OBJECTIVES:

• Evaluate whether 8 courses of primary chemotherapy before adequate surgery of breast tumor and locoregional radiotherapy plus tamoxifen for 5 years improves the disease-free and overall survival in women with operable breast carcinoma and tumor at diagnosis greater than 2 cm in diameter.
• Assess whether, in the postoperative arms, the addition of paclitaxel to doxorubicin before CMF (cyclophosphamide, methotrexate, and fluorouracil) improves disease-free and overall survival in these patients.
• Define the incidence of pathologic complete response (CR) induced by 8 courses of primary chemotherapy containing paclitaxel.
• Assess whether a pathologic CR is an independent predictor of disease-free and overall survival.
• Evaluate the effects of primary chemotherapy on the rate and quality of breast conserving surgery.

OUTLINE: This is a randomized, multicenter study. Patients are stratified by center, tumor diameter at mammography, nuclear or histological grade, and estrogen/progesterone receptor status. Patients are randomized to one of three treatment arms.

• Arm I: Patients receive doxorubicin IV over 15 minutes once every 3 weeks for 4 courses. Beginning 21 days after the last administration of doxorubicin, patients receive cyclophosphamide IV, methotrexate IV, and fluorouracil IV on days 1 and 8. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
• Arms II and III: Patients receive doxorubicin IV over 15 minutes and paclitaxel IV over 3 hours once every 3 weeks for 4 courses. Beginning 21 days after the last administration of doxorubicin and paclitaxel, patients receive cyclophosphamide IV, methotrexate IV, and fluorouracil IV on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

All patients have either mastectomy or breast conserving surgery; patients with unclear surgical margins may have second surgery (re-resection or total mastectomy) or radiotherapy. Lymph node axillary dissection is performed up to at least the second level. For patients in the 2 adjuvant arms (arms I and II), adjuvant chemotherapy starts by day 21 after surgery. For patients in the primary chemotherapy arm (arm III), surgery is performed by day 28 after the last course of chemotherapy or at resolution of all possible hematological or infective complications.

At the end of the combined surgery plus chemotherapy approach (i.e., after the last course of CMF (arms I and II) or after surgery (arm III)), patients enrolled after June 30, 2000 with estrogen or progesterone receptor positive disease receive oral tamoxifen daily for 5 years.

All patients who have breast conserving surgery receive postoperative irradiation within 4 weeks after completing chemotherapy and surgery (i.e., within 4 weeks from last dose of adjuvant chemotherapy (arms I and II) or from surgery (arm III)). All patients who have mastectomy and have pT4 disease must receive irradiation to the chest wall.

Patients are followed at 6, 12, 18, and 24 months, and then annually thereafter.

PROJECTED ACCRUAL: A total of 450 patients per arm will be accrued for this study within 5 years.