Abstract
A sensitive and convenient method for detecting epidermal growth factor receptor (EGFR) T790M mutations from circulating tumor DNA (ctDNA) in advanced non–small cell lung cancer (NSCLC) patients with acquired EGFR‐TKI resistance would be desirable to direct patient sequential treatment strategy. A comparison of two platforms for detecting EGFR mutations in plasma ctDNA was undertaken. Plasma samples and tumor samples were collected from patients with acquired EGFR‐TKI resistance in Zhejiang Cancer Hospital from December 2014 to December 2015. Extracted ctDNA was analyzed using two platforms (Droplet Digital PCR and ARMS [dPCR]). A total of 108 patients were enrolled in this study. One hundred and eight patient plasma samples were detected by ddPCR and 75 were detected by ARMS. And 16 patients obtained tissue re‐biopsy, using ARMS assay for detecting EGFR T790M mutation. In all, 43.7% (47/108) had acquired T790M mutation by ddPCR. In 75 patient plasma samples, comparing ddPCR with ARMS, the rates of T790M mutation were 46.7% (35/75) and 25.3% (19/75) by ddPCR and ARMS, respectively. Of all, 16 patients both had tumor and plasma samples, the T790M mutation rates were 56.3% (9/16) by ARMS in tissue and 50.5% (8/16) by ddPCR in plasma ctDNA. The progression mode tended to gradual progression in T790M mutation patients (40.4%), but the T790M negative was inclined to the mode of dramatic progression (39.3%). The patients with T790M‐positive tumors had a longer time to disease progression after treatment with EGFR‐TKIs (median, 13.1 months vs. 10.8 months; P = 0.010) and overall survival (median, 35.3 months vs. 30.3 months; P = 0.214) compared with those with T790M‐negative patients. Our study demonstrates ddPCR assay may provide a highly sensitive method to detect EGFR T790M gene in plasma. And T790M‐positive patients have better clinical outcomes to EGFR‐TKIs than T790M‐negative patients.
Highlights
In recent years, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are clinically effective in patients with non–small cell lung cancer (NSCLC) harboring sensitizing EGFR mutations
Seventy patients were with deletion in exon 19 and 33 patients had mutation Droplet Digital PCR (ddPCR) and amplification refractory mutation system (ARMS) Detecting T790M in NSCLC
The secondary EGFR T790M mutation has been discovered in rebiopsy tumor tissue from about 50% of NSCLC patients with acquired resistance to EGFR- TKI therapy [26, 27]
Summary
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are clinically effective in patients with non–small cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. The T790M mutation in the EGFR gene is regarded as the most common cause of acquired resistance to EGFR-T KIs [11] This T790M resistant mutation was found in approximately 50% of rebiopsy samples obtained from patients with acquired resistance to EGFRTKI therapy [11]. This is challenging in clinical practice to obtain serial tumor rebiopsies. Detection rates of T790M ctDNA in plasma from NSCLC patients with acquired TKI resistance ranged from 30% to 50% using qualitative PCR-based assays [20,21,22,23]. Our study shows the clinical efficacy and sequential treatment strategy between EGFR T790M-positive and -negative patients
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