• Combined pathologic complete response rate in the breast and axillary lymph nodes [ Designated as safety issue: No ]
• Cardiac event rate during treatment and follow-up [ Designated as safety issue: No ]
• LVEF by MUGA at baseline and 3 and 6 months [ Designated as safety issue: No ]
• Method of definitive surgery [ Designated as safety issue: No ]
• Adverse events by CTCAE version 3.0 [ Designated as safety issue: Yes ]
• Disease-free and overall survival at 5 years [ Designated as safety issue: No ]

• Combined pathologic complete response rate in the breast and axillary lymph nodes
• Cardiac event rate during treatment and follow-up
• LVEF by MUGA at baseline and 3 and 6 months
• Method of definitive surgery
• Adverse events by CTCAE version 3.0
• Disease-free and overall survival at 5 years

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether it is more effective to give combination chemotherapy before or after treatment with paclitaxel plus trastuzumab.

PURPOSE: This randomized phase III trial is studying giving fluorouracil together with epirubicin and cyclophosphamide followed by paclitaxel and trastuzumab to see how well it works compared with giving paclitaxel together with trastuzumab followed by fluorouracil, epirubicin, cyclophosphamide, and trastuzumab in treating women with palpable breast cancer that can be removed by surgery.

OBJECTIVES:

Primary

• To compare the pathologic complete response rate (pCR) within the breast of patients with breast cancer receiving neoadjuvant combination chemotherapy comprising fluoroucacil, epirubicin hydrochloride, and cyclophosphamide followed by paclitaxel and trastuzumab vs neoadjuvant paclitaxel with trastuzumab (Herceptin®) followed by combination chemotherapy comprising fluoroucacil, epirubicin hydrochloride, cyclophosphamide, and trastuzumab.

Secondary

• To estimate and compare the cardiotoxicity in patients receiving these regimens.
• To compare the combined pCR rate in the breast and ipsilateral axilla obtained with the two regimens evaluated in this study.
• To compare the clinical response rates of the two regimens evaluated in this study.
• To compare the non-cardiac toxicity of the two regimens evaluated in this study.
• To compare breast conservation rates achieved with the two regimens evaluated in this study.
• To evaluate disease-free survival and overall survival at 5 years post-randomization.
• To correlate pCR rate with potential molecular markers of response.

OUTLINE: Patients are stratified by tumor size (2.0 - 4.0 cm vs > 4.0 cm), age (< 50 vs ≥ 50) and hormone receptor status (estrogen receptor [ER]- and progesterone receptor [PgR]-negative vs ER- and/or PgR-positive). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive fluoroucacil IV, epirubicin hydrochloride IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. After completion of the fourth course and beginning 21 days later, patients receive paclitaxel IV and trastuzumab (Herceptin®) IV once weekly for 12 weeks. Within 4 weeks after completion of all chemotherapy, patients undergo surgery for tumor. After surgery and beginning 3-4 weeks after the last dose of neoadjuvant trastuzumab, patients receive trastuzumab IV once every 3 weeks for up to 52 weeks.
• Arm II: Patients receive paclitaxel IV once weekly for 12 weeks and trastuzumab IV once weekly for 13 weeks. Beginning 14 days after the last dose of paclitaxel, patients receive fluoroucacil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Patients also receive trastuzumab IV once weekly for an additional 12 weeks. Within 4 weeks after completion of all chemotherapy, patients undergo surgery. Beginning 3-4 weeks after the last dose of neoadjuvant trastuzumab, patients receive postoperative trastuzumab as in arm I.

After completion of study therapy, patients are followed every 3 months for 2 years and then every 6 months for 3 years.

• Biological: trastuzumab
• Drug: cyclophosphamide
• Drug: epirubicin hydrochloride
• Drug: fluorouracil
• Drug: paclitaxel
• Procedure: conventional surgery

• Active Comparator: Patients receive fluoroucacil IV, epirubicin hydrochloride IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. After completion of the fourth course and beginning 21 days later, patients receive paclitaxel IV and trastuzumab (Herceptin®) IV once weekly for 12 weeks. Within 4 weeks after completion of all chemotherapy, patients undergo surgery for tumor. After surgery and beginning 3-4 weeks after the last dose of neoadjuvant trastuzumab, patients receive trastuzumab IV once every 3 weeks for up to 52 weeks.
• Experimental: Patients receive paclitaxel IV once weekly for 12 weeks and trastuzumab IV once weekly for 13 weeks. Beginning 14 days after the last dose of paclitaxel, patients receive fluoroucacil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Patients also receive trastuzumab IV once weekly for an additional 12 weeks. Within 4 weeks after completion of all chemotherapy, patients undergo surgery. Beginning 3-4 weeks after the last dose of neoadjuvant trastuzumab, patients receive postoperative trastuzumab as in arm I.

DISEASE CHARACTERISTICS:

• Diagnosis of invasive adenocarcinoma of the breast meeting the following criteria:

  • Diagnosed by core needle biopsy (patients with excisional or incisional biopsy of the primary breast tumor are NOT eligible)
  • Breast tumor must meet criteria for measurable disease (≥ 2.0 cm) according to RECIST criteria

  • HER2-positive disease

    • Confirmation by fluorescent in situ hybridization (FISH) requires gene amplification
    • Confirmation by immunohistochemistry (IHC) requires a strongly positive (3+) staining intensity score

• Ductal carcinoma in situ (DCIS) or synchronous DCIS of the contralateral breast regardless of prior therapy allowed

  • Synchronous invasive breast cancer not allowed

• Ipsilateral DCIS treated by local excision with or without hormonal therapy allowed

  • Those treated with radiation therapy are not allowed
• No definitive clinical or radiologic evidence of metastatic disease
• No prior history of invasive breast cancer
• Hormone receptor status known

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• ECOG performance status of 0 -1
• Absolute neutrophil count ≥ 1,200/mm³
• Platelet count ≥ 100,000/mm³
• Total bilirubin normal unless the patient has a grade 1 bilirubin elevation (normal to 1.5 times upper limit of normal [ULN]) resulting from Gilbert disease or similar syndrome due to slow conjugation of bilirubin
• Alkaline phosphatase ≤ 2.5 times ULN
• AST ≤ 1.5 times ULN
• Creatinine normal
• LVEF ≥ 55.8 by MUGA scan within the past 3 months

• Patients with either skeletal pain or alkaline phosphatase that is > ULN but ≤ 2.5 times ULN allowed if bone scans fail to demonstrate metastatic disease

  • Suspicious findings on bone scan must be confirmed as benign by x-ray, MRI, or biopsy

• Prior non-breast malignancies allowed if disease-free for 5 years since completion of initial treatment regimen and deemed by their physician to be at low risk for recurrence

  • Patients who had the following cancers are eligible if diagnosed and treated within the past 5 years:

    • Carcinoma in situ of the cervix
    • Colon carcinoma in situ
    • Melanoma in situ
    • Basal cell and squamous cell carcinoma of the skin

• No cardiac disease that would preclude the use of epirubicin hydrochloride or trastuzumab (Herceptin®) including any of the following:

  • Active cardiac disease
  • Angina pectoris that requires the use of antianginal medication
  • Cardiac arrhythmia requiring medication
  • Severe conduction abnormality
  • Clinically significant valvular disease
  • Cardiomegaly on chest x-ray
  • Ventricular hypertrophy on EKG

  • Patient's with poorly controlled hypertension ( i.e., diastolic greater than 100 mm/Hg)

    • Patients with hypertension that is well controlled on medication are eligible
  • History of cardiac disease
  • Myocardial infarction documented as a clinical diagnosis or by EKG or any other tests
  • Documented congestive heart failure
  • Documented cardiomyopathy
• No sensory or motor neuropathy ≥ grade 2, as defined by the NCI's CTCAE v3.0
• Women of reproductive potential must agree to use an effective non-hormonal method of contraception during therapy
• Women of child bearing potential must have a negative urine or serum pregnancy test within 2 weeks of registration
• Not pregnant or nursing
• No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements
• No non-malignant systemic disease (e.g., cardiovascular, renal, hepatic) that would preclude treatment with either of the treatment regimens

PRIOR CONCURRENT THERAPY:

• No prior surgical axillary staging procedure

  • Prior fine-needle aspiration of an axillary node allowed

• No prior treatment for this breast cancer

  • Hormonal therapy allowed if had been given for up to a total of 28 days anytime after diagnosis and before study entry
  • Hormonal therapy must stop at or before study entry and be re-started, if indicated, following surgery
• No prior therapy with anthracyclines or taxanes for any malignancy
• No other investigational agents within the past 30 days
• No concurrent sex hormonal therapy (e.g., birth control pills, ovarian hormonal replacement therapy)
• No concurrent therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulator (SERM), either for osteoporosis or breast cancer prevention