Preoperative Window Opportunity Study With Giredestrant or Tamoxifen in Premenopausal Women With ER+/HER2[-] & Ki67≥10%

Inclusion criteria

Patients must meet ALL the following inclusion criteria to be eligible for enrolment into the study:

• Signed Informed Consent Form (ICF) prior to beginning specific protocol procedures.
• Aged ≥ 18 years at time of signing ICF.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Women in a well-determined premenopausal status as indicated in the protocol Section 4.1.
• Histologically confirmed invasive breast carcinoma, with all the following characteristics:
• Documented ER-positive tumor in accordance with American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines (Allison et al., 2020), assessed locally and defined as ≥ 1% of tumor cells stained positive.
• Documented HER2-negative tumor in accordance with 2018 ASCO/CAP guidelines (Wolff et al., 2018), assessed locally at baseline.

Note: Diagnostic biopsy taken no more than 8 weeks prior to initiation of study treatment can be used as baseline.

• Ki67 score ≥10% analyzed locally and centrally confirmed (Nielsen et al., 2021).

Note: Ki67 will be analyzed locally at the time of inclusion. Patients with basal Ki67 ≥20% will be assessed locally and centrally confirmed retrospectively and patients with 10-19% will be assessed centrally before inclusion.

• Tumor size must be ≥1.0 cm in longest diameter by ultrasound as per Response Evaluation Criteria in solid Tumors (RECIST) criteria.

Note: Patients with multifocal or multicentric breast cancer with a at least one tumor lesion ≥1.0 cm in the longest diameter by ultrasound (reference lesion) are also eligible if the two largest lesions have been histologically confirmed in the clinical evaluation and meet pathologic criteria for ER positivity and HER2 negativity.

• Willingness to provide a primary tumor tissue and blood sample obtained at baseline as well as a post-treatment tumor tissue and blood samples (breast biopsy or from breast surgery).
• Patient has adequate bone marrow, liver, and renal function:

Hematological: absolute neutrophil count (ANC) ≥ 1.5 x 109/L (1500/mL), platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 9 g/dL (≥ 90g/L).

Note: The blood counts are to meet the specified criteria without transfusion or growth factor support, unless it is clear that the bone marrow function is adequate and that any aberration has a clear and correctable cause, and the correction undertaken.

Hepatic: total serum bilirubin ≤ 1.5' institutional upper limit of normal (ULN) (patients with known Gilbert's syndrome: ≤ 3' ULN); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3' times ULN.

Coagulation: The international normalized ratio (INR) 470 ms by at least three ECGs >30 minutes apart.

History of long or short QT syndrome, Brugada syndrome or known history of corrected QT interval prolongation, or torsades de pointes.

History or presence of an abnormal ECG that is clinically significant in the investigator's opinion.

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophic cardiomyopathy, infiltrative cardiomyopathy, moderate-to-severe valve disease), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of long QT syndrome.

• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study.
• Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug elimination half-lives (whichever is longer) prior to randomization.
• Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery incl