency of adverse events.Secondary objectives include an assessment of weight-loss interventions on endometrial cancer-specific survival, weight loss achieved, cardiovascular event frequency and quality of life both overall and stratified according to patient body mass index (BMI), where possible. SEARCH METHODS: This review searched Cochrane Central Register of Controlled Trials, MEDLINE, Embase and reference lists of articles, trial registries, and international gynaecological oncology conference abstracts from inception to January 2018. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions to facilitate weight loss in overweight or obese women undergoing treatment for, or previously treated for, endometrial cancer were selected. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed trial quality, and extracted data with disagreements resolved by a third review author. Study authors were contacted to obtain missing data, including details of any adverse events. MAIN RESULTS: We included three RCTs in the review, randomising a total of 161 overweight and obese women with endometrial cancer. All studies compared combined behavioural and lifestyle interventions to facilitate weight loss through dietary modification and increased physical activity. The included RCTs were of low or very low quality, due to high risk of bias by failing to blind participants, personnel and outcome assessors, and significant loss to follow-up (attrition rate up to 29%).Combined behaviour and lifestyle interventions were not associated with improved overall survival (risk ratio (RR mortality), 0.23 95% confidence interval (CI) 0.01 to 4.55, P = 0.34, one RCT, 37 participants; very low-certainty evidence) compared with usual care at 24 months. There was no evidence that such interventions were associated with improvements in cancer-specific survival or cardiovascular event frequency as no cancer-related deaths, myocardial infarctions or strokes were reported in the included studies. None of the included RCTs reported data for the outcome of recurrence-free survival. Combined behaviour and lifestyle interventions were not associated with significant weight loss at either six months (mean difference (MD) -1.88 kg, 95% CI -5.98 to 2.21 kg, P = 0.37, three RCTs, 131 participants, I2= 0%; low-certainty evidenc e)or 12 months (MD -8.98 kg, 95% CI -19.88 to 1.92 kg, P = 0.11, two RCTs, 91 participants, I2= 0%; very low-certainty evidence) when compared with usual care. Combined behaviour and lifestyle interventions were not associated with increased quality of life, when measured using either the SF-12 Physical Health questionnaire or FACT-G at six months (FACT-G MD 2.51, 95% CI -5.61 to 10.64, P = 0.54, two RCTs, 95 participants, I2= 83%; very low-certainty evidence), or by FACT-G alone at 12 months (MD 2.77, 95% CI -0.65 to 6.20, P = 0.11, two RCTs, 89 participants, I2= 0%; very low-certainty evidence) when compared with usual care. No serious adverse events, for example hospitalisation or deaths, were reported in included trials. Lifestyle and behavioural interventions were associated with a higher risk of musculoskeletal symptoms (RR 19.03, 95% CI 1.17, 310.52, P = 0.04, two RCTs, 91 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: There is currently insufficient high-quality evidence to determine the effect of combined lifestyle and behavioural interventions on survival, quality of life, or significant weight loss in women with a history of endometrial cancer compared to those receiving usual care. The limited evidence suggests that there is little or no serious or life-threatening adverse effects due to these interventions, although musculoskeletal problems were increased, presumably due to increased activity levels. Our conclusion is based on low- and very low-quality evidence from a small number of trials and very few patients. We therefore have very little confidence in the evidence: the true effect of weight-loss interventions in obese women with endometrial cancer is currently not known.Further methodologically-rigorous, adequately-powered RCTs are required with follow-up of 5 to 10 years duration. These should focus on the effects of varying dietary modification regimens, pharmacological treatments associated with weight loss and bariatric surgery on survival, quality of life, weight loss and adverse events.

Women's Risk Perceptions and Willingness to Engage in Risk-Reducing Interventions for the Prevention of Obesity-Related Endometrial Cancer.

INTRODUCTION: Endometrial cancer rates are rising in parallel with the global obesity epidemic. Our aim was to assess the willingness of women at greatest risk of obesity-related endometrial cancer to engage with risk-reducing strategies and establish perceived barriers that may preclude their participation in a randomized controlled trial of primary endometrial cancer prevention. MATERIALS AND METHODS: Women attending gynecology, obesity and sleep apnea clinics in Manchester Academic Health Sciences Centre-affiliated hospitals with obesity classes II (BMI 35-39.9kg/m2) and III (BMI ≥40kg/m2) were invited to participate in a cross-sectional survey. We asked women about their perceived risk, knowledge of risk factors and willingness to engage with endometrial cancer risk-reducing interventions. RESULTS: Seventy-four women with a median age of 51 years (range 22-73) and BMI of 47kg/m2 (range 34-81) took part in the study. Two-thirds (65.6%) knew that obesity was a risk factor for endometrial cancer but few were able to recall other major risk factors. Just over half (53.5%) perceived their risk of developing endometrial cancer to be higher than average. Women were prepared to lose weight (94%), eat healthily (91%), exercise more (87%), take a pill every day (74%) or receive an intra-uterine device (49%) for primary endometrial cancer prevention. Perceived barriers included cost, forgetting, willpower, finding time, physical fitness, social anxiety, possible side effects and previous bad experiences. CONCLUSION: Women at highest risk of obesity-related endometrial cancer may not always appreciate their susceptibility. However, willingness to engage in risk-reducing strategies suggests recruitment to a randomized controlled trial for primary endometrial cancer prevention could be feasible.

PROgesterone Therapy for Endometrial Cancer Prevention in Obese Women (PROTEC) Trial: A Feasibility Study.

Obesity is the major etiologic driver for endometrial cancer. The levonorgestrel intrauterine system (LNG-IUS) reduces the risk of endometrial cancer and its precursor, atypical hyperplasia. We assessed feasibility and uptake of the LNG-IUS for primary prevention of endometrial cancer in high-risk women and its impact on endometrial tissue biomarkers. Women with class-III obesity [body mass index (BMI) > 40 kg/m2] and histologically normal endometrium were invited to participate in a clinical trial of the LNG-IUS for endometrial protection. Recruitment, successful LNG-IUS insertion, and adherence to trial procedures were recorded. We measured impact of the LNG-IUS on circulating biomarkers of endometrial cancer risk, endometrial proliferation (Ki-67, pAKT, PTEN), endometrial hormone receptor status [estrogen receptor and progesterone receptor (PR)], mental wellbeing, and menstrual function. At 6 months, women chose to keep their LNG-IUS or have it removed. In total, 103 women were approached, 54 were offered a participant information sheet, 35 agreed to participate, and 25 received a LNG-IUS. Their median age and BMI were 54 years [interquartile range (IQR) 52-57] and 47 kg/m2 (IQR 44-51), respectively. Three women (3/35, 9%) were ineligible due to atypical hyperplasia/endometrial cancer on their baseline biopsy. The LNG-IUS was well tolerated and had a positive overall effect on bleeding patterns and mental wellbeing. The LNG-IUS was associated with endometrial morphologic change, reduced Ki-67, and PR expression, but circulating biomarkers of endometrial cancer risk were unchanged. All but one woman (96%) kept her LNG-IUS. The LNG-IUS appears to be acceptable to some women with class-III obesity for primary prevention of endometrial cancer, which could provide a strategy for a prevention trial.Prevention Relevance: Novel strategies are urgently needed to prevent the rise in endometrial cancer diagnoses predicted by escalating obesity rates. Here, we show that women with class III obesity are willing to engage in risk reduction with a levonorgestrel intrauterine system, which could provide a strategy for an endometrial cancer prevention trial.

Metabolomic Biomarkers for the Detection of Obesity-Driven Endometrial Cancer.

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) ≥30kg/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.

Weight Loss During Intrauterine Progestin Treatment for Obesity-associated Atypical Hyperplasia and Early-Stage Cancer of The Endometrium.

Intrauterine progestin is a treatment option for women with atypical hyperplasia or low-risk endometrial cancer who wish to preserve their fertility, or whose poor surgical fitness precludes safe hysterectomy. We hypothesized that in such women with obesity, weight loss during progestin treatment may improve oncological outcomes. We conducted a prospective nonrandomized study of women with obesity and atypical hyperplasia or low-grade stage 1a endometrial cancer undergoing progestin treatment. Women with a body mass index (BMI) ≥ 35 kg/m2 were offered bariatric surgery; those who declined and those with a BMI of 30 to 34.9 kg/m2 were encouraged to lose weight by low-calorie diet. We assessed uptake of bariatric surgery; weight lost during progestin treatment; and the impact of more than 10% total body weight loss on progestin treatment response at 12 months. 71 women [median age 58 years (interquartile range; IQR 35-65); mean BMI 48 kg/m2 (SD 9.3)] completed the study. Twenty-three women (32%) had bariatric surgery, on average 5 months (IQR 3-8) after progestin treatment commenced. Weight change during progestin treatment was -33.4 kg [95% confidence interval (CI) -42.1, -24.7] and -4.6 kg (95% CI -7.8, -1.4) in women receiving bariatric surgery and low-calorie diet, respectively (P < 0.001). Forty-three women (61%) responded to progestin, while 23 (32%) showed stabilized and 5 (7%) progressive disease. Response at 12 months was not predicted by age or baseline BMI, but women who lost more than 10% of their total body weight were more likely to respond to progestin than those who did not (adjusted odds ratio 3.95; 95% CI 1.3, 12.5; P = 0.02). Thus weight loss may improve oncological outcomes in women with obesity-associated endometrial neoplastic abnormalities treated with progestin. PREVENTION RELEVANCE: This study found that weight loss improves response rates in women with obesity and atypical hyperplasia or low-risk endometrial cancer undergoing conservative management with intrauterine progestin. Given the additional benefits of weight loss for fertility, cardiovascular health and quality of life, future research should focus on how best to accomplish it.

Detecting Endometrial Cancer by Blood Spectroscopy: A Diagnostic Cross-Sectional Study.

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.

Impact of surgical site infection (SSI) following gynaecological cancer surgery in the UK: a trainee-led multicentre audit and service evaluation.

OBJECTIVES: Surgical site infection (SSI) complicates 5% of all surgical procedures in the UK and is a major cause of postoperative morbidity and a substantial drain on healthcare resources. Little is known about the incidence of SSI and its consequences in women undergoing surgery for gynaecological cancer. Our aim was to perform the first national audit of SSI following gynaecological cancer surgery through the establishment of a UK-wide trainee-led research network. DESIGN AND SETTING: In a prospective audit, we collected data from all women undergoing laparotomy for suspected gynaecological cancer at 12 specialist oncology centres in the UK during an 8-week period in 2015. Clinicopathological data were collected, and wound complications and their sequelae were recorded during the 30 days following surgery. RESULTS: In total, 339 women underwent laparotomy for suspected gynaecological cancer during the study period. A clinical diagnosis of SSI was made in 54 (16%) women. 33% (18/54) of women with SSI had prolonged hospital stays, and 11/37 (29%) had their adjuvant treatment delayed or cancelled. Multivariate analysis found body mass index (BMI) was the strongest risk factor for SSI (OR 1.08[95% CI 1.03 to 1.14] per 1 kg/m2 increase in BMI [p=0.001]). Wound drains (OR 2.92[95% CI 1.41 to 6.04], p=0.004) and staple closure (OR 3.13[95% CI 1.50 to 6.56], p=0.002) were also associated with increased risk of SSI. CONCLUSIONS: SSI is common in women undergoing surgery for gynaecological cancer leading to delays in discharge and adjuvant treatment. Resultant delays in adjuvant treatment may impact cancer-specific survival rates. Modifiable factors, such as choice of wound closure material, offer opportunities for reducing SSI and reducing morbidity in these women. There is a clear need for new trials in SSI prevention in this patient group; our trainee-led initiative provides a platform for their successful completion.