This is a single-center, open, randomized, controlled phase 2 clinical trial designed to compare low-dose-bevacizumab and pemetrexed with TPC in metastatic HER2-negative breast cancer patients after failure of taxanes and anthracycline-containing regimens.

There is no standard therapy for advanced human epidermal growth factor receptor 2 (HER2) -negative breast cancer patients after failure of taxanes and anthracycline-containing regimens at present. Pemetrexed is a multitargeted antimetabolite. Its efficacy in metastatic breast cancer has been confirmed in several small sample size studies and meta-analyses. Its response rate (RR) is about 30%, and will be higher in HER2-negative breast cancer. However, there is no study focused on this subtype of breast cancer. Bevacizumab is also an effective alternative for metastatic breast cancer. Several studies indicate that the combination of bevacizumab and chemotherapy could improve both RR and overall survival, but its use is confined by its severe side effect and far from adequate treatment. Recent years, a lot of studies have assessed the efficacy of metronomic chemotherapy. Metronomic therapy refers to the chronic administration of low doses of cytotoxic drugs at close, regular intervals. It could promote the apoptosis of tumor endothelial cell , continuously inhibit tumor angiogenesis, and exhibit a significant superiority of low toxicity, reduced cost and prolonged combination therapy period. According to reports in literature, the expression of anti-angiogenic biomarkers, such as,vascular endothelial growth factor(VEGF)-A, VEGF-C, soluble vascular endothelial growth factor receptor (sVEGFR)-1, sVEGFR-2,thrombospondin-1(TSP-1), platelet factor 4 (PF-4) might be concerned with the efficacy of metronomic therapy. Since there are no reported clinical trials according to metronomic bevacizumab in HER2-negative breast cancer, the investigators come up with this study. In this study, the investigators try to make a comparison of the efficacy and safety of low-dose-bevacizumab and pemetrexed with treatment of physician's choice (TPC) in metastatic breast cancer after failure of taxanes and anthracycline-containing regimens, to validate the correlative biomarkers and to find an optimal choice for previously treated metastatic breast cancer patients.

Inclusion Criteria:

1. Metastatic breast cancer females confirmed by pathological and/or cytological examination;
2. Breast cancer patients who received taxanes and anthracycline-containing regimens previously;
3. HER2-negative breast cancer patients confirmed by immunohistochemical test or fluorescent in situ hybridization(FISH);
4. Patients aged from 18-70 years old, and patients with Eastern Cooperative Oncology Group（ECOG） performance status scored 0-2;
5. One or more measurable lesions in imaging examination,with a diameter no less than 20mm in ordinary computed tomography (CT) or magnetic resonance imaging (MRI), or a scanning diameter no less than 10mm in spiral CT;
6. Any other kind of concomitant chemotherapy is not allowed during the research. If the patients had accepted other chemotherapy before recruitment, he can enter into the study until the drug is eliminated 30 days later;
7. Patients without any kind of major organ dysfunction: normal blood test results, normal function of heart, liver, kidney, marrow and so on.

Exclusion Criteria:

1. Patients who had received any chemotherapy, radiotherapy, biotherapy, or drugs and physical treatment in other clinical trials four weeks within the enrollment;
2. Patients who has no measurable or assessable lesions ;
3. Patients with moderate or severe liver dysfunction
4. Pregnant or lactational patients;
5. Patients with severe complications, including severe heart disease, cerebrovascular disease, uncontrolled diabet and hypertension, severe infection , active peptic ulcer and so on;
6. Patient who had previously received pemetrexed-containing regimens in metastatic setting.