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

Inclusion Criteria:

• Histologic confirmation of invasive cancer of the female breast in either the primary or metastatic setting

  • Stage IIIB disease not amenable to local therapy or stage IV disease

• Must have measurable or nonmeasurable disease by RECIST criteria, with radiologic scans (CT scan of the chest/abdomen)

  • Measurable disease is defined as 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 CT scan

  • Nonmeasurable disease is defined as all other lesions, including small lesions (longest diameter < 2.0 cm with conventional techniques or < 1.0 cm with spiral CT scan) and truly nonmeasurable lesions, including any of 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

• Baseline bone scans required for all patients for determination of metastatic bone disease

  • CT scan with bone windows required only for patients with bone metastases as the only site of disease
• No known CNS metastases or leptomeningeal disease(screening with brain imaging is not required for asymptomatic patients)
• Hormone receptor status: tumors (from either primary or metastatic sites) must express estrogen receptor (ER)and/or progesterone receptor (PgR) in ≥ 1% of cells

• Menopausal status: pre- or postmenopausal, meeting 1 of the following criteria:

  • Age ≥ 55 years and one year or more of amenorrhea
  • Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20pg/ml
  • Age < 55 with prior hysterectomy but intact ovaries, with an estradiol assay < 20 pg/ml
  • Surgical menopause with bilateral oophorectomy

  • Ovarian suppression on a luteinizing hormone-releasing hormone agonist (goserelin acetate or leuprolide acetate)

    • Premenopausal women must undergo ovarian suppression prior to beginning protocol therapy

      • Ovarian radiation is not permitted for induction of ovarian suppression
• ECOG (Zubrod) performance status 0-1
• Life expectancy ≥ 12 weeks
• Granulocytes ≥ 1,000/μl
• Platelet count ≥ 100,000/μl
• Creatinine ≤ 2.0 mg/dL
• Bilirubin ≤ 1.5 times upper limit of normal (ULN) unless due to Gilbert's syndrome
• Transaminases (ALT, AST) ≤ 2.5 times ULN
• INR ≤ 1.6 unless on full dose warfarin

• Urinalysis ≤ 1+ protein

  • Proteinuria ≥ 2 + at baseline must demonstrate < 1 g of protein/24 hr or protein:creatinine ratio < 1 on 24-hoururine collection

• No "currently active" second malignancy other than nonmelanoma 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
• Taxane-related neurotoxicity must have resolved to sensory grade < 2
• No motor neuropathy of any grade
• No significant traumatic injury within 28 days prior to study registration
• No history of abdominal fistula, or intra-abdominal abscess within the past 6 months
• No history of GI perforation within the past 12 months
• No history of significant bleeding episodes (e.g., hemoptysis, upper or lower GI bleeding) within the past 6 months

• No clinically significant cardiovascular disease, including any of the following:

  • Uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg and/or diastolic BP > 90 mm Hg on antihypertensive medications
  • Prior history of hypertensive crisis or hypertensive encephalopathy
  • Myocardial infarction or unstable angina within past 6 months
  • New York Heart Association class II-IV congestive heart failure
  • Symptomatic peripheral vascular disease
  • Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
  • Significant arterial thrombotic events
• No history of stroke or transient ischemic attack within the past 6 months
• History of seizures must be well controlled with standard medication
• No known allergies to imidazole drugs, (e.g., clotrimazole, ketoconazole, miconazole, econazole, sulconazole, ticonazole, or terconazole) or compounds structurally similar to bevacizumab (for patients treated with aromatase inhibitors)
• No known allergies to selective estrogen receptor modulators (e.g., tamoxifen, raloxifene, or toremifene) or compounds structurally similar to bevacizumab (for patients treated with tamoxifen) NOTE: As of 5/15/2011, patients only receive letrozole.
• No serious, non-healing wound, ulcer, or bone fracture
• Not pregnant or nursing
• Negative pregnancy test

• No prior endocrine therapy in the metastatic setting unless tamoxifen or an aromatase inhibitor was initiated within 4 weeks prior to registration

  • If prior endocrine therapy was initiated within the past 4 weeks, the patients should remain on that chosen hormonal therapy (tamoxifen or aromatase inhibitor) as the study therapy. NOTE: As of 5/15/2011, patients only receive letrozole.
  • Patients who began therapy with tamoxifen (after 5/15/2011), anastrozole or exemestane must switch to letrozole
• Prior endocrine therapy in the adjuvant setting allowed

• 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
• At least 28 days since surgical castration with bilateral oophorectomy
• At least 2 weeks since prior radiotherapy and all toxicities resolved
• At least 12 months since the completion of prior adjuvant or neoadjuvant chemotherapy and all toxicities must have resolved
• No prior anti-VEGF or VEGFR tyrosine kinase inhibitor therapy
• May have received 1 prior chemotherapy regimen for metastatic disease
• More than 28 days since prior major surgical procedure or open biopsy and fully recovered from any such procedure
• No core biopsy or other minor surgical procedure (except placement of a vascular access device) within 7 days prior to study registration
• Prior palliative irradiation of a symptomatic lesion, or one that may produce disability (e.g., unstable femur) prior to study initiation, provided other measurable or non-measurable disease is present, is allowed
• Palliative radiotherapy may not be administered during protocol therapy
• Must not have anticipation of need for major surgical procedure during the course of the study

• Concurrent full-dose anticoagulation therapy is allowed for the treatment of prior conditions such as venous thromboses 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 INR (usually between 2 and 3) or be on a stable dose flow molecular weight heparin
• Concurrent antiplatelet agents, daily prophylactic aspirin, or anticoagulation for atrial fibrillation allowed
• Concurrent treatment with bisphosphonates is allowed and recommended
• No concurrent hormones or other chemotherapeutic agents except for steroids given for adrenal failure or chronic non-cancer related diseases, hormones administered for non-disease-related conditions (e.g., insulin for diabetes), and intermittent use of dexamethasone as an antiemetic in solid tumor protocols