Activation state (phosphorylated) EGFR and STAT3 as prognostic markers in resected non-small cell lung cancer (NSCLC)

Abstract

7090 Background: Epidermal Growth Factor Receptor (EGFR) has been extensively evaluated in NSCLC with approximately 70% of formalin-fixed paraffin-embedded (FFPE) specimens positive on immunohistochemistry (IHC). The total EGFR expression has failed to demonstrate prognostic importance. Activation of EGFR results in downstream STAT-3 activation. We hypothesized that activation (phosphorylated) state (pEGFR, pSTAT-3) rather than total mass protein will have prognostic value in NSCLC. Methods: 105 patients underwent lung resection for NSCLC at University Hospitals of Cleveland from 1998–2001 with FFPE samples evaluable for analysis. A database with patient characteristics (TNM stage, gender, age, time to recurrence, and survival) was established. pEGFR and pSTAT-3 antibodies were used for IHC. Specimens were divided into negative, 1+ (>5% of tumor cells showing + staining), 2+ or 3+ staining. Cox proportional hazard model was used for multivariate analysis. Results: Median age was 71years. 55% (58/105) were female. 63% had adenocarcinoma. Stage breakdown was as follows: stage I: 57%, stage II: 29%, stage III: 14%. Only 31% of the specimens were + for pEGFR (higher in squamous 44% compared to adenocarcinoma 28%). pSTAT-3 + staining was seen in 39% of samples. There was a significant positive correlation between pEGFR and pSTAT-3 (p=0.028). No such correlation was seen with pERK or pAKT. After controlling for age, sex, stage and pSTAT3, the hazard of dying for patients with + pEGFR was 1.64 times higher compared to negative pEGFR (p = 0.121). The estimated 5 year Kaplan-Meier probabilities of overall survival (OS) was 60.2% for pEGFR negative versus 46.9% for pEGFR positive patients. Conclusions: Although total EGFR is commonly expressed in NSCLC (∼70%), the activation form (pEGFR) is seen in only 1/3 of patients. There is a trend toward worse survival in early stage NSCLC that express pEGFR. pEGFR and pSTAT-3 were commonly co-expressed compatible with known signal transduction pathway in lung cancer. The use of activated rather than total mass receptors should be further evaluated as prognostic and predictive factors for response to EGFR-targeted therapies. (Supported by American Cancer Society) No significant financial relationships to disclose.