RATIONALE: Drugs used in chemotherapy, such as paclitaxel, use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies, such as trastuzumab, can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known which of two regimens of paclitaxel, with or without trastuzumab, is more effective in treating women with inoperable, recurrent, or metastatic breast cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of two regimens of paclitaxel, with or without trastuzumab, in treating women who have breast cancer that is inoperable, recurrent, or metastatic, with or without overexpression of HER2/neu.

OBJECTIVES:

• Compare the response rate in women with inoperable, recurrent, or metastatic breast cancer treated with paclitaxel via one-hour infusion every week vs 3-hour infusion every 3 weeks, regardless of HER2/neu status and assignment to trastuzumab (Herceptin®).
• Compare the response rate and quality of life of patients with HER2/neu-nonoverexpressing disease treated with 1 of these 2 paclitaxel regimens with or without trastuzumab.
• Correlate amplification and overexpression of the growth factor receptor ErbB2 by immunohistochemistry and fluorescent in situ hybridization (FISH) with response rate, time to progression, and overall survival of patients treated with these regimens.
• Correlate ErbB2 shed extracellular domain (ECD) with response rate, time to progression, and overall survival of patients treated with these regimens.
• Assess the patterns of ErbB2/ECD after treatment with these regimens and upon relapse in these patients.
• Compare the time to progression and survival of patients with HER2/neu-overexpressing disease treated with these regimens.
• Compare the time to progression and survival of patients with HER2/neu-nonoverexpressing disease treated with these regimens.
• Compare the cardiac toxicity of these regimens as measured by changes in left ventricular ejection fraction from baseline to follow-up measurements in these patients.

OUTLINE: This is a randomized study. Patients are stratified according to prior chemotherapy for metastatic disease (none or recurrence more than 6 months after adjuvant therapy vs one or none but recurrence less than 6 months after adjuvant therapy) and HER2/neu overexpression (yes vs no). Patients are assigned to 1 of 2 treatment groups based on HER2/neu status.

• Group A (HER2/neu-nonoverexpressing): Patients are randomized to 1 of 4 treatment arms.

  • Arm I: Patients receive paclitaxel IV over 3 hours on day 1.
  • Arm II: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15.
  • Arm III: Patients receive paclitaxel as in arm I. Patients receive an initial loading dose of trastuzumab (Herceptin®) IV over 90 minutes on day 1 of course 1 and maintenance dose of trastuzumab IV over 30 minutes on day 1 of subsequent courses and on days 8 and 15 of all courses. Trastuzumab is administered immediately after completion of paclitaxel infusion on weeks of concurrent administration.
  • Arm IV: Patients receive paclitaxel as in arm II and trastuzumab as in arm III.

• Group B: (HER2/neu-overexpressing): Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive treatment as in arm III (group A).
  • Arm II: Patients receive treatment as in arm IV (group A). In both groups, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and then at 3, 6, and 9 months.

Patients are followed at 6, 12, and 18 months and then annually for 5 years or until death.

PROJECTED ACCRUAL: A total of 580 patients will be accrued for this study within 3 years.

• Biological: trastuzumab
• Drug: paclitaxel

• Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9.
• Polite BN, Cirrincione C, Fleming GF, Berry DA, Seidman A, Muss H, Norton L, Shapiro C, Bakri K, Marcom K, Lake D, Schwartz JH, Hudis C, Winer EP. Racial differences in clinical outcomes from metastatic breast cancer: a pooled analysis of CALGB 9342 and 9840--Cancer and Leukemia Group B. J Clin Oncol. 2008 Jun 1;26(16):2659-65.

DISEASE CHARACTERISTICS:

• Histologically proven inoperable, recurrent, or metastatic adenocarcinoma of the breast
• Known HER2/neu status
• Measurable disease
• No CNS metastases unless at least 6 months since prior cranial radiotherapy and the patient is asymptomatic and not receiving corticosteroids for this condition at time of enrollment
• No leptomeningeal carcinoma (carcinomatous meningitis)

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Sex:

• Female

Menopausal status:

• Not specified

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

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

Hepatic:

• Bilirubin normal
• SGOT no greater than 3 times upper limit of normal

Renal:

• Creatinine no greater than 2.0 mg/dL

Cardiovascular:

• Left ventricular ejection fraction at least 45%

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior trastuzumab (Herceptin®)
• Concurrent epoetin alfa allowed

Chemotherapy:

• No more than 1 prior chemotherapy regimen for locally advanced or metastatic breast cancer
• No prior taxane for locally advanced or metastatic breast cancer
• No more than 1 prior adjuvant chemotherapy regimen
• At least 12 months since prior adjuvant taxane and recovered
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, melphalan, or mitomycin)
• No other concurrent chemotherapy

Endocrine therapy:

• See Disease Characteristics
• More than 4 weeks since prior hormonal therapy
• More than 1 week since prior hormonal therapy if documented tumor progression

• No concurrent hormonal therapy except any of the following:

  • Steroids for documented CNS metastases, adrenal failure, septic shock, or prevention of serious allergic reaction or emesis
  • Hormonal therapy for nonmalignant conditions (e.g., insulin for diabetes)

Radiotherapy:

• See Disease Characteristics
• No concurrent radiotherapy except whole brain irradiation for CNS disease

Surgery:

• More than 2 weeks since prior surgery, other than biopsy or placement of venous access device

Other:

• Concurrent bisphosphonate (e.g., pamidronate) therapy allowed