S1222 Trial (Everolimus, Anastrozole and Fulvestrant) in Post-Menopausal Stage IV Breast Cancer

OBJECTIVES: Primary * To test the benefit of interfering with the function of the estrogen receptor (ER) and providing downstream target inhibition (PI3K/AKT/mTOR) with a combination of optimal dose fulvestrant and everolimus (Arm 2) to improve progression-free survival compared to the optimal dose fulvestrant alone (Arm 1). * To test the benefit of adding the non-steroidal aromatase inhibitor anastrozole to optimal dose fulvestrant and everolimus (Arm 3) in order to improve progression free survival over optimal dose fulvestrant (Arm 1). Secondary * To compare progression-free survival among those receiving fulvestrant + everolimus + anastrozole (Arm 3) versus fulvestrant + everolimus (Arm 2). * To compare overall survival among the treatment arms in post-menopausal patients with hormone-receptor positive (HR+) Stage IV breast cancer. * To assess and compare toxicities, feasibility and compliance among the study regimens. * To compare response rates and clinical benefit rates among the study regimens. * To test molecular determinants of response to endocrine therapy and everolimus in circulating tumor cells: 1. CTC-Endocrine Therapy Index (CTC ETI) on the CellSearch® platform. 2. CTC-Next Generation Sequencing Analysis (CTC-NGS) of single cells captured on the HD-CTC® platform. OUTLINE: This is a multicenter study. Patients will be stratified according to the following factors: * Measurable versus evaluable non-measurable disease * Prior adjuvant hormonal therapy completed more than 5 years ago vs. prior adjuvant hormonal therapy completed 1-5 years ago vs. de novo presentation of metastatic disease or no prior adjuvant hormonal therapy. ARMS: * Arm 1: fulvestrant + placebo (everolimus) + placebo (anastrozole) * Arm 2: fulvestrant + everolimus + placebo (anastrozole) * Arm 3: fulvestrant + everolimus + anastrozole Blood and tissue samples are collected for correlative science studies. After completion of study treatment, patients are followed up every 6 months for 2 years and then yearly thereafter for 5 years.