Assessing the Role of [11C] Vorozole in the Detection of Aromatase in Breast Cancer

? DESCRIPTION (provided by applicant): Breast cancer (BC) is the most common form of malignancy in women and a major cause of morbidity and mortality. Increased aromatase expression and activity is found in the majority (>60%) of breast tumors, and aromatase inhibitors (AI) are commonly in use for hormonal therapy of BC. A non-invasive method for assessing aromatase availability in breast cancer may provide a sensitive non-invasive tool for early diagnosis, help identify patients more likely to respond to AI therapy, assist in management of patients treated with AI and provide a tool for early determination of pharmacokinetics and pharmacodynamics of new AI drugs in development and thus have a significant impact on breast cancer diagnosis and treatment. Vorozole is a selective and potent aromatase inhibitor and [11C]vorozole was shown to be a specific and sensitive radiotracer for detection of changes in aromatase availability in the brains of rodents, non-human primates and human subjects using positron emission tomography (PET). The objective of the proposed studies is to evaluate and validate [11C]vorozole as a PET radiotracer for aromatase overexpressing tumors in postmenopausal women with breast cancer. Three hypotheses will be tested through three specific aims: (1) Tracer uptake in aromatase- overexpressing breast tumors will be significantly higher than in unaffected breast tissue in the same women and breasts of healthy volunteers; (2) Administration of a pharmacological dose of an aromatase inhibitor in clinical use (Ietrozole, brand name Femara) will block specific radiotracer uptake by breast tumors, eliminating the difference in standard uptake values (SUV) between tumor and healthy breast and; (3) Immunohistochemistry for aromatase will demonstrate concordance with radiotracer uptake in breast tumors. For Aim 1, tracer SUVs in the affected breast of 30 women with biopsy-confirmed breast cancer will be compared to the uptake in the unaffected breast of the same women and to values in healthy volunteers scanned in a prior study. For Aim 2, the patients scanned in aim 1 will be administered a clinical (2.5mg) oral dose of letrozole (Femara) and rescanned 2 hours later. In Aim 3, sections obtained from the tumors surgically removed from the same patient group will be stained with an antibody specific to human aromatase. Positive cell density and staining intensity will be compared in tumor, breast around tumor and archival specimens of normal breasts.