Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HR-positive, HER2-positive Metastatic Breast

This is a multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab is proposed as first-line therapy in metastatic hormone receptor-positive, HER2-positive breast cancer patients. In this phase I/II clinical trial, the researchers aim to establish the safety and efficacy of dual HER2 therapy in combination with palbociclib and anastrozole, which represents a novel and all biologic approach to the treatment of HR+, HER2+ metastatic breast cancer. Additionally, the researchers aim to examine potential biomarkers of response to palbociclib including cyclin D1, cyclin E1 and cyclin E2 expression levels, CDK 2, 4, and 6 levels, phosphorylated retinoblastoma expression and p16 levels. The researchers intend to use RNA sequencing to assess for other predictors of response in an unbiased manner to see if this correlates with inhibition of Ki-67 and phosphorylated retinoblastoma expression as well as evaluate for potential mechanisms of resistance.

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 \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) \