This is an international, randomized, open-label, controlled, multicenter phase II clinical trial to investigate and compare the safety and efficacy of palbociclib combined with fulvestrant or letrozole in women with ER+, HER2- locally advanced or metastatic breast cancer.

Patients will be stratified by site of disease (visceral vs. non-visceral) and by onset of metastatic disease diagnose (patients metastatic de novo versus non de novo).

Inclusion Criteria:

1. Women 18 years or older with metastatic or locally advanced disease, not amenable to curative therapy
2. Confirmed diagnosis of HR+/HER2- breast cancer
3. Post-menopausal status
4. No prior chemotherapy line in the metastatic setting
5. Measurable disease defined by RECIST version 1.1, or non-measurable disease
6. Eastern Cooperative Oncology Group (ECOG) PS 0-1
7. Adequate organ and marrow function, resolution of all toxic effects of prior therapy or surgical procedures
8. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCICTCAE version 4.0 Grade equal or minor than 1

Exclusion Criteria:

1. ER or HER2 unknown disease
2. HER2 positive disease based on local laboratory results
3. Locally advanced breast cancer candidate for a radical treatment
4. Prior (neo)adjuvant endocrine treatment with DFI ≤ 12-months from completion of treatment.
5. Patients with rapidly progressive visceral disease or visceral crisis.
6. Major surgery within 4 weeks of start of study drug
7. Patients with an active, bleeding diathesis
8. Serious concomitant systemic disorder incompatible with the study
9. Are unable to swallow tablets
10. Chronic daily treatment with corticosteroids with a dose of ≥ 10mg/day methylprednisolone equivalent
11. Known active uncontrolled or symptomatic CNS metastases
12. Known hypersensitivity to letrozole, fulvestrant or any of their excipients, or to any PD-0332991 excipients
13. QTc > 480 msec on basal assessments, personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes
14. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug