Abstract
Circulating tumor DNA (ctDNA) in peripheral blood is a “liquid biopsy” that contains representative tumor information including gene mutations. Additionally, repeated ctDNA samples can be easily obtained to monitor response to treatment and disease progression, which may be especially valuable to lung cancer patients with tumors that cannot be easily biopsied or removed. To investigate the changes in ctDNA after surgical tumor resection, tumor and blood samples obtained before and after surgery were collected prospectively from 41 non-small lung cancer (NSCLC) patients. Somatic driver mutations in tumor DNA (tDNA) and pre- and post-op plasma ctDNA sample pairs were identified by targeted sequencing in several genes including EGFR, KRAS, and TP53 with an overall study concordance of 78.1% and sensitivity and specificity of 69.2% and 93.3%, respectively. Importantly, the frequency of 91.7% of ctDNA mutations decreased after surgery and these changes were observed as little as 2 days post-op. Moreover, the presence of ctDNA had a higher positive predictive value than that of six tumor biomarkers in current clinical use. This study demonstrates the use of targeted sequencing to reliably identify ctDNA changes in response to treatment, indicating a potential utility of this approach in the clinical management of NSCLC.
Highlights
CtDNA represents a small fraction of the total plasma DNA, and as most ctDNA exists as [160–200] bp fragments[18,19], sensitive detection methods are necessary
The focus of most research on ctDNA mutations in lung cancer patients has been limited to a few genes that are frequently mutated in lung cancers with clinical implications, namely EGFR and KRAS17,21–23
The aims of the present prospective study were to determine if a targeted sequencing approach could identify changes in plasma ctDNA mutation frequencies in blood samples obtained from non-small cell lung cancer (NSCLC) patients before and after surgical tumor resection, if the mutations identified in plasma ctDNA correspond to those in primary tDNA with high concordance, sensitivity, specificity, and positive predictive values (PPV), and if detecting plasma ctDNA is a more sensitive method than detecting certain clinically used tumor protein biomarkers
Summary
CtDNA represents a small fraction of the total plasma DNA, and as most ctDNA exists as [160–200] bp fragments[18,19], sensitive detection methods are necessary. Useful tools in the clinical characterization of plasma ctDNA from lung cancer patients may be the next-generation sequencing platforms as they have previously been demonstrated to have high sensitivity and can perform mutation screening in multiple genes simultaneously[24,25,26,27]. These instruments and individual assays are relatively affordable with rapid run times[28], making this targeted sequencing approach an attractive option for clinical use. The aims of the present prospective study were to determine if a targeted sequencing approach could identify changes in plasma ctDNA mutation frequencies in blood samples obtained from NSCLC patients before and after surgical tumor resection, if the mutations identified in plasma ctDNA correspond to those in primary tDNA with high concordance, sensitivity, specificity, and positive predictive values (PPV), and if detecting plasma ctDNA is a more sensitive method than detecting certain clinically used tumor protein biomarkers
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