title: Relevance of the mammalian target of rapamycin pathway in the prognosis of patients with high-risk non-muscle invasive bladder cancer.
abstract: High-risk non-muscle invasive bladder cancer (NMIBC) is associated with higher rates of recurrence and progression. Molecular markers within aberrant signaling pathways in cancer need further evaluation of their role as prognostic indicators and potential future targets for prevention of recurrence. Our objective was to investigate the role of the mammalian target of rapamycin (mTOR) signaling pathway on the stage and outcome of patients with high-risk NMIBC. Tissue microarrays were built from archival bladder tumor specimens (n = 142). Various clinicopathologic variables were collected retrospectively from patients treated with transurethral resection. Immunohistochemical staining was performed for phosphatase and tensin homolog, phosphorylated Akt, phosphorylated mTOR, phosphorylated S6 (p-S6), eukaryotic translation initiation factor 4E-binding protein-1, and p27. Multivariate analysis using Cox regression models addressed recurrence-free survival (RFS), progression-free survival, and worsening-free survival. In multivariate analysis, p-S6 was an independent predictor of shorter RFS (hazard ratio, 3.55; 95% CI, 1.31-9.64). Expression of p27 was inversely correlated with RFS (hazard ratio, 0.27; 95% CI, 0.10-0.74). Low levels of phosphatase and tensin homolog expression were associated with worsening-free survival (P < .03). None of the markers showed correlation with progression-free survival. Our results demonstrate that activation of the mTOR pathway, as assessed by p-S6 and expression of p27, might be used to provide prognostic information, particularly as a predictor of recurrence among patients with high-risk NMIBC.
authors.affiliation: McGill Urologic Oncology Research, Division of Urology, McGill University Health Center and Research Institute, Montreal, Canada H3G 1A4.
authors.forename: Mona
authors.initials: M
authors.lastname: Fahmy
authors.forename: Jose Joao
authors.initials: JJ
authors.lastname: Mansure
authors.forename: Fadi
authors.initials: F
authors.lastname: Brimo
authors.forename: Faysal A
authors.initials: FA
authors.lastname: Yafi
authors.forename: Robert
authors.initials: R
authors.lastname: Segal
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Althunayan
authors.forename: Jessica
authors.initials: J
authors.lastname: Hicks
authors.forename: Alan
authors.initials: A
authors.lastname: Meeker
authors.forename: George
authors.initials: G
authors.lastname: Netto
authors.forename: Wassim
authors.initials: W
authors.lastname: Kassouf
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002278:Carcinoma in Situ / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002295:Carcinoma, Transitional Cell / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D046888:Tissue Array Analysis; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: High-risk non–muscle invasive bladder cancer; Prognosis; Tissue microarray; mTOR pathway