Chemotherapy and Peripheral Stem Cell Transplantation Followed by Trastuzumab in Treating Women With Metastatic Breast Cancer

OBJECTIVES: I. Determine the safety and toxicity profile, specifically cardiac toxicity, of
trastuzumab (Herceptin) following high dose chemotherapy and autologous peripheral blood stem
cell transplantation in women with metastatic breast cancer. II. Determine the time to
disease progression and disease free survival in these patients when treated with this
regimen. III. Determine the impact of trastuzumab (Herceptin) on minimal residual disease
after autologous peripheral blood stem cell transplantation as evidenced by serial
immunocytochemical analysis of bone marrow. IV. Determine the relationship between
posttransplant reconstitution of antibody dependent cellular toxicity and the efficacy of
trastuzumab (Herceptin) in these patients.

OUTLINE: This is a multicenter study. Patients undergo stem cell mobilization with growth
factors alone (filgrastim (G-CSF) and/or sargramostim (GM-CSF)) or chemotherapy followed by
growth factors (depending on center). Peripheral blood stem cells (PBSC) are then collected
by leukapheresis. Patients then receive high dose chemotherapy consisting of cyclophosphamide
IV over 1 hour and cisplatin IV over 72 hours on days -6 to -4 and carmustine IV on day -3 or
cyclophosphamide IV, thiotepa IV, and carboplatin IV over 96 hours on days -7 to -4
(depending on center). PBSC are reinfused on day 0. Patients then receive trastuzumab IV over
30-90 minutes weekly for 1 year or until disease progression beginning 5-8 weeks after PBSC
reinfusion.

PROJECTED ACCRUAL: A total of 70 patients will be accrued for this study.

DISEASE CHARACTERISTICS: Histologically confirmed stage IV breast cancer that overexpresses
HER2/neu Evidence of at least a partial response (at least 50% reduction) to salvage
chemotherapy as initial chemotherapy for metastatic disease Measurable disease not required
if there is no disease progression at induction chemotherapy Bone lesions as only site of
metastatic disease allowed if evidence of clinical improvement and no new lesions on x-ray
No CNS metastases Hormone receptor status: Not specified

PATIENT CHARACTERISTICS: Age: 18 to physiologic 65 Sex: Female Menopausal status: Pre or
postmenopausal Performance status: Karnofsky 80-100% Life expectancy: At least 6 months
Hematopoietic: WBC at least 2,500/mm3 Absolute neutrophil count at least 1,000/mm3 Platelet
count at least 100,000/mm3 Hepatic: Bilirubin no greater than 1.5 times upper limit of
normal (ULN) SGOT no greater than 2.5 times ULN Renal: Creatinine no greater than 2.0 mg/dL
Cardiovascular: LVEF at least 45% by radionucleotide ventriculogram No uncontrolled
hypertension No unstable angina No New York Heart Association class IV heart disease or
congestive heart failure No coronary angioplasty or myocardial infarction within past 6
months No uncontrolled atrial or ventricular cardiac arrhythmias Pulmonary: FEV1 and DLCO
at least 50% Other: Not pregnant or nursing Negative pregnancy test Fertile patients must
use effective contraception HIV negative No insulin dependent diabetes mellitus No
uncontrolled active systemic infection No other significant nonmalignant disease No other
malignancy in past 5 years except surgically cured nonmelanoma skin cancer or carcinoma in
situ of the cervix

PRIOR CONCURRENT THERAPY: Biologic therapy: Prior trastuzumab allowed No prior bone marrow
or peripheral blood stem cell transplantation Chemotherapy: See Disease Characteristics
Prior doxorubicin not to exceed total cumulative dose of 360 mg/m2 No more than 6 standard
courses of pretransplant salvage chemotherapy No more than 3 months of prior weekly taxane
therapy More than 1 chemotherapy regimen allowed with no progression during chemotherapy
Endocrine therapy: Concurrent tamoxifen therapy allowed for estrogen receptor positive
patients who have not received prior hormonal therapy No other concurrent hormonal therapy
Radiotherapy: No concurrent radiotherapy Surgery: Not specified Other: Concurrent
pamidronate allowed for bone lesions