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THE USE OF COGNITIVE FUNCTION TESTING TO IDEN- TIFY POTENTIAL COGNITION ENHANCERS IN PHASE I: CASE HISTORIES OF TRANSLATIONAL MEDICINE

PIII-48 ASSOCIATION OF ESTROGEN RECEPTOR HAPLOTYPE WITH AROMATASE INHIBITOR-INDUCED PLATELET CHANGES. J. Miao, Y. Kreutz, A. T. Nguyen, S. M. Lemler, Z. Desta, D. A. Flockhart, Y. Jin; West China Hospital, Sichuan University, Chengdu, P.R. China; The division of clinical pharmacology of IUPUI, Indianapolis, IN BACKGROUND: Estrogen regulates platelet function via platelet estrogen receptors. Therefore, depletion of estrogen by aromatase inhibitors may increase cardiovascular risk. We tested the hypothesis that polymorphisms in estrogen receptor genes may influence platelet function after aromatase inhibitor treatment. METHODS: Postmenopausal women with estrogen receptor(ER) positive breast cancer were randomized to receive exemestane (25mg/ day) or letrozole (2.5 mg/day). Blood samples were collect before and 3 months after initiating treatment. Platelet counts were measured using a COULTER@AC.T10 Analyzer. Platelet aggregation was assessed by light transmission aggregometry after stimulation with adenosine diphosphate (ADP), arachidonic acid (AA), and collagen. Polymorphisms in ER genes: ESR1-03 (ERα PvuII), ESR1-39 (ERα XbaI) and ESR2-02 were determined by TaqManTM Assays. EAR1 haplotype was estimated using the PHASE II. RESULTS: Four common haplotypes [T-A (47.9%), C-G (34.8%), C-A (15.9%), T-G (1.0%)] were observed based on the ESR1-03 and ESR1-39 genotypes in 67 patients. While mean platelet count increased in the entire cohort, this increase was most evident in women who carried 1 or none T-A allele (21.62±59.98×106μl, P=0.011), or in subjects who carried at least 1 C-G allele (24.54±57.14×106μl, P=0.01). ESR2-02 genotypes were not associated with changes in platelet counts. Associations between ESR genotype and changes in platelet aggregations were evaluated in subjects who used consistently cyclooxygenase-1 inhibitors (n=47). No associations between polymorphisms in either ESR genes and changes in platelet aggregation were observed. CONCLUSION: ESR1 genetic polymorphisms may influence aromatase inhibitor-induced increases in platelet count and may alter the cardiovascular risk of these medications in selected patients as a result.