Drilon Alexander, Wang Lu, Arcila Maria E, Balasubramanian Sohail, Greenbowe Joel R, Ross Jeffrey S, Stephens Phil, Lipson Doron, Miller Vincent A, Kris Mark G, Ladanyi Marc, Rizvi Naiyer A
Memorial Sloan Kettering Cancer Center, New York, New York.
Foundation Medicine, Inc., Cambridge, Massachusetts.
Clin Cancer Res. 2015 Aug 15;21(16):3631-9. doi: 10.1158/1078-0432.CCR-14-2683. Epub 2015 Jan 7.
Broad, hybrid capture-based next-generation sequencing (NGS), as a clinical test, uses less tissue to identify more clinically relevant genomic alterations compared with profiling with multiple non-NGS tests. We set out to determine the frequency of such genomic alterations via this approach in tumors in which previous extensive non-NGS testing had not yielded a targetable driver alteration.
We enrolled patients with lung adenocarcinoma with a ≤ 15 pack-year smoking history whose tumors previously tested "negative" for alterations in 11 genes (mutations in EGFR, ERBB2, KRAS, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1 and fusions involving ALK, ROS1, and RET) via multiple non-NGS methods. We performed hybridization capture of the coding exons of 287 cancer-related genes and 47 introns of 19 frequently rearranged genes and sequenced these to deep, uniform coverage.
Actionable genomic alterations with a targeted agent based on NCCN guidelines were identified in 26% [8 of 31: EGFR G719A, BRAF V600E, SOCS5-ALK, HIP1-ALK, CD74-ROS1, KIF5B-RET (n = 2), CCDC6-RET]. Seven of these patients either received or are candidates for targeted therapy. Comprehensive genomic profiling using this method also identified a genomic alteration with a targeted agent available on a clinical trial in an additional 39% (12 of 31).
Broad, hybrid capture-based NGS identified actionable genomic alterations in 65% [95% confidence interval (CI), 48%-82%] of tumors from never or light smokers with lung cancers deemed without targetable genomic alterations by earlier extensive non-NGS testing. These findings support first-line profiling of lung adenocarcinomas using this approach as a more comprehensive and efficient strategy compared with non-NGS testing. See related commentary by McCutcheon and Giaccone, p. 3584.
作为一种临床检测方法，基于杂交捕获的广泛二代测序（NGS）与多种非NGS检测分析相比，使用更少的组织来识别更多临床相关的基因组改变。我们着手通过这种方法确定在先前广泛的非NGS检测未产生可靶向驱动改变的肿瘤中此类基因组改变的频率。
我们纳入了吸烟史≤15包年的肺腺癌患者，其肿瘤先前通过多种非NGS方法检测11个基因（EGFR、ERBB2、KRAS、NRAS、BRAF、MAP2K1、PIK3CA和AKT1的突变以及涉及ALK、ROS1和RET的融合）的改变为“阴性”。我们对287个癌症相关基因的编码外显子和19个频繁重排基因的47个内含子进行杂交捕获，并对这些进行深度、均匀覆盖的测序。
根据NCCN指南，在26%（31例中的8例）中鉴定出可通过靶向药物治疗的基因组改变：EGFR G719A、BRAF V600E、SOCS5-ALK、HIP1-ALK、CD74-ROS1、KIF5B-RET（2例）、CCDC6-RET。这些患者中有7例已接受或有资格接受靶向治疗。使用这种方法进行的综合基因组分析还在另外39%（31例中的12例）中鉴定出一种可在临床试验中使用靶向药物治疗的基因组改变。
基于杂交捕获的广泛NGS在65%[95%置信区间（CI），48%-82%]的从未吸烟或轻度吸烟肺癌患者的肿瘤中鉴定出可通过靶向药物治疗的基因组改变，这些肿瘤通过早期广泛的非NGS检测被认为没有可靶向的基因组改变。这些发现支持将这种方法作为肺腺癌一线分析方法，与非NGS检测相比，这是一种更全面、有效的策略。见McCutcheon和Giaccone的相关评论，第3584页。
