Clinical Next Generation Sequencing Application in Mesothelioma: Finding a Golden Needle in the Haystack

Our plain-English summary of Clinical Next Generation Sequencing Application in Mesothelioma: Finding a Golden Needle in the Haystack, by L. Cerbone, S. Orecchia, P. Bertino, et al (Cancers, 2023).

The study

• Authors: L. Cerbone, S. Orecchia, P. Bertino, S. Delfanti, A.M. de Angelis, F. Grosso
• Journal: Cancers
• Published: 2023;15(24)
• Type of article: Review
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma comprises a group of rare cancers arising from the mesothelium of the pleura, peritoneum, tunica vaginalis testis and pericardium. Mesothelioma is generally associated with asbestos exposure and has a dismal prognosis, with few therapeutic options. Several next generation sequencing (NGS) experiments have been performed on mesothelioma arising at different sites. These studies highlight a genomic landscape mainly characterized by a high prevalence (>20%) of genomic aberrations leading to functional losses in oncosuppressor genes such as BAP1, CDKN2A, NF2, SETD2 and TP53. Nevertheless, to date, evidence of the effect of targeting these alterations with specific drugs is lacking. Conversely, 1-2% of mesothelioma might harbor activating mutations in oncogenes with specifically approved drugs. The goal of this review is to summarize NGS applications in mesothelioma and to provide insights into target therapy of mesothelioma guided by NGS.

In plain English

This review summarized next generation sequencing (NGS) studies, which read many genes in tumors, of pleural, peritoneal, pericardial and tunica vaginalis testis mesothelioma, plus trials of drugs targeting these changes. The authors found these studies agreed that mesothelioma is mainly marked by changes switching off tumor suppressor genes such as BAP1, CDKN2A and NF2. In the largest study (1468 patients), drug-targetable changes were rare: 0 to 1% for genes such as KRAS and EGFR, above 1% for ALK and others. Abemaciclib, given as later-line treatment for pleural mesothelioma with negative p16ink4A staining, met its goal: disease control at 12 weeks in 14/26 patients (54%). Olaparib did not: 1 of 23 patients (4%) had a partial response. The authors concluded that most phase II trials of this targeted approach failed their main goals, and that evidence for treating rare targetable changes is mainly case reports. The review did not study asbestos exposure, but noted mesothelioma's association with asbestos, and that in one reviewed study of 88 peritoneal mesothelioma patients, the 3 with ALK fusions were not exposed to asbestos.

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 of published next generation sequencing studies and targeted-drug trials in mesothelioma
• Who was studied: Published studies of patients with pleural, peritoneal, pericardial and tunica vaginalis testis mesothelioma. The largest study reviewed covered 1468 patients (1113 pleural, 355 peritoneal).
• Exposure: The review did not analyze asbestos exposure itself. It concerns genetic changes in tumors and drugs targeting them. It notes that mesothelioma is generally associated with asbestos exposure. It also reports one reviewed study of 88 patients with peritoneal mesothelioma, in which the 3 patients with ALK fusions had not been exposed to asbestos.
• Main results:
  • The authors found that the reviewed NGS studies, across all mesothelioma subtypes, agreed that the disease is mainly characterized by inactivating mutations in tumor suppressor genes.
  • In the reviewed Hiltbrunner study (1113 pleural and 355 peritoneal cases), actionable mutations were rare. They occurred in 0 to 1% of cases in genes such as KRAS, EGFR, PDGFRA/B, ERBB2 and FGFR3, and in more than 1% of cases in ALK, PTCH1, SUFU and BRCA2.
  • In a reviewed series of 50 peritoneal mesotheliomas, mutations occurred most often in BAP1 (30/50, 60%), NF2 (12/50, 24%), SETD2 (11/50, 22%) and TP53 (8/50, 16%).
  • In the reviewed abemaciclib arm of the MiST trial, abemaciclib was given as second and subsequent line treatment to pleural mesothelioma patients with negative p16ink4A staining. The 12-week disease control goal was met by 14/26 patients (54%), of whom 3 had partial responses.
  • In the reviewed olaparib phase II trial (pleural or peritoneal mesothelioma), the primary endpoint was not met: 1 of 23 patients (4%) had a partial response.
  • In the reviewed defactinib maintenance trial in pleural mesothelioma, progression-free survival was not improved over placebo (4.1 vs. 4.0 months).
  • In a reviewed retrospective study of 88 patients with peritoneal mesothelioma, ALK fusions were found in 3/88 (3.4%).
  • In that same study, all patients with ALK fusions were women, were not exposed to asbestos, and were younger than the other patients (32 vs. 69 years).
• The authors' conclusion: The authors concluded that targeting the pathways downstream of these gene changes seems logical, but most phase II studies using this strategy failed to meet their primary endpoints. They also concluded that 1–2% of patients may carry activating mutations in oncogenes. They advised that future trials use refined molecular stratification.
• Limitations the authors state:
  • The authors stated that evidence on treating the rare activating mutations is scarce and consists mainly of case reports.
  • The authors noted that NGS is expensive and not routinely affordable at every institution.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Mesothelium, Pleura, Peritoneum, Tunica Vaginalis, Pericardium, Asbestos Exposure, Prognosis.

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