Expression of phosphorylated ribosomal protein S6 in mesothelioma patients - correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project

Our plain-English summary of Expression of phosphorylated ribosomal protein S6 in mesothelioma patients - correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project, by J.H. Rüschoff, M. Haberecker, Z. Tsourti, et al (Modern Pathology, 2022).

The study

• Authors: J.H. Rüschoff, M. Haberecker, Z. Tsourti, K. Nackaerts, M. de Perrot, L. Brcic, E. Nadal, S. Tsimpoukis, S.G. Gray, L. Ampollini, J.G. Aerts, E. Felley-Bosco, M.B. Kirschner, K. Monkhorst, B. Weynand, F. Bavaghar-Zaeimi, M. Samarzija, R. Llatjos, S.P. Finn, E. Silini, J. von der Thüsen, N. Marti, K. Vervita, R. Kammler, S. Peters, R.A. Stahel, P. Baas, I. Opitz, ETOP Mesoscape consortium
• Journal: Modern Pathology
• Published: 2022;35(12):1888-1899
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies.

© 2022. The Author(s).

In plain English

This retrospective study examined tumour tissue from 364 people with pleural mesothelioma diagnosed in 1999–2017 at 9 centres of the European Thoracic Oncology Platform (ETOP) Mesoscape project. The authors stained it for phosphorylated ribosomal protein S6 (pS6), a protein linked to cell growth, and split patients at the median score into pS6-high (181) and pS6-low (183) groups. Asbestos was not the focus: 76.8% of patients with known exposure status were definitely or possibly exposed, and exposure was not significant in the survival models. Across all patients, median overall survival did not differ significantly: 18.3 months (95% CI 16.4–20.9) for pS6-high and 21.7 months (16.7–23.7) for pS6-low (p = 0.52). In non-epithelioid (biphasic or sarcomatoid) mesothelioma, pS6-high patients had shorter median overall survival (10.7 months, 95% CI 7.4–13.6, versus 16.9, 11.5–22.7) and progression-free survival (6.2 months, 4.1–8.9, versus 10.8, 7.8–14.8), both p less than 0.001. Removal of all visible tumour (macroscopic complete resection) was less common in the pS6-high group. The authors called the findings exploratory and hypothesis-generating and named the retrospective design and small tissue samples as limitations.

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 multi-centre study of a tumour-tissue marker (pS6 immunostaining on tissue microarrays) compared with clinical data and survival
• Who was studied: 364 patients with pleural mesothelioma from 9 centres (in Switzerland, the Netherlands, Belgium, Italy, Canada, Croatia, Spain, Greece and Ireland), diagnosed between 1999 and 2017. Tumours were 70.3% epithelioid, 24.2% biphasic and 5.5% sarcomatoid. 86.5% of patients were male.
• Exposure: The factor studied was the level of pS6 protein in tumour tissue. It was scored as a semi-quantitative H-score from 0 to 3, and patients were split at the median of 1.41. Asbestos exposure was recorded only as a patient characteristic: 76.8% of patients with known status were definitely or possibly exposed, and exposure status was unknown or missing for 28 patients. Asbestos fibres were detected in the lung in 45 exposed patients (29.0%). Fiber types were not named.
• Main results:
  • All patients: median overall survival was 18.3 months (95% CI 16.4–20.9) for pS6-high and 21.7 months (95% CI 16.7–23.7) for pS6-low patients. The difference was not statistically significant (p = 0.52).
  • All patients: median progression-free survival was 12.4 months in both the pS6-high and pS6-low groups (p = 0.97).
  • Non-epithelioid (biphasic and sarcomatoid) patients: median overall survival was 10.7 months (95% CI 7.4–13.6) for pS6-high versus 16.9 months (95% CI 11.5–22.7) for pS6-low (p less than 0.001). In the multivariable model, the hazard ratio for high versus low was 2.12 (95% CI 1.42–3.17).
  • Non-epithelioid patients: median progression-free survival was 6.2 months (95% CI 4.1–8.9) for pS6-high versus 10.8 months (95% CI 7.8–14.8) for pS6-low (p less than 0.001). The multivariable hazard ratio was 2.06 (95% CI 1.39–3.07).
  • Epithelioid patients: high pS6 was associated with a lower risk of a progression event in the multivariable model, the reverse of the non-epithelioid finding (hazard ratio 0.74, 95% CI 0.57–0.97, p = 0.028).
  • Macroscopic complete resection (removal of all visible tumour) was less common in pS6-high patients (60.8%) than in pS6-low patients (p = 0.0032). For pS6-low patients, the text gives 76.8%, while Table 1 gives 139 of 183 (76.0%).
  • High pS6 was found in 66.0% of 188 treatment-naive tissue samples versus 12.9% (95% CI 6.9–21.5%) of 93 samples taken after treatment (p less than 0.001).
  • Asbestos exposure was not a significant factor in the multivariable model for overall survival (p = 0.58).
• The authors' conclusion: The authors concluded that pS6 was not associated with outcome in the full cohort. In subgroup analysis, high pS6 was associated with significantly shorter overall and progression-free survival in non-epithelioid pleural mesothelioma. They called these results exploratory and hypothesis-generating, suggesting PI3K pathway activation in non-epithelioid PM that might inform future targeted treatment.
• Limitations the authors state:
  • Retrospective design.
  • Each patient was represented by 3 to 8 small tissue punches, which might not fully represent the variation within each tumour. The authors note that a comparison with whole slides showed no significant difference in H-scores.
  • A significantly higher percentage of pS6-high patients was found among more recently diagnosed cases. However, the authors found no interaction between diagnosis timing and pS6 on outcome.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Prognosis, Histology, Biomarker, Progression-Free Survival, Overall Survival, Epithelioid.

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