Longitudinal monitoring by next-generation sequencing of plasma cell-free DNA in ALK rearranged NSCLC patients treated with ALK tyrosine kinase inhibitors.
Longitudinal monitoring by next-generation sequencing of plasma cell-free DNA in ALK rearranged NSCLC patients treated with ALK tyrosine kinase inhibitors.
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ALK重排非小细胞肺癌（ALK+ NSCLC）患者不可避免地获得对ALK抑制剂的耐药性。纵向监测无细胞血浆DNA （cfDNA）下一代测序（NGS）可以预测ALK+ NSCLC对酪氨酸激酶抑制剂（TKI）治疗的反应和耐药性。通过标准组织检测确定并计划接受TKI治疗的ALK+ NSCLC患者被前瞻性招募。在治疗前、治疗后2个月和进展时收集血浆进行cfDNA - NGS分析，Guardant 360。在入选的92例患者中，69例基线样本（75%）检测到循环肿瘤DNA (ctDNA)， 43例ALK融合（62.3%）和2例未融合的ALK突变（2.8%）。2例患者服用西瑞替尼后出现ALK -耐药突变；G1202R和共发生的G1202R和T1151R。8例患者接受克唑替尼治疗后出现ALK耐药突变；L1196M (n = 5), G1269A (n = 1), G1202R (n = 1)，以及共发生的F1174L， G1202R和G1269A （n = 1）。基线时ctDNA缺失与更长的无进展生存期（PFS；中位36.1个月vs 11.4个月，p = 0.0049）和总生存期（OS；未达到vs 29.3个月，p = 0.0200）显著相关。2个月时ctDNA清除率（n = 29）与无清除率的患者（n = 22）相比，PFS（25.4个月vs. 11.6个月，p = 0.0012）和OS（未达到vs. 26.1个月，p = 0.0307）显著延长。基线时同时发生TP53改变和ALK融合的患者（n = 16）的PFS（7.28个月vs 13.0个月，p = 0.0307）明显短于无TP53改变的患者（n = 25）。cfDNA - NGS有助于检测ALK融合和耐药突变，评估预后，并监测ALK - TKI治疗的ALK+ NSCLC基因组改变的动态变化。为了研究cfDNA - NGS的纵向监测是否可以预测ALK+ NSCLC对TKI治疗的反应和耐药性，我们前瞻性地招募了92例经标准组织检测确定并计划接受TKI治疗的ALK+晚期NSCLC患者。cfDNA的NGS不仅可用于检测ALK融合和耐药突变，还可用于评估ALK+ NSCLC经ALK‐TKI治疗后的预后和监测基因组改变的动态变化。
Patients with ALK‐rearranged non‐small cell lung cancer (ALK+ NSCLC) inevitably acquire resistance to ALK inhibitors. Longitudinal monitoring of cell‐free plasma DNA (cfDNA) next‐generation sequencing (NGS) could predict the response and resistance to tyrosine kinase inhibitor (TKI) therapy in ALK+ NSCLC. Patients with ALK+ NSCLC determined by standard tissue testing and planned to undergo TKI therapy were prospectively recruited. Plasma was collected at pretreatment, 2 months‐post therapy, and at progression for cfDNA‐NGS analysis, Guardant 360. Among 92 patients enrolled, circulating tumor DNA (ctDNA) was detected in 69 baseline samples (75%): 43 ALK fusions (62.3%) and two ALK mutations without fusion (2.8%). Two patients showed ALK‐resistance mutations after ceritinib; G1202R, and co‐occurring G1202R and T1151R. Eight patients developed ALK resistance mutations after crizotinib therapy; L1196M (n = 5), G1269A (n = 1), G1202R (n = 1), and co‐occurring F1174L, G1202R, and G1269A (n = 1). Absence of ctDNA at baseline was significantly associated with longer progression‐free survival (PFS; median 36.1 vs. 11.4 months, p = 0.0049) and overall survival (OS; not reached vs. 29.3 months, p = 0.0200). ctDNA clearance at 2 months (n = 29) was associated with significantly longer PFS (25.4 vs. 11.6 months, p = 0.0012) and OS (not reached vs. 26.1 months, p = 0.0307) than those without clearance (n = 22). Patients with co‐occurring TP53 alterations and ALK fusions at baseline (n = 16) showed significantly shorter PFS (7.28 vs. 13.0 months, p = 0.0307) than those without TP53 alterations (n = 25). cfDNA‐NGS facilitates detection of ALK fusions and resistance mutations, assessment of prognosis, and monitoring dynamic changes of genomic alterations in ALK+ NSCLC treated with ALK‐TKI. To investigate whether longitudinal monitoring of cfDNA‐NGS could predict the response and resistance of TKI therapy in ALK+ NSCLC, we recruited prospectively 92 patients with ALK+ advanced NSCLC determined by standard tissue testing and planned for TKI therapy. NGS of cfDNA is useful not only for the detection of ALK fusions and resistance mutations, but also for assessing prognosis and monitoring the dynamic changes of genomic alterations in ALK+ NSCLC treated with ALK‐TKI.
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影响因子：
28.5
作者：
Hu J;Cao J;Topatana W;Juengpanich S;Li S;Zhang B;Shen J;Cai L;Cai X;Chen M
通讯作者：
Chen M
DOI：
10.1200/jco.20.02341
发表时间：
2021-05-10
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Sallman DA;DeZern AE;Garcia-Manero G;Steensma DP;Roboz GJ;Sekeres MA;Cluzeau T;Sweet KL;McLemore A;McGraw KL;Puskas J;Zhang L;Yao J;Mo Q;Nardelli L;Al Ali NH;Padron E;Korbel G;Attar EC;Kantarjian HM;Lancet JE;Fenaux P;List AF;Komrokji RS
通讯作者：
Komrokji RS
DOI：
10.1158/1078-0432.ccr-17-2588
发表时间：
2018-06-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
McCoach CE;Blakely CM;Banks KC;Levy B;Chue BM;Raymond VM;Le AT;Lee CE;Diaz J;Waqar SN;Purcell WT;Aisner DL;Davies KD;Lanman RB;Shaw AT;Doebele RC
通讯作者：
Doebele RC
影响因子：
7.3
作者：
Alidousty, Christina;Baar, Till;Schultheis, Anne Maria
通讯作者：
Schultheis, Anne Maria
影响因子：
158.5
作者：
Peters, Solange;Camidge, D. Ross;Mok, Tony
通讯作者：
Mok, Tony