F-18 16 Alpha-Fluoroestradiol-Labeled Positron Emission Tomography in Predicting Response to First-Line Hormone Therapy in Patients With Stage IV Breast Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well F-18 16 alpha-fluoroestradiol (FES) imaging works in predicting response to first-line hormone therapy in women with hormone receptor-positive metastatic breast cancer. Diagnostic procedures, such as FES imaging, may help predict how well patients will respond to hormone therapy and may help plan the best treatment.

Detailed Description
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PRIMARY OBJECTIVES: I. Estimate the ability of [^18F] FES positron emission tomography (PET) or PET/computed tomography (CT) uptake at the level of standard uptake value (SUV) < 1.5 to predict overall response (OR) to first line endocrine therapy for metastatic breast cancer. SECONDARY OBJECTIVES: I. Evaluate the independent role of [^18F] FES in predicting response and time to progression in patients treated with first-line endocrine therapy for metastatic breast cancer. II. Examine the role of [^18F] FES in predicting OR or clinical benefit (CB), in concert with tissue assay of levels of estrogen receptor (ER) messenger ribonucleic acid (mRNA) measured using quantitative polymerase chain reaction (PCR), and semi-quantitative interpretation of estrogen receptor (ER), progesterone receptor (PgR), androgen receptor (AR), and human epidermal growth factor-2 (HER2), in addition to serial measures of hormone levels in plasma. III. Evaluate the relationships among [^18F] FES, semi-quantitative ER from immunohistochemistry (IHC), and ER mRNA as measured by quantitative PCR. IV. Document the safety profile of [^18F] FES PET in newly diagnosed patients with metastatic breast cancer. V. Evaluate FES SUV < 1.5 as the optimal cutpoint for predicting OR to first-line endocrine therapy for metastatic breast cancer. VI. Estimate the rate of [^18F] FES SUV < 1.5 in newly diagnosed metastatic breast cancer patients planning a course of endocrine therapy. OUTLINE: Patients undergo [^18F] FES PET scan. Patients also undergo standard clinical fludeoxyglucose F 18 (FDG)-PET or FDG-PET/CT scan up to 14 days prior to [^18F] FES PET scan. After completion of study treatment, patients are followed up for at least 6 months.

Official Title
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A Phase 2 Study of [18F] Fluoroestradiol (FES) as a Marker of Hormone Sensitivity of Metastatic Breast Cancer

Conditions
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Estrogen Receptor-positive Breast Cancer, Progesterone Receptor-negative Breast Cancer, Progesterone Receptor-positive Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Radiation: F-18 16 alpha-fluoroestradiol
* Radiation: fludeoxyglucose F 18
* Procedure: positron emission tomography
* Procedure: positron emission tomography
* Procedure: computed tomography
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients will have pathologically confirmed invasive breast cancer with clinical, radiographic and/or pathologic evidence of stage IV disease; patients must have tissue blocks available from biopsy of at least one site of metastatic disease and/or from diagnosis of their primary breast cancer Disease may be measurable (by Response Evaluation Criteria in Solid Tumors [RECIST] criteria) or non-measurable but must be present in at least one non-liver site and imageable on FDG PET scan; in patients with non-measurable disease by RECIST criteria, one of the following may be used to assess and follow disease: MUC-1 antigen level (either cancer antigen [CA] 27.29 or carcinoembryonic antigen [CEA]) > 2 x upper limit of normal (ULN), Circulating tumor cell assay > 5, or FDG-PET SUV > 2.5 in purely lytic lesions; elevated tumor markers alone are insufficient No prior endocrine therapy for breast cancer or Off adjuvant endocrine therapy for > 6 months or Greater than 2 years of a single adjuvant endocrine therapy at the time of first recurrence and plan to change to alternate endocrine therapy; use of tamoxifen must be discontinued 6-8 weeks prior to entrance into the study Prior chemotherapy regimens in the adjuvant or neoadjuvant setting are allowed Women treated with adjuvant LHRH (luteinizing hormone-releasing hormone) analog are eligible Be assessed for menopausal status; for study purposes, postmenopausal is defined as: A prior documented bilateral oophorectomy, or A history of at least 12 months without spontaneous menstrual bleeding, or Age 60 or older with a prior hysterectomy without oophorectomy, or Age less than 60 with a prior hysterectomy without oophorectomy (or in whom the status of the ovaries is unknown), with a documented follicle stimulating hormone (FSH) level demonstrating confirmatory elevation in the postmenopausal range for the lab Premenopausal patients must have a baseline FSH, and estradiol levels to determine menopausal status; measures will be repeated at 3-6 months to confirm menopausal status Patients must be positive for estrogen receptor (ER) and may or may not be positive for progesterone receptor (PgR) by IHC in the primary tumor and/or metastatic site; the pathology report for assay of ER will be reviewed by one of the investigators prior to enrollment, the study pathologist will review the pathology report if necessary for determination of study eligibility Tumor HER2/neu expression must be determined prior to study enrollment; assessment may be by fluorescence in situ hybridization (FISH) assay or by immunohistochemistry (ICC); if determination is intermediate by ICC, FISH must be performed Life expectancy > 16 weeks Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Absolute neutrophil count (ANC) >= 1,000 Platelet count >= 50,000 Hemoglobin within normal limits (WNL) for the institution Serum creatinine =< 1.5 x institutional ULN (IULN) and estimated creatinine clearance > 50 mL/min using the Cockroft-Gault formula Bilirubin =< 1.5 x ULN Serum glutamic oxaloacetic transaminase (SGOT)/ serum glutamic pyruvate transaminase (SGPT) =< 1.5 x ULN Alkaline phosphatase =< 2.5 x ULN Patients must be planning a course of endocrine therapy with one of the following: tamoxifen +/- ovarian suppression, aromatase inhibitor +/- fulvestrant (with ovarian suppression in pre-menopausal patients) or fulvestrant alone After entry into the study, patients are expected to be followed for at least 6 months after the injection of [^18F] FES Have a negative pregnancy test within 7 days prior to registration if of childbearing potential No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or any other cancer from which the patient has been disease-free for 5 years Be informed of the investigational nature of this study and provide written informed consent in accordance with institutional and federal guidelines prior to study-specific screening procedures Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Exclusion Criteria: Patients with a history of prior endocrine therapy for metastatic disease are NOT eligible; adjuvant endocrine therapy for < 2 years total or discontinued less than 6 months before first disease recurrence also excludes the patient Patients with disease in the liver only are NOT eligible for the study Patients who are HER2/neu positive disease and planning to undergo HER2-directed therapy (trastuzumab or lapatinib) are NOT eligible for the study Pregnant or lactating; women of childbearing potential with either a positive or no pregnancy test at baseline are excluded Visceral crisis characterized by rapidly progressive hepatic or lymphangitic lung metastases History of uncontrolled seizures, central nervous system disorders, or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent Any other life-threatening illness (e.g., serious, uncontrolled concurrent infection or clinically significant cardiac disease - congestive heart failure, symptomatic coronary artery disease, cardiac arrhythmia not well controlled with medication) Unwillingness to give informed consent Medically unstable as judged by the patient's physician Psychological, familial, sociological, or geographical conditions which do not permit compliance with the study protocol Patients with known allergic or hypersensitivity reactions to previously administered radiopharmaceuticals; patients with significant drug or other allergies or autoimmune diseases may be enrolled at the investigator's discretion Patient weight greater than 400 lbs (exceeds weight limit for tomograph table) Uncontrolled diabetes mellitus (fasting glucose > 200 mg/dL) Adult patients who require monitored anesthesia for PET scanning

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Diagnostic (FES)<br>Patients undergo [^18F] FES PET scan. Patients also undergo standard clinical fludeoxyglucose F 18 (FDG)-PET or FDG-PET/CT scan up to 14 days prior to [^18F] FES PET scan. | Radiation: F-18 16 alpha-fluoroestradiol<br>* Undergo [^18F] FES PET<br>* Other names: fluorine-18 16 alpha-fluoroestradiol;Radiation: fludeoxyglucose F 18<br>* Undergo standard clinical FDG PET/CT<br>* Other names: FDG;Procedure: positron emission tomography<br>* Undergo [^18F] FES PET<br>* Other names: tomography, emission computed;Procedure: positron emission tomography<br>* Undergo standard clinical FDG PET/CT<br>* Other names: tomography, emission computed;Procedure: computed tomography<br>* Undergo standard clinical FDG PET/CT<br>* Other names: tomography, computed;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | Patients were expected to start endocrine therapy within 2 weeks of the FES PET scan. Response assessment was evaluated at 3 and 6 months. For patients with at least one site of measurable disease [per response evaluation criteria in solid tumors (RECIST, version 1.1)], size-based response criteria were used to assess response. For patients without disease evaluable by RECIST 1.1, largely patients with bone-dominant metastatic breast cancer, serial FDG PET scanning was used to determine response. A decline in the FDG PET SUV (standard uptake value) of 30% or more was considered as response and an increase of 20% or more was considered to be progressive disease (PD). The initial (baseline) FES uptake was compared to clinical benefit (PD versus other outcome at 6 months). | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Benefit | FES SUV prior to endocrine treatment (dichotomized and as a continuous predictor) will also be tested as predictor of clinical benefit. Patients were expected to start endocrine therapy within 2 weeks of the FES PET scan. Response assessment was evaluated at 3 and 6 months. The initial (baseline) FES uptake was compared to clinical benefit (PD versus other outcome at 6 months). | Up to 6 months | 
| Time to Progression | FES SUV prior to endocrine treatment (dichotomized and as a continuous predictor) will also be tested as predictor of time to progression. Analysis will be conducted using (respectively) logistic regression and Cox proportional hazards regression. This will include univariate analysis of FES and other predictive measures (ER/PgR expression, serum sex steroid levels), followed by an exploratory multivariate analysis combining FES SUV with other measures showing predictive capability univariate analysis. | Up to 6 months | 
| Correlation of FES Uptake With ER Assays | Graphical and numerical studies of bivariate relationships will be examined, as well as factors (i.e., tumor size, tumor location, patient age) to explain concurrence, lack of concurrence, and sources of measurement error for measurements of ER function. | Up to 6 months |