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