Weight Gain with Metabolic Dysfunction is Associated with Obesity‐Related Cancer
Authors: Chadid Susan , Singer Martha R. , Kreger Bernard E. , Moore Lynn L. 
Published: November 2023

Excess body fat, diabetes, and metabolic syndrome are associated with the development of certain cancers. Weight gain during the middle‐adult years is linked with the development of metabolic dysfunction although not all individuals who gain weight develop these complications. The objective of this study was to examine prospectively the independent and combined effects of weight change and metabolic dysfunction on obesity‐related cancer risk. We used data for 3,850 45–69 year‐old individuals who were followed every four years in the Framingham Offspring Study. For each subject, weight (pounds) was regressed on age (years) starting at the baseline visit and ending (~12–20 years later) at the first exam at which they had complete data for fasting glucose and lipid levels (generally exam 3). The slope of weight change (per year) was used to classify each subject as gaining ≥ 1lb/year over 12–20 years, losing ≥ 1lb/year, or remaining weight stable (neither gaining nor losing ≥ 1lb/year per year). Since the risk of obesity‐related cancer may be linked with the duration and intensity of chronic inflammation, long‐term weight gain during the middle‐adult years may better capture the risk of adiposity on obesity‐related cancers. Thus, in a second analysis, we classified subjects into one of three groups based on weight status over the 12–20 year exposure period: those who were of normal weight throughout (including those who lost weight), those who were overweight/obese at baseline and remained so, and those who were of normal weight at baseline and became overweight/obese. Subjects with metabolic dysfunction (MetDys) were those identified with impaired fasting glucose/diabetes, dyslipidemia (elevated serum triglycerides or low HDL‐cholesterol), or hypertension. MetDys for each subject was classified as having 2 or more (vs. 0 or 1) metabolic abnormalities prior to the start of follow up for incident cancer. Primary obesity‐related cancers included postmenopausal breast, endometrial, and colorectal cancers. Cox proportional hazards were used to evaluate the effect of weight change with and without MetDys, adjusting for potential confounding by sex, age, height, education, smoking, alcohol intake, and physical activity. Subjects gaining ≥ 1lb/year had statistically significant increases in obesity‐related cancer risk: HR=1.8 (95%CI: 1.2–2.6) and HR=1.3 (95%CI: 1.0–1.7) for those with and without concurrent MetDys, respectively. Those with stable weights (or who lost weight), regardless of prevalent MetDys, had no increased cancer risk. Compared with the referent group (normal weight with one or fewer metabolic abnormalities), subjects who became obese during the middle‐adult years and whose weight gain was accompanied by greater MetDys had a two‐fold increased risk of developing obesity‐related cancer (HR=2.1; 95%CI: 1.2–3.6); weight gain not accompanied by MetDys still led to a 70% increase risk of cancer (HR=1.7; 95%CI: 1.3–2.4). Normal‐weight subjects with MetDys also a 60% increased risk (HR=1.6; 95%CI: 1.1–2.4) of developing an obesity‐related cancer. This study demonstrates that individuals who gain weight during the middle‐adult years, especially when their weight gain is accompanied by metabolic dysfunction, are at much higher risk for developing an obesity‐related cancer.Support or Funding InformationNHLBI, Framingham Heart Study, (NHLBI/NIH Contract #N01‐HC‐25195) and the Boston University School of Medicine