Exploratory analysis of activation of PTEN-PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM)

Our plain-English summary of Exploratory analysis of activation of PTEN-PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM), by S. Cedrés, M.A. Montero, P. Martinez, et al (Lung Cancer, 2012).

The study

• Authors: S. Cedrés, M.A. Montero, P. Martinez, A. Martinez, V. Rodríguez-Freixinós, D. Torrejon, A. Gabaldon, M. Salcedo, S. Ramon Y Cajal, E. Felip
• Journal: Lung Cancer
• Published: 2012;77(1):192-8
• Cited by: 59 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with elevated AKT/mTOR activity. We aimed to identify the expression and phosphorylation status of PTEN, PI3K and downstream signaling in MPM.

Patients And Methods: Thirty consecutive MPM patients were identified. Clinical data analyzed: sex, age, histology, performance status (PS), white blood count, and neutrophil-lymphocyte ratio (NLR). Paraffin-embedded biopsies were used for immunohistochemical analysis.

Results: Overexpression of PTEN, pMAPK, mTOR, pAKT, 4E-BP1, p4E-BP1, eIF-4E, peIF-4E, p-S6 and FOXO3a in MPM was found in 90%, 100%, 93.3%, 80%, 100%, 43.3%, 96.7%, 100%, 63.3% and 100% of tumors respectively. There was a significant correlation between low pS6 protein expression and longer progression free survival (PFS: 7.9 vs 5.6 months; p = 0.04) and overall survival (OS: 23.4 vs 5.6 months; p = 0.05). Patients with concomitant low expression of pS6 and p4E-BP1 and overexpression of FOXO3a had significantly better prognosis (34.6 vs 1.9 months; p = 0.004). In multivariate analysis, histology and NLR were independent prognostic factors (p = 0.02 and p = 0.04 respectively), but pS6 only showed a trend (p = 0.8).

Conclusions: This study shows PI3K pathway and downstream proteins in MPM are frequently activated and provides prognostic information. The role of PI3K pathway is worth of prospective validation in future studies on MPM.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

In plain English

This retrospective study at Vall d'Hebron University Hospital in Barcelona, Spain, examined tumor biopsies from 30 consecutive patients with malignant pleural mesothelioma, collected from 2002 to 2009. Asbestos exposure was recorded for 12 of the 30 patients (40%), but the article reports no analysis of asbestos exposure. The authors stained the tissue for proteins in the PI3K cell-signaling pathway and compared protein levels with survival. Results varied by protein. For example, pmTOR was positive in 27 of 29 testable biopsies, but cytoplasmic p4E-BP1 was positive in 13 of 30. Among patients tested for pS6, those with low levels had longer progression-free survival (7.9 vs 5.6 months, p = 0.04) and overall survival (23.4 vs 5.6 months, p = 0.05). In a combined analysis, epithelial tumor type and the neutrophil-to-lymphocyte ratio remained significant predictors of survival, but pS6 did not (hazard ratio 1.2, CI 0.3 to 4.2). The authors concluded that the pathway is frequently activated in this cancer and that its role deserves prospective validation. They noted that limited tissue prevented some tests. Some figures differ between the article's tables and its text.

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, exploratory laboratory study of stored tumor biopsies (immunohistochemistry) with survival analysis
• Who was studied: 30 consecutive patients with histologically proven malignant pleural mesothelioma treated at Vall d'Hebron University Hospital, Barcelona, Spain, 2002 to 2009. Median age was 68 (range 52 to 83), and 25 (83.3%) were male.
• Exposure: Tumor levels of PI3K-pathway proteins (PTEN, pMAPK, pmTOR, pAKT, 4E-BP1, p4E-BP1, eIF-4E, peIF-4E, pS6, FOXO3a), each scored and split into high and low at the median score. Asbestos exposure was recorded in 12 patients (40%), with no fiber types or doses given.
• Main results:
  • Median survival of the whole group of 30 patients was 16.4 months (95% CI 3.02 to 29.69), after an average follow-up of 8.8 months.
  • pmTOR could be assessed in 29 biopsies and was positive in 27 of them. The article reports this as 93.3%.
  • Cytoplasmic p4E-BP1 was positive in 13 tumors (43.3%) out of 30 assessed.
  • Patients with low pS6 levels (26 patients tested) had longer progression-free survival (7.9 vs 5.6 months, p = 0.04) and overall survival (23.4 vs 5.6 months, p = 0.05) than those with high pS6.
  • Patients with high pS6, high p4E-BP1 and low FOXO3a had overall survival of 1.9 months, compared with 34.6 months for patients with low pS6, low p4E-BP1 and high FOXO3a (p = 0.004).
  • Patients with epithelial-type tumors survived longer than those with other types (23.4 vs 2.3 months, p less than 0.001).
  • In multivariate analysis, epithelial histology (HR 7.9, CI 1.3 to 47.9) and neutrophil-to-lymphocyte ratio (HR 3.6, CI 1.0 to 13.2) remained significant prognostic factors. pS6 did not reach statistical significance (HR 1.2, CI 0.3 to 4.2).
  • Better survival with high FOXO3a (16.3 vs 4.0 months, p = 0.06) was a trend that the authors describe as not statistically significant.
• The authors' conclusion: The authors concluded that the PI3K pathway and its downstream proteins are frequently activated in malignant pleural mesothelioma and provide prognostic information. They said the pathway's role is worth prospective validation in future studies.
• Limitations the authors state:
  • Limited tissue meant not every protein could be tested in every patient (FOXO3a in 27 of 30 patients, pS6 in 26 of 30).
  • There was not enough tissue left to confirm the pS6 findings with a second method (Western blot).

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, Neoplasm, Histology, Performance Status, Overall Survival, Prognosis, Multivariate Analysis.

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• Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing — A. Miyanaga, M. Masuda, et al. (2015)

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