Division of Thoracic Diseases, Chiba Cancer Center, Chiba, Japan.
Lung Cancer. 2012 Jan;75(1):66-72. doi: 10.1016/j.lungcan.2011.05.027. Epub 2011 Jul 14.
Anaplastic lymphoma kinase (ALK) fusion gene-positive lung cancer accounts for 4-5% of non-small cell lung carcinoma. A clinical trial of the specific inhibitor of ALK fusion-type tyrosine kinase is currently under way.
ALK fusion gene products were analyzed immunohistochemically with the materials obtained by surgery or by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The echinoderm microtubule-associated protein-like 4(EML4)-ALK or kinesin family member 5B (KIF5B)-ALK translocation was confirmed by the reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). After eligibility criteria were met and informed consent was obtained, 3 patients were enrolled for the Pfizer Study of Crizotinib (PF02341066), Clinical Trial A8081001, conducted at Seoul National University.
Out of 404 cases, there were 14 of EML4-ALK non-small cell carcinoma (NSCLC) and one KIF5B-ALK NSCLC case (8 men, 7 women; mean age, 61.9 years, range 48-82). Except for 2 light smokers, all patients were non-smokers. All cases were of adenocarcinoma with papillary or acinar subtypes. Three were of stage IA, 5 of stage IIIA, 1 of stage IIIB and 6 of stage IV. Ten patients underwent thoracotomy, 3 received chemotherapy and 2 only best supportive care (BSC). One BSC and 2 chemotherapy cases were enrolled for the clinical trial. Patients with advanced stages who received chemotherapy or best supportive care were younger (54.0±6.3) than those who were surgically treated (65.8±10.1) (p<0.05). The powerful effect of ALK inhibitor on EML4-ALK NSCLC was observed. Soon after its administration, almost all the multiple bone and lymph node metastases quickly disappeared. Nausea, diarrhea and the persistence of a light image were the main side effects, but they diminished within a few months.
ALK-fusion gene was found in 3.7% (15/404) NSCLC cases and advanced disease with this fusion gene was correlated with younger generation. The ALK inhibitor presented in this study is effective in EML4-ALK NSCLC cases. A further study will be necessary to evaluate the clinical effectiveness of this drug.
间变性淋巴瘤激酶（ALK）融合基因阳性肺癌占非小细胞肺癌的 4-5%。目前正在进行针对 ALK 融合型酪氨酸激酶的特异性抑制剂的临床试验。
通过手术或支气管内超声引导经支气管针吸活检（EBUS-TBNA）获得的材料，用免疫组织化学方法分析 ALK 融合基因产物。通过逆转录聚合酶链反应（RT-PCR）和荧光原位杂交（FISH）证实棘皮动物微管相关蛋白样 4（EML4）-ALK 或驱动蛋白家族成员 5B（KIF5B）-ALK 易位。符合入选标准并获得知情同意后，3 例患者入组首尔国立大学开展的辉瑞克唑替尼（PF02341066）研究（ClinicalTrials.gov 注册号：A8081001）。
在 404 例患者中，有 14 例为 EML4-ALK 非小细胞肺癌（NSCLC），1 例为 KIF5B-ALK NSCLC（8 例男性，7 例女性；平均年龄 61.9 岁，范围 48-82 岁）。除了 2 例轻度吸烟者外，所有患者均为不吸烟者。所有病例均为腺癌，具有乳头状或腺泡亚型。3 例为 IA 期，5 例为 IIIA 期，1 例为 IIIB 期，6 例为 IV 期。10 例患者接受了手术治疗，3 例接受了化疗，2 例仅接受最佳支持治疗（BSC）。1 例 BSC 和 2 例化疗患者入组临床试验。接受化疗或 BSC 的晚期患者较接受手术治疗的患者更年轻（54.0±6.3 岁 vs 65.8±10.1 岁）（p<0.05）。ALK 抑制剂对 EML4-ALK NSCLC 具有显著疗效。在开始治疗后不久，几乎所有多发性骨和淋巴结转移迅速消失。主要副作用为恶心、腹泻和轻微的视觉障碍，但在几个月内减轻。
本研究中在 3.7%（15/404）的 NSCLC 病例中发现了 ALK 融合基因，并且具有该融合基因的晚期疾病与年轻一代相关。本研究中出现的 ALK 抑制剂在 EML4-ALK NSCLC 病例中有效。需要进一步研究来评估该药物的临床疗效。
