Glynn, Sarah E.Lanier, Claire M.Choi, Ariel R.D'Agostino, Ralph, Jr.Farris, MichaelAbdulhaleem, MohammedWang, YuezhuSmith, MargaretRuiz, JimmyLycan, ThomasPetty, William JeffreyCramer, Christina K.Tatter, Stephen B.Laxton, Adrian W.White, Jaclyn J.Su, JingWhitlow, Christopher T.Soto-Pantoja, David R.Xing, FeiJiang, YumingChan, MichaelHelis, Corbin A.2025-04-172025-04-172025-03-15Glynn SE, Lanier CM, Choi AR, et al. Genomic Signature for Initial Brain Metastasis Velocity (iBMV) in Non-Small-Cell Lung Cancer Patients: The Elusive Biomarker to Predict the Development of Brain Metastases?. Cancers (Basel). 2025;17(6):991. Published 2025 Mar 15. doi:10.3390/cancers17060991https://hdl.handle.net/1805/47099Background/Objectives: No prior studies have attempted to identify a biomarker for initial brain metastasis velocity (iBMV), with limited studies attempting to correlate genomic data with the development of brain metastases. Methods: Patients with non-small-cell lung cancer (NSCLC) who underwent next-generation sequencing (NGS) were identified in our departmental database. iBMV was calculated by dividing the number of BMs by the interval of time between primary cancer and BM diagnosis. Two-sample t-testing was used to identify mutations statistically associated with iBMV (p < 0.1). A value of +1 was assigned to each mutation with a positive association ("deleterious genes"), and a value of -1 to each with an inverse association ("protective genes"). The sum of these values was calculated to define iBMV risk scores of -1, 0 and 1. Pearson correlation test was used to determine the association between iBMV risk score and calculated iBMV, and a competing risk analysis assessed for death as a competing risk to the development of BMs. Results: A total of 312 patients were included in the analysis, 218 of whom (70%) developed brain metastases. "Deleterious genes" included ARID1A, BRAF, CDK4, GNAQ, MLH1, MSH6, PALB2, RAD51D, RB1 and TSC1; "protective genes" included ARAF, IDH1, MYC, and PTPN11. iBMV risk scores of 1, 0 and -1, predicted an 88%, 61% and 65% likelihood of developing a BM (p < 0.01). A competing risk analysis found a significant association between iBMV risk scores of 1 vs. 0 and 1 vs. -1, and the likelihood of developing a BM using death as a competing risk. Overall survival (OS) at 1 and 2 years for patients with iBMV risk scores of 1, 0 and -1 was 72% vs. 84% vs. 85% and 46% vs. 69% vs. 70% (p < 0.02). Conclusions: Development of a genomic signature for iBMV via non-invasive liquid biopsy appears feasible in NSCLC patients. Patients with a positive iBMV risk score were more likely to develop brain metastases. Validation of this signature could lead to a biomarker with the potential to guide treatment recommendations and surveillance schedules.en-USAttribution 4.0 InternationalBrain metastasesBrain surveillanceGenetic biomarkersNext-generation sequencingNon-small-cell lung cancerRadiotherapyArticle