Lino Möhrmann, Lysann Rostock, Maximilian Werner, Małgorzata Oleś, Jonas S Arnold, Nagarajan Paramasivam, Korinna Jöhrens, Luise Rupp, Marc Schmitz, Daniela Richter, Sebastian Uhrig, Martina Fröhlich, Barbara Hutter, Jennifer Hüllein, Arne Jahn, Marie Arlt, Elena E Möhrmann, Dorothea Hanf, Laura Gieldon, Simon Kreutzfeldt, Christoph E Heilig, Maria-Veronica Teleanu, Daniel B Lipka, Katja Beck, Annika Baude-Müller, Andreas Mock, Ivan Jelas, Damian T Rieke, Marcel Wiesweg, Christian Brandts, Melanie Boerries, Anna L Illert, Alexander Desuki, Thomas Kindler, Angela M Krackhardt, C Benedikt Westphalen, Petros Christopoulos, Leonidas Apostolidis, Albrecht Stenzinger, Michael Allgäuer, Olaf Neumann, Irina A Kerle, Peter Horak, Christoph Heining, Heidrun Grosch, Evelin Schröck, Daniel Hübschmann, Stefan Fröhling, Hanno Glimm
{"title":"Genomic landscape and molecularly informed therapy in thymic carcinoma and other advanced thymic epithelial tumors.","authors":"Lino Möhrmann, Lysann Rostock, Maximilian Werner, Małgorzata Oleś, Jonas S Arnold, Nagarajan Paramasivam, Korinna Jöhrens, Luise Rupp, Marc Schmitz, Daniela Richter, Sebastian Uhrig, Martina Fröhlich, Barbara Hutter, Jennifer Hüllein, Arne Jahn, Marie Arlt, Elena E Möhrmann, Dorothea Hanf, Laura Gieldon, Simon Kreutzfeldt, Christoph E Heilig, Maria-Veronica Teleanu, Daniel B Lipka, Katja Beck, Annika Baude-Müller, Andreas Mock, Ivan Jelas, Damian T Rieke, Marcel Wiesweg, Christian Brandts, Melanie Boerries, Anna L Illert, Alexander Desuki, Thomas Kindler, Angela M Krackhardt, C Benedikt Westphalen, Petros Christopoulos, Leonidas Apostolidis, Albrecht Stenzinger, Michael Allgäuer, Olaf Neumann, Irina A Kerle, Peter Horak, Christoph Heining, Heidrun Grosch, Evelin Schröck, Daniel Hübschmann, Stefan Fröhling, Hanno Glimm","doi":"10.1016/j.medj.2025.100612","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Thymic epithelial tumors (TETs) are rare malignancies with limited treatment options and underexplored molecular features.</p><p><strong>Methods: </strong>We examined the genomic landscape and therapeutic outcomes in 81 patients with advanced TETs, including thymic carcinomas (TCs), thymomas, and thymic neuroendocrine neoplasms (TNENs), who were enrolled in the MASTER trial, a prospective observational precision oncology trial.</p><p><strong>Findings: </strong>Using whole-genome-sequencing and whole-exome-sequencing analysis, transcriptome analysis, and methylome analysis, we identified distinct molecular features across TET subtypes, including a higher tumor mutational burden in TC and pathogenic germline variants in 18% of cases. We performed transcriptome- and methylome-based unsupervised clustering and were able to divide TCs into immunologically hot and cold subsets, with hot TCs exhibiting higher T cell infiltration and significantly longer overall survival. In 65 out of 76 (86%) patients, we recommended molecularly informed therapies, which were applied in 29 out of 65 (45%) cases, leading to a disease control rate of 62% and an objective response rate of 23% (both n = 26). The progression-free survival ratio (PFSr) was > 1.3 in 8 out of 24 (33%) patients, 7 of them having TC. Among TCs, patients achieved a mean PFSr of 1.4, indicating potential therapeutic advantages in this subgroup. The PFSr between the PFS of immune checkpoint inhibition and preceding therapies was significantly higher in the hot cluster compared to the cold cluster (median 1.7 vs. 0.3; p = 0.01945).</p><p><strong>Conclusions: </strong>Our findings expand the understanding of TET biology and emphasize the role of precision oncology in informing treatment decisions and improving outcomes for patients with advanced TETs, particularly in TCs.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100612"},"PeriodicalIF":12.8000,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Med","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.medj.2025.100612","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Thymic epithelial tumors (TETs) are rare malignancies with limited treatment options and underexplored molecular features.
Methods: We examined the genomic landscape and therapeutic outcomes in 81 patients with advanced TETs, including thymic carcinomas (TCs), thymomas, and thymic neuroendocrine neoplasms (TNENs), who were enrolled in the MASTER trial, a prospective observational precision oncology trial.
Findings: Using whole-genome-sequencing and whole-exome-sequencing analysis, transcriptome analysis, and methylome analysis, we identified distinct molecular features across TET subtypes, including a higher tumor mutational burden in TC and pathogenic germline variants in 18% of cases. We performed transcriptome- and methylome-based unsupervised clustering and were able to divide TCs into immunologically hot and cold subsets, with hot TCs exhibiting higher T cell infiltration and significantly longer overall survival. In 65 out of 76 (86%) patients, we recommended molecularly informed therapies, which were applied in 29 out of 65 (45%) cases, leading to a disease control rate of 62% and an objective response rate of 23% (both n = 26). The progression-free survival ratio (PFSr) was > 1.3 in 8 out of 24 (33%) patients, 7 of them having TC. Among TCs, patients achieved a mean PFSr of 1.4, indicating potential therapeutic advantages in this subgroup. The PFSr between the PFS of immune checkpoint inhibition and preceding therapies was significantly higher in the hot cluster compared to the cold cluster (median 1.7 vs. 0.3; p = 0.01945).
Conclusions: Our findings expand the understanding of TET biology and emphasize the role of precision oncology in informing treatment decisions and improving outcomes for patients with advanced TETs, particularly in TCs.
期刊介绍:
Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically.
Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.