Abstract：
Liquid biopsy has been widely researched for early diagnosis, prognostication and disease monitoring in lung cancer, but there is a need to investigate its clinical utility for early-stage non-small cell lung cancer (NSCLC).
We performed a meta-analysis and systematic review to evaluate diagnostic and prognostic values of liquid biopsy for early-stage NSCLC, regarding the common biomarkers, circulating tumor cells, circulating tumor DNA (ctDNA), methylation signatures, and microRNAs. Cochrane Library, PubMed, EMBASE databases, ClinicalTrials.gov, and reference lists were searched for eligible studies since inception to 17 May 2022. Sensitivity, specificity and area under the curve (AUC) were assessed for diagnostic values. Hazard ratio (HR) with a 95% confidence interval (CI) was extracted from the recurrence-free survival (RFS) and overall survival (OS) plots for prognostic analysis. Also, potential predictive values and treatment response evaluation were further investigated.
In this meta-analysis, there were 34 studies eligible for diagnostic assessment and 21 for prognostic analysis. The estimated diagnostic values of biomarkers for early-stage NSCLC with AUCs ranged from 0.84 to 0.87. The factors TNM stage I, T1 stage, N0 stage, adenocarcinoma, young age, and nonsmoking contributed to a lower tumor burden, with a median cell-free DNA concentration of 8.64 ng/ml. For prognostic analysis, the presence of molecular residual disease (MRD) detection was a strong predictor of disease relapse (RFS, HR, 4.95; 95% CI, 3.06-8.02; p < 0.001) and inferior OS (HR, 3.93; 95% CI, 1.97-7.83; p < 0.001), with average lead time of 179 ± 74 days between molecular recurrence and radiographic progression. Predictive values analysis showed adjuvant therapy significantly benefited the RFS of MRD + patients (HR, 0.27; p < 0.001), while an opposite tendency was detected for MRD - patients (HR, 1.51; p = 0.19). For treatment response evaluation, a strong correlation between pathological response and ctDNA clearance was detected, and both were associated with longer survival after neoadjuvant therapy.
In conclusion, our study indicated liquid biopsy could reliably facilitate more precision and effective management of early-stage NSCLC. Improvement of liquid biopsy techniques and detection approaches and platforms is still needed, and higher-quality trials are required to provide more rigorous evidence prior to their routine clinical application.
We performed a meta-analysis and systematic review to evaluate diagnostic and prognostic values of liquid biopsy for early-stage NSCLC, regarding the common biomarkers, circulating tumor cells, circulating tumor DNA (ctDNA), methylation signatures, and microRNAs. Cochrane Library, PubMed, EMBASE databases, ClinicalTrials.gov, and reference lists were searched for eligible studies since inception to 17 May 2022. Sensitivity, specificity and area under the curve (AUC) were assessed for diagnostic values. Hazard ratio (HR) with a 95% confidence interval (CI) was extracted from the recurrence-free survival (RFS) and overall survival (OS) plots for prognostic analysis. Also, potential predictive values and treatment response evaluation were further investigated.
In this meta-analysis, there were 34 studies eligible for diagnostic assessment and 21 for prognostic analysis. The estimated diagnostic values of biomarkers for early-stage NSCLC with AUCs ranged from 0.84 to 0.87. The factors TNM stage I, T1 stage, N0 stage, adenocarcinoma, young age, and nonsmoking contributed to a lower tumor burden, with a median cell-free DNA concentration of 8.64 ng/ml. For prognostic analysis, the presence of molecular residual disease (MRD) detection was a strong predictor of disease relapse (RFS, HR, 4.95; 95% CI, 3.06-8.02; p < 0.001) and inferior OS (HR, 3.93; 95% CI, 1.97-7.83; p < 0.001), with average lead time of 179 ± 74 days between molecular recurrence and radiographic progression. Predictive values analysis showed adjuvant therapy significantly benefited the RFS of MRD + patients (HR, 0.27; p < 0.001), while an opposite tendency was detected for MRD - patients (HR, 1.51; p = 0.19). For treatment response evaluation, a strong correlation between pathological response and ctDNA clearance was detected, and both were associated with longer survival after neoadjuvant therapy.
In conclusion, our study indicated liquid biopsy could reliably facilitate more precision and effective management of early-stage NSCLC. Improvement of liquid biopsy techniques and detection approaches and platforms is still needed, and higher-quality trials are required to provide more rigorous evidence prior to their routine clinical application.
摘要：
背景：液体活检已被广泛研究用于早期诊断，肺癌的预后和疾病监测，但有必要研究其在早期非小细胞肺癌（NSCLC）中的临床应用。
方法：我们进行了荟萃分析和系统评价，以评估液体活检对早期NSCLC的诊断和预后价值。关于常见的生物标志物，循环肿瘤细胞，循环肿瘤DNA（ctDNA），甲基化签名，和microRNA。科克伦图书馆,PubMed,EMBASE数据库,ClinicalTrials.gov,我们检索了自开始至2022年5月17日的符合条件的研究的参考文献列表.灵敏度,评估诊断价值的特异性和曲线下面积(AUC).从无复发生存期（RFS）和总生存期（OS）图中提取具有95％置信区间（CI）的风险比（HR）用于预后分析。此外，进一步研究了潜在预测值和治疗反应评估.
结果：在本荟萃分析中，有34项研究符合诊断性评估条件,21项研究符合预后分析条件.具有AUC的早期NSCLC的生物标志物的估计诊断值范围为0.84至0.87。因素TNM阶段I，T1级,N0阶段，腺癌,年轻的年龄,不吸烟有助于降低肿瘤负担，中位无细胞DNA浓度为8.64ng/ml。对于预后分析，分子残留病(MRD)检测的存在是疾病复发的强预测因子(RFS，HR,4.95；95%CI，3.06-8.02；p<0.001）和较差的OS（HR，3.93；95%CI，1.97-7.83；p<0.001），分子复发和影像学进展之间的平均前导时间为179±74天。预测值分析显示，辅助治疗显著受益于MRD+患者的RFS(HR，0.27；p<0.001)，而MRD患者检测到相反的趋势(HR，1.51；p=0.19）。对于治疗反应评估，检测到病理反应和ctDNA清除之间的强相关性，两者均与新辅助治疗后的生存期延长相关.
结论：结论：我们的研究表明,液体活检可以可靠地促进早期NSCLC的更精确和有效的治疗.仍然需要改进液体活检技术以及检测方法和平台，在常规临床应用之前，需要更高质量的试验来提供更严格的证据。
方法：我们进行了荟萃分析和系统评价，以评估液体活检对早期NSCLC的诊断和预后价值。关于常见的生物标志物，循环肿瘤细胞，循环肿瘤DNA（ctDNA），甲基化签名，和microRNA。科克伦图书馆,PubMed,EMBASE数据库,ClinicalTrials.gov,我们检索了自开始至2022年5月17日的符合条件的研究的参考文献列表.灵敏度,评估诊断价值的特异性和曲线下面积(AUC).从无复发生存期（RFS）和总生存期（OS）图中提取具有95％置信区间（CI）的风险比（HR）用于预后分析。此外，进一步研究了潜在预测值和治疗反应评估.
结果：在本荟萃分析中，有34项研究符合诊断性评估条件,21项研究符合预后分析条件.具有AUC的早期NSCLC的生物标志物的估计诊断值范围为0.84至0.87。因素TNM阶段I，T1级,N0阶段，腺癌,年轻的年龄,不吸烟有助于降低肿瘤负担，中位无细胞DNA浓度为8.64ng/ml。对于预后分析，分子残留病(MRD)检测的存在是疾病复发的强预测因子(RFS，HR,4.95；95%CI，3.06-8.02；p<0.001）和较差的OS（HR，3.93；95%CI，1.97-7.83；p<0.001），分子复发和影像学进展之间的平均前导时间为179±74天。预测值分析显示，辅助治疗显著受益于MRD+患者的RFS(HR，0.27；p<0.001)，而MRD患者检测到相反的趋势(HR，1.51；p=0.19）。对于治疗反应评估，检测到病理反应和ctDNA清除之间的强相关性，两者均与新辅助治疗后的生存期延长相关.
结论：结论：我们的研究表明,液体活检可以可靠地促进早期NSCLC的更精确和有效的治疗.仍然需要改进液体活检技术以及检测方法和平台，在常规临床应用之前，需要更高质量的试验来提供更严格的证据。
