Clinical Features and Outcome of Patients With Non-Small-Cell Lung Cancer Who Harbor EML4-ALK
Clinical Features and Outcome of Patients With Non-Small-Cell Lung Cancer Who Harbor EML4-ALK
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DOI：
10.1200/jco.2009.22.6993
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发表时间：
2009-09-10
影响因子：
45.3
通讯作者：
Iafrate, A. John
中科院分区：
文献类型：
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作者：
Shaw, Alice T.;Yeap, Beow Y.;Iafrate, A. John
EML4-ALK融合癌基因代表了一小部分非小细胞肺癌（NSCLC）的一个新的分子靶点。为了帮助识别和治疗这些患者，我们检查了伴有和不伴有EML4-ALK的NSCLC患者的临床特征和治疗结果。患者和方法根据以下两个或多个特征选择NSCLC患者进行遗传筛查：女性，亚洲种族，从不/轻度吸烟史和腺癌组织学。EML4-ALK通过荧光原位杂交检测ALK重排，免疫组织化学检测ALK表达。通过DNA测序检测EGFR和KRAS突变。结果在筛选的141例肿瘤中，19例（13%）为EML4-ALK突变体，31例（22%）为EGFR突变体，91例（65%）为ALK和EGFR的野生型（WT/WT）。与EGFR突变组和WT/WT组相比，EML4-ALK突变肿瘤患者明显更年轻（P < 0.001和P < 0.005），且男性患者更多（P < 0.036和P < 0.039）。与WT/WT队列患者相比，eml4 - alk阳性肿瘤患者，如携带EGFR突变的患者，也更有可能成为从不吸烟/轻度吸烟的患者（P < 0.001）。19例EML4-ALK肿瘤中有18例为腺癌，主要为印戒细胞亚型。在转移性疾病患者中，EML4-ALK阳性与对EGFR酪氨酸激酶抑制剂（TKIs）的耐药性相关。EML4-ALK组和WT/WT组的患者对铂类联合化疗的反应率相似，总生存期无差异。结论eml4 - alk定义了一个具有不同临床特征的NSCLC分子亚群。携带这种突变的患者不能从EGFR TKIs中获益，应直接进行alk靶向药物的试验。
PurposeThe EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK.Patients and MethodsPatients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing.ResultsOf 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P < .005) and were more likely to be men (P < .036 and P < .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival.ConclusionEML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.