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

Inclusion Criteria:

• 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
      • pT2 and ER positive (PgR status may be positive or negative) and either grade 3histology or Oncotype DX Recurrence Score of >= 25; or
      • pT3 regardless of hormone receptor status, histologic grade, and Oncotype DX Recurrence Score
• No T4 tumors including inflammatory breast cancer

• No 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
• No synchronous or previous contralateral invasive breast cancer (patients with synchronous and/or previous contralateral DCIS or lobular carcinoma in situ [LCIS] are eligible)
• No previous ipsilateral invasive breast cancer or ipsilateral DCIS (patients with synchronous or previous ipsilateral LCIS are eligible)

• 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 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

• No 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

• 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 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 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 RT of the chest wall will be administered)
  • 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 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
  • Axillary lymphadenectomy with or without SN isolation procedures
• 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
• Pre- or postmenopausal
• Eastern Cooperation Oncology Group (ECOG) performance status of 0 or 1
• 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 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 (CT, MRI, 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, positron emission tomography (PET)-computed tomography (CT) scan, or PET scan performed within 90 days prior to randomization does not demonstrate metastatic disease
• The most recent post operative serum creatinine performed within 6 weeks prior to randomization must be =< ULN for the lab
• Not pregnant or nursing
• Negative pregnancy test

• Left ventricular ejection fraction (LVEF) assessment must be performed within 90 days prior to randomization; LVEF assessment performed by 2-dimensional (D) echo cardiogram 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
• No 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

• No cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens, including, but not limited 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

• No 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 OR 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
• No active hepatitis B or hepatitis C with abnormal liver function tests
• No intrinsic lung disease resulting in dyspnea
• No poorly controlled diabetes mellitus
• No active infection or chronic infection requiring chronic suppressive antibiotics
• No nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) >= grade 2, per the Common Terminology Criteria for Adverse Events (CTCAE) v4.0
• No conditions that would prohibit administration of corticosteroids
• No known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80 and Cremophor EL
• No other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up
• No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements
• Concurrent participation in NSABP-B-39 allowed
• No previous therapy with anthracyclines, taxanes, or trastuzumab for any malignancy
• No chemotherapy or HER2-targeted therapy administered for the currently diagnosed breast cancer prior to randomization
• No whole-breast radiation therapy (RT) prior to randomization or partial-breast RT that cannot be completed on or before the date of randomization
• No use of any investigational product within 30 days prior to randomization
• No continued endocrine therapy such as raloxifene or tamoxifen (or other SERM) or an aromatase inhibitor (patients are eligible if these medications are discontinued prior to randomization)
• No 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)
• No chronic daily treatment with corticosteroids with a dose of >= 10 mg/day methylprednisol one equivalent (excluding inhaled steroids)
• No other concurrent chemotherapy
• No other concurrent targeted therapy for malignancy
• No partial-breast irradiation following randomization