A Randomized Trial Comparing the Safety and Efficacy of Adriamycin and Cyclophosphamide Followed by Taxol (AC-T) to That of Adriamycin and Cyclophosphamide Followed by Taxol Plus Herceptin (AC-T+H) in Node-Positive Breast Cancer Patients Who Have Tumors That Overexpress HER2

Inclusion Criteria

Inclusion criteria

- The patient must have a life expectancy of at least 10 years, excluding her diagnosis
of breast cancer. (Comorbid conditions should be taken into consideration, but not
the diagnosis of breast cancer.)

- The interval between the last surgery for breast cancer treatment (lumpectomy,
mastectomy, axillary dissection, or re-excision of lumpectomy margins) and
randomization must be less than or equal to 84 days.

- All of the following staging criteria must be met:

- Primary tumor must be T1-3 by clinical and pathologic evaluation.

- Ipsilateral nodes must be cN0-1 by clinical evaluation.

- Ipsilateral nodes must be pN1, pN2a, or pN3a by pathologic evaluation.

- M0

- Patients must have undergone either a total mastectomy and an axillary dissection or
a lumpectomy and an axillary dissection. Sentinel node biopsy is permitted, but must
be followed by an axillary dissection.

- The tumor must be invasive adenocarcinoma on histologic examination.

- The tumor must be determined to be HER2-positive prior to randomization. Assays
performed using fluorescent in situ hybridization (FISH) require gene amplification
to be eligible. Assays using immunohistochemistry (IHC) must be performed at an
NSABP-approved reference laboratory and require a strongly positive staining score.

- Patients must have an analysis of both estrogen and progesterone receptors performed
on the primary tumor prior to randomization. "Marginal," "borderline," etc., results
(i.e., those not definitely negative) will also be considered positive regardless of
the methodology used.

- At the time of randomization, the patient must have had the following: history and
physical exam, EKG, and PA and lateral chest x-ray within the past 3 months; and a
bilateral mammogram (or unilateral if patient has had a mastectomy) and a pelvic exam
(for women who have a uterus and who will be taking tamoxifen) within the past year.

- Within 3 months prior to entry, the patient must have a baseline left ventricular
ejection fraction (LVEF) measured by MUGA scan equal to or greater than the lower
limit of normal for the radiology facility. (If LVEF is > 75%, the investigator
should consider having the LVEF determination reviewed prior to randomization.
Following randomization, the LVEF determination may be reviewed up until the time of
the post-AC MUGA. Please note that if a more accurate value is obtained from the
review of the baseline MUGA, the corrected value must be submitted to the NSABP
Biostatistical Center before the post-AC MUGA is performed.)

- At the time of randomization:

- The postoperative absolute neutrophil count (ANC) must be ≥ 1500/mm3 (or
<1500/mm3 if, in the opinion of the investigator, this represents an ethnic or
racial variation of normal).

- Postoperative platelet count must be ≥ 100,000/mm3. Significant underlying
hematologic disorders must be excluded when the platelet count is above the
upper limit of normal for the lab.

- There must be postoperative evidence of adequate hepatic function, i.e., total
bilirubin must be ≤ ULN for the lab unless the patient has a chronic grade 1
bilirubin elevation (>ULN to ≤1.5 x ULN) due to Gilbert's disease or similar
syndrome; and alkaline phosphatase must be <2.5 times the ULN for the lab; and the
serum glutamic-oxaloacetic transaminase (SGOT [AST]) must be <1.5 times the ULN for
the lab.

- There must be postoperative evidence of adequate renal function (serum creatinine
within or less than the institution's normal range).

- Patients must have no clinical or radiologic evidence of metastatic disease.
Suspicious findings must be confirmed as benign by radiologic evaluation or biopsy.
A patient with skeletal pain is eligible for inclusion in the study if bone scan
and/or roentgenological examination fails to disclose metastatic disease.

- Patients with a history of non-breast malignancies are eligible if they have been
disease-free for 5 or more years prior to randomization and are deemed by their
physician to be at low risk for recurrence. Patients with the following cancers are
eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the
cervix, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.

- Prior to randomization, the investigator must designate whether the patients who had
a lumpectomy will receive local or locoregional radiation therapy. For patients who
had a mastectomy, the investigator must designate whether or not the patient will
receive radiation therapy. (Pre-randomization discussion and/or consultation with a
radiation oncologist is encouraged.) Note: Irradiation of any internal mammary nodes
is prohibited in this trial.

- Special conditions for eligibility of lumpectomy patients: irradiation and surgery

- Patients treated by lumpectomy and axillary node dissection to be followed by breast
radiation therapy must meet all the eligibility criteria in addition to the
following: Generally, lumpectomy should be reserved for tumors <5 cm. However, at
the investigator's discretion, patients treated with lumpectomy for tumors ≥ 5 cm are
eligible. The margins of the resected specimen must be histologically free of
invasive tumor and DCIS as determined by the local pathologist. In patients in whom
pathologic examination demonstrates tumor present at the line of resection,
additional operative procedures may be performed to obtain clear margins. This is
permissible even if axillary dissection has been performed. Patients in whom tumor
is still present at the resected margin after re-excision(s) must undergo total
mastectomy to be eligible. Whole breast irradiation is required. Irradiation of
regional lymph nodes is optional, but partial breast irradiation and irradiation of
any internal mammary nodes are prohibited in this trial. Intent to irradiate the
axilla or other regional node groups must be declared by the investigator prior to
randomization for stratification purposes.

- Special conditions for eligibility of mastectomy patients: irradiation. The decision
to use locoregional irradiation in patients who have undergone total mastectomy and
axillary node dissection must be declared by the investigator prior to randomization
for stratification purposes. Failure to adhere to the radiation therapy plan will be
a protocol violation.

Exclusion criteria

- Bilateral malignancy or a mass or mammographic abnormality in the opposite breast
suspicious for malignancy unless there is biopsy proof that the mass is not
malignant.

- Primary tumor staged as T4 for any reason.

- Nodes staged as clinical N2 or N3 for any reason and nodes staged as pathologic pN2b,
pN3b, or pN3c.

- Prior history of breast cancer, including DCIS (patients with a history of lobular
carcinoma in situ [LCIS] are eligible).

- Treatment including radiation therapy, chemotherapy, biotherapy, and/or hormonal
therapy administered for the currently diagnosed breast cancer prior to
randomization. The only exception is hormonal therapy, which may have been given for
up to a total of 28 days anytime after diagnosis and before randomization. In such a
case, hormonal therapy must stop at or before randomization and be re-started if
indicated following chemotherapy.

- Prior anthracycline or taxane therapy for any malignancy.

- Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement
therapy, etc. (These patients are eligible only if this therapy is discontinued
prior to randomization.)

- Therapy with any hormonal agents such as raloxifene (Evista®), tamoxifen, or other
selective estrogen receptor modulators (SERMs), either for osteoporosis or
prevention. (Patients are eligible only if these medications are discontinued prior
to randomization. These medications are not permitted while on the study except for
the use of tamoxifen as described in the protocol)

- Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would
preclude a patient from being subjected to any of the treatment options or would
prevent prolonged follow-up.

- Cardiac disease that would preclude the use of Adriamycin, Taxol or Herceptin. This
includes:

- Active cardiac disease:

- angina pectoris that requires the use of antianginal medication;

- cardiac arrhythmia requiring medication;

- severe conduction abnormality;

- clinically significant valvular disease;

- cardiomegaly on chest x-ray;

- ventricular hypertrophy on EKG; or

- patients with poorly controlled hypertension, i.e., diastolic greater than 100
mm/Hg. (Patients with hypertension who are well controlled on medication are
eligible for entry.)

- History of cardiac disease:

- myocardial infarction documented as a clinical diagnosis or by EKG or any other
tests;

- documented congestive heart failure; or

- documented cardiomyopathy.

- Psychiatric or addictive disorders that would preclude obtaining informed consent.

- Pregnancy or lactation at the time of proposed randomization. This protocol excludes
pregnant or lactating women based on the fetal toxicity of both tamoxifen and Taxol
which are listed as Pregnancy Category D agents. Pregnant women who received
tamoxifen have experienced fetal deaths, birth defects, spontaneous abortions, and
vaginal bleeding. Women of reproductive potential must agree to use an effective
barrier method of contraception. Hormonal birth control methods are not permitted.

- Sensory/motor neuropathy ≥ grade 2, as defined by the NCI's Common Toxicity Criteria
version 2.0.

- Contraindications to corticosteroid use which, in the opinion of the investigator,
would preclude participation in this study.

- Concurrent treatment with other investigational agents.

- Sensitivity to benzyl alcohol.

- Special conditions for ineligibility of lumpectomy patients: irradiation and surgery.
For patients treated by lumpectomy with axillary dissection, breast irradiation is
required. Please see guidelines for radiation therapy in Appendix A. In addition,
the following patients will also be ineligible:

- Patients with diffuse tumors (as demonstrated on mammography) that would not be
considered surgically amenable to lumpectomy.

- Patients treated with lumpectomy in whom there is another clinically dominant
mass or mammographically suspicious abnormality within the ipsilateral breast
remnant. Such a mass must be biopsied and demonstrated to be histologically
benign prior to randomization or, if malignant, must be surgically removed with
clear margins.

- Patients in whom the margins of the resected specimen are involved with invasive
tumor or ductal carcinoma in situ (DCIS). Additional surgical resections to
obtain free margins are allowed. Patients in whom tumor is still present after
the additional resection(s) must undergo mastectomy to be eligible.