SAT-291 Impact of the Incretin Mimetic Drug Tirzepatide on Obesity-Associated Breast Cancer Growth: Findings from a Preclinical Model

Abstract Disclosure: A. Kucinskas: None. K. Sanchez: None. E. Bailey: None. E.D. Giles: None. The ∼70% of women who are overweight or obese at the time of menopause have significantly increased risk of breast cancer and poorer outcomes if they develop this disease. Recently, several incretin mimetic agents targeting satiety-related receptors have been approved for obesity and diabetes treatment and have been shown to induce significant weight loss. Limited data suggest these agents may also reduce obesity-related tumor growth. A recent preclinical study in a mouse model of triple-negative breast cancer reported that tirzepatide, a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonist, reduced obesity-associated tumor growth. Here, we assessed the effect of tirzepatide on the growth of obesity-associated, hormone-dependent tumors. 9-week-old C57BL/6 mice were fed a 46% high-fat diet (HFD) and housed under thermoneutral conditions to induce obesity. At 32 weeks of age, obese mice were randomized to receive every-other-day subcutaneous injections of tirzepatide (dose escalation over 15 weeks to reach 75 nM) or vehicle control for the duration of the study. At 35 weeks of age, hormone-dependent mammary tumors were initiated by injection of Py230 cells, and tumor volumes were measured twice weekly. Mice were terminated when tumor volume reached 2 cm3 or at 48 weeks of age (after 16 weeks of tirzepatide treatment). As expected, tirzepatide treatment resulted in ∼20% body weight loss, primarily due to a loss of adipose mass, with a reduction in mesenteric (-69%, p=0.01), pericardial (-56%, p=0.01), and gonadal (-35%, p=0.06) adipose depot weights compared to controls. Tirzepatide also had beneficial effects on tumor outcomes, with a trend for reduction in tumor volume, compared to control mice. In addition, tumor volume at the study end was significantly correlated with body weight (R2=0.60), total adipose mass (R2=0.50), and percent body fat (R2=0.39). Together, these data suggest that tirzepatide may play a beneficial role in the reduction of obesity-associated hormone-dependent tumor growth. Additional studies to separate the weight loss vs tumor-specific effects of tirzepatide are ongoing. Presentation: Saturday, July 12, 2025