Glucagon-Like Peptide-1 Receptor Agonists in Breast Cancer: Metabolic, Clinical, and Survivorship Implications

Breast cancer is increasingly recognized as an obesity-associated disease, with obesity linked to higher risk of postmenopausal estrogen receptor-positive disease and adverse outcomes across stages. Adipose tissue dysfunction in chronic energy excess drives a tumor-supportive milieu: Crown-like structures and macrophage inflammation increase local aromatase and estrogen production, while elevated free fatty acids contribute to hyperinsulinemia and IGF-1 signaling with activation of PI3K/Akt/mTOR and MAPK pathways; leptin is increased and adiponectin reduced, amplifying proliferative and inflammatory cues. Standard breast cancer therapies can further worsen weight gain and insulin resistance, increasing symptom burden, reducing quality of life, and potentially compromising treatment delivery. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are highly effective agents for obesity and type 2 diabetes that improve glycemic control and reduce cardiovascular risk, prompting growing use in patients with breast cancer. Available breast cancer-specific data are largely retrospective and suggest clinically meaningful but attenuated weight loss compared with pivotal obesity trials, with concurrent aromatase inhibitor or tamoxifen use associated with smaller reductions. No unique breast cancer toxicities have been identified to date, to our knowledge, but clinicians should monitor GI tolerability, hydration and nutrition, and changes in body composition, including potential lean mass loss that may be mitigated with resistance training and adequate protein intake. Clinical considerations include changes in breast imaging during rapid weight loss (including possible increases in mammographic density), uncertainty regarding perioperative use in reconstructive surgery, and careful attribution of GI symptoms to GLP-1RA therapy versus chemotherapy. Studies also suggest potential survivorship benefits relevant to lymphedema and cardio-oncology, although causality is unproven. Prospective cancer-specific trials and implementation studies are needed to define safety; optimal timing; patient selection; and effects on oncologic outcomes, function, and quality of life.