Identifying High-Risk Women for Endometrial Cancer …

1 ReviewIdentifying High-Risk Women for EndometrialCancer prevention Strategies: Proposal of anEndometrial Cancer Risk Prediction ModelSarah J. Kitson1,2, D. Gareth Evans3, and Emma J. Crosbie1,2 AbstractAlready the fourth most common Cancer in Women in thedeveloped world, the incidence of Endometrial Cancer isincreasing rapidly, in line with the increasing prevalence ofobesity. Relatively few studies have been undertaken of risk-reducing interventions aimed at limiting the impact of thedisease on both individuals and the health service. Those thathave been performed have demonstrated only modest resultsdue to their application in relatively unselected populations.

2 Avalidated risk prediction model is therefore urgently required toidentify individuals at particularly high risk of endometrialcancer who may benefit from targeted primary preventionstrategies and to guide trial eligibility. On the basis of asystematic review of the literature, the evidence for inclusionof measures of obesity, reproduction, insulin resistance, andgenetic risk in such a model is discussed, and the strength ofassociation between these risk factors and Endometrial Cancer isused to guide the development of a pragmatic risk predictionscoring system that could be implemented in the generalpopulation.

3 Provisional cutoff values are described pendingrefinement of the model and external validation in largeprospective cohorts. Potential risk-reducing interventions aresuggested, highlighting the need for future studies in this area ifthe increasing tide of Endometrial Cancer is to be Prev Res; 10(1); 1 13. 2016 Cancer is the fourth most common Cancer inwomen in the United Kingdom, with more than 9,000 newdiagnoses made in 2013 (1). The incidence is increasing not onlyin the developed world, where case numbers have more thandoubled in the last 20 years but is also expected to increase inlower income countries as the global burden of obesity worsens(2).

4 Given the current trajectory, it is predicted that by 2030, therewill be an additional 3,700 new cases of Endometrial cancerdiagnosed each year in the United Kingdom (Fig. 1; , 4).In line with this, mortality rates are also increasing, albeit to alesserextent,withafurther850endometrial cancerdeathsperyearanticipated in England and Wales alone by 2030 (3). Whileendometrial Cancer usually presents early, the morbidityassociated with treatment, particularly in an increasingly elderlypopulation, is not insignificant and disease recurrence, despiteadjuvant treatment, continues to be a problem.

5 Intervention isurgently required to stem this increasing tide of endometrialcancer if the effects, both for individual patients and for the healthservice, are not to become the incidence of Endometrial Cancer requires theintroduction of risk-reducing measures used selectively in thoseat greatest disease risk and targeted at key mechanisms drivingendometrial carcinogenesis. Previously studied interventionshave often been found to have only a modest effect on diseaserisk, mainly due to their application in relatively unselectedpopulations with the result that more pronounced benefits forspecific subgroups may be diluted (Table 1).

6 This highlights theimportance of developing better risk prediction models toidentify specific patient groups in whom these candidaterisk-reducing interventions can be trialed to maximize theirpotential , we propose a pragmatic risk prediction model to stratifythe general female population into low-, medium-, and high-riskgroups for endometrioid Endometrial Cancer , the most commonhistologic subtype (75% of all Endometrial cancers; ref. 5) and forwhichthereisthegreatestunderstandingo funderlyingriskfactorsand potential carcinogenic mechanisms. Given that the numberof cases peaks when Women are in their mid to late 60s, such amodel would be aimed at Women aged 45 55 years with an intactuterus, allowing sufficient time for any benefit from prophylaxisto be realized.

7 Experimental and epidemiologic evidence will beused to argue for the inclusion of measures of obesity (obesityscore), unopposed estrogen exposure (reproductive risk score),insulin resistance (insulin resistance risk score), and family his-tory (genetic risk score) to identify individuals at greatest risk andwill include protective factors which may negate these risks. Therationale for using specific risk-reducing measures in subgroupsbased on their predominant Endometrial Cancer risk factor willalso be of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicineand Health, University of Manchester, St Mary's Hospital, Manchester, of Obstetrics and Gynaecology, Central ManchesterUniversity Hospitals NHS Foundation Trust, Manchester Academic Health Sci-ence Centre, Manchester, United for Genomic Medicine,Division of Evolution and Genomic Medicine, University of Manchester, St Mary'sHospital.

8 Central Manchester University Hospitals NHS Foundation Trust, Man-chester Academic Health Science Centre, Manchester, United Author:Emma J. Crosbie, University of Manchester, 5th Floor Research, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UnitedKingdom. Phone: 0161-701-6942; Fax: 0161-701-6919; 2016 American Association for Cancer on March 17, 2021. 2017 American Association for Downloaded from Published OnlineFirst December 13, 2016; DOI: There are 2 limitations to this approach, which must be appre-ciated at the outset. While such a model is likely to have maximalimpact on disease burden, it may not significantly reduce endo-metrial Cancer mortality, as non-endometrioid tumors are morebiologically aggressive and associated with poorer prognosis.

9 Thesecond point is that it may fail to protect Women with undiag-nosed Lynch syndrome in whom Endometrial Cancer often pre-sents at an earlier age (<45 years); however, the model is designedto target the general population rather than those at a particularlyhigh genetic risk of the disease (6).Obesity ScoreAny risk prediction model for Endometrial Cancer will becentered on measures of excess adiposity. It is estimated that upto 41% of Endometrial Cancer cases are directly attributable towomenbeingoverweight orobese andendometrialcancerhasthestrongest link with obesity of the 20 most common tumor types(6, 7).

10 Several underlying mechanisms linking excess adiposityand Endometrial Cancer have been described; excess estrogenproduction, insulin resistance, and inflammation (Fig. 2). Eachis discussed further in the relevant measures of obesity exist, but the most commonlyused, cheapest and easiest to apply in a clinic setting is bodymass index (BMI), calculated using the formula weight (kg)/height (m) of prospective observational studies have shownthat a 5 kg/m2increase in BMI is associated with a 60% increase inthe relative risk of developing Endometrial Cancer (6,8).