Background/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-samplet-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.
背景/目的：目前尚无研究尝试确定初始脑转移速度（iBMV）的生物标志物，且将基因组数据与脑转移发展相关联的研究也较为有限。 方法：通过本部门数据库筛选出接受下一代测序（NGS）的非小细胞肺癌（NSCLC）患者。iBMV的计算方法为脑转移数量除以原发癌确诊至脑转移诊断的时间间隔。采用双样本t检验识别与iBMV具有统计学关联的基因突变（p<0.1）。对呈正相关的突变（"有害基因"）赋值为+1，负相关的突变（"保护性基因"）赋值为-1，通过计算这些值的总和定义iBMV风险评分为-1、0和1三个等级。采用皮尔逊相关性检验分析iBMV风险评分与计算所得iBMV的关联性，并通过竞争风险分析评估死亡作为脑转移发展的竞争风险。 结果：研究共纳入312例患者，其中218例（70%）发生脑转移。"有害基因"包括ARID1A、BRAF、CDK4、GNAQ、MLH1、MSH6、PALB2、RAD51D、RB1和TSC1；"保护性基因"包括ARAF、IDH1、MYC和PTPN11。iBMV风险评分为1、0和-1的患者发生脑转移的可能性分别为88%、61%和65%（p<0.01）。竞争风险分析显示，以死亡作为竞争风险时，iBMV风险评分1级与0级、1级与-1级之间在脑转移发生风险上存在显著关联。iBMV风险评分1、0、-1级患者的1年总生存率分别为72% vs. 84% vs. 85%，2年总生存率为46% vs. 69% vs. 70%（p<0.02）。 结论：通过无创液体活检建立NSCLC患者iBMV基因组特征具有可行性。iBMV风险评分阳性患者更易发生脑转移。该特征的验证有望形成可指导治疗决策与随访计划的生物标志物。
肿瘤(癌症)患者之家