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
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.