Abstract Background: Achieving and sustaining the ≥10% weight loss sufficient to reduce risk for breast cancer has been difficult with diet and exercise alone. Tirzepatide is a dual agonist of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. It is FDA-approved for obesity treatment with average weight loss of 14% at 24 weeks. Genetic variants of the GIP receptor (GIPR) that reduce GIPR signaling have been associated with increased breast cancer risk; however, little is known about the presence or localization of GIPR within breast tissue. High mammographic density, breast adipocyte size, breast epithelial Ki-67 ≥2%, and visceral fat of 1kg (iDXA) are all associated with increased risk of breast cancer. With the exception of BMI and insulin resistance, there is little information on the effect of tirzepatide on risk biomarkers for breast cancer. We sought to assess feasibility of a convenient clinical cohort trial model and gain preliminary information on biomarker modulation in a pilot study. Methods: Women with obesity and additional risk factors for breast cancer seen in the KUMC Weight Management Clinic (WMC) and Breast Cancer Prevention Clinic (BCPC), considering clinical use of tirzepatide, were approached for study participation. Procedures for assessment of risk biomarkers were performed by BCPC personnel before and after 6 months of tirzepatide. Inclusion criteria were age 35-64, BMI ≥30 kg/m2, ≥2x population risk for breast cancer, and self-pay or insurance coverage for tirzepatide. Exclusion criteria included prior invasive cancer or current insulin or antiestrogens. Prior to tirzepatide initiation, women underwent a fasting blood draw, 3D mammography, iDXA, random periareolar fine needle aspiration, and optional stool for microbiome. Tirzepatide was started at a dose of 2.5 mg/week, escalated every 4 weeks to a maximum of 15 mg under the guidance of the WMC. Key imaging risk biomarkers are absolute fibroglandular volume (FGV) via Volpara™ and visceral fat via iDXA. Tissue biomarkers performed in the BCPC or Biomarker Validation Core laboratories include Ki-67, GIPR, and estrogen response gene expression. Systemic markers include estradiol, estrone, SHBG, progesterone, insulin, adipocytokines, circulating microRNA, and Klotho. Breast adipocyte size is measured at the University of Michigan and microbiome analyzed at Wake Forest University. Objectives: 1) Feasibility as defined by ≥1 enrollee/month and 70% completion of study including biomarker procurement; 2) Proportion of women with detected GIPR in breast epithelium; and 3) Identification of reliably modulated biomarkers of breast cancer risk. Results: 23 women have been enrolled in 9 months with median age 49, BMI 35 kg/m2, IBIS 10-year breast cancer risk 6.3%, and visceral fat mass 1.7 kg. 13 are pre or perimenopausal and 10 postmenopausal. Of the 12 women completing study to date, median relative change in BMI is -15%, visceral fat -19%, lean mass -8%, FGV -22%, and HOMA-IR -31%. Median relative change in Ki-67 for the seven women with baseline Ki-67 ≥ 2% is -50%. Five of seven initial entrants have shown evidence at baseline of low, but detectable, levels of GIPR in breast epithelium by spatial genomics. Conclusions: Rapidity of recruitment, high retention, and completion of off-study biomarker assessments support expansion to a larger phase II trial where the directionality and magnitude of biomarker change can be evaluated with greater precision and confidence. Citation Format: C. J. Fabian, C. R. Beaver, K. R. Powers, L. Ranallo, A. L. Kreutzjans, K. Pittman, C. Altman, T. Metheny, R. Biswell, A. Zelenchuk, H. Pathak, A. Mitra, A. K. Godwin, D. P. Mudaranthakam, E. D. Giles, S. D. Hursting, K. L. Cook, B. F. Kimler. Effects of 6 Months of Tirzepatide on Risk Biomarkers for Development of Breast Cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-01-28.
Fabian et al. (Tue,) studied this question.