阿法替尼治疗一例ALK突变阳性肺鳞癌患者疗效分析
Analysis of the Efficacy of Afat-inib in the Treatment of ALK-Positive Squamous Cell Carcinoma
DOI: 10.12677/ACRPO.2022.111001, PDF, HTML, XML, 下载: 85  浏览: 271  国家自然科学基金支持
作者: 李 伟:山东大学附属省立医院肿瘤中心放疗科,山东 济南
关键词: 肺鳞癌ALK突变阿法替尼 Lung Squamous Cell Carcinoma ALK Mutation Afatinib
摘要: 探讨针对ALK突变阳性肺鳞癌患者的肿瘤靶向治疗,提高对其诊治水平。报道一例ALK突变阳性肺鳞癌及其靶向治疗,同时对国内外报道的相关文献进行复习。患者,男,54岁,因“干咳伴发热1月余”入院。经气管镜活检诊断为肺鳞状细胞癌,基因检测(NGS)示EML4-ALK基因融合。行阿来替尼靶向联合化疗治疗2周期,后单药阿来替尼靶向治疗6周,复查CT显示病情进展。猜测可能含有ALK重排的肺鳞癌对阿来替尼的反应较低,但肺鳞癌中ALK基因融合非常罕见,针对ALK基因突变阳性肺鳞癌患者的ALK-TKI治疗效果尚需进一步的研究证实。
Abstract: To explore the tumor targeted therapy for patients with ALK mutation positive lung squamous cell carcinoma and to improve the level of diagnosis and treatment. This paper reports a case of ALK mutation positive lung squamous cell carcinoma and its targeted therapy, and reviews the relevant literature at home and abroad. The patient, male, 54 years old, suffered from “dry cough with fever for more than 1 month” be hospitalized. Lung squamous cell carcinoma was diagnosed by tracheoscopic biopsy. Gene detection (NGS) showed EML4-ALK gene fusion. The patients were treated with targeted combination chemotherapy of afatinib for 2 cycles, followed by targeted treatment of single drug afatinib for 6 weeks, and the CT reexamination showed the progress of the disease. It is speculated that lung squamous cell carcinoma with ALK rearrangement may have a low response to afatinib. But ALK gene fusion in lung squamous cell carcinoma is very rare, the therapeutic effect of afatinib on patients with ALK gene mutation positive lung squamous cell carcinoma needs to be confirmed by further research.
文章引用:李伟. 阿法替尼治疗一例ALK突变阳性肺鳞癌患者疗效分析[J]. 亚洲肿瘤科病例研究, 2022, 11(1): 1-5. https://doi.org/10.12677/ACRPO.2022.111001

1. 引言

根据2020年全球癌症统计报告,肺癌仍是当前中国人群中发病率和死亡率最高的肿瘤。其中,肺鳞癌(SCC)是非小细胞肺癌(NSCLC)中常见的病理类型,约占总发生率的20%~30% [1]。在非小细胞肺癌中,针对特定的靶点开展个体化治疗已成为现实。其中,针对间变性淋巴瘤激酶(anaplastic lymphoma kinase, ALK)的靶向治疗研究于2007年开始见诸NSCLC相关研究报告 [2],并成为近年靶向研究的新宠。ALK基因融合常见于肺腺癌中,最新NCCN-NSCLC指南便指出,对晚期腺癌、大细胞癌、未分型癌的患者推荐进行ALK检测。但是在肺鳞癌中ALK基因融合则非常罕见,其突变率不足2.5% [3] [4],我们很少有机会在日常临床实践中见到这些患者。下面通过分享我科一例ALK突变阳性肺鳞癌患者的临床资料,探讨针对ALK突变阳性肺鳞癌患者的肿瘤靶向治疗。该病例报道得到患者及家属的知情同意,并签署知情同意书。

2. 病历资料

患者,男,54岁,因“干咳伴发热1月余”于2021年7月入院。无痰干咳,伴发热,体温最高达38℃,无寒战、胸痛、憋喘等不适。既往病史回顾无异常,一般情况较好,吸烟史30余年,每天30支。查体:双肺呼吸音粗,双肺可闻及干湿啰音。PS评分1分。胸部CT示左肺上叶及左肺门处见不规则软组织灶,截面约4.5 × 8.8cm,累及左肺门结构,左肺上叶、左肺门肿瘤,符合左肺癌并肺门淋巴结转移累及左肺门结构CT表现(图1)。行气管镜活检,病理诊断:(左主支气管)鳞状细胞癌,免疫组化染色结果:CK(AE1/AE3)(+),TTF1(+)NapsinA(−),p40(+),CK5/6(+),Syn(−),CgA(−),CD56(−),Ki67+(50%),p63(+)。行双侧锁骨上彩超检查,未见明显肿大淋巴结,腹部肝胆胰腺彩超未见明显异常,全腹及盆腔CT、颅脑MR、全身骨显象均未见明显转移灶。临床诊断:左肺鳞癌(T4N3M0, IIIC期)。患者于2021年7月22日于我院行第一周期化疗联合免疫治疗,方案为:替雷利珠单抗200mg d0+白蛋白结合型紫衫醇40mg d1、5+奈达铂100 mg d2-4。患者在化疗间歇期行基因检测(NGS)显示:1个基因突变:TP53外显子错义突变,c.733G>T,p.G245C,突变丰度:13%、37%;1个基因融合:EML4-ALK基因融合。而该基因检测中未检测到EGFR突变,PD-L1表达:TPS: 0%,CPS: 5。根据患者基因检测结果,给予患者阿来替尼(二代ALK抑制剂)单药靶向治疗。

Figure 1. Chest CT when the patient was admitted

图1. 患者入院时胸部CT

Figure 2. Chest CT Reexamination after the patient was treated with targeted therapy for 8 weeks

图2. 患者靶向治疗8周后复查胸部CT

患者在家自行口服阿来替尼,在服药期间,患者出现无明显诱因咳嗽,伴少量白痰,感憋喘、胸闷、活动受限,于2021年9月10日再次就诊于我院,无痛气管镜下局部支气管内应用电刀、氩气等予以综合治疗,并给予白蛋白结合型紫衫醇40 mg d1、5+奈达铂100 mg d2-4治疗,患者症状好转后出院。靶向治疗8周后复查胸部CT显示:左肺上叶、左肺门肿瘤,符合左肺癌并左肺门淋巴结转移累及左肺门结构CT表现,总体较前减轻;双肺新见异常密度灶,建议抗炎治疗后两周复查,除外转移可能。双肺慢性炎性灶,部分较前加重(图2)。继续在家口服阿来替尼6周,后感憋气,间断咳嗽,痰不能咳出,夜间平躺时憋气加重。于2021年12月6日再次来院就诊。再次复查CT显示:局部肿块较前增大,评估病情进展(图3)。给予更换化疗方案:力朴素240 mg d1+顺铂60 mg d2-3。随后给予患者放射治疗,暂时停用阿来替尼靶向治疗。目前患者规律放疗,身体状况可。

Figure 3. Chest CT Reexamination after the patient was treated with targeted therapy for 14 weeks

图3. 患者靶向治疗14周后复查胸部CT

3. 讨论

ALK是Morris等人于1994年首先在间变性大细胞淋巴瘤中发现的,是隶属于胰岛素受体家族的一种单链跨膜蛋白 [5]。ALK-EML4融合基因是其主要的一种致癌基因突变,是由于2号染色体短臂插入引起,根据断裂位点不同,融合基因也各不相同,但都包括EML4基因的碱基区、疏水的棘皮动物微管相关蛋白区(HELP区)、部分WD重复区以及ALK基因中的Kinase功能区。其合成的EML4-ALK蛋白可以绕过组织信号和配体的调控,通过自身磷酸化异常激活下游信号通路,从而引起细胞向恶性转化 [6] [7] [8]。ALK融合基因的发现标志着NSCLC中又一个肿瘤靶向治疗新模式的形成。其最具针对性的靶向药物克唑替尼,是肺腺癌精准靶向治疗、个体化治疗方面的又一重要发现,与传统化疗方案相比,以克唑替尼为核心的综合治疗模式将患者的中位无进展生存期延长了近5个月,极大改善了该亚型患者的预后 [9]。

既往研究中显示,ALK突变阳性的肺腺癌患者确实能够在ALK-TKI靶向治疗中获益,但由于肺鳞癌中EML4-ALK重排十分罕见,相关临床研究难以展开,仅有少数个案报道。例如,Mikes [10] 等报道一例36岁从不吸烟的晚期肺鳞状细胞癌患者ALK突变阳性,进行克唑替尼一线治疗,12周后复查显示肿瘤部分缓解。Vergne [11] 等报道一例58岁女性患者,转移性肺鳞状细胞癌ALK突变阳性,二线克唑替尼治疗后肿瘤部分缓解。可以看出,在个案报道中,ALK-TKI克唑替尼对肺鳞癌ALK突变阳性患者治疗有一定的效果,而相比于克唑替尼,阿来替尼是一种更具选择性的ALK-TKI,可降低31%的死亡风险 [12],理论上可能对ALK阳性肺鳞癌有更高的疗效。然而,从本例患者治疗情况看来,行阿来替尼靶向联合化疗治疗2周期,靶向治疗8周后复查CT显示局部病灶缩小,但肺部炎症情况较严重,后单药阿来替尼靶向治疗6周,显示病情进展。总之,我们对患者连续使用14周阿来替尼,但仍未能观察到其对于ALK突变阳性肺鳞癌有效的治疗效果,由此我们猜测,可能含有ALK突变阳性的肺鳞癌对阿来替尼的反应较低,阿来替尼在此类患者中疗效较差。但由于样本量所限,阿来替尼对ALK基因突变阳性的肺鳞癌患者的治疗效果尚需更加深入的研究和更严谨的临床数据论证。

基金项目

国家自然科学基金资助项目(82172672)。

参考文献

[1] Sung, H., Ferlay, J., Siegel, R.L., et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71, 209-249.
https://doi.org/10.3322/caac.21660
[2] Soda, M., Choi, Y.L., Enomoto, M., et al. (2007) Identification of the Transforming EML4-ALK Fusion Gene in Non-Small-Cell Lung Cancer]. Nature, 448, 561-566.
https://doi.org/10.1038/nature05945
[3] Zhao, W., Choi, Y.L., Song, J.Y., et al. (2016) ALK, ROS1 and RET Rearrangements in Lung Squamous Cell Carcinoma Are Very Rare. Lung Cancer, 94, 22-27.
https://doi.org/10.1016/j.lungcan.2016.01.011
[4] Kim, Y., Hammerman, P.S., Kim, J., et al. (2014) Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients. Journal of Clinical On-cology, 32, 121-128.
https://doi.org/10.1200/JCO.2013.50.8556
[5] Morris, S.W., Kirstein, M.N., Valentine, M.B., et al. (1995) Fu-sion of a Kinase Gene, ALK, to a Nucleolar Protein Gene, NPM, in Non-Hodgkin’s Lymphoma. Science, 267, 316-317.
https://doi.org/10.1126/science.267.5196.316.c
[6] Koivunen, J.P., Mermel, C., Zejnullahu, K., et al. (2008) EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer. Clinical Cancer Research, 14, 4275-4283.
https://doi.org/10.1158/1078-0432.CCR-08-0168
[7] Inamura, K., Takeuchi, K., Togashi, Y., et al. (2009) EML4-ALK Lung Cancers Are Characterized by Rare Other Mutations, a TTF-1 Cell Lineage, an Acinar Histol-ogy, and Young Onset. Modern Pathology, 22, 508-515.
https://doi.org/10.1038/modpathol.2009.2
[8] Martelli, M.P., Sozzi, G., Hernandez, L., et al. (2009) EML4-ALK Rearrangement in Non-Small Cell Lung Cancer and Non-Tumor Lung Tissues. The American Journal of Pathology, 174, 661-670.
https://doi.org/10.2353/ajpath.2009.080755
[9] Camidge, D., Bang, Y., Kwak, E., et al. (2011) Progression-Free Survival (PFS) from a Phase 1 Study of Crizotinib (PF-02341066) in Patients with ALK-Positive Non-Small Cell Lung Cancer (NSCLC). Journal of Clinical Oncology, 29, 2501.
https://doi.org/10.1200/jco.2011.29.15_suppl.2501
[10] Mikes, R.E., Jordan, F., Hutarew, G., et al. (2015) First Line Crizotinib in Anaplastic Lymphoma Kinase (ALK) Rearranged Squamous Cell Lung Cancer. Lung Cancer, 90, 614-616.
https://doi.org/10.1016/j.lungcan.2015.10.013
[11] Vergne, F., Quéré, G., Andrieu-Key, S., et al. (2016) ALK-Rearranged Squamous Cell Lung Carcinoma Responding to Crizotinib: A Missing Link in the Field of Non-Small Cell Lung Cancer? Lung Cancer, 91, 67-69.
https://doi.org/10.1016/j.lungcan.2015.11.010
[12] Seto, T., Kiura, K., Nishio, M., et al. (2013) CH5424802(RO5424802) for Patients with ALK-Rearranged Advanced Non-Small-Cell Lung Cancer (AF-001JP Study): A Single-Arm, Open-Label, Phase 1-2 Study. The Lancet Oncology, 14, 590-598.
https://doi.org/10.1016/S1470-2045(13)70142-6