Breast Cancer Burden in BRICS Countries Attributable to Smoking, High Alcohol Use, High Body Mass Index, and Low Physical Activity, 1990–2021: Findings from the Global Burden of Disease 2021 and Mendelian Randomization

Xiao Yan,1,* Chenyi Liao,1,* Shuangqiang Qian,1,* Chen Zhang,2,3 Jiangzhuo Wu,1 Jiang Fang,1 Xiaobo Zhao,1,* Lin Peng1,* 1Department of Thyroid and Breast Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of China; 2Department of General Surgery, Wusheng County People’s Hospital (Wusheng Hospital Affiliated Hospital of North Sichuan Medical College), Guangan, People’s Republic of China; 3Department of Clinical Medicine, North Sichuan Medical College, Nanchong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaobo Zhao, Email [email protected] Lin Peng, Email [email protected]: Breast cancer remains the leading cause of cancer incidence and mortality among women globally. However, studies that not only compare the population-level burden but also interrogate the underlying causal mechanisms to explain the observed cross-national disparities are lacking. This limits the ability to translate descriptive findings into mechanistically informed prevention strategies. This study evaluates the burden of female breast cancer attributable to four modifiable risk factors: smoking, high alcohol use, high body-mass index (BMI), and low physical activity, among women of reproductive age (15 to 49 years) in BRICS countries from 1990 to 2021.Methods: We employed a two-tiered analytical framework. First, using data from the Global Burden of Disease (GBD) 2021 study, we quantified and compared the national burden (deaths, DALYs) and temporal trends (EAPC, ARIMA projections) attributable to each risk factor. Second, to provide mechanistic insight into these population-level patterns, we conducted a two-sample Mendelian randomization (MR) analysis to assess the potential causal relationships of the same risk factors with breast cancer.Results: Substantial heterogeneity in attributable burden was observed across BRICS nations. MR analysis supported the potential causal roles of high alcohol use, smoking, and low physical activity. Critically, the genetic evidence for causality aligned with and helped to mechanistically explain the dominant risk drivers identified in the descriptive burden analysis: the rising burden linked to high alcohol use in Brazil and India, and the increasing burden from smoking in the Russian Federation. A consistent protective association of high BMI with premenopausal breast cancer was observed in both analyses.Conclusion: By integrating comparative burden assessment with causal inference, this study moves beyond describing disparities to offering mechanistically plausible explanations for the distinct risk factor profiles in BRICS countries. This approach provides a stronger evidence base for developing etiologically informed, targeted prevention strategies that address the specific drivers of breast cancer in different national contexts. The infographic presents an analysis of breast cancer burden in BRICS countries using GBD 2021 data from 1990 to 2021. It includes trends from 1990 to 2021, age distribution proportions, age distribution for EAPCs and forecasting from 2021 to 2030. On the right, MR-based analyses of risk factors in breast cancer are shown, highlighting high alcohol use, low physical activity, smoking and high BMI as risk factors. The analysis uses GWAS and FinnGen data. Illustrations depict high alcohol use, low physical activity, smoking as risk factors and high BMI as a protective factor.Infographic on breast cancer burden in BRICS, risk factors and protective factors using GBD 2021 data.Keywords: breast cancer, BRICS countries, reproductive age women, global burden of disease, mendelian randomization