Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non-Small Cell Lung Cancer.
Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non-Small Cell Lung Cancer.
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DOI：
10.1158/1078-0432.ccr-17-2588
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发表时间：
2018-06-15
期刊：
影响因子：
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通讯作者：
Doebele RC
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文献类型：
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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
晚期非小细胞肺癌（NSCLC）患者的肿瘤携带间变性淋巴瘤激酶（ALK）基因融合，可从ALK抑制剂（ALKi）治疗中获益。无细胞循环肿瘤DNA（cfDNA）的分析可以提供一种非侵入性方法来识别ALK融合和可行的耐药机制，而无需侵入性活检。查询了Guardant 360（G360）去识别NSCLC病例数据库，以识别88例连续患者，其中96例血浆检测到ALK融合。G360是临床cfDNA下一代测序（NGS）测试，其检测血浆中的点突变、选择拷贝数增加、融合、插入和缺失。鉴定的融合伴侣包括EML 4（85.4%）、STRN（6%）和KCNQ、KLC 1、KIF 5 B、PPM 1B和TGF（总计8.3%）。42例ALK阳性患者无靶向治疗史（队列1），21例患者尝试了组织ALK分子检测（5例阴性，5例阳性，11例组织不足）。5例组织阴性患者中有3例随访显示对ALKi有反应。31例患者在已知或假定ALKi进展时接受检测（队列2）; 16份样本（53%）含有1 - 3个ALK耐药突变。在13例患者中，临床状态未知（队列3），未发现耐药突变或旁路途径。在6例已知EGFR激活突变的患者中，在进展时发现ALK融合（队列4）（4例STRN，1例EML 4; 1例STRN和EML 4），5例携带EGFR T790 M。在这个cfDNA检测到的ALK融合的队列中，我们证明了全面的cfDNA NGS提供了检测靶向改变的非侵入性方法，并表征了进展时的耐药机制。ALK阳性非小细胞肺癌患者的成功治疗和靶向治疗耐药机制的鉴定取决于肿瘤细胞中的遗传改变。然而，肿瘤组织并不总是可用的。我们的数据表明，全面的cfDNA NGS测试通常可以非侵入性地检测新诊断患者的靶向改变以及在靶向治疗进展的患者中的耐药突变和可能的旁路途径。此外，我们证明了cfDNA的实用性，以提供在异质性肿瘤细胞群体中的耐药机制的多样性和复杂性的全面视图。
Patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a non-invasive way to identify ALK fusions and actionable resistance mechanisms without an invasive biopsy. The Guardant360 (G360) de-identified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected ALK fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma. Identified fusion partners included EML4 (85.4%), STRN (6%), and KCNQ, KLC1, KIF5B, PPM1B, and TGF (totaling 8.3%). Forty-two ALK positive patients had no history of targeted therapy (cohort 1) with tissue ALK molecular testing attempted in 21 (5 negative, 5 positive, 11 tissue insufficient). Follow-up of 3 of the 5 tissue negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 – 3 ALK resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known EGFR activating mutations, an ALK fusion was identified on progression (cohort 4) (4 STRN, 1 EML4; one both STRN and EML4), five harbored EGFR T790M. In this cohort of cfDNA detected ALK fusions, we demonstrate that comprehensive cfDNA NGS provides a non-invasive means of detecting targetable alterations, and characterizing resistance mechanisms on progression. The successful treatment of patients with ALK positive non-small cell lung cancer and identification of resistance mechanisms to targeted therapy is predicated on identifying genetic alterations in tumor cells. However, tumor tissue is not always available. Our data demonstrate that comprehensive cfDNA NGS testing can often non-invasively detect targetable alterations in newly diagnosed patients as well as resistance mutations and possible bypass pathways in patients progressing on targeted therapy. Additionally, we demonstrate the utility of cfDNA to provide a comprehensive view of the diversity and complexity of resistance mechanisms in a heterogeneous tumor cell population.