Inclusion Criteria:

• Women affected by histologically proven metastatic breast cancer.
• Tumor not susceptible to therapy with trastuzumab, defined as FISH negative for HER-2 amplification or immunohistochemistry 0-1+ for HER-2 expression.
• Female, age ≥ 18.
• Documented measurable disease by appropriate radiologic imaging according to RECIST criteria (see Appendix E). Lesions in previously irradiated areas are not considered measurable disease, unless progression has been documented post-radiation.
• ECOG performance status 0-1 (see Appendix B)
• Life expectancy > 6 months.

• Adequate bone marrow function, as indicated by:

  • Hemoglobin ≥ 90 g/L
  • Neutrophils ≥ 1.5 x 109/L
  • Platelets ≥ 100 x 109/L
• Adequate renal function, as indicated by serum creatinine ≤1.5 times the upper limit of normal and/or Creatinine Clearance calculated as >50% lower normal limit, or estimated as ≥ 50 ml/min (Appendix C).

• Adequate liver function, as indicated by:

  • bilirubin ≤ 1.5 times upper normal limit;
  • AST and ALT ≤ 2 times upper normal limit.
• Left ventricular ejection fraction (LVEF) ≥50% as measured by either multigated acquisition (MUGA) scan or echocardiogram (ECHO).
• No therapy for breast cancer in the 4 weeks preceding the therapy start.
• Women of childbearing potential must be using adequate contraception and have a negative pregnancy test at the time of enrollment.
• Patient able to understand and give written informed consent.

Exclusion Criteria:

• Patients with locally advanced breast cancer or stage IIIb only.
• Presence of only non-measurable disease.
• Previous (neo)adjuvant chemotherapy with vinorelbine.
• Any previous anti-angiogenic therapy.
• Any previous chemotherapy for metastatic breast cancer. Previous hormonal treatments or radiotherapy for metastatic disease are allowed.
• Radiotherapy, chemotherapy or hormonal therapy for breast cancer in the last 4 weeks prior to starting the study treatment.
• Major surgery within 4 weeks of first study treatment, or minor surgery (including placement of an access device) within 7 days of therapy start.
• Presence of life-threatening disease or central nervous system localizations.
• Evidence of HER-2 positive breast cancer, defined as FISH-positive for amplification or score 3+ by immunohistochemistry.
• Any other possibly active primary tumor, except basal cell carcinoma of the skin, or carcinoma in situ of the cervix.
• Clinically significant hepatic disease with respect to hepatitis B, hepatitis C, cirrhosis or other liver diseases.
• Uncontrolled bacterial, viral or fungal infection.
• Previous history of ischemic disease.
• Patients with previous history of thrombo-embolic events, or with documented risk factors for thrombotic disease other than cancer.
• History of gross hemorrhage within the past 6 months (e.g., hemoptysis or hematuria requiring medical intervention).
• Uncontrolled hypertension.
• Other serious medical conditions, such as uncontrolled cardiac disease, severe pulmonary disease, uncontrolled diabetes.
• Patient exhibiting confusion or disorientation.
• Any condition (medical, social, psychological, geographical) that would prevent adequate follow-up.
• Patient is pregnant, or is breast-feeding, or is unwilling to use adequate contraception.
• Failure to give informed consent.