Background: Overexpression or amplification of HER2 occurs in approximately 15 – 20% of patients and about half of these tumors are hormone receptor (HR) positive. Studies suggest that this 10% of all breast cancer cases may derive less benefit from endocrine therapy than those with HR+ disease without HER2 overexpression. The use of aromatase inhibitors in the metastatic setting is well established while significant improvement in overall survival has been established with the use of trastuzumab or pertuzumab in HER2-overexpressing tumors. To date, no studies have examined the combination of endocrine therapy, palbociclib, and dual HER2 therapy with pertuzumab and trastuzumab in this patient population. Trial Design: Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HR-positive, Her2-positive Metastatic Breast Cancer. Eligibility Criteria: Stage IV HR+, HER2+ breast cancer patients. Specific Aims: Phase I: To determine the maximum dose tolerated of palbociclib. Phase II: To determine the clinical benefit rate (CBR) of treatment with anastrozole, palbociclib, trastuzumab, and pertuzumab in HR+, HER2+ metastatic breast cancer patients. Exploratory: Examine potential biomarkers of response to palbociclib including expression of cyclin D1, cyclin E1 and E2, retinoblastoma, phosphorylated retinoblastoma, and p16 levels. RNA sequencing will be used to assess for other predictors of response in an unbiased manner to assess for correlation with inhibition of Ki-67 and phosphorylated retinoblastoma expression as well as evaluate for potential mechanisms of resistance. Methods: This study will evaluate the maximum tolerated dose (MTD) of the Anastrozole, Palbociclib, Trastuzumab and Pertuzumab. If ≥ 33 % of patients experience a dose limiting toxicity (DLT) at any dose level, the dose level below that level will be considered the MTD. Or, if the highest level has been reached and < 33% of patients have experienced DLT, that will be considered the MTD. Once the MTD is reached, we will assess the clinical benefit rate using a Simon's II stage design among a maximum 30 patients. Accrual: Maximum of 36 subjects. Clinical trial information: NCT03304080