Visceral and Subcutaneous Fat Deposits Exhibit Distinct Roles in the Initiation and Progression of Breast Cancer

Yu Zhang,1,* Qi Li,2,* Li Zhao,3,* Yi Pang,2 Lin Li,2 Wei-Wei Niu,2 Yu Xing,2 Yu Liu,2 Fu-Quan Zhang,2 Yu-Chen Fan,2 Yuan-Yuan Bao,1 Chun-Wei Li,4 Kang Yu1 1Department of Clinical Nutrition, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of General Surgery, Central Hospital, Tianjin University/Tianjin Third Central Hospital, Tianjin, People’s Republic of China; 3Department of General Surgery, Tianjin Third Central Hospital Branch (Tianjin Institute of Geriatrics), Tianjin, People’s Republic of China; 4Department of Clinical Nutrition, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kang Yu, Department of Clinical Nutrition, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China, Tel +86-10-69155550, Fax +86-10-65253037, Email [email protected] Chun-Wei Li, Department of Clinical Nutrition, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China, Tel +86-10-69155550, Fax +86-10-65253037, Email [email protected]: Evidence suggests that ectopic fat deposition and muscle atrophy may contribute to tumor development and progression; however, their dual roles in breast cancer (BC) remain incompletely understood. This study aims to elucidate the complex relationships between specific body composition features and both BC initiation and progression.Patients and methods: A multicenter observational study was conducted from March 2020 to May 2025, integrating case-control and longitudinal data on body composition parameters, covariates, and survival outcomes from 213 BC patients and 430 cancer-free controls. The case-control analysis employed inverse probability weighting, lasso and logistic regression to evaluate associations between body composition and BC risk. The XGBoost model was used to further identify key body composition predictors. Kaplan-Meier and Cox regression analyses were conducted to evaluate the effect of body composition parameters on distant metastasis-free survival (DMFS) in BC patients following radical mastectomy.Results: Trunk muscle mass (TMM) exerted a protective effect against BC development (OR=0.965, 95% CI: 0.949~0.982), whereas muscle mass (MM: OR=1.027, 95% CI: 1.008~1.047) trunk fat mass (TFM: OR=1.046, 95% CI: 1.025~1.068) and visceral adipose tissue (VAT: OR=1.003, 95%: 1.0005~1.005) emerged as independent risk factors, even after adjusting for menopause status, comorbidities, laboratory indices, and lifestyle factors. The XGBoost model corroborated TFM, VAT, and TMM as pivotal predictors of carcinogenesis. Paradoxically, in post-mastectomy BC patients, higher subcutaneous adipose tissue compartments, specifically TFM (HR= 0.794, 95% CI: 0.634~0.994) was significantly correlated with improved DMFS, particularly among postmenopausal women (HR=0.721, 95% CI: 0.530~0.981), while VAT showed no significant impact on survival. Higher LMM was also associated with improved DMFS in postmenopausal women.Conclusion: This study reveals a paradoxical role of adipose tissue in breast cancer, as it may promote tumorigenesis yet confer a post-mastectomy survival advantage. Body composition’s prognostic complexity necessitates targeted therapies targeting fat-muscle crosstalk in cancer management.Keywords: breast carcinogenesis, fat distribution, risk factor, distant metastasis-free survival