Detection of Tumor DNA in the Blood of Patients Receiving Standard Therapy for Hormone Receptor-positive (HR+) Non-HER2 Expressing (HER2-) Metastatic Breast Cancer as a Tool to Select Those Who May Benefit From the Next Course of Fulvestrant in Combination With Alpelisib or Ribociclib

SCREENING PHASE (SAFIR 03 - SCREENING) Inclusion Criteria: 1. Patient must have signed a written informed consent prior to any study-specific screening procedures (the consent form specifically for the screening phase must be signed). 2. Patient is ≥18 years of age. 3. Patient has an histologically or cytologically confirmed metastatic breast cancer. 4. Patient has a HER2- breast cancer (without HER2 overexpression according to the ASCO-CAP 2018 guidelines). 5. Patient has hormone receptor-positive (HR+) breast cancer, defined as having oestrogen receptor (ER) and/or progesterone receptor (PR) expression in ≥10% of tumour cells. 6. Patient had a metastatic relapse during or within 1 year after termination of the adjuvant endocrine therapy. 7. Patient has not yet been treated in the metastatic breast cancer setting. 8. Patient is eligible for a first-line treatment with a marketed CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) in combination with fulvestrant, according to its marketing authorisation. 9. Eastern Cooperative Oncology Group (ECOG) performance status is ≤1. 10. Patient has an adequate bone marrow and organ function. 11. Measurable or evaluable disease according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1). 12. Patients must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures. 13. Patient must be affiliated to the national social security (or equivalent). Exclusion Criteria: 1. Prior exposure to PIK3CA-AKT or CDK4/6 inhibitors. 2. Patient that has initiated the CDK4/6 inhibitor treatment. 3. Patient with spinal cord compression and/or symptomatic or progressive brain metastases (unless asymptomatic or treated and stable off steroids for ≥30 days before initiating the study treatment). 4. Participant with an established diagnosis of diabetes mellitus type I or not controlled type II (based on FG and HbA1c). 5. Patient unable to swallow tablets. 6. Patient with known hypersensitivity to any of the study treatment excipients, in particular patients with allergies to soya or peanuts. 7. Patients with a history of malabsorption syndrome or other condition that may interfere with enteral absorption: including but not limited to active intestine inflammation (e.g., Crohn's disease or ulcerative colitis) requiring immunosuppressive therapy. 8. Patient with any condition/disease for which the investigator considers that participating in the study is inappropriate or that may jeopardize treatment and protocol compliance. 9. Patient deprived of liberty or under the authority of a tutor. RANDOMISED PHASE ( SAFIR 03 -ARRIBA) Inclusion Criteria: 1. Patient must have signed a written informed consent prior to any procedures for the randomised study phase (the consent form specifically for the randomised study phase must be signed). 2. Patient has a circulating PIK3CA level of exon 4, 9 or 20 mutant\* of PIK3CA ctDNA determined by circulating tumour DNA (ctDNA) assay after 4 weeks of treatment with any CDK4/6 inhibitor combined with fulvestrant. 3. Patient must have discontinued CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) at least 7 days before randomisation. 4. ECOG performance status is ≤1. 5. Patient's life expectancy is deemed ≥3 months. 6. Patient has an adequate bone marrow and organ function as defined by the following laboratory values: * Absolute neutrophil count (ANC) ≥1500/mm³, * Platelet count ≥100,000/mm³, * Haemoglobin ≥9.0 g/dL, * International normalised ratio (INR) ≤1.5 (unless the participant is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose of study drug), * Serum creatinine ≤1.5 × upper limit of normal (ULN) or creatinine clearance ≥50 mL/min, * Total bilirubin ≤2× ULN (\<3 ULN with documented Gilbert's disease) or direct bilirubin ≤ 1.5 × ULN, * aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN, or \<5.0 x ULN if patient has liver metastasis, * Fasting Serum amylase ≤ 2 × ULN, * Fasting Serum lipase ≤ ULN, * Fasting plasma glucose (FPG) ≤140 mg/dL (or ≤7.7 mmol/L) and glycosylated haemoglobin (HbA1c) ≤6.4%. 7. Participant must have the following laboratory values within normal limits or corrected to within normal limits with supplements before randomisation * Potassium * Magnesium * Total Calcium (corrected for serum albumin) 8. Patient with parameters of standard 12-lead ECG (defined as the mean of triplicate ECGs performed) as follows, before randomisation: * QTcF interval \<450ms (using Fridericia's correction), * Resting heart rate between 50-90 bpm. 9. Women of childbearing potential must have a negative serum pregnancy test result within 14 days of enrolment in the randomised trial phase. 10. Men or Women of childbearing potential must agree to the use of effective contraceptive for the study duration and for at least 2 year after the last dose of study treatment for women, and at least 21 days for men. 11. Patients must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures. * Also numbered exon 5, 10 and 21 according to recent classification: Ensembl Transcript ID: ENST00000263967.4, RefSeq: NM\_006218.4. Exclusion Criteria: 1. Patient is eligible to chemotherapy because of visceral crisis. 2. Pregnant or lactating women. 3. Patient has received more than 2 cycles of the ongoing CDK4/6 inhibitor treatment combined with fulvestrant before randomisation. 4. Patient has interrupted the ongoing CDK4/6 inhibitor treatment for more than 14 days before randomisation. 5. Patient has evidence of clinical or radiological disease progression before randomisation. 6. Patient has unresolved adverse events (grade ≥1), except alopecia and grade ≥2 unresolved adverse events related to fulvestrant or the LH-RH analogue which are acceptable to randomisation. 7. Patient is considered at high medical risk because of severe or uncontrolled systemic disease, including but not limited to diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, chronic pancreatitis, chronic active hepatitis, active untreated/uncontrolled fungal, bacterial, or viral infections, as well as known active viral infections with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). 8. Participant has currently documented pneumonitis/interstitial lung disease (the chest CT scan performed before start of study treatment for the purpose of tumour assessment should be reviewed to confirm that there are no relevant pulmonary complications present). 9. Participant has a history of severe cutaneous reaction, such as Stevens-Johnson Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 10. Participant with unresolved osteonecrosis of the jaw. 11. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities including any of the following: * Uncontrolled hypertension, * Symptomatic congestive heart failure: New York Heart Association (NYHA) class ≥2, * Unstable angina pectoris, * Stroke or myocardial infarction within the 6 months before randomisation, * Serious cardiac arrhythmia requiring treatment, except treated atrial fibrillation and paroxysmal supraventricular tachycardia, or conduction abnormality for which the patient is no longer at risk of serious arrhythmia (e.g., Patient with Wolff-Parkinson-White syndrome treated with surgical ablation), * Left ventricular ejection fraction (LVEF) \<50% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) before randomisation. * Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following before randomisation: * Presence of risk factors for Torsades de Pointe, including uncorrected hypokalaemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia, * Concomitant use of medication(s) known to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 days prior to initiating the study treatment) or cannot be replaced by a safe alternative, * Unable to determine the QTcF (using Fridericia's correction), * Systolic blood pressure (SBP) \>160 mmHg or \<90 mmHg. 12. Patient who has received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2 weeks prior to starting study drug, or who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom ≥ 25% of the bone marrow was irradiated 13. Patient is currently consuming any of the following foods, supplements, herbal preparations or medications that cannot be discontinued within 7 days of initiating the study treatment: * Known strong inducers or inhibitors of CYP3A4/5 (including grapefruits), * Medications predominantly metabolised through CYP3A4/5, with a narrow therapeutic window, 14. Patient has known hypersensitivity to any of the study treatment excipients, in particular patients with allergies to soya or peanuts. 15. Patient is or plans to participate in another interventional therapeutic clinical trial. Concurrent participation in an observational study is acceptable. 16. Patient has malignancies, other than that under study, except for adequately treated cone-biopsied in situ carcinoma of the cervix and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, with no evidence of relapse/recurrence within ≥5 years, and at negligible risk for recurrence are eligible for the study. 17. Patient has any condition/disease, for which the investigator considers that participating in the trial is inappropriate or that may jeopardize treatment and protocol compliance. 18. Patient deprived of liberty or under the authority of a tutor.