Efficacy comparison of targeted next-generation sequencing in the identification of somatic mutations in circulating tumor DNA from different stages of lung cancer

Abstract

This study aims to assess the potential clinical application of targeted next generation sequencing (NGS)-based deep sequencing for the detection of clinically relevant mutations in circulating tumor DNA (ctDNA) obtained from non-small cell lung cancer (NSCLC) patients. Targeted deep sequencing was performed to identify High Confidence Somatic Variants (HCSVs) in matched tumor tissue DNA (tDNA) and ctDNA in 50 NSCLC patients. Our results demonstrated that NSCLC patients with Stage IV (61.5%) exhibited a higher concordance rate at the mutation level between plasma ctDNA and tDNA samples than patients with Stage I-III (14.5%). Moreover, it is noteworthy that the allele frequency of these detected HCSVs in ctDNA increased with the advance in tumor stage. Besides, using tDNA as a reference, the sensitivity of plasma ctDNA analyzed by deep NGS for actionable EGFR was much higher in patients with Stage IV (66.6%) than in patients with Stage I-III (7.7%). In conclusion, it appears that ctDNA NGS-based deep sequencing is a feasible approach to identify mutations in patients with Stage IV NSCLC. However, additional methods with higher sensitivity and specificity are needed to improve the successful application of this platform in the earlier stages of NSCLC.

Clinical validity and utility of circulating tumor DNA (ctDNA) testing in advanced non-small cell lung cancer (aNSCLC): a systematic literature review and meta-analysis

“…A total of 20 publications corresponding to 20 studies were selected for inclusion (Figure 1). Sixteen studies [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] reported CV only, one study 60 reported CU only, and one study 61 provided information on both CV and CU.…”

“…The majority of the included CV studies [45][46][47][49][50][51][53][54][55][56][57][58][59]61,62 used a prospective cohort design (83.3%, 15/18), and three studies 44,48,52 used retrospective medical record data. All studies evaluated ctDNA-based NGS technologies, with eleven studies [44][45][46][48][49][50][51][52]58,61,62 evaluating branded ctDNA tests and seven studies 47,[53][54][55][56][57]59 describing the ctDNA technologies without a specific brand name (Table 1).…”

“…TB was the reference standard in all included studies. Seven studies 45,46,50,51,55,56,61 included only untreated patients, five studies 44,47,48,53,58 included 24-92% of untreated patients, and in six studies 49,52,54,57,59,62 the proportion of untreated patients was unclear. Among studies reporting patient racial/ethnic information 46,51,52,61 , most patients were Caucasian (Table S3).…”

“…Sensitivity and specificity for detecting EGFR with ctDNA were reported in 14 studies. 46,47,[49][50][51][52][53][54][55][56][57][58]61,62 Study-specific sensitivity estimates varied between 0.56 and 0.83, and specificity estimates varied between 0.68 and 1 (Figure S2). The pooled sensitivity and specificity as estimated with the meta-analysis were 0.68 and 0.98 respectively, with a BAUC of 0.71 (95% CI, 0.68-0.73).…”

<p>Impact of Somatic Mutations in Non-Small-Cell Lung Cancer: A Retrospective Study of a Chinese Cohort</p>

“…7 Importantly, clinical evidence indicates that there is a substantial discordance in the genomic alterations and efficacy between the tumor tissue and blood ctDNA samples from the same patient. 8,9 Thus, it is important to carefully evaluate these different profiling methods in order to provide more information about whether ctDNA is useful for molecular diagnostics.…”