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 Citation Format: Timothy F. Burns, Sanja Dacic, Maria A. Velez, Ashwin Somasundaram, Saveri Bhattacharya, Anish Chakka, Zachary A. Yochum, Jingxiao Jin, Ethan Miller, Brenda F. Kurland, Riyue Bao, Danielle P. Normolle, Sameer Agnihotri, Uma R. Chandran, Laura P. Stabile. MET alterations are enriched in lung adenocarcinoma brain metastases and define a distinct molecular and transcriptomic subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2218.