This phase II trial studies how well estradiol works in treating patients with estrogen receptor beta (ER beta) positive, triple negative breast cancer that has spread to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic). Hormone receptors like ER beta allow the body to respond appropriately to hormones. Triple negative means that the breast cancer does not express other hormone receptors called ER alpha, progesterone, and HER2. In some people with triple negative breast cancer, ER beta is overexpressed. Tumor cells that overexpress ER beta grow slower in the laboratory and this growth is slowed in the presence of estrogen. Estradiol is a form of estrogen. This study may help doctors determine whether tumor cells that overexpress ER beta shrink in the presence of estradiol.
PRIMARY OBJECTIVE: I. To assess the anti-tumor activity of estradiol in patients with locally advanced or metastatic triple negative breast cancer (TNBC) that expresses ERbeta (\> 25% moderate or strong nuclear staining). SECONDARY OBJECTIVES: I. To examine the safety profile of estradiol when administered at a dose of 2 mg three times daily (TID) to women with locally advanced or metastatic TNBC that expresses ERbeta. II. To examine the changes in phosphorylated (phospho)-ERbeta, cystatins 1, 2, 4 and 5, phospho-Smad2/3 and Ki-67 in tumor biopsies taken before and after the first cycle of treatment. EXPLORATORY OBJECTIVES: I. To examine changes in plasma estradiol, serum cytokine and cystatin levels before/after 1 cycle of estradiol. II. Analyze the global gene expression profiles of paired biopsies prior to and following 1 cycle of therapy. III. To develop patient derived xenografts (PDX) that are ERalpha negative, HER2 negative and ERbeta positive (Mayo only). IV. To examine changes in the relative abundance of circulating immune cell populations after the first cycle of treatment and whether these changes differ with respect to whether the patient is still on treatment after 6 cycles of treatment or not. OUTLINE: Patients receive estradiol orally (PO) TID for days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo a tissue biopsy at the end of cycle 1, collection of blood samples on day 1 of cycle 1 (C1D1), at the end of cycle 1, and at the end of treatment. In addition, patients undergo computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) scans at baseline, at the end of cycles 2, 4, and 6, and then every 8 weeks until disease progression. After completion of study treatment, patients are followed up annually for 5 years from study registration.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
5
Undergo tissue biopsy
Undergo CT
Undergo MRI
Undergo PET
Given PO
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
UCSF Medical Center-Mission Bay
San Francisco, California, United States
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, United States
Mayo Clinic in Florida
Jacksonville, Florida, United States
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States
Mayo Clinic in Rochester
Rochester, Minnesota, United States
Montefiore Medical Center-Einstein Campus
The Bronx, New York, United States
FHCC South Lake Union
Seattle, Washington, United States
University of Washington Medical Center - Montlake
Seattle, Washington, United States
Clinical benefit rate
A patient is said to have derived clinical benefit rate at the 6 month time point if the patient's disease meets the Response Evaluation Criteria in Solid Tumors (RECIST) for complete response (CR), partial response (PR), or stable disease (SD) for \> 6 months following initiation of treatment. The 6 month clinical benefit rate is the percentage of patients who are found to meet the criteria for clinical benefit at least 6 months among all the patients who have started estradiol treatment. As the number of patients with discordant ERbeta findings are expected to be small, a 90% exact binomial confidence interval will be constructed for the proportion of patients who were found to have no to weak ERβbeta expressing metastatic triple-negative breast cancer (TNBC) and who derived clinical benefit rate at the 6 month time point.
Time frame: 6 months
Incidence of adverse events
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. All grade 2, 3, 4 or 5 adverse events will be documented and assigned an attribute by treating clinician as to its relationship to treatment. For a given AE, the proportion of patients who report developing a grade 2-5 of this AE are determined. The number of dose reductions per patient and the reasons for the dose reduction are summarized.
Time frame: 5 years
Tumor response rate among those patients with measurable disease
The tumor response rate is defined as the 100% time the number of patients with a CR or PR (as defined by the RECIST criteria) on 2 consecutive evaluations at least 8 weeks apart divided by the total number of eligible patients who began study treatment. A 90% binomial confidence interval is constructed for the true response rate.
Time frame: 5 years
Progression free survival (PFS) distribution
PFS is defined as the time from registration to the first of the following events: local, regional, or distant recurrence, second primary disease of death due to any cause. The distribution of PFS times will be estimated using the method of Kaplan-Meier.
Time frame: Up to 5 years
Overall survival (OS) distribution
OS is defined as the time from registration to death due to any cause. The distribution of survival times are estimated using the method of Kaplan-Meier.
Time frame: Up to 5 years
Changes in phospho-ERbeta, cystatins 1, 2, 4 and 5, phospho-Smad2/3 and Ki-67
Patients undergo tumor biopsies prior to the start of treatment and at completion of cycle 1 treatment. These specimens will be undergoing immunohistochemistry (IHC) staining with the following antibodies: phosphorylated (phospho)-ERbeta, cystatins 1, 2, 4 and 5, phospho-Smad2/3 and Ki-67. For each of these biomarkers, a times series plot are constructed so that an individual patient's data will be represented using the same color for each of the five graphs. These graphs are visually inspected for trends within each of the graphs (variation between individuals) as well as across the five graphs (profile of biomarker changes within an individual).
Time frame: 5 years
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