Sarah J. Kitson

Predicting risk of endometrial cancer in asymptomatic women (PRECISION): Model development and external validation

AbstractObjectivesDevelop an endometrial cancer risk prediction model and externally validate it for UK primary care use.DesignCohort study.SettingThe UK Biobank was used for model development and a linked primary (Clinical Practice Research Datalink, CPRD) and secondary care (HES), mortality (ONS) and cancer register (NRCAS) dataset was used for external validation.PopulationWomen aged 45–60 years with no history of endometrial cancer or hysterectomy.MethodsModel development was performed using a flexible parametric survival model and stepwise backward selection aiming to minimise the Akaike information criterion. Model performance on external validation was assessed through flexible calibration plots, calculation of the expected to observed ratio and C‐statistic and decision curve analysis.Main outcome measuresEndometrial cancer diagnosis within 1–10 years of the index date.ResultsModel development included 222 031 women (902 incident endometrial cancer cases) and external validation 3 094 371 women (8585 endometrial cancer cases). The final model (with equation provided) incorporated age, body mass index, waist circumference, age at menarche, menopause and last birth, hormone replacement, tamoxifen and oral contraceptive pill use, type 2 diabetes, smoking and family history of bowel cancer. It was well calibrated on external validation (calibration slope 1.14, 95% confidence interval [CI] 1.11–1.17, E/O 1.03, 95% CI 1.01–1.05), with moderate/good discrimination (C‐statistic 0.70, 95% CI 0.69–0.70) and had improved net benefit compared with previously developed models.ConclusionsThe Predicting risk of endometrial cancer in asymptomatic women model (PRECISION), using easily measurable anthropometric, reproductive, personal and family history, accurately quantifies a woman's 10‐year risk of endometrial cancer. Its use could determine eligibility for primary endometrial cancer prevention trials and for targeted resource allocation in UK general practices.

Lay and general practitioner attitudes towards endometrial cancer prevention: a cross-sectional study

Abstract Background Effective and targeted endometrial cancer prevention strategies could reduce diagnoses by 60%. Whether this approach is acceptable to individuals and general practitioners (GPs) is currently unknown. This study sought to determine attitudes towards the provision of personalised endometrial cancer risk assessments and the acceptability of potential prevention strategies. Methods Specific online questionnaires were developed for individuals aged 45–60 years with a uterus and UK-practising GPs, with social media, charity websites, and email used to advertise the study. Individuals completed the questionnaires between February and April 2022. Results Of 660 lay questionnaire respondents, 90.3% (n = 596) thought that undergoing an endometrial cancer risk assessment was a good or very good idea and 95.6% (n = 631) would be willing to undergo such an assessment. The commonest reasons for wanting to participate were “to try and reduce my risk” (n = 442, 67.0%), “to be informed” (n = 354, 53.6%), and “it could save my life’ (n = 315, 47.7%). Over 80% of respondents would make lifestyle changes to reduce their endometrial cancer risk (n = 550), with half accepting a pill, Mirena, or hysterectomy for primary prevention. GPs were similarly engaged, with 93.0% (n = 106) willing to offer an endometrial cancer risk assessment if a tool were available, potentially during a Well Woman screen. Conclusion Personalised endometrial cancer risk assessments are acceptable to potentially eligible individuals and GPs and could be accommodated within routine practice. Clinical trials to determine the effectiveness of lifestyle modification and Mirena for endometrial protection are urgently required and should be targeted at those at greatest disease risk.

Quantifying the Effect of Physical Activity on Endometrial Cancer Risk

Abstract Endometrial cancer incidence is rising, with 435,000 global cases in 2019. An effective, low-cost primary prevention strategy is required to reduce disease burden. Obesity, insulin resistance, and inflammation contribute to endometrial carcinogenesis and physical activity targets these pathways. This study sought to quantify the amount of physical activity required to impact upon endometrial cancer risk. Physical activity data from 222,031 female participants with an intact uterus in the UK Biobank study were analyzed using a multivariable Cox proportional hazards model. A systematic review of the literature was performed, searching CENTRAL, Embase, and MEDLINE databases up to April 19, 2021. Studies including participants with and without endometrial cancer investigating the effect of physical activity measured in MET-hours/week (MET-h/week) on disease risk were included. Two reviewers independently selected studies, extracted data, and evaluated the risk of bias. Within the UK Biobank, each 1 MET-h/week increase in total physical activity was associated with a 0.2% [95% confidence interval (CI), 0.1–0.4; P = 0.020] reduction in endometrial cancer risk, equating to a 10.4% reduction if performing 50 MET-h/week or 7 hours of jogging per week. Eleven cohort and 12 case–control studies were identified in the systematic review, including 821,599 participants. One study reported a nonsignificant effect of 1 MET-h/week increases in physical activity on endometrial cancer risk (OR, 1.00; 95% CI, 0.99–1.00). Eight studies found significant reductions in disease risk of 15%–53%, but only in the most physically active individuals. Physical activity reduces endometrial cancer risk, but the effect size appears small. Regular vigorous activity should be encouraged to maximize the health benefit observed. Prevention Relevance: Effective, low-cost primary prevention strategies are urgently needed to tackle the rapid global increase in endometrial cancer. We sought to quantify the effect of physical activity on endometrial cancer risk, noting a linear inverse relationship influenced by body mass index. The most beneficial type and amount of activity remain unclear.

BRCA1 and BRCA2 pathogenic variant carriers and endometrial cancer risk: A cohort study

An association between BRCA pathogenic variants and an increased endometrial cancer risk, specifically serous-like endometrial cancer, has been postulated but remains unproven, particularly for BRCA2 carriers. Mechanistic evidence is lacking, and any link may be related to tamoxifen exposure or testing bias. Hysterectomy during risk-reducing bilateral salpingo-oophorectomy is, therefore, of uncertain benefit. Data from a large, prospective cohort will be informative. Data on UK BRCA pathogenic variant carriers were interrogated for endometrial cancer diagnoses. Standardised incidence ratios (SIRs) were calculated in four distinct cohorts using national endometrial cancer rates; either from 1/1/1980 or age 20, prospectively from date of personal pathogenic variant report, date of family pathogenic variant report or date of risk-reducing salpingo-oophorectomy. Somatic BRCA sequencing of 15 serous endometrial cancers was performed to detect pathogenic variants. Fourteen cases of endometrial cancer were identified in 2609 women (1350 BRCA1 and 1259 BRCA2), of which two were prospectively diagnosed. No significant increase in either overall or serous-like endometrial cancer risk was identified in any of the cohorts examined (SIR = 1.70, 95% confidence interval = 0.74-3.33; no cases of serous endometrial cancer diagnosed). Results were unaffected by the BRCA gene affected, previous breast cancer or tamoxifen use. No BRCA pathogenic variants were detected in any of the serous endometrial cancers tested. Women with a BRCA pathogenic variant do not appear to have a significant increased risk of all-type or serous-like endometrial cancer compared with the general population. These data provide some reassurance that hysterectomy is unlikely to be of significant benefit if performed solely as a preventive measure.