Tamoxifen Citrate or Letrozole With or Without Bevacizumab in Treating Women With Stage IIIB or Stage IV Breast Cancer
Condition: Invasive Breast Carcinoma; Recurrent Breast Carcinoma; Stage III Breast Cancer AJCC v6; Stage IV Breast Cancer AJCC v6 and v7
MeSH terms: Carcinoma; Breast Neoplasms
Intervention: Bevacizumab; Laboratory Biomarker Analysis; Letrozole; Questionnaire Administration; Tamoxifen Citrate
Intervention description: Given IV; Correlative studies; Given PO; Ancillary studies; Given PO
Intervention MeSH terms: Tamoxifen; Bevacizumab; Antineoplastic Agents, Immunological; Letrozole; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 394.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase III trial studies tamoxifen citrate or letrozole together with
      bevacizumab to see how well it works compared with tamoxifen citrate or letrozole alone in
      treating women with stage IIIB or stage IV breast cancer. Estrogen can cause the growth of
      breast cancer cells. Hormone therapy using tamoxifen citrate or letrozole may fight breast
      cancer by blocking the use of estrogen by the tumor cells. Immunotherapy with monoclonal
      antibodies, such as bevacizumab, may induce changes in the body's immune system and may
      interfere with the ability of tumor cells to grow and spread. It is not yet known whether
      giving hormone therapy is more effective with or without bevacizumab in treating advanced
      breast cancer.
    

Eligibility criteria:

        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