Background: Genomic fusions of the anaplastic lymphoma kinase gene (ALK) are a well-established therapy target in non-small cell lung cancer (NSCLC). From a survey of 114,200 clinical cases, we determined the prevalence of ALK rearrangements (rALK) in non-NSCLC tumors and report their responsiveness to therapies targeting ALK.
Materials and methods: Comprehensive genomic profiling of 114,200 relapsed and metastatic malignancies, including both solid tumors and hematolymphoid cancers, was performed using a hybrid-capture, adaptor ligation-based next-generation sequencing assay.
Results: Of 114,200 clinical samples, 21,522 (18.8%) were NSCLC and 92,678 (81.2%) were other tumor types. Of the 876 (0.8%) cases with ALK fusions (fALK) or rALK, 675 (77.1%) were NSCLC and 201 (22.9%) were other tumor types. ALK fusions were significantly more frequent in NSCLC (3.1%) than non-NSCLC (0.2%; p < .0001). Patients with non-NSCLC tumors harboring fALK were significantly younger (p < .0001) and more often female (p < .0001) than patients with fALK-positive NSCLC. EML4 was more often the fusion partner in NSCLC (83.5%) versus non-NSCLC tumors (30.9%; p < .0001).
Conclusion: ALK rearrangements can be identified in a wide variety of epithelial and mesenchymal malignancies beyond NSCLC. Anti-ALK therapies can be effective in non-NSCLC tumors driven by fALK, and further study of therapies targeting ALK in clinical trials involving a wider variety of cancer types appears warranted.
Implications for practice: Rearrangements involving the ALK gene have been detected in dozens of cancer types using next-generation sequencing. Patients whose tumors harbor ALK rearrangements or fusions respond to treatment with crizotinib and alectinib, including tumors not normally associated with ALK mutations, such as non-Langerhans cell histiocytosis or renal cell carcinoma. Comprehensive genomic profiling using next-generation sequencing can detect targetable ALK fusions irrespective of tumor type or fusions partner.
摘要
背景.间变性淋巴瘤激酶基因（ALK）融合是非小细胞肺癌（NSCLC）治疗的确定靶点。根据对114 200例临床病例展开的调查, 我们确定了非NSCLC肿瘤患者中ALK重排（rALK）的发生率, 并报告了他们对靶向ALK的疗法的反应。
材料与方法.通过基于杂交捕获和适配器连接的下一代测序法对114 200例复发及转移性恶性肿瘤患者（包括实体瘤和淋巴造血系统癌）进行了全面的基因组测序。
结果.在这114 200例临床病例中, 21 522例（18.8%）罹患NSCLC, 92 678例（81.2%）罹患其他类型肿瘤。876例（0.8%）患者出现ALK融合（fALK）或rALK, 其中675例（77.1%）罹患NSCLC, 201例（22.9%）罹患其他类型肿瘤。NSCLC患者（3.1%）中ALK融合的发生率明显高于非NSCLC患者（0.2%）（p < 0.0001）。与fALK‐阳性 NSCLC患者相比, 负荷fALK的非NSCLC患者的年龄明显更小（p < 0.0001）, 并且女性患者的比例通常更高（p < 0.0001）。NSCLC患者（83.5%）中出现融合伴侣EML4的比例通常高于非NSCLC患者（30.9%; p < 0.0001）。
结论.除NSCLC外, 多种上皮和间质恶性肿瘤中均存在ALK重排。抗ALK疗法可有效治疗fALK驱动的非NSCLC肿瘤, 因此, 有必要在涉及各类癌症的临床试验中对靶向ALK的疗法进行进一步研究。
对临床实践的启示：下一代测序技术已被使用对多种癌症类型进行了ALK基因重排检测。负荷ALK重排或融合的肿瘤患者对克唑替尼和alectinib治疗产生反应, 其中包括通常无ALK突变的肿瘤, 例如, 非朗格罕组织细胞增多症或肾细胞癌。使用下一代测序技术进行的全面基因组测序可检测靶向ALK融合, 而这与肿瘤类型或融合伴侣无关。
Keywords: ALK; Alectinib; Comprehensive genomic profiling; Crizotinib; Fusion; Rearrangement.
© AlphaMed Press 2017.