For treating non-small cell lung cancer (NSCLC), liquid biopsy (LB) was analyzed using circulating-tumor DNA (ctDNA)/cell-free DNA (cfDNA) as an upcoming alternative to tissue profiling. LB is utilized for outcomes, including treatment decisions, detecting resistance mechanisms, and response prediction. A systematic and meta-analysis evaluation was conducted to study the impact of LB qualification on clinical outcomes of advanced NSCLC that have been molecularly altered and undergoing targeted therapies.
A systematic search was conducted across multiple databases, including Embase, MEDLINE, PubMed, and Cochrane Database, spanning the time period from January 1, 2000, to August 1, 2022. The main focus was on evaluating the primary outcomes of progression-free survival (PFS) and overall survival (OS). Secondary outcomes encompassed the objective response rate (ORR) and the sensitivity and specificity of the test employed. To account for age variations within the individual study populations, stratification was performed based on the mean age. Newcastle-Ottawa Scale (NOS) was used to assess the quality of the studies.
A comprehensive review of 27 studies involving 2,424 patients was conducted. Among these studies, 11 (n = 1,359) examined the association between baseline circulating tumor DNA (ctDNA) levels and clinical outcomes, while 16 (n = 1,649) investigated the correlation between dynamic changes in ctDNA levels post-treatment and outcomes such as progression-free survival (PFS) and overall survival (OS). Results revealed that patients who tested negative for baseline ctDNA exhibited significantly improved PFS (pooled hazard ratio [pHR] = 2.97; 95% CI: 1.92-4.85; I2 = 97.4%) and OS (pHR = 3.49; 95% CI: 1.73-6.95; I2 = 84.2%) compared to those who tested positive. Notably, Egger’s test indicated the presence of publication bias (p < 0.001). Patients who demonstrated early reduction or clearance of ctDNA levels following treatment demonstrated enhanced PFS (pHR = 3.78; 95% CI: 1.91-7.38; I2 = 98.4%) and OS (pHR = 2.20; 95% CI: 1.49-3.28; I2 = 90.6%) compared to those with persistently high or non-responsive ctDNA levels. When stratifying patients by age, PFS outcomes were comparable between two age groups: age ≤60 years (pHR = 2.92; 95% CI: 1.43-5.93; I2 = 98.3%) and age >60 years (pHR = 3.94; 95% CI: 1.54-10.07; I2 = 83.6%). In a sensitivity analysis based on study quality using the Newcastle-Ottawa Scale (NOS), only studies categorized as good quality demonstrated improved PFS (pHR = 3.67; 95% CI: 1.79-7.54; I2 = 91.6%), whereas poor or fair quality studies did not show significant improvement.
The comprehensive systematic review revealed compelling evidence supporting baseline negative ctDNA levels and early reduction in ctDNA following treatment as robust prognostic markers for progression-free survival (PFS) and overall survival (OS) in advanced NSCLC patients undergoing targeted therapies. Future randomized clinical trials should consider integrating serial ctDNA monitoring to establish its clinical utility in managing advanced NSCLC effectively.
