Clinical Study of Local and Systemic Biological Impact of GLP1/GIP-Receptor Agonists in Patients With Breast Cancer: The CLARA Trial

Inclusion Criteria:

1. Voluntary written informed consent of the participant has been obtained prior to any screening procedures
2. Patient is \>18 years of age
3. Patient is postmenopausal, as defined per local practice
4. Tumour size of ≥1 cm
5. The patient has a biopsy-confirmed diagnosis of GII-III ER+, HER2 - early stage breast cancer scheduled for primary surgery as per standard-of-care

   1. To fulfil the requirement for HR+ disease by local testing on primary disease specimen, tumour must be ER positive defined by immunohistochemistry (IHC) according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for hormone receptor testing.
   2. To fulfil the requirement of HER2- disease by local testing on primary disease specimen, tumour must be HER2- according to ASCO/CAP guidelines for HER2 testing
   3. All histological subtypes are eligible, including but not limited to invasive breast cancer of no special type (IBC-NST) , invasive lobular carcinoma (ILC) etc.
6. Have a BMI of

   1. ≥30 kg/m2 or
   2. ≥27 kg/m2 and previously diagnosed with at least 1 of the following weight-related comorbidities:

   i. Hypertension: treated or with systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg ii. Dyslipidaemia: treated or with LDL ≥160 mg/dL (4.1 mmol/L) or triglycerides ≥150 mg/dL (1.7 mmol/L), or HDL iii. Obstructive sleep apnoea iv. Cardiovascular disease, for example, ischemic cardiovascular disease, New York Heart Association Functional Classification Class I-III heart failure
7. Patient should be able to read/understand Dutch, French or English
8. Willing to commit to the study program and comply with all related protocol procedures
9. Willing to undergo a new biopsy of the breast lesion in case no formalin-fixed paraffin-embedded (FFPE) block can be made available for the trial.

Exclusion Criteria:

1. Have Type 1 or 2 diabetes mellitus, history of ketoacidosis, or hyperosmolar state or coma.
2. Have at least 1 laboratory value suggestive of diabetes during screening : HbA1c ≥6.5% (≥48 mmol/mol) or fasting glucose ≥126 mg/dL (≥7.0 mmol/L)
3. Have a history of BC exceptions are made for:

   1. Contralateral in situ BC without systemic treatment
   2. Ipsilateral in situ BC without systemic treatment or radiation therapy
4. Have a history of an additional invasive malignancy that is progressing or that has required active treatment in the 3 years prior to breast cancer diagnosis. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
5. Are receiving or has received within 3 months prior to screening systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, intra-articular, or inhaled preparations) or have evidence of a significant, active autoimmune that has required (within the last 3 months) or is likely to require, in the opinion of the investigator, concurrent treatment with systemic treatment (such as glucocorticoids (excluding topical, intraocular, intranasal, intra-articular, or inhaled preparations)) during the course of the study.

   Note: Replacement therapy with thyroxine is not a contraindication for inclusion if patient is already on same dose for 3 months
6. Have a history of any other condition, such as known drug or alcohol abuse, diagnosed eating disorder, or other psychiatric disorder, that, in the opinion of the investigator, may preclude the participant from following and completing the protocol
7. Family or personal history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN-2)
8. Have a self-reported change in body weight \>5 kg within 3 months prior to screening
9. Have a prior surgical treatment for obesity, excluding liposuction or abdominoplasty
10. Have endoscopic and/or device-based therapy for obesity or have had device removal within the last 6 months prior to screening
11. Have renal impairment measured as eGFR \<30L/min/1.73m2
12. Have a known clinically significant gastric emptying abnormality (for example, severe gastroparesis or gastric outlet obstruction) or chronically take drugs that directly affect GI motility
13. Have a history of chronic or acute pancreatitis
14. Is treated with insulin or other hypoglycaemic drugs
15. Participation in another interventional Trial with an investigational medicinal product (IMP) or device in the neoadjuvant setting
16. Have obesity induced by other endocrinologic disorders, for example, Cushing syndrome, or diagnosed monogenetic or syndromic forms of obesity
17. Has acute or chronic hepatitis, signs and symptoms of any other liver disease other than NAFLD, or any of the following, as determined by the central laboratory during screening:

    1. Alanine aminotransferase (ALT) level \>3.0x ULN for the reference range
    2. Alkaline phosphatase (ALP) level \>2.0x ULN for the reference range, or
    3. Total bilirubin level \>1.5x ULN for the reference range (except for cases of known Gilbert's Syndrome) Note: Participants with non-alcoholic fatty liver disease (NAFLD) are eligible to participate in this trial if their ALT level is ≤3.0x ULN for the reference range
18. Has used systemic hormonal substitution therapy within 2 months before screening
19. Has used a GLP1/(GIP)/(GC) Receptor Agonist within 2 months of screening
20. Has used medications (prescribed or over-the-counter) within 2 months prior to screening that promote weight loss.