Biomarker-guided targeted and immunotherapies in malignant pleural mesothelioma

Our plain-English summary of Biomarker-guided targeted and immunotherapies in malignant pleural mesothelioma, by H. Yang, D. Xu, R.A. Schmid, et al (Therapeutic Advances in Medical Oncology, 2020).

The study

• Authors: H. Yang, D. Xu, R.A. Schmid, R.W. Peng
• Journal: Therapeutic Advances in Medical Oncology
• Published: 2020;12:1758835920971421
• Type of article: Review
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a lethal thoracic malignancy whose incidence is still increasing worldwide. MPM is characterized by frequent inactivation of tumor-suppressor genes (TSGs), e.g., the homozygous deletion of CDKN2A/2B and various genetic alterations that inactivate BAP1, NF2, LATS1/2, and TP53. The leading cause for the poor prognosis of patients with MPM is the lack of effective treatment options, with conventional chemotherapy being the standard of care in the clinic, which has remained unchanged for almost 20 years. Precision oncology, a burgeoning effort to provide precise cancer treatment tailored to unique molecular changes in individual patients, has made tremendous progress in the last decade in several cancers, but not in MPM. Recent studies indicate a high degree of tumor heterogeneity in MPM and the importance to optimize histological and molecular classifications for improved treatment. In this review, we provide an up-to-date overview of recent advances in MPM by focusing on new stratifications of tumor subgroups, specific vulnerabilities associated with functional loss of TSGs and other biomarkers, and potential clinical implications. The molecularly based subdivisions not only deepen our understanding of MPM pathobiology, but more importantly, they may raise unprecedented new hopes for personalized treatment of MPM patients with biomarker-guided targeted and immunotherapies.

© The Author(s), 2020.

In plain English

This article was a review of recent research on treating malignant pleural mesothelioma (MPM), a cancer of the lining around the lung. The authors noted that MPM is mainly attributed to occupational asbestos exposure, but the review did not examine exposure. It focused on genes commonly inactivated in MPM (CDKN2A/2B, BAP1, NF2, LATS1/2 and TP53) and on targeted drugs and immunotherapies that might suit tumors with particular genetic changes or tissue subtypes. The authors also re-analysed public data. Using Cancer Genome Atlas MPM patient data, they reported that among the common gene changes, only CDKN2A/2B loss was associated with poorer survival, and that it remained an independent survival predictor after adjusting for other clinical and genetic factors. In drug-sensitivity data on 20 MPM cell lines, some cells with and without BAP1 changes were sensitive to PARP inhibitors, while some BAP1-mutant cells were highly resistant. The authors concluded that BAP1 status appeared irrelevant to that sensitivity. They also concluded that precision oncology is still in its infancy in MPM, and that emerging biomarkers could help provide targeted therapies and immunotherapies in the future.

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: Narrative review, with the authors' own re-analysis of public genomic and drug-sensitivity databases
• Who was studied: Published studies on MPM. For the authors' re-analysis: a Cancer Genome Atlas (TCGA) MPM patient cohort (n = 81 for gene-alteration frequencies; survival figures label the cohort N=86 or N=80), and drug-sensitivity data on 20 MPM cell lines
• Exposure: No asbestos exposure was studied. The authors stated in the introduction that MPM is mainly attributable to occupational asbestos exposure. The review concerned tumor genetic changes and drug or immune treatments.
• Main results:
  • In the authors' analysis of TCGA MPM patients, only CDKN2A/2B alterations, among the common tumor-suppressor gene changes, were associated with poor survival. CDKN2A/2B loss was an independent survival predictor after adjustment.
  • In the TCGA MPM cohort, 46.9% of MPM patients (15 out of 38) had both CDKN2A loss and co-occurring BAP1 mutations
  • In the authors' analysis of drug-sensitivity data that included 20 MPM cell lines, some BAP1-altered and some BAP1 wild-type cells were particularly sensitive to PARP inhibitors, while some BAP1-mutant cells were highly resistant
  • Reviewed study (Illei et al., not this study): of 95 MPM patients, 70 (74%) had homozygous deletion of CDKN2A, and 64 (91%) of those also had co-deletion of MTAP
  • Reviewed trial (not this study): in a phase II study, the FAK inhibitor defactinib, given after first-line chemotherapy, did not improve progression-free or overall survival in patients with low NF2 status
• The authors' conclusion: The authors concluded that precision oncology is still in its infancy in MPM. In their view, molecular classifications and an emerging set of biomarkers could help provide MPM patients with targeted therapies and immunotherapies in the future.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Pleural Mesothelioma, Homozygous Deletion, CDKN2A, BAP1, Prognosis, Chemotherapy.

Related studies

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• Randomised controlled trial to compare the diagnostic yield of positron emission tomography CT (PET-CT) TARGETed pleural biopsy versus CT-guided pleural biopsy in suspected pleural malignancy (TARGET trial) — D. de Fonseka, W. Underwood, et al. (2018)
• A Comparative Study of 157Gd and 10B Effect in a Carborane-Based Theranostic Agent for Membrane-Targeted Carbonic Anhydrase IX Inhibition and MRI-Guided Neutron Capture Therapy in Mesothelioma Treatment — S. Rakhshan, A. Lanfranco, et al. (2025)
• Circulating Biomarkers and Targeted Therapy in Pleural Mesothelioma — C.R. Grant, L. Bazhenova, et al. (2025)
• Immunotherapies for non-small-cell lung cancer and mesothelioma — A. Thomas, R. Hassan (2012)
• BAP1 Deficiency Inflames the Tumor Immune Microenvironment and Is a Candidate Biomarker for Immunotherapy Response in Malignant Pleural Mesothelioma — D. Xu, Y. Gao, et al. (2024)

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