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. 2025 Feb 3;18(2):63-72.
doi: 10.1158/1940-6207.CAPR-24-0082.

Metabolic Phenotype and Risk of Obesity-Related Cancers in the Women's Health Initiative

Prasoona Karra  1   2   3 , Sheetal Hardikar  1   2   4 , Maci Winn  2   4 , Garnet L Anderson  5 , Benjamin Haaland  2   4 , Aladdin H Shadyab  6 , Marian L Neuhouser  5 , Rebecca A Seguin-Fowler  7 , Cynthia A Thomson  8 , Mace Coday  9 , Jean Wactawski-Wende  10 , Marcia L Stefanick  11 , Xiaochen Zhang  12 , Ting-Yuan David Cheng  12 , Shama Karanth  13 , Yangbo Sun  9 , Nazmus Saquib  14 , Margaret S Pichardo  15 , Su Yon Jung  16 , Fred K Tabung  12 , Scott A Summers  1 , William L Holland  1 , Thunder Jalili  1 , Marc J Gunter  17   18 , Mary C Playdon  1   2   4
Affiliations

Metabolic Phenotype and Risk of Obesity-Related Cancers in the Women's Health Initiative

Prasoona Karra et al. Cancer Prev Res (Phila). .

Abstract

Body mass index (BMI) may misclassify obesity-related cancer (ORC) risk, as metabolic dysfunction can occur across BMI levels. We hypothesized that metabolic dysfunction at any BMI increases ORC risk compared with normal BMI without metabolic dysfunction. Postmenopausal women (n = 20,593) in the Women's Health Initiative with baseline metabolic dysfunction biomarkers [blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, fasting glucose, homeostatic model assessment for insulin resistance (HOMA-IR), and high-sensitive C-reactive protein (hs-CRP)] were included. Metabolic phenotype (metabolically healthy normal weight, metabolically unhealthy normal weight, metabolically healthy overweight/obese, and metabolically unhealthy overweight/obese) was classified using four definitions of metabolic dysfunction: (i) Wildman criteria, (ii) National Cholesterol Education Program Adult Treatment Panel III, (iii) HOMA-IR, and (iv) hs-CRP. Multivariable Cox proportional hazards regression, with death as a competing risk, was used to assess the association between metabolic phenotype and ORC risk. After a median (IQR) follow-up duration of 21 (IQR, 15-22) years, 2,367 women developed an ORC. The risk of any ORC was elevated among metabolically unhealthy normal weight (HR = 1.12, 95% CI, 0.90-1.39), metabolically healthy overweight/obese (HR = 1.15, 95% CI, 1.00-1.32), and metabolically unhealthy overweight/obese (HR = 1.35, 95% CI, 1.18-1.54) individuals compared with metabolically healthy normal weight individuals using Wildman criteria. The results were similar using Adult Treatment Panel III criteria, hs-CRP alone, or HOMA-IR alone to define metabolic phenotype. Individuals with overweight or obesity with or without metabolic dysfunction were at higher risk of ORCs compared with metabolically healthy normal weight individuals. The magnitude of risk was greater among those with metabolic dysfunction, although the CIs of each category overlapped. Prevention Relevance: Recognizing metabolic dysfunction as a significant risk factor for ORCs underscores the importance of preventive measures targeting metabolic health improvement across all BMI categories.

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Conflict of interest statement

Conflict of Interest statement: The authors do not report any conflict of interest.

Figures

Figure 1.
Figure 1.
Hazard ratios and 95% confidence intervals for the association of metabolic phenotype defined by the Wildman criteria with obesity-related cancer risk among postmenopausal women in the Women’s Health Initiative. Model adjusted for demographics (age, education, race/ethnicity, marital status), lifestyle (smoking status, physical activity, alcohol use, fruits and vegetable intake, fiber intake, read meat intake), hormonal factors for female cancers (parity, hormone therapy use), family history of ORC and study ID. MUNW=metabolically unhealthy normal weight; MHO=metabolically healthy overweight/obese; MUO= metabolically unhealthy overweight/obese. Metabolically healthy normal weight (MHNW) is the comparison group.
Figure 2.
Figure 2.
Hazard ratios and 95% confidence intervals for the association of metabolic phenotype defined by ATP III criteria with obesity-related cancer risk among postmenopausal women in the Women’s Health Initiative. Model adjusted for demographics (age, education, race/ethnicity, marital status), lifestyle (smoking status, physical activity, alcohol use, fruits and vegetable intake, fiber intake, read meat intake), hormonal factors for female cancers (parity, hormone therapy use), family history of ORC and study ID. MUNW=metabolically unhealthy normal weight; MHO=metabolically healthy overweight/obese; MUO= metabolically unhealthy overweight/obese. Metabolically healthy normal weight (MHNW) is the comparison group.
Figure 3.
Figure 3.
Hazard ratios and 95% confidence intervals for the association of metabolic phenotype defined by C-Reactive Protein (hs-CRP) (A) ≥ 3 mg/L, (B) ≥ 10 mg/L with obesity-related cancer risk among postmenopausal women in the Women’s Health Initiative. Model adjusted for demographics (age, education, race/ethnicity, marital status), lifestyle (smoking status, physical activity, alcohol use, fruits and vegetable intake, fiber intake, read meat intake), hormonal factors for female cancers (parity, hormone therapy use), family history of ORC and study ID. MUNW=metabolically unhealthy normal weight; MHO=metabolically healthy overweight/obese; MUO= metabolically unhealthy overweight/obese. Metabolically healthy normal weight (MHNW) is the comparison group.
Figure 4.
Figure 4.
Hazard ratios and 95% confidence intervals for the association of metabolic phenotype defined by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) with obesity-related cancer risk among postmenopausal women in the Women’s Health Initiative. Model adjusted for demographics (age, education, race/ethnicity, marital status), lifestyle (smoking status, physical activity, alcohol use, fruits and vegetable intake, fiber intake, read meat intake), hormonal factors for female cancers (parity, hormone therapy use), family history of ORC and study ID. MUNW=metabolically unhealthy normal weight; MHO=metabolically healthy overweight/obese; MUO= metabolically unhealthy overweight/obese. Metabolically healthy normal weight (MHNW) is the comparison group.
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