A RANDOMIZED MULTICENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED COMPARISON OF CHEMOTHERAPY PLUS TRASTUZUMAB PLUS PLACEBO VERSUS CHEMOTHERAPY PLUS TRASTUZUMAB PLUS PERTUZUMAB AS ADJUVANT THERAPY IN PATIENTS WITH OPERABLE HER2-POSITIVE PRIMARY BREAST CANCER

INTERVENTION: TO PARTICIPATE IN THE TRIAL, A PATIENT MUST FULFILL ALL INCLUSION CRITERIA, MUST NOT MEET ANY OF THE EXCLUSION CRITERIA, AND WILL NEED TO CONSENT TO COLLECTION AND STORAGE OF BLOOD SAMPLES AND TUMOR TISSUE SAMPLES FO BIOMARKER RESEARCH AS SPECIFIED IN SECTION 5.6. THE INVESTIGATOR SHOULD SELECT ONE OF THE PROTOCOL APPROVED ADJUVANT CHEMOTHERAPY REGIMENS (DESCRIBED BELOW) WITH WHICH TO TREAT THE PATIENT. ONCE THE THE INVESTIGATORS´ CHOICE OF CHEMOTHERAPY HAS BEEN MADE AND ELIGIBILITY CONFIRMED, THE PATIENT WILL BE RANDOMIZED TO RECEIVE TRASTUZUMAB PLUS PLACEBO OR TRASTUZUMAB PLUS PERTUZUMAB. THE INVESTIGATORS´ CHOICE OF ADJUVANT CHEMOTHERAPY MUST BE RECORDED ON THE ELECTRONIC CASE RCORD (eCRF) AND THIS CHOICE MUST BE MAINTAINED THROUGHOUT ADJUVANT CHEMOTHERAPY. PATIENTS WILL BE RECRUITED IN APPROXIMATELY 700 CENTERS WORLDWIDE. CONDITION: PRIMARY OUTCOME: Time between randomization and date of first ocurrence of an IDFS event (invasive disease‐free survival); NAME OF THE RESULT: Invasive disease‐free survival; USED MEASURING METHOD :The stratified log‐rank test will be used to compare IDFS between the two treatment arms. The Kaplan‐Meier approach will be used to estimate 3‐year IDFS rates for each treatment arm.; PERIOD OF TIME WHERE THE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: 3 years SECONDARY OUTCOME: OS, DFS, IDFS, including second primary non‐breast cancer, RFI and DRFI ; NAME OF THE RESULT: Overall Survival, Disease Free Survival, Invasive Disease‐Free Survival including second primary non‐breast cancer, Recurrence‐Free Interval and Distant Recurrence‐Free Interval. ; USED MEASURING METHOD :The two treatment arms will be compared using the stratified log rank test, estimate 3‐year event rates (5‐year event rates for OS) and the HR between treatment arms with 95% CI. Analyses will be based on the ITT population. ; PERIOD OF TIME WHERE THE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE SECONDARY RESULT: Up to 13 years. INCLUSION CRITERIA: 1. AGE ≥ 18 YEARS. 2. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS ≤ 1. 3. NON‐METASTATIC OPERABLE PRIMARY INVASIVE CARCINOMA OF THE BREAST THAT IS: A) HISTOLOGICALLY CONFIRMED; B) ADEQUATELY EXCISED: • PATIENTS MUST HAVE UNDERGONE EITHER A TOTAL MASTECTOMY OR BREAST CONSERVING SURGERY. • FOR PATIENS WHO UNDERGO CONSERVATIVE SURGERY, THE MARGINS OF THE RESECTED SPECIMEN MUST BE HISTOLOGICALLY FREE OF INVASIVE TUMOR AND DUCTAL CARCINOMA IN SITU (DCIS), AS DETERMINED BY THE LOCAL PATHOLOGIST. IF PATHOLOGIC EXAMINATION DEMONSTRATES TUMOR AT THE LINE OF RESECTION, ADDITIONAL OPERATIVE PROCEDURES MAY BE PERFORMED TO OBTAIN CLEAR MARGINS. IF TUMOR IS STILL PRESENT AT THE RESECTED MARGIN RE‐EXCISION(S), THE PATIENT MUST UNDERGO TOTAL MASTECTOMY TO BE ELIGIBLE. PATIENTS WITH MARGINS POSITIVE FOR LOBULAR CARCINOMA IN SITU (LCIS) ARE ELIGIBLE WITHOUT ADDITIONAL RESECTION. • FOR PATIENTS WHO UNDERGO MASTECTOMY, MARGINS MU