This randomized phase III trial studies the side effects and how well different chemotherapy regimens with or without bevacizumab work in treating patients with stage IIIC or stage IV breast cancer. Drugs used in chemotherapy, such as paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), and ixabepilone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab may block tumor growth by targeting certain cells and slowing the growth of blood vessels to the tumor. It is not yet known which treatment regimen is more effective in treating patients with breast cancer.

PRIMARY OBJECTIVES:

I. To compare the progression-free survival (PFS) in patients with metastatic breast cancer receiving nab-paclitaxel versus paclitaxel (control arm).

II. To compare PFS in patients receiving ixabepilone versus paclitaxel.

SECONDARY OBJECTIVES:

I. To compare the objective response rate, duration of response, and time to treatment failure in patients receiving nab-paclitaxel versus paclitaxel, and to separately compare these endpoints in patients receiving ixabepilone versus paclitaxel.

II. To compare the 12-month rate of progression in patients receiving nab-paclitaxel versus paclitaxel, and to separately compare this endpoint in patients receiving ixabepilone versus paclitaxel.

III. To determine toxicities in patients receiving nab-paclitaxel as compared to paclitaxel, and in patients receiving ixabepilone as compared to paclitaxel.

IV. To compare overall survival in patients receiving nab-paclitaxel versus paclitaxel, and to separately compare overall survival in patients receiving ixabepilone versus paclitaxel.

V. To evaluate the relationships between secreted protein, acidic, cysteine-rich (SPARC) overexpression and changes in blood levels of caveolin-1 (Cav-1) to PFS and secondary endpoints of response during treatment with nab-paclitaxel as compared to paclitaxel, and with ixabepilone as compared to paclitaxel.

VI. To evaluate the relationships between changes in blood levels of circulating tumor cells (CTCs) and circulating endothelial cells (CECs) to PFS and secondary endpoints of response during treatment with nab-paclitaxel as compared to paclitaxel, and with ixabepilone as compared to paclitaxel.

VII. To evaluate the association of expression levels of the microtubule associated proteins tau and beta-tubulin isotype composition with PFS and secondary endpoints of response during treatment with nab-paclitaxel as compared to paclitaxel, and with ixabepilone as compared to paclitaxel.

VIII. To investigate a potential cytochrome P450, family 2, subfamily C polypeptide 8, 2, 3 (CYP2C8*2/*3) by paclitaxel interaction with respect to progression-free survival (PFS).

IX. To determine if CYP2C8*2 and CPY2C8*3 are associated with paclitaxel-induced peripheral neuropathy.

X. To perform exploratory analysis of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5), ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) and ATP-binding cassette, sub-family C (CFTR/MRP), member 2 (ABCC2) polymorphisms with response and toxicity profiles.

XI. To prospectively collect data on sociodemographics, non-cancer morbidities, and receipt of post-trial therapy to evaluate the role of potential disparities on survival from cancer.

XII. To evaluate the relationship between physical activity behaviors at the time of enrollment in the protocol and progression-free and overall survival.

XIII. To identify baseline factors that predict the risk of grade 3, 4, or 5 toxicity in patients receiving treatment with weekly paclitaxel, nab-paclitaxel, or ixabepilone combined with or without bevacizumab.

XIV. To perform an exploratory analysis of whether other factors included in patient assessments (either individually or in combination) predict the risk of grade 3, 4, or 5 toxicity in patients receiving weekly paclitaxel, nab-paclitaxel, or ixabepilone combined with or without bevacizumab, with a specific focus on the relationship between pre-existing hypertension or neuropathy.

XV. To compare the associations of baseline factors to grade 3, 4, or 5 toxicity in patients receiving weekly paclitaxel, nab-paclitaxel, or ixabepilone combined with or without bevacizumab.

XVI. To explore whether longitudinal changes in factors are in association with the occurrence of grade 3, 4, or 5 toxicities in patients with weekly paclitaxel, nab-paclitaxel, or ixabepilone combined with or without bevacizumab.

XVII. To explore the association between grade 2-4 neuropathy and longitudinal changes in the following functional status measures: a) Older Americans Resources and Services (OARS) Multidimensional Functional Assessment Questionnaire (MFAQ) (Instrumental Activities of Daily Living [IADL]); b) Medical Outcomes Study (MOS) Physical Functioning; c) Karnofsky Performance Status Rated Healthcare Professional; d) Timed "Up and Go"; e) OARS Physical Health Section.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM A (WEEKLY PACLITAXEL): Patients receive paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15. Patients may also receive bevacizumab IV over 30-90 minutes on days 1 and 15.

ARM B (WEEKLY NAB-PACLITAXEL): Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive bevacizumab as in Arm A.

ARM C (WEEKLY IXABEPILONE): Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive bevacizumab as in Arm A. (closed to accrual as of 7/18/11)

In all arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed every 6 months for 2 years and then annually for up to 3 years.

Inclusion Criteria:

• Histologic confirmation of invasive cancer of the breast

• Stage IV disease or stage IIIC disease (using American Joint Committee on Cancer [AJCC] criteria, 6th edition) not amenable to local therapy

• Patients may not have a "currently active" second malignancy other than non-melanoma skin cancers; patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse

• Patients with human epidermal growth factor receptor 2 (HER2) negative disease are eligible; patients with HER2+ disease are eligible providing they have previously received trastuzumab or lapatinib; documentation of progression on HER2 directed therapy is not required; Her2/neu status must be known at the time of protocol registration

• Estrogen receptor (ER) and progesterone receptor (PgR) status must be known at the time of registration; ER and/or PgR >= 1% cells will be considered positive

• Prior treatment may include adjuvant or neoadjuvant taxane, however, the interval between completion of adjuvant or neoadjuvant therapy and disease recurrence must be >= 12 months

• No prior chemotherapy for metastatic breast cancer

• Any number of prior hormonal therapies are allowed; the last dose should have been administered at least 7 days prior to the initiation of protocol therapy

• Prior radiotherapy must be completed at least 2 weeks prior to study entry

• Treatment with bisphosphonates is allowed and recommended as per American Society of Clinical Oncology (ASCO) guidelines

• Prior trastuzumab or lapatinib required for patients with HER2 overexpressing tumors

• Prior treatment with bevacizumab is allowed

• Patients must not have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study registration, and must have fully recovered from any such procedure

  • The following are not considered to be major procedures: thoracentesis, paracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies and routine dental procedures

• Patients must not have anticipation of need for a major surgical procedure during the course of the study

• There are no restrictions on core biopsies, placement of a vascular access device or other minor procedures prior to registration

  • Placement of a vascular access device after starting study therapy should be performed between day 15 and 28 of a treatment cycle (but not less than 48 hours before the next dose of bevacizumab) to allow for sufficient healing

• Patients must have measurable disease (target lesions): measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 2.0 cm with conventional techniques or as >= 1 cm with spiral computed tomography (CT) scan

  • Lesions that are considered non-measurable include the following:

    • Bone lesions
    • Leptomeningeal disease
    • Ascites
    • Pleural/pericardial effusion
    • Inflammatory breast disease
    • Lymphangitis cutis/pulmonitis
    • Abdominal masses that are not confirmed and followed by imaging techniques
    • Cystic lesions

• Patients with pre-existing peripheral neuropathy >= grade 2 are not eligible for this study

• Patients must have an Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status of =< 1 to be eligible for this trial

• Women must not be pregnant or breast feeding; premenopausal women must have a negative serum or urine beta-human chorionic gonadotropin (Hcg)

• Patients with a history of Common Terminology Criteria for Adverse Events (CTCAE) grade >= 3 hypersensitivity to paclitaxel or Cremophor® EL are not eligible

• Patients with a history of abdominal fistula, or intra-abdominal abscess within 6 months prior to study registration are not eligible

• Patients with a history of gastrointestinal (GI) perforation within 12 months prior to registration are not eligible

• Patients with a history of significant bleeding episodes (e.g., hemoptysis, upper or lower GI bleeding) within 6 months prior to registration are not eligible

• Patients must not have a history of clinically significant cardiovascular disease that includes the following:

  • Uncontrolled hypertension defined as systolic blood pressure > 150 and/or diastolic blood pressure > 90 mmHg on antihypertensive medications or any prior history of hypertensive crisis or hypertensive encephalopathy
  • History of myocardial infarction or unstable angina within past 6 months
  • New York Heart Association (NYHA) congestive heart failure grade 2 or greater
  • Symptomatic peripheral vascular disease
  • Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or arterial thrombotic events

• Patients on full dose anticoagulants must be on a stable dose of warfarin, or be on a stable dose of low molecular weight (LMW) heparin; patients receiving anti-platelet or on daily prophylactic dose aspirin are eligible, as are patients receiving stable doses of anticoagulation for atrial fibrillation

• Patients may not have a history of stroke or transient ischemic attack within 6 months prior to study registration

• Patients with a history of seizures must be well controlled with standard medication

• Patients must not have progressing or untreated central nervous system (CNS) metastases or leptomeningeal disease; patients with a history of resected brain metastases with stable magnetic resonance imaging (MRI) scans for 3 months including within 4 weeks of study start are eligible; patients with a history of gamma knife radiosurgery or whole brain radiation with stable MRI scans for 3 months including within 4 weeks of study start are eligible

• No serious, non-healing wound, ulcer or bone fracture

• Life expectancy of >= 12 weeks

• Granulocytes >= 1,500/ul

• Platelet count >= 100,000/ul

• Creatinine =< 2.0 mg/dL

• Bilirubin < 1.5 mg/dL (unless due to Gilbert's syndrome)

• Transaminases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) =< 2.5 x upper limit of normal (ULN)

• Serum or urine beta-Hcg negative in premenopausal women of child-bearing potential

• Urine protein =< 1+ protein* or urine protein: creatinine ratio (UPC) < 1

  • Patients discovered to have >= 2+ proteinuria at baseline must undergo a 24-hour urine collection that must demonstrate < 1 g of protein/24 hr or UPC ratio =< 1 to allow participation in the study