Inclusion Criteria:

• Women ≥ 18 years of age with clinical stage IV ER+/HER2- breast cancer, or with locally recurrent ER+/HER2- disease not amenable to therapy for curative intent.
• Patient must have been treated with an anti-estrogen at any time in their disease history. Combination regimens that include an anti-estrogen and any biologic, or targeted therapy, are permitted (e.g., any CDK inhibitor, everolimus, or any other novel biologics), and are considered to be a single hormonal therapy based regimen.
  • Any number of prior lines of anti-estrogen (i.e., hormonal) therapy is permissible. 
  • One line of prior chemotherapy for advanced/metastatic disease is permissible.
• Histologic documentation of ER strongly+/HER2- breast cancer by core needle biopsy, fine needle aspiration, incisional biopsy, or surgical biopsy of ≥1 site(s) of metastatic or locally advanced disease performed as standard of care within the past 4 months for assessment of eligibility for study participation (except as noted below in c/d/e).
  • ER strongly+ status defined as ER staining by immunohistochemistry in ≥ 50% of malignant cell nuclei with an intensity ≥ 2+ on a scale of 0-3+. These criteria are equivalent to an Allred score ≥ 6.
  • HER2-negative status is defined as immunohistochemistry score of 0-1+, or with a FISH ratio of < 2 if IHC is 2+ or if IHC has not been done (as per ASCO/CAP definitions). In cases of borderline or equivocal HER2 status, eligibility will be determined by the PI.
  • Archived tumor specimens: Excess tumor tissue must be available for research purposes. This will include tumor tissue sufficient to make ≥ 10 five-micron sections; more tumor tissue is preferred. Freshly acquired tumor specimens: As part of a clinically indicated biopsy procedure, an additional 1-3 cores or tissue fragments will be obtained by core needle or surgical biopsy for research purposes and FFPE.
  • Patients with bone-only metastatic disease with a history of ER+/HER2- breast cancer are eligible, and bone biopsy is not required, providing their primary cancer is consistent with the above-described ER and HER2 criteria.
  • Patients with non-bone metastatic disease in whom a safe and accurate biopsy of recurrent/metastatic disease cannot be readily obtained are also eligible, providing their primary cancer is consistent with the above-described ER and HER2 criteria.
  • Patient must be a candidate for treatment with 17B-estradiol and an aromatase inhibitor.
  • If the most recent therapy was in the adjuvant setting, the recurrence-free interval (time from initiation of adjuvant anti-estrogen therapy to clinical evidence of disease recurrence) must have been ≥ 2 years. If the most recent therapy was in the advanced/metastatic setting, the progression-free interval must have been ≥ 4 months (except in the case of investigational hormonal therapies).
  • Patient must be post-menopausal based on either a history of an oophorectomy, or ≥ 1 year of amenorrhea. An elevated serum gonadotropin level and estradiol level in the postmenopausal range (as locally defined) can be used to confirm menopausal status in a subject with < 1 year of amenorrhea.
  • Baseline radiographic staging, including specifically either PET/CT, or CT (CAP) and bone scan.
  • Patient must be capable and willing to provide informed written consent for study participation.
  • The following laboratory values must be confirmed for eligibility within 28 days prior to initiation of study therapy:
    • Hematology panel
      • hemoglobin > 9 g/dL;
      • white blood cell (WBC) count (≥ 2,000/uL);
      • platelet count ≥ 75,000/uL.
    • Serum biochemistry/metabolic panel 
      • creatinine ≤ 1.5 x upper limits of normal (ULN);
      • total bilirubin ≤ 1.5 x upper limits of normal (ULN);
      • ALT and AST ≤ 3.0 x upper limits of normal (ULN) For patients with liver metastasis: < 5 x upper limits of normal (ULN).

Exclusion Criteria:

• Treatment with fulvestrant within 16 weeks prior to study enrollment.
• Any other concurrent systemic anti-cancer treatments, including conventional chemotherapeutic agents and biological agents, during the study period.
  • Anti-resorptive bone therapies (e.g., bisphosphonates, denosumab) are permitted.
• Any investigational cancer therapy in the last 3 weeks.
• Known CNS disease, unless clinically stable for ≥ 3 months.
• History of any of the following:
  • deep venous thrombosis;
  • pulmonary embolism;
  • stroke;
  • acute myocardial infarction;
  • congestive heart failure;
  • previous malignancy not treated with curative intent, or with an estimated recurrence risk ≥ 30%.