Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer.
Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer.
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DOI：
10.1200/jco.2017.76.2294
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发表时间：
2018-04-20
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影响因子：
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通讯作者：
Ou SI
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作者：
Lin JJ;Zhu VW;Yoda S;Yeap BY;Schrock AB;Dagogo-Jack I;Jessop NA;Jiang GY;Le LP;Gowen K;Stephens PJ;Ross JS;Ali SM;Miller VA;Johnson ML;Lovly CM;Hata AN;Gainor JF;Iafrate AJ;Shaw AT;Ou SI
晚期间变性淋巴瘤激酶（ALK）融合阳性非小细胞肺癌（NSCLCs）可通过ALK酪氨酸激酶抑制剂（TKI）有效治疗。然而，这些患者的临床结局各不相同，由于获得性耐药，TKI的获益有限。新出现的数据表明，ALK融合变体可能影响临床结局，但这种关联的分子基础尚不清楚。我们确定了129例ALK阳性NSCLC病例，这些病例具有已知的ALK变体。根据ALK变体回顾性评价ALK耐药突变和ALK TKI的临床结局。还检查了577例ALK阳性NSCLC病例的Foundation Medicine数据集。最常见的ALK变体为EML 4-ALK变体1（55例患者，43%）和变体3（51例患者，40%）。我们分析了77例接受ALK TKI治疗后发生进展的变异1型和变异3型患者的肿瘤活检。ALK耐药突变在变体3中的发生率显著高于变体1（57% vs 30%，P = 0.023）。特别是，ALK G1202 R在变异体3中比变异体1中更常见（32% vs 0%，P < 0.001）。Foundation Medicine数据库的分析显示，变异体3与ALK耐药突变和G1202 R的相关性相似（分别为P = 0.010和P = 0.015）。在接受第三代ALK TKI劳拉替尼治疗的患者中，与变体1相比，变体3与无进展生存期显著延长相关（风险比，0.31 [95% CI，0.12-0.79]，P = 0.011）。这些结果表明，特定的ALK变体与ALK耐药突变的发生相关，特别是G1202 R，并提供了变体与临床结局之间的分子联系。因此，ALK变体代表了选择下一代ALK抑制剂的潜在重要因素。
Advanced anaplastic lymphoma kinase (ALK) fusion-positive non-small cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes in these patients vary, and the benefit of TKIs is limited due to acquired resistance. Emerging data suggest that the ALK fusion variant may impact clinical outcome, but the molecular basis for this association is unknown. We identified 129 ALK-positive NSCLC cases with known ALK variants. ALK resistance mutations and clinical outcomes on ALK TKIs were retrospectively evaluated according to ALK variant. A Foundation Medicine dataset of 577 ALK-positive NSCLC cases was also examined. The most frequent ALK variants were EML4-ALK variant 1 in 55 (43%) and variant 3 in 51 (40%) patients. We analyzed 77 tumor biopsies from patients with variants 1 and 3 who had progressed on an ALK TKI. ALK resistance mutations were significantly more common in variant 3 than variant 1 (57% vs 30%, P = 0.023). In particular, ALK G1202R was more common in variant 3 than variant 1 (32% vs 0%, P < 0.001). Analysis of the Foundation Medicine database revealed similar associations of variant 3 with ALK resistance mutation and with G1202R (P = 0.010 and P = 0.015, respectively). Among patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival compared to variant 1 (hazard ratio, 0.31 [95% CI, 0.12–0.79], P = 0.011). These findings suggest that specific ALK variants are associated with the development of ALK resistance mutations, particularly G1202R, and provide a molecular link between variant and clinical outcome. ALK variant thus represents a potentially important factor in the selection of next-generation ALK inhibitors.