Combination Chemotherapy and Paclitaxel Plus Trastuzumab in Treating Women With Palpable Breast Cancer That Can Be Removed by Surgery

PRIMARY OBJECTIVES:

I. The primary objective of this study is to compare the pathologic complete response rate
(pCR) within the breast of a sequential regimen of concurrent weekly paclitaxel and
trastuzumab, followed by continued weekly trastuzumab administered concurrently with FEC-75
(Arm 2), to the pCR rate of a sequential regimen of FEC-75 alone followed by concurrent
weekly paclitaxel and trastuzumab (Arm 1).

SECONDARY OBJECTIVES:

I. To estimate the cardiotoxicity of a sequential regimen of concurrent weekly paclitaxel and
trastuzumab, followed by continued weekly trastuzumab administered concurrently with FEC-75,
followed postoperatively by q 3 week trastuzumab for a total duration of trastuzumab therapy
through 52 weeks from the first dose (Arm 2), and compare the cardiotoxicity to that of a
sequential regimen of FEC-75 alone followed by concurrent weekly paclitaxel and trastuzumab,
followed by q 3 week trastuzumab for a total duration of trastuzumab therapy through 52 weeks
from the first dose (Arm 1).

II. To compare the combined pCR rate in the breast and ipsilateral axilla obtained with the
two regimens evaluated in this study.

III. To compare the clinical response rates (cRR) of the two regimens evaluated in this
study.

IV. To compare the non-cardiac toxicity of the two regimens evaluated in this study.

V. To compare breast conservation rates achieved with the two regimens evaluated in this
study.

VI. To evaluate disease-free survival and overall survival at 5 years post-randomization.

VII. To correlate pCR rate with potential molecular markers of response.

OUTLINE: Patients are stratified by clinical tumor size (breast tumor size < 2 cm and nodal
metastases < 2 cm vs breast tumor size < 2 cm and nodal metastases ≥ 2 cm vs breast tumor
size 2-4 cm [any nodal status] vs breast tumor size ≥ 4 cm [any nodal status]), age (< 50 vs
≥ 50) and hormone receptor status (estrogen receptor [ER]- and progesterone receptor
[PgR]-negative vs ER- and/or PgR-positive). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive FEC comprising fluoroucacil intravenously (IV), epirubicin
hydrochloride IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4
courses. Beginning 21 days after completion of FEC, patients receive paclitaxel IV once
weekly and trastuzumab (Herceptin) IV once weekly for 12 weeks. Within 6 weeks after
completion of paclitaxel and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after
surgery, patients receive trastuzumab IV once every 3 weeks for up to 52 weeks.

ARM II: Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12
weeks. Beginning 7 days after completion of paclitaxel and trastuzumab, patients receive FEC
comprising fluoroucacil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment
repeats every 21 days for 4 courses. Patients also receive trastuzumab IV once weekly for an
additional 12 weeks. Within 6 weeks after completion of FEC and trastuzumab, patients undergo
surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab as in arm I.

After completion of study therapy, patients are followed every 3 months for 1 year and then
every 6 months for 4 years.

Inclusion Criteria:

- Diagnosis of invasive adenocarcinoma by core needle biopsy

- Fine needle aspiration allowed provided primary tumor size < 2 cm and lymph node
metastases are present

- Excisional biopsy of the primary tumor allowed provided biopsy-positive lymph
nodes are present

- Primary tumor ≥ 2 cm and/or ≥ 1 biopsy-positive lymph node

- HER2-positive disease

- Confirmation by fluorescent in situ hybridization (FISH) requires gene
amplification

- Confirmation by immunohistochemistry (IHC) requires a strongly positive (3+)
staining intensity score

- Ductal carcinoma in situ (DCIS) or synchronous DCIS of the contralateral breast
regardless of prior therapy allowed

- Synchronous invasive breast cancer not allowed

- Ipsilateral DCIS treated by local excision with or without hormonal therapy allowed

- Those treated with radiation therapy are not allowed

- No definitive clinical or radiologic evidence of metastatic disease

- No history of invasive breast cancer

- Hormone receptor status known

- Menopausal status not specified

- ECOG performance status of 0 -1

- Absolute neutrophil count ≥ 1,200/mm³

- Platelet count ≥ 100,000/mm³

- Total bilirubin normal unless the patient has a grade 1 bilirubin elevation (normal to
1.5 times upper limit of normal [ULN]) resulting from Gilbert disease or similar
syndrome due to slow conjugation of bilirubin

- Alkaline phosphatase ≤ 2.5 times ULN

- AST ≤ 1.5 times ULN

- Creatinine normal

- Left ventricular ejection fraction (LVEF) ≥ 55 by multi gated acquisition scan (MUGA)
or echocardiogram (ECHO) within the past 3 months

- Patients with either skeletal pain or alkaline phosphatase that is > ULN but ≤ 2.5
times ULN allowed if bone scans fail to demonstrate metastatic disease

- Suspicious findings on bone scan must be confirmed as benign by x-ray, MRI, or
biopsy

- Prior non-breast malignancies allowed if disease-free for 5 years since completion of
initial treatment regimen and deemed by their physician to be at low risk for
recurrence

- Patients who had the following cancers are eligible if diagnosed and treated
within the past 5 years:

- Carcinoma in situ of the cervix

- Colon carcinoma in situ

- Melanoma in situ

- Basal cell and squamous cell carcinoma of the skin

- No cardiac disease that would preclude the use of epirubicin hydrochloride or
trastuzumab (Herceptin®) including any of the following:

- 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

- Patient's with poorly controlled hypertension ( i.e., diastolic greater than 100
mm/Hg)

- Patients with hypertension that is well controlled on medication are
eligible

- History of cardiac disease

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

- Documented congestive heart failure

- Documented cardiomyopathy

- No sensory or motor neuropathy ≥ grade 2, as defined by the NCI's CTCAE v3.0

- Women of reproductive potential must agree to use an effective non-hormonal method of
contraception during therapy

- Women of child bearing potential must have a negative urine or serum pregnancy test
within 2 weeks of registration

- Not pregnant or nursing

- No psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements

- No non-malignant systemic disease (e.g., cardiovascular, renal, hepatic) that would
preclude treatment with either of the treatment regimens

- No prior surgical axillary staging procedure

- Prior non-excisional biopsy of an axillary node allowed

- No prior treatment for this breast cancer

- Hormonal therapy allowed if had been given for up to a total of 28 days anytime
after diagnosis and before study entry

- Hormonal therapy must stop at or before study entry and be re-started, if
indicated, following surgery

- No prior therapy with anthracyclines or taxanes for any malignancy

- No other investigational agents within the past 30 days

- No concurrent sex hormonal therapy (e.g., birth control pills, ovarian hormonal
replacement therapy)

- No concurrent therapy with any hormonal agent such as raloxifene, tamoxifen, or other
selective estrogen receptor modulator (SERM), either for osteoporosis or breast cancer
prevention