title: Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients.
abstract: Background:Purpose of this study was to evaluate the contribution of the Extracellular-regulated protein kinase (ERK)-1/2 pathway to oncogenic signaling elicited by the tyrosine kinase receptor HER2 in Non-Small Cell Lung Cancer (NSCLC) and to assess the prognostic value of these oncoproteins in NSCLC patients.Methods:Immunohistochemistry was performed to determine expression and activation of HER2 and ERK1/2 (detected by phosphorylation of Y1248 and T202/Y204, respectively) using Tissue Micro Arrays (TMA) containing matched normal and neoplastic tissues from 132 NSCLC patients. Survival analysis was carried out using the Kaplan-Meier method. Univariate and multivariate analysis were used to evaluate the prognostic value of pERK1/2, pHER2 and a combination thereof with clinical-pathological parameters such as age, lymph node status (N), size (T), stage (TNM) and grade.Results:We found that HER2 was overexpressed in 33/120 (27%) and activated in 41/114 (36%) cases; ERK1/2 was activated in 44/102 (43%) cases. A direct association was found between pERK1/2 and pHER2 (23/41; p=0.038). In addition, patients positive for pERK1/2 and for both pHER2 and pERK1/2 showed significantly worse overall survival (OS) and disease-free survival (DFS) compared with negative patients. Univariate and multivariate analysis of patients' survival revealed that positivity for pHER2-pERK1/2 and for pERK1/2 alone were independent prognostic factors of poor survival in NSCLC patients. In particular, this association was significantly important for DFS in stage I+II patients.Conclusion:This study provides evidence that activated ERK1/2 and/or the combined activation of HER2 and ERK1/2 are good indicators of poor prognosis in NSCLC patients, not only in unselected patients but also in early stage disease.
authors.affiliation: Biogem scarl, Institute of Genetic Research, Ariano Irpino (AV), Italy.; Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Scrima
authors.affiliation: Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Zito Marino
authors.affiliation: Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Duarte Mendes
authors.initials: DM
authors.lastname: Oliveira
authors.affiliation: Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Marinaro
authors.affiliation: Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: La Mantia
authors.affiliation: Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Rocco
authors.affiliation: Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: De Marco
authors.affiliation: Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Malanga
authors.affiliation: Hospital "Monaldi-Cotugno-CTO", Naples, Italy.
authors.forename: Nicla
authors.initials: N
authors.lastname: De Rosa
authors.affiliation: Department of Medical and Surgical Sciences, University "Magna Graecia" Medical School, Catanzaro, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Rizzuto
authors.affiliation: Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Botti
authors.affiliation: Pathology Unit, Second University of Naples, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Franco
authors.affiliation: Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Zoppoli
authors.affiliation: Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viglietto
keywords: ERK1/2; HER2; NSCLC; Tissue Micro Array; survival.