Medical Oncology Department, Gustave Roussy, Villejuif, France.
Department of Biopathology, Gustave Roussy, Villejuif, France.
J Thorac Oncol. 2018 Jan;13(1):27-45. doi: 10.1016/j.jtho.2017.10.021. Epub 2017 Nov 8.
Since the discovery in 2012 of rearranged during transfection proto-oncogene gene (RET) rearrangements in NSCLC, at least 12 different fusion variants have been identified, with kinesin family member 5B gene (KIF5B)-RET being the most frequent and the best characterized. Unlike ALK receptor tyrosine kinase gene (ALK) and ROS1 rearrangements, RET fusion genes cannot be adequately detected by immunohistochemistry (IHC), although fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction are fully complementary diagnostic tools. In large retrospective studies, RET rearrangements correlate with adenocarcinoma histologic subtype, never-smoking status, younger age, more advanced disease stage, potentially higher chemosensitivity (in particular, to pemetrexed-based regimens), and coexistence of other genomic alterations. To date, several preclinical models, clinical trials, and retrospective studies have investigated multitarget inhibitors with anti-rearranged during transfection proto-oncogene (RET) activity in patients with RET-rearranged lung cancer. In the clinical setting, the benefit in terms of response (16%-47%) and progression-free survival (2-7 months) is clearly not comparable to that seen with other targeted agents in oncogene-addicted NSCLC. Furthermore, multikinase agents showed high rates of severe toxicities, leading to frequent dose reduction and drug discontinuation. To date, no definitive conclusions about a potentially different impact of anti-RET therapies according to RET fusion variants have been drawn on account of discordant data coming mostly from small subgroup analyses. Importantly, the absence of a striking clinical benefit in RET oncogene-addicted NSCLC underscores the clear need for development of more selective and potent RET inhibitors and for better characterization of concomitant genomic alterations and mechanisms of resistance to RET inhibition in patients with lung cancer.
自 2012 年发现非小细胞肺癌中的转染过程中重排原癌基因基因（RET）重排以来，已经鉴定出至少 12 种不同的融合变体，其中驱动蛋白家族成员 5B 基因（KIF5B）-RET 最为常见和特征最佳。与 ALK 受体酪氨酸激酶基因（ALK）和 ROS1 重排不同，RET 融合基因不能通过免疫组织化学（IHC）充分检测到，尽管荧光原位杂交和逆转录聚合酶链反应是完全互补的诊断工具。在大型回顾性研究中，RET 重排与腺癌组织学亚型、从不吸烟状态、年轻年龄、更晚期的疾病阶段、潜在的更高化疗敏感性（特别是基于培美曲塞的方案）以及其他基因组改变的共存相关。迄今为止，已有几项临床前模型、临床试验和回顾性研究调查了针对 RET 重排肺癌患者具有抗转染过程中重排原癌基因（RET）活性的多靶点抑制剂。在临床环境中，反应（16%-47%）和无进展生存期（2-7 个月）的获益显然无法与其他依赖癌基因的 NSCLC 中的靶向药物相媲美。此外，多激酶药物表现出严重毒性的高发生率，导致频繁剂量减少和药物停药。迄今为止，由于主要来自小亚组分析的不一致数据，尚未得出关于根据 RET 融合变体抗 RET 治疗可能具有不同影响的明确结论。重要的是，在依赖 RET 致癌基因的 NSCLC 中缺乏明显的临床获益，突出表明迫切需要开发更具选择性和更有效的 RET 抑制剂，并更好地描述肺癌患者中伴随的基因组改变和对 RET 抑制的耐药机制。
