Alternating Estradiol and Aromatase Inhibitor Therapies for the Treatment of ER+/HER2- Advanced or Metastatic Breast Cancer, POLLY Study

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 * 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 fluorescence in situ hybridization (FISH) ratio of < 2 if immunohistochemistry (IHC) is 2+ or if IHC has not been done (as per American Society of Clinical Oncology/College of American Pathologists [ASCO/CAP] definitions). In cases of borderline or equivocal HER2 status, eligibility will be determined by the principal investigator (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 formalin-fixed-paraffin-embedded (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 17 beta-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 >= 3 months (except in the case of investigational hormonal therapies, or investigational combinations that include an endocrine agent)
• 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 performed as standard of care, including specifically either positron emission tomography (PET)/computed tomography (CT), or CT chest abdomen pelvis (CAP) and bone scan
• Patient must be capable and willing to provide informed written consent for study participation
• Hemoglobin > 9 g/dL (within 28 days prior to initiation of study therapy)
• White blood cell (WBC) count >= 2,000/uL (within 28 days prior to initiation of study therapy)
• Platelet count >= 75,000/uL (within 28 days prior to initiation of study therapy)
• Creatinine =< 1.5 x upper limits of normal (ULN) (within 28 days prior to initiation of study therapy)
• Total bilirubin =< 1.5 x upper limits of normal (ULN) (within 28 days prior to initiation of study therapy)
• Alanine aminotransferase (AST) and aspartate aminotransferase (AST) =< 3.0 x upper limits of normal (ULN) (within 28 days prior to initiation of study therapy). 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 central nervous system (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%