Estradiol Therapy for the Treatment of ESR1-Mutant and ESR1-Wild-Type ER Positive Metastatic or Advanced Breast Cancer, ESTHER Trial

Inclusion Criteria

• Women >= 18 years of age with metastatic ER+ breast cancer, or with locally recurrent ER+ disease not amenable to therapy for curative intent
• Patient must have been treated with an anti-estrogen-containing therapy as their most recent line of therapy All combination regimens that include an anti-estrogen are permitted (e.g., a CDK4/6 inhibitor, everolimus, alpelisib, or any biologics), and are considered to be a single anti-estrogen-based regimen * Any number of prior lines of systemic therapy is permissible, including anti-estrogens and chemotherapy
• Histologic documentation of strongly ER+ breast cancer by core needle biopsy, fine needle aspiration, incisional biopsy, or surgical biopsy of >= 1 site(s) of metastatic or locally recurrent disease performed as standard of care * Exceptions: Patients with bone-dominant metastatic disease, or non-bone metastatic disease in whom a safe and accurate biopsy of recurrent/metastatic disease cannot be readily obtained, with a history of ER+ breast cancer are eligible, and biopsy is not required, providing their primary cancer is consistent with the ER criteria described below
• Strong ER+ 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
• If available, archived tumor tissue must be accessible for research purposes, sufficient to make >= 10 five-micron sections; more tumor tissue is preferred
• Patient must be a candidate for treatment with 17b-estradiol
• Patient must be post-menopausal per National Comprehensive Cancer Network (NCCN) guidelines
• Baseline radiographic staging performed as standard of care, including specifically either PET/CT, or contrast 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 limit of normal (ULN) (within 28 days prior to initiation of study therapy)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 28 days prior to initiation of study therapy)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x upper limits of normal (ULN) (within 28 days prior to initiation of study therapy) *Exception: In patients with liver metastasis, < 5 x upper limits of normal (ULN)

Exclusion Criteria

• During the study treatment phase with 17b-estradiol, no concurrent anti-cancer therapies are allowed with the following exceptions: * Exception: Trastuzumab is allowed for the treatment of subjects with a history of HER2+ disease, and will be used at the physician’s discretion * Exception: 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%