Genomic Signature for Oligometastatic Disease in Non-Small Cell Lung Cancer Patients with Brain Metastases

Abstract

Biomarkers for oligometastatic disease remain elusive and few studies have attempted to correlate genomic data to the presence of true oligometastatic disease. Patients with non-small cell lung cancer (NSCLC) and brain metastases were identified in our departmental database. Electronic medical records were used to identify patients for whom liquid biopsy-based comprehensive genomic profiling (Guardant Health) was available. Oligometastatic disease was defined as patients having ≤5 non-brain metastases without diffuse involvement of a single organ. Widespread disease was any spread beyond oligometastatic. Fisher's exact tests were used to identify mutations statistically associated (p<0.1) with either oligometastatic or widespread extracranial disease. A score of +1 was assigned for every mutation present associated with oligometastatic disease, and -1 was assigned for mutations associated with widespread disease. Scores were summed for each patient to create a risk score for the likelihood of oligometastatic disease, with scores subsequently correlated to the likelihood of having oligometastatic disease vs widespread disease. For oligometastatic patients, a competing risk analysis was done to assess for cumulative incidence of oligometastatic progression accounting for the potential competing risks of widespread progression of extracranial disease or death. Cox regression was used to determine the association between oligometastatic risk score and oligometastatic progression. One hundred thirty patients met study criteria and were included in the analysis. 51 patients (39%) had oligometastatic disease. Genetic mutations included in the Guardant panel associated (p<0.1) with the presence of oligometastatic extracranial disease included ATM, JAK2, MAP2K2, and NTRK1; ARID1A and CCNE1 were associated with widespread disease. Patients with a positive, neutral and negative risk score for oligometastatic disease had a 78%, 41% and 11.5% likelihood of having oligometastatic disease, respectively (p<0.0001). Overall survival for patients with positive, neutral and negative risk scores for oligometastatic disease was 86% vs 82% vs 64% at 6 months (p = 0.2). The competing risk analysis found that the oligometastatic risk score was significantly associated with the likelihood of oligometastatic progression based on the Wald Chi-square test. Patients with positive, neutral and negative risk scores for oligometastatic disease had a cumulative incidence of oligometastatic progression of 77% vs 35% vs 33% at 6 months (p = 0.03 from competing risk model). Elucidation of a genomic signature for oligometastatic disease derived from non-invasive liquid biopsy appears feasible for NSCLC patients. Patients with the oligometastatic signature exhibited higher rates of early oligometastatic progression. Validation of this signature could lead to a biomarker that has the potential to direct local therapies in oligometastatic patients.