Impact of Pegfilgrastim on Trastuzumab Anti-tumor Effect and ADCC in Operable HER2+ Breast Cancer Breast Cancer

Inclusion Criteria:

• Female patients aged ≥ 18 years at time of inform consent signature.

• Histologically proven HER2 positive breast cancer defined as 3+ staining intensityby immunohistochemistry (IHC) or a 2+ IHC staining intensity and HER2 geneamplification by FISH.Note: HER2 status will be determined as per institutionalpractice.

• Operable breast tumor with tumor size and staging: > 20 mm, cN0 or cN1, M0 beforeany AC or FEC chemotherapy, and at least one measurable lesion ≥10 mm in longestdiameter at inclusion according to RECIST 1.1.

• No radiological sign of disease progression at time of randomisation.

• Patient previously treated by 4 cycles of AC or 3 to 4 cycles of FEC without febrileneutropenia and without prior pegfilgrastim treatment.

• Availability of a representative formalin-fixed paraffin-embedded (FFPE) tumorspecimen from initial diagnosis (i.e. an archival paraffin block is preferred; or atleast 20 unstained slides) with its histological report.

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Adequate organ function as defined by the following lab tests (to be carried outwithin 7 days prior C1D1):Bone marrow (Absolute neutrophil count ≥ 1.5 x 109/L,Platelet count > 100 x 109/L, (without transfusion within 21 days prior to C1D1),Hemoglobin value ≥ 9 g/dL), Renal function (Calculated creatinine clearance by MDRDor CKD-EPI >50 mL/min/1.73m2 or serum creatinine < 1.5ULN), Liver function (Alanineaminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3ULN, Total serumbilirubin ≤ 1.5 ULN (except for patients with Gilbert disease for whom a total serumbilirubin ≤3 ULN is acceptable), Coagulation (INR and aPTT≤ 1.5 ULN)

• Adequate cardiac function with Mean resting corrected QT interval (QTc), calculatedusing Fridericia's formula, ≤470ms obtained from 3 electrocardiograms (ECGs) andSystolic blood pressure <160mmHg and Diastolic blood pressure <100mmHg (hypertensioncontrolled by standard medical treatment is allowed)

• Women of childbearing potential (entering the study after a confirmed menstrualperiod and who have a negative pregnancy test within 7 days before C1D1) must agreeto use two methods of medically acceptable forms of contraception from the date ofnegative pregnancy test to 3 months after the last study drug intake

• Patients should be able and willing to comply with study visits and procedures asper protocol

• Patients should understand, sign, and date the written voluntary informed consentform at the screening visit prior to any protocol-specific procedures performed.

• Patients must be covered by a medical insurance.

Exclusion Criteria:

• Patients with inflammatory breast cancer.

• Previous exposure to pegfilgrastim or trastuzumab. Note: the use of filgrastim (nonpegylated form only) is authorized prior to the randomisation.

• Patients requiring the concomitant use of any forbidden treatment including: Anyother anti-cancer treatments not listed in the protocol, including chemotherapy,radiotherapy, immunotherapy, targeted therapy or biologic therapy for cancertreatment, Any investigational treatment.

• Any contra-indication to trastuzumab, paclitaxel, and pegfilgrastim respective SPCsincluding:Hypersensitivity to trastuzumab, murine proteins, or to any of theexcipients listed in trastuzumab SPC, Severe dyspnea at rest due to complications ofadvanced malignancy or requiring supplementary oxygen therapy, Hypersensitivity topegfilgrastim or filgrastim, or to any of the excipients listed in SPC, Hereditaryproblems of fructose intolerance, Hypersensitivity to paclitaxel or to anyexcipient, particularly macrogolglycerol ricinoleate, Patients with history of oractive cardiac disease including myocardial infarction (MI), angina pectorisrequiring medical treatment, congestive heart failure NYHA (New York HeartAssociation) Class ≥II, other cardiomyopathy, cardiac arrhythmia requiring medicaltreatment, clinically significant cardiac valvular disease, and hemodynamiceffective pericardial effusion.

• Active secondary malignancy unless this malignancy is not expected to interfere withthe evaluation of study endpoints and is approved by the sponsor. Examples of thelatter include basal or squamous cell carcinoma of the skin, in-situ carcinoma ofthe cervix. Patients with a completely treated prior malignancy and no evidence ofdisease for ≥ 2 years are eligible.

• Pregnant or breast-feeding female patients.