RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide and methotrexate, work in different ways to stop tumor cells from dividing so they stop growing or die. Bevacizumab may stop the growth of breast cancer by stopping blood flow to the tumor. Giving metronomic (regularly timed) low-dose cyclophosphamide and methotrexate together with bevacizumab may kill more tumor cells.

PURPOSE: This randomized phase II trial is studying metronomic low-dose cyclophosphamide and methotrexate to see how well they work compared to metronomic low-dose cyclophosphamide, methotrexate, and bevacizumab in treating women with metastatic breast cancer.

OBJECTIVES:

Primary

• Compare the overall response rate in women with metastatic breast cancer treated with metronomic low-dose cyclophosphamide and methotrexate with or without bevacizumab.

Secondary

• Compare the progression-free survival of patients treated with these regimens.
• Compare the toxicity of these regimens in these patients.
• Correlate markers of angiogenesis, including vascular endothelial growth factor and circulating endothelial cells, at baseline and during treatment, with response in patients treated with these regimens.

OUTLINE: This is a randomized study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive low-dose oral cyclophosphamide once daily on days 1-28, low-dose oral methotrexate twice daily on days 1, 2, 8, 9, 15, 16, 22 and 23, and bevacizumab IV over 30-90 minutes on days 1 and 15.
• Arm II: Patients receive cyclophosphamide and methotrexate as in arm I. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients in arm II who have progressive disease have the option of discontinuing treatment or crossing over to arm I.

PROJECTED ACCRUAL: A total of 36-66 patients (18-33 per treatment arm) will be accrued for this study within 7-12 months.

• Biological: bevacizumab
• Drug: cyclophosphamide
• Drug: methotrexate

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed invasive breast cancer

  • Metastatic (stage IV) disease confirmed by histology or cytology, physical exam, or radiologic study

• Measurable disease

  • At least one unidimensionally measurable lesion at least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan
  • Measurable lesions in a previously irradiated field must have progressed after radiotherapy
• HER2-positive patients must have received prior trastuzumab (Herceptin^®) for advanced disease or in the adjuvant setting
• No evidence of brain metastases by brain CT scan or MRI

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Female

Menopausal status

• Not specified

Performance status

• ECOG 0-1 OR
• Karnofsky 70-100%

Life expectancy

• More than 6 months

Hematopoietic

• Absolute neutrophil count ≥ 1,000/mm^3
• Platelet count ≥ 100,000/mm^3
• No bleeding diatheses (including hemoptysis)

Hepatic

• AST and ALT ≤ 4.0 times upper limit of normal (ULN)
• Bilirubin ≤ 2 times ULN

Renal

• Creatinine ≤ 2.0 mg/dL
• Urinary protein < 500 mg/24-hour-urine collection OR
• Protein urinalysis < 1+

Cardiovascular

• LVEF ≥ 50% by echocardiogram or nuclear medicine gated study
• No poorly controlled hypertension
• No prior blood clots
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of grade 3 or 4 allergic reaction to compounds of similar chemical or biological composition to cyclophosphamide or methotrexate
• No concurrent uncontrolled illness
• No active or ongoing infection
• No psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• No prior experimental angiogenesis inhibitors
• No concurrent filgrastim (G-CSF)
• Concurrent epoetin alfa growth factor support allowed

Chemotherapy

• Prior adjuvant chemotherapy for early-stage breast cancer allowed, including cyclophosphamide-based chemotherapy
• No more than 1 prior chemotherapy regimen for metastatic breast cancer
• No prior oral cyclophosphamide- or methotrexate-based therapy for metastatic disease

Endocrine therapy

• Prior hormonal therapy in the adjuvant or metastatic setting or for early-stage breast cancer allowed
• No concurrent hormonal therapy, including luteinizing hormone-releasing hormone agonists

Radiotherapy

• See Disease Characteristics
• Prior radiotherapy in the metastatic or early-stage setting allowed
• Concurrent radiotherapy allowed

Surgery

• More than 28 days since prior surgery except for venous access device or diagnostic study

Other

• Recovered from prior therapy

• No concurrent anticoagulation or chronic aspirin therapy (> 325 mg/day)

  • Concurrent low-dose anticoagulation or thrombolytic agents for venous access patency allowed
• No other concurrent investigational or experimental therapy
• No other concurrent anticancer agents or therapies

• Concurrent bisphosphonates allowed provided skeletal sites are not the primary sites used in assessing response

  • If skeletal sites are being followed for measurable response, bisphosphonates must be initiated at least 4 weeks before study entry