This is a multicenter neoadjuvant trial conducted under the sponsorship and overall trial management of the Fondazione Michelangelo in Italy.

Women with a diagnosis of invasive unilateral non metastatic ER-positive breast cancer expressing HER2 and suitable for neoadjuvant therapy Patients in this study will receive: Trastuzumab+Pertuzumab+Palbociclib with or without Fulvestrant (HPPF)

Trastuzumab 8 mg/kg loading dose IV, then 6 mg/kg IV q.3 wks (repeat for a total of 6 administrations) Pertuzumab 840 mg loading dose IV, then 420 mg IV q. 3 wks (repeat for a total of 6 administrations) Palbociclib 125 mg po q.d. x 21 q. 4 wks (= 1 cycle; repeat for a total of 5 cycles) Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks (repeat for 5 times) with an additional 500 mg dose given two weeks after the initial dose (total administrations including the additional one = 6)

The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and fulvestrant (5 administrations every 4 weeks plus the additional dose given two weeks after the initial dose) was selected to match as closely as possible the total duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab

Definitive surgery will be performed not earlier than 14 days and not later than 28 days after the last dose of any of the drugs in the combination reported above

After completion of the neoadjuvant and surgical treatment patients will receive irradiation as locally acceptable.

Patients will also continue to receive systemic drug therapy including chemotherapy (plus standard anti-HER2 treatment until completion of full 1 year if HER2 3+ or neu amplified, i.e. cohorts A and B) and endocrine therapy according to local guidelines at the Investigator's discretion.

This is a multicenter neoadjuvant trial conducted under the sponsorship and overall trial management of the Fondazione Michelangelo in Italy.

Three cohorts of patients are planned

Patients with ER positive tumors (> 10%) and HER2 3+ or neu amplified Cohort A Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF)

Cohort B Trastuzumab+Pertuzumab+Palbociclib (HPP) Allocation to Cohort B will be started after recruitment to Cohort A has been completed

Patients with ER positive tumors (> 10%), PgR positive, HER2 1+/2+ (without amplification) and Ki67 > 20% Cohort C Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF)

Trastuzumab 8 mg/kg loading dose IV, then 6 mg/kg IV q.3 wks (repeat for a total of 6 administrations) Pertuzumab 840 mg loading dose IV, then 420 mg IV q. 3 wks (repeat for a total of 6 administrations) Palbociclib 125 mg po q.d. x 21 q. 4 wks (= 1 cycle; repeat for a total of 5 cycles) Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks (repeat for 5 times) with an additional 500 mg dose given two weeks after the initial dose (total administrations including the additional one = 6)

The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and fulvestrant (5 administrations every 4 weeks plus the additional dose given two weeks after the initial dose) was selected to match as closely as possible the total duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab

Definitive surgery will be performed not earlier than 14 days and not later than 28 days after the last dose of any of the drugs in the combination reported above

After completion of the neoadjuvant and surgical treatment patients will receive irradiation as locally acceptable.

Patients will also continue to receive systemic drug therapy including chemotherapy (plus standard anti-HER2 treatment until completion of full 1 year if HER2 3+ or neu amplified, i.e. cohorts A and B) and endocrine therapy according to local guidelines at the Investigator's discretion.

Primary objectives:

• Characterize changes of Ki67 from baseline before therapy and at 2 weeks and at surgery (approximately 22 weeks after start of neoadjuvant therapy with HPPF).
• Characterize changes in apoptosis from baseline before therapy and at surgery (approximately 22 weeks after start of neoadjuvant therapy with HPPF).
• Study the tolerability profile of the combination

Secondary objectives:

• Assess the rate of pathological complete response (pCR) defined as ypT0-ypTis ypN0 at surgery
• Define the clinical objective response rate at the end of the combination
• Conduct molecular and clinical analyses to assess the presence of informative markers of benefit in addition to Ki67 and apoptosis

Inclusion Criteria:

1. Female patients aged 18 years or older with tumors suitable for neoadjuvant treatment
2. Early (> 1.5 cm) or locally advanced untreated breast cancer
3. Histologically confirmed invasive unilateral breast cancer
4. HER2 status to be centrally confirmed (HER2 3+ of neu amplified for cohorts A and B; HER2 1+/2+ without amplification for cohort C)
5. Positive estrogen receptor (ER) > 10% and known progesterone receptor (PgR). Note: PgR assessment must be positive for cohort C
6. Ki67 > 20% for cohort C
7. Available paraffin-embedded tumor block taken at diagnostic biopsy for central retrospective confirmation of HER2 and ER eligibility and for assessment of Ki67 value and apoptosis is mandatory
8. All patients must agree to provide tumor tissues for centralized assessment of KI67 values and apoptosis at the required timelines (2 weeks from starting protocol therapy and at surgery)
9. ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1
10. Written informed consent to participate in the trial (approved by the Institutional Review Board/ Independent Ethics Committee) obtained prior to any study specific screening procedures
11. Willing and able to comply with the protocol

Exclusion Criteria:

1. Evidence of bilateral invasive breast cancer or metastatic disease (M1)
2. Pregnant or lactating women.
3. Women with childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception
4. Previous treatment with chemotherapy, hormonal therapy or an investigational drug for any type of malignancy
5. Previous extensive radiotherapy
6. Previous investigational treatment for any condition within 4 weeks of registration date
7. Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol
8. Previous or concomitant malignancy of any other type that could affect compliance with the protocol or interpretation of results.
9. Other serious illness or medical condition including: history of documented congestive cardiac failure; angina pectoris requiring anti-anginal medication; evidence of transmural infarction on ECG; poorly controlled hypertension; clinically significant valvular heart disease; high-risk uncontrolled arrhythmias
10. Baseline left ventricular ejection fraction (LVEF) < 55% by echocardiography or multi-gated scintigraphic scan (MUGA)
11. QTc (corrected QT interval) >480 msec or a family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP)
12. Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and precluding informed consent or adversely affecting compliance with study drugs
13. Serious uncontrolled infections (bacterial or viral) or poorly controlled diabetes mellitus
14. Current use or anticipated need for food or drugs that are known strong CYP3A4 (cytochrome P450 3A4) inhibitors or inducers
15. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia)
16. Abnormal baseline hematological values:
17. Abnormal baseline liver function, bilirubin, creatinine and/or INR (international normalized ratio)