Enrico Diego, Lacroix Ludovic, Chen Jeanne, Rouleau Etienne, Scoazec Jean-Yves, Loriot Yohann, Tselikas Lambros, Jovelet Cécile, Planchard David, Gazzah Anas, Mezquita Laura, Ngo-Camus Maud, Michiels Stefan, Massard Christophe, Recondo Gonzalo, Facchinetti Francesco, Remon Jordi, Soria Jean-Charles, André Fabrice, Vassal Gilles, Friboulet Luc, Besse Benjamin
Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
INSERM U981, Gustave Roussy Cancer Campus, Villejuif, France.
JTO Clin Res Rep. 2020 Mar 7;1(2):100023. doi: 10.1016/j.jtocrr.2020.100023. eCollection 2020 Jun.
Despite initial benefit, virtually all patients suffering from -mutant NSCLC experience acquired resistance to tyrosine kinase inhibitors (TKIs), driven by multiple mechanisms. Recent reports have identified oncogenic kinase fusions as off-target resistance mechanisms; however, these alterations have been rarely investigated at EGFR TKIs progression.
Patients with -mutated metastatic NSCLC (N = 62) with tissue and plasma biopsies at EGFR TKI progression between January 2015 and June 2019, at a French hospital and optionally before progression, were identified from the prospective MATCH-R study (NCT02517892). Postprogression biopsy samples were analyzed for gene fusions using targeted gene panel sequencing, whole-exome sequencing, RNA sequencing, and comparative genomic hybridization array.
Six gene fusions were detected in tumor progression biopsies under an EGFR TKI from 62 consecutive patients (9.7%) with -mutated advanced NSCLC. Among 31 patients progressing to first- or second-generation EGFR TKIs, one (3%) had an Eukaryotic translation initiation factor 4 gamma 2-GRB2 associated binding protein 1 () fusion. Among 31 patients progressing to the third-generation osimertinib, five (16%) presented oncogene fusions of fibroblast growth factor receptor 3-transforming acidic coiled-coil containing protein 3 () (n = 2), kinesin family member 5B-Ret proto-oncogene () (n = 1), striatin-anaplastic lymphoma kinase () (n = 1), and zinc finger DHHC-Type palmitoyltransferase 20-Thr790Met () (n = 1) transcripts. Out of two patients that received osimertinib at first-line, one acquired an fusion at progression. In all patients, fusions co-occurred with the original activating mutation; however, among four patients with an acquired T790M mutation, three (75%) lost the T790M mutation.
Oncogenic fusions at the time of EGFR TKI resistance were identified at a relatively high frequency, mainly after the third-generation TKI osimertinib. Patients progressing to EGFR TKIs may have a new opportunity for targeted therapy when oncogenic fusions are identified.
尽管酪氨酸激酶抑制剂（TKIs）最初具有疗效，但几乎所有患有 - 突变非小细胞肺癌（NSCLC）的患者都会通过多种机制产生获得性耐药。最近的报告已将致癌激酶融合确定为脱靶耐药机制；然而，在表皮生长因子受体（EGFR）TKIs治疗进展时，这些改变很少被研究。
从前瞻性MATCH-R研究（NCT02517892）中确定了2015年1月至2019年6月期间在法国一家医院就诊的62例患有 - 突变转移性NSCLC的患者，这些患者在EGFR TKI治疗进展时进行了组织和血浆活检，部分患者在进展前也进行了活检。使用靶向基因panel测序、全外显子测序、RNA测序和比较基因组杂交阵列对进展后活检样本进行基因融合分析。
在62例连续的患有 - 突变晚期NSCLC的患者中，有6例（9.7%）在EGFR TKI治疗进展的肿瘤活检中检测到6种基因融合。在31例进展至第一代或第二代EGFR TKIs的患者中，1例（3%）有真核翻译起始因子4γ2 - GRB2相关结合蛋白1（）融合。在31例进展至第三代奥希替尼的患者中，5例（16%）出现成纤维细胞生长因子受体3 - 转化酸性卷曲螺旋蛋白3（）（n = 2）、驱动蛋白家族成员5B - 原癌基因Ret（）（n = 1）、条纹蛋白 - 间变性淋巴瘤激酶（）（n = 1）和锌指DHHC型棕榈酰转移酶20 - Thr790Met（）（n = 1）转录本的致癌基因融合。在2例一线接受奥希替尼治疗的患者中，1例在进展时获得了融合。在所有患者中，融合与原始激活的突变同时出现；然而，在4例获得性T790M突变的患者中，3例（75%）失去了T790M突变。
在EGFR TKI耐药时，致癌融合的发现频率相对较高，主要发生在第三代TKI奥希替尼治疗后。当发现致癌融合时，进展至EGFR TKIs的患者可能有新的靶向治疗机会。
