This is a multi-center, observational study designed to explore the regulatory mechanism of palbociclib correlative pathways in therapeutic process of breast cancer, employing next generation sequencing (NGS) on DNA and RNA. This study also monitor the clonal evolution of genes by tracing the ctDNA.

Inclusion Criteria:

• women aged 18-70 years old at the time of sign informed consent
• patients diagnosed as breast cancer with evidence supporting metastatic disease, unsuitable for radical operation or radiotherapy, with no chemotherapy indication
• full histological or cytological assessment of ER+, HER2- breast cancer
• refractory to the most recent endocrine therapy, or progression within 12 months of endocrine therapy
• Eastern Cooperative Oncology Group (ECOG) performance status score 0 or 1, no refractory within recent 2 weeks
• patients with at least 1 measuralbe lesion; lesions will be excluded if received radiotherapy, unless had confirmed progression
• life expectancy of 12 weeks or more
• clinical laboratory test indicators meet the following criteria:
• PLT≥100×10^9/L
• ANC≥1.5×10^9/L
• Hgb≥90 g/L
• TBil≤1.5 ULN
• ALT and AST ≤3 ULN
• creatinine≤1.5 ULN or creatinine clearance rate≥50 mL/min
• patients who signed informed consents before any projects, sampling and analysis; be available of tumor tissue biopsy and liquid biopsy; be cooperative for observation period
• patients can swallow oral drugs
• In addition to alopecia and stable peripheral neurotoxicity below grade 2, any clinical toxicity associated with previous treatment prior to enrollment must be restored to baseline or grade 1.

Exclusion Criteria:

• no prior treatment
• receiving treatment other than the trial 4 weeks prior to the study, or participating in another clinical study
• unwilling to provide tissue and blood for genetic testing
• non-resistant on endocrine therapy before treating with palbociclib
• progress of ≥ 2nd line endocrine therapy
• patients with advanced disease, symptoms, visceral spread, and life-threatening complications in the short term (including large uncontrollable spills [thoracic, pericardium, abdominal cavity], pulmonary lymphangitis, and liver involvement>50%)
• patients with active, uncontrolled or symptomatic central nervous system metastases, cancerous meningitis or clinical signs suggesting pia mater disease, brain edema and/or tumor growth. Patients with a history of central nervous system metastasis or spinal cord compression, if they have received local treatment (such as radiation therapy, stereotactic surgery) and are clinically stable, they need to stop convulsions and steroids for at least 4 weeks before randomization.
• patients received major surgery, chemotherapy, radiation therapy, or other anticancer treatments within 2 weeks prior to enrollment
• diagnosis of any other malignant tumor, within 3 years prior to the enrollment, except adequately treated basal/squamous cell skin cancer or cervical carcinoma
• assessed as not eligible to participate in the trial
• infused whole blood without leukocytes removing within 120 days prior to sampling
• during lactation or with positive blood or urine pregnancy test

metastatic breast cancer patients of ER+/HER2- with resistance of first line endocrine therapy