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502 Background: Data from preclinical studies and small numbers of IBC patients inPhase I clinical trials suggest that IBC may be particularly sensitive to the anti-tumor effects of lapatinib, an inhibitor of ErbB1/ErbB2 tyrosine kinases. EGF103009 was initiated to confirm and expand these initial observations and identify a tumor profile predicting for the sensitivity of IBC to lapatinib. Methods: Patients with relapsed/refractory IBC based on clinical criteria, were assigned to Cohort A (ErbB2 overexpressors: 2/3+ IHC/FISH+) or B (ErbB1 +/ErbB2 non-overexpressors) after analysis of a fresh tumor biopsy in a central reference lab. Patients received lapatinib daily (1500mg/d). Clinical response was documented at day 56 and in the case of CR/PR, confirmed on day 84 and every 8 weeks thereafter. Target lesions were assessed according to RECIST criteria and response in skin disease documented by digital photography. Tumor expression of ErbB2, p-ErbB2, ErbB1, p-ErbB3, IGF-IR, PTEN, ER/PR, E-cadherin, β-catenin, and Rho B/C was analyzed by quantitative IHC from a fresh, pre-treatment biopsy. Results: Of 34 patients enrolled, clinical response data is available from 22 patients of which 17 had biopsies analyzed at a reference lab and assigned to Cohorts A (N=11) and B (N=6). Eight of 11 patients (72%) in Cohort A had a clinical response (CR/PR) to lapatinib documented by RECIST, skin disease, or both. There were no responders in Cohort B. All responders (i) overexpressed ErbB2 (2/3+ IHC or FISH+), (ii) increased p-ErbB2 (2/3+), (iii) co-expressed IGF-IR, and (iv) expressed activated, p-ErbB3. PTEN status did not affect response to lapatinib. Toxicity was generally grade I/II skin and G.I. with one grade III cardiotoxicity necessitating withdrawal from study. Conclusions: ErbB2 overexpression but not ErbB1 expression alone, predicts for sensitivity to lapatinib in IBC. High ErbB2, p-ErbB2 and IGF-IR co-expression predict for clinical response to lapatinib monotherapy in patients with relapsed/refractory IBC, illustrating the importance of selecting patients based on biology rather than histology alone, to maximize the clinical efficacy of ErbB kinase inhibitors in breast carcinomas. [Table: see text]