Analysis of epidermal growth factor receptor (EGFR) pathway in oropharyngeal squamous cell cancer patients in vivo (OSCC)

Abstract

5518 Background: EGFR is important target in OSCC. Dissecting the molecular events associated with activation of this pathway in OSCC patients in vivo presents an important challenge that has implications for the development and clinical testing of EGFR pathway inhibitors. Methods: The cohort was assembled from patients with primary OSCC treated at Yale with external beam radiotherapy (EBRT) or surgery and EBRT. Patients with metastases at presentation or those who failed to receive a full course of EBRT were excluded. Tumors were analyzed using a method of in situ quantitative protein expression analysis (AQUA) for expression of EGFR and downstream molecules (p-Akt, phosphatase PTEN and ERK2). AQUA uses molecular methods to define subcellular compartments. It then quantifies the amount of protein expressed within the compartment by co-localization. Primary study endpoints were local recurrence rate (LRR), disease-free survival (DFS) and overall survival (OS). Survival analysis was performed by Kaplan-Meier method with log-rank test for determining statistical significance. Correlation of protein expression levels with clinical and pathological variables was performed by chi-square test. Results: There were 84 OSCC patients with a median follow-up of 35 months in this cohort that met inclusion criteria. High tumor and nuclear EGFR expression were predictive for high LRR (p=0.0078 and p=0.027, respectively) and inferior DFS {p= 0.029 and 0.038, respectively}. Low tumor p-Akt expression was protective against LRR (p=0.012) and was predictive for better DFS (p=0.04). High PTEN expression was predictive for low LLR (p=0.005) and favorable DFS (p=0.001). In multivariate analysis adjusting for known prognostic variables these markers retained their prognostic significance. There was no association between ERK2 levels and outcome. There was no association between EGFR and p-Akt levels. To the contrary, PTEN and p-Akt levels were highly inversely correlated (p<0.005). Conclusions: The lack of association between EGFR and p-Akt suggests that Akt activation in OSCC is not entirely EGFR-dependent. Therefore, combination of EGFR and Akt inhibitors may be useful therapeutic strategy in OSCC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration HistoRx HistoRx HistoRx