Department of Pathology.
Department of Internal Medicine.
Ann Oncol. 2015 Feb;26(2):348-54. doi: 10.1093/annonc/mdu530. Epub 2014 Nov 17.
Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation are considered mutually exclusive in nonsmall-cell lung cancer (NSCLC). However, sporadic cases having concomitant EGFR and ALK alterations have been reported. The present study aimed to assess the prevalence of NSCLCs with concomitant EGFR and ALK alterations using mutation detection methods with different sensitivity and to propose an effective diagnostic and therapeutic strategy.
A total of 1458 cases of lung cancer were screened for EGFR and ALK alterations by direct sequencing and flourescence in situ hybridization (FISH), respectively. For the 91 patients identified as having an ALK translocation, peptide nucleic acid (PNA)-clamping real-time PCR, targeted next-generation sequencing (NGS), and mutant-enriched NGS assays were carried out to detect EGFR mutation.
EGFR mutations and ALK translocations were observed in 42.4% (612/1445) and 6.3% (91/1445) of NSCLCs by direct sequencing and FISH, respectively. Concomitant EGFR and ALK alterations were detected in four cases, which accounted for 4.4% (4/91) of ALK-translocated NSCLCs. Additional analyses for EGFR using PNA real-time PCR and ultra-deep sequencing by NGS, mutant-enriched NGS increased the detection rate of concomitant EGFR and ALK alterations to 8.8% (8/91), 12.1% (11/91), and 15.4% (14/91) of ALK-translocated NSCLCs, respectively. Of the 14 patients, 3 who were treated with gefitinib showed poor response to gefitinib with stable disease in one and progressive disease in two patients. However, eight patients who received ALK inhibitor (crizotinib or ceritinib) showed good response, with response rate of 87.5% (7/8 with partial response) and durable progression-free survival.
A portion of NSCLC patients have concomitant EGFR and ALK alterations and the frequency of co-alteration detection increases when sensitive detection methods for EGFR mutation are applied. ALK inhibitors appear to be effective for patients with co-alterations.
表皮生长因子受体（EGFR）突变和间变性淋巴瘤激酶（ALK）易位被认为在非小细胞肺癌（NSCLC）中相互排斥。然而，已经报道了一些同时存在 EGFR 和 ALK 改变的散发病例。本研究旨在使用不同敏感性的突变检测方法评估同时存在 EGFR 和 ALK 改变的 NSCLC 的患病率，并提出有效的诊断和治疗策略。
通过直接测序和荧光原位杂交（FISH）分别对 1458 例肺癌患者进行 EGFR 和 ALK 改变筛查。对于 91 例被鉴定为 ALK 易位的患者，进行肽核酸（PNA）夹实时 PCR、靶向下一代测序（NGS）和突变富集 NGS 检测以检测 EGFR 突变。
直接测序和 FISH 分别检测到 42.4%（612/1445）和 6.3%（91/1445）的 NSCLC 中存在 EGFR 突变和 ALK 易位。在 4 例中检测到同时存在 EGFR 和 ALK 改变，占 ALK 易位 NSCLC 的 4.4%（4/91）。通过 PNA 实时 PCR 和 NGS 的超深度测序对 EGFR 进行额外分析，将同时存在 EGFR 和 ALK 改变的检出率提高到 ALK 易位 NSCLC 的 8.8%（8/91）、12.1%（11/91）和 15.4%（14/91）。在 14 例患者中，3 例接受吉非替尼治疗的患者对吉非替尼反应不佳，1 例患者病情稳定，2 例患者病情进展。然而，8 例接受 ALK 抑制剂（克唑替尼或塞瑞替尼）治疗的患者反应良好，反应率为 87.5%（7/8 例部分缓解），无进展生存期持久。
一部分 NSCLC 患者同时存在 EGFR 和 ALK 改变，应用 EGFR 突变的敏感检测方法可增加共改变的检出率。ALK 抑制剂似乎对共改变患者有效。
