Combination Chemotherapy and Filgrastim Before Surgery in Treating Patients With HER2-Positive Breast Cancer That Can Be Removed By Surgery

PRIMARY OBJECTIVES:

I. To assess the pathologic response rate in patients with operable breast cancer treated
with a two part, neoadjuvant regimen consisting of weekly doxorubicin (doxorubicin
hydrochloride) and daily oral cyclophosphamide given with G-CSF (filgrastim) support for 12
weeks followed weekly paclitaxel for 12 weeks.

SECONDARY OBJECTIVES:

I. To assess the clinical response rate in patients with surgically resectable breast cancer
treated with weekly doxorubicin and daily oral cyclophosphamide given with G-CSF support for
12 weeks.

II. To assess the clinical response rate in patients with surgically resectable breast cancer
treated with weekly paclitaxel for 12 weeks.

III. To assess the relapse rate, overall and disease-free survival in patients with operable
breast cancer treated with neoadjuvant chemotherapy consisting of weekly doxorubicin and
daily oral cyclophosphamide given with G-CSF support for 12 weeks followed weekly paclitaxel
for 12 weeks and adjuvant chemotherapy with Xeloda (capecitabine), Methotrexate and Navelbine
(vinorelbine tartrate) (XMN).

IV. To assess the toxicity associated with these regimens. V. To assess whether the phenotype
of breast cancer changes with treatment. VI. To assess whether phenotypic changes in breast
tumors predict outcome.

OUTLINE:

PART I: Patients receive doxorubicin hydrochloride intravenously (IV) on day 1 of each week,
cyclophosphamide orally (PO) once daily (QD), and filgrastim subcutaneously (SC) QD on days
2-7 of each week. Treatment continues for 12 weeks in the absence of disease progression or
unacceptable toxicity.

PART II: Patients* receive paclitaxel IV over 1 hour on day 1 of each week. Treatment
continues for 12 weeks in the absence of disease progression or unacceptable toxicity.
Patients then undergo definitive surgical resection by partial mastectomy (lumpectomy) or
mastectomy after completion of neoadjuvant chemotherapy.

PART III: Patients** unable to achieve complete pathologic response (pCR) or disease that has
been down-staged to =< 1 cm with no positive nodes following surgery receive capecitabine PO
twice daily (BID) on days 1-14, methotrexate IV on days 1, 8 and 15, and vinorelbine tartrate
IV over 6-10 minutes on days 1, 8, and 15. Treatment repeats every 3 weeks for 4 courses in
the absence of disease progression or unacceptable toxicity.

NOTE: *Patients with HER2/neu-positive disease also receive trastuzumab IV over 30-90 minutes
once weekly or every 3 weeks for 1 year beginning in Part II.

NOTE: **Patients with hormone receptor-positive disease also receive tamoxifen PO QD for 5
years (premenopausal) OR letozole PO QD or tamoxifen PO QD for 5 years (postmenopausal)
beginning in Part III.

After completion of study treatment, patients are followed up every 3 months for 3 years,
every 6 months for 2 years, and then annually thereafter.

Inclusion Criteria:

- Have known tumor HER-2/neu expression; if determination is "intermediate" by
immunohistochemistry, fluorescent in situ hybridization (FISH) must be performed;
protocol therapy is determined by HER-2/neu result

- Have histologically confirmed, operable breast cancer that is either:

- Hormone receptor (estrogen receptor [ER] or progesterone receptor [PR]) positive and
HER2/neu positive or

- ER/PR negative

- Have radiographically measurable breast cancer > 1cm (Operable lesions are T1c-T3 and
N0-N2a; histologic confirmation should be by core needle biopsy only)

- Be chemotherapy naïve

- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

- Absolute neutrophil count (ANC) >= 1,500

- Platelet count >= 100,000

- Serum creatinine =< 1.5 x international upper limit of normal (IULN)

- Bilirubin < 2.0

- Serum glutamic oxaloacetic transaminase (SGOT)/serum glutamic pyruvate transaminase
(SGPT) =< 2 x IULN

- Alkaline phosphatase =< 2 x IULN

- Have staging studies and tumor assessment prior to registration; staging studies
include physical exam with bidimensional tumor measurements and mammography,
ultrasound, or magnetic resonance imaging (MRI) to assess tumor volume; sentinel lymph
node dissection or axillary needle biopsy must be completed prior to enrollment; MRI
and positron emission tomography (PET) (fluorodeoxyglucose [FDG],
methoxyisobutylisonitrile [MIBI] and fluoroestradiol [FES]) imaging will be done
before enrollment if clinically indicated to assess tumor volume or may be done within
the first month of study participation on another institutional protocol

- Patients with clinically apparent cardiac disease, or history of same, are not
eligible; patients who are >= 60 years of age or who have a history of hypertension
must have an echocardiogram or multi gated acquisition scan (MUGA) prior to
enrollment; patients with breast cancer that is HER-2/neu positive who will receive
herceptin (trastuzumab) must have an echocardiogram or MUGA scan; the left ventricular
ejection fraction (LVEF) must be within the institutional normal range; if LVEF is >
75%, the investigator should consider having the LVEF reviewed or repeating the MUGA
prior to registration

- Women of childbearing potential must have a negative pregnancy test within seven days
prior to registration

- Be informed of the investigational nature of this study and provide written informed
consent in accordance with institutional and federal guidelines prior to study
specific screening procedures

Exclusion Criteria:

- Primary tumor =< 1 cm, not measurable; inflammatory disease

- Pregnant or lactating; woman of childbearing potential with either a positive or no
pregnancy test at baseline are excluded; postmenopausal woman must have been
amenorrheic for at least 12 months to be considered of non-childbearing potential;
patients must agree to continue contraception for 30 days from the date of the last
study drug administration; woman of childbearing potential not using a reliable and
appropriate contraceptive method are excluded

- Evidence of distant metastatic disease

- Prior chemotherapy or hormonal therapy for breast cancer

- Except for the following no other malignancy is allowed: synchronous ipsilateral
breast cancer of the same subtype (ER/PR, HER-2/neu), adequately treated basal cell or
squamous cell skin cancer, in situ cervical cancer or other stage I or II cancer from
which the patient has been disease free for at least 5 years

- Prior unanticipated severe reaction to fluoropyrimidine therapy, or known sensitivity
to 5-fluorouracil

- Previous enrollment in an investigational drug study within the past four weeks

- History of uncontrolled seizures, central nervous system disorders, or psychiatric
disability judged by the investigator to be clinically significant, precluding
informed consent, or interfering with compliance with oral drug intake

- Patients with cardiac disease that would preclude the use of Adriamycin, Taxol or
Herceptin are not eligible

- 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 electrocardiogram (EKG)

- Uncontrolled hypertension, (diastolic greater than 100 mm/Hg or systolic > 200 mm/hg)

- Current use of digitalis or beta blockers for congestive heart failure (CHF)

- Clinically significant pericardial effusion

- History of cardiac disease:

- Myocardial infarction documented as a clinical diagnosis or by EKG or any other test

- Documented congestive heart failure

- Documented cardiomyopathy

- Documented arrhythmia or cardiac valvular disease that requires medication or is
medically significant

- Major surgery within 4 weeks of the start of study treatment without complete recovery

- Lack of physical integrity of the upper gastrointestinal tract or malabsorption
syndrome

- Known, existing uncontrolled coagulopathy

- Unwillingness to give written informed consent

- Unwillingness to participate or inability to comply with the protocol for the duration
of the study