The role of EGFR amplification in trastuzumab resistance: A correlative analysis of TBCRC003

528 Background: To identify mechanisms of resistance to trastuzumab (T), we developed and characterized T-resistant HER2+ breast cancer (BC) cell lines; these lines acquired EGFR amplification and were sensitive to both lapatinib (L) and gefitinib. To validate this finding, we prospectively assessed EGFR copy number in circulating tumor cells (CTC) from patients (pts) on TBCRC003, a multicenter clinical trial of L and T. Methods: Pts with measurable, HER2+ metastatic BC (MBC) were eligible. Cohort 1: No prior T, L, or chemotherapy (CT) for MBC, and > 1 yr from adjuvant T, if received. Cohort 2: 1-2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). CTC were collected using a modification of the CellSearch Profile Kit (Veridex) at baseline, 4wk, and progression. CTC were analyzed by FISH for EGFR and CEP7 and amplification was defined as EGFR/CEP7≥2. Results: EGFR amplification was present in CTC at baseline in 11/39...