Inclusion Criteria:

          1. Adult women (≥ 18 years of age) with proven diagnosis of adenocarcinoma of the breast
             with evidence of loco-regional recurrent or metastatic disease not amenable to
             resection or radiation therapy with curative intent and for whom chemotherapy is not
             clinically indicated.

          2. Documentation of histologically or cytologically confirmed diagnosis of
             estrogen-receptor (ER) expression >10% and/or progesterone receptor (PR) expression
             >10% breast cancer based on local laboratory results.

          3. Previously untreated with any systemic anti-cancer therapy for loco-regional recurrent
             or metastatic HR+ disease, with the exception of recently started (within 28 days of
             randomization) endocrine therapy.

          4. Women who are not post-menopausal must use LHRH agonist. Postmenopausal status is
             defined as:

               1. prior bilateral surgical oophorectomy, or

               2. spontaneous cessation of regular menses for at least 12 consecutive months
                  without OAC

               3. in case of doubt serum estradiol <20 umol/l and follicle stimulating hormone
                  (FSH) levels >15 IU/L at screening

          5. Measurable or evaluable disease as defined per RECIST v.1.1 (see Appendix 3) or
             bone-only disease. Tumor lesions previously irradiated or subjected to other
             locoregional therapy will only be deemed measurable if disease progression at the
             treated site after completion of therapy is clearly documented.

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

          7. Adequate organ and marrow function defined as follows:

               1. ANC ≥1,000/mm3 (1.0 x 10e9 /L);

               2. Platelets ≥50,000/mm3 (50 x 10e9 /L);

               3. Estimated creatinine clearance ≥ 30 mL/min as calculated using the method
                  standard for the institution;

               4. Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if Gilbert's disease);

               5. AST and ALT ≤3 x ULN (≤5.0 x ULN if liver metastases present);

          8. 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.

          9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
             tests, and other study procedures.

         10. Evidence of a personally signed and dated informed consent document indicating that
             the patient (or a legal representative) has been informed of all pertinent aspects of
             the study before any study-specific activity is performed.

        Exclusion Criteria:

          1. Patients with advanced, symptomatic, visceral spread, who are at risk of
             life-threatening complications in the short term (including patients with massive
             uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and
             over 50% liver involvement).

          2. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or
             leptomeningeal disease as indicated by clinical symptoms, cerebral edema, 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 without the use of
             steroids for at least 4 weeks before randomization

          3. Prior neoadjuvant or adjuvant treatment with an aromatase inhibitor (i.e.,
             anastrozole, letrozole or exemestane) with disease recurrence while on or within 12
             months of treatment.

          4. Prior treatment with any CDK4/6 inhibitor.

          5. Patients treated within the last 7 days prior to randomization with:

               1. Food or drugs that are known to be CYP3A4 inhibitors (ie, amprenavir, atazanavir,
                  boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin,
                  fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil,
                  miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,
                  telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or grapefruit
                  juice);

               2. Drugs that are known to be CYP3A4 inducers (ie, carbamazepine, felbamate,
                  nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin,
                  and St. John's wort).

          6. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other
             anti-cancer therapy within 2 weeks before randomization. Patients who received prior
             radiotherapy to ≥25% of bone marrow are not eligible independent of when it was
             received.

          7. Diagnosis of any other malignancy prior to randomization, except those that are not
             believed to influence the patient's prognosis and do not require any further
             treatment. This includes, but is not limited to adequately treated basal cell or
             squamous cell skin cancer and carcinoma in situ of the cervix.

          8. QTc >480 msec at baseline

          9. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any
             upper gastrointestinal surgery including gastric resection.

         10. Known hypersensitivity to letrozole or anastrozole, or any of its excipients, or to
             any palbociclib excipients.

         11. Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or
             investigational product administration or may interfere with the interpretation of
             study results and, in the judgment of the investigator, would make the patient
             inappropriate for entry into this study.

         12. Recent or active suicidal ideation or behavior.