Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression
Background Despite prolonged tumor response to immune checkpoint inhibitors (ICIs) for a subset of patients with advanced non-small cell lung cancer (NSCLC), a secondary resistance will occur for a majority of these patients. The understanding of late progression mechanisms with ICIs is important to...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2020-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/1/e000527.full |
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| author | Jean-François Emile Coraline Dumenil Jennifer Dumoulin Violaine Giraud Sylvie Labrune Catherine Julie Thierry Chinet Etienne Giroux Leprieur Zofia Hélias-Rodzewicz Paul Takam Kamga Adrien Costantini Alexandre Corjon Simon Garinet |
| author_facet | Jean-François Emile Coraline Dumenil Jennifer Dumoulin Violaine Giraud Sylvie Labrune Catherine Julie Thierry Chinet Etienne Giroux Leprieur Zofia Hélias-Rodzewicz Paul Takam Kamga Adrien Costantini Alexandre Corjon Simon Garinet |
| author_sort | Jean-François Emile |
| collection | DOAJ |
| description | Background Despite prolonged tumor response to immune checkpoint inhibitors (ICIs) for a subset of patients with advanced non-small cell lung cancer (NSCLC), a secondary resistance will occur for a majority of these patients. The understanding of late progression mechanisms with ICIs is important to improve future treatment strategies.Methods We performed whole-exome sequencing (WES) on circulating tumor DNA and compared molecular profiles between the beginning of ICI treatment and tumor progression in patients with advanced NSCLC treated with ICIs and who had initial and prolonged tumor response with secondary progression, after at least 6 months of treatment.Results We identified eight patients who experienced initial and durable tumor response, and secondary tumor progression after 6 months of treatment, with available paired blood samples (diagnosis and progression). All had lung adenocarcinoma, three had programmed-death ligand-1 expression ≥50% in immunohistochemistry and all presented low blood tumor mutational burden (bTMB). Seven patients received nivolumab in second-line or more, and one received pembrolizumab as first-line treatment. WES at progression showed clonal selection with molecular alterations of Wnt pathway-related genes, increase of copy number aberrations in cancer-related genes and loss of tumor-suppressor genes (such as PTEN) or of genes associated with immune response (such as B2M). No difference in term of bTMB was observed at progression.Conclusions This is the first study describing putative molecular mechanisms associated with late progression under ICI in lung cancer. Studies on treatment strategies adapted to these mechanisms are needed. |
| format | Article |
| id | doaj-art-03dd415e5a6e46c3a728013a99b7763e |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-03dd415e5a6e46c3a728013a99b7763e2024-11-08T17:55:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2020-000527Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progressionJean-François Emile0Coraline Dumenil1Jennifer Dumoulin2Violaine Giraud3Sylvie Labrune4Catherine Julie5Thierry Chinet6Etienne Giroux Leprieur7Zofia Hélias-Rodzewicz8Paul Takam Kamga9Adrien Costantini10Alexandre Corjon11Simon Garinet12EA4340-BECCOH, Versailles Saint-Quentin-en-Yvelines University, Versailles, Île-de-France, France2 Department of Respiratory DIseases and Thoracic Oncology, APHP - Hopital Ambroise Pare, Boulogne-Billancourt, France2 Department of Respiratory DIseases and Thoracic Oncology, APHP - Hopital Ambroise Pare, Boulogne-Billancourt, France2 Department of Respiratory DIseases and Thoracic Oncology, APHP - Hopital Ambroise Pare, Boulogne-Billancourt, France2 Department of Respiratory DIseases and Thoracic Oncology, APHP - Hopital Ambroise Pare, Boulogne-Billancourt, France1 Université Paris-Saclay, UVSQ, EA 4340 BECCOH, Boulogne-Billancourt, France1 Université Paris-Saclay, UVSQ, EA 4340 BECCOH, Boulogne-Billancourt, France1 Université Paris-Saclay, UVSQ, EA 4340 BECCOH, Boulogne-Billancourt, FranceDepartment of Pathology, Hôpital Ambroise-Pare, Boulogne-Billancourt, Île-de-France, France1 Université Paris-Saclay, UVSQ, EA 4340 BECCOH, Boulogne-Billancourt, France1 Université Paris-Saclay, UVSQ, EA 4340 BECCOH, Boulogne-Billancourt, France1 Université Paris-Saclay, UVSQ, EA 4340 BECCOH, Boulogne-Billancourt, France4 Department of Molecular Biology, APHP - Hopital Europeen Georges Pompidou, Paris, FranceBackground Despite prolonged tumor response to immune checkpoint inhibitors (ICIs) for a subset of patients with advanced non-small cell lung cancer (NSCLC), a secondary resistance will occur for a majority of these patients. The understanding of late progression mechanisms with ICIs is important to improve future treatment strategies.Methods We performed whole-exome sequencing (WES) on circulating tumor DNA and compared molecular profiles between the beginning of ICI treatment and tumor progression in patients with advanced NSCLC treated with ICIs and who had initial and prolonged tumor response with secondary progression, after at least 6 months of treatment.Results We identified eight patients who experienced initial and durable tumor response, and secondary tumor progression after 6 months of treatment, with available paired blood samples (diagnosis and progression). All had lung adenocarcinoma, three had programmed-death ligand-1 expression ≥50% in immunohistochemistry and all presented low blood tumor mutational burden (bTMB). Seven patients received nivolumab in second-line or more, and one received pembrolizumab as first-line treatment. WES at progression showed clonal selection with molecular alterations of Wnt pathway-related genes, increase of copy number aberrations in cancer-related genes and loss of tumor-suppressor genes (such as PTEN) or of genes associated with immune response (such as B2M). No difference in term of bTMB was observed at progression.Conclusions This is the first study describing putative molecular mechanisms associated with late progression under ICI in lung cancer. Studies on treatment strategies adapted to these mechanisms are needed.https://jitc.bmj.com/content/8/1/e000527.full |
| spellingShingle | Jean-François Emile Coraline Dumenil Jennifer Dumoulin Violaine Giraud Sylvie Labrune Catherine Julie Thierry Chinet Etienne Giroux Leprieur Zofia Hélias-Rodzewicz Paul Takam Kamga Adrien Costantini Alexandre Corjon Simon Garinet Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression Journal for ImmunoTherapy of Cancer |
| title | Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression |
| title_full | Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression |
| title_fullStr | Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression |
| title_full_unstemmed | Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression |
| title_short | Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression |
| title_sort | sequential ctdna whole exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression |
| url | https://jitc.bmj.com/content/8/1/e000527.full |
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