Abstract 6063: Genomic characterization of non-small cell lung cancer (NSCLC) brain metastasis (BM) patients identifies novel alterations associated with tropisms and disease progression

Abstract Intro: Half of all patients with NSCLC develop BM during their clinical course. While modern NSCLC-directed agents yield excellent systemic response, most patients require focal BM treatment. Prior reports of BM genomics have been limited by low numbers and a lack of matched specimens. Here, we report the largest cohort to date of molecularly-profiled NSCLC BM samples with comprehensive clinical follow-up. Methods: Clinical data and outcomes for 244 patients with NSCLC and resected BM were identified. Samples were assessed using MSK-IMPACT, a custom tumor-normal next generation sequencing assay. 51 (20.9%) patients had matched primary site tissue, and 44 (18%) patients had matched tissue from another metastatic site or CSF. Genomic alterations were filtered for driver variants using OncoKB. Publicly available genomic data for NSCLC primary samples was used for comparison against the primary samples from our BM cohort. Results: The most frequently altered genes in BM tumors were TP53 (72%), CDKN2A (34%), KRAS (31%), KEAP1 (26%), and EGFR (21%). CDKN2A was more frequently altered in BM samples compared to NSCLC primary lesions (34% vs 14%, p = 0.003). Additionally, cell cycle pathway alterations were enriched in BM (56% vs 31%, p = 0.002). BM samples also had a significantly higher fraction of genome altered (FGA) relative to primary samples (p < 0.0001). We then compared primary samples from BM patients against primary samples from metastatic NSCLC patients without BM and primary samples from non-metastatic NSCLC patients. We found an enrichment of alterations in TP53 (68.6% vs 27.7%, p < 0.0001), NKX2-1 (11.4% vs 1.7%, p = 0.006), SMARCA4 (11.4% vs 2.1%, p = 0.01), RB1 (11.4% vs 1.7%, p = 0.006), and FOXA1 (11.4% vs 0.9%, p = 0.001) in the primary samples from BM patients compared to non-metastatic patients. Next, we grouped patients based on CNS progression patterns and found that EGFR alterations were enriched in patients with leptomeningeal progression when compared to patients without progression (42% vs 18%, p = 0.03). Conclusions: In our cohort of molecularly-profiled NSCLC BM, we found an enrichment of cell cycle pathway alterations and a higher FGA in BMs compared to their primary tumor controls. Additionally, several genes were enriched in the primary tissue of patients that developed BM compared to primary tissue from non-metastatic patients. EGFR alterations were enriched in patients who develop leptomeningeal disease (LMD). Our work herein characterizes the genomic profiles of NSCLC patients with BM and identifies specific genes enriched in the primary tissue of BM patients compared to primary tissue from both non-BM metastatic patients and non-metastatic patients. Finally, our finding that EGFR alterations were enriched in patients with LMD suggests specific biologic underpinnings driving patterns of CNS progression. Citation Format: Henry Walch, Anna Skakodub, Kathryn R. Tringale, Harish N. Vasudevan, Jordan Eichholz, Daniel W. Kelly, Emily Lebow, Nelson S. Moss, Kenny Kwok Hei Yu, Bob T. Li, Boris Mueller, Atif Khan, Yao Yu, Simon Powell, Jorge S. Reis-Filho, Brandon S. Imber, Pedram Razavi, Daniel R. Gomez, Nikolaus Schultz, Luke R. Pike. Genomic characterization of non-small cell lung cancer (NSCLC) brain metastasis (BM) patients identifies novel alterations associated with tropisms and disease progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6063.