Normal weight obesity, circulating biomarkers and risk of breast cancer: a prospective cohort study and meta-analysis

Background: Individuals with normal weight obesity (NWO) often escape the attention of healthcare providers who may assume that a normal body mass index (BMI) correlates with low health risks. However, it remains unknown whether NWO increases the risk of breast cancer. Methods: This study included 22,257 and 52,506 pre- and postmenopausal females with normal BMI in the UK Biobank. NWO was defined as participants with a normal BMI (18.5-24.9 kg/m2) and an excess percent body fat (PBF > 33.3%). Cox proportional hazard models were used to investigate the associations of NWO and NWO-related biomarkers with incident breast cancer. Results: NWO was not associated with premenopausal breast cancer, whereas it was associated with a higher risk of postmenopausal breast cancer (hazard ratio = 1.19, 95% CI: 1.08-1.31). In our meta-analysis, per 5-unit increment in percent body fat level was linked to a 15% (95% CI: 10-19%) elevated risk of postmenopausal breast cancer in females with normal BMI. Stratified analyses showed a stronger positive association in females with higher genetic risk. In our NWO-biomarkers analyses, NWO was linked to 34 identified biomarkers, of which three inflammation markers (monocyte count, neutrophil count, and C-reactive protein), and one ketone body metabolite (beta-Hydroxybutyrate) also indicated a positive association with postmenopausal breast cancer. Conclusions: NWO is associated with an increased risk of postmenopausal breast cancer, indicating that relying solely on BMI neglects the higher risk faced by non-obese postmenopausal women.