LCCC2415 examines the antiproliferative effect of tirzepatide on the endometrium of endometrial cancer (EC). This is a pre-operative window clinical study. Endometrial biopsy samples from patients before tirzepatide treatment will be compared to their post-intervention hysterectomy specimens. If archival tissue is unavailable, a fresh biopsy will be taken before tirzepatide treatment. Post-intervention tissue will be collected from the hysterectomy specimen.

The hypothesis is that tirzepatide's anti-tumorigenic effects are due to both an improvement in the host's metabolic milieu (indirect effect) and a direct effect on the EC tumor microenvironment via the inter-related pathways of insulin, lipid, and mTOR signaling. Therefore, tirzepatide may be an innovative approach to effectively induce weight loss and inhibit tumor growth in EC, the most obesity-driven of all cancers.

The primary objective is to determine if tirzepatide decreases proliferation in the tumors of EC patients. The effect of tirzepatide on the endometrium of 20 obese women with EC will be evaluated by comparing each patient's endometrial biopsy before tirzepatide treatment to their post-treatment hysterectomy specimen, through a pre- operative window study. These women will begin tirzepatide treatment for 4 weeks prior to standard-of-care (SOC) surgery. Subjects will have a single end-of-treatment visit 4 weeks after completing therapy and will be followed for 24 months via medical record abstraction to monitor weight loss maintenance.

Inclusion Criteria:

• Current diagnosis of endometrioid histology cancer and scheduled to undergo hysterectomy and staging.
• Agree to comply with all required study assessments and visits including internet capabilities.
• Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information.
• Age ≥ 18 at the time of consent.
• Body mass index of ≥30 kg/m2.
• Presumed clinically early-stage disease (disease confined to uterus only).
• ECOG ≤ 2 or Karnofsky Performance Status of > 50

Exclusion Criteria:

• Active infection requiring systemic therapy.
• Subject is pregnant or breast feeding.
• Taking any prescription medications or other drugs that may influence metabolism per discretion of investigator.
• Taking a central nervous system stimulant.
• Current psychological conditions that would be incompatible with participation in this study, as determined by investigator.
• Known sensitivities (i.e., urticaria and eczema) to GIP and GLP-1 receptor agonists.
• Have type 1 diabetes mellitus or latent autoimmune diabetes in adults or receiving treatment with insulin.
• Have a history of severe hypoglycemia or not be able to communicate an understanding of hypoglycemic symptoms.