Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
J Thorac Oncol. 2013 Jan;8(1):45-51. doi: 10.1097/JTO.0b013e3182781e35.
Non-small-cell lung cancers (NSCLCs) containing EGFR mutations are exquisitely sensitive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). This is the case of the most common EGFR mutations affecting exon 18 (G719X), 19 (inframe deletions), and 21 (L858R and L861Q). However, the frequency of compound (i.e., double or complex) EGFR mutations-where an EGFR TKI sensitizing or other mutation is identified together with a mutation of unknown clinical significance-and their pattern of response/resistance to EGFR TKIs are less well described.
We analyzed the EGFR mutation pattern of 79 cases of NSCLC harboring EGFR mutations and compiled the genotype-response data for patients with NSCLCs with compound EGFR mutations treated with EGFR TKIs.
Of the 79 EGFR-mutated tumors identified, 11 (14%) had compound mutations. Most involved the EGFR TKI-sensitizing G719X (n = 3, plus S768I or E709A), L858R (n = 4, plus L747V, R776H, T790M, or A871G), L861Q (n = 1, plus E709V), and delL747_T751 (n = 1, plus R776H). Eight patients received an EGFR TKI: three cases with G719X plus another mutation had partial responses (PRs) to erlotinib; of three cases with L858R plus another mutation, two displayed PRs and one (with EGFR-L858R+A871G) progressive disease (PD) to erlotinib; one NSCLC with EGFR-L861Q+E709A and one with delL747_T751+R776S had PRs to EGFR TKIs.
Compound EGFR mutations comprised 14% of all mutations identified during routine sequencing of exons 18-21 of EGFR in our cohort. Most patients with an EGFR TKI-sensitizing mutation (G719X, exon 19 deletion, L858R, and L861Q) in addition to an atypical mutation responded to EGFR TKIs. Reporting of the genotype-response pattern of NSCLCs with EGFR compound and other rare mutations, and the addition of this information to searchable databases, will be helpful to select the appropriate therapy for EGFR-mutated NSCLC.
含有 EGFR 突变的非小细胞肺癌（NSCLC）对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）非常敏感。这种情况最常见的 EGFR 突变影响外显子 18（G719X）、19（内含子缺失）和 21（L858R 和 L861Q）。然而，复合（即双或复杂）EGFR 突变的频率——即同时存在 EGFR TKI 敏感或其他突变与未知临床意义的突变——以及它们对 EGFR TKI 的反应/耐药模式描述得较少。
我们分析了 79 例 EGFR 突变 NSCLC 患者的 EGFR 突变模式，并为接受 EGFR TKI 治疗的具有复合 EGFR 突变的 NSCLC 患者编译了基因型-反应数据。
在 79 例 EGFR 突变肿瘤中，有 11 例（14%）存在复合突变。大多数涉及 EGFR TKI 敏感的 G719X（n = 3，外加 S768I 或 E709A）、L858R（n = 4，外加 L747V、R776H、T790M 或 A871G）、L861Q（n = 1，外加 E709V）和 delL747_T751（n = 1，外加 R776H）。8 例患者接受了 EGFR TKI 治疗：3 例 G719X 加另一种突变的患者对厄洛替尼有部分反应（PR）；3 例 L858R 加另一种突变的患者中有 2 例 PR，1 例（EGFR-L858R+A871G）对厄洛替尼进展为疾病（PD）；1 例 NSCLC 患者 EGFR-L861Q+E709A 和 1 例 delL747_T751+R776S 对 EGFR TKI 有 PR。
在我们的队列中，常规测序 EGFR 外显子 18-21 时，复合 EGFR 突变占所有突变的 14%。大多数具有 EGFR TKI 敏感突变（G719X、外显子 19 缺失、L858R 和 L861Q）加非典型突变的患者对 EGFR TKI 有反应。报告 EGFR 复合和其他罕见突变的 NSCLC 的基因型-反应模式，并将这些信息添加到可搜索数据库中，将有助于为 EGFR 突变型 NSCLC 选择适当的治疗方法。
