Comprehensive genomic and transcriptomic analysis enables molecularly guided therapy options in peritoneal and pleural mesothelioma

Our plain-English summary of Comprehensive genomic and transcriptomic analysis enables molecularly guided therapy options in peritoneal and pleural mesothelioma, by L. Möhrmann, M. Werner, M. Oleś, et al (ESMO Open, 2025).

The study

• Authors: L. Möhrmann, M. Werner, M. Oleś, L. Knol, J.S. Arnold, T. Mundt, N. Paramasivam, D. Richter, M. Fröhlich, B. Hutter, J. Hüllein, A. Jahn, C. Scheffold, E.E. Möhrmann, D. Hanf, S. Kreutzfeldt, C.E. Heilig, M.V. Teleanu, D.B. Lipka, K. Beck, A. Baude-Müller, I. Jelas, D.T. Rieke, L.V. Klotz, R. Shah, T. Herold, M. Boerries, A.L. Illert, M. Allgäuer, A. Stenzinger, I.A. Kerle, P. Horak, C. Heining, E. Schröck, D. Hübschmann, S. Fröhling, H. Glimm
• Journal: ESMO Open
• Published: 2025;10(4):104532
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Peritoneal, pericardial and pleural mesothelioma (PeM/PcM/PM) are rare and aggressive diseases with limited survival. Molecularly guided therapy is currently not part of standard care.

Methods: This study integrates molecular and clinical data from 51 patients (among them 28 PM, one PcM, 21 PeM and one synchronous PeM/PM) enrolled in the National Center for Tumor Diseases and the German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER), a multicenter precision oncology registry trial addressing adults with rare advanced-stage cancers. Analysis comprised both somatic and germline whole exome sequencing/whole genome sequencing and transcriptome analysis leading to personalized treatment recommendations issued by a dedicated molecular tumor board. To assess clinical efficacy, progression-free survival (PFS) ratios comparing molecularly informed therapies (PFS2) to preceding systemic therapies (PFS1) were calculated. Efficacy of immune checkpoint inhibition applied during the observation period was assessed accordingly.

Results: Cancer-related genes altered in more than 5 out of 44 assessable patients were BAP1, CDKN2A, NF2, SETD2 and TP53. Somatic (n = 23) or germline (n = 9) alterations in homologous recombination-related genes were detected in 27/44 patients. In 21/44 cases, they were supported by positive combined homologous recombination deficiency scores or BRCAness signature. Following American College of Medical Genetics and Genomics guidelines, (likely) pathogenic germline variants in autosomal dominant cancer predisposition genes were found in 8/51 patients. Molecular tumor board recommendations were issued in 46 cases and applied in 6 cases. Mean PFS ratio was 2.45 (n = 5). Median PFS2 was 6.5 months (n = 6), median PFS1 was 4.0 months (n = 5). A total of 27 patients received immune checkpoint inhibition during the observation period leading to a mean PFS ratio of 1.69 (n = 19).

Conclusions: In mesothelioma, comprehensive molecular analysis can provide valuable clinically actionable information. Molecularly informed therapy recommendations can lead to clinical benefit.

Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.

In plain English

The study analysed 51 adults with advanced mesothelioma (28 pleural, 21 peritoneal, one pericardial, one both pleural and peritoneal) enrolled in the German MASTER precision oncology registry trial from 2014 to 2024. All had tumour and inherited DNA analysed. Tumour data were re-analysed for this report in 44, because seven samples were of low quality, and RNA was sequenced successfully in 38 of those 44. Asbestos exposure was documented in 12 patients (24%). Alterations in DNA repair (homologous recombination) genes appeared in 27 of 44 assessable patients. Of 51 patients, 13 carried inherited variants judged (likely) pathogenic, 8 in autosomal dominant cancer predisposition genes, including 3 in BAP1. Five of the 10 with such variants in DNA repair genes had documented asbestos exposure. A tumour board gave 130 recommendations to 46 patients. Six were documented as receiving a recommended therapy; 40 had no documented application, often because of short follow-up. In 5 evaluable patients, the mean ratio of progression-free time on that therapy to the previous one was 2.45. The authors concluded that molecularly informed therapy can provide substantial clinical benefit. They noted that the few treated patients limit generalisation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Analysis of patients enrolled in a prospective, multicenter precision oncology registry trial (NCT/DKTK MASTER), using whole genome or exome sequencing, RNA sequencing and molecular tumor board treatment recommendations
• Who was studied: 51 adults with advanced mesothelioma (28 pleural, 21 peritoneal, 1 pericardial, 1 synchronous pleural and peritoneal), enrolled March 2014 to September 2024 at five comprehensive cancer centers in Germany, with follow-up to November 2024. All 51 underwent somatic and germline analysis within the MASTER workflow. The retrospective secondary somatic analysis covered 44 patients; seven were left out because their samples were of low quality. Tumour RNA was successfully sequenced in 38 of those 44.
• Exposure: The study examined genomic and transcriptomic tumour alterations and molecularly guided therapy, not asbestos dose. Asbestos exposure was documented in 12 patients (24%) and smoking history in 13 (25%), with 7 patients having both. No fiber types are named.
• Main results:
  • Of 44 assessable patients, 27 (61%) had alterations in homologous recombination (HR)-related genes.
  • Of 51 patients, 13 (25%) carried heterozygous (likely) pathogenic germline variants. Eight of these were in autosomal dominant cancer predisposition genes: 3 in BAP1 and one each in ATM, BRCA2, CHEK2, NF1 and SDHB.
  • Five of the 10 patients with pathogenic germline variants in HR-relevant genes had documented asbestos exposure. Two of these five carried variants in BAP1.
  • Homozygous deletions in CDKN2A were found only in pleural mesothelioma: 14 of 25 pleural cases versus 0 of 15 peritoneal cases.
  • Of 51 patients, 46 (90%) received a total of 130 therapy recommendations from the molecular tumor board. Recommended therapies were documented as applied in 6 of 51 patients (12%).
  • Of 51 patients, 40 received recommendations without documented application. In 25 of these 40, this was due to a short follow-up period, with no documentation of therapies given after the tumor board date.
  • PARP inhibition was recommended for 23 of 46 patients (50%) but was never applied.
  • In patients who received recommended therapies, the mean ratio of progression-free survival on the recommended therapy to that on the preceding therapy was 2.45 (range 0.5 to 7.1; 5 patients). The ratio exceeded 1.3 in 2 of 5 evaluable cases. Median progression-free survival was 6.5 months on the recommended therapy (6 patients) and 4.0 months on the preceding therapy (5 patients).
  • Across 7 applications of recommended treatment, the overall response rate was 29% and the disease control rate was 86%.
  • Overall survival from enrollment trended longer for the 6 patients who received recommended therapies (median not reached) than for the 45 who did not (median 11.2 months). The difference was not statistically significant (p = 0.113).
  • Twenty-seven patients received immune checkpoint inhibition during the observation period. Their mean progression-free survival ratio was 1.69 (19 patients), and the ratio exceeded 1.3 in 7 of 19 assessable cases (37%). The overall response rate was 27% and the disease control rate 50% (26 patients).
• The authors' conclusion: The authors concluded that comprehensive molecular analysis can provide clinically actionable information in mesothelioma. They also concluded that differences between pleural and peritoneal disease are noticeable but limited, and that composite biomarker analysis identifies a subgroup of HR-deficient patients. Finally, they concluded that molecularly informed therapy can provide substantial clinical benefit.
• Limitations the authors state:
  • The low number of patients who actually received recommended therapies limits how far the results can be generalised.
  • In many cases, follow-up was too short to detect whether recommended therapies were applied.
  • The small number of patients limits transferability, because these tumours are very rare.
  • The finding that CDKN2A and MTAP were affected only in pleural mesothelioma may be due to low patient numbers.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pericardial, Tumor Board, Progression-Free Survival, BAP1, CDKN2A, Germline Mutation, Mesothelioma.

Related studies

• Genomic and transcriptomic analyses identify a prognostic gene signature and predict response to therapy in pleural and peritoneal mesothelioma — N.U. Nair, Q. Jiang, et al. (2023)
• Insights Into Genomic Drivers, Transcriptomic Heterogeneity, and Therapeutic Vulnerabilities From Novel Mesothelioma Cell Lines — Y. Wu, F. Cao, et al. (2026)
• Transcriptomic analysis-guided assessment of precision-cut tumor slices (PCTS) as an ex-vivo tool in cancer research — S. Trivedi, C. Tilsed, et al. (2024)
• Translating mesothelioma molecular genomics and dependencies into precision oncology-based therapies — T.K. Hinz, L.E. Heasley (2020)
• Genomics of MTAP Loss in >500,000 Solid Tumor Specimens Profiled Using Comprehensive Genomic Profiling Platforms — D.C. Pavlick, S. Rengarajan, et al. (2026)
• Genomic Landscape of Malignant Mesotheliomas — S. Kato, B.N. Tomson, et al. (2016)

Browse more research in ESMO Open, or return to medical research.