Elacestrant for Treating ER+/HER2- Breast Cancer Patients With ctDNA Relapse (TREAT ctDNA)

Inclusion criteria

• 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.
• 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