Studio di fase 3 su elacestrant alla comparsa di DNA tumorale nel sangue nel tumore della mammella con recettori per gli estrogeni e HER2-negativo

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