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

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.

Keywords: Key words: precision oncology; homologous repair deficiency; peritoneal mesothelioma; pleural mesothelioma; targeted therapy.

Figure 1

Oncoplot showing sequencing information, measures of chromosomal instability and the most frequently mutated genes. The 44 samples that were used for somatic analysis are represented in the columns. The top annotation bars include which analysis was carried out for which samples, the results of the histological assessment of each sample and measures of genomic instability. Overall genome ploidy is rounded to the nearest integer. The presence of SNVs, InDels, fusions and homozygous deletions (HDEL) are annotated in the body of the oncoplot by rectangles of different colors and sizes. Only genes with SNVs, InDels and/or fusions in three or more samples are shown here. The vertical bar indicates whether these genes are annotated as oncogenes and/or tumor suppressor genes (TSG) according to the Cosmic Gene Census (consulted October 2024). HRD, homologous recombination deficiency; InDel, insertion/deletion; LOH, loss of heterozygosity; LST, large-scale transitions; NOS, not otherwise specified; seq, sequencing; SNV, small nucleotide variant; WES, whole exome sequencing; WGS, whole genome sequencing.

Figure 2

Sankey plot depicting biomarkers and classes of derived therapy recommendations grouped by therapy baskets in peritoneal mesothelioma cases. Sankey plot depicting biomarkers utilized by the MTB for patients with PeM, linked to the corresponding classes of derived therapy recommendations. Biomarkers are sorted by frequency and grouped into baskets as described by Horak et al., reflecting the pathways targeted by the recommended therapies. For each basket group, the number of biomarkers, source of information (DNA or RNA), and type of alteration (expression, gain/amplification, loss/deletion, SNV, InDel) are indicated. In cases where biomarkers led to a recommendation involving combined therapy regimes associated with different therapy baskets (e.g. immune checkpoint inhibition and mTOR inhibition), biomarkers are depicted in both relevant baskets and linked to each corresponding treatment class. InDel, insertion/deletion; MTB, molecular tumor board; PeM, peritoneal mesothelioma; SNV, small nucleotide variant.

Figure 3

Sankey plot depiciting biomarkers and classes of derived therapy recommendations grouped by therapy baskets in pleural mesothelioma cases. Sankey plot depicting biomarkers utilized by the MTB for patients with PM, linked to classes of derived therapy recommendations. Biomarkers are sorted as described in Figure 2.

Figure 4

Swimmer plot depicting application of molecular tumor board (MTB) recommended therapies. Every bar depicts the duration of disease from diagnosis to end of follow-up or in case of bars annotated with x death. Plotted inside the bars is progression-free survival of the first applied molecularly guided therapy (PFS2, red) and its last preceding systemic therapy (PFS1, green). Continued response beyond end of observation period is marked with an arrow.