Genomic characterization of malignant pleural mesothelioma and associated clinical outcomes

Our plain-English summary of Genomic characterization of malignant pleural mesothelioma and associated clinical outcomes, by P. Markowitz, M. Patel, R. Groisberg, et al (Cancer Treatment and Research Communications, 2020).

The study

• Authors: P. Markowitz, M. Patel, R. Groisberg, J. Aisner, S.K. Jabbour, S. De, S. Ganesan, J. Malhotra
• Journal: Cancer Treatment and Research Communications
• Published: 2020;25:100232
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a rare malignancy with a poor prognosis. While treatment with a platinum-based chemotherapy is the standard of care, many patients have rapid progression of disease with a median overall survival of ~12 months. Limited data exist about the genomic alterations associated with MPM and their clinical implications.

Methods: We report genomic alterations and clinical data for 17 patients with MPM who had next generation sequencing performed. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan-Meier method.

Results: Median age at diagnosis was 70 years (range 55-85), and 47% of the patients were male. The most common genomic alterations in the 17 patients were NF2 (53%), BAP1 (41%), CDKN2A (41%) and TP53 (29%). The median OS was 10.8 months. When stratified by mutational status, patients had better median OS if they had a BAP1 alteration compared to TP53 alteration (median OS 14.5 vs 7.2 months). Median PFS with first-line chemotherapy was 7 months (SD ± 3.3). However, patients with TP53 mutations had worse PFS with chemotherapy with median of only 3.9 months. Tumor mutation burden (TMB) was available for 12 patients and all had low TMB (range 1 to 8.1 mutation/Mb). Median PFS with immunotherapy was poor with at 1.5 months (SD ±0.4) and there was no significant difference in PFS with immunotherapy based on molecular profile.

Conclusion: Our study has identified that TP53 confers worse survival and response to platinum chemotherapy compared to BAP1. Overall PDL1 expression and TMB is low in patients with MPM resulting in limited benefit from single agent PD-1/PD-L1 agent.

Copyright © 2020. Published by Elsevier Ltd.

In plain English

The authors reviewed records of 17 patients with malignant pleural mesothelioma and tumor genetic testing, seen at a Rutgers Cancer Institute of New Jersey clinic from 2013 to 2018. Ten (59%) confirmed past asbestos exposure; the others were unsure. The commonest tumor gene changes were NF2 (53%), CDKN2A (41%), BAP1 (41%) and TP53 (29%). Median overall survival was 10.8 months from diagnosis. Median survival was 14.5 months with BAP1 or NF2 changes. The text gives 7.2 and 5.7 months for TP53 and CDKN2A/2B changes, though its table lists these as survival after advanced diagnosis. After adjusting for other factors, TP53 mutation was associated with poorer survival (hazard ratio 4.31; 95% confidence interval 1.01 to 18.3). On first-line chemotherapy, median progression-free survival (time until documented tumor progression or death from any cause) was 7 months overall and 3.9 months with TP53 mutations. On immunotherapy it was 1.5 months, with no significant difference by gene profile. All 12 patients tested had low tumor mutation burden. The authors concluded TP53-mutated tumors had a worse prognosis, and said their small study needs confirming in larger ones.

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: Retrospective review of electronic health records and tumor genetic test results from a single clinic (small case series)
• Who was studied: 17 patients with malignant pleural mesothelioma seen in the Thoracic Oncology clinic at Rutgers Cancer Institute of New Jersey (New Brunswick, NJ) between 2013 and 2018. All had tumor genetic testing through Foundation One. Median age was about 70 years (range 55 to 85); 47% were male.
• Exposure: The main factors studied were tumor genetic alterations (BAP1, NF2, TP53, CDKN2A) found by next-generation sequencing, compared against survival and treatment outcomes. Asbestos exposure history was recorded but not analyzed by fiber type or amount: 10 patients (59%) confirmed past exposure and 7 (41%) were unsure.
• Main results:
  • Among the 17 patients' tumors, the most common gene alterations were NF2 (53%), CDKN2A (41%), BAP1 (41%) and TP53 (29%).
  • For all patients, median overall survival was 10.8 months from initial diagnosis and 8.6 months from diagnosis of advanced/metastatic disease.
  • The text reports median overall survival of 14.5 months for patients with BAP1 and for those with NF2 mutations, versus 7.2 months for TP53 and 5.7 months for CDKN2A/2B mutations. Table 3 lists 7.2 and 5.7 as survival after metastatic diagnosis; from initial diagnosis the table gives 8.6 months for TP53 and 10.8 months for CDKN2A.
  • In a multivariate analysis controlling for age at diagnosis, gender, histology, ECOG status and mutational status, TP53-mutated tumors were associated with poorer overall survival compared with non-mutated tumors (HR 4.31; 95% CI 1.01 to 18.3).
  • Median progression-free survival (time from start of a therapy until documented tumor progression or death from any cause) with first-line chemotherapy was 7 months overall, similar for BAP1 and NF2 mutations. It was 3.9 months for patients with TP53 mutations.
  • Among patients who received PD-1 or PD-L1 immunotherapy, median progression-free survival was 1.5 months, with no significant difference by molecular profile. The discussion notes only 1 documented response.
  • Tumor mutation burden was available for 12 patients and was low in all 12 (median 3.1, range 1 to 8.1 mutations per Mb). PD-L1 expression was available for only 3 patients and was below 5% in all three.
  • When patients were grouped by both BAP1 and TP53 status, median overall survival was 29 months for BAP1-positive/TP53-negative, 19 months for BAP1-negative/TP53-negative, 8.6 months for BAP1-positive/TP53-positive and 3 months for BAP1-negative/TP53-positive tumors. The number of patients in each group is not given.
• The authors' conclusion: The authors concluded that molecular subtypes can affect prognosis and response to systemic therapy in malignant pleural mesothelioma. They reported a worse prognosis for TP53-mutated tumors, which they attributed to resistance to chemotherapy and immunotherapy. They also concluded that MPM patients overall show low tumor mutation burden and poor response to single-agent immunotherapy.
• Limitations the authors state:
  • The authors state that the study is limited by its small sample size and that the finding needs to be confirmed in a larger study.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Chemotherapy, Median Overall Survival, Overall Survival, Progression-Free Survival, BAP1, CDKN2A.

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