title: Evaluation of the prognostic significance of altered mammalian target of rapamycin pathway biomarkers in upper tract urothelial carcinoma.
abstract: OBJECTIVE
  To evaluate the prognostic value of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper tract urothelial carcinoma (UTUC).
  
  
  METHODS
  We performed a multi-institutional review of clinical and pathologic information on patients receiving extirpative surgery for UTUC from 1990 to 2008. Immunohistochemistry for phosphorylated-S6, mTOR, phosphorylated-mTOR, PI3K, phosphorylated-4EBP1, phosphorylated-AKT, PTEN, HIF-1a, raptor, and cyclin D was performed on tissue microarrays from radical nephroureterectomy (RNU) specimens. Prognostic markers were identified and the significance of altered markers was assessed with the Kaplan-Meier analysis and the Cox regression analysis.
  
  
  RESULTS
  Six hundred twenty patients were included. Over a median follow-up of 27.3 months, 24.6% of patients recurred and 21.8% died of UTUC. On multivariate analysis, PI3K (odds ratio, 1.28; P = .001) and cyclin D (odds ratio, 3.45; P = .05) were significant predictors of clinical outcomes. Cumulative marker score was defined as low risk (no altered markers or 1 altered marker) or high risk (cyclin D and PI3K altered). Patients with high-risk marker score had a significantly higher proportion of high-grade disease (91% vs 71%; P <.001), non-organ-confined disease (61% vs 33%; P <.001), and lymphovascular invasion (35% vs 20%; P = .001). The Kaplan-Meier analysis demonstrated a significant difference in cancer-specific mortality (CSM) based on the risk groups. On Cox regression multivariate analysis for CSM incorporating non-organ-confined disease, grade, lymphovascular invasion, tumor architecture, and marker score, high-risk biomarker score was an independent predictor of CSM (hazard ratio, 1.5; 95% confidence interval, 1.04-2.3; P = .03).
  
  
  CONCLUSIONS
  Alterations in mTOR pathway correlate with established adverse pathologic features and independently predict inferior oncologic outcomes. Incorporation of mTOR-based marker profiles may allow for enhanced patient counseling, risk stratification, and individualized treatment regimens.
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Aditya
authors.initials: A
authors.lastname: Bagrodia
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Urology, University of Muenster Medical Center, Muenster, Germany.
authors.forename: Laura-Maria
authors.initials: LM
authors.lastname: Krabbe
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Bishoy A
authors.initials: BA
authors.lastname: Gayed
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Division of Biostatistics, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Ira
authors.initials: I
authors.lastname: Bernstein
authors.affiliation: Division of Biostatistics, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Department of Urology, MD Anderson Cancer Center, Houston, TX.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
authors.affiliation: Department of Urology, MD Anderson Cancer Center, Houston, TX.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Karam
authors.affiliation: Department of Urology, University of Michigan Cancer Center, Ann Arbor, MI.
authors.forename: Alon Z
authors.initials: AZ
authors.lastname: Weizer
authors.affiliation: Department of Urology, Penn State Hershey Medical Center, Hershey, PA.
authors.forename: Jay D
authors.initials: JD
authors.lastname: Raman
authors.affiliation: Department of Urology, Medical University of Vienna, Vienna, Austria.
authors.forename: Mesut
authors.initials: M
authors.lastname: Remzi
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire de Rennes, Rennes, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux-Leclerq
authors.affiliation: Department of Pathology, Medical University Vienna, Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Haitel
authors.affiliation: Department of Urology, Ospedali Riuniti of Bergamo, Bergamo, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Roscigno
authors.affiliation: Department of Urology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bolenz
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire de Rennes, Rennes, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Bensalah
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Sagalowsky
authors.affiliation: Department of Urology, Medical University of Vienna, Vienna, Austria.
authors.forename: Shahrokh F
authors.initials: SF
authors.lastname: Shariat
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address: Vitaly.margulis@utsouthwestern.edu.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Margulis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D012008:Recurrence; D012189:Retrospective Studies; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019459:Urothelium / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human