Doxorubicin Hydrochloride, Cyclophosphamide, and Pacltaxel With or Without Trastuzumab in Treating Women With HER2-Positive Node-Positive or High-Risk Node-Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To compare the combination of doxorubicin hydrochloride and cyclophosphamide (AC) followed
by weekly paclitaxel with the combination of AC followed by the combination of weekly
paclitaxel and trastuzumab in terms of disease free survival (DFS). (Stage I) II. To compare
the combination of AC followed by weekly paclitaxel with the combination of AC followed by
the combination of weekly paclitaxel and trastuzumab in terms of the rate of cardiac events.
(Stage I) III. To compare the combination AC followed by weekly paclitaxel with the
sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of
DFS. (Stage II) IV. To compare the sequential schedule of the combination of AC, weekly
paclitaxel, and trastuzumab with the combination of AC followed by the combination of weekly
paclitaxel and trastuzumab in terms of DFS. (Stage II) V. To compare the combination AC
followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly
paclitaxel, and trastuzumab in terms of the rate of cardiac events. (Stage II)

SECONDARY OBJECTIVES:

I. To compare the combination of AC followed by weekly paclitaxel with the sequential
schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of overall
survival (OS).

II. To compare the combination AC followed by weekly paclitaxel with the combination of AC
followed by the combination of weekly paclitaxel and trastuzumab in terms of OS.

III. To compare the sequential schedule of the combination AC, weekly paclitaxel, and
trastuzumab with the combination of AC followed by the combination of weekly paclitaxel and
trastuzumab in terms of OS.

TERTIARY OBJECTIVES:

I. To determine whether higher levels of shed ECD (extracellular domain) or autoantibodies to
human epidermal growth factor receptor (HER)-2 and HER-1 measured in the serum prior to
treatment are prognostic for DFS and survival.

II. To determine the concordance of central review of HER-2 overexpression as measured by the
HercepTest (DAKO) and Vysis fluorescence in situ hybridization (FISH).

III. For each treatment arm, levels of brain natriuretic peptide (BNP), troponin-T (TnT),
troponin-I (cTnI), tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and
interleukin-6 (IL-6), CD40 ligand, and troponin levels will be compared and contrasted.

IV. To determine whether genetic markers are prognostic for cardiac adverse events associated
with treatment.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I*: Patients receive doxorubicin hydrochloride intravenously (IV) and cyclophosphamide IV
over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then
receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12
courses in the absence of disease progression or unacceptable toxicity. NOTE: *Patients who
completed paclitaxel on or after October 25, 2004 may receive trastuzumab for a maximum of 52
weeks either concurrently with paclitaxel or following completion of paclitaxel treatment.

ARM II*: Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in
arm I. Patients then receive trastuzumab IV over 30-90 minutes beginning on day 1 of week 25
and continuing weekly for 52 courses in the absence of disease progression or unacceptable
toxicity. NOTE: *Patients who completed paclitaxel on or after October 25, 2004 may receive
trastuzumab for a maximum of 52 weeks either concurrently with paclitaxel or following
completion of paclitaxel treatment.

ARM III: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I.
Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes
beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive
trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40
courses in the absence of disease progression or unacceptable toxicity.

Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All
postmenopausal estrogen receptor (ER)- or progesterone receptor (PR)-positive patients
receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later
than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase
inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive
tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until
they have received a total of 5 years of adjuvant hormonal therapy.

After completion of study treatment, patients are followed up every 3 months for 1 year,
every 6 months for 4 years, and then annually for 15 years or until disease progression.

Inclusion Criteria:

- Required tumor parameters for node positive disease: NOTE: This study will continue to
use the American Joint Committee on Cancer (AJCC) 5th edition for TNM classification
and staging

- Operable, histologically confirmed adenocarcinoma of the female breast and
positive lymph nodes

- Node positivity may be determined by either an axillary node dissection or a
positive sentinel node finding by hematoxylin and eosin (H&E)

- NOTE: Positive nodes refers to H&E visible nodal metastases;
immunohistochemistry (IHC) positive only cells in lymph nodes will not
be considered positive nodes

- One or more positive lymph nodes whose tumors are T1-3, pN1-2, M0 are
eligible

- cN2 disease is not eligible

- pN2 disease is eligible

- One positive lymph node by sentinel node biopsy or at least 6 axillary nodes
must be examined on axillary node dissection with at least one positive
lymph node

- Metaplastic carcinoma is eligible

- ER/PgR determination

- HER-2 positive (pre-entry requirement for registration)

- FISH must show gene amplification OR

- IHC assay must show a strong positive (3+) staining score

- NOTE: ductal carcinoma in situ (DCIS) components should not be counted
in the determination of degree of IHC staining or FISH amplification

- Required tumor parameters for high-risk node-negative disease; NOTE: This study will
continue to use the AJCC 5th edition for TNM classification and staging

- Operable, histologically confirmed adenocarcinoma of the female breast and
negative lymph nodes

- Node status may be determined by either axillary node dissection or sentinel
node biopsy with H&E staining; to be considered node negative, either of the
following must be true: 1) negative sentinel node biopsy or 2) no positive
lymph nodes found among at least 6 axillary nodes examined on axillary node
dissection

- NOTE: IHC positive only cells in lymph nodes will not be considered positive
nodes

- Tumors > 2.0 cm (irrespective of hormonal receptor status) or > 1.0 cm if
ER-negative and PR-negative disease

- ER/PgR determination

- HER-2 positive (pre-entry requirement for registration)

- FISH must show gene amplification OR

- IHC assay must show a strong positive (3+) staining score

- NOTE: DCIS components should not be counted in the determination of
degree of IHC staining or FISH amplification

- =< 84 days from mastectomy or =< 84 days from axillary dissection or sentinel node
detection if the patient's most extensive breast surgery was a breast sparing
procedure; (This timing is per a decision by the Breast Intergroup)

- Surgical resection margins. All tumor should be removed by either a modified radical
mastectomy or a segmental mastectomy with axillary node dissection

- Mastectomy: There will be no evidence of gross or microscopic tumor (invasive or
DCIS) at the surgical resection margins noted in the final surgery or pathology
reports; patients with close margins are eligible

- Segmental mastectomy (lumpectomy): Margins must be clear of invasive cancer and
DCIS

- Axillary dissection or sentinel node dissection: There will be no gross residual
adenopathy

- TAM therapy

- May have received up to four weeks of TAM therapy, or any other hormonal agent,
for this malignancy

- May have received TAM or raloxifene for purposes of chemoprevention (e.g., Breast
Cancer Prevention Trial) or for other indications (including previous breast
cancer if lobular carcinoma in situ [LCIS]) but must be discontinued before
registration on this study

- May never have received TAM, raloxifene, or any other hormonal agent

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelets (PLT) >= 100,000/mm^3

- Total bilirubin =< 1.5 x upper normal limit (UNL)

- Aspartate aminotransferase (AST) =< 2.0 x UNL

- Left ventricular ejection fraction (LVEF) within institutional normal range; if LVEF
is > 75%, the investigator should consider performing a second review of the
multigated acquisition (MUGA)/echocardiogram or performing a repeat
MUGA/echocardiogram prior to registration; such re-reviews or repeat
MUGA/echocardiogram are not permitted after registration

- Willingness to discontinue sex hormonal therapy, e.g., birth control pills, ovarian
hormonal replacement therapy, etc., prior to registration and while on study

- Willingness to discontinue any hormonal agent such as raloxifene (Evista) prior to
registration and while on study

- Non-breast malignancies that have not recurred within the last 5 years and are deemed
to be at low risk for recurrence

EXCEPTIONS: These non-breast malignancies are eligible even if diagnosed =< 5 years prior
to registration:

- Squamous or basal cell carcinoma of the skin that has been effectively treated

- Carcinoma in situ of the cervix that has been treated by surgery only

- Lobular carcinoma in situ (LCIS) of the ipsilateral or contralateral breast treated by
surgery and/or tamoxifen only

- Patients undergoing breast conservation therapy (i.e., lumpectomy and axillary
dissection) must have plans to receive radiation therapy to the breast +/-
regional lymphatics following completion of the chemotherapy; for patients
treated with mastectomy, the use of radiation therapy is required for 4 or more
positive lymph nodes and must be started after completion of chemotherapy; the
use of radiation therapy is at the discretion of the investigator for 0-3
positive lymph nodes but, if used, must be started after the completion of
chemotherapy

- Prior to registration, the physician must designate if it is planned for the
patient to receive radiation therapy (for adjuvant radiation therapy
post-mastectomy or, less commonly, post-conservative therapy but not primary
breast radiation as part of breast conserving treatment)

- Willing and able to sign an informed consent

- Gene amplified by FISH or strong positivity (3+) by HercepTest on central review;
Note: The patient registers based on community HER-2 testing using FISH or IHC,
AC chemotherapy is initiated; the tumor block or slides must be received =< 2
weeks from time of registration to the North Central Cancer Treatment Group
(NCCTG) Operations Office for central HER-2 testing

Exclusion Criteria:

- Any of the following:

- Pregnant women

- Nursing women

- Women of childbearing potential or their sexual partners who are unwilling to
employ adequate contraception (condoms, diaphragm, intrauterine device [IUD],
surgical sterilization, or abstinence, etc.); hormonal birth control methods are
not permitted

- Locally advanced tumors (classification T4) at diagnosis including tumors fixed to
chest wall, peau d'orange, skin ulcerations/nodules, or clinical inflammatory changes
(diffuse brawny cutaneous induration with an erysipeloid edge)

- Prior history of breast cancer, except LCIS

- Bilateral invasive carcinoma, either metachronous or synchronous (EXCEPTION: Patients
diagnosed with unilateral invasive carcinoma and metachronous or synchronous DCIS of
the contralateral breast treated with mastectomy are eligible)

- Prior chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer

- Active, unresolved infection

- Active cardiac disease

- Any prior myocardial infarction

- History of documented congestive heart failure (CHF)

- Current use of digitalis or beta-blockers for CHF

- Any prior history of arrhythmia or cardiac valvular disease requiring medications
or clinically significant

- Current use of medications for treatment of arrhythmias or angina pectoris

- Current uncontrolled hypertension (diastolic > 100 mmHg or systolic > 200 mmHg)

- Clinically significant pericardial effusion

- Prior anthracycline or taxane therapy for any malignancy

- Sensitivity to benzyl alcohol

- Neurology/Neuropathy-Sensory >= grade 2 per the National Cancer Institute's (NCI's)
Common Toxicity Criteria Version 2.0; EXCEPTION: Any chronic neurologic disorder will
be looked at on a case-by-case basis by the study chair