Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2

OBJECTIVES:

- Compare the cardiotoxicity of doxorubicin and cyclophosphamide followed by paclitaxel
with or without trastuzumab (Herceptin®) in women with operable, node-positive breast
cancer that overexpresses HER2.

- Compare the effect of these regimens on disease-free and overall survival of these
patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to number
of positive nodes (1-3 vs 4-9 vs 10 or more), administration of hormonal therapy (tamoxifen
vs anastrozole vs neither), surgery/radiotherapy (lumpectomy plus breast irradiation vs
lumpectomy plus breast irradiation plus regional irradiation vs mastectomy without
radiotherapy vs mastectomy with radiotherapy), paclitaxel schedule (every 3 weeks vs weekly),
and participating center. Patients are randomized to one of two treatment arms.

- Arm 1: Patients receive doxorubicin IV and cyclophosphamide IV over 30 minutes on day 1.
Treatment repeats every 21 days for 4 courses. Approximately 3 weeks after the last
course, patients receive paclitaxel IV over 3 hours every 21 days for 4 courses OR
paclitaxel IV over 1 hour once weekly for 12 weeks (12 doses).

- Arm 2: Patients receive chemotherapy as in arm I and trastuzumab (Herceptin®) IV over 90
minutes on day 1 of the first course of paclitaxel. Trastuzumab is then administered IV
over 30 minutes weekly for 51 weeks, beginning on day 8.

All patients with estrogen or progesterone receptor-positive tumors receive hormonal therapy*
for at least 5 years, beginning within 3-12 weeks after the last dose of chemotherapy.
Patients who have received prior tamoxifen for prevention may be treated with additional
tamoxifen for no more than 5 years at the discretion of the principal investigator (PI).

NOTE: *Other hormonal therapeutic agents are allowed in sequence with or as an alternative to
tamoxifen therapy.

All patients previously treated with lumpectomy undergo breast irradiation beginning after
completion of chemotherapy and concurrently with trastuzumab (in arm 2) administration.
Patients previously treated with mastectomy may also receive radiotherapy. Radiotherapy is
administered daily for 5-6 weeks.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 2,700 patients will be accrued for this study within 4.75
years.

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.