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  • Title: Genetic Profiling of Non-Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA.
    Author: Otsubo K, Sakai K, Takeshita M, Harada D, Azuma K, Ota K, Akamatsu H, Goto K, Horiike A, Kurata T, Nakagaki N, Nosaki K, Iwama E, Nakanishi Y, Nishio K, Okamoto I.
    Journal: Oncologist; 2019 Aug; 24(8):1022-1026. PubMed ID: 31023862.
    Abstract:
    Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually acquire resistance to these drugs. The identification of various resistance mechanisms for determination of subsequent treatment for these patients will require a method for simultaneous detection of multiple genetic alterations with high sensitivity. We performed cancer personalized profiling by deep sequencing (CAPP-Seq) with circulating tumor DNA obtained from patients with NSCLC who acquired resistance to first- or second-generation EGFR-TKIs. Plasma samples from 27 patients were analyzed, and 24 samples underwent CAPP-Seq successfully. Original activating EGFR mutations were detected in 23 patients, with the remaining patient showing MET amplification. With regard to known mechanisms of EGFR-TKI resistance, the T790M mutation of EGFR was detected in 17 of the 24 patients, MET amplification in 9 patients (6 of whom also harbored T790M), ERBB2 amplification in 2 patients (1 of whom also harbored T790M), and EGFR amplification in 4 patients (all of whom harbored T790M). Our results thus show that CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations in circulating tumor DNA obtained from patients with NSCLC at the time of disease progression during treatment with first- or second-generation EGFR-TKIs. Patients positive for the T790M mutation of EGFR were also found to constitute a molecularly heterogeneous population. KEY POINTS: CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations.The T790M mutation of EGFR is associated with amplification of MET, ERBB2, or EGFR in NSCLC patients resistant to EGFR-TKIs.T790M-positive patients are molecularly heterogeneous, and genetic alterations coexisting with T790M may differ between patients treated with first-generation or second-generation EGFR-TKIs. 摘要 接受表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 治疗的非小细胞肺癌 (NSCLC) 患者最终会对此类药物获得性耐药。为了确定这些患者的后续治疗，需要了解各种耐药机制，而这需要一种可以同时检测多种高灵敏度遗传变异情况的方法。研究从对第一代或第二代 EGFR‐TKI 获得性耐药的 NSCLC 患者中提取了循环肿瘤 DNA，然后通过深度测序 (CAPP‐Seq) 对肿瘤进行了个性化分析。分析 27 例患者血浆标本，其中 24 例最终进行了CAPP‐Seq 检测。23 例患者检测到 EGFR 原始激活突变，另一名患者出现 MET 扩增。关于已知的 EGFR‐TKI 耐药机制，在 24 例患者中，有 17 例出现了 EGFR 的 T790M 突变，9 例出现 MET 扩增(其中 6 例也存在 T790M)，2 例患者出现 ERBB2 扩增(其中 1 例还存在 T790M)，4 例患者出现 EGFR 扩增(所有患者都存在 T790M)。因此，研究结果表明，CAPP‐Seq 适用于临床样本，可用于确定疾病进展期间采用第一代或第二代 EGFR‐TKI 药物治疗的NSCLC患者体内循环肿瘤 DNA 中的多个体细胞突变。同时还发现，EGFR T790M 突变阳性患者存在分子异质性。 主要重点 • CAPP‐Seq 适用于临床样本，可用于确定多个体细胞突变。 • EGFR T790M 突变与对 EGFR‐TKI耐药的 NSCLC 患者出现 MET、ERBB2 或 EGFR扩增相关。 • T790M 阳性患者存在分子异质性，在采用第一代或第二代 EGFR‐TKI 治疗的患者中，与 T790M 共存的遗传变异可能有所不同。
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