Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, 10043, Orbassano, TO, Italy.
Laboratory of Oncology, Fondazione IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Foggia, Italy.
Eur J Cancer. 2022 Oct;174:200-211. doi: 10.1016/j.ejca.2022.07.026. Epub 2022 Aug 28.
Anaplastic lymphoma kinase (ALK) fusions identify a limited subset of non-small cell lung cancer (NSCLC) patients, whose therapeutic approach have been radically changed in recent years. However, diagnostic procedures and clinical-radiological responses to specific targeted therapies remain heterogeneous and intrinsically resistant or poor responder patients exist.
A total of 290 patients with advanced NSCLC defined as ALK+ by immunohistochemistry (IHC) and/or fluorescent in situ hybridisation (FISH) test and treated with single or sequential multiple ALK inhibitors (ALKi) from 2011 to 2017 have been retrospectively retrieved from a multicentre Italian cancer network database. In 55 patients with enough leftover tumour tissue, specimens were analysed with both targeted and customised next generation sequencing panels. Identified fusion variants have been correlated with clinical outcomes.
Of the 55 patients, 24 received crizotinib as first-line therapy, 1 received ceritinib, while 30 received chemotherapy. Most of the patients (64%) received ALKi in sequence. An ALK fusion variant was identified in 73% of the cases, being V3 variant (E6A20) the most frequent, followed by V1 (E13A20) and more rare ones (e.g. E6A19). In three specimens, four new EML4-ALK fusion breakpoints have been reported. Neither fusion variants nor brain metastases were significantly associated with overall survival (OS), while it was predictably longer in patients receiving a sequence of ALKi. The presence of V1 variant was associated with progression-free survival (PFS) improvement when crizotinib was used (p = 0.0073), while it did not affect cumulative PFS to multiple ALKi.
Outcomes to sequential ALKi administration were not influenced by fusion variants. Nevertheless, in V1+ patients a prolonged clinical benefit was observed. Fusion variant identification by NGS technology may add relevant information about rare chromosomal events that could be potentially correlated to worse outcomes.
间变性淋巴瘤激酶（ALK）融合鉴定了一小部分非小细胞肺癌（NSCLC）患者，近年来，其治疗方法发生了根本性变化。然而，诊断程序和针对特定靶向治疗的临床-放射学反应仍然存在异质性，存在内在耐药或反应不佳的患者。
从 2011 年至 2017 年，通过免疫组织化学（IHC）和/或荧光原位杂交（FISH）试验将 290 名晚期 NSCLC 患者（定义为 ALK+）纳入一个意大利多中心癌症网络数据库，这些患者接受了单一或序贯多种 ALK 抑制剂（ALKi）治疗。在 55 名有足够剩余肿瘤组织的患者中，使用靶向和定制的下一代测序面板对标本进行了分析。鉴定的融合变体与临床结果相关。
在 55 名患者中，24 名患者接受克唑替尼作为一线治疗，1 名患者接受色瑞替尼，而 30 名患者接受化疗。大多数患者（64%）接受了序贯 ALKi 治疗。73%的病例中鉴定出 ALK 融合变体，最常见的是 V3 变体（E6A20），其次是 V1（E13A20）和更罕见的变体（例如 E6A19）。在三个标本中，报告了四个新的 EML4-ALK 融合断点。融合变体和脑转移均与总生存期（OS）无显著相关性，而接受序贯 ALKi 治疗的患者 OS 更长。在使用克唑替尼时，V1 变体的存在与无进展生存期（PFS）的改善相关（p=0.0073），而它并不影响对多种 ALKi 的累积 PFS。
序贯 ALKi 给药的结果不受融合变体的影响。然而，在 V1+患者中观察到了更长的临床获益。通过 NGS 技术鉴定融合变体可能会提供有关罕见染色体事件的相关信息，这些事件可能与更差的结果相关。
