Inclusion Criteria:

          1. Women with proven loco-regionally recurrent or metastatic adenocarcinoma of the breast
             not amenable to curative therapy with disease considered potentially sensitive to
             aromatase inhibitors Note: patients relapsing while on adjuvant tamoxifen or other
             non-aromatase inhibitor adjuvant endocrine therapy are eligible for the present study;
             patient relapsing after 6 years or more under adjuvant aromatase inhibitor are
             eligible.

          2. Age ≥18 years;

          3. Life expectancy > 3 months;

          4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2;

          5. Estrogen Receptor (ER)-positive and HER2-negative breast cancer. Where available,
             assessment of Estrogen Receptor status should be based on the most recent tumor
             sample; to be considered as ER-positive, the most recent breast cancer tissue examined
             must display at least 10% of cancer cells with positive ER staining;

          6. Tumor block (primary tumor or metastasis) available;

          7. No prior systemic anti-cancer therapy for metastatic or advanced disease
             (chemotherapy, targeted therapy or hormone therapy); prior initiation of LHRH agonist
             or bone-directed agents is however allowed);

          8. Menopausal patients or patients with suppressed ovarian function Women with bilateral
             oophorectomy

             Postmenopausal women, as defined by any of the following criteria:

             Age 60 or over;

             Age 50 to 59 years and meets one of the following criteria:

             Amenorrhea for ≥ 24 months and follicle-stimulating hormone within the postmenopausal
             range; patients with hysterectomy or chemotherapy-induced amenorrhea must display
             follicle-stimulating hormone within the postmenopausal range; Other women, provided
             they are being treated with monthly LHRH analogues (first injection performed ≥7 days
             before the treatment initiation) and are willing to continue to receive LHRH agonist
             therapy for the duration of the trial;

          9. Patients may have measurable (according to Response Evaluation Criterion in Solid
             Tumors (RECIST v1.1) or not measurable disease Patients with only blastic bone lesions
             are not eligible; Patients with only pleural, cardiac or peritoneal effusion or
             meningeal carcinomatosis are not eligible;

         10. Adequate organ and marrow function as defined below:

             Hemoglobin ≥ 90 g/L Absolute neutrophil count ≥ 1.5 G/L Platelet count ≥ 100 G/L Serum
             bilirubin ≤ 1.5 × ULN. This will not apply to patients with confirmed Gilbert's
             syndrome.

             ALT and AST ≤ 3 × ULN; Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone or liver
             metastases present) Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥
             60 mL/min as determined by Cockcroft-Gault (using actual body weight) formula for
             females [creatinine clearance =Weight (kg) × (140 - Age) × 0.85 (mL/min)/ (72 × serum
             creatinine (mg/dL))

         11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
             tests, and any protocol-related procedures including screening evaluations;

         12. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical
             procedures to NCI CTCAE version 4.0 Grade 1 (except alopecia or other toxicities not
             considered a safety risk for the patient at investigator's discretion);

         13. Written informed consent obtained prior to performing any protocol-related procedures
             including screening evaluations;

         14. Patient affiliated to a social security system.

        Exclusion Criteria:

          1. Locally advanced breast cancer or loco-regional relapse amenable for any treatment
             with curative intent;

          2. Her2-positive or equivocal tumor status either on the primary or on the recurrent
             tumor, defined as IHC3+, Fish/Cish amplified or Fish/Cish equivocal according to the
             ASCO2015 criteria;

          3. Prior endocrine therapy in the metastatic setting is not allowed;

          4. Prior treatment with any CDK 4/6 inhibitor in the adjuvant or metastatic setting
             (neoadjuvant/preoperative treatment is allowed); however, prior therapy with another
             targeted treatment in the adjuvant setting is allowed;

          5. Visceral crisis: Advanced, symptomatic, visceral spread that is at risk of
             life-threatening complication in the short term and that requires chemotherapy;

          6. Any major surgery (defined as requiring general anaesthesia) or significant traumatic
             injury within 4 weeks of treatment initiation or patients that may require major
             surgery during the course of the study; however, surgical diagnostic procedure is
             allowed (even if performed under general anaesthesia);

          7. Known, active bleeding diathesis;

          8. Any serious known concomitant systemic disorder (e.g. known active infection including
             HIV, or cardiac disease) incompatible with the study (at the discretion of
             investigator), previous history of bleeding diathesis, or anti-coagulation treatment
             (the use of low molecular weight heparin is allowed);

          9. Patients unable to swallow tablets;

         10. History of mal-absorption syndrome or other condition that would interfere with
             enteral absorption;

         11. Chronic daily treatment with corticosteroids with a dose of ≥ 10mg/day
             methylprednisolone equivalent (excluding inhaled steroids);

         12. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or
             leptomeningeal disease as indicated by clinical symptoms, cerebral oedema, and/or
             progressive growth. Patients with a history of CNS metastases or cord compression are
             eligible if they have been definitively treated with local therapy (e.g.,
             radiotherapy, stereotactic surgery) and are clinically stable and off anticonvulsants
             and steroids for at least 4 weeks before treatment start;

         13. Known hypersensitivity to letrozole, anastrozole, exemestane, fulvestrant, palbociclib
             or any of their excipients;

         14. QTcF >480 msec on basal assessment, personal history of long or short QT syndrome,
             Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP);

         15. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging
             drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia);

         16. Patients treated within the last 7 days prior to treatment start in the trial with
             drug that are known to be CYP3A4 inhibitors, drugs that are known to be CIP3A4
             inducers, drugs that are known to prolong the QT interval; who underwent a grapefruit
             cure;

         17. Patients already included in another therapeutic trial evaluating an investigational
             medicinal product or having received an investigational medicinal product within 3
             months;

         18. History of previous:

             Any other stage II, III, IV cancer within 5 years preceding patient enrollment in the
             trial - however, multiple primary breast cancers (controlateral/ipsilateral
             cancers/local relapses) are allowed pending all tumor masses were ER+; Any history of
             hematological malignancy;

         19. Persons deprived of their freedom or under guardianship or incapable of giving
             consent;

         20. Pregnancy or lactation period. Women of childbearing potential must implement adequate
             non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive
             devices, sterilization; LHRH agonist cannot be considered as an efficient
             contraceptive measure) during study treatment and for 90 days after discontinuation. A
             serum pregnancy test must be negative in premenopausal women or women with amenorrhea
             of less than 12 months.