C-MET Subcellular Localization in Patients with Malignant Mesothelioma in a Series of 157 Cases from the MESOPATH Center
G Levallet, N Le Stang, G Zalcman, F Galateau-Salle. CHU Caen, Caen, France
Background: C-Mesenchymal-Epithelial Transition factor (C-MET) receptor tyrosine kinase a critical pathway for lung carcinoma and malignant mesothelioma (MM) is activated by binding of Hepatocyte Growth Factor, inducing autophosphorylation. The resulting phospho-C-MET is rapidly translocated to the nucleus and concomitantly initiates intracellular signaling transduction pathways, that result in alteration of cell functions such as spreading and migration, leading to metastasis. It is therefore anticipated that c-met targeted therapy could result in efficient antiproliferative and anti-metastasis drugs. We aim to analyse the expression of C-MET and its activated form on our series.
Design: We investigated the correlation between immunostaining of both C-MET and its activated form, phospho-C-MET and overall survival (OS) in 174 MM specimens referred in our pathological center for expert pathological diagnosis certification. A semi-quantitative score was attributed taking account the number (0 to 100%) of stained cells and the intensity (0 to 3) of staining. Semi-quantitative scores (0 to 300) were studied as continuous variables, without any pre-determined cut-off.
Results: Among the 157 slides giving reliable immunostaining results, positive C-MET expression was found in 119 MM (75.8%), mostly in epithelioïd subtype (87%, p<0.0001). Among those 119 +ve C-MET specimens, 77 (64.7%) were also +ve for Phospho-C-MET. Both C-MET and Phospho-C-MET scoring were independent of patient gender (p= 0.98 and p=0.36 respectively) or age (p= 0.296 and p=0.62 respectively). Neither Phospho-C-MET scoring nor Phospho-C-MET localization discriminate patients subgroups with different median OS. Conversely, in patients with a C-MET scoring either higher than 100 or intensity higher than 1 when exclusively confined to plasma membrane, median OS was 25 months versus 13 months for other patients. Compared with patients having C-MET scoring lower than 100 (p=0.0012) or patients with C-MET cytoplasmic or nucleus localizations, the survival differences were significant either in univariate (p=0.02) or multivariate analysis (Cox model, p=0.043), adjusted for age.
Conclusions: Our results suggest that immunodetection of C-met receptor-tyrosine kinase specifically at plasma membrane, could be relevant to stratify a subgpoup of patients with worse prognosis. Whether those patients could benefit from c-met targeted therapies, remains to be established in future prospective clinical trials.
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 251, Tuesday Afternoon