Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
Southern Medical University, Guangzhou, Guangdong, China.
Genes Chromosomes Cancer. 2022 Apr;61(4):177-186. doi: 10.1002/gcc.23005. Epub 2021 Nov 1.
Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) respond well to ALK tyrosine kinase inhibitors (TKIs), and echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged NSCLC accounts for the majority of those patients. However, few studies have evaluated ALK-TKIs treatment for patients with huntingtin-interacting protein 1 (HIP1)-ALK fusions. This retrospective study evaluated the clinicopathological characteristics, genomic features, response to ALK-TKIs, and resistance mechanisms in 11 cases with HIP1-ALK fusions from five Chinese centers. Patients who received crizotinib at the Chinese centers had an objective response rate of 90% [9/10 cases, 95% confident index (CI): 54.1%-99.5%], median progression-free survival of 17.9 months (95% CI: 5.8-NA months), and median overall survival of 58.8 months (95% CI: 24.7-NA months). One patient who received first-line lorlatinib treatment achieved partial response for > 26.5 months. Despite the small sample size, HIP1-ALK (H21:A20) variant was the most common variant (four of 11 cases, 36.4%) and associated with better outcomes. Among the 11 cases, there were eight patients having available specimens for genetic testing before ALK-TKIs treatment and four patients undergoing biopsy after ALK-TKIs failure. The most common coexisting gene was TP53 among 11 patients and two of four patients after crizotinib failure harbored acquired ALK mutations (e.g., L1152V/Q1146K and L1196M). Brigatinib treatment appeared to be effective for a patient who failed crizotinib treatment because of the L1152V/Q1146K mutations, which might be related to increased binding affinity to these mutants. Although HIP1-ALK-rearranged NSCLC appears to initially respond well to ALK-TKIs, crizotinib resistance may be correlated with the AKAP9-BRAF fusion, ALK compound mutations (L1152V/Q1146K), and the ALK L1196M mutation. Larger studies are needed to evaluate the significance of HIP1-ALK-rearranged NSCLC.
棘皮动物微管相关蛋白样 4 (EML4)-ALK 重排非小细胞肺癌 (NSCLC) 对 ALK 酪氨酸激酶抑制剂 (TKI) 反应良好，而棘皮动物微管相关蛋白样 4 (EML4)-ALK 重排 NSCLC 占此类患者的大多数。然而，很少有研究评估棘皮动物微管相关蛋白样 4 (EML4)-ALK 重排 NSCLC 患者使用棘皮动物微管相关蛋白样 4 (EML4)-ALK 重排 NSCLC 治疗。这项回顾性研究评估了来自中国五个中心的 11 例棘皮动物微管相关蛋白样 4 (EML4)-ALK 重排 NSCLC 患者的临床病理特征、基因组特征、对 ALK-TKIs 的反应和耐药机制。在中国中心接受克唑替尼治疗的患者客观缓解率为 90%[9/10 例，95%置信区间 (CI)：54.1%-99.5%]，中位无进展生存期为 17.9 个月 (95%CI：5.8-N/A 个月)，中位总生存期为 58.8 个月 (95%CI：24.7-N/A 个月)。一名接受一线洛拉替尼治疗的患者的部分缓解持续时间超过 26.5 个月。尽管样本量较小，但棘皮动物微管相关蛋白样 4 (EML4)-ALK (H21:A20) 变体是最常见的变体 (11 例中的 4 例，36.4%)，与更好的结局相关。在 11 例患者中，有 8 例在接受 ALK-TKIs 治疗前有可供基因检测的标本，有 4 例在 ALK-TKIs 治疗失败后进行了活检。在 11 例患者中最常见的共存基因是 TP53，在 4 例接受克唑替尼治疗失败的患者中有 2 例存在获得性 ALK 突变 (如 L1152V/Q1146K 和 L1196M)。因 L1152V/Q1146K 突变而对克唑替尼耐药的患者，接受 brigatinib 治疗似乎有效，这可能与这些突变体结合的亲和力增加有关。尽管棘皮动物微管相关蛋白样 4 (EML4)-ALK 重排 NSCLC 似乎对 ALK-TKIs 初始反应良好，但克唑替尼耐药可能与 AKAP9-BRAF 融合、ALK 复合突变 (L1152V/Q1146K) 和 ALK L1196M 突变有关。需要更大规模的研究来评估棘皮动物微管相关蛋白样 4 (EML4)-ALK 重排 NSCLC 的意义。
