Combination Chemotherapy With Trastuzumab in Treating Women With Metastatic Breast Cancer

OBJECTIVES:

• Compare the incidence of clinical heart failure in women with c-erbB2-positive metastatic breast cancer treated with cyclophosphamide, methotrexate, and fluorouracil in combination with trastuzumab (Herceptin®).
• Compare the therapeutic activity of this regimen, in terms of objective response rate, in these patients.
• Compare the duration of response and time to progression in patients treated with this regimen.
• Compare the toxic effects of this regimen in these patients.

OUTLINE: This is a multicenter study.

Patients receive CMF comprising cyclophosphamide orally on days 1-14 or IV on days 1 and 8 and methotrexate IV and fluorouracil IV on days 1 and 8. Patients also receive trastuzumab (Herceptin®) IV over 30-90 minutes once weekly beginning on day 1. Treatment repeats every 4 weeks for 8 courses. Patients then receive trastuzumab once every 3 weeks in the absence of disease progression, unacceptable toxicity, or patient refusal.

Patients are followed every 8 weeks until documentation of disease progression or initiation of a new anticancer therapy. Patients developing disease progression are followed every 12 weeks.

PROJECTED ACCRUAL: A total of 66 patients will be accrued for this study within 2 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed metastatic breast cancer c-erbB2 positive (3+ overexpression by the HercepTest™ method) in the primary tumor or metastatic site
• At least 1 unidimensionally measurable target lesion

• At least 20 mm by conventional techniques OR
• At least 10 mm by spiral CT scan
• Lesions that have been irradiated in the preceding 3 months cannot be used as target lesions unless they have appeared or clearly progressed since prior irradiation
• No bone lesions as the only target lesions
• No contralateral breast cancer that is c-erbB2-positive or c-erbB2-negative/unknown, with status determined on a metastatic site
• No CNS metastases

• CT scan of brain and CSF cytology are required if neurologic symptoms are present
• Hormone receptor status:

• Any estrogen or progesterone receptor status

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Sex:

• Female

Menopausal status:

• Any status

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.25 times upper limit of normal (ULN)
• Transaminases less than 2.5 times ULN (5 times ULN if liver metastases present)

Renal:

• For patients age 18 to 69:

• Creatinine no greater than ULN
• For patients age 70 and over:

• Creatinine clearance normal

Cardiovascular:

• LVEF normal by MUGA or echocardiogram
• No clinical heart failure

Pulmonary:

• No malignancy-associated dyspnea at rest
• No requirement for supportive oxygen therapy

Other:

• Not pregnant or nursing
• No other prior or concurrent malignancy within the past 5 years except adequately treated carcinoma in situ of the cervix or basal cell skin cancer
• No psychological, familial, sociological, or geographical condition that would preclude compliance with study therapy and follow-up schedule

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior anti-c-erbB2 antibody, including trastuzumab (Herceptin®)
• No other concurrent biologic therapy

Chemotherapy:

• No more than 1 prior chemotherapy regimen for metastatic breast cancer
• Prior combination of cyclophosphamide, methotrexate, and fluorouracil (CMF) allowed in the adjuvant or metastatic setting only if the disease-free interval after completion of CMF was at least 12 months
• Prior anthracyclines and/or taxanes allowed
• At least 4 weeks since prior anthracyclines
• No prior cumulative dose of doxorubicin more than 360 mg/m^2
• No prior cumulative dose of epirubicin more than 720 mg/m^2
• No prior cumulative dose of mitoxantrone more than 90 mg/m^2
• No other concurrent chemotherapy

Endocrine therapy:

• More than 2 weeks since prior hormonal therapy in the adjuvant or metastatic setting
• No concurrent hormonal therapy

Radiotherapy:

• See Disease Characteristics
• No concurrent radiotherapy

Surgery:

• Not specified

Other:

• No other concurrent anticancer therapy or investigational drugs
• No concurrent bisphosphonates started after study enrollment except for hypercalcemia