Apatinib Combined With Oral Etoposide in Metastatic HER2 Negative Breast Cancer

Inclusion Criteria:

* Age between 18 and 75 year-old women; HER2 negative(immunohistochemistry or fluorescence in situ hybridization);
* ECOG score: 0-1, expected survival time ≥ 3months;
* Pathologically or cytologically confirmed breast cancer;
* 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 previously received anti-VEFG of anti-VEGFR therapies;
* 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 have good compliance to the therapy.