Abstract 4905: Comprehensive characterization of MET alterations in a large cohort of 610 advanced non-small cell lung cancer patients
Authors: Esteban Cristina Aguado , Teixidó Cristina , Román Ruth , Capitán Ana María Gimenez , Cabrera Carlos , García Mireia , Casas Clara D. Mayo De Las , Arcocha Ainara , Rodriguez Sonia , Reyes Roxana , Marín Elba , Rosado Ana Perez , Karachaliou Niki , Prat Aleix , Rosell Rafael , Martinez-Bueno Alejandro , Molina-Vila Miguel Angel , Reguart Noemi 
Published: August 2019

Abstract
Background: A variety of alterations in MET have been described in advanced non-small cell lung cancer (NSCLC) patients, including gene amplification, protein overexpression, splicing variants and point mutations. MET alterations are receiving increasing attention as targets in precision medicine, and several clinical trials of anti-MET agents are ongoing in NSCLC.
Methods: A cohort of 610 patients with stage IIIb-IV NSCLC from two institutions was retrospectively analyzed for MET alterations by next-generation sequencing (NGS) (Ion Torrent PGM® or GeneReader®), nCounter, reverse transcriptase polymerase chain reaction (RT-PCR) or immunohistochemistry (IHC) during a 2-year period. Patients positive for MET amplification by NGS or MET overexpression by nCounter and/or IHC were submitted to fluorescence in situ hybridization (FISH). Representative patients positive for MET exon 14-skipping (METΔex14) mutations by nCounter and/or RT-PCR were confirmed by sequencing exons 13-15 of the METgene.
Results: Overall, MET alterations were found in 116/610 patients (19%). Some patients had ≥2 MET aberrations. The most frequent finding was MET overexpression (58/333; 17.6%), followed by METΔex14 (31/610; 5.1%) and MET point mutations (3/129; 2.3%). Regarding MET amplification, it was found in 24/157 patients (15.3%). MET positivity by IHC (3+, &gt;50%) showed a 90.8% concordance with MET mRNA overexpression by nCounter, with a 0.768 Cohen’s kappa (confidence interval, CI 95% 0.575-0.961). A moderate agreement between RT-PCR and nCounter was found for METΔex14 (Cohen’s kappa 0.629; CI 95% 0.434-0.825). METamplification by FISH was found in the subset of MET-overexpressing patients with the highest mRNA levels by nCounter. Interestingly, a patient with a concomitant EGFR mutation and MET overexpression derived two years clinical benefit from crizotinib.
Conclusions: MET aberrations are present in 19% of advanced NSCLC patients and represent one of the most frequent targetable alterations in this malignancy. A comprehensive testing of MET alterations in advanced NSCLC patients, including NGS and nCounter techniques, is needed to identify a broader number of patients’ candidates for targeted therapies.
Citation Format: Cristina Aguado Esteban, Cristina Teixidó, Ruth Román, Ana María Gimenez Capitán, Carlos Cabrera, Mireia García, Clara D. Mayo De Las Casas, Ainara Arcocha, Sonia Rodriguez, Roxana Reyes, Elba Marín, Ana Perez Rosado, Niki Karachaliou, Aleix Prat, Rafael Rosell, Alejandro Martinez-Bueno, Miguel Angel Molina-Vila, Noemi Reguart. Comprehensive characterization of MET alterations in a large cohort of 610 advanced non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4905.