Metabolic health also factors in obesity-related cancer risk in postmenopausal women

New research suggests that metabolic health, not just weight, plays a significant role in the development of obesity-related cancers in postmenopausal women.

In a large cohort of postmenopausal women from the US, the risk of any obesity-related cancers was elevated even in those who had normal weight but were metabolically unhealthy, being 12 percent higher when compared with normal-weight women who were metabolically healthy (control) (hazard ratio [HR], 1.12, 95 percent confidence interval [CI], 0.90–1.39). [Clin Cancer Res 2025;18:63-72]

The risk was highest among women who had overweight or obesity and were metabolically unhealthy—a 35-percent increase relative to controls (HR, 1.35, 95 percent CI, 1.18–1.54). Meanwhile, the risk increased by 15 percent among those who had overweight or obesity but were metabolically healthy (HR, 1.15, 95 percent CI, 1.00–1.32).

Metabolic health was defined according to the Wildman criteria, and the results were consistent across analyses using different definitions of metabolic phenotype (ie, Adult Treatment Panel III criteria, high-sensitivity C-reactive protein [hs-CRP] alone, or HOMA-IR alone).

Overall, the findings suggest that a combined approach of using both obesity metrics and metabolic health measures could inform obesity-related cancer risk stratification, the investigators said.

“Mechanisms dysregulated in obesity that are relevant to the development of cancer include insulin resistance, dyslipidaemia, inflammation, oxidative stress, gut microbiome dysbiosis, and dysregulated hormone and adipokine metabolisms,” they said. “Among individuals with a BMI <25 kg/m², higher visceral adiposity or unhealthy expansion of adipose tissue and their associated metabolic sequelae may contribute to the ‘metabolically unhealthy normal weight’ phenotype, although this phenomenon remains understudied.” [Int J Mol Sci 2019;20:2358; Nat Rev Endocrinol 2020;16:731-739; Front Oncol 2020;10:615375; Nat Rev Gastroenterol Hepatol 2018;15:683-698]

Less-studied mechanisms such as alterations in adipose-derived extracellular vesicle signalling and the FGFR signalling network may also contribute to obesity-related metabolic dysregulation relevant to cancer aetiology, the investigators noted. Beyond BMI, genetic factors and environmental factors, including suboptimal dietary intake and physical inactivity, may influence the development of cancer-related metabolic dysfunction, they added. [Biochem Biophys Res Commun 2024;690:149242; Front Endocrinol 2023;14:1217875; BMJ Open Gastroenterol 2022;9:e000817; Nutr Rev 2016;74:558-570]

A total of 20,593 postmenopausal women (59.4 percent White) between 50 and 79 years of age (mean 64.1 years) who participated in the Women’s Health Initiative were included in the current analysis. More than 50 percent of the women had some college education, were married, and were nonsmokers. Most participants (90 percent) did not report alcohol intake, and 60 percent had a family history of cancer.

Of the women, 9,318 were in the metabolically unhealthy obese category, 6,425 were in the metabolically healthy obese, 1,345 were in the metabolically unhealthy normal weight, and 3,505 were in the metabolically heathy normal weight.

Mean baseline fasting glucose was 102.2 mg/dL, fasting insulin was 103.3 pmol/L, systolic blood pressure was 130.2 mm Hg, high-density lipoprotein cholesterol was 53.9 mg/dL, CRP was 5.0 mg/dL, and waist circumference was 89.8 mm.

Over a median follow-up of 21 years, a total of 2,367 incident cases of obesity-related cancers were documented, of which 60 percent were breast, 14 percent colorectal, 6 percent endometrial, 6 percent pancreatic, and 5 percent ovarian cancers.