Tirzepatide Weight Loss for MRD+ Early Breast Cancer

Inclusion Criteria:

1. Female or male patients ≥18 years of age

2. Have a diagnosis of node-positive, hormone receptor-positive (ER+ > 10%), andHER2-negative breast cancer within the past 15 years per the American Society ofClinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines

3. If patients have synchronous bilateral ER+ breast cancers, tissue from bothprimary cancers should be submitted for next-generation sequencing (NGS) toinform ctDNA testing

4. Patients with multifocal/multicentric cancers are eligible and the largestfocus of cancer should be submitted for NGS evaluation. If tested, all tumorfoci must meet have ER > 10%

5. For patients who received neoadjuvant therapy and have discordant hormonereceptor and/or HER2 results between the diagnostic biopsy (pre-treatment) andthe surgical pathology (post-neoadjuvant treatment), the hormone receptorstatus and HER2 status of the post-treatment specimen will determineeligibility

6. Overweight or obesity defined as body mass index (BMI) > 27 kg/m2

7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

8. Have received at least 1 year of or having completed standard neo/adjuvant endocrinetherapy. If adjuvant cyclin dependent kinase (CDK) 4/6 inhibitor therapy wasprescribed, patients must have completed this therapy

9. Positive ctDNA blood test as determined by the Haystack Oncology Haystack MRDtumor-informed ctDNA assay

10. Patients must have formalin-fixed paraffin-embedded (FFPE) tissue from the primarytumor available for submission to Haystack Oncology to perform whole genomesequencing (WGS) to build customized mutation panel to monitor for plasma ctDNA

11. No clinical evidence of metastatic breast cancer found on history, physicalexamination, complete blood count (CBC), comprehensive metabolic panel (CMP), andradiologic imaging following a finding of positive ctDNA

12. Have adequate hematologic function, defined by:

13. Absolute neutrophil count (ANC) >1500/µL

14. Platelet count ≥100,000/ µL

15. Hemoglobin ≥9 g/dL or ≥5.6 mmol/L

16. Have adequate liver function, defined by:

17. Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤3 x the upperlimit of normal (ULN)

18. Total bilirubin ≤1.5 x ULN OR direct bilirubin ≤ULN for patients with totalbilirubin levels >1.5 × ULN

19. Have adequate renal function, defined by: a. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance of ≥30 mL/min

20. Patients must be accessible for treatment and follow-up

21. All patients must be able to understand the investigational nature of the study andgive written informed consent prior to study entry

Exclusion Criteria:

1. Prior bariatric surgery and/or endoscopic procedures for weight loss (e.g.,intragastric balloon, sleeve gastrostomy) following diagnosis of breast cancer

2. Treatment with a GLP-1/Glucagon receptor agonist, GIP/GLP-1/Glucagon receptoragonist, GIP/GLP receptor agonist, or any combinations with GLP-1 receptor agonisttherapies within the last 3 months

3. History of severe hypersensitivity reaction to GLP-1/Glucagon receptor agonist,GIP/GLP-1/Glucagon receptor agonist, or any combinations with GLP-1 receptor agonisttherapies

4. Insulin-dependent diabetes

5. Has clinical evidence of diabetic retinopathy

6. Clinical evidence or suspicion of metastatic breast cancer

7. Current or past invasive cancers, other than breast cancer, are not allowed exceptfor:

8. Adequately treated basal or squamous cell carcinoma of the skin

9. Previously diagnosed invasive cancer treated with curative intent, with noevidence of disease recurrence for at least 5 years, and are considered lowrisk for future recurrence by the treating physician

10. Patients with a second synchronous primary HER2-positive or triple negative breastcancer

11. Has an active infection requiring systemic therapy

12. Has a known history of human immunodeficiency virus (HIV) or active or persistenthepatitis B or hepatitis C virus

13. Has significant cardiovascular disease, such as:

14. History of stroke, myocardial infarction, acute coronary syndrome, or coronaryangioplasty/stenting/bypass grafting within the last 6 months

15. Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV,or history of CHF NYHA class III or IV.

16. Has a known history of active tuberculosis

17. Women who are pregnant or lactating. All patients of reproductive potential mustagree to use effective contraception from time of study entry until at least 3months after the last administration of study drug

18. Patients who have any severe and/or uncontrolled medical conditions or otherconditions that could affect their participation such as:

19. severe impaired lung functions as defined as spirometry and diffusing capacityof lung for carbon monoxide (DLCO) that is 50% of the normal predicted valueand/or O2 saturation that is 88% or less at rest on room air

20. liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh classC)

21. history of gastroparesis, impaired gastrointestinal (GI) function, or GIdisease that may significantly alter the absorption of the study drug (e.g.,ulcerative diseases, uncontrolled nausea vomiting and/or diarrhea,malabsorption syndrome, or small bowel resection)

22. Has a history of pancreatitis or current symptoms of untreated cholelithiasis

23. Has a family history of Multiple Endocrine Neoplasia Syndrome Type 2 (MEN 2) ormedullary thyroid cancer (MTC)

24. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thepatient's full participation for the full duration of the study, or results in trialparticipation not being in the patient's best interest, in the opinion of theTreating Physician

25. Has received an investigational agent within 4 weeks prior to study treatment;investigational monoclonal antibodies should have a 4-week (28 day) or 5 half-lifewashout period

26. Any other investigational or anti-cancer treatments while participating in thisstudy with the exception of standard adjuvant endocrine therapy, zoledronic acid, ordenosumab