Targeted therapy, represented by epidermal growth factor receptor-targeting tyrosine kinase inhibitors (EGFR-TKIs) , has significantly prolonged the survival time of patients with EGFR mutations with relatively mild adverse reactions, and become a prior choice for advanced non-small cell lung cancer (NSCLC) patients with driver genes. Dynamic monitoring of treatment progress and gene mutations in NSCLC patients by means of gene detection will help to provide a more effective, long-term and stable individualized targeted therapy for such patients.

To compare the gene mutations before and after the progression of NSCLC, and to analyze the regularities of gene mutations dynamically monitored and related prognostic value in NSCLC patients.

NSCLC outpatients and inpatients undergoing genetic tests were selected from Department of Integrated Medicine and Lung Cancer Center of China-Japan Friendship Hospital from 2007 to 2021. Their data were collected and used to establish a lung cancer genes testing database. Tissue samples or peripheral blood circulating tumor DNA (ctDNA) before and after progression were obtained for full-coding area detection of lung cancer genes, and the number of gene mutations and testing results were recorded. We divided enrolled patients into gene clearance group and non-gene clearance group, and compared baseline characteristics and survival status between the groups.

A total of 217 cases were enrolled and followed until their clinical endpoint. The total changes in gene mutations in tissue samples before and after the disease progression were as follows: the number of patients with wild type increased from 70 (32.3%) to 95 (43.8%) , the number of patients with mutant type decreased from 147 (67.7%) to 122 (56.2%) , the number of patients with 19DEL mutation increased from 64 (29.5%) to 67 (19.8%) , the number of patients with 21 L858R mutations decreased from 74 (34.1%) to 64 (24.0%) , the number of patients with T790M mutations increased from 2 (0.9%) to 45 (20.7%) , and the number of those with rare mutations or concomitant rare mutations such as TP53 increased from 20 (9.2%) to 84 (38.7%) . Gene clearance group (n=67) and non-gene clearance group (n=150) had significant differences in clinical features except the history of lung disease (P=0.032) and the history of targeted therapy (P=0.001) . The median progression-free survival (PFS) of patients in the two groups was 9.8 months and 11.8 months, respectively, with no significant difference〔HR=0.89, 95%CI (0.66, 1.20) , P=0.310〕. The median PFS of 134 patients with advanced NSCLC in two groups was 8.1 months and 9.8 months, respectively, with no significant difference〔HR=0.83, 95%CI (0.58, 1.19) , P=0.359〕. The median overall survival (OS) of patients in two groups was 50.5 months and 28.5 months, respectively, with statistically significant difference〔HR=0.56, 95%CI (0.41, 0.78) , P<0.000 1〕. The median OS of 134 patients with advanced NSCLC in two groups were 45.5 months and 24.9 months, respectively, showing statistically significant difference〔HR=0.55, 95%CI (0.37, 0.81) , P=0.000 2〕.

The gene mutation status before and after disease progression for patients with NSCLC changed dynamically. After the progression, the proportion of wild type increased significantly compared with mutant type. The proportion of classical mutation decreased, but the proportion of concomitant mutations increased. Patients with 19DEL mutations developed a higher rate of T790M after disease progression. Monitoring gene clearance could not help to predict a PFS, but the gene clearance type predicted better OS benefits. Dynamic monitoring of changes in gene status could help guide treatment promptly for optimal clinical benefits.

以表皮生长因子酪氨酸激酶抑制剂（EGFR-TKIs）为代表的靶向治疗显著延长了EGFR突变患者的生存期，且不良反应相对较轻，已成为晚期驱动基因阳性非小细胞肺癌（NSCLC）患者的首选治疗方式。以基因检测的方式动态监测NSCLC患者治疗进展及进展后的基因突变规律，将有助于为患者提供更切实有效、更长期稳定的个体化靶向治疗指导。

比较NSCLC疾病进展前后的基因突变特征差异，分析动态监测肺癌患者基因规律及其预后意义。

本研究收集2007—2021年于中日友好医院中西医结合肿瘤内科及肺癌中心门诊或住院进行基因检测的NSCLC患者数据，建立肺癌基因检测数据库，记录患者进展前后基因检测的数目和结果。根据基因清除情况分为基因清除型组与非基因清除型组，比较两组的基线特征、生存情况。

筛选入组并成功随访至临床终点患者共217例。进展前后组织样本总基因突变分布，野生型由70例（32.3%）变化为95例（43.8%），突变型由147例（67.7%）到122例（56.2%），19DEL突变由64例（29.5%）到67例（19.8%），21 L858R突变由74例（34.1%）到64例（24.0%），T790M突变由2例（0.9%）到45例（20.7%），TP53等少见突变或合并少见突变由20例（9.2%）到84例（38.7%）。217例NSCLC患者基因清除型67例，非基因清除型150例。基因清除型组与非基因清除型组患者除肺病史（P=0.032）及靶向治疗史（P=0.001）比较，差异有统计学意义。基因清除型组与非基因清除型组中位无进展生存期（PFS）分别为9.8个月和11.8个月，差异无统计学意义〔HR=0.89，95%CI（0.66，1.20），P=0.310〕。134例晚期患者基因清除型与非基因清除型中位PFS分别为8.1个月和9.8个月，差异无统计学意义〔HR=0.83，95%CI（0.58，1.19），P=0.359〕。基因清除型组与非基因清除型组中位总生存期（OS）分别为50.5个月和28.5个月，差异有统计学意义〔HR=0.56，95%CI（0.41，0.78），P<0.000 1〕。134例晚期NSCLC患者基因清除型与非基因清除型中位OS分别为45.5个月和24.9个月，差异有统计学意义〔HR=0.55，95%CI（0.37，0.81），P=0.000 2〕。

NSCLC患者疾病进展前后基因突变状态是动态变化的，肺癌进展后患者野生型较突变型显著上升，且经典突变比例下降；伴随突变比例上升。19DEL突变患者进展后出现T790M比例更高。监测基因清除对PFS的预测能力不足，但基因清除型可能预示更长的OS获益。动态监测基因状态的变化有助于及时指导治疗，以达到最佳临床获益。