Inclusion Criteria:
* Women or men with metastatic breast cancer, measurable or evaluable disease including bone metastasis only (as per the Response Evaluation Criteria in Solid Tumors \[RECIST\] v1.1)
* No prior systemic treatment for metastatic breast cancer
* Pathologic confirmation of metastatic breast cancer diagnosed by core needle biopsy
* Metastatic breast cancer with any evidence of ER or PR positivity in ≥ 1% cells in biopsy specimens from either a primary or metastatic site
* Evidence of HER2 positive metastatic breast cancer in either a primary or metastatic site, if 3+ by an IHC method defined as uniform membrane staining for HER2 in 10% or more of tumor cells or demonstrate HER2 gene amplification by an ISH method (single probe, average HER2 copy number ≥6.0 signals/cell; dual probe HER2/CEP17 ratio ≥2.0 with an average HER2 copy number ≥4.0 signals/cell; dual probe HER2/chromosome enumeration probe (CEP) 17 ratio ≥2.0 with an average HER2 cop number \<4.0 signals/cell; and HER2/CEP17 ratio \<2.0 with an average HER2 copy number ≥6.0 signals/cell) or amplified by FISH \> 2.0. High average copy number of HER2 (≥6.0 signals/cell) is considered positive regardless of the HER2/CEP17 ratio.
* Women or men 18 years and older
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
* Stable brain metastasis allowed (\>2 weeks, clinically stable post treatment with surgery +/- radiation or radiation alone and off steroids)
* Transthoracic echocardiogram with ejection fraction \> 50%
* Postmenopausal status or receiving ovarian ablation with a GnRH agonist such as goserelin or leuprolide. Postmenopausal status is defined by any one of the following criteria:
* Prior bilateral oophorectomy.
* Prior ovarian radiation for the purpose of ablation.
* Age ≥ 60 years.
* Age \< 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, or ovarian suppression) and FSH, LH, and estradiol in the postmenopausal range per local normal.
* Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements
* A baseline CT chest/abdomen/pelvis and bone scan or PET/CT
* Negative serum or urine pregnancy test within 7 days prior to starting treatment
* Women of child-bearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
Note: Recommended methods of birth control are: The consistent use of an intrauterine device (IUD), double barrier methods (diaphragm with spermicidal gel or condoms with contraceptive foam), sexual abstinence (no sexual intercourse) or sterilization.
Men must agree to use a condom and not father a child for the duration of the study and for 90 days after completion of therapy
Laboratory values (≤ 28 days prior to registration)
* Absolute Neutrophil Count (ANC) ≥ 1,500/mm3
* Platelet Count ≥ 75,000/ mm3
* Hg \>9 g/dL
* Total Bilirubin ≤1.5 x upper limits of normal (ULN)
* Serum ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN in patients with liver metastasis)
* Creatinine ≤ 1.5 x ULN
Exclusion Criteria:
* HER2 negative metastatic breast carcinoma defined as 0 or 1+ by IHC or with a FISH ratio (HER2 gene copy/ chromosome 17) \<2 if IHC 2+ by local institution standard protocol
* Any prior treatment for metastatic breast cancer. (excluding radiation therapy for the purpose of ovarian ablation). Note: Prior adjuvant therapy with trastuzumab and pertuzumab is permitted after a 6 month window following completion of adjuvant therapy has passed.
* Patients currently receiving anticancer therapies or who have received anticancer therapies within 2 weeks of the start of study drug (including chemotherapy, radiation therapy, and biologics). Patients who have received prior endocrine therapy for fertility purposes will be eligible.
* Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
* Prior treatment with any investigational drug within the preceding 2 weeks
* Co-administration with strong CYP3A4 inducers (e.g., phenytoin, rifampin, carbamazepine, St John's Wort, bosentan, efavirenz, etravirine, modafinil, and nafcillin), strong CYP3A4 inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole), and CYP3A4 substrates (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus). For a current table of Substrates, Inhibitors and Inducers please access the following website:http://www.fda.gov/Drugs/DevelopmentApprovalProcess/" See Appendix C.
* Uncontrolled brain metastases
* Leptomeningeal metastases
* Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
* Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
* Symptomatic congestive heart failure of New York heart Association Class III or IV
* Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
* Severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 89% or less at rest on room air
* Uncontrolled diabetes as defined by fasting serum glucose \>1.5 x ULN
* Active (acute or chronic) or uncontrolled severe infections
* Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
* Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of palbociclib (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
* Patients with an active, bleeding diathesis
* History of noncompliance to medical regimens
* Patients unwilling to or unable to comply with the protocol
* Ongoing alcohol or drug addiction
* Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a method of contraception. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to starting treatment)
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib, anastrozole, trastuzumab or pertuzumab.
