title: PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy.
abstract: BACKGROUND
  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.
authors.affiliation: *Division of Thoracic Surgery, University Hospital of Zürich, Zürich, Switzerland; †Institute of Surgical Pathology, University Hospital Zürich, Zürich, Switzerland; ‡Laboratory of Molecular Oncology, University of Zürich, Zürich, Switzerland; §Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; ‖Division of Thoracic Surgery, Toronto General Hospital, Toronto, Canada; and ¶Division of Biostatistics, Institute for Social and Preventative Medicine, University of Zürich, Zürich, Switzerland.
authors.forename: Byron K Y
authors.initials: BK
authors.lastname: Bitanihirwe
authors.forename: Mayura
authors.initials: M
authors.lastname: Meerang
authors.forename: Martina
authors.initials: M
authors.lastname: Friess
authors.forename: Alex
authors.initials: A
authors.lastname: Soltermann
authors.forename: Lukas
authors.initials: L
authors.lastname: Frischknecht
authors.forename: Svenja
authors.initials: S
authors.lastname: Thies
authors.forename: Emanuela
authors.initials: E
authors.lastname: Felley-Bosco
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Ghassan
authors.initials: G
authors.lastname: Allo
authors.forename: Marc
authors.initials: M
authors.lastname: de Perrot
authors.forename: Burkhardt
authors.initials: B
authors.lastname: Seifert
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Rolf
authors.initials: R
authors.lastname: Stahel
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.forename: Isabelle
authors.initials: I
authors.lastname: Opitz
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D015331:Cohort Studies; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D060828:Induction Chemotherapy; D008297:Male; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008875:Middle Aged; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D000068437:Pemetrexed; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010997:Pleural Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011013:Pneumonectomy; D011379:Prognosis; D012074:Remission Induction; D015398:Signal Transduction; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D046888:Tissue Array Analysis; D000093542:Gemcitabine
chemical_list: D014408:Biomarkers, Tumor; D005971:Glutamates; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D002945:Cisplatin; D000093542:Gemcitabine