Exploration of resistance mechanisms for epidermal growth factor receptor-tyrosine kinase inhibitors based on plasma analysis by digital polymerase chain reaction and next-generation sequencing.
Exploration of resistance mechanisms for epidermal growth factor receptor-tyrosine kinase inhibitors based on plasma analysis by digital polymerase chain reaction and next-generation sequencing.
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DOI：
10.1111/cas.13820
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发表时间：
2018-12
期刊：
影响因子：
5.7
通讯作者：
Okamoto I
中科院分区：
文献类型：
--
作者：
Iwama E;Sakai K;Azuma K;Harada D;Nosaki K;Hotta K;Nishio M;Kurata T;Fukuhara T;Akamatsu H;Goto K;Shimose T;Kishimoto J;Nakanishi Y;Nishio K;Okamoto I
液体活检为检测癌症遗传学改变提供了组织活检的潜在替代方法，并已引入临床实践，用于检测非小细胞肺癌（NSCLC）患者表皮生长因子受体（EGFR）的酪氨酸激酶抑制剂（TKI）耐药T790 M突变。我们前瞻性地收集了25例携带EGFR激活突变且阿法替尼治疗失败的NSCLC患者的肿瘤和血浆样本。通过数字PCR（dPCR）和下一代测序（NGS）分析样本。相对于相应肿瘤样品的分析，通过dPCR检测血浆中的T790 M，其灵敏度和特异性分别为83.3%和70.0%，通过NGS检测T790 M，其灵敏度和特异性分别为50.0%和70.0%。基于T790 M等位基因数量与活化突变等位基因数量之比（T/A比）的T790 M定量将dPCR和NGS的血浆分析特异性提高至100%，而灵敏度未降低。尽管在肿瘤样本中发现了T790 M以外的几种阿法替尼耐药机制（包括NRAS或MET拷贝数增加），但在血浆中未检测到相应的遗传改变。在血浆和肿瘤样本中经常发现TP 53突变，大多数此类突变也在阿法替尼治疗前检出。新发TP 53突变的存在与无进展生存期降低相关。因此，血浆中T790 M的定量是确定肿瘤T790 M状态的临床相关方法。此外，与EGFR突变共存的遗传改变可影响EGFR‐TKI治疗的疗效。
Liquid biopsy offers a potential alternative to tissue biopsy for detection of genetic alterations in cancer, and it has been introduced into clinical practice to detect the tyrosine kinase inhibitor (TKI) resistance‐conferring T790M mutation of epidermal growth factor receptor (EGFR) in patients with non‐small‐cell lung cancer (NSCLC). We prospectively collected tumor and plasma samples from 25 NSCLC patients who harbored activating mutations of EGFR and experienced failure of treatment with afatinib. The samples were analyzed by digital PCR (dPCR) and next‐generation sequencing (NGS). T790M was detected in plasma with a respective sensitivity and specificity of 83.3% and 70.0% by dPCR and 50.0% and 70.0% by NGS relative to analysis of corresponding tumor samples. Quantitation of T790M based on the ratio of the number of T790M alleles to that of activating mutation alleles (T/A ratio) improved the specificity of plasma analysis to 100% for both dPCR and NGS without a reduction in sensitivity. Although several afatinib resistance mechanisms other than T790M—including copy number gain of NRAS or MET—were identified in tumor samples, the corresponding genetic alterations were not detected in plasma. TP53 mutations were frequently identified in plasma and tumor samples, with most such mutations also having been detected before afatinib treatment. The presence of de novo TP53 mutations was associated with reduced progression‐free survival. Quantitation of T790M in plasma is thus a clinically relevant approach to determine the T790M status of tumors. In addition, genetic alterations coexisting with EGFR mutations can affect the efficacy of EGFR‐TKI treatment.
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DOI：
10.1158/1078-0432.ccr-15-0584
发表时间：
2015-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Frenel JS;Carreira S;Goodall J;Roda D;Perez-Lopez R;Tunariu N;Riisnaes R;Miranda S;Figueiredo I;Nava-Rodrigues D;Smith A;Leux C;Garcia-Murillas I;Ferraldeschi R;Lorente D;Mateo J;Ong M;Yap TA;Banerji U;Gasi Tandefelt D;Turner N;Attard G;de Bono JS
通讯作者：
de Bono JS
影响因子：
17.1
作者：
Chmielecki J;Foo J;Oxnard GR;Hutchinson K;Ohashi K;Somwar R;Wang L;Amato KR;Arcila M;Sos ML;Socci ND;Viale A;de Stanchina E;Ginsberg MS;Thomas RK;Kris MG;Inoue A;Ladanyi M;Miller VA;Michor F;Pao W
通讯作者：
Pao W
影响因子：
30.8
作者：
Blakely CM;Watkins TBK;Wu W;Gini B;Chabon JJ;McCoach CE;McGranahan N;Wilson GA;Birkbak NJ;Olivas VR;Rotow J;Maynard A;Wang V;Gubens MA;Banks KC;Lanman RB;Caulin AF;St John J;Cordero AR;Giannikopoulos P;Simmons AD;Mack PC;Gandara DR;Husain H;Doebele RC;Riess JW;Diehn M;Swanton C;Bivona TG
通讯作者：
Bivona TG
影响因子：
16.6
作者：
Chabon JJ;Simmons AD;Lovejoy AF;Esfahani MS;Newman AM;Haringsma HJ;Kurtz DM;Stehr H;Scherer F;Karlovich CA;Harding TC;Durkin KA;Otterson GA;Purcell WT;Camidge DR;Goldman JW;Sequist LV;Piotrowska Z;Wakelee HA;Neal JW;Alizadeh AA;Diehn M
通讯作者：
Diehn M
影响因子：
51.1
作者：
Mitsudomi, Tetsuya;Morita, Satoshi;Fukuoka, Masahiro
通讯作者：
Fukuoka, Masahiro