Marius Ilié1, Julien Mazières2, Emmanuel Chamorey3, Simon Heeke4, Jonathan Benzaquen5, Brice Thamphya3, Jacques Boutros6, Angélica Tiotiu7, Julien Fayada8, Jacques Cadranel9, Michel Poudenx10, Denis Moro-Sibilot11, Fabrice Barlesi12, Juliette Thariat13, Christelle Clément-Duchêne14, Pascale Tomasini15, Véronique Hofman1, Charles-Hugo Marquette5, Paul Hofman16. 1. Laboratory of Clinical and Experimental Pathology, FHU OncoAge, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Hospital-Related Biobank (BB-0033-00025), FHU OncoAge, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Institute of Research on Cancer and Ageing of Nice (IRCAN), CNRS, INSERM, FHU OncoAge, Université Côte d'Azur, Nice, France. 2. Department of Pulmonology, Centre Hospitalier Universitaire Toulouse, Institut Universitaire du Cancer, Université Paul Sabatier, Toulouse, France. 3. Biostatistics Unit, Antoine Lacassagne Comprehensive Cancer Center, Nice, France. 4. Laboratory of Clinical and Experimental Pathology, FHU OncoAge, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Hospital-Related Biobank (BB-0033-00025), FHU OncoAge, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Institute of Research on Cancer and Ageing of Nice (IRCAN), CNRS, INSERM, FHU OncoAge, Université Côte d'Azur, Nice, France; Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 5. Institute of Research on Cancer and Ageing of Nice (IRCAN), CNRS, INSERM, FHU OncoAge, Université Côte d'Azur, Nice, France; Department of Pulmonary Medicine and Oncology, FHU OncoAge, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France. 6. Department of Pulmonary Medicine and Oncology, FHU OncoAge, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France. 7. Department of Pulmonology, Centre Hospitalier Régional Universitaire de Nancy, Nancy, France; Development, Adaptation and Disadvantage, Cardio-Respiratory Regulations and Motor Control, Université de Lorraine, Nancy, France. 8. Hospital-Related Biobank (BB-0033-00025), FHU OncoAge, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France. 9. Department of Pulmonology, APHP, Hôpital Tenon and GRC04 Theranoscan, Sorbonne Université, Paris, France. 10. Department of Pulmonary Medicine and Oncology, FHU OncoAge, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Department of Oncology, Centre Antoine Lacassagne, Nice, France. 11. Thoracic Oncology Unit, Centre hospitalier universitaire Grenoble-Alpes, Grenoble, France. 12. Centre d'Essais Précoces en Cancérologie de Marseille CLIP(2), Aix Marseille University, CNRS, INSERM, CRCM, APHM, Marseille, France; Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France. 13. Department of Radiation Therapy, Centre François Baclesse-ARCHADE, Université de Caen Normandie, Caen, France. 14. Oncology Department, Institut de Cancérologie de Lorraine, Nancy, France. 15. Centre d'Essais Précoces en Cancérologie de Marseille CLIP(2), Aix Marseille University, CNRS, INSERM, CRCM, APHM, Marseille, France. 16. Laboratory of Clinical and Experimental Pathology, FHU OncoAge, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Hospital-Related Biobank (BB-0033-00025), FHU OncoAge, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Institute of Research on Cancer and Ageing of Nice (IRCAN), CNRS, INSERM, FHU OncoAge, Université Côte d'Azur, Nice, France. Electronic address: hofman.p@chu-nice.fr.
Abstract
INTRODUCTION: Patients with advanced-stage NSCLC whose tumors harbor an ALK gene rearrangement benefit from treatment with multiple ALK inhibitors (ALKi). Approximately 30% of tumor biopsy samples contain insufficient tissue for successful ALK molecular characterization. This study evaluated the added value of analyzing circulating tumor cells (CTCs) as a surrogate to ALK tissue analysis and as a function of the response to ALKi. METHODS: We conducted a multicenter, prospective observational study (NCT02372448) of 203 patients with stage IIIB/IV NSCLC across nine French centers, of whom 81 were ALK positive (immunohistochemistry or fluorescence in situ hybridization [FISH]) and 122 ALK negative on paraffin-embedded tissue specimens. Blood samples were collected at baseline and at 6 and 12 weeks after ALKi initiation or at disease progression. ALK gene rearrangement was evaluated with CTCs using immunocytochemistry and FISH analysis after enrichment using a filtration method. RESULTS: At baseline, there was a high concordance between the detection of an ALK rearrangement in the tumor tissue and in CTCs as determined by immunocytochemistry (sensitivity, 94.4%; specificity 89.4%). The performance was lower for the FISH analysis (sensitivity, 35.6%; specificity, 56.9%). No significant association between the baseline levels or the dynamic change of CTCs and overall survival (hazard ratio = 0.59, 95% confidence interval: 0.24-1.5, p = 0.244) or progression-free survival (hazard ratio = 0.84, 95% confidence interval: 0.44-1.6, p = 0.591) was observed in the patients with ALK-positive NSCLC. CONCLUSIONS: CTCs can be used as a complementary tool to a tissue biopsy for the detection of ALK rearrangements. Longitudinal analyses of CTCs revealed promise for real-time patient monitoring and improved delivery of molecularly guided therapy in this population.
INTRODUCTION:Patients with advanced-stage NSCLC whose tumors harbor an ALK gene rearrangement benefit from treatment with multiple ALK inhibitors (ALKi). Approximately 30% of tumor biopsy samples contain insufficient tissue for successful ALK molecular characterization. This study evaluated the added value of analyzing circulating tumor cells (CTCs) as a surrogate to ALK tissue analysis and as a function of the response to ALKi. METHODS: We conducted a multicenter, prospective observational study (NCT02372448) of 203 patients with stage IIIB/IV NSCLC across nine French centers, of whom 81 were ALK positive (immunohistochemistry or fluorescence in situ hybridization [FISH]) and 122 ALK negative on paraffin-embedded tissue specimens. Blood samples were collected at baseline and at 6 and 12 weeks after ALKi initiation or at disease progression. ALK gene rearrangement was evaluated with CTCs using immunocytochemistry and FISH analysis after enrichment using a filtration method. RESULTS: At baseline, there was a high concordance between the detection of an ALK rearrangement in the tumor tissue and in CTCs as determined by immunocytochemistry (sensitivity, 94.4%; specificity 89.4%). The performance was lower for the FISH analysis (sensitivity, 35.6%; specificity, 56.9%). No significant association between the baseline levels or the dynamic change of CTCs and overall survival (hazard ratio = 0.59, 95% confidence interval: 0.24-1.5, p = 0.244) or progression-free survival (hazard ratio = 0.84, 95% confidence interval: 0.44-1.6, p = 0.591) was observed in the patients with ALK-positive NSCLC. CONCLUSIONS: CTCs can be used as a complementary tool to a tissue biopsy for the detection of ALK rearrangements. Longitudinal analyses of CTCs revealed promise for real-time patient monitoring and improved delivery of molecularly guided therapy in this population.
Authors: Giovanni Maria Iannantuono; Silvia Riondino; Stefano Sganga; Mario Roselli; Francesco Torino Journal: Int J Mol Sci Date: 2022-04-03 Impact factor: 5.923
Authors: Simon Heeke; Jonathan Benzaquen; Audrey Vallee; Maryline Allegra; Julien Mazieres; Julien Fayada; Jaya Rajamani; Michael Lee; Ellen Ordinario; Angelica Tiotiu; Jacques Cadranel; Michel Poudenx; Denis Moro-Sibilot; Fabrice Barlesi; Radj Gervais; Juliette Thariat; Virginie Tanga; Jacques Boutros; Marius Ilié; Véronique Hofman; Charles-Hugo Marquette; Marc G Denis; Paul Hofman Journal: Ann Transl Med Date: 2021-06