Docetaxel,Carboplatin,Trastuzumab and Bevacizumab for Breast Cancer and Bone Marrow Micrometastases

Inclusion Criteria

* Patient with biopsy-proven primary stage I-III infiltrating adenocarcinoma of the breast.
* HER-2/neu (+) as determined by either IHC (3+) or FISH (≥ 2.2-fold amplification).
* Age ≥ 18 years.
* ECOG performance status 0-1.
* Negative CT C/A/P and TBBS.
* LVEF \> 50% by MUGA or echocardiogram performed within 28 days prior to enrollment
* Positive BM aspirate for BC micrometastases by CLIA-certified laboratory.
* Adequate hematologic, hepatic, and renal function. All tests must be obtained ≤ 4 weeks prior to randomization.

  * Hematologic: Absolute neutrophil count \> 1,500/mm3 Hemoglobin \> 10.0 g/dl Platelet count \> 100,000/mm3.
  * Hepatic: Total bilirubin must be within normal limits. Transaminases (AST and/or ALT) may be \< 2.5 x institutional upper limit of normal (ULN) if alkaline phosphatase is \< ULN, or alkaline phosphatase may be \< 4 x ULN if transaminases are \< ULN
  * Renal: Normal creatinine and BUN; if abnormal, calculated creatinine clearance must be\> 60 mg/dL
* Patients must be disease-free of prior invasive malignancies for ≥ 5 years, with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
* Surgery: all patients must have completed surgery with sentinel and/or axillary lymph node dissection according to participating institutional guidelines.
* Women of childbearing potential must have a negative pregnancy test and must be willing to consent to using an accepted and effective barrier form method of contraception while on treatment and for a reasonable period thereafter.
* Patients must provide written informed consent.
* Note: Hormonal therapy: patients with ER+ and/or PR+ tumors may receive concurrent hormonal therapy according to participating institutional guidelines. The choice of hormonal therapy is at the discretion of the treating physician.
* Note: Radiation therapy: patients receiving adjuvant radiation therapy to the involved breast (after partial mastectomy) or chest wall (after mastectomy) may receive concurrent trastuzumab and bevacizumab therapy.

Exclusion Criteria

* Known metastatic BC.
* Concomitant malignancies or previous malignancies within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
* Pregnant or lactating women.
* Prior chemotherapy, hormonal therapy, trastuzumab and bevacizumab therapy.
* History of significant cardiac disease, cardiac risk factors or uncontrolled arrhythmias
* Ejection fraction \<50% or below the lower limit of the institutional normal range, whichever is lower.
* Hypersensitivity to trial medications.
* Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in dyspnea at rest.
* Active or uncontrolled infection.
* Psychiatric, addictive, or any disorder that compromises the ability to give informed consent to participate in or to comply with the requirements of the study.

Bevacizumab-Specific Exclusions

* Inadequately controlled hypertension (defined as systolic blood pressure \>150 and/or diastolic blood pressure \> 100 mmHg on antihypertensive medications)
* Any prior history of hypertensive crisis or hypertensive encephalopathy
* New York Heart Association (NYHA) Grade II or greater congestive heart failure
* History of stroke or transient ischemic attack within 6 months prior to study enrollment
* Known CNS disease
* Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
* Symptomatic peripheral vascular disease
* Evidence of bleeding diathesis or coagulopathy
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study
* Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
* Serious, non-healing wound, ulcer, or bone fracture
* Proteinuria at screening as demonstrated by either
* Urine protein:creatinine (UPC) ratio \>/= 1.0 at screening OR
* Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
* Known hypersensitivity to any component of bevacizumab
* Pregnant (positive pregnancy test) or lactating. Use of effective means of contraception (men and women) in subjects of child-bearing potential
* History of stroke or transient ischemic attack at any time
* History of myocardial infarction or unstable angina within 12 months of study enrollment