Tamoxifen Citrate or Letrozole With or Without Bevacizumab in Treating Women With Stage IIIB or Stage IV Breast Cancer

For females ages 18 years and up

Inclusion Criteria:

• Histologic confirmation of invasive cancer of the female breast in either the primary or metastatic setting
  • Stage IV disease or stage IIIB 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
• Tumors (from either primary or metastatic sites) must express estrogen receptor (ER) and/or progesterone receptor (PgR) in >= 1% of cells will be considered positive
• Postmenopausal women are eligible for this trial; before study registration, menopausal status must be defined according to the criteria below:
  • Age >= 55 years and one year or more of amenorrhea
  • Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20 pg/ml
  • For women age < 55 with prior hysterectomy but intact ovaries, with an estradiol assay < 20 pg/ml
  • Surgical menopause with bilateral oophorectomy (at least 28 days must elapse from surgery to time of study registration)
  • Ovarian suppression on a luteinizing hormone-releasing hormone (LH-RH) agonist
• Premenopausal women who do not meet the postmenopausal criteria above are also eligible, but are required to undergo ovarian suppression; this can be initiated any time prior to or on day 1 of protocol therapy, regardless of chosen endocrine therapy, and will continue for the duration of protocol therapy
• Patients must have measurable or non-measurable disease by RECIST criteria, with radiologic scans within 28 days of study registration
  • Measurable disease: lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 2.0 cm with conventional techniques or as >= 1.0 cm with spiral computed tomography (CT) scan
  • Non-measurable disease: all other lesions, including small lesions (longest diameter < 2.0 cm with conventional techniques or < 1.0 cm with spiral CT scan) and truly non-measurable lesions

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

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

• Prior endocrine therapy is not required
  • Prior endocrine therapy in the metastatic setting is not permitted (unless tamoxifen or an aromatase inhibitor was initiated within 4 weeks prior to registration to facilitate enrollment of patients who recently started first-line endocrine therapy for metastatic breast cancer); if prior letrozole therapy was initiated within the past 4 weeks, the patients should remain on letrozole as the study therapy; patients who began therapy with tamoxifen, anastrozole or exemestane must switch to letrozole to be eligible to participate in this study
  • Prior endocrine therapy in the adjuvant setting is permitted; there is no time restriction for how long the patient must be on the adjuvant endocrine therapy, nor is there a time restriction for how long the patient needs to be off prior adjuvant endocrine therapy before beginning protocol therapy on 40503
  • Prior treatment with ovarian suppression is allowed in either the adjuvant or metastatic setting; if medical ovarian suppression is being administered it can be initiated any time prior to or at the start of protocol therapy, and continued throughout the duration of the trial; surgical castration with bilateral oophorectomy must be performed at least 28 days prior to study registration (due to concerns of poor wound healing on bevacizumab)
• Patients may not have received any prior anti-VEGF or VEGFR tyrosine kinase inhibitor therapy
• Prior radiotherapy must have been completed and all toxicities resolved at least two weeks prior to registration
• Chemotherapy in the adjuvant or neoadjuvant setting is permitted; at least twelve months prior to registration must have elapsed since the completion of adjuvant or neoadjuvant chemotherapy and all toxicities must have resolved; taxane-related neurotoxicity must have resolved to sensory grade < 2 and no motor neuropathy of any grade is allowed
• Patients may have received one prior chemotherapy regimen for metastatic disease; the final dose of prior chemotherapy must have been administered at least 3 weeks prior to study registration
• Treatment with bisphosphonates is allowed and recommended as per American Society of Clinical Oncology (ASCO) guidelines
• 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
• Patients must not have anticipation of need for major surgical procedure during the course of the study
• Patients must not have had a core biopsy or other minor surgical procedure, within 7 days prior to study registration; placement of a vascular access device is allowed within 7 days of registration
• Patients must not have a history of abdominal fistula, or intra-abdominal abscess within 6 months prior to study registration
• 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 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) grade 2 or greater congestive heart failure
  • Symptomatic peripheral vascular disease
  • Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or arterial thrombotic events
• Full dose anticoagulation therapy is allowed for the treatment of prior conditions such as venous thrombosis or atrial fibrillation, but not for the treatment of prior arterial thrombotic events; patients on full dose anticoagulants must be on a stable dose of warfarin and have an in-range international normalized ratio (INR) (usually between 2 and 3) or be on a stable dose of low-molecular weight (LMW) heparin; patients receiving antiplatelet agents are eligible, as are patients on daily prophylactic aspirin or 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 known central nervous system (CNS) metastases or leptomeningeal disease (screening with brain imaging is not required for asymptomatic patients)
• In aromatase inhibitor (AI)-treated patients: no known allergies to imidazole drugs, (e.g. clotrimazole, ketoconazole, miconazole, econazole, sulconazole, tioconazole, or terconazole) or compounds structurally similar to bevacizumab
• In tamoxifen treated patients: no known allergies to selective estrogen receptor modulators (e.g. tamoxifen, raloxifene or toremifene) or compounds structurally similar to bevacizumab; for patients enrolled after Update #5, endocrine therapy will consist of letrozole only and this criterion will no longer apply
• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status =< 1
• No serious, non-healing wound, ulcer, or bone fracture
• Life expectancy of >= 12 weeks
• All patients who are premenopausal (if not already receiving ovarian suppression therapy/surgical oophorectomy) must have a negative beta-human chorionic gonadotropin (beta-Hcg) prior to starting on study treatment; patients may not be pregnant or nursing at any time during the study; ovarian suppression is required in women of childbearing potential by the start of protocol therapy, and will continue for the duration of protocol therapy
• Granulocytes >= 1,000/ul
• Platelet count >= 100,000/ul
• Creatinine =< 2.0 mg/dL
• Bilirubin =< 1.5 times upper limit of normal (ULN) unless due to Gilbert's syndrome
• Transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) =< 2.5 times ULN
• International normalized ratio (INR) =< 1.6, unless on full dose warfarin
• Beta-Hcg negative in premenopausal women
• Urine protein =< 1+ or urine to plasma creatinine (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