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RFP2. Comprehensive molecular profiling predicts survival among North American patients with mesothelioma

Friday, March 6, 2026
4:24 PM - 4:31 PM MST
Location: 106A-C
Introduction:

Mesothelioma is a rare but highly aggressive cancer with limited data on the prognostic impact of somatic mutational profiles. This study evaluated a large patient cohort with mesothelioma to investigate mutational profile differences among pleural and peritoneal subtypes and to identify key somatic mutations associated with survival.


Methods:

Patients with pleural or peritoneal mesothelioma (n=199) at a large tertiary institution from 2010-2022 who had somatic mutation testing were included in the study. Manual chart review collected patient demographics, treatment, pathologic, and survival data. Patient groups underwent analysis with Kaplan-Meier (KM) survival curves, oncoplots, and bivariate analysis followed by multivariable Cox regression to evaluate impact of somatic mutations and treatment modalities on survival.


Results:

KM analysis identified somatic mutations significantly associated with worse overall survival (OS) including CDKN2A, NF2, and TERT. Pleural mesothelioma patients had significantly worse OS for somatic mutations in either CDKN2A (log-rank p< 0.001), NF2 (log-rank p=0.024), or TERT (log-rank p=0.001) compared to wildtype. Multivariable Cox regression confirmed independent association of worse survival with NF2 mutation (HR: 1.91 [95% CI=1.12-3.26], p=0.018) and TERT mutation (HR: 2.67 [95%CI=1.26-5.69], p=0.011). KM analysis also showed peritoneal mesothelioma patients with CDKN2A mutation had significantly worse OS (log-rank p=0.036) but no significant differences were seen for NF2 or TERT mutations in the peritoneal cohort.

Oncoplots revealed the mutational patterns in patients with extended survival ( > 5-year OS) versus shortened survival ( < 1-year OS) (Figure 1). Patients with shortened survival were significantly more likely to have CDKN2A mutation (67% vs 5%, p< 0.001) or NF2 mutation (43% vs 10%, p=0.018) compared to patients with extended survival. Furthermore, among patients with < 1-year OS, 83% of CDKN2A mutations in pleural patients were large chromosomal deletions whereas 100% of CDKN2A mutations in peritoneal patients were chromosomal rearrangements.


Conclusions:

Pleural and peritoneal mesothelioma are two distinct cancer biologies which have unique somatic mutational profiles impacting survival. This large cohort study identified key prognostic mutations and specific mutational variants which influence survival. Future studies will evaluate the impact of mutational profiles on predicting treatment response and treatment resistance to allow for more personalized, targeted treatment strategies.

Learning Objectives:

  • Understand how somatic mutational profiles differ between pleural and peritoneal mesothelioma and how specific mutational variants in these groups may influence overall survival outcomes.
  • Identify key somatic mutations, including CDKN2A, NF2, and TERT, which may serve as prognostic markers for predicting survival in patients with mesothelioma.
  • Recognize how comprehensive molecular profiling enables improved prognostication and may support future development of personalized, mutation-guided treatment strategies for mesothelioma.