The objective of this study is to evaluate the efficacy of combination of palbociclib, trastuzumab and pyrotinib with fulvestrant in ER/PR positive and HER2-positive breast cancer patients with brain metastasis.

Inclusion Criteria

1. Age greater than 18 years old
2. Female patients aged 18 years or older
3. Histologically confirmed ER/PR positive, HER2-positive metastatic breast cancer (ER/PR≥1% by IHC; HER-2 3+ by immunohistochemistry (IHC); if IHC score of 2, fluorescence in situ hybridization (FISH) ratio must be greater than 2.0; if FISH less than 2.0, HER2 copy number must be greater than 6; NOTE: Brain lesions are not required to have pathologic confirmation)
4. Patients must have a life expectancy of at least 12 weeks at the time of registration
5. Eastern Cooperative Oncology Group (ECOG) performance status >= 2
6. Measurable disease in the brain, defined as at least 1 lesion measuring >= 10 mm on MRI at the time of registration
7. If patients are on corticosteroids, they must have been on a stable or decreasing dose >= 5 days prior to obtaining their baseline gadolinium (Gd)-magnetic resonance imaging (MRI) of brain; this MRI is to be obtained within 28 days of registration; NOTE: If patient needs escalation of steroids prior to therapy, or are on unstable doses of steroids they are not eligible
8. Patients who have a history of hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol; AND/OR patients who have had prior exposure to fulvestrant, everolimus, pyrotinib or CDK4/6 inhibitors and had a disease progression during treatment are not eligible.
9. Patients must not have received systemic therapy within 2 weeks of initiating palbociclib; NOTE: For patients on trastuzumab, they can remain on the drug; no break or washout period required
10. Patients must exhibit adequate bone marrow, liver, and renal function, within 14 days prior to registration, defined as:
11. Absolute neutrophil count (ANC) >= 1,000/mm^3 (growth factor support is permitted)
12. Platelets >= 50,000/mm^3 (may be reached by transfusion)
13. Hemoglobin >= 10 gm/dl (may be reached by transfusion)
14. Glutamate pyruvate transaminase (GPT)/glutamate oxaloacetate transaminase (GOT) < 3 x upper limit of normal (ULN) (or < 5 x ULN in case of liver metastasis)
15. Bilirubin < 3 x ULN (or < 5 x ULN in case of liver metastasis)
16. Creatinine < 1.5 x ULN
17. Women of childbearing age must have a serum pregnancy test within 7 days before enrollment, and the result should be negative, and are willing to use a medically recognized high-efficiency contraceptive during the study period and within 1 year after the last administration of the study drug.
18. Has not undergone a hysterectomy or bilateral oophorectomy
19. Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)
20. Female patients must have a negative urine pregnancy test within 7 days prior to registration; if urine test is positive, it should be followed by serum pregnancy test
21. Patients must sign an informed consent prior to registration and before undergoing any study-specific procedures indicating that they are aware of the investigational nature of this study
22. Patient must have the ability to comply with all study requirements

Exclusion Criteria

1. Any uncontrolled neurological symptom attributed to CNS metastasis
2. Brain metastasis must not be impending herniation or other significant vasogenic edema requiring increasing steroid doses; lesions must not have frank hemorrhage
3. Patients with leptomeningeal disease are not eligible for participation
4. Patients have been treated with WBRT. The selected intracranial target lesion has received local treatment (surgical resection or SRS). Acute effects related to surgery or SRS have not recover
5. Any significant medical illnesses or infection that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy are not eligible for participation
6. Known human immunodeficiency virus (HIV) positive status
7. Known active hepatitis B and/or C
8. Patients who have a history of hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol; AND/OR patients who have had prior exposure to compounds of similar chemical or biologic composition to palbociclib or lapatinibpyrotinib and PD during treatment are not eligible.
9. Patients being treated with any other experimental agents/clinical trials are not eligible for participation; if the patient is on any investigational agent, a wash-out period of minimum 2 weeks prior to registration is mandatory for the patient to be eligible for the study
10. Inability to swallow capsules, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of study drugs, major resection of the stomach or small bowel, or gastric bypass procedure
11. Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible:
12. Ongoing or active infection requiring systemic treatment
13. Symptomatic congestive heart failure
14. Unstable angina pectoris
15. Cardiac arrhythmia: except atrial fibrillation (AF) and supraventricular tachycardia (SVT) that are controlled by medication
16. Psychiatric illness/social situations that would limit compliance with study requirements
17. Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints