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

Ahmed Q. Haddad, Payal Kapur, Nirmish Singla, Jay D. Raman, Matthew T. Then, Philipp Nuhn, Alexander Buchner, Patrick Bastian, Christian Seitz, Shahrokh F. Shariat, Karim Bensalah, Nathalie Rioux-Leclercq, Arthur I Sagalowsky, Yair Lotan, Vitaly Margulis

Research output: Contribution to journalArticle

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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; 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.

Original languageEnglish (US)
Pages (from-to)43-50
Number of pages8
JournalCancer
Volume121
Issue number1
DOIs
StatePublished - Jan 1 2015

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Sirolimus
Renal Cell Carcinoma
Biomarkers
S 6
Carrier Proteins
1-Phosphatidylinositol 4-Kinase
Phosphoric Monoester Hydrolases
Recurrence
Survival
Proportional Hazards Models
Area Under Curve
Multivariate Analysis
Lymph Nodes
Immunohistochemistry

Keywords

  • Biomarkers
  • Mammalian target of rapamycin
  • Renal cell carcinoma
  • Validation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Validation of mammalian target of rapamycin biomarker panel in patients with clear cell renal cell carcinoma. / Haddad, Ahmed Q.; Kapur, Payal; Singla, Nirmish; Raman, Jay D.; Then, Matthew T.; Nuhn, Philipp; Buchner, Alexander; Bastian, Patrick; Seitz, Christian; Shariat, Shahrokh F.; Bensalah, Karim; Rioux-Leclercq, Nathalie; Sagalowsky, Arthur I; Lotan, Yair; Margulis, Vitaly.

In: Cancer, Vol. 121, No. 1, 01.01.2015, p. 43-50.

Research output: Contribution to journalArticle

Haddad, AQ, Kapur, P, Singla, N, Raman, JD, Then, MT, Nuhn, P, Buchner, A, Bastian, P, Seitz, C, Shariat, SF, Bensalah, K, Rioux-Leclercq, N, Sagalowsky, AI, Lotan, Y & Margulis, V 2015, 'Validation of mammalian target of rapamycin biomarker panel in patients with clear cell renal cell carcinoma', Cancer, vol. 121, no. 1, pp. 43-50. https://doi.org/10.1002/cncr.28976
Haddad, Ahmed Q. ; Kapur, Payal ; Singla, Nirmish ; Raman, Jay D. ; Then, Matthew T. ; Nuhn, Philipp ; Buchner, Alexander ; Bastian, Patrick ; Seitz, Christian ; Shariat, Shahrokh F. ; Bensalah, Karim ; Rioux-Leclercq, Nathalie ; Sagalowsky, Arthur I ; Lotan, Yair ; Margulis, Vitaly. / Validation of mammalian target of rapamycin biomarker panel in patients with clear cell renal cell carcinoma. In: Cancer. 2015 ; Vol. 121, No. 1. pp. 43-50.
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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; 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.",
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AU - Haddad, Ahmed Q.

AU - Kapur, Payal

AU - Singla, Nirmish

AU - Raman, Jay D.

AU - Then, Matthew T.

AU - Nuhn, Philipp

AU - Buchner, Alexander

AU - Bastian, Patrick

AU - Seitz, Christian

AU - Shariat, Shahrokh F.

AU - Bensalah, Karim

AU - Rioux-Leclercq, Nathalie

AU - Sagalowsky, Arthur I

AU - Lotan, Yair

AU - Margulis, Vitaly

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N2 - 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.

AB - 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.

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