Genomic analysis and clinical correlations of non-small cell lung cancer (NSCLC) brain metastasis (BM).
Authors: Skakodub Anna , Tringale Kathryn Ries , Walch Henry S. , Vasudevan Harish , Eichholz Jordan , Kelly Daniel W. , Moss Nelson S. , Yu Kenny Kwok Hei , Li Bob T. , Mueller Boris , Yang Jonathan T. , Beal Kathryn , Imber Brandon S. , Gomez Daniel Richard , Schultz Nikolaus , Pike Luke Roy George 
Published: June 2022

2008 Background: Approximately 30% of patients with NSCLC present with BM, and up to 50% of patients ultimately develop BM. While modern NSCLC-directed agents yield excellent systemic response, most patients require focal treatment. Prior reports of BM genomics have been limited by low numbers, missing clinical data, and lack of matched specimens. Here, we report the largest cohort to date of molecularly profiled NSCLC BM samples with clinical correlates. Methods: Clinical data and outcomes for 244 patients with NSCLC and resected BM were identified, and BM samples were assessed with one of four versions (341, 410, 468, 505) of MSK-IMPACT, a custom FDA-approved next generation sequencing-based tumor 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. Results: Median age was 66 years (range 31-91), and median follow-up was 2.3 years (IQR 1.3-4.3). Adenocarcinoma was the most common histology (183, 78%). Half presented with a single BM, and 121 (51%) patients were treatment naive. Most (197, 83%) received adjuvant stereotactic radiosurgery (SRS) to the resection site and 28% received SRS to additional BM. After resection, 130 (55.1%) had CNS progression, often regional (54, 42%). SRS to new BMs (32%) was the most common salvage treatment. Median overall survival from BM diagnosis was 2.5 years (95%CI 2.1-3.2). Median CNS-progression-free survival was 1.2 years (95%CI 0.9-1.4). The most frequently altered genes in BM samples were TP53 (72%), CDKN2A (34%), KRAS (31%), KEAP1 (26%), and EGFR (21%). CDKN2A was more frequently altered in BM samples when compared to NSCLC primary samples (34% vs 14%, p = 0.003, q = 0.034). With regard to overrepresented gene sets, cell cycle pathway alterations were enriched in BM (56% vs 31%, p = 0.002, q = 0.022). BM samples had a significantly higher fraction of genome altered relative to the primary samples (p < 0.0001, q < 0.0001). After grouping patients based on type of CNS progression, we found that EGFR alterations were enriched in patients with leptomeningeal failures when compared to both patients without progression (42% vs 18%, p = 0.03, q = 0.93) and to patients with either local or regional progression (42% vs 19%, p = 0.03, q = 0.9). Conclusions: In the largest-ever assembled cohort of genomically-profiled NSCLC BM, we found significant enrichment for CDKN2A and cell cycle pathway alterations in BM compared to extracranial disease, as well as a higher fraction of genome altered, in BMs compared to matched primary tumor controls. We also observed EGFR alteration enrichment in patients who develop LMD, suggesting specific biologic underpinnings driving patterns of CNS failure. Further investigation into the role of systemic therapy and time course will elucidate potential mechanisms for CNS failure in patients with NSCLC.