Inclusion Criteria:

• Required tumor parameters for node positive disease: NOTE: This study will continue to use the American Joint Committee on Cancer (AJCC) 5th edition for TNM classification and staging
  • Operable, histologically confirmed adenocarcinoma of the female breast and positive lymph nodes
    • Node positivity may be determined by either an axillary node dissection or a positive sentinel node finding by hematoxylin and eosin (H&E)
      • NOTE: Positive nodes refers to H&E visible nodal metastases; immunohistochemistry (IHC) positive only cells in lymph nodes will not be considered positive nodes
    • One or more positive lymph nodes whose tumors are T1-3, pN1-2, M0 are eligible
    • cN2 disease is not eligible
    • pN2 disease is eligible
    • One positive lymph node by sentinel node biopsy or at least 6 axillary nodes must be examined on axillary node dissection with at least one positive lymph node
    • Metaplastic carcinoma is eligible
  • ER/PgR determination
  • HER-2 positive (pre-entry requirement for registration)
    • FISH must show gene amplification OR
    • IHC assay must show a strong positive (3+) staining score
      • NOTE: ductal carcinoma in situ (DCIS) components should not be counted in the determination of degree of IHC staining or FISH amplification
• Required tumor parameters for high-risk node-negative disease; NOTE: This study will continue to use the AJCC 5th edition for TNM classification and staging
  • Operable, histologically confirmed adenocarcinoma of the female breast and negative lymph nodes
    • Node status may be determined by either axillary node dissection or sentinel node biopsy with H&E staining; to be considered node negative, either of the following must be true: 1) negative sentinel node biopsy or 2) no positive lymph nodes found among at least 6 axillary nodes examined on axillary node dissection
    • NOTE: IHC positive only cells in lymph nodes will not be considered positive nodes
    • Tumors > 2.0 cm (irrespective of hormonal receptor status) or > 1.0 cm if ER-negative and PR-negative disease
  • ER/PgR determination
  • HER-2 positive (pre-entry requirement for registration)
    • FISH must show gene amplification OR
    • IHC assay must show a strong positive (3+) staining score
      • NOTE: DCIS components should not be counted in the determination of degree of IHC staining or FISH amplification
• ≤ 84 days from mastectomy or ≤ 84 days from axillary dissection or sentinel node detection if the patient's most extensive breast surgery was a breast sparing procedure; (This timing is per a decision by the Breast Intergroup)
• Surgical resection margins. All tumor should be removed by either a modified radical mastectomy or a segmental mastectomy with axillary node dissection
  • Mastectomy: There will be no evidence of gross or microscopic tumor (invasive or DCIS) at the surgical resection margins noted in the final surgery or pathology reports; patients with close margins are eligible
  • Segmental mastectomy (lumpectomy): Margins must be clear of invasive cancer and DCIS
  • Axillary dissection or sentinel node dissection: There will be no gross residual adenopathy
• TAM therapy
  • May have received up to four weeks of TAM therapy, or any other hormonal agent, for this malignancy
  • May have received TAM or raloxifene for purposes of chemoprevention (e.g., Breast Cancer Prevention Trial) or for other indications (including previous breast cancer if lobular carcinoma in situ [LCIS]) but must be discontinued before registration on this study
  • May never have received TAM, raloxifene, or any other hormonal agent
• Absolute neutrophil count (ANC) ≥ 1500/mm^3
• Platelets (PLT) ≥ 100,000/mm^3
• Total bilirubin ≤ 1.5 x upper normal limit (UNL)
• Aspartate aminotransferase (AST) ≤ 2.0 x UNL
• Left ventricular ejection fraction (LVEF) within institutional normal range; if LVEF is > 75%, the investigator should consider performing a second review of the multigated acquisition (MUGA)/echocardiogram or performing a repeat MUGA/echocardiogram prior to registration; such re-reviews or repeat MUGA/echocardiogram are not permitted after registration
• Willingness to discontinue sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc., prior to registration and while on study
• Willingness to discontinue any hormonal agent such as raloxifene (Evista) prior to registration and while on study
• Non-breast malignancies that have not recurred within the last 5 years and are deemed to be at low risk for recurrence

EXCEPTIONS: These non-breast malignancies are eligible even if diagnosed ≤ 5 years prior to registration:

• Squamous or basal cell carcinoma of the skin that has been effectively treated
• Carcinoma in situ of the cervix that has been treated by surgery only
• Lobular carcinoma in situ (LCIS) of the ipsilateral or contralateral breast treated by surgery and/or tamoxifen only
  • Patients undergoing breast conservation therapy (i.e., lumpectomy and axillary dissection) must have plans to receive radiation therapy to the breast +/- regional lymphatics following completion of the chemotherapy; for patients treated with mastectomy, the use of radiation therapy is required for 4 or more positive lymph nodes and must be started after completion of chemotherapy; the use of radiation therapy is at the discretion of the investigator for 0-3 positive lymph nodes but, if used, must be started after the completion of chemotherapy
  • Prior to registration, the physician must designate if it is planned for the patient to receive radiation therapy (for adjuvant radiation therapy post-mastectomy or, less commonly, post-conservative therapy but not primary breast radiation as part of breast conserving treatment)
  • Willing and able to sign an informed consent
  • Gene amplified by FISH or strong positivity (3+) by HercepTest on central review; Note: The patient registers based on community HER-2 testing using FISH or IHC, AC chemotherapy is initiated; the tumor block or slides must be received ≤ 2 weeks from time of registration to the North Central Cancer Treatment Group (NCCTG) Operations Office for central HER-2 testing

Exclusion Criteria:

• Any of the following:
  • Pregnant women
  • Nursing women
  • Women of childbearing potential or their sexual partners who are unwilling to employ adequate contraception (condoms, diaphragm, intrauterine device [IUD], surgical sterilization, or abstinence, etc.); hormonal birth control methods are not permitted
• Locally advanced tumors (classification T4) at diagnosis including tumors fixed to chest wall, peau d'orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse brawny cutaneous induration with an erysipeloid edge)
• Prior history of breast cancer, except LCIS
• Bilateral invasive carcinoma, either metachronous or synchronous (EXCEPTION: Patients diagnosed with unilateral invasive carcinoma and metachronous or synchronous DCIS of the contralateral breast treated with mastectomy are eligible)
• Prior chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer
• Active, unresolved infection
• Active cardiac disease
  • Any prior myocardial infarction
  • History of documented congestive heart failure (CHF)
  • Current use of digitalis or beta-blockers for CHF
  • Any prior history of arrhythmia or cardiac valvular disease requiring medications or clinically significant
  • Current use of medications for treatment of arrhythmias or angina pectoris
  • Current uncontrolled hypertension (diastolic > 100 mmHg or systolic > 200 mmHg)
  • Clinically significant pericardial effusion
• Prior anthracycline or taxane therapy for any malignancy
• Sensitivity to benzyl alcohol
• Neurology/Neuropathy-Sensory ≥ grade 2 per the National Cancer Institute's (NCI's) Common Toxicity Criteria Version 2.0;

EXCEPTION: Any chronic neurologic disorder will be looked at on a case-by-case basis by the study chair