• Disease-free survival [ Designated as safety issue: No ]
• Overall survival and systemic disease-free survival [ Designated as safety issue: No ]
• Toxicity [ Designated as safety issue: Yes ]
• Quality of life [ Designated as safety issue: No ]

• Disease-free survival
• Overall survival and systemic disease-free survival
• Toxicity
• Quality of life

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known which combination chemotherapy regimen is more effective after surgery in treating breast cancer.

PURPOSE: Randomized phase III trial to compare different combination chemotherapy regimens in treating patients who have stage I, stage II, or stage III breast cancer.

OBJECTIVES:

• Determine the efficacy of adjuvant induction chemotherapy with or without cyclophosphamide and methotrexate as maintenance chemotherapy in patients with stage I, II, or III breast cancer.
• Compare the disease-free survival, overall survival, and systemic disease-free survival of patients treated with these regimens.
• Compare the toxic effects of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to participating center, menopausal status (pre vs post), and approved induction chemotherapy (doxorubicin and cyclophosphamide vs other agents). Patients are randomized to one of two treatment arms.

• Arm I: Patients receive one of the following approved adjuvant induction chemotherapy regimens:

  • AC comprising doxorubicin and cyclophosphamide IV on day 1 every 21 days for 4 courses followed by paclitaxel IV or docetaxel IV on day 1 every 21 days for 4 courses
  • EC comprising epirubicin and cyclophosphamide IV on day 1 every 21 days for 4 courses followed by paclitaxel IV or docetaxel IV on day 1 every 21 days for 4 courses
  • FAC comprising cyclophosphamide, doxorubicin, and fluorouracil IV on days 1 every 21 days for 4 courses
  • Doxorubicin every 21 days for 4 courses followed by CMF comprising cyclophosphamide IV, methotrexate IV, and fluorouracil IV on days 1 and 8 every 28 days for 4 courses
  • AC OR EC and paclitaxel IV with filgrastim (G-CSF) every 14 days for 4 courses
  • FEC comprising cyclophosphamide IV, epirubicin IV and fluorouracil IV on day 1 every 21 days for 3 courses followed by docetaxel IV on day 1 every 21 days for 3 courses
  • TAC comprising docetaxel, doxorubicin, and cyclophosphamide IV on day 1 every 21 days for 6 courses
  • AT comprising doxorubicin IV and docetaxel IV every 21 days for 3 courses followed by CMF for 3 courses
• Arm II: Patients receive adjuvant induction chemotherapy as in arm I. Beginning within 56 days after the first day of the last course of induction chemotherapy, patients receive CM (maintenance chemotherapy) comprising oral cyclophosphamide once daily and oral methotrexate two times a day twice weekly for 1 year.

Patients with breast-conserving surgery receive radiotherapy following completion of induction chemotherapy.

Patients with HER2-positive primary breast cancer may also receive trastuzumab (Herceptin) during or following induction, and/or during and following CM.

Quality of life is assessed at baseline, at the beginning of each course of induction chemotherapy, and at months 9, 12, 18, and 24.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: Approximately 900 patients will be accrued for this study within 5 years.

• Drug: CAF regimen
• Drug: CMF regimen
• Drug: cyclophosphamide
• Drug: doxorubicin hydrochloride
• Drug: epirubicin hydrochloride
• Drug: fluorouracil
• Drug: methotrexate
• Procedure: adjuvant therapy

DISEASE CHARACTERISTICS:

• Histologically confirmed stage I, II, or III breast cancer

  • T1-3, N0-2, M0

    • Patients with sentinel node biopsy positive disease must have undergone axillary dissection
    • Tumor must be confined to the breast without detected metastases elsewhere
  • T4 disease with minimal dermal invasion allowed
  • No T4 disease with ulceration of skin, infiltration of skin (except pathologically minimal dermal involvement), peau d'orange, or inflammatory breast cancer
• No bilateral breast cancer (except in situ carcinoma) or suspicious mass in opposite breast that has not been proven benign

• No distant metastases

  • No skeletal pain of unknown cause, elevated alkaline phosphatase, or bone scan showing hot spots that cannot be ruled out as metastases by x-ray, MRI, and/or CT

• Must have undergone prior total mastectomy OR breast-conserving procedure (e.g., lumpectomy, quadrantectomy, or partial mastectomy with negative margins)

  • Patients must begin or have begun induction chemotherapy within 8 weeks after definitive surgery
• Negative surgical margins
• Axillary clearance with at least 6 lymph nodes examined OR
• Negative sentinel node biopsy OR
• Positive lymph nodes and unsuitable for taxane-based chemotherapy
• Known HER2 status by immunohistochemistry or fluorescence in situ hybridization

• Hormone receptor status:

  • Estrogen and progesterone receptor negative

    • Less than 10% positive tumor cells by immunohistochemistry

PATIENT CHARACTERISTICS:

Age:

• Not specified

Sex:

• Not specified

Menopausal status:

• Premenopausal, defined as less than 6 months since last menstrual period (LMP) AND no prior bilateral ovariectomy AND not on estrogen replacement (OR under age 50) OR
• Postmenopausal, defined as prior bilateral ovariectomy OR more than 12 months since LMP without prior hysterectomy (OR age 50 and over)

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• WBC greater than 3,000/mm3
• Platelet count greater than 100,000/mm3

Hepatic:

• See Disease Characteristics
• Bilirubin less than 2.0 mg/dL
• ALT less than 1.5 times upper limit of normal OR
• AST less than 60 IU/L

Renal:

• Creatinine less than 1.2 mg/dL

Other:

• Not pregnant or lactating within the past 6 months
• Fertile patients must use effective barrier contraception
• No other prior or concurrent malignancy except adequately treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or contralateral or ipsilateral in situ breast carcinoma
• No psychiatric or addictive disorders that would preclude study
• No non-malignant systemic disease that would preclude study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Prior trastuzumab (Herceptin) allowed

Chemotherapy:

• See Disease Characteristics
• No prior adjuvant or neoadjuvant chemotherapy for breast cancer

Endocrine therapy:

• No prior endocrine therapy for breast cancer or prevention
• No prior tamoxifen or raloxifene for breast cancer

Radiotherapy:

• No prior radiotherapy for breast cancer except primary irradiation

Surgery:

• See Disease Characteristics

Other:

• No prior preventative therapy for breast cancer