513 Background: Expression of the epidermal growth factor receptor (EGFR) in preclinical models of breast cancer is associated with increased proliferation and resistance to apoptosis. In clinical studies, EGFR has been inconsistently linked to poor outcome. We hypothesized that EGFR expression, when objectively and uniformly assessed, is associated with an aggressive biologic phenotype and resistance to systemic adjuvant therapy. Methods: In a database of 54,865 patients with breast cancer, EGFR status was known on 2,567. EGFR levels were measured centrally by ligand binding assay performed on frozen tissue. Tumors with ≥10 fmol/mg of cytosol protein were prospectively deemed positive. Clinical and biological features of EGFR positive and negative tumors were compared. Disease-free survival (DFS) and overall survival (OS) were assessed in systemically untreated patients (untreated patients, n=1068) and those who received hormonal and/or chemotherapy (treated patients, n=1256). Results: 475 out of 2,567 tumors (18.5%) were EGFR positive. Compared to EGFR negative tumors, EGFR positive tumors were more common in younger (<50 years, 40% vs 24% p<0.0001), premenopausal (20% vs 10%, p<0.0001), and black women (10% vs 6% p=0.005). EGFR expression was associated with larger tumors (64% vs 46%, p<0.0001), aneuploidy (68% vs 46%, p<0.0001), high S-phase fraction (53% vs 22%, p<0.0001), and nodal involvement (43% vs 37%, p=0.009). Co-expression of other biomarkers was also studied. EGFR positive tumors were more likely to be HER2 positive (26% vs 16%, p<0.0001), but less likely to be ER positive (60% vs 88%, p<0.0001), and PR positive (26% vs 65%, p<0.0001). In a multivariate analysis, EGFR expression independently correlated with worse DFS (HR=1.6, 95%CI=1.2–2.2, p=0.001) and OS (HR=1.7, 95% CI=1.2–2.4, p=0.001) in treated patients, but not in untreated patients. Conclusions: EGFR expression is more common in breast tumors in young and black women. It is associated with lower hormone receptor levels, higher proliferation, genomic instability, nodal involvement, and HER2 over-expression. It is correlated with significant resistance to adjuvant hormonal and chemotherapy. Blocking EGFR activity may help overcome this resistance in selected patients. No significant financial relationships to disclose.