Validation of mammalian target of rapamycin biomarker panel in patients with clear cell renal cell carcinoma

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; P5.02 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; P5.003 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.