DETERMINATION OF ESTROGEN RECEPTOR CONTENT IN BREAST CANCER BY PET

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Treatment and prognosis of breast cancer is dependent in large part on the tumor content of estrogen receptor. Patients who have high levels of estrogen receptor will respond to treatment with hormonal agents and have a longer disease free interval than patients with estrogen receptor negative tumor. When a patient presents with primary breast cancer, treatment is based on estrogen receptor level determined on resected tumor tissue. PET imaging offers the capability of making the determination of estrogen receptor content in vivo in both primary and disseminated disease. We will test the hypothesis that the estrogen receptor content of breast cancers can be determined in vivo with PET imaging using [F-18] fluoroestradiols. In patients with primary tumors, [F-18] uptake expressed as the percent of the injected dose per gram will be correlated with estrogen receptor density determined on excised tissue independently by radioimmunoassay and immunocytochemistry. We will also evaluate metastases in breast cancer patients for site-to-site variation in estrogen receptor expression. Because separate metastatic sites have variable responses to hormonal therapy, up to three sites in an individual patient will be studied. Uptake of [F-18] fluoroestradiol will be correlated with response to hormonal therapy on a site by site basis. In the same group of patients, we will observe changes in [F-18] estradiol uptake over time while the patient is receiving hormonal therapy. Tumor estrogen receptor content will be correlated with time to progression of disease on a sit-by-site basis. We will also synthesize several new [F-18] estradiols with characteristics designed to reduce metabolism at the receptor site and reduce uptake in non-target tissues. Newly synthesized radiopharmaceuticals will be evaluated for binding characteristics in a bioassay utilizing human uterus tissue. Biodistribution in target and non-target tissues will be evaluated in young female Sprague-Dawley rats. When pre-clinical evaluations are completed, we will perform complete biodistribution studies in breast cancer patients to evaluate these various estradiols for suitability for PET imaging. Biodistribution studies will also include analysis of patient serial blood samples for the presence of active metabolites. When patient biodistribution studies show good correlation of [F-18] uptake with radioimmune assay determination of tumor estrogen level, we will use the patient derived biodistribution data in combination with in vitro binding affinity values to determine absolute estrogen receptor content using compartmental models for receptor systems.