Inclusion Criteria:

• Patients must have histologically or cytologically confirmed breast cancer with metastatic disease. Patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis using the RECIST criteria.
• The HER2 status of the tumor will be used to stratify patients. Tumors that are HER2 FISH+ will receive vinflunine and trastuzumab. Patients with tumors which are HER2 FISH negative or if the HER2 status is unknown/not performed will remain on study and will receive single agent vinflunine. HER2 positivity based on IHC testing (2+ or 3+) must be confirmed by FISH testing. If a patient's tumor scores IHC 2+ or 3+ and is found to be FISH negative, this patient is not eligible for treatment with trastuzumab and will receive vinflunine alone.
• Patients must have measurable disease not directly irradiated as per RECIST criteria.
• Measurable disease- is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. See section 10.0 for the evaluation of measurable disease.
• Prior Therapy: Chemotherapy: metastatic breast cancer. Patients must not have received prior chemotherapy in the metastatic breast setting. Patients who have not received prior anthracyclines or taxanes should be considered for these agents. Chemotherapy: early stage breast cancer. Patients may have received prior chemotherapy and/or hormonal therapy for early stage breast cancer. The chemotherapy regimen may have included an anthracycline and/or a taxane as long as it has been > 6 months since completion of the regimen. Adjuvant trastuzumab is allowed. Radiation therapy. Patients may have received prior radiation therapy in either the metastatic or early stage setting as long as <25% of the bone marrow has been treated. Prior radiation to the whole pelvis is not allowed. Radiation therapy must be completed at least 7 days prior to study registration, and all radiation related toxicities must be resolved to grade ≤ 1 before patient is eligible for study inclusion. Hormonal therapy. Patients may have received any number of hormonal therapies in the neo-adjuvant, adjuvant or metastatic setting. Patients must discontinue hormonal therapy at least one week prior to starting study treatment.
• Age >18 years. Only women are eligible for the study.
• Life expectancy of > 6 months.
• ECOG performance status <2.
• Patients must have normal organ and marrow function as defined below. Laboratory tests should be completed within 14 days prior to starting study treatment. Only for patients who will be receiving trastuzumab, a left ventricular ejection fraction (LVEF) may be determined by either echocardiography or MUGA scan, and should be obtained within 4 weeks prior to starting study treatment.
• ANC >1,500/µl
• Platelets >100,000/µl
• Hgb > 10 g/dL
• Total bilirubin within normal institutional limits
• AST (SGOT) or ALT (SGPT) <5.0 X institutional ULN (for patients with liver metastasis) <3.0X institutional ULN (for patients without liver metastasis)
• Creatinine < 1.5 mg/dl x ULN
• Calcium <1.2 x ULN
• LVEF > 50%
• Concurrent Therapy. Patients may not receive concurrent hormonal therapy, chemotherapy, or radiation treatments while on study. Patients who develop brain metastases during protocol-based treatment will be recorded as having progressive disease on therapy and will be taken off study. Patients may not receive other experimental treatments while on study.
• Fertility/reproduction. Patients must not be pregnant, expect to become pregnant or conceive a child from time of first signing study consent until at least 12 weeks after last dose of study treatment. The effects of trastuzumab and vinflunine on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of childbearing potential must agree to use a method of contraception that is acceptable to their physicians from time of first signing study consent until at least 12 weeks after the end of drug administration. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

• Patients who have not recovered to < grade 1 toxicity due to prior chemotherapy (for early stage breast cancer) or prior radiation therapy are not eligible for study.
• Patients who have received prior vinca alkaloid chemotherapy are not eligible unless treatment was completed > 5 years ago.
• Patients in which the HER2 status is unknown or is FISH negative will not receive trastuzumab but are eligible for treatment with single agent vinflunine.
• Patients that have received prior chemotherapy for metastatic breast cancer.
• Patients receiving trastuzumab must have received a cumulative dose of doxorubicin less than 360mg/m2, and/or an epirubicin cumulative dose less than 720mg/m2 for study entry.
• Patients with known leptomeningeal carcinomatosis are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with brain metastasis can participate if they have undergone appropriate treatment, are at least 1-month post treatment, have no significant neurologic symptoms, and are not on steroids. Screening for CNS disease is not required if patients do not have symptoms that might be related to CNS metastasis. Patients with such symptoms should be evaluated for the possibility of CNS disease prior to study participation.
• History of grade 3 or 4 allergic reactions attributed to trastuzumab. Patients who experienced grade 1 or 2 hypersensitivity reactions to prior trastuzumab therapies are eligible if these reactions did not prevent further administration of such agents. Patients in whom trastuzumab is contraindicated but whose tumor expresses HER2, may be entered and treated with vinflunine alone. These patients will be evaluated on the non-trastuzumab arm.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because the study drugs are agents that may have the potential for teratogenic effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these drugs, breastfeeding should be discontinued if the mother is treated on study.
• History of other non-breast cancer malignancy except for carcinoma in situ of the cervix or non-melanoma skin cancer, or in patients with greater than a 5-year disease free interval from a prior malignancy.
• Patients may not receive other investigational agents while on study.
• Patients who have received prior chemotherapy for early stage breast cancer with the completion of the regimen being < 6 months will not be eligible.