RATIONALE: Drugs used in chemotherapy, such as paclitaxel and docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether chemotherapy is more effective with lapatinib or trastuzumab in treating patients with breast cancer.

PURPOSE: This randomized phase III trial is studying chemotherapy and lapatinib to see how well they work compared with chemotherapy and trastuzumab in treating women with HER2/neu-positive metastatic breast cancer.

OBJECTIVES:

Primary

• To compare the progression-free survival of women with HER2/neu-positive metastatic breast cancer treated with taxane-based chemotherapy in combination with lapatinib ditosylate or trastuzumab (Herceptin®).

Secondary

• To compare the overall survival.
• To compare the time to CNS metastases at the time of first progression.
• To compare the incidence rates of CNS metastases at the time of progression.
• To compare the overall objective response rate (complete or partial response), time to response, and duration of response in patients with measurable disease at baseline.
• To compare the clinical benefit response rate.
• To compare the adverse event profile.
• To compare the quality of life.
• To compare clinical outcomes using biomarker changes in biological samples.
• To compare health economics, including healthcare utilization and health utilities.

OUTLINE: This is a multicenter study. Patients are stratified according to prior neoadjuvant/adjuvant anti-HER2/neu-targeted therapy (yes vs no), prior neoadjuvant/adjuvant taxane chemotherapy (yes vs no), planned taxane therapy (paclitaxel vs docetaxel), and liver metastasis (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive either paclitaxel IV on days 1, 8, and 15 OR docetaxel IV on day 1. Treatment with paclitaxel repeats every 4 weeks for 6 courses and treatment with docetaxel repeats every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral lapatinib ditosylate once daily in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive paclitaxel IV on days 1, 8, and 15 and trastuzumab (Herceptin®) IV on days 1, 8, 15, and 22. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Alternatively, patients may receive docetaxel IV and trastuzumab IV on day 1. Treatment repeats every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. After completion of taxane chemotherapy and trastuzumab, all patients receive trastuzumab alone IV once every 3 weeks in the absence of disease progression or unacceptable toxicity.

Formalin-fixed paraffin-embedded tissue samples are analyzed for ER, PgR, EGFR, CK5/6, Ki67, and other molecular biomarkers by tissue microarray and immunohistochemistry.

Patients complete quality of life questionnaires (EORTC QLQ-C30 and a Trial Specific Checklist) at baseline, every 12 weeks for 96 weeks, and then every 24 weeks until disease progression.

After completion of study treatment, patients are followed at 4 weeks, 12 weeks, and then every 12 weeks thereafter.

• Biological: trastuzumab
  Given IV
• Drug: lapatinib ditosylate
  Given orally

• Arm I: Experimental
  Patients receive either paclitaxel IV on days 1, 8, and 15 OR docetaxel IV on day 1. Treatment with paclitaxel repeats every 4 weeks for 6 courses and treatment with docetaxel repeats every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral lapatinib ditosylate once daily in the absence of disease progression or unacceptable toxicity.
  Intervention: Drug: lapatinib ditosylate
• Arm II: Active Comparator
  Patients receive paclitaxel IV on days 1, 8, and 15 and trastuzumab (Herceptin®) IV on days 1, 8, 15, and 22. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Alternatively, patients may receive docetaxel IV and trastuzumab IV on day 1. Treatment repeats every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. After completion of taxane chemotherapy and trastuzumab, all patients receive trastuzumab alone IV once every 3 weeks in the absence of disease progression or unacceptable toxicity.
  Intervention: Biological: trastuzumab

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the breast

  • Metastatic (stage IV) disease at primary diagnosis or at relapse after curative intent therapy

• HER2/neu* overexpressing and/or amplified disease in the invasive component of the primary or metastatic lesion as defined by the following:

  • 3+ overexpression (in > 30% of invasive tumor cells) by immunohistochemistry (IHC)
  • 2+ or 3+ overexpression (in ≤ 30% of invasive tumor cells) by IHC AND demonstrates HER2/neu gene amplification by fluorescence in situ hybridization (FISH)
  • HER2/neu gene amplification by FISH (> 6 HER2/neu gene copies per nucleus, or a FISH ratio [HER2 gene copies to chromosome 17 signals] of ≥ 2.2) NOTE: *Patients with a negative or equivocal overall result (FISH ratio of < 2.2, < 6.0 HER2/neu gene copies per nucleus, or staining scores of 0, 1+, 2+, or 3+ [in ≤ 30% of invasive tumor cells] by IHC) are not eligible
• Formalin-fixed paraffin-embedded tumor specimen available
• No CNS metastases (including leptomeningeal involvement)
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• ECOG performance status 0-2
• Life expectancy > 6 months
• Absolute granulocyte count > 1,500/mm³
• Platelet count > 75,000/mm³
• Hemoglobin > 10 g/dL
• Serum creatinine ≤ 2.0 times upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 times ULN (< 3 times ULN for patients with Gilbert's disease)
• AST and/or ALT ≤ 2.5 times ULN (< 5 times ULN for patients planning to receive paclitaxel-based therapy)
• LVEF ≥ 50% by MUGA or ECHO
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Must be accessible for study treatment and follow-up
• No history of other malignancies, except adequately treated ductal carcinoma in situ, adequately treated nonmelanoma skin cancer, curatively treated carcinoma in situ of the cervix, or other curatively treated solid tumor (non-breast) with no evidence of disease for > 5 years

• No serious cardiac illness or condition including, but not limited to, any of the following:

  • History of documented congestive heart failure or systolic dysfunction (LVEF < 50%)
  • High-risk uncontrolled arrhythmias (i.e., ventricular tachycardia, high-grade atrioventricular block, or supraventricular arrhythmias that are not adequately rate-controlled)
  • Unstable angina pectoris requiring anti-anginal medication
  • Clinically significant valvular heart disease
  • Evidence of transmural infarction on ECG
  • Inadequately controlled hypertension (i.e., systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg)
  • New York Heart Association class III-IV functional status

• No serious illness or medical condition that would not allow the patient to be managed according to the protocol including, but not limited to, any of the following:

  • History of significant neurologic or psychiatric disorder that would impair the ability to obtain informed consent or limit compliance with study requirements
  • Active uncontrolled infection
  • Serious or nonhealing wound, ulcer, or bone fracture
• No peripheral neuropathy ≥ grade 2

• No gastrointestinal (GI) tract disease resulting in an inability to take oral medication including, but not limited to, any of the following:

  • Malabsorption syndrome
  • Requirement for IV alimentation
  • Uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative colitis)

• No history of allergic or hypersensitivity reactions to any study drug or their excipients or to compounds with similar chemical composition to any of the study drugs

  • Prior allergic reactions to taxanes are allowed provided they were adequately treated and, according to the treating physician, would not prohibit further treatment with taxanes

PRIOR CONCURRENT THERAPY:

• Recovered from all prior therapy
• No prior chemotherapy, immunotherapy, biological therapy, or anti-HER2/neu-targeted therapy for recurrent or metastatic breast cancer
• At least 12 months since prior chemotherapeutic agents, including taxanes, in the neoadjuvant or adjuvant setting
• At least 12 months since prior anti-HER2/neu-targeted therapy in the neoadjuvant or adjuvant setting
• Prior treatment with endocrine therapy in the neoadjuvant, adjuvant, or metastatic setting allowed

• At least 2 weeks since prior radiotherapy in the adjuvant or metastatic setting

  • Prior radiotherapy to a solitary metastatic lesion allowed provided there is documented disease progression after completion of radiotherapy
• More than 30 days (or 5 half-lives) since prior investigational drugs
• At least 7 days since prior and no concurrent CYP3A4 inhibitors (6 months for amiodarone)
• At least 14 days since prior and no concurrent CYP3A4 inducers
• No prior surgical procedures affecting absorption (e.g., resection of stomach or small bowel)
• No concurrent palliative radiotherapy
• No other concurrent anticancer treatment
• No other concurrent investigational drugs for breast cancer