Combined estrogen blockade of the breast with raloxifene and exemestane in postmenopausal women for breast cancer prevention
Antineoplastic Combined Chemotherapy Protocols
Clinical Trials as Topic
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Selective estrogen receptor modulators (SERMS) reduce the incidence of breast cancer in women at increased risk. Intracellular estrogen (E) biosynthesis, mediated by aromatase action on androgens, is thought to maintain E concentrations at a relatively high level in the breast tumor tissue of postmenopausal women despite lower circulating E in this population. In theory, this intracellular E may competitively inhibit the AE effect of SERMs. Anti-aromatase agents (AA) reduce breast tumor aromatase activity and intratumoral E. Preclinical models suggest that AEs are more effective in a low E environment, supported by recent clinical data demonstrating superiority of tamoxifen in combination with buserelin compared to either agent alone (Klijn et al., JNCI 92:903;2000). To explore the potential of combined E blockade of the breast using an AE and an AA for breast cancer prevention, we are currently enrolling postmenopausal women with a history of Stage 0-III breast cancer who have not received AEs as part of adjuvant treatment (e.g. ER/PR-negative tumors). These women remain at increased risk for second primary tumors and represent a population in which to test promising chemoprevention regimens. Patients (pts.) receive raloxifene 60 mg PO daily and exemestane 25 mg PO daily, plus calcium and vitamin D. By random assignment they receive either agent alone for the first 2 weeks to allow for pharmacokinetic/pharmacodynamic (pharm) evaluation followed by combination treatment for one year. Endpoints include safety and tolerability, and changes in markers of bone turnover, bone mineral density, lipids, quality of life and pharm. Eight pts. are on study, and 2 pts. have completed one year of therapy. The combination has been well tolerated, with side effects limited to moderate hot flashes (3 pts.) and mild arthralgias (3 pts.). Pharm data will be presented on all pts. Correlative studies will assess changes in radiographic breast density by mammography and breast MRI, and breast biopsies will evaluate the effects of 3 months of treatment on breast tissue aromatase activity, E, and potential surrogate endpoint biomarkers. Preliminary analysis suggests that the combination is tolerable and further accrual is warranted to confirm this observation.