Breast cancer and metabolic comorbidities: From epidemiology and molecular mechanisms to precision interventions

Abstract

Breast cancer is increasingly recognized as a systemic disease influenced by the metabolic environment. Growing evidence suggests that obesity, type 2 diabetes mellitus, metabolic syndrome, and associated cardiovascular diseases significantly elevate the incidence, recurrence, and mortality of breast cancer, while also affecting treatment outcomes and prognosis. These metabolic disruptions alter the tumor microenvironment through mechanisms such as chronic inflammation, insulin/insulin-like growth factor signaling, adipose-immune interactions, gut microbiota imbalance, and epigenetic reprogramming, converging on critical signaling pathways including phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin and interleukin-6/Janus kinase/signal transducer and activator of transcription 3. Clinically, this metabolic-tumor axis is reflected in altered molecular subtypes, reduced treatment efficacy, and increased therapy-related toxicity, highlighting the need for integrated management approaches. Traditional cancer treatment models may not fully meet the needs of contemporary patients, necessitating the development of precision interventions and comprehensive management strategies. Repurposing metabolic agents (e.g., metformin, glucagon-like peptide-1 receptor agonists), implementing structured lifestyle changes, and considering bariatric surgery, alongside emerging technologies such as multi-omics, spatial transcriptomics, and artificial intelligence-driven multimodal risk prediction, are key to advancing precision prevention and personalized survivorship care. Incorporating metabolic health into breast cancer management has become an essential paradigm shift, pivotal for disease prevention, personalized treatment, and prolonged, high-quality survivorship.

Keywords: Breast cancer; Metabolic comorbidities; Obesity; Type 2 diabetes mellitus; Precision interventions

Core Tip: Reframes metabolic comorbidities as active, modifiable drivers of breast cancer. Integrates epidemiology, tumour microenvironment, signalling and gut microbiota. Maps obesity, type 2 diabetes mellitus and metabolic syndrome pathways to pharmacologic and lifestyle interventions. Highlights glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors and bariatric surgery as precision tools. Proposes a metabolic oncology model with artificial intelligence-enabled multimodal risk prediction.