Objectives

Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. Materials and Methods: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. Results: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p < 0.001). Among ALK fusions identified by ctDNA, 93% (13/14, 95% CI 66%–99%) were concordant with tissue evaluation. Among ALK fusions detected by tissue NGS, 54% (13/24, 95% CI 33%–74%) were concordant with plasma ctDNA. ctDNA matched patients to ALK-directed therapy with subsequent clinical response, including four patients matched on the basis of ctDNA results alone due to inadequate or delayed tissue testing. Serial ctDNA analysis detected MET amplification (n = 2) and ALK G1202R mutation (n = 2) as mechanisms of acquired resistance to ALK-directed therapy. Conclusion: Our findings support a complementary role for ctDNA in detection of ALK fusions and other alterations at diagnosis and therapeutic resistance settings.

中文翻译：

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用于常见和新型 ALK 融合的下一代基于测序的 ctDNA 检测的临床应用

目标

用于血浆循环肿瘤 DNA (ctDNA) 下一代测序 (NGS) 的液体活检可以检测ALK融合，尽管该技术在现实世界中的临床应用数据有限。材料和方法：没有已知致癌驱动因素或对治疗产生耐药性的肺癌患者（n = 736）接受了前瞻性血浆 ctDNA NGS。该队列的一个子集 ( n  = 497) 也有组织 NGS。我们评估了ALK融合检测、周转时间 (TAT)、血浆和组织一致性、治疗匹配和治疗反应。结果： ctDNA 在 21 名患者 (3%) 中鉴定出ALK融合，具有多种断点和融合伙伴，包括EML4、CLTC和PON1，一种新型的ALK融合伙伴。ctDNA NGS 的 TAT 比组织 NGS 短（10 天对 20 天；p < 0.001）。在ctDNA 鉴定的ALK融合中，93% (13/14, 95% CI 66%–99%) 与组织评估一致。在组织 NGS 检测到的ALK融合中，54% (13/24, 95% CI 33%–74%) 与血浆 ctDNA 一致。ctDNA 将患者与 ALK 导向的治疗相匹配，并具有随后的临床反应，其中包括 4 名因组织检测不充分或延迟而仅根据 ctDNA 结果匹配的患者。连续 ctDNA 分析检测到MET扩增（n  = 2）和ALK G1202R 突变（n = 2) 作为对 ALK 导向治疗的获得性耐药机制。结论：我们的研究结果支持 ctDNA 在诊断和治疗耐药环境中检测ALK融合和其他改变中的互补作用。