In non-small cell lung cancer (NSCLC), HER family receptor signaling pathway abnormalities have been associated to pathogenesis, tumor prognosis and response to targeted therapy. However, there is controversial and limited information on the concurrent expression and clinical effect of HER ligands and receptors in large series of NSCLC. To better understand the correlations between HER ligands and receptors expression and their clinicopathological implications in NSCLC, we investigated the immunohistochemical (IHC) expression of HER ligands EGF, TGF-α, amphiregulin, and receptors EGFR, Her2/neu, p-EGFR (phosphorylated EGFR), p-Her3 (phosphorylated-Her3) in a series of NSCLCs placed in tissue microarrays (TMA). Correlations with clinicopathological characteristics and survival analyses were performed. In a subset of NSCLSs with adenocarcinoma histology, mutation status of EGFR, KRAS, HER2 and BRAF genes was correlated with IHC expression. Three hundred fifty-nine surgically resected tumors, 219 adenocarcinomas, 20 bronchioloalveolar carcinomas (BAC) and 120 squamous cell carcinomas, from patients with stage I-II-IIIA NSCLC were studied. A semi-quantitative analysis of nuclear, cytoplasmic and membranous localization expression was performed for each marker. Different patterns of correlation between ligands and receptors IHC expression were identified. Significant p-EGFR cytoplasmic and membranous expression was found in TGF-α (p<0.0001, p=0.008) and amphiregulin (p<0.0001, p=0.01) positive and not in EGF-positive cases. Lower expression of EGFR and nuclear p-EGFR was found in never smokers (p=0.01, p=0.01) and in adenocarcinoma and BAC histologies (p<0.0001, p=0.01). Her2/neu was overexpressed in adenocarcinoma and BAC (p=0.0005). Moderate/high levels of cytoplasmic and membranous p-EGFR were found in stage II-IIIA cases (p=0.001, p=0.04). The 14 (23.7%) EGFR-mutated cases expressed Her2/neu (p=0.03) and the frequency of mutations was higher in never smokers (p=0.03). The 10 (17.5%) KRAS-mutated cases showed decreased Her2/neu and nuclear p-EGFR expression (p=0.02, p=0.03). With a median follow up of 3.4 years and a median recurrence-free survival of 4.7 years, independent of the age and stage, TGF-α expression demonstrated a favorable impact on recurrence-free (p=0.001, RR=0.32, 95% CI 0.16, 0.64) and overall survival (p=0.004, RR=0.30, 95% CI 0.13, 0.69). The cases with p-EGFR cytoplasmic overexpression had reduced recurrence-free (p=0.01, RR=2.00, 95% CI 1.18, 3.38) and overall survival (p=0.001, RR=2.60, 95% CI 1.46, 4.65) compared to the ones with low and negative expression. In summary, TGF-α expression and p-EGFR overexpression have been shown to play a prognostic role (the first positive and the second negative) in stage I-IIIA NSCLC as indicators of recurrence-free and overall survival. Grant Support: P50CA097007 and W81XWH0520027.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]