1050 Background: Endocrine therapy for ER+ breast cancer is effective and relatively nontoxic, but is limited by de novo and acquired resistance. Preclinical studies suggest that complete ER blockade along with inhibition of co-expressed growth factor receptors enhances endocrine response and overcomes resistance. Methods: We conducted a phase II trial of combined anastrazole and fulvestrant with gefitinib, an EGFR tyrosine kinase inhibitor, as intial therapy in postmenopausal women with locoregional or metastatic ER+ breast cancer. A tumor core biopsy was done at baseline and after 3 weeks. Patients received treatment for 4 months. Surgery was then offered if the tumor was operable. Primary endpoint was clinical response as defined by RECIST criteria and secondary endpoints were safety/tolerability, complete pathologic response rate (pCR), and biomarker analysis. Planned sample size was 60 patients, but the study closed after 15 patients were enrolled because of poor accrual. Results: Median age at diagnosis was 67 years. Median clinical tumor size was 7 cm and 4 patients had metastases. 11 patients (73%) had ER+/PgR+ tumors and 4 (27%) had ER+/PgR- disease. 3 patients withdraw from the study before response was assessed. Of the12 remaining patients there were 2 complete responses (17%), 5 partial responses (42%), 5 with stable disease (42%), and 2 (17%) with progressive disease. Of the 7 patients who had surgery at 4 months, none had pCR. Most common adverse events were rash in 4 patients, Diarrhea in 4, joint symptoms in 3, and abnormal LFT’s in 3. All adverse events were reversible. Biomarkers, including arrays and Ki67, are pending and will be presented at the meeting. Conclusions: Complete ER blockade using anastrazole and fulvestrant with EGFR inhibition is well-tolerated and has activity in this cohort of patients with relatively advanced ER+ breast cancer. Despite its documented benefit and low toxicity, accrual to neoadjuvant endocrine therapy studies remains poor in the US, largely because of physician hesitance to refer patients for non-chemotherapy studies. More effort is needed to increase physician awareness about the value of endocrine therapy, and to increase accrual to trials that address the question of endocrine resistance. [Table: see text]