Abstract
Mutations in the epidermal growth factor receptor (EGFR) are associated with various solid tumors. This study aimed to compare two methods for the detection of EGFR mutations in circulating tumor DNA (ctDNA) from lung adenocarcinoma (LUAD) patients and to evaluate the clinical significance of EGFR mutations in ctDNA. In this prospective cohort study, the EGFR mutation status of 77 patients with stage IIIB or IV LUAD was first determined using lung cancer tissue. The amplification refractory mutation system (ARMS) and single allele base extension reaction combined with mass spectroscopy (SABER/MassARRAY) methods were also used to detect EGFR mutations in plasma ctDNA from these patients and then compared using the EGFR mutation status in lung cancer tissue as a standard. Furthermore, the relationship between the presence of EGFR mutations in ctDNA after receiving first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and survival was evaluated. The overall sensitivity and specificity for the detection of EGFR mutations in plasma ctDNA by ARMS and SABER/MassARRAY were 49.1% vs. 56% and 90% vs. 95%, respectively. The agreement level between these methods was very high, with a kappa-value of 0.88 (95% CI 0.77–0.99). Moreover, 43 of the patients who carried EGFR mutations also received first-line EGFR-TKI therapy. Notably, patients with EGFR mutations in plasma ctDNA had significantly shorter progression-free survival (9.0 months, 95% CI 7.0–11.8, vs. 15.0 months, 95% CI 11.7–28.2; p = 0.02) and overall survival (30.6 months, 95% CI 12.4–37.2, vs. 55.6 months, 95% CI 25.8–61.8; p = 0.03) compared to those without detectable EGFR mutations. The detection of EGFR mutations in plasma ctDNA is a promising, minimally invasive, and reliable alternative to tumor biopsy, and the presence of EGFR mutations in plasma ctDNA after first-line EGFR-TKI therapy is associated with poor prognosis.
Highlights
The epidermal growth factor receptor (EGFR) pathway plays an important role in the growth, proliferation, and survival of various solid tumors, including non-small cell lung cancer (NSCLC) [1].Cancers 2019, 11, 803; doi:10.3390/cancers11060803 www.mdpi.com/journal/cancersEGFR is, an important potential target for lung cancer therapy
In order to compare the efficiency of amplification refractory mutation system (ARMS) and SABER/MassARRAY in detecting EGFR mutations in plasma circulating tumor DNA (ctDNA), we first determined the EGFR mutation status of the 77 lung adenocarcinoma (LUAD) patients enrolled in our study using the ARMS method
Using DNA isolated from lung cancer tissue, EGFR mutations were detected in 57 patients, whereas the other 20 patients carried only wild-type (WT) EGFR alleles (Figure 1)
Summary
The epidermal growth factor receptor (EGFR) pathway plays an important role in the growth, proliferation, and survival of various solid tumors, including non-small cell lung cancer (NSCLC) [1].Cancers 2019, 11, 803; doi:10.3390/cancers11060803 www.mdpi.com/journal/cancersEGFR is, an important potential target for lung cancer therapy. Several clinical trials have demonstrated that, in NSCLC patients, exon 19 deletions and exon 21 missense mutations were associated with a favorable response to first-line treatment with EGFR-TKIs, including gefitinib [7], erlotinib [8], and afatinib [9], compared to conventional chemotherapy. Another missense mutation, T790M in exon 20, is associated with EGFR-TKI resistance and has been detected in 30%–50% of the patients that initially responded to EGFR-TKI therapy but eventually acquired EGFR-TKI resistance. Recent evidence indicates that osimertinib, a third-generation EGFR-TKI, can overcome T790M-mediated resistance to first- and second-generation EGFR-TKIs
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