Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.
Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.
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DOI：
10.1158/1078-0432.ccr-12-2246
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发表时间：
2013-04-15
期刊：
影响因子：
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通讯作者：
Riely GJ
中科院分区：
文献类型：
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作者：
Yu HA;Arcila ME;Rekhtman N;Sima CS;Zakowski MF;Pao W;Kris MG;Miller VA;Ladanyi M;Riely GJ
所有患有 EGFR 突变肺癌的患者最终都会对 EGFR 酪氨酸激酶抑制剂 (TKI) 产生获得性耐药。较小的系列研究已经确定了各种耐药机制，但尚未对大量患者进行系统评估以明确确定各种机制的发生频率。对厄洛替尼或吉非替尼获得性耐药的肺腺癌患者参加了前瞻性活检方案，并在出现获得性耐药后接受了重新活检。回顾了组织学。对样本进行 EGFR、AKT1、BRAF、ERBB2、KRAS、MEK1、NRAS 和 PIK3CA 突变基因分型，并对 MET 和 HER2 进行 FISH 检测。从 155 名患者身上获得了足够的肿瘤样本用于分子分析。 98 例有第二位点 EGFR T790M 突变（63%，95% CI 55-70%），4 例有小细胞转化（3%，95% CI 0-6%）。 MET 扩增发生率为 4/75（5%，95% CI 1-13%）。 3/24 出现 HER2 扩增（13%，95% CI 3-32%）。我们没有检测到 PIK3CA、AKT1、BRAF、ERBB2、KRAS、MEK1 或 NRAS 中的任何获得性突变。 （0/88、0%、95% CI 0-4%）。获得性耐药机制之间的重叠率为 4%。这是 EGFR TKI 治疗获得性耐药机制的最大系列报告。我们确定 EGFR T790M 是最常见的获得性耐药机制，而 MET 扩增、HER2 扩增和小细胞组织学转化的发生频率较低。需要更全面的方法来表征这种情况下的分子改变，以提高我们对 EGFR TKI 获得性耐药的理解。
All patients with EGFR mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been performed. Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a re-biopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2. Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations (63%, 95% CI 55-70%) and four had small cell transformation (3%, 95% CI 0-6%). MET amplification was seen in 4/75 (5%, 95% CI 1-13%). HER2 amplification was seen in 3/24 (13%, 95% CI 3-32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS. (0/88, 0%, 95% CI 0-4%). Overlap among mechanisms of acquired resistance was seen in 4%. This is the largest series reporting mechanisms of acquired resistance to EGFR TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, while MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR TKIs.