{"title":"Putative mechanisms of primary resistance to EGFR-targeted therapies: A retrospective study","authors":"","doi":"10.1016/j.lungcan.2024.107998","DOIUrl":null,"url":null,"abstract":"<div><h3>Backgrounds</h3><div>Advanced lung adenocarcinoma (LUAD) patient with <em>EGFR</em> mutations often experience resistance to first-line epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) therapy. Nonetheless, the mechanism and biomarkers of primary resistance remain unclear. Further exploration of independent prognostic factors will help clinicians identify patients who may not respond to EGFR-TKIs and select appropriate treatment strategies.</div></div><div><h3>Methods</h3><div>A retrospective study involving 124 patients with stage IV LUAD harboring a common sensitizing <em>EGFR</em> mutation (exon 19 deletion or L858R mutation) who received EGFR-TKIs as first-line therapy was performed. All participants were tested by DNA-targeted sequencing in baseline samples, and there were 19 patients with progression-free survival (PFS) ≤ 3 months (cohort 1, C1, primary resistance), 22 patients with 3 < PFS < 8 months (cohort 2, C2, poor response) without known mutations associated with resistance, and 83 patients with PFS ≥ 8 months (cohort 3, C3, normal).</div></div><div><h3>Results</h3><div>The most commonly mutated genes at baseline in patients prior to treatment within the entire study population. were <em>TP53</em> (65 %), <em>MYC</em> (19 %), <em>CDKN2A</em> (12 %), <em>MUC16</em> (12 %) and <em>RBM10</em> (12 %). The baseline characteristics, except for the proportions of patients with <em>EGFR</em> L858R mutation and exon 19 deletion in C1 plus C2 compared to C3 (<em>p</em> = 0.036), were not significantly different among the cohorts. The frequencies of <em>PIK3C2G</em>, <em>STK11</em>, <em>EPAS1</em>, <em>RARA</em> and <em>BTG2</em> variation were significantly higher in C1, the primary resistance group. Multivariate Cox analysis revealed that <em>PIK3C2G</em> (HR 15.70 95 % CI 3.24–76.05, <em>p</em> < 0.001), <em>STK11</em> (HR 17.04, 95 % CI 3.68–78.92, <em>p</em> < 0.001), <em>EPAS1</em> (HR 11.99, 95 % CI 2.57–56.03, <em>p</em> = 0.002), and <em>BTG2</em> amplification (HR 9.53, 95 % CI 1.67–54.28, <em>p</em> = 0.011) were significantly associated with shorter PFS.</div></div><div><h3>Conclusions</h3><div>The genomic landscape varies significantly among patients with LUAD, which should be considered when making personalized treatment decisions. This information could provide insights into molecular changes and their effects on clinical treatment in diverse patients with LUAD harboring sensitizing <em>EGFR</em> mutations.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":null,"pages":null},"PeriodicalIF":4.5000,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Lung Cancer","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0169500224005324","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Backgrounds
Advanced lung adenocarcinoma (LUAD) patient with EGFR mutations often experience resistance to first-line epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) therapy. Nonetheless, the mechanism and biomarkers of primary resistance remain unclear. Further exploration of independent prognostic factors will help clinicians identify patients who may not respond to EGFR-TKIs and select appropriate treatment strategies.
Methods
A retrospective study involving 124 patients with stage IV LUAD harboring a common sensitizing EGFR mutation (exon 19 deletion or L858R mutation) who received EGFR-TKIs as first-line therapy was performed. All participants were tested by DNA-targeted sequencing in baseline samples, and there were 19 patients with progression-free survival (PFS) ≤ 3 months (cohort 1, C1, primary resistance), 22 patients with 3 < PFS < 8 months (cohort 2, C2, poor response) without known mutations associated with resistance, and 83 patients with PFS ≥ 8 months (cohort 3, C3, normal).
Results
The most commonly mutated genes at baseline in patients prior to treatment within the entire study population. were TP53 (65 %), MYC (19 %), CDKN2A (12 %), MUC16 (12 %) and RBM10 (12 %). The baseline characteristics, except for the proportions of patients with EGFR L858R mutation and exon 19 deletion in C1 plus C2 compared to C3 (p = 0.036), were not significantly different among the cohorts. The frequencies of PIK3C2G, STK11, EPAS1, RARA and BTG2 variation were significantly higher in C1, the primary resistance group. Multivariate Cox analysis revealed that PIK3C2G (HR 15.70 95 % CI 3.24–76.05, p < 0.001), STK11 (HR 17.04, 95 % CI 3.68–78.92, p < 0.001), EPAS1 (HR 11.99, 95 % CI 2.57–56.03, p = 0.002), and BTG2 amplification (HR 9.53, 95 % CI 1.67–54.28, p = 0.011) were significantly associated with shorter PFS.
Conclusions
The genomic landscape varies significantly among patients with LUAD, which should be considered when making personalized treatment decisions. This information could provide insights into molecular changes and their effects on clinical treatment in diverse patients with LUAD harboring sensitizing EGFR mutations.
期刊介绍:
Lung Cancer is an international publication covering the clinical, translational and basic science of malignancies of the lung and chest region.Original research articles, early reports, review articles, editorials and correspondence covering the prevention, epidemiology and etiology, basic biology, pathology, clinical assessment, surgery, chemotherapy, radiotherapy, combined treatment modalities, other treatment modalities and outcomes of lung cancer are welcome.