This randomized phase III trial studies cyclophosphamide and doxorubicin hydrochloride compared with paclitaxel as adjuvant therapy in treating breast cancer in women with 0-3 positive axillary lymph nodes. Giving additional cancer treatment after surgery may help to lower the risk that the cancer will come back (adjuvant therapy). Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether the standard adjuvant therapy of cyclophosphamide and doxorubicin hydrochloride is more effective than paclitaxel in treating women with breast cancer

PRIMARY OBJECTIVES:

I. To determine the equivalence of paclitaxel given every two weeks with cyclophosphamide and doxorubicin hydrochloride (CA) given every two weeks as adjuvant therapy for women with 0-3 positive axillary lymph nodes, for disease-free survival.

II. To determine if longer therapy, 12 weeks, is superior to shorter therapy, 8 weeks, of either CA or paclitaxel for disease-free survival for women with primary breast cancer with 0-3 positive axillary lymph nodes.

SECONDARY OBJECTIVES:

I. To determine the equivalence of paclitaxel given every two weeks with CA given every two weeks, and the potential superiority of longer vs. shorter therapy, in relation to overall survival, local control (regardless of metastatic status) and time to distant metastases (regardless of local recurrence status).

II. To compare toxicities of short and long course CA and paclitaxel as adjuvant therapy for women with 0-3 positive axillary lymph node breast cancer.

III. To determine the effect of long and short course CA and paclitaxel on the induction of menopause for pre-menopausal patients.

IV. To assess the discrepancy of myelosuppression among the common multidrug resistance protein 1 (MDR1) haplotypes in the CA treatment arm.

V. To assess the effect of MDR1 haplotypes on disease-free survival (DFS) adjusted for treatment.

VI. Exploratory analysis of the effect of cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5), cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8), and cytochrome P450, family 2, subfamily B, polypeptide 6 (CYP2B6) polymorphisms on DFS and toxicity.

VII. To identify genetic markers associated with the risk of developing neutropenia in adriamycin/ cyclophosphamide-treated breast cancer patients.

VIII. To identify genetic markers associated with the risk of developing peripheral neuropathy in paclitaxel-treated breast cancer patients.

IX. To identify genetic markers associated with differences in the efficacy of each chemotherapy regimen.

X. To examine genetic associations with other response and toxicity phenotypes that become apparent during future analysis of Cancer and Leukemia Group B (CALGB) 40101 data.

XI. To identify copy number variants associated with adriamycin/cyclophosphamide-induced neutropenia and paclitaxel-induced peripheral neuropathy.

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM I: Patients receive cyclophosphamide intravenously (IV) and doxorubicin hydrochloride IV on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive cyclophosphamide IV and doxorubicin hydrochloride IV on day 1. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.

ARM III: Patients receive paclitaxel IV over 3 hours on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM IV: Patients receive paclitaxel IV over 3 hours on day 1. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Note: Randomization to Arms II and IV is no longer available, effective 12/15/2007.

After completion of study treatment patients are followed up for 4-6 weeks, every 6 months for 2 years, and then annually for up to 13 years.

Eligibility Criteria:

• Patients must have histologically confirmed invasive carcinoma of the female breast, with 0-3 positive axillary lymph nodes

• Patients must have 0-3 positive axillary lymph nodes to be eligible for this study; patients with node-negative breast cancer should have sufficiently "high risk" disease to warrant chemotherapy; as general guidelines, node-negative patients with tumors of >= 1 cm or estrogen or progesterone receptor negative tumors of any size may be eligible; ultimately though, the definition of "high risk" may be determined by the treating physician, and if the treating physician feels the patient warrants chemotherapy, the patient is eligible; for patients with 1-3 positive axillary nodes, the patient is eligible regardless of primary breast tumor characteristics, if in the opinion of the treating physician, chemotherapy is deemed potentially beneficial to the patient

• If the patient has had a negative sentinel node biopsy, then no further axillary dissection is required, and the patient is determined to be node-negative; if an axillary dissection, without a sentinel node biopsy, is performed to determine nodal status, at least six axillary lymph nodes must be removed and analyzed and negative for the patient to be considered node-negative; axillary nodes with single cells or tumor clusters =< 0.2 mm by either hematoxylin and eosin stain (H&E) or immunohistochemistry (IHC), will be considered node-negative; lymph nodes positive for polymerase chain reaction (PCR) with tumor cells/clusters =< 0.2 mm will be considered node-negative; any axillary lymph node with tumor clusters > 0.2 mm will be considered positive

• If the patient has a sentinel node biopsy and one of the sentinel nodes is positive, as defined by tumor clusters > 0.2 mm, an axillary dissection must be performed; a total of at least 6 axillary lymph nodes, including sentinel nodes plus the subsequent dissection, must be removed for the patient to be eligible; of all the lymph nodes removed from both the sentinel node procedure and the axillary dissection, 1-3 must be positive for the patient to be eligible as a node-positive patient; if an axillary dissection is done without a sentinel node procedure, at least 6 lymph nodes must be removed and a 1-3 nodes must be positive for the patient to be considered node-positive and eligible for this study

• Determination of involvement of axillary nodes with metastatic cancer will follow the revised tumor-node-metastasis (TNM) staging system: axillary nodes with single cells with tumor clusters =< 0.2 mm, by either H&E or immunohistochemistry (IHC), will be considered negative axillary node; lymph nodes positive for PCR with tumor cells/clusters < 0.2 mm will be considered negative axillary node; any axillary lymph node with clusters > 0.2 mm will be considered to be positive

• Patients with estrogen-receptor and/or progesterone receptor negative, positive, or unknown tumors are eligible; estrogen-receptor (ER) and progesterone receptor (PgR) assays should be performed by immunohistochemical methods according to the local institution's standard protocol

• Patients with human epidermal growth factor receptor 2 (HER2) positive, negative or unknown disease are eligible for this trial; patients whose tumors are HER2 positive by either immunohistochemistry 3+ staining or demonstrate gene amplification by fluorescence in situ hybridization (FISH) may receive trastuzumab

• There must be negative tumor margins for invasive cancer and ductal carcinoma in situ (DCIS) in the case of mastectomy or lumpectomy; lobular carcinoma in situ (LCIS) is acceptable at the margin

• Patients with multi-centric breast cancer are eligible as long as all known disease is resected with negative margins, and have 0-3 positive axillary lymph nodes

• Patients must be registered within 84 days of the last breast surgery; patients must have undergone either modified radical mastectomy or lumpectomy; for patients undergoing sentinel node sampling or axillary dissection a simple mastectomy is acceptable; lumpectomy patients must receive radiation therapy; for patients treated with radiation therapy prior to chemotherapy, the patients should be registered on this study after the conclusion of radiation, with chemotherapy administration beginning within 7 days of registration

  * All primary breast and axillary node surgery must be completed prior to enrollment on study

• No previous trastuzumab, chemotherapy or hormonal therapy for this malignancy, except for tamoxifen therapy

• No previous anthracycline chemotherapy for any disease

• Patients with locally advanced breast cancer, inflammatory breast cancer or metastatic breast cancer are not eligible; patients with involvement of dermal lymphatics on pathology are not eligible, even if there are no clinical signs of inflammatory cancer

• Patients with bilateral, synchronous invasive breast cancer are eligible as long as both primary tumors; if a patient has an invasive cancer on one side that meets the eligibility criteria, and DCIS or LCIS on the contralateral side, the patient is eligible; DCIS or LCIS should be managed according to institutional guidelines

• Patients must be disease free from prior malignancies for > 5 years, except for curatively treated basal cell or squamous cell carcinoma of the skin or carcinoma-in-situ of the cervix; patients with a history of invasive breast cancer, or DCIS are eligible if they have been disease free for > 5 years; patients with a history of LCIS are eligible regardless of the interval from diagnosis

• Common Toxicity Criteria (CTC) performance status 0-1

• Women must not be pregnant or nursing

• Concomitant exogenous hormone therapy, including oral contraceptives, post-menopausal hormone replacement therapy, and raloxifene must be stopped before patients can be enrolled

• Patients may have received up to 4 weeks of tamoxifen therapy for this malignancy and still be eligible for this study; patients who received tamoxifen or another selective estrogen receptor modulator (SERM) for prevention or for other indicators (e.g. osteoporosis) are eligible; tamoxifen therapy or other SERMs must be discontinued before the patient is enrolled on this study

  * The use of bisphosphonates for the treatment of osteoporosis is permitted; the use of raloxifene is not permitted are enrollment on this study

• Patients must have adequate organ function including no active congestive heart failure, and no myocardial infarction < 6 months from time of registration

• Absolute neutrophil count (ANC) >= 1,000/mm^3

• Platelet count >= 100,00/mm^3

• Creatinine =< 2.0 mg/dl

• Bilirubin =< 1.5 x upper limits of institutional normal

• Patients may be enrolled on adjuvant bisphosphonate studies; patients may be enrolled concurrently or sequentially on 40101 and bisphosphonate trials

• Patients may be enrolled on adjuvant hormonal studies approved by CALGB or Cancer Trials Support Unit (CTSU), such as the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) trials