外周血ctDNA与组织检测一致性在NSCLC EGFR-TKI耐药评估中的价值及诊疗方案优化

The value of consistency between peripheral blood ctDNA and tissue biopsy in resistance assessment of EGFR-TKI in NSCLC and optimization of diagnosis and treatment protocol

摘要

目的 明确外周血循环肿瘤DNA（circulating tumor DNA,ctDNA）与组织检测在非小细胞肺癌（non-small cell lung cancer,NSCLC）表皮生长因子受体-酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI）耐药评估中的一致性,对有高耐药风险患者基线采用联合治疗策略,基于一致性特征优化临床诊疗方案,并通过130例临床验证评估其有效性和安全性。方法 选取2021年12月—2024年6月中晚期表皮生长因子受体（epidermal growth factor receptor,EGFR）阳性NSCLC患者130例,采用随机数字表法分为优化组与传统组,各65例。传统组给予一代或三代EGFR-TKI单药治疗,定期评估疗效,疾病进展后行组织活检明确耐药机制并调整方案。优化组采用ctDNA动态监测、组织检测验证、个体化干预的闭环诊疗方案：第一步基线同步行组织与ctDNA检测,识别高耐药风险基因标签[①基线伴有除核心变异之外的其他EGFR变异;②基线伴有肿瘤蛋白53（tumor protein 53,TP53）、视网膜母细胞瘤蛋白1（retinoblastoma protein 1,RB1）、磷酸酶及张力蛋白同源物（phosphatase and tensin homolog,PTEN）等肿瘤抑癌基因突变;③基线伴有间质上皮细胞转化因子（mesenchymal-epithelial transition factor,MET）突变或扩增、成红细胞白血病病毒癌基因同源物2（erythroblastic leukemia viral oncogene homolog 2,ERBB2）扩增等旁路变异],据此调整初始治疗;第二步治疗中每2个月ctDNA动态监测基因变异,结合影像学评估分级预警耐药并及时经组织检测验证;第三步耐药后依据组织活检结果实施个体化干预,后续持续动态监测并调整方案,比较2组客观缓解率（objective response rate,ORR）、疾病控制率（disease control rate,DCR）、无进展生存期（progressionfree survival,PFS）、总生存期（overall survival,OS）及安全性相关指标。结果 ctDNA检测与组织检测的总体一致率为82.3%,Kappa值为0.642（P<0.001）,敏感度78.4%,特异度88.1%,阳性预测值92.1%,阴性预测值70.3%,整体一致性良好。其中EGFR通路核心变异（19外显子缺失、21外显子L858R、T790M）检测一致率为83.2%（Kappa=0.661,P<0.001）,旁路变异[MET扩增、表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）扩增等],检测一致率为78.5%（Kappa=0.598,P<0.001）,二者均呈良好一致性。疗效方面,优化组ORR（63.1%）、DCR（89.2%）显著高于传统组（41.5%、72.3%）,差异有统计学意义（P=0.018、P=0.013）;远期生存上,优化组中位PFS（11.2个月）、中位OS（24.8个月）显著长于传统组（7.1个月、18.3个月）,差异有统计学意义（P=0.004、P=0.007）。耐药相关指标中,优化组原发性耐药发生率（7.7%）显著低于传统组（20.0%）（P=0.042）,获得性耐药干预响应率（81.0%）显著高于传统组（56.8%）（P=0.031）。安全性方面,优化组不良反应发生率为33.8%,传统组为38.5%,2组比较差异无统计学意义（P=0.568）,且不良反应均以1~2级为主,无严重不良反应发生。结论 外周血ctDNA与组织检测在NSCLC的相关基因检测具有良好一致性。同时构建的ctDNA动态监测、组织检测验证、个体化干预的优化诊疗方案,通过基线风险分层和源头覆盖显著降低了原发性耐药,通过早期分子预警和精准靶向联合显著提升了获得性耐药干预响应率,最终转化为生存获益,且安全性良好。

Abstract

Objective To clarify the consistency between circulating tumor DNA （ctDNA） in peripheral blood and tissue biopsy in the evaluation of epidermal growth factor receptor-tyrosine kinase inhibitor （EGFR-TKI） resistance in non-small cell lung cancer （NSCLC）, to adopt a combination treatment strategy at baseline for patients with high risk of drug resistance, to optimize the clinical diagnosis and treatment protocol based on the consistency characteristics, and to evaluate its efficacy and safety through clinical validation of 130 patients. Methods A total of 130 patients with advanced epidermal growth factor receptor （EGFR）-positive NSCLC admitted from December 2021 to June 2024 were enrolled and divided into the optimized group （n=65） and the traditional group （n=65） by random number table method. The traditional group was given first-generation or third-generation EGFR-TKI monotherapy, with regular efficacy evaluation. After disease progression, tissue biopsy was performed to clarify the drug resistance mechanism and adjust the treatment protocol. The optimized group adopted a closed-loop diagnosis and treatment protocol consisting of dynamic ctDNA monitoring, tissue biopsy validation, and individualized intervention： The first step was to simultaneously perform tissue and ctDNA testing at baseline to identify genetic signatures associated with high risk of resistance, including [①the presence of additional EGFR variants beyond the core mutations at baseline; ②baseline mutations in tumor suppressor genes such as tumor protein 53 （TP53）, retinoblastoma protein 1 （RB1）, and phosphatase and tensin homolog （PTEN）; ③baseline presence of bypass alterations such as mesenchymal-epithelial transition factor （MET） mutation or amplification, and erythroblastic leukemia viral oncogene homolog 2 （ERBB2） amplification, based on which the initial treatment was adjusted]. The second step was to perform dynamic ctDNA monitoring for genetic variations every 2 months during treatment, combined with imaging assessment for graded early warning of drug resistance which was promptly verified by tissue biopsy. The third step was to implement individualized intervention based on tissue biopsy results after drug resistance, with continuous dynamic monitoring and treatment protocol adjustment thereafter. The objective response rate （ORR）, disease control rate （DCR）, progression-free survival （PFS）, overall survival （OS）, and safety-related indicators were compared between the two groups. Results The overall consistency rate between ctDNA testing and tissue biopsy was 82.3%, with a Kappa value of 0.642 （P<0.001）, a sensitivity of 78.4%, a specificity of 88.1%, a positive predictive value of 92.1%, and a negative predictive value of 70.3%, showing good overall consistency. Among them, the consistency rate for detecting EGFR pathway core variations （exon 19 deletion, exon 21 L858R mutation, T790M mutation） was 83.2% （Kappa=0.661, P<0.001）, and the consistency rate for detecting bypass variations [MET amplification, human epidermal growth factor receptor 2 （HER2） amplification] was 78.5% （Kappa=0.598, P<0.001）, both of which showed good consistency. In terms of efficacy, the ORR （63.1%） and DCR （89.2%） of the optimized group were significantly higher than those of the traditional group （41.5%, 72.3%） respectively, with significant differences （P=0.018, P=0.013）. In terms of long-term survival, the median PFS （11.2 months） and median OS （24.8 months） of the optimized group were significantly longer than those of the traditional group （7.1 months, 18.3 months） respectively, with significant differences （P=0.004, P=0.007）. Among drug resistance-related indicators, the incidence of primary drug resistance in the optimized group （7.7%） was significantly lower than that in the traditional group （20.0%） （P=0.042）, and the response rate to acquired drug resistance intervention in the optimized group （81.0%） was significantly higher than that in the traditional group （56.8%） （P=0.031）. In terms of safety, the incidence of adverse reactions was 33.8% in the optimized group and 38.5% in the traditional group, with no significant difference between the two groups （P=0.568）. Moreover, the adverse reactions were mainly grade 1―2, with no severe adverse reactions observed. Conclusion ctDNA testing in peripheral blood and tissue biopsy show good consistency in the detection of relevant genes in NSCLC. Meanwhile, the constructed optimized diagnosis and treatment protocol, which integrates dynamic ctDNA monitoring, tissue biopsy validation and individualized intervention, significantly reduces primary drug resistance through baseline risk stratification and source coverage, and significantly improves the response rate to acquired drug resistance intervention through early molecular warning and precise targeted combination therapy, ultimately translating into survival benefits with a good safety profile.

关键词

癌,非小细胞肺 / EGFR-TKI / 方案优化

Key words

carcinoma,non-small-cell lung / EGFR-TKI / optimization of the protocol