Baty Florent, Joerger Markus, Früh Martin, Klingbiel Dirk, Zappa Francesco, Brutsche Martin
Department of Pulmonary Medicine, Cantonal Hospital St. Gallen, Roschacherstrasse 95, 9007, St. Gallen, Switzerland.
Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, Roschacherstrasse 95, 9007, St. Gallen, Switzerland.
J Transl Med. 2017 Mar 30;15(1):66. doi: 10.1186/s12967-017-1174-z.
The SAKK 19/05 trial investigated the safety and efficacy of the combined targeted therapy bevacizumab and erlotinib (BE) in unselected patients with advanced non-squamous non-small cell lung cancer (NSCLC). Although activating EGFR mutations were the strongest predictors of the response to BE, some patients not harboring driver mutations could benefit from the combined therapy. The identification of predictive biomarkers before or short after initiation of therapy is therefore paramount for proper patient selection, especially among EGFR wild-types. The first aim of this study was to investigate the early change in blood gene expression in unselected patients with advanced non-squamous NSCLC treated by BE. The second aim was to assess the predictive value of blood gene expression levels at baseline and 24h after BE therapy.
Blood samples from 43 advanced non-squamous NSCLC patients taken at baseline and 24h after initiation of therapy were profiled using Affymetrix' exon arrays. The 24h gene dysregulation was investigated in the light of gene functional annotations using gene set enrichment analysis. The predictive value of blood gene expression levels was assessed and validated using an independent dataset.
Significant gene dysregulations associated with the 24h-effect of BE were detected from blood-based whole-genome profiling. BE had a direct effect on "Pathways in cancer", by significantly down-regulating genes involved in cytokine-cytokine receptor interaction, MAPK signaling pathway and mTOR signaling pathway. These pathways contribute to phenomena of evasion of apoptosis, proliferation and sustained angiogenesis. Other signaling pathways specifically reflecting the mechanisms of action of erlotinib and the anti-angiogenesis effect of bevacizumab were activated. The magnitude of change of the most dysregulated genes at 24h did not have a predictive value regarding the patients' response to BE. However, predictive markers were identified from the gene expression levels at 24h regarding time to progression under BE.
The 24h-effect of the combined targeted therapy BE could be accurately monitored in advanced non-squamous NSCLC blood samples using whole-genome exon arrays. Putative predictive markers at 24h could reflect patients' response to BE after adjusting for their mutational status. Trial registration ClinicalTrials.gov: NCT00354549.
SAKK 19/05试验研究了联合靶向治疗贝伐单抗和厄洛替尼（BE）在未经选择的晚期非鳞状非小细胞肺癌（NSCLC）患者中的安全性和疗效。尽管激活的EGFR突变是对BE反应的最强预测指标，但一些没有驱动基因突变的患者也可能从联合治疗中获益。因此，在治疗开始前或开始后不久识别预测性生物标志物对于正确选择患者至关重要，尤其是在EGFR野生型患者中。本研究的首要目的是调查接受BE治疗的未经选择的晚期非鳞状NSCLC患者血液基因表达的早期变化。第二个目的是评估BE治疗基线和24小时后血液基因表达水平的预测价值。
使用Affymetrix外显子阵列对43例晚期非鳞状NSCLC患者在基线和治疗开始后24小时采集的血样进行分析。使用基因集富集分析根据基因功能注释研究24小时基因失调情况。使用独立数据集评估并验证血液基因表达水平的预测价值。
从基于血液的全基因组分析中检测到与BE的24小时效应相关的显著基因失调。BE对“癌症通路”有直接影响，通过显著下调参与细胞因子-细胞因子受体相互作用、MAPK信号通路和mTOR信号通路的基因。这些通路促成凋亡逃避、增殖和持续血管生成现象。其他特异性反映厄洛替尼作用机制和贝伐单抗抗血管生成作用的信号通路被激活。24小时时失调最严重的基因的变化幅度对患者对BE的反应没有预测价值。然而，从24小时的基因表达水平中识别出了关于BE治疗下疾病进展时间的预测标志物。
使用全基因组外显子阵列可以在晚期非鳞状NSCLC血样中准确监测联合靶向治疗BE 的24小时效应。24小时时的假定预测标志物在调整突变状态后可以反映患者对BE的反应。试验注册ClinicalTrials.gov：NCT00354549。
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