2594 - Genomic Signature to Predict Neurologic Death in Non-Small Cell Lung Cancer Patients
Presenter(s)
S. E. Glynn1, C. M. Lanier1, A. R. Choi1, R. D'Agostino 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. Helis1,10; 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 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): Brain metastases (BM) are common in patients with non-small cell lung cancer (NSCLC). However, with modern therapy many patients who develop BM do not pass away from their neurologic disease. Due to limited data and biomarker information, predicting which patients are at increased risk of dying as a result of their BM remains a challenge.
Materials/Methods: Patients with NSCLC who underwent next-generation sequencing (NGS) were identified in our departmental database. Neurologic death, defined as death with progressive neurologic dysfunction or severe neurologic disability, was determined by medical record review. Proportional hazards regression models considering death from non-neurologic causes as a competing risk were used to identify mutations statistically associated with the occurrence of neurologic death (p<0.1). A value of +1 was assigned to each mutation with a positive association with neurologic death (“deleterious genes”), and a value of -1 to each mutation with an inverse association (“protective genes”). The sum of these values was calculated to define a 3-level risk score (high, moderate and low risk), with respective scores of >0, 0 and <0. A competing risk proportional hazards regression model with non-neurologic death as a competing risk, was then used to assess the association between 3-level risk score and neurologic death, and to calculate hazard ratios (HR) predicting neurologic death between risk groups.
Results: 307 patients were included in the analysis. Neurologic death occurred in 63 (21%) patients. Genetic mutations in the NGS panel found to be associated with neurologic death (“deleterious genes”) included CDK4, PALB2, GNAQ, STK11 and RAF1; those with an inverse association to neurologic death (“protective genes”) included CDK12, JAK2, TERT, CCND1, CHEK2, EZH2, HRAS, IDH2, JAK3, MAPK1, ARAF, IDH1, VHL, NPM1, GNA11, MPL and MAP2K1. Patients in high and moderate risk groups had a significantly increased risk of neurologic death when compared to those in the low-risk group, with respective HRs of 20.2 (95% CI 4.7-87.1) and 6.8 (95% CI 1.6-28.5), (p<0.0001). A competing risk analysis found a significant association between risk groups and the likelihood of neurologic death using non-neurologic death as a competing risk. The cumulative incidence of neurologic death in high, moderate and low risk groups was 49.0%, 19.7% and 3.1% with 3-year survival rates of 56.2%, 82.8%, and 96.3%, respectively (p<0.0001).
Conclusion: Development of a genomic signature to predict neurologic death via non-invasive liquid biopsy appears feasible in NSCLC patients. Patients with high and moderate risk scores were more likely to experience neurologic death. Validation of this signature could lead to a biomarker to guide treatment recommendations, with patients at high risk of neurologic death considered for more aggressive local therapy and CNS-penetrant systemic therapy regimens.