Longitudinal Cell-Free DNA Analysis in Patients with Small Cell Lung Cancer Reveals Dynamic Insights into Treatment Efficacy and Disease Relapse.
Longitudinal Cell-Free DNA Analysis in Patients with Small Cell Lung Cancer Reveals Dynamic Insights into Treatment Efficacy and Disease Relapse.
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DOI：
10.1016/j.jtho.2017.09.1951
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Lovly CM
中科院分区：
文献类型：
--
作者：
Almodovar K;Iams WT;Meador CB;Zhao Z;York S;Horn L;Yan Y;Hernandez J;Chen H;Shyr Y;Lim LP;Raymond CK;Lovly CM
小细胞肺癌（SCLC）患者预后不良，治疗选择有限。由于在患有这种疾病的患者中获得纵向肿瘤样本非常有限，我们选择将研究重点放在血浆游离DNA（cfDNA）的表征上，以快速，非侵入性地监测疾病负担。我们开发了定量cfDNA中的体细胞变体的液体活检测定。该检测试剂盒可检测SCLC中常见突变的1 - 4种基因的单核苷酸变异、拷贝数改变以及插入或缺失，包括TP 53、RB 1、BRAF、KIT、NOTCH 1 -4、PIK 3CA、PTEN、FGFR 1、MYC、MYCL 1和MYCN。在26个月的外周血采集过程中，我们检查了27名患者的140份血浆样本。我们在85%的患者样本中检测到疾病相关突变，突变等位基因频率（AF）范围为≤0.1%至84%。在我们的队列中，59%的患者患有广泛期疾病，最常见的突变发生在TP 53（70%）和RB 1（52%）。除了TP 53和RB 1的突变，我们还在我们的患者人群中检测到另外10个基因（PTEN、NOTCH 1 -4、MYC、MYCL 1、PIK 3CA、KIT和BRAF）的改变。观察到的AF和CNA与治疗反应密切相关。值得注意的是，在几种情况下，cfDNA的分析提供了常规成像之前疾病复发的证据。这些结果表明，液体活检很容易适用于SCLC患者，并可能提供改善的疾病负担监测，治疗反应的深度，并及时警告这种疾病的患者疾病复发。
Patients with small cell lung cancer (SCLC) have a poor prognosis and limited treatment options. Since access to longitudinal tumor samples is very limited in patients with this disease, we chose to focus our studies on the characterization of plasma cell-free DNA (cfDNA) for rapid, noninvasive monitoring of disease burden. We developed a liquid biopsy assay that quantifies somatic variants in cfDNA. The assay detects single nucleotide variants, copy number alterations, and insertions or deletions in 14 genes that are frequently mutated in SCLC, including TP53, RB1, BRAF, KIT, NOTCH1–4, PIK3CA, PTEN, FGFR1, MYC, MYCL1, and MYCN. Over 26 months of peripheral blood collection, we examined 140 plasma samples from 27 patients. We detected disease-associated mutations in 85% of patient samples with mutant allele frequencies (AFs) ranging from ≤0.1% to 84%. In our cohort, 59% of the patients had extensive stage disease, and the most common mutations occurred in TP53 (70%) and RB1 (52%). In addition to mutations in TP53 and RB1, we detected alterations in 10 additional genes in our patient population (PTEN, NOTCH1–4, MYC, MYCL1, PIK3CA, KIT, and BRAF). Observed AFs and CNAs tracked closely with treatment responses. Notably, in several cases analysis of cfDNA provided evidence of disease relapse before conventional imaging. These results suggest that liquid biopsies are readily applicable in patients with SCLC and can potentially provide improved monitoring of disease burden, depth of responses to treatment, and timely warning of disease relapse in patients with this disease.
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影响因子：
12.3
作者：
Kidess E;Jeffrey SS
通讯作者：
Jeffrey SS
影响因子：
6.4
作者：
Meder L;König K;Ozretić L;Schultheis AM;Ueckeroth F;Ade CP;Albus K;Boehm D;Rommerscheidt-Fuss U;Florin A;Buhl T;Hartmann W;Wolf J;Merkelbach-Bruse S;Eilers M;Perner S;Heukamp LC;Buettner R
通讯作者：
Buettner R
影响因子：
158.5
作者：
Aupérin, A;Arriagada, R;Aisner, J
通讯作者：
Aisner, J
影响因子：
51.1
作者：
Antonia, Scott J.;Lopez-Martin, Jose A.;Calvo, Emiliano
通讯作者：
Calvo, Emiliano
影响因子：
30.8
作者：
Peifer M;Fernández-Cuesta L;Sos ML;George J;Seidel D;Kasper LH;Plenker D;Leenders F;Sun R;Zander T;Menon R;Koker M;Dahmen I;Müller C;Di Cerbo V;Schildhaus HU;Altmüller J;Baessmann I;Becker C;de Wilde B;Vandesompele J;Böhm D;Ansén S;Gabler F;Wilkening I;Heynck S;Heuckmann JM;Lu X;Carter SL;Cibulskis K;Banerji S;Getz G;Park KS;Rauh D;Grütter C;Fischer M;Pasqualucci L;Wright G;Wainer Z;Russell P;Petersen I;Chen Y;Stoelben E;Ludwig C;Schnabel P;Hoffmann H;Muley T;Brockmann M;Engel-Riedel W;Muscarella LA;Fazio VM;Groen H;Timens W;Sietsma H;Thunnissen E;Smit E;Heideman DA;Snijders PJ;Cappuzzo F;Ligorio C;Damiani S;Field J;Solberg S;Brustugun OT;Lund-Iversen M;Sänger J;Clement JH;Soltermann A;Moch H;Weder W;Solomon B;Soria JC;Validire P;Besse B;Brambilla E;Brambilla C;Lantuejoul S;Lorimier P;Schneider PM;Hallek M;Pao W;Meyerson M;Sage J;Shendure J;Schneider R;Büttner R;Wolf J;Nürnberg P;Perner S;Heukamp LC;Brindle PK;Haas S;Thomas RK
通讯作者：
Thomas RK