在随机 III 期 EURTAC 试验中，接受厄洛替尼或化疗治疗的 EGFR 突变型 NSCLC 患者中，EGFR T790M 突变和 BIM mRNA 表达对结局的影响。
The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial.
机构信息
Authors' Affiliations: Pangaea Biotech, Barcelona, Spain; Hospital Sant Pau, Barcelona, Spain; Hospital Vall d'Hebron, Barcelona, Spain; Molecular Oncology Research (MORe) Foundation, Barcelona, Spain; Pivotal, Madrid; Hospital General de Alicante, Alicante, Spain; Catalan Institute of Oncology, Badalona, Barcelona, Spain; Complejo Hospitalario Universitario, La Coruña, Spain; Centre François Baclesse, Caen, France; Drum Tower Hospital, Nanjing, China; Kyushu University, Fukuoka, Japan; Cancer Therapeutics Innovation Group, New York, New York, USA; and Helen Diller Comprehensive Cancer Center, University of California, San Francisco, California, USA.
出版信息
Clin Cancer Res. 2014 Apr 1;20(7):2001-10. doi: 10.1158/1078-0432.CCR-13-2233. Epub 2014 Feb 3.
PURPOSE
Concomitant genetic alterations could account for transient clinical responses to tyrosine kinase inhibitors of the EGF receptor (EGFR) in patients harboring activating EGFR mutations.
EXPERIMENTAL DESIGN
We have evaluated the impact of pretreatment somatic EGFR T790M mutations, TP53 mutations, and Bcl-2 interacting mediator of cell death (BCL2L11, also known as BIM) mRNA expression in 95 patients with EGFR-mutant non-small-cell lung cancer (NSCLC) included in the EURTAC trial (trial registration: NCT00446225).
RESULTS
T790M mutations were detected in 65.26% of patients using our highly sensitive method based on laser microdissection and peptide-nucleic acid-clamping PCR, which can detect the mutation at an allelic dilution of 1 in 5,000. Progression-free survival (PFS) to erlotinib was 9.7 months for those with T790M mutations and 15.8 months for those without, whereas among patients receiving chemotherapy, it was 6 and 5.1 months, respectively (P < 0.0001). PFS to erlotinib was 12.9 months for those with high and 7.2 months for those with low/intermediate BCL2L11 expression levels, whereas among chemotherapy-treated patients, it was 5.8 and 5.5 months, respectively (P = 0.0003). Overall survival was 28.6 months for patients with high BCL2L11 expression and 22.1 months for those with low/intermediate BCL2L11 expression (P = 0.0364). Multivariate analyses showed that erlotinib was a marker of longer PFS (HR = 0.35; P = 0.0003), whereas high BCL2L11 expression was a marker of longer PFS (HR = 0.49; P = 0.0122) and overall survival (HR = 0.53; P = 0.0323).
CONCLUSIONS
Low-level pretreatment T790M mutations can frequently be detected and can be used for customizing treatment with T790M-specific inhibitors. BCL2L11 mRNA expression is a biomarker of survival in EGFR-mutant NSCLC and can potentially be used for synthetic lethality therapies.
目的
伴有激活 EGFR 突变的患者中，伴随的遗传改变可能导致对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂的短暂临床反应。
实验设计
我们评估了 95 名 EGFR 突变非小细胞肺癌（NSCLC）患者预处理体细胞 EGFR T790M 突变、TP53 突变和 Bcl-2 相互作用的细胞死亡介体（BCL2L11，也称为 BIM）mRNA 表达对 EURTAC 试验（试验注册：NCT00446225）的影响。
结果
使用我们基于激光微切割和肽核酸夹 PCR 的高度敏感方法，在 65.26%的患者中检测到 T790M 突变，该方法可以在等位基因稀释度为 1/5000 的情况下检测到该突变。T790M 突变患者的厄洛替尼无进展生存期（PFS）为 9.7 个月，无 T790M 突变患者为 15.8 个月，而接受化疗的患者分别为 6 和 5.1 个月（P <0.0001）。厄洛替尼治疗的患者中，BCL2L11 表达水平高的患者 PFS 为 12.9 个月，低/中度表达的患者 PFS 为 7.2 个月，而接受化疗的患者分别为 5.8 和 5.5 个月（P = 0.0003）。BCL2L11 表达水平高的患者总生存期为 28.6 个月，低/中度 BCL2L11 表达的患者总生存期为 22.1 个月（P = 0.0364）。多变量分析表明，厄洛替尼是 PFS 延长的标志物（HR = 0.35；P = 0.0003），而高 BCL2L11 表达是 PFS 延长（HR = 0.49；P = 0.0122）和总生存期（HR = 0.53；P = 0.0323）的标志物。
结论
预处理时可频繁检测到低水平 T790M 突变，可用于定制 T790M 特异性抑制剂治疗。BCL2L11 mRNA 表达是 EGFR 突变型 NSCLC 生存的生物标志物，可能可用于合成致死疗法。
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