Biomarker-guided targeted and immunotherapies in malignant pleural mesothelioma

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.

Keywords: immunotherapy; malignant pleural mesothelioma (MPM); molecularly based stratifications; precision oncology; tumor-suppressor gene.

Figure 1.

The global burden of MPM. The number of death (a) and disability-adjusted life years (b) of patients with MPM over the last three decades (1990–2017). Data represented here were downloaded from the database of GBD 2017. The expected number of death (c) and the expected number at the risk of death (d) caused by MPM. GPD, Global Burden of Disease; MPM, malignant pleural mesothelioma.

Figure 2.

The landscape of major genetic alterations in MPM. (a) Frequency of the major genetic alterations in TCGA MPM cohort (n = 81). Data were downloaded from cBioPortal (https://www.cbioportal.org/). (b) Venn diagram visualizing the intersections of the major genetic alterations in a. (c) The top 10 genes co-deleted with CDKN2A in MPM. Data were downloaded from cBioPortal for subsequent re-analysis. (d) The frequency of genetic alterations of CDKN2A/2B and PRPRB in MPM. Data were downloaded from a TCGA cohort of patients with MPM (n = 81). (e) The top 20 genes co-deleted with BAP1 in MPM. Data were downloaded from cBioPortal and reanalyzed. MPM, malignant pleural mesothelioma; TCGA, The Cancer Genome Atlas.

Figure 3.

Prognostic values of histology and major genetic alterations in patients with MPM. Association of histology (a), CDKN2A/2B homozygous deletions (b) and other major genetic alterations (c) with prognosis in patients with MPM. The p-value was calculated using the log-rank test. (d) Multivariate Cox regression analyses-based forest plot shows the factors significantly influencing overall survival of TCGA patients with MPM. MPM, malignant pleural mesothelioma; TCGA, The Cancer Genome Atlas.

Figure 4.

Precision oncology tailored to histology subtypes and major genetic alterations in MPM.