Dhiab R Ben, Loyaux R, Garinet S, Bastide M, Léonard-Goyet S, Fabre Elizabeth, Mansuet-Lupo Audrey, Gibault Laure, Jouveshomme S, Giroux-Leprieur E, Leroy K, Wislez M, Blons H
Department of Pneumology, Institut du Cancer Paris Carpem, APHP, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.
Department of Biochemistry, Pharmacogenetics and Molecular Oncology, Institut du Cancer Paris Carpem, APHP, Hopital Européen Georges Pompidou, Paris, France.
Sci Rep. 2025 Jun 2;15(1):19347. doi: 10.1038/s41598-025-99541-4.
MET exon 14 skipping is an oncogenic driver observed in 1 to 4% of non-small cell lung cancer (NSCLC). MET exon 14 mutations affect splice sites and are highly heterogeneous which makes them difficult to detect. Because of the approval of capmatinib for patients with MET exon 14 mutated tumors and the related poor response to immunotherapy (ICI) for a subset of patients with MET mutated tumors, MET screening has become mandatory for first line treatment decision. Here we report our testing experience based on 1143 consecutive NSCLC addressed for molecular diagnosis. Two strategies using either DNA sequencing (NGS) and fragment analysis or DNA-RNA sequencing (NGS) were developed and validated to accurately detect MET exon 14 alterations including large deletions. For patients with MET tumors (n = 46), demographic characteristics, treatments and outcomes were obtained from medical records and discussed. 46 MET exon 14 alterations were identified, 4 were not called by DNA sequencing and rescued by fragment analysis or RNA sequencing. Sixty-seven percent tumors had a high PD-L1 expression > 50 and 42% of cases had co-occurring alterations, mainly TP53 mutations (24%) and PIK3CA mutations (9%). Response to MET inhibitors (Crizotinib and Capmatinib) was evaluated for 15 patients. The ORR (Objective Response Rate) and the median of PFS (Progression Free Survival) were 44% and 5.5 months [1.6-18.2 months] respectively. Thirteen patients were treated by immunotherapy, ORR and median PFS (Progression Free Survival) median were 30% and 4 months [0.7-55.5 months] respectively. The response to immunotherapy was not correlated with PD-L1 status but smokers seemed to better respond to ICIs. This study highlights that a multimodal approach may be necessary to detect MET exon 14 mutations as large deletions may not be detected by DNA sequencing. Targeted DNA-ARN sequencing strategies broadly interrogate the diverse druggable genomic variations and permits direct detection of altered splicing or gene fusions. Because patients with MET exon 14 mutated tumors, demonstrate low response to immunotherapy despite high PDL1 and because MET exon 14 is druggable the detection of MET mutations is mandatory to optimize treatment.
MET外显子14跳跃是在1%至4%的非小细胞肺癌（NSCLC）中观察到的致癌驱动因素。MET外显子14突变影响剪接位点，且高度异质，这使得它们难以检测。由于卡马替尼已获批用于治疗MET外显子14突变肿瘤患者，且一部分MET突变肿瘤患者对免疫疗法（ICI）反应不佳，因此MET检测已成为一线治疗决策的必要环节。在此，我们报告基于1143例连续接受分子诊断的NSCLC患者的检测经验。我们开发并验证了两种策略，即使用DNA测序（NGS）和片段分析或DNA-RNA测序（NGS），以准确检测MET外显子14改变，包括大片段缺失。对于MET肿瘤患者（n = 46），从病历中获取其人口统计学特征、治疗情况和预后，并进行讨论。共鉴定出46例MET外显子14改变，其中4例DNA测序未检测到，通过片段分析或RNA测序得以挽救。67%的肿瘤PD-L1高表达>50，42%的病例存在共发改变，主要是TP53突变（24%）和PIK3CA突变（9%）。对15例患者评估了对MET抑制剂（克唑替尼和卡马替尼）的反应。客观缓解率（ORR）和无进展生存期（PFS）中位数分别为44%和5.5个月[1.6 - 18.2个月]。13例患者接受了免疫治疗，ORR和PFS中位数分别为30%和4个月[0.7 - 55.5个月]。免疫治疗反应与PD-L1状态无关，但吸烟者似乎对ICI反应更好。这项研究强调，由于大片段缺失可能无法通过DNA测序检测到，因此可能需要采用多模式方法来检测MET外显子14突变。靶向DNA-ARN测序策略广泛探究各种可靶向治疗的基因组变异，并允许直接检测剪接改变或基因融合。由于MET外显子14突变肿瘤患者尽管PD-L1高表达，但对免疫治疗反应较低，且MET外显子14可靶向治疗，因此检测MET突变对于优化治疗至关重要。
