S0221 Adjuvant Doxorubicin, Cyclophosphamide, and Paclitaxel in Treating Patients With Breast Cancer

OBJECTIVES:

• Compare the disease-free survival of patients with node-positive or high-risk node-negative breast cancer treated with 2 different schedules of adjuvant doxorubicin, cyclophosphamide, and paclitaxel.
• Compare the overall survival of patients treated with these regimens.
• Compare the toxic effects of these regimens in these patients.
• Correlate outcome with putative prognostic markers in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms (arms V and VI) (arms I-IV closed 11/10/10).

• Arm I: (closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses.

Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.

• Arm II: (closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses.

Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I.

• Arm III: (closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I.

Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.

• Arm IV: (closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II.

Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III.

• Arm V: Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.

Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.

• Arm VI: Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim as in arm V.

Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.

In all arms, treatment continues in the absence of disease progression or unacceptable toxicity.

In all arms patients with HER2/neu-positive tumors also receive trastuzumab (Herceptin®) weekly or every 3 weeks beginning concurrently with paclitaxel OR 3 months after the last dose of paclitaxel and continuing for up to 52 weeks.

In all arms, patients with estrogen-receptor or progesterone-receptor positive tumors receive hormonal therapy beginning within 28 days of the completion of adjuvant chemotherapy or radiotherapy (if given).

After finishing study treatment patients are followed up every 6 months for 5 years and then once a year for up to 15 years.

PROJECTED ACCRUAL: A total of 3,250 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed stage I-III invasive breast cancer

• Operable disease
• Stage I, II, IIIA, and IIIC (T1-3, N3a only)
• No T4 tumors
• High-risk disease, defined by 1 of the following:

• Tumor ≥ 2 cm in greatest diameter (includes both invasive and intraductal component)

• Patients with nodal status of N0+ (i.e., no cluster of tumor cells in any node greater than 0.2 mm) are considered to be node negative and must have a primary tumor ≥ 2 cm in size or have a tumor ≥ 1 cm with high risk features
• Patients who are node negative on the basis of a sentinel node procedure and fewer than 6 axillary nodes are removed are eligible OR at least 6 axillary or intramammary nodes must be negative
• Tumor ≥ 1 cm in diameter and meeting 1 of the following criteria:

• ER-negative and PgR-negative
• ER-positive or PgR-positive with a Genomic Health Recurrence Score of ≥ 26
• One or more axillary or intramammary nodes are involved by metastatic breast cancer

• If one or more nodes is involved, a minimum of 6 axillary or intramammary nodes must have been examined histologically
• Patients with N0(I+) disease will be considered node negative
• HER2/neu-positive tumors (3+ by immunohistochemical staining or amplified by fluorescence in-situ hybridization) allowed
• Bilateral synchronous breast cancer diagnosed within 1 month of each other allowed provided the higher TNM stage primary tumor meets the eligibility criteria
• Prior modified radical mastectomy OR local excision of all tumors with axillary lymph node dissection or sentinel node resection required

• No more than 84 days since prior surgery for the primary tumor and/or axilla
• Final resection margins for the primary tumor must be histologically negative for invasive cancer and ductal carcinoma in situ
• Resection margins positive for lobular carcinoma in situ are allowed
• Hormone receptor status:

• Estrogen receptor status known
• Progesterone receptor status known

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Male or female

Menopausal status

• Not specified

Performance status

• Zubrod 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count at least 1,200/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• Bilirubin no greater than upper limit of normal (ULN)
• Alkaline phosphatase no greater than 2 times ULN
• SGOT or SGPT no greater than 2 times ULN

Renal

• Creatinine no greater than ULN

Cardiovascular

• No congestive heart failure
• No active angina pectoris
• LVEF greater than or equal to the lower limit of normal* by MUGA or echocardiogram NOTE: Patients age 60 and over OR with a history of hypertension

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, in situ cervical carcinoma, or lobular carcinoma in situ of the breast

• Prior invasive breast cancer or ductal carcinoma in situ allowed if disease-free for 5 years
• HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior cytotoxic chemotherapy for this breast cancer
• No prior chemotherapy with an anthracycline, anthracenedione, or taxane

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy for this malignancy
• At least 2 weeks since prior radiotherapy for ductal carcinoma in situ

Surgery

• See Disease Characteristics