Association of Phosphorylated Epidermal Growth Factor Receptor with Survival in Patients with Locally Advanced Non-small Cell Lung Cancer Treated with Radiotherapy

INTRODUCTION: The epidermal growth factor receptor (EGFR) and its downstream effector kinases are thought to have important roles in lung cancer cell proliferation and response to treatment. METHODS: In a prospective cohort of patients with locally advanced non-small cell lung cancer (NSCLC) undergoing high-dose radiotherapy with or without chemotherapy, we examined by immunohistochemistry (IHC) the tumor levels of EGFR and phosphorylated/ activated-EGFR (P-EGFR), P-Erk, P-Akt, P-Stat3, and the cell cycle marker Ki67. We examined the relationships among marker expression, at the plasma membrane (M), cytoplasm (C) and nucleus, as well as the radiologic tumor response, and overall survival (OS). RESULTS: Fifty patients were recruited in this study. Their median survival was 18.3 months. No correlation was detected between total EGFR and P-EGFR levels in any subcellular compartment. M P-EGFR correlated positively with C P-Akt (p = 0.01). C P-Erk correlated negatively with radiologic response (p = 0.022), and on univariate regression analysis, this approached significance (p = 0.059). M and C P-EGFR correlated negatively with OS (p = 0.020), and on univariate analysis higher M P-EGFR predicted for poor OS (p = 0.001). Patients with high M P-EGFR levels had median survival of 7.8 months versus 17.7 months for patients with low M P-EGFR. CONCLUSIONS: Our results support a role of activated M P-EGFR, (but not total EGFR), as a predictor of OS in locally advanced-NSCLC. It is suggested that detailed evaluation of the subcellular distribution and activation state of EGFR and its downstream effectors is required to unravel the predictive value of these markers in NSCLC.