A New Player in the Adjuvant Setting? GLP-1 Agonists and the Fight Against Breast Cancer Metastasis

It’s a scenario we see all too often in our clinics: a patient with breast cancer who is also navigating the complexities of obesity and type 2 diabetes. For years, the conversation has centered on the established links between metabolic health and poorer cancer outcomes. Now, a class of drugs that many of our patients are already taking for diabetes and weight management—glucagon-like peptide-1 (GLP-1) receptor agonists—is generating significant buzz, for its metabolic benefits, as well as for its potential to directly combat breast cancer progression.

Recent real-world data presented at the 2026 ASCO Annual Meeting have caught the attention of the oncology community. The study, which analyzed the health records of 12,112 patients, found that those with stage I to III obesity-related cancers, including breast adenocarcinoma, who were receiving GLP-1 receptor agonists had a significantly lower rate of progression to metastatic disease compared with those not receiving GLP 1 receptor agonists.¹ For patients with breast cancer specifically (n = 2374), the rate of metastasis was significantly lower, at 20% in the control arm vs 10% in the GLP-1 receptor agonist group (HR, 0.57; 95% CI, 0.46-0.71; P < .001).

Although these findings are from a retrospective analysis, they are bolstered by preclinical evidence. A 2024 study using a mouse model of breast cancer found that semaglutide significantly delayed tumor emergence, reduced tumor size, and decreased metastatic spread to the liver.² This growing body of evidence compels us to ask: How might these drugs be exerting such a powerful anticancer effect?

The mechanisms at play appear to be multifaceted, extending beyond the clear benefits of weight management. Although reducing adiposity, a known driver of inflammation and estrogen production, is a crucial factor, GLP-1 receptor agonists seem to have more direct anti-neoplastic properties. Their proposed mechanisms include:

• Modulating the Immune System: The aforementioned semaglutide study in mice pointed to an intriguing conclusion: the antitumor effect was not from direct cytotoxicity but was instead dependent on adaptive immunity. The drug appeared to enhance the acquired antitumor immune response by increasing the infiltration and activity of CD8+ T cells and promoting the maturation of dendritic cells.
• Direct Cellular Effects: At a cellular level, GLP-1 receptor activation can trigger a cascade of signaling pathways that inhibit tumor cell proliferation, induce apoptosis (programmed cell death), and suppress the cellular machinery responsible for migration and invasion.³
• Metabolic Reprogramming: Beyond weight loss, GLP-1 receptor agonists improve insulin sensitivity and glycemic control. This helps to dismantle the tumor-promoting environment fueled by hyperinsulinemia and insulin resistance, which are known to activate pathways that foster cellular proliferation and migration.

Of course, we must proceed with cautious optimism. Some early preclinical studies using very high concentrations of liraglutide (Victoza) in cell lines suggested a potential for tumor promotion, though this has not been borne out in large-scale human studies. Additionally, the phase 3b LEADER trial (NCT01179048), which followed 9340 patients with type 2 diabetes at high cardiovascular risk for a median follow-up of 3.8 years, found no imbalance in breast cancer events between the liraglutide and placebo arms.⁴

The ultimate verdict will come from prospective, randomized clinical trials. Several are already underway, including trials designed to determine whether tirzepatide (Zepbound)–induced weight loss can prevent the development of metastatic disease and improve disease-free survival in patients with high-risk, hormone receptor–positive, HER2-negative breast cancer.

For now, these emerging data provides a compelling rationale for prioritizing metabolic health in our patients. Although we await definitive trial results, the potential for GLP-1 receptor agonists to not only manage comorbidities but also to potentially act as an adjuvant therapy to reduce the risk of metastasis is a tantalizing prospect. It represents a potential paradigm shift, where a drug for diabetes could become a weapon in our arsenal against breast cancer recurrence. The conversation in our clinics is changing, and the future of adjuvant therapy may be more metabolically focused than ever before.

Deena Graham, MD, is a breast medical oncologist at John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

References

1. Orland MD, Mandala A, Unlu S, et al. Can GLP-1 receptor agonists mitigate cancer progression? A propensity-matched analysis across seven solid tumors. J Clin Oncol. 2026;44(suppl 16):3143. doi:10.1200/JCO.2026.44.16_suppl.3143
2. Stanisavljevic I, Pavlovic S, Simovic Markovic B, et al. Semaglutide decelerates the growth and progression of breast cancer by enhancing the acquired antitumor immunity. Biomed Pharmacother. Published online December 2024. doi:10.1016/j.biopha.2024.117668
3. Lin A, Ding Y, Li Z, et al. Glucagon-like peptide 1 receptor agonists and cancer risk: advancing precision medicine through mechanistic understanding and clinical evidence. Biomark Res. 2025;13(suppl 1):50. doi:10.1186/s40364-025-00765-3
4. Nauck MA, Jensen TJ, Rosenkilde C, Calanna S, Buse JB. Neoplasms reported with liraglutide or placebo in people with type 2 diabetes: results from the LEADER randomized trial. Diabetes Care. 2018;41(8):1663-1671. doi:10.2337/dc17-1825