The hypothesis of this study is to discover if the anlotinib can shrink or slow the growth of pretreated HER2 negative metastatic breast cancer.

Breast cancer is one of the most common malignant tumors in women, which is a serious threat to women's health. Despite the continuous improvement of treatment, 30% of breast cancer eventually develops into advanced breast cancer. The median survival of advanced breast cancer after routine treatment is 2-3 years. The main treatments include chemotherapy, endocrine therapy, and targeted therapy. The treatment of metastatic breast cancer (MBC) aims to improve quality of life, reduce pain and prolong survival.

Angiogenesis plays an important role in tumor cell proliferation and metastasis. Various anti-angiogenic drugs such as bevacizumab, sunitinib, sorafenib, etc. have been developed and widely used in various tumors. Treatments such as colon cancer, lung cancer, and renal cell carcinoma significantly improve PFS and OS in patients with advanced disease, and the adverse reactions are well tolerated. However, anti-angiogenic therapy has certain limitations in the treatment of advanced breast cancer.

Anrotinib hydrochloride capsule is a new drug independently developed in China. It is a multi-target receptor tyrosine kinase inhibitor targeting angiogenesis-related kinases such as VEGFR1/2/3, FGFR1/2/3 and other kinases such as cell growth-related kinases such as PDGFRα/β, c-Kit, and Ret , and it was approved by China Food and Drug Administation for the treatment of patients with locally advanced or metastatic non-small cell lung cancer who have progressed or relapsed after receiving at least 2 systemic chemotherapy. Basic research shows that anlotinib is effective in breast cancer cell lines, but lacks the results of clinical application of advanced breast cancer. This study is based on the results of phase I clinical trials of allerinib in a variety of advanced solid tumors, to explore its efficacy and safety in HER2-negative advanced breast cancer.

Inclusion Criteria:

• Age between 18 and 75 year-old women; Pathologically or cytologically confirmed breast cancer; HER2 negative(immunohistochemistry or fluorescence in situ hybridization);
• ECOG score: 0-1, expected survival time ≥ 3months;
• Anthracycline- / taxane- pretreated (adjuvant, neoadjuvant) breast cancer patients who have failed from 1-2 standard chemotherapies after recurrence and metastasis;
• According to RECIST 1.1, exist at least ≥1 measurable lesion(CT >1cm，other examination >2cm);
• The patients have enough organ function. The laboratory test indexes must comply with the following requirements:

Blood routine: neutrophil≥1.5G/L, platelet count ≥80G/L, hemoglobin ≥90g/L Liver function: serum bilirubin ≤ 1.5 times the upper limit of normal value; ALT and AST≤2.5 times the upper limit of normal value; ALT and AST≤5 times the upper limit of normal value when liver metastasis Renal function: serum creatinine ≤ 1.0times the upper limit of normal value, creatinine clearance >50ml/min（Cockcroft-Gault formula)

• Women of child-bearing age should be carried out pregnancy test (serum or urine) within 7 days before recruit, the results should be negative; and are willing to adopt the appropriate methods of contraception during the trial and 8 weeks after last administration；
• Can swallow oral drugs;
• The patients have good compliance to the therapy and follow-up to be scheduled and are able to understand the study protocol and sign the Informed Consent Form.

Exclusion Criteria:

• The patients in pregnancy or lactation growth period and did not take effective contraception;
• The patients who received ≥3 chemotherapies（Do not include endocrine therapy）after recurrence and metastasis; involved in other clinical trials four weeks prior to the start of the study;
• The patients with a variety of factors that affect the oral administration and absorption of drugs;
• The patients with rapid progression of viscera invasion(liver lesion >1/2 viscera area or liver dysfunction);
• The patients have uncontrollable mental illness.
• The patients who had serious adverse effect to oral etoposide or were allergic to etoposide.
• The patients who have only bone metastasis without other measurable lesion;
• The patients experience severe cardiovascular diseases;
• The patients experience severe upper gastrointestinal ulcer or malabsorption syndrome.
• Abnormal bone marrow functions(neutrophil<1.5G/L, platelet count <75G/L, hemoglobin <90g/L);
• Abnormal renal function(serum creatinine > 1.5 times the upper limit of normal value);
• Abnormal liver function(serum bilirubin ≤ 1.5 times the upper limit of normal value);
• The patients have uncontrollable brain metastasis;
• The patients do not have good compliance to the therapy.