Abstract
We evaluated the use of droplet digital PCR (ddPCR) to detect plasma cell-free DNA (cfDNA) epidermal growth factor receptor (EGFR) mutations in advanced non-small cell lung cancer (NSCLC) patients. Compared with tumor-tissue-based detection, the sensitivity of ddPCR for detecting plasma cfDNA tyrosine kinase inhibitor (TKI)-sensitizing EGFR mutations was 61.3%, the specificity was 96.7%, and the consistency rate was 81.4% (?=0.605, 95% confidence interval: 0.501-0.706, p <0.0001). The sensitivity declined from 82.6% to 46.7% with decreasing cfDNA inputs (p=0.028). The plasma cfDNA concentration correlated with gender (males vs.females =11.69 ng/mL vs. 9.508 ng/mL; p=0.044), EGFR mutation status (tumor-tissue EGFR mutation-positive (EGFR M+) vs. EGFR mutation-negative (EGFR M-) = 9.61 ng/mL vs. 12.82 ng/mL; p =0.049) and specimen collection time (=2 years vs. >2 years=13.83 ng/mL vs. 6.575 ng/mL; p <0.001), and was greater in tumor-tissue EGFR M+ / plasma EGFR M+ patients than in tumor-tissue EGFR M+/plasma EGFR M- patients (11.61 vs. 7.73 ng/mL, respectively; p=0.003). Thus total cfDNA input crucially influences the sensitivity of plasma cfDNA EGFR mutation testing with ddPCR. Such analysis could be an effective supplemental test for advanced NSCLC patients.
Highlights
Lung cancer has become the leading cause of cancer death [1]
Our study revealed that the sensitivity of droplet digital PCR (ddPCR) was 61.3% when tumor-tissue Epidermal growth factor receptor (EGFR) mutation was used as the gold standard
While ddPCR can accurately determine the quantity and quality of cell-free DNA (cfDNA), this study revealed for the first time that the cfDNA concentration/input is a crucial factor affecting the sensitivity of cfDNA EGFR mutation tests
Summary
It is well known that targeted therapy is an important treatment strategy for advanced non-small cell lung cancer (NSCLC) patients. Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the most important targeted therapies for NSCLC, given their high clinical efficacy in NSCLC patients with TKIsensitizing EGFR mutations [2,3,4,5]. Tumor tissue samples are not always available for EGFR mutation detection in clinical practice. Rigorous clinical practice often requires the safe, effective, and dynamic real-time monitoring of the EGFR mutation status, and liquid biopsy may serve as a source of specimens [6, 7]. Plasma specimens can be obtained with minimal trauma, and can be monitored dynamically in real time [10, 11]. Many methods have been used to detect cfDNA EGFR mutations [11,12,13,14,15,16], and their sensitivities have ranged from 35.6% to 81.8% for EGFR mutation detection in cfDNA compared with tumor tissue
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