Abstract 2218: MET alterations are enriched in lung adenocarcinoma brain metastases and define a distinct molecular and transcriptomic subtype

Lung cancer has the highest incidence of metastases to the brain, with up to 40% of non-small cell lung cancer (NSCLC) patients developing brain metastases (BM). There is a critical need to develop novel treatments to effectively prevent and treat NSCLC BM. MET is a receptor tyrosine kinase that upon binding hepatocyte growth factor (HGF), mediates proliferation, epithelial-mesenchymal transition (EMT), invasion, angiogenesis and metastasis. Recent studies have suggested that the MET pathway may be a significant determinant of metastatic potential to the brain. We evaluated 125 lung adenocarcinoma (LUAD) BM and 477 primary LUAD for MET amplification (amp) by FISH (MET/CEP > 2) as well as other molecular alterations using targeted next-generation sequencing in a subset of LUAD BM (N=74) and primary LUAD (N=171) samples, including 13 paired primary and brain sets. We identified a significant enrichment of MET amp in LUAD BM (19%) compared to primary LUAD (3%; p5) was present in 6.5% of BM compared to 1.3% of primary LUAD cases (p=0.0006). In matched samples, BM-specific MET amp was observed. Non-exon 14 skipping MET activating mutations were also significantly more frequent in LUAD BM (22%) compared to primary LUAD (12%; p=0.05), as well as TP53, KRAS, SMAD4, APC, RB1, RET, ABL1, ALK, and VHL variants (adj. p values