This review synthesizes emerging evidence on modifiable risk factors for endometrial cancer (EC)—the sixth most common female malignancy globally—with rising incidence despite diagnostic advances. Obesity drives ~60% of preventable cases, positioning diet and lifestyle as critical prevention targets. This work evaluates current evidence, unresolved controversies, and pathways toward personalized prevention frameworks.
Introduction
EC incidence increased 1.5% annually post-2010, notably among premenopausal women in developed nations. Obesity underlies 40–60% of preventable cases, establishing diet and physical activity as pivotal modifiable factors. The review maps evidence from 2014–2024 to clarify EC prevention mechanisms and address population-specific variability.
Dietary Patterns: Evidence and Controversies
Mediterranean Diet: Associated with 13% EC risk reduction (high fruit/vegetable/whole grain intake; anti-inflammatory effects), but efficacy varies by BMI, ethnicity, and socioeconomic status.
Ketogenic Diet (KD): Improves insulin sensitivity and weight management (key for EC prevention) but risks nutritional imbalance and hepatic/renal toxicity.
Diabetes Risk Reduction Diet (DRRD): High-fiber, low-sugar patterns reduce EC risk, though less effective in older, obese, or non-white subgroups.
Soy Isoflavones: Show dual effects—protective in Asian populations with high dietary intake but potentially harmful in hormone-sensitive subgroups or cancer survivors.
Key Debate: Whether diet impacts EC directly or indirectly via BMI mediation (e.g., BMI explains 84–93% of diet-EC associations in cohort studies). Regional variations (e.g., Asia vs. West) necessitate population-specific guidelines.
Lifestyle Factors Beyond Diet
Physical Activity: 7.5–15 MET-hours/week reduces EC risk by improving insulin sensitivity and reducing inflammation. Sedentary behavior increases risk by 28–30%.
Smoking: Paradoxically lowers EC risk (anti-estrogenic effects) but elevates all-cause mortality.
Alcohol: Low intake may lower risk in obese/insulin-resistant women; higher intake shows neutral effects.
Psychological Stress: Depression/anxiety correlate with poor prognosis, mediated by immune-endocrine disruption.
Hereditary (Lynch Syndrome [LS]) vs. Sporadic EC
LS Patients: Younger onset, lower BMI. Lifestyle changes show limited efficacy; aspirin (600 mg/day) reduces EC risk by 52% in MLH1 carriers after 2+ years.
Contraceptives:
Oral Contraceptives (OCs): 40–60% EC risk reduction, lasting 35+ years post-use. Caution in obese women (thromboembolism risk).
Levonorgestrel IUDs (LNG-IUS): Effective for obesity-driven EC but may alter cervical-endometrial microbiota (e.g., Prevotella increase).
Nutrient Debate: Reductionist vs. Holistic Approaches
Reductionist View: Focuses on single nutrients:
Omega-3 fatty acids show conflicting results (15–23% risk reduction vs. 9% increase with docosahexaenoic acid).
Selenium/vitamin C exhibit pro-/anti-tumor effects contingent on dose and context.
Holistic View: Emphasizes dietary patterns (e.g., Mediterranean/plant-based diets outperform isolated nutrients). Challenges include marketing influences and cultural dietary preferences.
Consensus: Hybrid approach—prioritize whole-diet patterns, then refine with nutrient-specific insights.
The "Dose-Effect" Paradox in Interventions
Low-intensity interventions (e.g., walking) often outperform high-intensity regimens due to better adherence and metabolic sustainability.
Obese women require higher exercise intensity (≥15 MET-hours/week) for significant EC risk reduction.
Self-reporting bias overestimates compliance; wearable devices improve data accuracy.
Toward Personalized Prevention
Metabolic Phenotyping: Targeting insulin resistance/inflammation. Example: Omega-3 benefits are pronounced in overweight women.
Genetic Stratification: LS patients need distinct strategies (e.g., aspirin prophylaxis over OCs).
Barriers:
Limited multi-omics cohorts (genomics/metabolomics).
Lack of validated biomarkers (e.g., inflammatory markers like IL-6).
Cost-effective screening tools for high-risk subgroups.
Clinical Integration: Digital health tools, culturally tailored interventions, and multidisciplinary teams (dietitians/oncologists) enable feasible, sustained prevention.
Limitations and Future Directions
Evidence Gaps: Heterogeneous methodologies, BMI confounding, self-reporting biases, and understudied populations (racial/age/genetic subgroups).
Priorities:
Large cohorts integrating genomics/lifestyle data.
Culturally adapted interventions and digital health integration (apps/wearables).
Policy support for public education and inter-disciplinary collaboration.
Conclusions
Diet (Mediterranean/plant-based patterns) and lifestyle (activity/sedentary reduction) significantly lower EC risk, but efficacy is modulated by BMI, genetics, and sociocultural factors. Personalized prevention—stratified by metabolic phenotype, genetic risk (e.g., LS), and cultural context—is essential. Future work must bridge research-practice gaps through multi-omics, digital monitoring, and tailored public health strategies.
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The study was recently published in the Oncology Advances .
Oncology Advances is dedicated to improving the diagnosis and treatment of human malignancies, advancing the understanding of molecular mechanisms underlying oncogenesis, and promoting translation from bench to bedside of oncological sciences. The aim of Oncology Advances is to publish peer-reviewed, high-quality articles in all aspects of translational and clinical studies on human cancers, as well as cutting-edge preclinical and clinical research of novel cancer therapies.
