Dynamics of circulating tumor DNA represented by the activating and resistant mutations in epidermal growth factor receptor tyrosine kinase inhibitor treatment.
Dynamics of circulating tumor DNA represented by the activating and resistant mutations in epidermal growth factor receptor tyrosine kinase inhibitor treatment.
复制标题
表皮生长因子受体酪氨酸激酶抑制剂治疗中的激活突变和耐药突变代表循环肿瘤 DNA 的动态。
DOI：
10.1111/cas.12860
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发表时间：
2016-03
期刊：
影响因子：
5.7
通讯作者：
Kato K
中科院分区：
文献类型：
--
作者：
Uchida J;Imamura F;Kukita Y;Oba S;Kumagai T;Nishino K;Inoue T;Kimura M;Kato K
循环肿瘤DNA(CtDNA)是肿瘤研究的一个新兴领域。对于肺癌，无创基因分型是EGFR的首要应用。激活突变代表所有癌细胞的ctDNA，耐T790M突变代表耐药细胞的ctDNA。我们使用大规模并行DNA测序仪进行深度测序，检测了EGFR突变的ctDNA动力学。我们在治疗过程中的不同时间采集了57例患者的190份血浆样本，并根据治疗情况进行了分类。外显子19缺失/L858R突变的检出率在表皮生长因子受体酪氨酸激酶抑制剂治疗开始时较高(P=0.001)，在疾病进展前被抑制，在疾病进展后升高(P=0.023)。T790M基因突变率在发病前较低，发病后升高(P=0.01)。疾病进展过程中的样本来自10名患者，显示ctDNA水平升高与疾病进展之间存在相关性。在6名符合条件的患者中，有4名患者的ctDNA水平因EGFR-TKI的启动而降低。在两名患者中，ctDNA动力学表明只存在T790M突变的癌细胞群体。在另一名患者中，T790M ctDNA代表了对细胞毒剂的反应与主要人群不同的细胞亚群。鉴于该病发病率较高，ctDNA可作为补充图像分析信息的临床参数。
Circulating tumor DNA (ctDNA) is an emerging field of cancer research. For lung cancer, non‐invasive genotyping of EGFR is the foremost application. The activating mutations represent the ctDNA from all cancer cells, and the T790M‐resistant mutation represents that from resistant cells. We examined the ctDNA dynamics of EGFR mutations by using deep sequencing with a massively parallel DNA sequencer. We obtained 190 plasma samples from 57 patients at various times during the treatment course and classified them according to treatment status. The mutation detection rate of exon 19 deletion/L858R in plasma was high at the initiation of treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI; P = 0.001), suppressed during EGFR‐TKI treatment before disease progression, and elevated after the onset of disease progression (P = 0.023). The mutation detection rate of T790M was low until the onset of disease progression and elevated thereafter (P = 0.01). Samples across the development of disease progression were obtained from 10 patients and showed a correlation between increased ctDNA level and disease progression. Decreased ctDNA level in response to the initiation of EGFR‐TKI was observed in 4 of 6 eligible patients. In two patients, the ctDNA dynamics suggested the presence of cancer cell populations only with the T790M mutation. In another patient, the T790M ctDNA represented cell subpopulations that respond to cytotoxic agents differently from the major population. Considering the high incidence, ctDNA could be a clinical parameter to complement information from image analyses.