c-Met Amplification and Protein Expression in Non-Small Cell Lung Cancers.
Koji Tsuta, Akihiko Yoshida, Hitoshi Tsuda. National Cancer Center Hospital, Tsukiji, Tokyo, Japan
Background: c-Met is a transmembrane receptor tyrosine kinase that is occsionally amplified and/or expressed in patients with non-small cell lung cancer (NSCLC). Signaling through the hepatocyte growth factor/MET pathway has been shown to cause tumor growth, angiogenesis, and development of an invasive phenotype in several malignancies, including lung cancer. Here, we investigated the clinicopathologic characteristics of c-Met amplification and expression using dual-color chromogenic in situ hybridization (DISH) and a novel rabbit monoclonal antibody, respectively.
Design: For constructing tissue microarray, we used 2-mm tissue core specimens obtained from 906 patients (704 patients with adenocarcinoma [ADC]; 150, squamous cell carcinoma [SCC]; 43, sarcomatoid carcinoma [SaC]; and 9, large cell carcinoma [LCC]) who underwent surgical resection. The BenchMark® XT system (Ventana) was used for immunohistochemical analysis of c-Met (SP44; Ventana) and DISH (c-Met DNA Probe and Chromosome 7 Probe; Ventana). An immunohistochemically positive case was defined as strong complete homogeneous membrane staining in >30% of cells. We used the updated Colorado score (>40% of cells displaying >4 copies, c-Met to CEP7 ratio of >2, >4 spots gene, or ≥15 copies cluster in >10% of tumor cells) for c-Met amplification.
Results: The patient cohort included 332 women and 574 men. The mean follow-up time was 52.3 months, at which time, 631 patients were alive. c-Met expression was observed in 117/906 (12.9%) NSCLCs and was statistically correlated with the histological type (P < 0.0001) as follows: 108/704 (15.3%) ADCs, 1/150 (0.7%) SCCs, 8/43 (18.6%) SaCs, and 0/6 (0%) LCCs. c-Met amplification was observed in 92/844 (10.9%) NSCLCs and was statistically correlated with the histological type (P < 0.0001) as follows: 75/655 (11.5%) ADCs, 1/142 (0.7%) SCCs, 15/41 (36.6%) SaCs, and 1/6 (16.7%) LCCs. Half of c-Met amplified cases showed c–Met expression and that was statistically significant correlated (P < 0.0001). Analysis of all cases showed that c-Met expression did not correlate with overall survival (OS) and that c-Met amplification marginally correlated with OS (P = 0.077). However, when SCC cases were excluded, both univariate (P = 0.0021) and multivariate (P = 0.020) analyses revealed significant correlation between c-Met amplification and OS.
Conclusions: The subset of NSCLCs shows c-Met amplification. c-Met amplification/expression rate is significantly different among NSCLC histotypes, and it is particularly high ACC and SaC. In non-squamous NSCLC, c-Met amplification is significantly correlated with OS.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 257, Tuesday Afternoon