A RANDOMIZED PHASE II STUDY OF CONCOMITANT TRASTUZUMAB, BEVACIZUMAB WITH PACLITAXEL VERSUS TRASTUZUMAB AND BEVACIZUMAB FOLLOWED BY THE COMBINATION OF TRASTUZUMAB, BEVACIZUMAB AND PACLITAXEL AT PROGRESSION AS FIRST-LINE TREATMENT OF PATIENTS WITH METASTATIC BREAST CANCER WITH HER2-NEU OVEREXPRESSION

1. Patients age >= 18 years
2. Able to comply with the protocol
3. ECOG PS of <= 1
4. Life expectancy of >= 12 weeks
5. Written informed consent [informed consent document to be approved by the institution*s Independent Ethics Committee (IEC)] obtained prior to any study specific screening activities.
6. Pre- or postmenopausal patients with histologically confirmed breast cancer (adenocarcinoma) with measurable or non-measurable, locally recurrent breast cancer that cannot be treated with curative intent by local treatment (surgery, radiotherapy +/- hyperthermia) or metastatic lesions, who are candidates for chemotherapy. ER/PgR and HER2 status must be documented.
7. Measurable lesions have at least one dimension (longest diameter to be recorded) as >=1 cm (10 mm) with spiral CT scan or >= 2 cm on conventional imaging methods. In case of a lung metastasis fully surrounded by air, a chest X-ray may be used instead of CT-scanning, provided the lung lesion is unidimensionally measurable and has a diameter of >= 2 cm (20 mm). Index lesions should not be in a previously irradiated area. Ultrasound is not allowed for measurements of liver metastases.
8. Patients must have HER2 protein overexpression (3+) as determined by immunohistochemistry (IHC); or amplification of HER2/c-erbB2 as determined by fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) of the primary tumor or a metastasis.
9. Patients who received trastuzumab in the adjuvant setting are eligible as long provided they received at least 10 months of therapy with trastuzumab and >= 6 months have elapsed since last adjuvant administration of trastuzumab.
10. Patients who were treated with anthracyclines in adjuvant or neo-adjuvant setting are only eligible if they received their last dose > 6 months prior to randomization. The maximum cumulative dose must not exceed 360 mg/m2 for doxorubicin and 720 mg/m2 for epirubicin.
11. Patients who were treated with a taxane are only eligible if they received their last adjuvant or neo-adjuvant chemotherapy > 6 months prior to randomization and taxane-associated toxicity has resolved to less than grade 2.
12. Baseline Left Ventricular Ejection Fraction (LVEF) not below 50% measured by either echocardiography or MUGA.
13. The use of full-dose oral or parenteral anticoagulants is permitted as long as the patient has been on a stable level of anticoagulation for at least two weeks at the time of randomization.
14. Previous radiotherapy for treatment of metastatic breast cancer is allowed in case:
• Less than 30% of marrow-bearing bone has been irradiated
• The last fraction of radiotherapy has been administered more than 4 weeks prior to randomization
Prior adjuvant radiotherapy for breast cancer is allowed, provided it has stopped at least 6 months prior to randomization.

1. Previous chemotherapy for metastatic or locally recurrent breast cancer. Prior hormonal therapy is allowed but must have been discontinued at least 2 weeks prior randomization.
2. Other primary tumor (including primary brain tumors) within the last 5 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer.
3. Evidence of spinal cord compression or current evidence of CNS metastasis. CT or MRI scan of the brain is mandatory in case of clinical suspicion of brain metastasis.
4. History or evidence upon physical/neurological examination of CNS disease (unrelated to cancer) (unless adequately treated with standard medical therapy) e.g. uncontrolled seizures.
5. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to to study treatment start, or anticipation of the need for major surgery during the course of the study treatment.
6. Existing peripheral neuropathy > CTC Grade 2 at randomization.
7. Inadequate bone marrow function: ANC < 1.5 x 109/L, Platelet count < 100 x 109/L and Hb < 6.0 mmol/L.
8. Inadequate liver function:
• serum (total) bilirubin > ULN
• ASAT & ALAT > 2.5 x ULN ( > 5 x ULN in patients with liver metastases) or ASAT/ALAT levels > 1.5 x ULN concurrent with serum alkaline phosphatase levels of > 2.5 x ULN or ASAT/ALAT > ULN concurrent with alkaline phosphatase > 6 x ULN
• INR > 1.5 in patients not receiving anticoagulans.;9. Inadequate renal function:
i. calculated or measured creatinine clearance < 30 mL/min
ii. Urine dipstick for proteinuria > 2+. Patients with >*2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine collection and must demonstrate *1 g of protein/24 hr.
10. Current or recent use (within 10 days of first dose of bevacizumab) of aspirin (> 325 mg/day) or clopidogrel (> 75 mg/day).
11. Chronic daily use of corticosteroids (dose > 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
12. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: CVA/stroke (<= 6 months prior to randomization), myocardial infarction (<= 6 months prior to randomization), unstable angina, New York Heart Association (NYHA) class 2 or greater Congestive Heart Failure, or serious cardiac arrhythmia requiring medication.
13. Arterial or venous thrombosis <= 12 months prior to registration;14. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
15. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization.
16. Active infection requiring i.v. antibiotics at randomization.
17. Serious non-healing wound, peptic ulcer, or bone fracture.
18. Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or that may affect patient compliance with study routines, or place the patient at high risk from treatment complications.
19. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment start.
20. Patients of childbearing potential (women < 2 years after last menstruation) not using effective non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile). Male patients with a partner of childbearing potential should also use effective means of contraception.
21. Current or recent (within 30 days prior to starting study treatment) treatment with another investigational drug or participation in another investigational study.
22. Known hypersensitivity to any of the study drugs or excipients.
23. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.