PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy.
Details
Serval ID
serval:BIB_1DCDFEFFCBAF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy.
Journal
Journal of Thoracic Oncology
ISSN
1556-1380 (Electronic)
ISSN-L
1556-0864
Publication state
Published
Issued date
2014
Peer-reviewed
Oui
Volume
9
Number
2
Pages
239-247
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
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.
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.
Keywords
Adult, Aged, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Biomarkers, Tumor/metabolism, Cisplatin/administration & dosage, Cohort Studies, Combined Modality Therapy, Deoxycytidine/administration & dosage, Deoxycytidine/analogs & derivatives, Female, Follow-Up Studies, Glutamates/administration & dosage, Guanine/administration & dosage, Guanine/analogs & derivatives, Humans, Immunoenzyme Techniques, In Situ Hybridization, Fluorescence, Induction Chemotherapy, Male, Mesothelioma/metabolism, Mesothelioma/pathology, Middle Aged, Neoplasm Staging, PTEN Phosphohydrolase/genetics, PTEN Phosphohydrolase/metabolism, Pemetrexed, Phosphatidylinositol 3-Kinase/metabolism, Pleural Neoplasms/metabolism, Pleural Neoplasms/pathology, Pneumonectomy, Prognosis, Remission Induction, Signal Transduction, Survival Rate, TOR Serine-Threonine Kinases/metabolism, Tissue Array Analysis
Pubmed
Web of science
Open Access
Yes
Create date
03/08/2014 13:31
Last modification date
20/08/2019 12:54