Genomic landscape and molecularly informed therapy in thymic carcinoma and other advanced thymic epithelial tumors.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Med Pub Date : 2025-03-13 DOI:10.1016/j.medj.2025.100612
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
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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.

胸腺癌和其他晚期胸腺上皮肿瘤的基因组景观和分子知情治疗。
背景:胸腺上皮肿瘤(TETs)是一种罕见的恶性肿瘤,治疗方案有限,分子特征研究不足。方法:我们研究了81例晚期tet患者的基因组图谱和治疗结果,包括胸腺癌(TCs)、胸腺瘤和胸腺神经内分泌肿瘤(TNENs),这些患者参加了MASTER试验,这是一项前瞻性观察性精确肿瘤学试验。研究结果:通过全基因组测序和全外显子组测序分析、转录组分析和甲基组分析,我们确定了TET亚型的不同分子特征,包括TC较高的肿瘤突变负担和18%的致病性种系变异。我们进行了基于转录组和甲基组的无监督聚类,并能够将TCs分为免疫热亚群和冷亚群,热TCs表现出更高的T细胞浸润和更长的总生存期。在76例患者中的65例(86%)中,我们推荐了分子知情疗法,65例患者中的29例(45%)应用了分子知情疗法,导致疾病控制率为62%,客观缓解率为23%(均为n = 26)。24例患者中有8例(33%)无进展生存率(PFSr)为bbb1.3,其中7例患有TC。在TCs中,患者的平均PFSr为1.4,表明该亚组具有潜在的治疗优势。热组免疫检查点抑制的PFS与先前治疗之间的PFSr显著高于冷组(中位数1.7 vs 0.3;P = 0.01945)。结论:我们的研究结果扩大了对TET生物学的理解,并强调了精确肿瘤学在指导晚期TET患者的治疗决策和改善预后方面的作用,特别是在tc中。
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来源期刊
Med
Med MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
17.70
自引率
0.60%
发文量
102
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.
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