2517 - 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?

S. E. Glynn¹, C. M. Lanier¹, A. R. Choi¹, R. DAgostino Jr², M. Farris¹, M. Abdulhaleem³, Y. Wang⁴, M. Smith⁴, J. Ruiz⁵, T. Lycan⁵, W. Petty⁵, C. K. Cramer¹, S. B. Tatter⁶, A. Laxton⁶, J. White⁶, J. Su⁷, C. T. Whitlow⁸, F. Xing⁹, M. D. Chan¹, and C. A. Helis¹⁰; ¹Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, ²Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston -Salem, NC, ³Division of Hematology/Oncology, West Virginia University Cancer Institute, Morgantown, WV, ⁴Department of Molecular and Cellular Bioscience, Wake Forest University School of Medicine, Winston-Salem, NC, ⁵Department of Internal Medicine, Section of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, ⁶Department of Neurosurgery, Wake Forest University School of Medicine, Winston-Salem, NC, ⁷Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, ⁸Department of Diagnostic Radiology, Wake Forest University School of Medicine, Winston-Salem, NC, ⁹Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, ¹⁰Alexander T. Augusta Military Medical Center, Fort Belvoir, VA

Purpose/Objective(s): No prior studies have attempted to identify a biomarker for initial brain metastasis velocity (iBMV), with limited studies attempting to correlate genomic data to the development of brain metastases. Materials/

Methods: Patients with non-small cell lung cancer (NSCLC) were identified in our departmental database. Electronic medical records were used to identify patients for whom liquid biopsy-based next-generation sequencing (NGS) was available. The presence of brain metastasis (BM) was determined through review of magnetic resonance imaging of the brain, both at time of diagnosis and during follow-up. iBMV was calculated by dividing the number of BM by the interval of time between primary cancer and BM diagnosis. An iBMV of 300 was assigned to patients with BM at time of primary diagnosis and a score of 0 to patients who never developed BM during a minimum follow-up of 2 years. 2 sample t-testing was used to identify mutations statistically associated (p<0.1) with iBMV. A value of +1 was assigned to each mutation with a positive association with increased iBMV (“deleterious genes”), and a value of -1 to each mutation present with an inverse association (“protective genes”). The sum of these values was calculated to define iBMV risk scores, which ranged in values from -1 to +3. iBMV risk scores of +1, +2 and +3 were pooled into a single group and assigned a score of +1. A survival analysis model that allowed for competing risks was fit to examine the time to development of BM allowing for death as a competing risk.
Results: 312 patients met study criteria and were included in the analysis. 218 (70%) developed brain metastases. Genetic mutations in the NGS panel that were found to be associated with elevated iBMV (“deleterious genes”) included ARID1A, BRAF, CDK4, GNAQ, MLH1, MSH6, PALB2, RAD51D, RB1 and TSC1; those with an inverse association to iBMV (“protective genes”) included ARAF, IDH1, MYC, and PTPN11. Patients with a positive (n=95), neutral (n=197) and negative (n=20) iBMV risk score, had an 88%, 61% and 65% likelihood of developing BM, respectively (p<0.0001). A competing risk analysis found a statistically significant association between iBMV risk scores of 1 vs 0 and 1 vs -1, respectively, and the likelihood of developing BM using death as a competing risk (HR 2.35, 95% CI 1.77-3.11 and HR 2.57, 95% CI 1.57-4.20). Overall survival for patients with positive, neutral and negative iBMV risk scores was 72% vs 84% vs 85% and 46% vs 69% vs 70% at 1- and 2-years, respectively (p<0.023).
Conclusion: 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.