Epidermal growth factor receptor, HER-2/neu and related pathways in lung adenocarcinomas with bronchioloalveolar features

Lung adenocarcinomas with bronchioalveolar features (ABAF), formerly called bronchioloalveolar cancers (BAC), constitute a distinct clinical, radiological and pathological entity among lung malignancies. Epidermal growth factor receptor (EGFR) and to a less extent, HER-2/neu, are known to be overexpressed in non-small lung cancers, but their exact status in ABAF is not well-documented. Stimulation of these two receptors results in the initiation of two major cascades, namely phosphatidylinositol 3-kinase (PI-3K) and Ras-dependent pathways. We have therefore studied the expressions of EGFR, HER-2/neu as well as phosphorylated AKT (pAKT) and phosphorylated extracellular-signal regulated kinase (ERK), which are key molecules in these two pathways, in 15 ABAF patients. EGFR was found to be overexpressed in 9 of 15 patients (60%). HER-2/neu overexpression was detected in 6 of the 14 tumors tested (43%). pAKT and pERK were both found to be positive in 13 of 15 patients (87%). Six of the seven tumors with mucinous pattern were negative for EGFR, while all of the other eight cases were positive (P = 0.001). Mucinous tumors were also less likely than non-mucinous tumors to overexpress HER-2/neu (17% versus 63%, respectively). These findings suggest that ABAF, particularly those with non-mucinous histology, commonly harbors EGFR and HER-2/neu overexpression. PI-3K and Ras-dependant pathways that lie downstream are generally activated, even in the absence of EGFR and/or HER-2/neu overexpression. ABAF may be a particularly promising candidate for EGFR-targeted strategies and this possibility merits extensive evaluation in clinical trials.