Skip Navigation LinksHome > February 2014 - Volume 9 - Issue 2 > PI3K/mTOR Signaling in Mesothelioma Patients Treated with In...
Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000055
Original Articles

PI3K/mTOR Signaling in Mesothelioma Patients Treated with Induction Chemotherapy Followed by Extrapleural Pneumonectomy

Bitanihirwe, Byron K.Y. PhD*; Meerang, Mayura PhD*; Friess, Martina VMD*; Soltermann, Alex MD; Frischknecht, Lukas MD; Thies, Svenja MD; Felley-Bosco, Emanuela PhD; Tsao, Ming-Sound MD§; Allo, Ghassan MD§; de Perrot, Marc MD; Seifert, Burkhardt PhD; Moch, Holger MD; Stahel, Rolf MD; Weder, Walter MD*; Opitz, Isabelle MD*

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Abstract

Introduction:

The prognostic significance of activity biomarkers within the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway was assessed in two independent cohorts of malignant pleural mesothelioma (MPM) patients uniformly treated with a multimodal approach. We specifically assessed expression signatures in a unique set of pre- and postchemotherapy tumor samples.

Methods:

Biomarker expression was assessed in samples of two independent cohorts of 107 (cohort 1) and 46 (cohort 2) MPM cases uniformly treated with platinum-based induction chemotherapy followed by extrapleural pneumonectomy from two different institutions, assembled on tissue microarrays. Expression levels of phosphatase and tensin homologue (PTEN), phospho-mTOR, and p-S6 in addition to marker of proliferation (Ki-67) and apoptosis (cleaved caspase-3) were evaluated by immunohistochemistry and correlated with overall survival (OAS) and progression-free survival (PFS). To assess PTEN genomic status, fluorescence in situ hybridization was performed.

Results:

Survival analysis showed that high p-S6 and Ki-67 expression in samples of treatment naïve patients of cohort 1 was associated with shorter PFS (p = 0.02 and p = 0.04, respectively). High Ki-67 expression after chemotherapy remained associated with shorter PFS (p = 0.03) and OAS (p = 0.02). Paired comparison of marker expression in samples before and after induction chemotherapy of cohort 1 revealed that decreased cytoplasmic PTEN and increased phospho-mTOR expression was associated with a worse OAS (p = 0.04 and p = 0.03, respectively).

Conclusions:

These novel data reveal a prognostic significance of expression changes of PI3K/mTOR pathway components during induction chemotherapy if confirmed in other patient cohorts and support the growing evidence to target the PI3K/mTOR pathway in the treatment of MPM.

Copyright © 2013 by the International Association for the Study of Lung Cancer

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