To compare disease-free survival (DFS), overall survival (s), and toxicity of high-isk primary breast cancer patients with negative axillary lymph nodes or with one to three positive nodes treated with adjuvant high-dose chemotherapy with doxorubicin plus cyclophosphamide (AC), versus high-dose sequential chemotherapy with doxorubicin followed by cyclophosphamide (A-->C).

• Patients must have been diagnosed with primary invasive adenocarcinoma of the breast. Those patients with the special types including pure tubular, mucinous and papillary carcinoma are not eligible. Patients must not have sarcoma, lymphoma, or apocrine, adenocystic or squamous cell cancer of the breast. Patients must not have recurrent invasive breast cancer. Metaplastic carcinomas are eligible as a variant form of adenocarcinoma.

• Patients must have undergone an axillary dissection, and at least 6 nodes must have een removed and examined. Nodal involvement by tumor must be negative or must not xceed three positive nodes.

• disease must be considered sufficiently high-risk by the investigator to justify the use of chemotherapy. To be eligible, disease must satisfy one of the following requirements:

  1. Tumor is both ER negative and PgR negative and greater than 1.0 cm in greatest diameter. Negative is defined as c 10 fmollmg cytosol protein if measured in these units; othennrise negative is defined according to institutional standards.
  2. Tumor that is greater than 2.0 cm in greatest diameter irrespective of hormone receptor status (including unknown).
  3. Tumor involves one to three axillary lymph nodes.

• Breast cancer was not locally advanced at diagnosis. This is left to investigator judgement, but generally should exclude patients with fixed tumors, fixed nodes, peau d'orange skin changes, skin ulcerations or inflammatory changes (T4 disease).

• Patient Is currently free of breast cancer (no evidence of disease). This is also left to investigator judgement, but generally should include no evidence of distant disease on chest x-ray or mgmmogram of the opposite breast prior to registration, within 3 months prior to surgery; and no gross or microscopically positive surgical margins noted in the final surgery or pathology reports. Patients with synchronous bilateral breast cancer may be considered, provided both breasts are treated with curative intent and that eligibility is based on the side with the most adverse prognostic features.

• Registration must be within 84 days of mastectomy, or within 84 days of axillary dissection if the patient's most extensive breast surgery was a breast sparing procedure. Patients not having mastectomy or breast sparing surgery are ineligible. Patients must not have had prior chemotherapy for this breast cancer. Patients must not have had systemic therapy of any type for a previous breast cancer.

• Patients must not have had external beam radiotherapy for this breast cancer prior to registration. Brachytherapy (interstitial radiation therapy) at the time of breast sparing procedure is acceptable and would not render the patient Ineligible. (If external beam radiotherapy is planned to be given with brachytherapy, it must be delayed until after chemotherapy is complete.) Patients whose most extensive breast surgery was a breast sparing procedure must be planning to receive radiotherapy after chemotherapy is complete.

• Patients must have adequate hematologic, hepatic, renal and cardiac function for high dose chemotherapy and adequate health for long-term follow-up. This must Include normal WBC (2 4,0001pl). neutrophll count (2 1,50O/pl), platelet count (2 Institutional lower limit of normal), and LVEF (left ventricular ejection fraction by institutional criteria); bilirubin within 1.5 times institutional upper limit of normal; creatinine within 1.5 times institutional upper limit of normal; and no serious disease other than breast cancer.

• Pregnant or nursing women may not participate. Men are ineligible. Women of childbearing potential must be planning to use effective contraception.

• All patients must be informed of the Investigational nature of this study and give written informed consent in accordance with institution and federal guidelines.

• At the time of registration, the date of institutional review board approval for this study must be provided to the Statistical Center.