Michèle Beau-Faller1, Erwan Pencreach2, Charlotte Leduc3, Hélène Blons4, Jean-Philippe Merlio5, Pierre-Paul Bringuier6, Florence de Fraipont7, Fabienne Escande8, Antoinette Lemoine9, L'Houcine Ouafik10, Marc Denis11, Paul Hofman12, Roger Lacave13, Samia Melaabi14, Alexandra Langlais15, Pascale Missy16, Franck Morin16, Denis Moro-Sibilot17, Fabrice Barlesi18, Jacques Cadranel19. 1. Laboratory of Biochemistry and Molecular Biology, Centre Hospitalier Universitaire de Strasbourg, Hôpital de Hautepierre, Strasbourg, France; IRFAC UMR-S1113, Inserm, Université de Strasbourg, Strasbourg, France. Electronic address: michele.faller@chru-strasbourg.fr. 2. IRFAC UMR-S1113, Inserm, Université de Strasbourg, Strasbourg, France. 3. Chest Department, Centre Hospitalier Universitaire de Strasbourg, Nouvel Hôpital Civil, Strasbourg, France. 4. HEGP, Biochimie UF de Pharmacogénétique et Oncologie Moléculaire, Paris, France. 5. Department of Pathology and Tumor Biology, CHU and University Bordeaux, Hôpital Haut-Lévêque, Pessac, France. 6. Centre de Biologie et Pathologie Est, Service d'Anatomie et de Cytologie Pathologique, Hospices Civils de Lyon et Université Claude Bernard Lyon 1, Lyon, France. 7. UM de Génétique moléculaire: Maladies Héréditaires et Oncologie, Pôle de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France; UGA/INSERM U1209/CNRS 5309-Institute for Advanced Biosciences-Université Grenoble Alpes, Grenoble, France. 8. Laboratoire de Biochimie et Biologie moléculaire, CHRU Lille, LILLE, France. 9. Biochimie et Oncogénétique INSERM UMR-S1193, Hôpital Paul Brousse, Hôpitaux Universitaires Paris-Sud, Villejuif, France. 10. Aix Marseille Univ, APHM, CNRS, INP, Inst Neurophysiopathol, Faculté de Médecine Secteur Nord, Service de Transfert d'Oncologie Biologique, Marseille, France. 11. Laboratoire de Biochimie et Plateforme de Génétique Moléculaire des Cancers, CHU Nantes, Nantes, France. 12. Université Côte d'Azur, and FHU OncoAge, Laboratory of Clinical and Experimental Pathology, Inserm U1081/CNRS 7284, and Hospital-Integrated Biobank (BB-0033-00025) Pasteur Hospital, Nice, France. 13. Faculté de Médecine Sorbonne Université, and Groupe Hospitalier HUEP, Hôpital Tenon, Unité de Génomique des Tumeurs Solides, Assistance Publique-Hôpitaux de Paris, France. 14. Service de Génétique, Unité de Pharmacogénomique, Institut Curie, Paris, France. 15. Department of Biostatistics, French Cooperative Thoracic Intergroup, Paris, France. 16. Clinical Research Unit, French Cooperative Thoracic Intergroup, Paris, France. 17. Unité d'Oncologie Thoracique, Service Hospitalier Universitaire Pneumologie Physiologie Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, Grenoble, France. 18. Aix Marseille University, CNRS, INSERM, CRCM, Assistance Publique Hôpitaux de Marseille, Marseille, France. 19. AP-HP, Hôpital Tenon, Service de Pneumogie, GRC 04 Theranoscan, Sorbonne Université, Paris, France.
Abstract
OBJECTIVES: T790M mutations inEGFR-mutated non-small cell lung cancer (NSCLC) account for nearly 50% of acquired resistance mechanisms to EGFR-TKIs. Earlier studies suggested that tumor T790M could also be detected in TKI-naïve EGFR-mutated NSCLC. The aim of the study is to assess the prevalence and clinical significance of quantification of tumor pre-treatment T790M subclones. MATERIALS AND METHODS: We analyzed 366 EGFR-mutated NSCLC patients of the real-life IFCT Biomarkers France study with available pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor DNA before treatment by first/second-generation EGFR-TKI. We used ultra-sensitive Droplet Digital Polymerase Chain Reaction (ddPCR) QX200 (BIO-RAD®, Hercules, CA, USA). All samples were tested in duplicate. RESULTS: ddPCR identified T790M in 19/240 specimens (8%). T790M-positive and T790M-negative populations were not different for clinical baseline characteristics. T790M Variant Allele Frequency (VAF) was > 0.01% <0.1%, > 0.1% <1%, > 1% <10%, and >10% in five (26.3%), six (31.6%), six (31.6%), and two (10.5%) patients, respectively. T790M VAF was >0.1% in 11/13 (84%) patients with rapid (<3 months) or usual progression (3-20 months) compared to 0/3 with low progression (>20 months) (p = 0.02). In a Cox model, T790M mutation positivity was correlated with overall survival (OS) and progression-free survival (PFS) for 10% > VAF >1% (hazard ratio [HR] = 2.83, 95% confidence interval [CI] 1.13-7.07, p = 0.03; HR=3.62, 95%CI 1.43-4.92, p = 0.007, respectively) and for VAF >10% (HR = 19.14, 95%CI 4.35-84.26, p < 0.001; HR = 17.89, 95%CI 2.21-144.86, p = 0.007, respectively). CONCLUSION: Ultra-sensitive detection of tumor T790M mutation concerned 8% of EGFR-mutated TKI-naïve NSCLC patients and has a negative prognostic value only for T790M VAF over 1%.
OBJECTIVES:T790M mutations inEGFR-mutated non-small cell lung cancer (NSCLC) account for nearly 50% of acquired resistance mechanisms to EGFR-TKIs. Earlier studies suggested that tumorT790M could also be detected in TKI-naïve EGFR-mutated NSCLC. The aim of the study is to assess the prevalence and clinical significance of quantification of tumor pre-treatment T790M subclones. MATERIALS AND METHODS: We analyzed 366 EGFR-mutated NSCLC patients of the real-life IFCT Biomarkers France study with available pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor DNA before treatment by first/second-generation EGFR-TKI. We used ultra-sensitive Droplet Digital Polymerase Chain Reaction (ddPCR) QX200 (BIO-RAD®, Hercules, CA, USA). All samples were tested in duplicate. RESULTS: ddPCR identified T790M in 19/240 specimens (8%). T790M-positive and T790M-negative populations were not different for clinical baseline characteristics. T790M Variant Allele Frequency (VAF) was > 0.01% <0.1%, > 0.1% <1%, > 1% <10%, and >10% in five (26.3%), six (31.6%), six (31.6%), and two (10.5%) patients, respectively. T790MVAF was >0.1% in 11/13 (84%) patients with rapid (<3 months) or usual progression (3-20 months) compared to 0/3 with low progression (>20 months) (p = 0.02). In a Cox model, T790M mutation positivity was correlated with overall survival (OS) and progression-free survival (PFS) for 10% > VAF >1% (hazard ratio [HR] = 2.83, 95% confidence interval [CI] 1.13-7.07, p = 0.03; HR=3.62, 95%CI 1.43-4.92, p = 0.007, respectively) and for VAF >10% (HR = 19.14, 95%CI 4.35-84.26, p < 0.001; HR = 17.89, 95%CI 2.21-144.86, p = 0.007, respectively). CONCLUSION: Ultra-sensitive detection of tumorT790M mutation concerned 8% of EGFR-mutated TKI-naïve NSCLC patients and has a negative prognostic value only for T790MVAF over 1%.
Authors: Weiting Li; Klaas Kok; Geok Wee Tan; Pei Meng; Mirjam Mastik; Naomi Rifaela; Frank Scherpen; T Jeroen N Hiltermann; Harry J M Groen; Anthonie J van der Wekken; Anke van den Berg Journal: Cancers (Basel) Date: 2022-07-19 Impact factor: 6.575