Tavernari Daniele, Borgeaud Maxime, Liu Ximeng, Parikh Kaushal, Le Xiuning, Ciriello Giovanni, Addeo Alfredo
Department of Computational Biology, University of Lausanne (UNIL), 1011 Lausanne, Vaud, Switzerland; Swiss Cancer Center Léman, Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland; Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Oncology Service, University Hospital Geneva, Geneva, Switzerland.
J Thorac Oncol. 2025 Apr;20(4):500-506. doi: 10.1016/j.jtho.2024.12.012. Epub 2024 Dec 16.
EGFR mutations are key oncogenic drivers in lung adenocarcinoma (LUAD), predominantly affecting Asian, nonsmoking, and female populations. Although common mutations, such as exon 19 deletions and L858R, respond well to tyrosine kinase inhibitors (TKIs), uncommon EGFR mutations and compound variants exhibit variable treatment responses. This study aims to compare clinical characteristics and molecular profiles of patients with common, uncommon, and compound EGFR mutations, assessing their implications for therapy outcomes.
We analyzed a multi-cohort genomic dataset of 19,163 patients with LUAD (5,212 with EGFR mutations), categorizing mutations into common, uncommon, and compound classes. Patient demographics, mutational signatures, and tumor microenvironment factors were assessed, with particular attention to smoking status and concomitant alterations in KRAS and TP53. Treatment outcomes were analyzed by time under treatment as a surrogate measure of TKI efficacy.
Uncommon EGFR mutations, comprising 8.9% of EGFR-altered cases, were significantly more frequent among smokers and associated with tobacco-related mutational signatures. Compared with common EGFR-mutant cases, tumors harboring uncommon EGFR mutations reported higher rates of EGFR amplifications, KRAS, and TP53 mutations. Uncommon mutations also exhibited higher tumor mutational burden and distinct transcriptional profiles linked to cell cycle activity. Median time on treatment with TKIs was notably shorter in patients with uncommon mutations (4.1 mo) than those with common and compound mutations (10.9 mo and 12.4 mo, respectively).
This study underscores the clinical and molecular heterogeneity of EGFR mutation classes in LUAD, highlighting the unique profile of uncommon mutations, particularly their association with smoking and co-mutations in KRAS and TP53. Comprehensive molecular testing, including next-generation sequencing, is crucial to identify these uncommon mutations and inform therapeutic decisions. Further investigation into the role of immunotherapy in patients with uncommon EGFR mutations is warranted given the tobacco-related molecular signatures and high tumor mutational burden associated with this subgroup.
表皮生长因子受体（EGFR）突变是肺腺癌（LUAD）的关键致癌驱动因素，主要影响亚洲、不吸烟及女性人群。尽管常见突变，如19外显子缺失和L858R，对酪氨酸激酶抑制剂（TKIs）反应良好，但罕见的EGFR突变和复合变体的治疗反应各不相同。本研究旨在比较具有常见、罕见和复合EGFR突变患者的临床特征和分子图谱，评估其对治疗结果的影响。
我们分析了19163例LUAD患者（5212例有EGFR突变）的多队列基因组数据集，将突变分为常见、罕见和复合类别。评估了患者的人口统计学、突变特征和肿瘤微环境因素，特别关注吸烟状况以及KRAS和TP53的伴随改变。通过治疗时间分析治疗结果，作为TKI疗效的替代指标。
罕见EGFR突变占EGFR改变病例的8.9%，在吸烟者中明显更常见，且与烟草相关的突变特征有关。与常见EGFR突变病例相比，携带罕见EGFR突变的肿瘤报告的EGFR扩增、KRAS和TP53突变率更高。罕见突变还表现出更高的肿瘤突变负荷和与细胞周期活性相关的独特转录图谱。罕见突变患者使用TKIs治疗的中位时间（4.1个月）明显短于常见和复合突变患者（分别为10.9个月和12.4个月）。
本研究强调了LUAD中EGFR突变类别的临床和分子异质性，突出了罕见突变的独特特征，特别是它们与吸烟以及KRAS和TP53共突变的关联。全面的分子检测，包括二代测序，对于识别这些罕见突变并为治疗决策提供依据至关重要。鉴于该亚组与烟草相关的分子特征和高肿瘤突变负荷，有必要进一步研究免疫疗法在罕见EGFR突变患者中的作用。
