Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing
Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing
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DOI：
10.1093/annonc/mdt573
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发表时间：
2014-02-01
影响因子：
50.5
通讯作者：
Riely, G. J.
中科院分区：
文献类型：
--
作者：
Yu, H. A.;Arcila, M. E.;Riely, G. J.
EGFR T790M可以在基线肺癌标本中看到，其频率及其与EGFR酪氨酸激酶抑制剂反应的关系取决于检测方法。当通过标准敏感性基因分型方法鉴定时，基线EGFR T790M突变是罕见的，在肺癌中< 1%见过，并且预测对EGFR酪氨酸抑制剂缺乏反应，反应率为8%。EGFR T790M是与对EGFR酪氨酸激酶抑制剂（TKIs）获得性耐药相关的最常见突变。EGFR tki初发患者的基线EGFR T790M突变已有报道，但其频率及其与EGFR tki应答的关系尚不清楚。通过回顾我院2009 - 2013年的临床结果，通过常规分子基因分型检测EGFR T790M基线频率。我们还收集了EGFR TKIs治疗的结果数据。为了确定EGFR T790M的发病率，我们回顾了2774例接受分子质谱检测的肺癌患者，其中11例（0.5%）的基线EGFR T790M。综合几种分子技术的结果，我们在20例以前未接受过EGFR TKI治疗的患者的肿瘤中观察到EGFR T790M。在所有病例中，EGFR T790M与另一种EGFR突变L858R（80%, 16/20）或外显子19缺失（20%,4/20）同时发生。在所有治疗前的EGFR突变肺癌中，有2%携带EGFR T790M突变。13例患者接受厄洛替尼单药治疗作为转移性疾病的治疗。应答率为8%（1/13,95%置信区间为0% ~ 35%）。对于接受厄洛替尼的患者，中位无进展生存期为2个月，中位总生存期为16个月。用标准灵敏度方法鉴定时，新发EGFR T790M突变非常罕见（< 1%）。通过标准分子分析检测到基线EGFR T790M的患者，TKI治疗的获益有限。
EGFR T790M can be seen in baseline lung cancer specimens, with the frequency and association with response to EGFR tyrosine kinase inhibitor dependent on the method of detection. When identified by standard sensitivity genotyping methods, baseline EGFR T790M mutations are rare, seen in < 1% of lung cancers, and predict a lack of response to EGFR tyrosine inhibitors, with a response rate of 8%.EGFR T790M is the most common mutation associated with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Baseline EGFR T790M mutations in EGFR TKI-naive patients have been reported, but the frequency and their association with response to EGFR TKIs remain unclear.The frequency of baseline EGFR T790M as detected by routine molecular genotyping was determined by reviewing clinical results obtained at our institution from 2009 to 2013. We also collected outcome data for treatment with EGFR TKIs.To define the incidence of EGFR T790M, we reviewed 2774 sequentially tested patients with lung cancer who underwent molecular testing using a mass spectrometry-based assay, and 11 (0.5%) had baseline EGFR T790M. Compiling results from several molecular techniques, we observed EGFR T790M in tumors from 20 patients who had not previously been treated with an EGFR TKI. In all cases, EGFR T790M occurred concurrently with another EGFR mutation, L858R (80%, 16/20), or exon 19 deletion (20%, 4/20). Two percent of all pre-treatment EGFR-mutant lung cancers harbored an EGFR T790M mutation. Thirteen patients received erlotinib monotherapy as treatment for metastatic disease. The response rate was 8% (1/13, 95% confidence interval 0%-35%). For the patients who received erlotinib, the median progression-free survival was 2 months and the median overall survival was 16 months.De novo EGFR T790M mutations are rare (< 1%) when identified by standard sensitivity methods. TKI therapy for patients with baseline EGFR T790M detected by standard molecular analysis has limited benefit.