Four Versus Six Cycles of Cyclophosphamide/Doxorubicin or Paclitaxel in Adjuvant 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