Weight loss interventions for endometrial cancer prevention—is a clinical trial possible?

It is well established that obesity and endometrial cancer are strongly linked, with robust data from observational (1), Mendelian randomisation (2), and mechanistic studies (3) demonstrating a causal relationship. Indeed, obesity has the strongest link with endometrial cancer of the 20 most common tumour types (4) and is directly causative in up to 50% of endometrial cancer cases in high socio-economic index nations (5). The rising global prevalence of obesity is instrumental to the growing burden of endometrial cancer cases worldwide, alongside the growth and ageing of populations, and this trend is set to continue well into the next decade (6). Escalating obesity rates also appear to be driving a surge in endometrial cancer rates among younger, premenopausal women, many of whom are yet to complete their family and risk permanent infertility from standard of care surgery (7,8). Weight loss as an endometrial cancer prevention strategy is therefore appealing, but a number of unanswered questions remain, including when and how to intervene, as well as the target population most likely to benefit from such an approach. Heo et al. aimed to begin addressing some of these issues in their retrospective cohort study conducted using data from the Korean National Health Information Database and recently published in Cancer Epidemiology, Biomarkers and Prevention (9). Using a Cox proportional hazard model, the authors examined the effect of dichotomised weight change between obesity states over a 3-year period on early-onset endometrial cancer risk, noting that persistent obesity was associated with greatest endometrial cancer risk after adjusting for many, although not all, established risk factors [adjusted hazard ratio (aHR) 3.559, 95% confidence interval (CI): 3.015–4.200 to 4.394, 95% CI: 3.557–5.427] Contrary to expectation, however, the authors also found an increase in early-onset endometrial cancer amongst individuals who lost weight over the 3-year period, with individuals moving from an obese to non-obese state having a greater, although not statistically significantly different, endometrial cancer risk compared with those who gained weight (aHR 2.302, 95% CI: 1.684–3.146 compared with aHR 2.048, 95% CI: 1.581–2.651 for individuals in non-obese to obese group). Despite these findings, the authors emphasise the importance of addressing abdominal obesity as a preventative strategy for early-onset endometrial cancer. The question their study begs is, how close are we to conducting a clinical trial of weight loss interventions for primary endometrial cancer prevention?

How should we determine eligibility for a future endometrial cancer prevention trial?

Although the evidence supporting the causal link between obesity and endometrial cancer cannot be disputed, not all individuals with a uterus living with obesity develop endometrial cancer. The lifetime risk of endometrial cancer for an individual with a body mass index (BMI) ≥40 kg/m² is approximately 10%, suggesting that BMI is an inadequate predictor of future disease risk, and obesity alone may be insufficient to drive endometrial carcinogenesis. This is reflected in our PRECISION endometrial cancer risk prediction model, which includes and strongly emphasises BMI, but also incorporates waist circumference, diabetes, hormone and drug exposure, reproductive and genetic variables as independent predictors of 10-year endometrial cancer risk (10). There is debate as to whether obesity in early adulthood (variably defined but often referring to measured BMI between 18–25 years of age) is a greater predictor of subsequent endometrial cancer risk than adult BMI (1). The E2C2 (Epidemiology of Endometrial Cancer Consortium) pooled analysis of 20 studies demonstrated a significantly increased risk of endometrial cancer for individuals who have overweight or obesity in early adulthood, after adjustment for adult BMI and other endometrial cancer risk factors, but noted that endometrial cancer risk was significantly higher for those individuals with obesity in later adulthood and who gained weight over their lifetime [obese young adulthood: adjusted odds ratio (aOR) 1.26, 95% CI: 1.06–1.50, obese adulthood: aOR 2.85, 95% CI: 2.47–3.29, maintain/gain to obese: aOR 2.98, 95% CI: 2.57–3.45] (11). Whilst obesity in early adulthood appears to be predominantly a risk factor for pre/perimenopausal endometrial cancer in the study by Heo et al., they only evaluated obesity status and weight change over a 3-year period, meaning that they were unable to assess the impact of longer-term cumulative exposure to obesity on endometrial carcinogenesis. Prolonged exposure to obesity is likely to have the greatest impact on endometrial cancer risk, suggesting that there is no ’safe’ period of obesity and that it is never too early to intervene to promote weight loss.

As a single measurement, BMI fails to fully describe endometrial cancer risk, leading some researchers to assess whether the distribution of adiposity is more informative. Central adiposity, most frequently assessed through easy-to-perform waist circumference measurements, appears to be a BMI-independent predictor of endometrial cancer risk (1,12). In the study by Heo et al., abdominal obesity was a stronger predictor of premenopausal endometrial cancer than generalised adiposity, likely due to the association between central adiposity and metabolic dysfunction, particularly insulin resistance (13-15). The concept of ‘good’ and ‘bad’ obesity has been proposed by others, and it may be that we need to be more nuanced in our assessment of adiposity if we are to use it to stratify individuals according to their endometrial cancer risk for targeted intervention. This could include combining measures of absolute weight, distribution of adiposity and duration of obesity exposure with measures of insulin resistance when determining eligibility for a future clinical trial.

Can we expect a weight loss intervention to be a universal endometrial cancer prevention strategy?

Many of the observational and Mendelian randomisation studies that have explored the impact of obesity on endometrial cancer risk have used epidemiological and genetic data from North American and Northern European cohorts with limited ethnic diversity. The study by Heo et al. is one of the few conducted in an Asian population and confirms that obesity is an important endometrial cancer risk factor in this group, with odds ratios similar to those previously described in more Western-focussed studies. It is vital that endometrial cancer risk factors and preventative interventions are studied at a global level, particularly as rates of the disease are rising fastest amongst individuals from high-middle socioeconomic index nations in Asia Pacific, North Africa and the Middle East, the same populations who have been underrepresented in previous studies. Whilst similar factors may increase endometrial cancer risk in different populations, the individual importance of each may vary and thresholds for intervention may need to be adjusted depending upon baseline risk. The study by Heo et al. importantly uses WHO Asia Pacific BMI thresholds (BMI ≥25 kg/m², waist circumference ≥85 cm) to define the presence of obesity. This distinction is required as individuals of Asian ethnicity have higher rates of metabolic dysfunction and insulin resistance at lower BMI thresholds (16). The risk of endometrial cancer within Asian populations has been found to increase from a BMI of 23 kg/m², which would be considered a ‘normal’ BMI in European and North American populations (17). Much smaller increases in BMI over an individual’s lifetime also appear to negatively impact on endometrial cancer risk in Asian populations. Analysis of data from the Multi Ethnic Cohort study showed that a 5% increase in BMI from age 21 years to late middle age resulted in a two-fold rise in the risk of endometrial cancer in Japanese Americans but that a 35% increase in BMI was required for a similar increase in endometrial cancer risk to be observed for White, Latina and African American individuals (18). Endometrial cancer risk prediction models, therefore, need to be validated separately in geographically and ethnically diverse populations and may need re-calibrating or their coefficients amended to ensure that they accurately identify individuals for targeted intervention in these different settings. The higher prevalence of metabolic syndrome in Asian populations also raises the question as to whether strategies that aim to improve the metabolic profile of individuals may be more effective in reducing endometrial cancer risk in this group than those aimed at lowering BMI alone. Greater consideration of ethnic diversity is critical if existing disparities in endometrial cancer incidence and outcomes are to be tackled.

The rapid introduction of molecular classification of endometrial cancer into routine clinical care is a testament to its predictive and prognostic value. Whilst multiple groups have demonstrated variation in survival between individuals with POLE-mutant, MMR (mismatch repair) deficient and p53 abnormal tumours and molecular classification is increasingly used to safely personalise adjuvant treatment decisions, little is known about the risk factors that predispose to a particular subtype of endometrial cancer and, therefore, how to intervene to reduce risk (19-22). Unfortunately, many of the cohort studies conducted, including that by Heo et al., have relied on data from national registries for the determination of outcomes, which lack detail on specific endometrial cancer sub-groups. The E2C2 consortium was able to compare the effect of young and later adulthood BMI on endometrioid and non-endometrioid endometrial cancer, finding a similarly positive association between obesity and both histological subtypes, but acknowledged that in the era of increasing personalisation of endometrial cancer care, this distinction between historical dichotomised groups is inadequate (11). Future epidemiological studies need to explore the specific risk factor profiles of individuals with each of the four molecular subgroups of endometrial cancer and all cohort studies should strive to collect data on POLE, MMR and p53 status as a minimum to inform both prospective and updated retrospective analyses. This is a necessary step in determining whether weight loss interventions could be used to prevent all subtypes of endometrial cancer or if a clinical trial will focus on the prevention of tumours with no specific molecular profile as its primary outcome.

What are the options for a weight loss intervention for primary endometrial cancer prevention?

Given that endometrial cancer and obesity are so closely entwined, it seems logical to explore weight loss for endometrial cancer prevention as well as treatment (8,23). Much of the available data on the benefits of weight loss is derived from cohorts of individuals undergoing bariatric surgery, with meta-analyses demonstrating a 48–62% lower risk of endometrial cancer for those undergoing surgical weight loss procedures compared with individuals with obesity who did not lose weight (24,25). Importantly, though, bariatric surgery appears to be associated with a reduction in endometrial cancer risk even in individuals who have persistent obesity following the procedure [relative risk (RR) 0.48, 95% CI: 0.43–0.55] (26). The beneficial effect of bypass and restrictive gastric procedures on endometrial proliferation and phosphorylated markers of key carcinogenic pathways appears to occur before maximal weight loss is achieved, supporting the hypothesis that rapid improvements in insulin sensitivity may be driving at least some of the endometrial cancer risk reduction (27). Whilst bariatric surgery is the most effective way to achieve sustained weight-loss, it is not without potential side effects, including surgical morbidity, and is not accessible or appealing to all. Intentional weight loss through lifestyle intervention appears to have a similar beneficial effect on endometrial cancer risk, though of a smaller magnitude to surgically induced weight loss (28). Individuals in the Women’s Health Initiative (WHI) study with obesity who lost ≥5% of their body weight over a 3-year period had the greatest reduction in endometrial cancer risk (HR 0.44, 95% CI: 0.25–0.78) but, interestingly, even individuals with a BMI within the normal range (18.5 to <25 kg/m²) also experienced a non-significant reduction in disease risk (HR 0.61, 95% CI: 0.27–1.38). Whilst there is much interest currently in glucagon-like peptide-1 receptor agonists (GLP-1RAs) and their role in the treatment and prevention of obesity-related diseases, the evidence for an impact of this class of drug on endometrial cancer risk is lacking (29,30). Possible explanations include the limited length of drug use and follow-up in these studies, the lower risk phenotype of study participants, as well as methodological issues related to the risk of selection and survival bias in non-randomised studies.

With all of this observational data supporting the concept of weight loss as an endometrial cancer prevention strategy, it is surprising that obese individuals who lost weight in the study by Heo et al. continued to have an elevated risk of endometrial cancer (9). Reverse causation and unintended weight loss are unlikely to have contributed significantly to this, given that the authors excluded diagnoses made within 1 year of study recruitment and it is assumed that the majority of individuals will have been diagnosed with early-stage disease. It is possible that the magnitude of weight loss observed was insufficient to impact upon metabolic dysfunction, a notable driver of endometrial carcinogenesis in this population. This finding may also be a statistical anomaly related to the choice of reference group used for comparison within an observational study.

The study by Heo et al. used the normal, stable weight group as their reference point and, therefore, it is not surprising that individuals with obesity at any point in their lifetime were at elevated risk of endometrial cancer by comparison. By focusing on individuals with the lowest risk of endometrial cancer rather than those with stable obesity as the high-risk comparator, the potential impact of weight loss, as demonstrated in the bariatric surgery studies, may have been lost. Any future trial of weight loss as an endometrial cancer prevention strategy will need to be targeted at individuals with the greatest disease risk in order to ensure a time- and cost-efficient study design (3,10).

What are the challenges of conducting cancer prevention trials?

Conducting a weight loss trial for primary endometrial cancer prevention is likely to be extremely challenging. Using cancer incidence as a primary outcome measure would mean that the number of participants and length of follow-up are likely to be too expensive for funders to contemplate. Consistent access to weight loss drugs and surgery can also not be guaranteed, certainly based on our experience within the UK National Health Service, risking poor recruitment and trial protocol violations. Lifestyle interventions and GLP-1RAs, whilst effective in inducing weight loss in individuals while on treatment, can lead to weight cycling when therapy is withdrawn, which is potentially more detrimental to endometrial cancer risk than maintaining a stable, even elevated, weight (31). The amount of weight that needs to be lost to impact on endometrial cancer risk also remains unknown. Whilst the WHI study suggested that 5% body weight loss may be sufficient, others have found that 20 lbs/9 kg or a change in BMI category is required for an effect on cancer risk to be observed (9,28,31). Establishing the target weight loss that needs to be achieved is essential to the design of a future weight loss cancer prevention trial and may be possible through combined secondary analysis of some of the large GLP-1RA trials that have been conducted over the last decade, albeit with the caveat that maintenance of the weight loss beyond the 1–2 years of drug treatment is unlikely to be known. Rather than relying on endometrial (pre)cancer incidence as the primary outcome, surrogate biomarkers of future endometrial cancer risk may also offer a more practical alternative. The WID-EC test quantifies endometrial cancer risk by analysing the methylation status of 500 CpGs using DNA extracted from a vaginal swab and was found to correctly identify individuals who subsequently developed endometrial cancer with an accuracy of 77–89% in a small validation study (32). Importantly, the WID-EC test has a similar performance in clinician- and self-taken swabs, the latter potentially a more acceptable option, particularly if repeated testing is required. Further prospective validation of the WID-EC test in larger and more ethnically diverse populations is required, though, before it can be used in a future endometrial cancer prevention trial.

Conclusions

Obesity, particularly abdominal obesity, at any stage of life, is a significant endometrial cancer risk factor and weight management should be a key priority for all health services and governments. Individuals at greatest endometrial cancer risk may well benefit most from a targeted weight loss intervention, but there remain a number of unanswered questions as to what this intervention should look like and who to offer it to. A primary endometrial cancer prevention trial remains the hope for all affected by or caring for individuals with endometrial cancer; we just need to decide how best to go about it.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Cancer Epidemiology. The article has undergone external peer review.

Peer Review File: Available at https://ace.amegroups.com/article/view/10.21037/ace-2026-1-0014/prf

Funding: This work was supported by This work was supported by a National Institute for Health and Care Research (NIHR) Research Professorship (No. NIHR304303 to S.J.K. and E.J.D.) and the NIHR Manchester Biomedical Research Centre (No. NIHR203308 to S.J.K. and E.J.D.); the recipient of a Rosetree Fellowship and The Eve Appeal/North-West Cancer Research Fund Fellowship (No. NWCREVE2025.01 to S.J.K.); Cancer Grand Challenges (No. CGCATF-2021/100007 to H.B.R.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ace.amegroups.com/article/view/10.21037/ace-2026-1-0014/coif). H.B.R. received grants from Cancer Grand Challenges and British Gynaecological Cancer Society. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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