Clinical Research Directory

Inclusion Criteria: 1. ctDNA screening phase: Main inclusion criteria: • Female (both pre- and postmenopausal) or male patients with histologically confirmed ER positive (regardless of PR), HER2 negative breast cancer, according to local pathologist: * ER-positive defined as ≥ 10% of cells staining positive for ER or Allred proportion score ≥3 * HER2-negative defined as a score of 0, 1+ by immunohistochemistry (IHC) or a negative in situ hybridization (ISH) based on single-probe average HER2 copy number, as per American Society of Clinical Oncology guidelines * Intermediate to high risk of recurrence after definitive treatment for early breast cancer, defined as: FOR PATIENTS TREATED WITH PRIMARY SURGERY: * Any patient with ≥ 4 positive axillary lymph nodes (stage pN2-3). * 1-3 positive axillary lymph nodes (stage pN1) and either: * Tumour size ≥ 5 cm or/and * Histologic grade 3 or/and * Ki67≥20% or/and * High genomic risk defined as Oncotype Dx Recurrence Score \>=26, Mammaprint high risk, Prosigna score \>40 or EPclin risk score \>=4.0. * Negative axillary lymph nodes (stage pN0) and tumour size ≥ 2 cm and either * Histologic grade 3 a or/and * Ki67≥20% and/or * High genomic risk defined as Oncotype Dx Recurrence Score \>=26, Mammaprint high risk, Prosigna score \>60 or EPclin risk score \>=4.0. FOR PATIENTS TREATED WITH NEOADJUVANT SYSTEMIC TREATMENT FOLLOWED BY SURGERY: * Patient may have received neoadjuvant endocrine therapy or neoadjuvant chemotherapy provided that: * The initial tumour and/or the tumour after surgery meet the criteria above defined for patients treated with primary surgery or the initial tumour was staged as cT4anyN and * There is no pathological complete response, defined as no invasive disease in the breast and axilla (ypT0/is ypN0). * Age ≥18 years * Patients must have received at least 1 year and up to 7.5 years of ET and planned to continue adjuvant ET during ctDNA screening phase * Previous adjuvant CDK4/6 inhibitor or PARP-inhibitor treatment is allowed provided it is completed * Invasive multicentric / multifocal disease is allowed provided that all the tested foci are ER+ HER2-. A sample from the highest-risk one, according to the investigator decision based on the size and grade, should be sent to Natera to build the patient ctDNA assay. * Available tumour sample from resected or biopsied tissue, with a tumour content of ≥20% (30% preferred) either before or after macro dissection (if performed) and a cell viability of a minimum 100 cells. * Core Needle Biopsies (CNB): recommended minimum of four (4) cores per block * Fine Needle Aspirates (FNA) are not accepted * The following sample types are acceptable: * 6-10 unstained slides (charged and unbaked) of 10μm each (or 12-19 unstained slides at 5 μm each), PLUS one contiguous H\&E slide. Minimum total tissue thickness must be 60μm OR * FFPE tissue block with 25mm2 minimum surface area * Written informed consent must be given according to ICH/GCP, and national/local regulations. Main exclusion criteria: * Suspected recurrent disease or known conflicts with the inclusion and exclusion criteria for the randomised trial * Prior treatment with any SERD or investigational ER antagonist * Previous history of invasive breast cancer * Previous history of any other malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ. * Previous history of bone marrow and/or organ transplant * Bilateral invasive breast cancer * Participation in another clinical study, with the exception of the SURVIVE study and observational (non-interventional) and non-drug intervention clinical studies. Note: patients participating in interventional studies may participate once they enter the follow-up period of the study * Blood transfusion within 3 months prior to registration or during the screening. 2. Randomised trial: Main inclusion criteria: * ctDNA positive according to the Signatera ctDNA assay (main study ctDNA test) or other ctDNA assay approved for diagnostic purposes. * Patients must meet the eligibility criteria for the screening phase, with the exception of the tissue sample requirements. * Patients must receive adjuvant ET at the time of the ctDNA positive test * Absence of locoregional and/or metastatic disease and/or new malignancy, as investigated by: * Mammogram (unilateral in case of mastectomy; not required in patients having undergone bilateral mastectomy) NOTE: if local investigator plans to use MRIs instead of mammograms during the study, MRI will have to be performed at baseline. * CT thorax and abdomen/pelvis with IV contrast. In case of any contra-indications (medical or regulatory): CT thorax without contrast + MRI abdomen/pelvis. * Technetium-99m bone scintigraphy * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 * Adequate organ function * Women of childbearing potential (WOCBP) must have a negative highly sensitive serum or urine pregnancy test within 7 days prior to randomisation. Main exclusion criteria: * Any unresolved toxic effect of prior therapies or surgical procedures of Grade ≥ 2 according to Common Terminology Criteria of Adverse Events (CTCAE) v5.0, with the exception of alopecia, peripheral neuropathy and other toxicities not considered a safety risk for the participant at investigator's discretion * Unable or unwilling to avoid over-the-counter medications, dietary/herbal supplements, and/or foods that are moderate/strong inhibitors or inducers of CYP3A4 activity * Known difficulty in tolerating oral medications or conditions which would impair absorption of oral medications * Any of the following cardiovascular disorders within 3 months before enrolment: * myocardial infarction * stroke * severe/unstable angina * symptomatic cardiac arrhythmia * prolonged QTcF ≥ Grade 3 (i.e., \> 500 msec) * heart failure ≥ Class III as defined by the New York Heart Association (NYHA) guidelines * CTCAE version 5.0 grade 3 or 4 dyslipidemia at the time of screening, defined as cholesterol\>400 mg/dL or \>10.34 mmol/L and/or triglycerides\>500 mg/dL or \>5.7 mmol/L. * Child-Pugh Score greater than Class A * Uncontrolled significant active infections (≥ grade 3 according to CTCAE version 5), including active hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency Virus (HIV) * Coagulopathy or any history of coagulopathy within the past 6 months, including history of deep vein thrombosis or pulmonary embolism