First-line crizotinib therapy is effective for a novel SEC31A-anaplastic lymphoma kinase fusion in a patient with stage IV lung adenocarcinoma: a case report and literature reviews
First-line crizotinib therapy is effective for a novel SEC31A-anaplastic lymphoma kinase fusion in a patient with stage IV lung adenocarcinoma: a case report and literature reviews
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DOI：
10.1097/cad.0000000000001408
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发表时间：
2023-02-01
影响因子：
2.3
通讯作者：
Luo，Zhuang
中科院分区：
文献类型：
--
作者：
Wu，Rongrong;Liu，Shinan;Luo，Zhuang
间变性淋巴瘤激酶（ALK）融合在3-7%的非小细胞肺癌患者中发现。已经对ALK-酪氨酸激酶抑制剂（ALK-TKI）在EML 4-ALK中的疗效进行了广泛研究，但关于其在罕见ALK融合中的疗效的证据很少。在这里，我们报告了克唑替尼在一名50岁男性肺腺癌患者中的性能，该患者患有新型罕见的SEC 31 A-ALK融合。计算机断层扫描（CT）显示双肺多发斑片状高密度影。较大者位于右肺下叶脊柱附近（55× 34 mm）和左肺门区（45× 26 mm），纵隔和腋窝多发肿大淋巴结。支气管镜活检显示浸润性腺癌。T4 N3 M1 b的病理分期（临床分期：IVA）得到确认。下一代测序显示SEC 31 A：外显子20 ~ ALK：外显子20融合、ABCB 1扩增、FGF 19扩增、DAXX p. S213 L、MUTYH p. R19*（种系突变和致病性），肿瘤突变负荷为3.2个突变/Mb，微卫星稳定，错配修复能力强，PD-L1阳性[免疫组织化学，肿瘤比例评分（TPS）1-49%（TPS= 25%）]。基于这些结果，建议将克唑替尼作为一线治疗，剂量为250 mg，每日两次。治疗2个月后的首次CT评估显示两个较大病灶、双肺多发阴影和结节以及纵隔和腋窝淋巴结部分缓解（PR）。在接下来的9个月内，使用克唑替尼250 mg，每日两次。每3个月（诊断后1年）进行一次评估，结果显示所有病灶进一步吸收（持续PR）。我们报告了一种新的罕见ALK融合SEC 31 A：EXON 20 ~ ALK：exon 20，并显示了克唑替尼对融合的有效性。本研究为ALK-TKI治疗罕见ALK融合的有效性提供了强有力的证据。背景间变性淋巴瘤激酶（ALK）基因首先在间变性大细胞淋巴瘤中被发现，因此命名为间变性淋巴瘤激酶[1]。ALK是一种在许多癌症中发现的强效致癌启动子基因[2，3]。ALK蛋白位于细胞膜上，具有细胞外受体区和细胞内激酶区。在正常情况下，两种ALK蛋白通过细胞外配体偶联以激活细胞内信号传导途径并促进细胞生长[4]。目前已发现三种ALK基因变异类型，其中融合变异是最常见的类型，导致融合蛋白过度表达[5]。点突变相对罕见，主要发现于细胞内激酶区域，其激活下游途径细胞生长信号。扩增变异也相对罕见，通过增加与配体结合的机会来增强细胞生长的信号传导[5]。目前认为点突变和扩增是ALK-酪氨酸激酶抑制剂（TKI）耐药的主要机制[5]。
Anaplastic lymphoma kinase (ALK) fusion was found in 3–7% of all patients with nonsmall cell lung cancer. The efficacy of ALK-tyrosine kinase inhibitor (ALK-TKI) in EML4-ALK has been extensively studied, whereas little evidence is available on its efficacy in rare ALK fusions. Here, we report the performance of crizotinib in a 50-year-old male lung adenocarcinoma patient with a novel rare SEC31A-ALK fusion. Computed tomography (CT) scan revealed multiple patchy high-density shadows in both lungs. The larger ones are located near the spine in the right lung lower lobe (55× 34 mm) and the left hilar region (45× 26 mm), with multiple enlarged mediastinal and axillary lymph nodes. Biopsy by bronchoscopy revealed invasive adenocarcinoma. The pathological stage of T4N3M1b (clinical stage: IVA) was confirmed. Next-generation sequencing revealed SEC31A: exon20~ ALK: exon20 fusion, ABCB1 amplification, FGF19 amplification, DAXX p. S213L, MUTYH p. R19*(germline mutation and pathogenic) with tumor mutational burden at 3.2 mutations/Mb, microsatellite stable, proficient mismatch repair and PD-L1 positive [immunohistochemistry, tumor proportion score (TPS) 1–49%(TPS= 25%)]. Based on these findings, crizotinib was recommended for the first-line treatment at 250 mg twice daily. The first CT assessment after 2-month therapy showed partial response (PR) for the two larger lesions, multiple shadows and nodules in both lungs and the mediastinal and axillary lymph nodes. Crizotinib at 250 mg twice a day was applied in the following 9 months. Assessment at every 3 months (up to 1-year after diagnosis) showed further absorption for all lesions (continuous PR). We reported a novel rare ALK fusion SEC31A: EXON20~ ALK: exon20 and showed the effectiveness of crizotinib against the fusion. This study provided strong evidence for the efficacy of ALK-TKI for rare ALK fusion.BackgroundAnaplastic lymphoma kinase (ALK) gene was first identified in anaplastic large cell lymphoma; hence, the name anaplastic lymphoma kinase [1]. ALK is a potent oncogenic promoter gene [2, 3] found in many cancers. ALK protein is located on the cell membrane, with extracellular receptor region and intracellular kinase region. Under normal circumstances, the two ALK proteins are coupled by the extracellular ligand to activate the intracellular signaling pathway and promote cell growth [4]. Three types of ALK gene variations have been found so far, among which fusion variation is the most common type, leading to hyperactive expression of the fusion protein [5]. Point mutations are relatively rare and are mainly found in the intracellular kinase region, which activates downstream pathway cell growth signals. Amplification variations are also relatively rare, enhancing the signaling for cell growth by increasing the chance of binding to ligands [5]. Point mutations and amplifications are currently considered to be major mechanisms of ALK-tyrosine kinase inhibitor (TKI) resistance [5].