Longitudinal Whole-Exome Sequencing of Cell-Free DNA Reveals Molecular Evolution and Heterogeneous Clinical Outcomes in PD-L1 Stratified Advanced NSCLC Adenocarcinoma Patients Treated with Atezolizumab
Rattachement africain : it. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Programmed death-ligand 1 (PD-L1) expression is routinely used to guide immune checkpoint inhibitor (ICI) therapy in advanced non-small cell lung cancer (NSCLC), yet clinical benefit remains heterogeneous even among PD-L1–high tumors. Liquid biopsy based on cell-free DNA (cfDNA) enables minimally invasive, real-time monitoring of tumor evolution. We report four cases of metastatic lung adenocarcinoma treated with atezolizumab, integrating longitudinal whole-exome sequencing (WES) of cfDNA with radiological assessment. Four patients with PD-L1–positive (≥60%) metastatic NSCLC received atezolizumab monotherapy. Serial cfDNA samples (1–3 per patient) were analyzed by high-depth WES. Distinct molecular trajectories paralleled divergent clinical outcomes. One patient achieved a complete molecular response, characterized by progressive clearance of KRAS, ATM, and NF1 mutant clones, which was concordant with radiological remission. A second patient showed an initial molecular response, followed by clonal rebound of TP53, NF1, and NOTCH2 mutant populations and the emergence of PTEN and KIF1A variants, suggesting clinical progression. Two patients exhibited primary resistance despite high PD-L1 expression, with persistent or expanding clones and early subclonal diversification; in one case, new EGFR and BRAF alterations emerged under treatment pressure. Notably, switching to platinum-based chemotherapy in a non-responder induced a measurable molecular response, highlighting discordance between PD-L1 status and immunotherapy efficacy. Longitudinal cfDNA WES captured dynamic clonal remodeling under immunotherapy and anticipated radiological outcomes. These findings underscore the clinical necessity of integrating dynamic molecular monitoring by liquid biopsy to overcome the limitations of static PD-L1 assessment, refine therapeutic stratification, and identify early resistance mechanisms in advanced NSCLC.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Longitudinal Whole-Exome Sequencing of Cell-Free DNA Reveals Molecular Evolution and Heterogeneous Clinical Outcomes in PD-L1 Stratified Advanced NSCLC Adenocarcinoma Patients Treated with Atezolizumab
- Date Crossref
- 24/03/2026
- Éditeur
- MDPI AG
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
University of Siena Cancer Genomics & Systems Biology Lab pays non établi dans la noticeUniversité ou école supérieure
-
Azienda Ospedaliera Universitaria Senese pays non établi dans la noticeÉtablissement de santé
-
Magna Graecia University pays non établi dans la noticeUniversité ou école supérieure
-
Institute of Biomedical Technologies pays non établi dans la noticeStructure de recherche
-
National Research Council pays non établi dans la noticeOrganisation à but non lucratif
-
Oncology Unit pays non établi dans la noticeInstitution
-
Thoracic Surgery Unit pays non établi dans la noticeInstitution
-
University “Magna Graecia” of Catanzaro Department of Experimental and Clinical Medicine pays non établi dans la noticeUniversité ou école supérieure
-
Clinical Pathology Unit pays non établi dans la noticeÉtablissement de santé
-
Institute for Biomedical Technologies pays non établi dans la noticeStructure de recherche
Cancer Genomics & Systems Biology Lab — University of Siena, Azienda Ospedaliera Universitaria Senese et Magna Graecia University, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.