Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC.
Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC.
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cfDNA 的突变格局识别了与晚期 NSCLC 患者对一线铂类双联化疗的治疗反应相关的独特分子特征
DOI：
10.7150/thno.21687
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发表时间：
2017
期刊：
影响因子：
12.4
通讯作者：
Hirsch FR
中科院分区：
文献类型：
--
作者：
Jiang T;Li X;Wang J;Su C;Han W;Zhao C;Wu F;Gao G;Li W;Chen X;Li J;Zhou F;Zhao J;Cai W;Zhang H;Du B;Zhang J;Ren S;Zhou C;Yu H;Hirsch FR
研究目的：研究循环无细胞DNA（cfDNA）突变谱是否可以预测和动态监测晚期非小细胞肺癌（NSCLC）患者对一线含铂化疗的反应。方法纳入符合条件的患者，并从III期试验中采集血样。提取cfDNA片段和片段化的基因组DNA用于在覆盖1，086个基因的外显子区域的1.15 M大小的板中富集。计算分子突变负荷（MMB）以研究cfDNA的分子特征与对化疗的反应之间的关系。结果共纳入52例符合条件的患者，前瞻性采集基线、每个化疗周期和疾病进展时的血样。在基线时，共检测到17个基因的改变，部分缓解（PR）患者的这些基因的基线MMB值显著低于疾病稳定（SD）（P = 0.0006）或疾病进展（PD）（P = 0.0074）患者。进一步的分析显示，来自预处理血液样品的cfDNA的突变景观在PR患者与SD/PD患者之间明显不同。对于基线TP 53突变的患者，PR患者的MMB显著降低，而SD或PD患者在化疗2、3或4个周期后增加。此外，低MMB患者上级缓解率和无进展生存期明显长于高MMB患者。结论cfDNA突变谱对预测NSCLC患者一线铂类双药化疗的疗效具有潜在的临床价值。在单基因水平，TP 53分子突变负荷的动态变化对于监测基线时携带该突变的患者的疗效（因此，可能有助于早期识别耐药和复发）是有价值的。
Rationale To investigate whether the mutational landscape of circulating cell-free DNA (cfDNA) could predict and dynamically monitor the response to first-line platinum-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Methods Eligible patients were included and blood samples were collected from a phase III trial. Both cfDNA fragments and fragmented genomic DNA were extracted for enrichment in a 1.15M size panel covering exon regions of 1,086 genes. Molecular mutational burden (MMB) was calculated to investigate the relationship between molecular features of cfDNA and response to chemotherapy. Results In total, 52 eligible cases were enrolled and their blood samples were prospectively collected at baseline, every cycle of chemotherapy and time of disease progression. At baseline, alterations of 17 genes were found. Patients with partial response (PR) had significantly lower baseline MMB of these genes than those patients with either stable disease (SD) (P = 0.0006) or progression disease (PD) (P = 0.0074). Further analysis revealed that the mutational landscape of cfDNA from pretreatment blood samples were distinctly different among patients with PR vs. SD/PD. For patients with baseline TP53 mutation, those with PR experienced a significant reduction in MMB whereas patients with SD or PD experienced an increase after two, three or four cycles of chemotherapy. Furthermore, patients with low MMB had superior response rate and significantly longer progression-free survival than those with high MMB. Conclusion This study indicated that the mutational landscape of cfDNA has potential clinical value to predict the therapeutic response to first-line platinum-based doublet chemotherapy in NSCLC patients. At the single gene level, dynamic change of molecular mutational burden of TP53 is valuable to monitor efficacy (and, therefore, might aid in early recognition of resistance and relapse) in patients harboring this mutation at baseline.
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影响因子：
11.5
作者：
Choi, Seongmin;Kim, Hyeong Ryul;Jang, Se Jin
通讯作者：
Jang, Se Jin
血浆DNA监测能否应用于晚期肺癌患者的个体化化疗？
影响因子：
7.5
作者：
Pan, Shiyang;Xia, Wenying;Lu, Shan
通讯作者：
Lu, Shan
影响因子：
11.5
作者：
Mok, Tony;Wu, Yi-Long;Wu, Lin
通讯作者：
Wu, Lin
IV期或复发性非小细胞肺癌中的一线Nivolumab。
DOI：
10.1056/nejmoa1613493
发表时间：
2017-06-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Carbone DP;Reck M;Paz-Ares L;Creelan B;Horn L;Steins M;Felip E;van den Heuvel MM;Ciuleanu TE;Badin F;Ready N;Hiltermann TJN;Nair S;Juergens R;Peters S;Minenza E;Wrangle JM;Rodriguez-Abreu D;Borghaei H;Blumenschein GR Jr;Villaruz LC;Havel L;Krejci J;Corral Jaime J;Chang H;Geese WJ;Bhagavatheeswaran P;Chen AC;Socinski MA;CheckMate 026 Investigators
通讯作者：
CheckMate 026 Investigators
影响因子：
168.9
作者：
Hirsch, Fred R.;Suda, Kenichi;Bunn, Paul A., Jr.
通讯作者：
Bunn, Paul A., Jr.