伴有或不伴有心脏代谢危险因素的肥胖、生物标志物与新发肥胖相关癌症：女性健康研究

Obesity is an established risk factor for at least 13 types of cancers, yet the role of obesity-related cardiometabolic risk factors and biomarkers in mediating this relationship remains unclear. We classified 37,540 Women's Health Study participants as obese (body mass index [BMI]≥30 kg/m2) or non-obese and with or without any cardiometabolic risk factors (type 2 diabetes, high cholesterol, and hypertension), with status updated annually via questionnaire. Baseline blood biomarkers were measured in 27,210 women. We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risk of obesity-related cancers, adjusting for age, reproductive history, hormone therapy use, lifestyles, and cancer site-specific factors. The reference group in all models is women without obesity and without risk factors. Baseline mean age was 54.6 years, 19% of women had obesity, and ≥1 cardiometabolic risk factor was present in 65% of women who had obesity and 42% of those without obesity. We confirmed 4,895 incident obesity-related cancers over a median follow-up of 22 years. The obesity-related cancer risk was elevated among women with obesity without risk factors (HR=1.28; 95% CI=1.06,1.54) and with ≥1 risk factor (HR=1.42; 95% CI=1.29,1.56). Strongest association for obesity with risk factors was observed for endometrial cancer (585 cases; HR=3.58; 95% CI=2.70,4.76), followed by kidney (139 cases; HR=1.97; 95% CI=1.10,5.53), colorectal (626 cases; HR=1.69; 95% CI=1.27,2.25) and postmenopausal breast cancer (2,765 cases; HR=1.22; 95% CI=1.08,1.39); no association was observed for ovarian cancer (280 cases; HR=0.90; 95% CI=0.58,1.38). Obesity without risk factors was associated with an elevated risk of pancreatic (139 cases; HR=3.93; 95% CI=1.65,9.39) and endometrial cancer (HR=2.20; 95% CI=1.37,3.54). Higher obesity-related cancer risk was observed among women with obesity and elevated inflammation (C-reactive protein, soluble intercellular adhesion molecule-1, fibrinogen, and GlycA), glycemia (hemoglobin A1c), and dyslipidemia (ApoB/A1 ratio, cholesterol, high-density lipoprotein, low-density lipoprotein, and lipoprotein(a)) (HRs 1.15-1.38). Obesity with normal levels of inflammation, glycemia, and kidney function (creatinine and homocysteine) biomarkers was also related to a higher obesity-related cancer risk (HRs 1.08-1.38). In conclusion, obesity with and without cardiometabolic risk factors is positively associated with risk of several obesity-related cancers. Poor cardiometabolic health, glycemic and lipid metabolism, and inflammation may mediate obesity's association with cancer, although excess cancer risk persists among metabolically healthier women with obesity.