Chemotherapy With or Without Trastuzumab After Surgery in Treating Women With Invasive Breast Cancer

Inclusion Criteria:

   - Patients should have a life expectancy of at least 10 years, excluding their diagnosis
   of breast cancer; (comorbid conditions should be taken into consideration, but not the
   diagnosis of breast cancer)

   - Women of reproductive potential must agree to use an effective non-hormonal method of
   contraception (for example condoms, some intrauterine devices, diaphragms, tubal
   ligation, vasectomized partner, or abstinence) during therapy and for at least 6
   months (Arm 1 patients) and for at least 7 months (Arm 2 patients) after the last dose
   of study therapy (chemotherapy or trastuzumab)

   - Submission of tumor samples from the breast surgery is required for all patients;
   therefore, the local pathology department policy regarding release of tumor samples
   must be considered in the screening process; patients whose tumor samples are located
   in a pathology department that by policy will not submit any samples for research
   purposes should not be approached for participation in the B-47 trial

   - The patient must have signed and dated an Institutional Review Board (IRB)-approved
   consent form that conforms to federal and institutional guidelines

   - Eastern Cooperation Oncology Group (ECOG) performance status of 0 or 1

   - The tumor must be unilateral invasive adenocarcinoma of the breast on histologic
   examination

   - All of the following staging criteria (according to the 7th edition of the American
   Joint Committee on Cancer [AJCC] Cancer Staging Manual) must be met:

      - By pathologic evaluation, primary tumor must be pT1-3

      - By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b,
      pN1c), pN2a, pN2b, pN3a, or pN3b

         - If pN0, one of the following criteria must be met:

            - pT2 and estrogen receptor (ER) negative and progesterone receptor (PgR)
            negative; or

            - pT2 and ER positive (PgR status may be positive or negative) and either
            grade 3 histology or Oncotype DX Recurrence Score of >= 25; or

            - pT3 regardless of hormone receptor status, histologic grade, and
            Oncotype DX Recurrence Score

   - HER2 status of the primary tumor must be evaluated prior to randomization; all testing
   performed must indicate that the tumor is HER2-low as defined below

      - IHC must be performed and the IHC staining results must indicate a score of 1+
      (in situ hybridization [ISH] testing is not required) or 2+ (ISH must also be
      performed and must indicate that the tumor is HER2-low as described below)

      - If ISH testing is performed, test results must be as follows and IHC must be 1+
      or 2+: the ratio of HER2 to chromosome enumeration probe 17 (CEP17) must be < 2.0
      or, if a ratio was not performed, the HER2 gene copy number must be < 4 per
      nucleus

      - Note: If the IHC staining intensity is reported as a range, e.g., 0 to 1+ or 1+
      to 2+, the higher intensity score in the range should be used to determine
      eligibility

   - The patient must have undergone either a total mastectomy or breast-conserving surgery
   (lumpectomy); (patients who have had a nipple-sparing mastectomy are eligible)

   - For patients who undergo lumpectomy, 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 after 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 must be free of gross residual tumor;
   (patients with microscopic positive margins are eligible as long as post-mastectomy
   radiation therapy [RT] of the chest wall will be administered)

   - The patient must have completed one of the procedures for evaluation of pathologic
   nodal status listed below:

      - Sentinel lymphadenectomy alone:

         - If pathologic nodal staging based on sentinel lymphadenectomy is pN0 or pN1b

         - If pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or
         pN1a, the primary tumor must be T1 or T2 by pathologic evaluation and the
         nodal involvement must be limited to 1 or 2 positive nodes

      - Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph
      nodes if the sentinel node (SN) is positive; or

      - Axillary lymphadenectomy with or without SN isolation procedures

   - The interval between the last surgery for breast cancer (treatment or staging) and
   randomization must be no more than 84 days

   - The patient must have ER analysis performed on the primary tumor prior to
   randomization; if ER analysis is negative, then PgR analysis must also be performed
   (either the core biopsy or surgical resection specimen can be used for ER/PgR
   testing); patients with a primary tumor that is hormone receptor-positive or
   receptor-negative are eligible

   - Absolute neutrophil count (ANC) must be >= 1,200/mm^3

   - Platelet count must be >= 100,000/mm^3

   - Hemoglobin must be >= 10 g/dL

   - Total bilirubin must be =< upper limit of normal (ULN) for the lab unless the patient
   has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert disease or similar
   syndrome involving slow conjugation of bilirubin

   - Alkaline phosphatase must be =< 2.5 x ULN for the lab

   - Aspartate aminotransferase (AST) must be =< 1.5 x ULN for the lab (if alanine
   aminotransferase [ALT] is performed instead of AST [per institution's standard
   practice], the alanine aminotransferase [ALT] value must be =< 1.5 x ULN; if both were
   performed, the AST must be =< 1.5 x ULN)

   - Alkaline phosphatase and AST may not both be > the ULN

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

   - Patients with alkaline phosphatase that is > ULN but =< 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

   - The most recent postoperative serum creatinine performed within 6 weeks prior to
   randomization must be =< ULN for the lab

   - Left ventricular ejection fraction (LVEF) assessment must be performed within 90 days
   prior to randomization; LVEF assessment performed by 2-dimensional (D) echocardiogram
   is preferred, however, multi-gated acquisition (MUGA) scan maybe substituted based on
   institutional preferences

      - For patients who will receive the TC chemotherapy regimen, the LVEF must be >=
      50% regardless of the cardiac imaging facility's lower limit of normal

      - For patients who will receive the AC-->WP chemotherapy regimen, the LVEF must be
      >= 55% regardless of the cardiac imaging facility's lower limit of normal

      - NOTE: Since the pre-entry LVEF serves as the baseline for comparing subsequent
      LVEF assessments, it is critical that this baseline study be an accurate
      assessment; if the baseline LVEF is > 70%, the investigator is encouraged to have
      the accuracy of the initial LVEF result confirmed and repeat the test if the
      accuracy is uncertain

Exclusion Criteria:

   - Primary tumor with any of the following HER2 testing results:

      - IHC staining intensity:

         - 0 on all evaluations of specimens

         - 3+ on evaluation of any specimen

      - ISH with a ratio of HER2 to CEP17 >= 2.0 on evaluation of any specimen

      - ISH result indicating HER2 gene copy number >= 4 per nucleus on evaluation of any
      specimen

   - T4 tumors including inflammatory breast cancer

   - Definitive clinical or radiologic evidence of metastatic disease

      - NOTE: Chest imaging (mandatory for all patients) and other imaging (if required)
      must have been performed within 90 days prior to randomization

   - Synchronous or previous contralateral invasive breast cancer (patients with
   synchronous and/or previous contralateral DCIS or LCIS are eligible)

   - Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS;
   (patients with synchronous or previous ipsilateral LCIS are eligible)

   - History of non-breast malignancies (except for in situ cancers treated only by local
   excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior
   to randomization

   - Previous therapy with anthracyclines, taxanes, or trastuzumab for any malignancy

   - Chemotherapy or HER2-targeted therapy administered for the currently diagnosed breast
   cancer prior to randomization

   - Whole-breast RT prior to randomization or partial-breast RT that cannot be completed
   on or before the date of randomization

   - Continued endocrine therapy such as raloxifene or tamoxifen (or other selective
   estrogen receptor modulator [SERM]) or an aromatase inhibitor; patients are eligible
   if these medications are discontinued prior to randomization

   - Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone
   replacement therapy; patients are eligible if these medications are discontinued prior
   to randomization

   - Cardiac disease (history of and/or active disease) that would preclude the use of the
   drugs included in the treatment regimens; this includes but is not confined to:

      - Active cardiac disease:

         - Angina pectoris that requires the current use of anti-anginal medication

         - Ventricular arrhythmias except for benign premature ventricular contractions

         - Supraventricular and nodal arrhythmias requiring a pacemaker or not
         controlled with medication

         - Conduction abnormality requiring a pacemaker

         - Valvular disease with documented compromise in cardiac function

         - Symptomatic pericarditis

      - History of cardiac disease:

         - Myocardial infarction documented by elevated cardiac enzymes or persistent
         regional wall abnormalities on assessment of left ventricle (LV) function

         - History of documented congestive heart failure (CHF)

         - Documented cardiomyopathy

   - Hypertension defined according to the following ineligibility criteria:

      - For patients who will receive TC (regardless of the patient's age): uncontrolled
      hypertension defined as sustained systolic blood pressure (BP) > 150 mm Hg or
      diastolic BP > 90 mm Hg; (patients with initial BP elevations are eligible if
      initiation or adjustment of BP medication lowers pressure to meet entry criteria)

      - For patients < 50 years old who will receive AC-->WP: uncontrolled hypertension
      defined as sustained systolic BP > 150 mm Hg or diastolic BP > 90 mm Hg; patients
      with initial BP elevations are eligible if initiation or adjustment of BP
      medication lowers pressure to meet entry criteria

      - For patients >= 50 years old who will receive AC-->WP:

         - Uncontrolled hypertension defined as sustained systolic BP > 150 mm Hg or
         diastolic BP > 90 mm Hg

         - Controlled hypertension (systolic BP =< 150 mm Hg and diastolic BP =< 90
         mmHg), if anti-hypertensive medication(s) are needed

      - NOTE: Patients who are not eligible based on the AC-WP regimen BP criteria but
      who meet the TC regimen BP criteria are eligible for B-47, if the intended
      chemotherapy regimen is changed to TC

   - Active hepatitis B or hepatitis C with abnormal liver function tests

   - Intrinsic lung disease resulting in dyspnea

   - Poorly controlled diabetes mellitus

   - Active infection or chronic infection requiring chronic suppressive antibiotics

   - Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral
   sensory neuropathy) >= grade 2, per the Common Terminology Criteria for Adverse Events
   (CTCAE) version (v)4.0

   - Conditions that would prohibit administration of corticosteroids

   - Chronic daily treatment with corticosteroids with a dose of >= 10 mg/day
   methylprednisol one equivalent (excluding inhaled steroids)

   - Known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80
   and Cremophor EL

   - Pregnancy or lactation at the time of study entry; (Note: pregnancy testing must be
   performed within 2 weeks prior to randomization according to institutional standards
   for women of childbearing potential)

   - Other non-malignant systemic disease that would preclude the patient from receiving
   study treatment or would prevent required follow-up

   - Psychiatric or addictive disorders or other conditions that, in the opinion of the
   investigator, would preclude the patient from meeting the study requirements

   - Use of any investigational product within 30 days prior to randomization