Association of metabolic obesity phenotypes with risk of overall and site-specific cancers: a systematic review and meta-analysis of cohort studies

Adiposity is a known risk factor for certain cancers; however, it is not clear whether the risk of cancer differs between individuals with high adiposity but different metabolic health status. The aim of this systematic literature review and meta-analysis of cohort studies was to evaluate associations between metabolic obesity phenotypes and overall and site-specific cancer risk. PubMed and Embase databases were used to identify relevant cohort studies up to the 6th of June 2023. Random-effects models were used to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs) for the association between metabolic obesity phenotypes and cancer risk. Certainty of evidence was assessed using the Cochrane methods and the GRADE tool. This study is registered with PROSPERO, number CRD42024549511. A total of 15,556 records were screened, and 31 publications covering 15 unique cohort studies were included in this analysis. Of these studies, 22 were evaluated as being at low risk of bias and 9 at moderate risk of bias. Compared to metabolically healthy normal-weight individuals (MHNW), metabolically unhealthy overweight/obese (MUOW/OB) individuals had a higher risk of overall (SRR = 1.21, 95% CI = 1.02–1.44, n = 3 studies, high certainty) and obesity-related cancers (SRR = 1.42, 95% CI = 1.15–1.74, n = 3, very low certainty). Specifically, MUOW/OB individuals were at higher risk of cancers of the postmenopausal breast (SRR = 1.32, 95% CI = 1.17–1.48, n = 7, low certainty), colorectum (SRR = 1.24, 95% CI = 1.16–1.31, n = 6, moderate certainty), endometrium (SRR = 2.31, 95% CI = 2.08–2.57, n = 4, high certainty), thyroid (SRR = 1.42, 95% CI = 1.29–1.57, n = 4, moderate certainty), kidney (SRR = 1.71, 95% CI = 1.40–2.10, n = 3, low certainty), pancreas (SRR = 1.35, 95% CI = 1.24–1.47, n = 3, high certainty), liver (SRR = 1.81, 95% CI = 1.36–2.42, n = 2, moderate certainty), gallbladder (SRR = 1.42, 95% CI = 1.17–1.73, n = 2, high certainty), bladder (SRR = 1.36, 95% CI = 1.19–1.56, n = 2, moderate certainty), and stomach (SRR = 1.50, 95% CI = 1.12–2.01, n = 2, high certainty). In addition, we found elevated risks of most of these cancers among individuals classified as MUNW and MHOW/OB phenotypes compared to those with MHNW phenotype. Our stratified analyses according to metabolic obesity phenotypes suggested that the elevated risks of some cancers were stronger in individuals with MUOW/OB versus those with MHOW/OB or MUNW phenotypes. These findings suggest that both higher adiposity and metabolic dysfunction were independently associated with increased risk of several cancers, with the strongest associations generally observed among those with both metabolic dysfunction and obesity.