Detecting actionable mutations from matched plasma-based versus tissue next-generation sequencing in advanced non-small cell lung cancer: a retrospective single centre analysis on site
Abstract Background Liquid biopsies (LB) are used increasingly to detect actionable mutations in patients newly diagnosed with advanced non-small cell lung cancer (aNSCLC), though tissue biopsies (TB) still remain the gold standard. The value of systematically combining LB and TB next-generation seq...
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2025-08-01
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| Online Access: | https://doi.org/10.1186/s13046-025-03480-x |
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| author | Christophe Bontoux Caroline Lacoux Jonathan Benzaquen Jacques Boutros Guylène Rignol Elodie Long-Mira Sandra Lassalle Maryline Allegra Doriane Bohly Mathieu Garcia Christelle Bonnetaud Olivier Bordone Jean-Marc Félix Virginie Lespinet-Fabre Virginie Tanga Charles-Hugo Marquette Valérie Taly Aurélia Baurès Simon Heeke Marius Ilié Véronique Hofman Paul Hofman |
| author_facet | Christophe Bontoux Caroline Lacoux Jonathan Benzaquen Jacques Boutros Guylène Rignol Elodie Long-Mira Sandra Lassalle Maryline Allegra Doriane Bohly Mathieu Garcia Christelle Bonnetaud Olivier Bordone Jean-Marc Félix Virginie Lespinet-Fabre Virginie Tanga Charles-Hugo Marquette Valérie Taly Aurélia Baurès Simon Heeke Marius Ilié Véronique Hofman Paul Hofman |
| author_sort | Christophe Bontoux |
| collection | DOAJ |
| description | Abstract Background Liquid biopsies (LB) are used increasingly to detect actionable mutations in patients newly diagnosed with advanced non-small cell lung cancer (aNSCLC), though tissue biopsies (TB) still remain the gold standard. The value of systematically combining LB and TB next-generation sequencing (NGS) for genomic profiling in these patients remains controversial. Methods This single-centre retrospective study included 102 matched TB and LB samples collected from aNSCLC patients at diagnosis. Four circulating free DNA (cfDNA)-based NGS assays (1–4) were compared on site for performance and concordance with TB to detect ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) I/II. Additionally, cfDNA droplet digital PCR methylation (ddPCR-met) testing estimated the tumour fraction to refine the interpretation of wild-type (WT) results. Results Out of 102 patients, 13% had stage IIIB disease, and 11% presented with brain-only metastases. Adenocarcinoma was the predominant subtype (84%). Ninety LB samples yielded interpretable results across the four assays. Positive percent agreement with TB ranged from 56% (assay 2) to 79% (assay 4), with high concordance, particularly for single-nucleotide variants (SNVs). Hybrid capture-based assays (3 and 4) detected eight and seven gene fusions, respectively, while amplicon-based assays (1 and 2) detected only two each. Assay 3 only identified 12 MET amplifications, five of which were confirmed by fluorescence in situ hybridisation (FISH) but were missed by TB-based NGS. Five out of six negative cfDNA samples with ddPCR-met testing were WT across all assays. The plasma-first approach added incremental value, up to 21% (assay 3). Amplicon-based assays were faster and required less input of DNA for analysis. Patients with stage IIIB or brain-only metastases were significantly more likely to have negative/low levels of cfDNA ddPCR-met. Conclusions LB-based NGS demonstrated high concordance with TB in newly diagnosed aNSCLC, particularly for detection of SNV. Hybrid capture assays showed superior performance in identifying gene fusions and MET amplifications. The incremental value of a plasma-first strategy was limited in this real-life study. Thus, LB-based NGS on site should be seen as a complementary tool to TB-based NGS or an alternative when tissue samples are unavailable. Additionally, cfDNA methylation analysis enhances diagnostic accuracy in specific cases. |
| format | Article |
| id | doaj-art-055c7d9da73f404f8cedc11cdce42e73 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-055c7d9da73f404f8cedc11cdce42e732025-08-20T03:46:24ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-08-0144111510.1186/s13046-025-03480-xDetecting actionable mutations from matched plasma-based versus tissue next-generation sequencing in advanced non-small cell lung cancer: a retrospective single centre analysis on siteChristophe Bontoux0Caroline Lacoux1Jonathan Benzaquen2Jacques Boutros3Guylène Rignol4Elodie Long-Mira5Sandra Lassalle6Maryline Allegra7Doriane Bohly8Mathieu Garcia9Christelle Bonnetaud10Olivier Bordone11Jean-Marc Félix12Virginie Lespinet-Fabre13Virginie Tanga14Charles-Hugo Marquette15Valérie Taly16Aurélia Baurès17Simon Heeke18Marius Ilié19Véronique Hofman20Paul Hofman21Department of Pathology, Cancer University Institute of Toulouse-Oncopole, University Hospital of ToulouseInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceUniversité de Paris, UMR-S1138, CNRS SNC5096, Équipe Labélisée Ligue Nationale Contre le Cancer, Centre de Recherche des CordeliersMETHYS DxDepartment of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceInstitut Hospitalo-Universitaire RespirERA, Université Côte d’Azur, Hôpital Pasteur, CHU de NiceAbstract Background Liquid biopsies (LB) are used increasingly to detect actionable mutations in patients newly diagnosed with advanced non-small cell lung cancer (aNSCLC), though tissue biopsies (TB) still remain the gold standard. The value of systematically combining LB and TB next-generation sequencing (NGS) for genomic profiling in these patients remains controversial. Methods This single-centre retrospective study included 102 matched TB and LB samples collected from aNSCLC patients at diagnosis. Four circulating free DNA (cfDNA)-based NGS assays (1–4) were compared on site for performance and concordance with TB to detect ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) I/II. Additionally, cfDNA droplet digital PCR methylation (ddPCR-met) testing estimated the tumour fraction to refine the interpretation of wild-type (WT) results. Results Out of 102 patients, 13% had stage IIIB disease, and 11% presented with brain-only metastases. Adenocarcinoma was the predominant subtype (84%). Ninety LB samples yielded interpretable results across the four assays. Positive percent agreement with TB ranged from 56% (assay 2) to 79% (assay 4), with high concordance, particularly for single-nucleotide variants (SNVs). Hybrid capture-based assays (3 and 4) detected eight and seven gene fusions, respectively, while amplicon-based assays (1 and 2) detected only two each. Assay 3 only identified 12 MET amplifications, five of which were confirmed by fluorescence in situ hybridisation (FISH) but were missed by TB-based NGS. Five out of six negative cfDNA samples with ddPCR-met testing were WT across all assays. The plasma-first approach added incremental value, up to 21% (assay 3). Amplicon-based assays were faster and required less input of DNA for analysis. Patients with stage IIIB or brain-only metastases were significantly more likely to have negative/low levels of cfDNA ddPCR-met. Conclusions LB-based NGS demonstrated high concordance with TB in newly diagnosed aNSCLC, particularly for detection of SNV. Hybrid capture assays showed superior performance in identifying gene fusions and MET amplifications. The incremental value of a plasma-first strategy was limited in this real-life study. Thus, LB-based NGS on site should be seen as a complementary tool to TB-based NGS or an alternative when tissue samples are unavailable. Additionally, cfDNA methylation analysis enhances diagnostic accuracy in specific cases.https://doi.org/10.1186/s13046-025-03480-xLiquid biopsyCtDNANGSMethylationNon-small cell lung carcinomaActionable genomic alterations |
| spellingShingle | Christophe Bontoux Caroline Lacoux Jonathan Benzaquen Jacques Boutros Guylène Rignol Elodie Long-Mira Sandra Lassalle Maryline Allegra Doriane Bohly Mathieu Garcia Christelle Bonnetaud Olivier Bordone Jean-Marc Félix Virginie Lespinet-Fabre Virginie Tanga Charles-Hugo Marquette Valérie Taly Aurélia Baurès Simon Heeke Marius Ilié Véronique Hofman Paul Hofman Detecting actionable mutations from matched plasma-based versus tissue next-generation sequencing in advanced non-small cell lung cancer: a retrospective single centre analysis on site Journal of Experimental & Clinical Cancer Research Liquid biopsy CtDNA NGS Methylation Non-small cell lung carcinoma Actionable genomic alterations |
| title | Detecting actionable mutations from matched plasma-based versus tissue next-generation sequencing in advanced non-small cell lung cancer: a retrospective single centre analysis on site |
| title_full | Detecting actionable mutations from matched plasma-based versus tissue next-generation sequencing in advanced non-small cell lung cancer: a retrospective single centre analysis on site |
| title_fullStr | Detecting actionable mutations from matched plasma-based versus tissue next-generation sequencing in advanced non-small cell lung cancer: a retrospective single centre analysis on site |
| title_full_unstemmed | Detecting actionable mutations from matched plasma-based versus tissue next-generation sequencing in advanced non-small cell lung cancer: a retrospective single centre analysis on site |
| title_short | Detecting actionable mutations from matched plasma-based versus tissue next-generation sequencing in advanced non-small cell lung cancer: a retrospective single centre analysis on site |
| title_sort | detecting actionable mutations from matched plasma based versus tissue next generation sequencing in advanced non small cell lung cancer a retrospective single centre analysis on site |
| topic | Liquid biopsy CtDNA NGS Methylation Non-small cell lung carcinoma Actionable genomic alterations |
| url | https://doi.org/10.1186/s13046-025-03480-x |
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