Cumulative number of altered biomarkers in mammalian target of rapamycin pathway is an independent predictor of outcome in patients with clear cell renal cell carcinoma

Oussama M. Darwish, Payal Kapur, Ramy F. Youssef, Aditya Bagrodia, Michael Belsante, Feras Alhalabi, Arthur I Sagalowsky, Yair Lotan, Vitaly Margulis

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Abstract

Objective: To evaluate the association of the altered expression of the mammalian target of rapamycin (mTOR) pathway components with oncologic outcomes in patients with nonmetastatic clear cell renal cell carcinoma (ccRCC). Materials and Methods: Immunohistochemistry for phosphorylated-S6, phosphorylated-mTOR, mTOR, phosphorylated-AKT, hypoxia inducible factor-1α, Raptor, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and phosphorylated 4E-binding protein-1 was performed on tissue microarray constructs of patients treated for nonmetastatic kidney cancer from 1997 to 2010. The relationship between individual altered marker expression and a prognostic marker score (low, intermediate, and high, defined as ≤3, 4-5, >5 altered biomarkers, respectively) and oncologic outcome was assessed. Results: The study included 419 patients with nonmetastatic ccRCC, with a median follow-up period of 26 months (range 6-150). The tumors were nonorgan confined (pT3-T4) in 86 (20.5%) and high Fuhrman nuclear grade (3-4) in 131 (31%). A low, intermediate, and high prognostic marker score was found in 214 (51%), 152 (36%), and 53 (13%) patients, respectively. Kaplan-Meier analysis demonstrated a statistically significant correlation between the risk groups and disease recurrence and cancer-specific survival. In a multivariate Cox regression analysis controlling for tumor stage and grade, a high marker score was an independent predictor of disease recurrence (hazard ratio 3.3, 95% confidence interval 1.33-8.39, P =.01), and a combination of a high and an intermediate score was an independent predictor of survival (hazard ratio 4.8, 95% confidence interval 1.27-4.78, P =.008). Conclusion: The cumulative number of aberrantly expressed biomarkers correlated with aggressive tumor biology and inferior oncologic outcomes in patients with ccRCC. Our data support prospective pathway-based exploration of the mTOR signaling cascade to augment current clinicopathologic predictors of oncologic outcomes in patients with ccRCC.

Original languageEnglish (US)
Pages (from-to)581-586
Number of pages6
JournalUrology
Volume81
Issue number3
DOIs
StatePublished - Mar 2013

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Sirolimus
Renal Cell Carcinoma
Biomarkers
Neoplasms
Raptors
Confidence Intervals
S 6
Hypoxia-Inducible Factor 1
Recurrence
1-Phosphatidylinositol 4-Kinase
Survival
Kidney Neoplasms
Kaplan-Meier Estimate
Phosphoric Monoester Hydrolases
Carrier Proteins
Immunohistochemistry
Regression Analysis

ASJC Scopus subject areas

  • Urology

Cite this

@article{b85651476af048d2a0d75809d037c19f,
title = "Cumulative number of altered biomarkers in mammalian target of rapamycin pathway is an independent predictor of outcome in patients with clear cell renal cell carcinoma",
abstract = "Objective: To evaluate the association of the altered expression of the mammalian target of rapamycin (mTOR) pathway components with oncologic outcomes in patients with nonmetastatic clear cell renal cell carcinoma (ccRCC). Materials and Methods: Immunohistochemistry for phosphorylated-S6, phosphorylated-mTOR, mTOR, phosphorylated-AKT, hypoxia inducible factor-1α, Raptor, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and phosphorylated 4E-binding protein-1 was performed on tissue microarray constructs of patients treated for nonmetastatic kidney cancer from 1997 to 2010. The relationship between individual altered marker expression and a prognostic marker score (low, intermediate, and high, defined as ≤3, 4-5, >5 altered biomarkers, respectively) and oncologic outcome was assessed. Results: The study included 419 patients with nonmetastatic ccRCC, with a median follow-up period of 26 months (range 6-150). The tumors were nonorgan confined (pT3-T4) in 86 (20.5{\%}) and high Fuhrman nuclear grade (3-4) in 131 (31{\%}). A low, intermediate, and high prognostic marker score was found in 214 (51{\%}), 152 (36{\%}), and 53 (13{\%}) patients, respectively. Kaplan-Meier analysis demonstrated a statistically significant correlation between the risk groups and disease recurrence and cancer-specific survival. In a multivariate Cox regression analysis controlling for tumor stage and grade, a high marker score was an independent predictor of disease recurrence (hazard ratio 3.3, 95{\%} confidence interval 1.33-8.39, P =.01), and a combination of a high and an intermediate score was an independent predictor of survival (hazard ratio 4.8, 95{\%} confidence interval 1.27-4.78, P =.008). Conclusion: The cumulative number of aberrantly expressed biomarkers correlated with aggressive tumor biology and inferior oncologic outcomes in patients with ccRCC. Our data support prospective pathway-based exploration of the mTOR signaling cascade to augment current clinicopathologic predictors of oncologic outcomes in patients with ccRCC.",
author = "Darwish, {Oussama M.} and Payal Kapur and Youssef, {Ramy F.} and Aditya Bagrodia and Michael Belsante and Feras Alhalabi and Sagalowsky, {Arthur I} and Yair Lotan and Vitaly Margulis",
year = "2013",
month = "3",
doi = "10.1016/j.urology.2012.11.030",
language = "English (US)",
volume = "81",
pages = "581--586",
journal = "Urology",
issn = "0090-4295",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Cumulative number of altered biomarkers in mammalian target of rapamycin pathway is an independent predictor of outcome in patients with clear cell renal cell carcinoma

AU - Darwish, Oussama M.

AU - Kapur, Payal

AU - Youssef, Ramy F.

AU - Bagrodia, Aditya

AU - Belsante, Michael

AU - Alhalabi, Feras

AU - Sagalowsky, Arthur I

AU - Lotan, Yair

AU - Margulis, Vitaly

PY - 2013/3

Y1 - 2013/3

N2 - Objective: To evaluate the association of the altered expression of the mammalian target of rapamycin (mTOR) pathway components with oncologic outcomes in patients with nonmetastatic clear cell renal cell carcinoma (ccRCC). Materials and Methods: Immunohistochemistry for phosphorylated-S6, phosphorylated-mTOR, mTOR, phosphorylated-AKT, hypoxia inducible factor-1α, Raptor, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and phosphorylated 4E-binding protein-1 was performed on tissue microarray constructs of patients treated for nonmetastatic kidney cancer from 1997 to 2010. The relationship between individual altered marker expression and a prognostic marker score (low, intermediate, and high, defined as ≤3, 4-5, >5 altered biomarkers, respectively) and oncologic outcome was assessed. Results: The study included 419 patients with nonmetastatic ccRCC, with a median follow-up period of 26 months (range 6-150). The tumors were nonorgan confined (pT3-T4) in 86 (20.5%) and high Fuhrman nuclear grade (3-4) in 131 (31%). A low, intermediate, and high prognostic marker score was found in 214 (51%), 152 (36%), and 53 (13%) patients, respectively. Kaplan-Meier analysis demonstrated a statistically significant correlation between the risk groups and disease recurrence and cancer-specific survival. In a multivariate Cox regression analysis controlling for tumor stage and grade, a high marker score was an independent predictor of disease recurrence (hazard ratio 3.3, 95% confidence interval 1.33-8.39, P =.01), and a combination of a high and an intermediate score was an independent predictor of survival (hazard ratio 4.8, 95% confidence interval 1.27-4.78, P =.008). Conclusion: The cumulative number of aberrantly expressed biomarkers correlated with aggressive tumor biology and inferior oncologic outcomes in patients with ccRCC. Our data support prospective pathway-based exploration of the mTOR signaling cascade to augment current clinicopathologic predictors of oncologic outcomes in patients with ccRCC.

AB - Objective: To evaluate the association of the altered expression of the mammalian target of rapamycin (mTOR) pathway components with oncologic outcomes in patients with nonmetastatic clear cell renal cell carcinoma (ccRCC). Materials and Methods: Immunohistochemistry for phosphorylated-S6, phosphorylated-mTOR, mTOR, phosphorylated-AKT, hypoxia inducible factor-1α, Raptor, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and phosphorylated 4E-binding protein-1 was performed on tissue microarray constructs of patients treated for nonmetastatic kidney cancer from 1997 to 2010. The relationship between individual altered marker expression and a prognostic marker score (low, intermediate, and high, defined as ≤3, 4-5, >5 altered biomarkers, respectively) and oncologic outcome was assessed. Results: The study included 419 patients with nonmetastatic ccRCC, with a median follow-up period of 26 months (range 6-150). The tumors were nonorgan confined (pT3-T4) in 86 (20.5%) and high Fuhrman nuclear grade (3-4) in 131 (31%). A low, intermediate, and high prognostic marker score was found in 214 (51%), 152 (36%), and 53 (13%) patients, respectively. Kaplan-Meier analysis demonstrated a statistically significant correlation between the risk groups and disease recurrence and cancer-specific survival. In a multivariate Cox regression analysis controlling for tumor stage and grade, a high marker score was an independent predictor of disease recurrence (hazard ratio 3.3, 95% confidence interval 1.33-8.39, P =.01), and a combination of a high and an intermediate score was an independent predictor of survival (hazard ratio 4.8, 95% confidence interval 1.27-4.78, P =.008). Conclusion: The cumulative number of aberrantly expressed biomarkers correlated with aggressive tumor biology and inferior oncologic outcomes in patients with ccRCC. Our data support prospective pathway-based exploration of the mTOR signaling cascade to augment current clinicopathologic predictors of oncologic outcomes in patients with ccRCC.

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U2 - 10.1016/j.urology.2012.11.030

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