Neoadjuvant Dose-Dense For Early Her2Neu Positive Breast Cancer

A Phase II Randomized Trial Evaluating Neoadjuvant Dose-Dense Doxorubicin/Cyclophosphamide Followed by Paclitaxel/Trastuzumab/Pertuzumab (AC THP) and Docetaxel/Carboplatin/Trastuzumab/Pertuzumab (TCHP) For Early Her2Neu Positive Breast Cancer

Primary Objective:

• Determination of pathologic complete response (pCR) rates

Secondary Objective:

• Determination of cardiac toxicity as measured by: composite of LVEF, longitudinal strain and troponin.
• Breast conservation rates
• Overall survival

Study Design

• Approximately 34-74 patients with Her2 positive, Stage II-regional IV breast cancer will be enrolled.

• Patients will be stratified by ER/PR status.

• They will be randomized to ddACTHP vs TCHP.

  • Initially, 17 patients will be randomly assigned to each treatment arm.
  • If 3 or fewer patients have a pCR, then that arm will be terminated and no further patients will be entered on that treatment arm.
  • If 4 or more patients obtain a pCR, 20 additional patients (total of 37 patients) will be randomized to that treatment arm.
  • If 11 or more patients out of 37 have a pCR, the treatment will be of interest for further study.

Inclusion Criteria:

The patient must have signed and dated an IRB-approved consent form that conforms to federal and institutional guidelines.

• Female

• 18 years or older

• ECOG performance status of 0 or 1

• Eligible tumors must meet one of the following criteria:

  • Operable (T1c, T2-3, N0-1, M0)
  • Locally advanced (T2-3, N2-3, M0 or T4a-c, any N, M0)
  • Inflammatory breast cancer (T4d, any N, M0)

• Staging evaluation:

  • History and physical exam, cbc, chemistry profile
  • CT Chest/Abdomen/Pelvis and a bone scan or PET/CT as needed

• Diagnosis of invasive adenocarcinoma made by core needle biopsy

• Breast cancer determined to be:

• Confirmed HER2-positive : (ASCO CAP guidelines, 10/7/2013)

  • IHC 3+ based on circumferential membrane staining that is complete, intense
  • ISH positive based on:
  • Single probe average HER2 copy number ≥ 6 signals/cell
  • Dual probe HER2/CEP 17 ratio ≥ 2.0 with an average HER2 copy number ≥ 4.0 signals/cell
  • Dual probe HER2/CEP 17 ratio ≥ 2.0, with an average HER2 copy number of < 4.0 signals/cell
  • Dual probe HER2/CEP 17 ratio < 2.0 with the average HER2 copy number of ≥ 6.0 signals/cell

• any ER or PR receptor status

• LVEF assessment by echocardiogram within 30 days of initiation; EF of ≥ 55% considered normal.

• Normal troponin I level at baseline

• Blood counts must meet the following criteria:

  • ANC greater than or equal to 1500/mm3
  • Platelet count greater than or equal to 100,000/mm3
  • Hemoglobin greater than or equal to 10 g/dL

• Serum creatinine less than or equal 2.5 mg/100ml

• Adequate hepatic function by these criteria: total bilirubin must be less than or equal to 1.5 x the ULN for the lab unless the patient has a bilirubin elevation great than the ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin; and alkaline phosphatase must be less than or equal to 2.5 x ULN for the lab; and AST must be less than or equal to 1.5 x ULN for the lab. Both alkaline phosphatase and AST may not both be greater than the ULN.

• Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the study if liver imaging (CT, MRI, PET-CT or PET scan) performed within 90 days prior to randomization does not demonstrate metastatic disease and the requirements are met as above

• Patients with alkaline phosphatase that is > ULN but less than or equal to 2.5 x ULN or unexplained bone pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 90 days prior to randomization does not demonstrate metastatic disease.

Exclusion Criteria:

Patients with a history of decompensated congestive heart failure or an EF < 55% will be excluded

• Cardiac disease that would preclude the use of the drugs included in the above regimens. This includes but is not confined to:

• Active cardiac disease:
• angina pectoris requiring the use of anti-anginal medication;
• ventricular arrhythmias except for benign premature ventricular contractions controlled by medication;
• conduction abnormality requiring a pacemaker;
• supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; and
• clinically significant valvular disease
• symptomatic pericarditis
• pulmonary hypertension
• History of cardiac disease:
• myocardial infarction;
• congestive heart failure; or
• cardiomyopathy