title: Validation of mammalian target of rapamycin biomarker panel in patients with clear cell renal cell carcinoma.
abstract: BACKGROUND
  This was an external validation of the prognostic benefit of mammalian target of rapamycin (mTOR) marker panel in patients with clear cell renal cell carcinoma (ccRCC).
  
  
  METHODS
  Immunohistochemistry for 5 mTOR pathway markers was performed on tissue microarrays of patients with nonmetastatic ccRCC treated surgically at 4 centers. The markers employed were phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), phosphorylated-mTOR (p-mTOR), phosphorylated-S6 (p-S6), and phosphorylated 4E-binding protein-1 (p-4EBP1). Cox regression was used to correlate marker status and oncologic outcomes. Discrimination of the models was determined using area under the curve and net reclassification improvement.
  
  
  RESULTS
  Five hundred twenty-eight patients with a median follow-up of 56.5 months were included. Expression of PI3K, PTEN, p-mTOR, p-4EBP1, and p-S6 was altered in 52%, 78%, 25%, 86%, and 30% of patients, respectively. The number of altered biomarkers predicted recurrence-free survival (RFS) in multivariate analysis adjusted for stage, grade, and lymph node status (HR, 3.20; P = .02 for patients with 4-5 altered biomarkers compared with 0-1 altered markers). A biomarker panel consisting of only 2 markers (p-S6 and p-4EBP1) independently predicted for worse RFS (HR, 4.38; P = .003 for patients with 2 altered markers compared to patients with 0 altered markers). The biomarker score increased predictive accuracy when added to the clinical Cox regression model.
  
  
  CONCLUSIONS
  m-TOR pathway biomarkers add prognostic information in addition to standard clinicopathologic variables in ccRCC patients and may identify patients who could benefit from additional treatments or closer postoperative surveillance.
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Ahmed Q
authors.initials: AQ
authors.lastname: Haddad
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.forename: Nirmish
authors.initials: N
authors.lastname: Singla
authors.forename: Jay D
authors.initials: JD
authors.lastname: Raman
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Then
authors.forename: Philipp
authors.initials: P
authors.lastname: Nuhn
authors.forename: Alexander
authors.initials: A
authors.lastname: Buchner
authors.forename: Patrick
authors.initials: P
authors.lastname: Bastian
authors.forename: Christian
authors.initials: C
authors.lastname: Seitz
authors.forename: Shahrokh F
authors.initials: SF
authors.lastname: Shariat
authors.forename: Karim
authors.initials: K
authors.lastname: Bensalah
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux-Leclercq
authors.forename: Arthur
authors.initials: A
authors.lastname: Sagalowsky
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
authors.forename: Vitaly
authors.initials: V
authors.lastname: Margulis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D046888:Tissue Array Analysis; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: biomarkers; mammalian target of rapamycin; renal cell carcinoma; validation