Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors through Longitudinal Analysis of Circulating Tumor DNA.
Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors through Longitudinal Analysis of Circulating Tumor DNA.
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通过循环肿瘤DNA的纵向分析来跟踪对碱酪氨酸激酶抑制剂的耐药性的演变。
DOI：
10.1200/po.17.00160
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发表时间：
2018
影响因子：
4.6
通讯作者：
Gainor JF
中科院分区：
文献类型：
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作者：
Dagogo-Jack I;Brannon AR;Ferris LA;Campbell CD;Lin JJ;Schultz KR;Ackil J;Stevens S;Dardaei L;Yoda S;Hubbeling H;Digumarthy SR;Riester M;Hata AN;Sequist LV;Lennes IT;Iafrate AJ;Heist RS;Azzoli CG;Farago AF;Engelman JA;Lennerz JK;Benes CH;Leary RJ;Shaw AT;Gainor JF
ALK 重排可预测对 ALK 酪氨酸激酶抑制剂 (TKI) 的敏感性。然而，ALK TKI 的反应通常是短暂的。连续分子分析是识别耐药性遗传介质的一种信息丰富的策略。尽管多项研究支持重复组织取样的临床益处，但纵向循环肿瘤 DNA 分析在 ALK 阳性肺癌中的临床效用尚未确立。我们使用 566 基因杂交捕获下一代测序 (NGS) 测定法，对 22 名对 ALK TKI 获得性耐药的 ALK 阳性患者的血浆样本进行了纵向分析，以追踪治疗期间耐药性的演变。为了确定组织-血浆的一致性，我们将血浆结果与重复活检的结果进行了比较。在疾病进展时，我们在 22 名患者中的 19 名 (86%) 患者的血浆中检测到 ALK 融合，并在 11 名 (50%) 患者的血浆样本中发现了 ALK 耐药突变。组织检测和血浆检测的 ALK 融合之间 100% 一致。在可获得同期血浆和组织标本的 16 例病例中，我们观察到 ALK 突变检测之间具有 100% 的一致性。 ALK 突变在连续 ALK TKI 治疗期间出现并消失，表明血浆突变谱取决于所施用的特定 TKI。 ALK G1202R 是第二代 TKI 进展后检测到的最常见的血浆突变，在劳拉替尼治疗期间始终受到抑制。 NGS 血浆基因分型是检测 ALK TKI 治疗进展患者中 ALK 融合和 ALK 突变的有效方法。血浆 ALK 突变与对不同 ALK TKI 的反应之间的相关性凸显了血浆分析指导 ALK 靶向疗法选择的潜力。
ALK rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, responses to ALK TKIs are generally short-lived. Serial molecular analysis is an informative strategy for identifying genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer. Using a 566-gene hybrid-capture next-generation sequencing (NGS) assay, we performed longitudinal analysis of plasma specimens from 22 ALK-positive patients with acquired resistance to ALK TKIs to track the evolution of resistance during treatment. To determine tissue-plasma concordance, we compared plasma findings to results of repeat biopsies. At progression, we detected an ALK fusion in plasma from 19 (86%) of 22 patients, and identified ALK resistance mutations in plasma specimens from 11 (50%) patients. There was 100% agreement between tissue- and plasma-detected ALK fusions. Among 16 cases where contemporaneous plasma and tissue specimens were available, we observed 100% concordance between ALK mutation calls. ALK mutations emerged and disappeared during treatment with sequential ALK TKIs, suggesting that plasma mutation profiles were dependent on the specific TKI administered. ALK G1202R, the most frequent plasma mutation detected after progression on a second-generation TKI, was consistently suppressed during treatment with lorlatinib. Plasma genotyping by NGS is an effective method for detecting ALK fusions and ALK mutations in patients progressing on ALK TKIs. The correlation between plasma ALK mutations and response to distinct ALK TKIs highlights the potential for plasma analysis to guide selection of ALK-directed therapies.