Patients with NSCLCs Harboring Internal Inversions or Deletion Rearrangements of the ALK Gene Have Durable Responses to ALK Kinase Inhibitors.

IF 5.1 Q1 ONCOLOGY
Lung Cancer: Targets and Therapy Pub Date : 2020-04-17 eCollection Date: 2020-01-01 DOI:10.2147/LCTT.S239675
Alexa B Schrock, Russell Madison, Mark Rosenzweig, Justin M Allen, Rachel L Erlich, Siao-Yi Wang, Tarek Chidiac, Vodur Suresh Reddy, Jonathan W Riess, Ahmet Ersin Yassa, Abdur Shakir, Vincent A Miller, Brian M Alexander, Jeffrey Venstrom, Kimberly McGregor, Siraj M Ali
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引用次数: 2

Abstract

Background: ALK fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK variants that may predict sensitivity to multiple approved ALK inhibitors.

Methods: Comprehensive genomic profiling (CGP) of DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians.

Results: We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK internal inversions, RNA testing identified an EML4-ALK fusion in 2/2 cases evaluated, and 3/3 patients treated with ALK inhibitors had durable responses. A single patient with an ALK internal deletion and clinical data available responded to multiple ALK inhibitors. RNA data available for a subset of non-NSCLC cases suggest that ALK internal deletions removing a portion of the N-terminus are drivers themselves and do not result in ALK fusions. Fluorescence in situ hybridization (FISH) results were inconsistent for both classes of DNA events.

Conclusion: Rare internal inversions of ALK appear to be indicative of ALK fusions, which can be detected in RNA, and response to ALK inhibitors in patients with NSCLC. In contrast, ALK internal deletions are not associated with ALK fusions in RNA but likely represent targetable drivers themselves. These data suggest that CGP of DNA should be supplemented with immunohistochemistry or RNA-based testing to further resolve these events and match patients to effective therapies.

Abstract Image

携带ALK基因内部反转或缺失重排的非小细胞肺癌患者对ALK激酶抑制剂有持久的反应。
背景:ALK融合是非小细胞肺癌(NSCLC)的可靶向驱动因子。然而,在DNA中没有发现融合伙伴的ALK重排的NSCLC患者也被证明对ALK抑制剂有反应。我们的目的是表征复杂的ALK变异,这些变异可能预测对多种已批准的ALK抑制剂的敏感性。方法:在常规临床护理期间,对39159例非小细胞肺癌患者进行福尔马林固定石蜡包埋(FFPE)肿瘤组织或血液循环肿瘤DNA分离的DNA进行综合基因组谱分析(CGP)。对一部分病例进行RNA测序,并从治疗医生处收集先前的ALK检测结果和临床治疗信息。结果:我们查询了基础医学NSCLC数据库,分别在6例(0.02%)和3例(0.01%)病例中确定了ALK内部倒置和内部缺失作为唯一的ALK重排。在ALK内反转的病例中,RNA检测在2/2的评估病例中发现EML4-ALK融合,3/3的ALK抑制剂治疗患者有持久的反应。一名ALK内部缺失的患者和现有的临床数据对多种ALK抑制剂有反应。一部分非nsclc病例的RNA数据表明,去除部分n端的ALK内部缺失本身是驱动因素,不会导致ALK融合。荧光原位杂交(FISH)结果对这两类DNA事件不一致。结论:在非小细胞肺癌患者中,罕见的ALK内部反转似乎表明ALK融合,可以在RNA中检测到,并且对ALK抑制剂有反应。相反,ALK内部缺失与RNA中的ALK融合无关,但可能代表了可靶向的驱动因素本身。这些数据表明,DNA的CGP应该辅以免疫组织化学或基于rna的检测,以进一步解决这些事件,并为患者匹配有效的治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
8.10
自引率
0.00%
发文量
10
审稿时长
16 weeks
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