Abstract LB374: Losing weight, not risk: Persistent cancer risk despite weight loss in adults with obesity

Abstract Importance: WHO predicts that obesity will begin to surpass smoking as a leading preventable cause of cancer in some regions within the next decade. With nearly 1 billion adults living with obesity, it is critical to determine whether weight loss reduces cancer risk. Objective: To determine whether weight loss among adults with obesity is associated with reduced risk of obesity-associated cancer, any cancer, and selected cardiometabolic outcomes. Design, Setting, and Participants: This prospective population-based cohort study included 2 Danish cohorts with measured weight and height: the Copenhagen City Heart Study (1976-2019) and the Copenhagen General Population Study (2003-2019). Participants were followed for incident cancer through national registries. Baseline associations between obesity and cancer risk were examined among all participants. Analyses of weight change were restricted to participants with at least 2 measurements. The median interval between examinations was 7.5 years in the Copenhagen City Heart Study and 10.3 years in the Copenhagen General Population Study. Cox proportional hazards models were multivariable-adjusted. Results: Among 138 376 adults, baseline obesity was associated with increased risk of obesity-associated cancer (hazard ratio [HR], 1.26; 95% CI, 1.19-1.35) but not with risk of any cancer (HR, 1.04; 95% CI, 1.00-1.09), compared with normal weight. Among 33 190 participants with repeated measurements, weight loss ≥ 10% was not associated with reduced risk of obesity-associated cancer (HR, 1.06; 95% CI, 0.87-1.29), whereas weight gain ≥ 10% was associated with increased risk (HR, 1.20; 95% CI, 1.05-1.37). Among participants with obesity at baseline, transition to normal weight was not associated with reduced risk of obesity-associated cancer (HR, 0.95; 95% CI, 0.34-2.67). By contrast, weight loss was associated with lower risk of type 2 diabetes (HR, 0.54; 95% CI, 0.38-0.77) and hypertension (HR, 0.11; 95% CI, 0.02-0.83). Conclusions and Relevance: Among adults with obesity, even substantial weight loss was not associated with reduced risk of obesity-associated cancer or any cancer, whereas it was associated with lower risk of type 2 diabetes and hypertension. These findings suggest that prevention of obesity may be critical for cancer prevention. Citation Format: Maren Weischer, Morten Dahl, Shoaib Afzal, Boerge G. Nordestgaard. Losing weight, not risk: Persistent cancer risk despite weight loss in adults with obesity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB374.