Evaluation of the prognostic significance of altered mammalian target of rapamycin pathway biomarkers in upper tract urothelial carcinoma

Aditya Bagrodia, Laura Maria Krabbe, Bishoy A. Gayed, Payal Kapur, Ira Bernstein, Xian Jin Xie, Christopher G. Wood, Jose A. Karam, Alon Z. Weizer, Jay Raman, Mesut Remzi, Nathalie Rioux-Leclerq, Andrea Haitel, Marco Roscigno, Christian Bolenz, Karim Bensalah, Arthur I. Sagalowsky, Shahrokh F. Shariat, Yair Lotan, Vitaly Margulis

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Abstract

Objective To evaluate the prognostic value of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper tract urothelial carcinoma (UTUC).

Materials and 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).

Conclusion 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.

Original languageEnglish (US)
Pages (from-to)1134-1140
Number of pages7
JournalUrology
Volume84
Issue number5
DOIs
StatePublished - Jan 1 2014

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Sirolimus
Biomarkers
Cyclin D
Carcinoma
Phosphatidylinositol 3-Kinases
Kaplan-Meier Estimate
Mortality
Multivariate Analysis
Odds Ratio
Regression Analysis
Raptors
S 6
Neoplasms
Tumor Biomarkers
Counseling
Immunohistochemistry
Confidence Intervals

All Science Journal Classification (ASJC) codes

  • Urology

Cite this

Bagrodia, A., Krabbe, L. M., Gayed, B. A., Kapur, P., Bernstein, I., Xie, X. J., ... Margulis, V. (2014). Evaluation of the prognostic significance of altered mammalian target of rapamycin pathway biomarkers in upper tract urothelial carcinoma. Urology, 84(5), 1134-1140. https://doi.org/10.1016/j.urology.2014.07.050
Bagrodia, Aditya ; Krabbe, Laura Maria ; Gayed, Bishoy A. ; Kapur, Payal ; Bernstein, Ira ; Xie, Xian Jin ; Wood, Christopher G. ; Karam, Jose A. ; Weizer, Alon Z. ; Raman, Jay ; Remzi, Mesut ; Rioux-Leclerq, Nathalie ; Haitel, Andrea ; Roscigno, Marco ; Bolenz, Christian ; Bensalah, Karim ; Sagalowsky, Arthur I. ; Shariat, Shahrokh F. ; Lotan, Yair ; Margulis, Vitaly. / Evaluation of the prognostic significance of altered mammalian target of rapamycin pathway biomarkers in upper tract urothelial carcinoma. In: Urology. 2014 ; Vol. 84, No. 5. pp. 1134-1140.
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abstract = "Objective To evaluate the prognostic value of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper tract urothelial carcinoma (UTUC).Materials and 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).Conclusion 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.",
author = "Aditya Bagrodia and Krabbe, {Laura Maria} and Gayed, {Bishoy A.} and Payal Kapur and Ira Bernstein and Xie, {Xian Jin} and Wood, {Christopher G.} and Karam, {Jose A.} and Weizer, {Alon Z.} and Jay Raman and Mesut Remzi and Nathalie Rioux-Leclerq and Andrea Haitel and Marco Roscigno and Christian Bolenz and Karim Bensalah and Sagalowsky, {Arthur I.} and Shariat, {Shahrokh F.} and Yair Lotan and Vitaly Margulis",
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language = "English (US)",
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Bagrodia, A, Krabbe, LM, Gayed, BA, Kapur, P, Bernstein, I, Xie, XJ, Wood, CG, Karam, JA, Weizer, AZ, Raman, J, Remzi, M, Rioux-Leclerq, N, Haitel, A, Roscigno, M, Bolenz, C, Bensalah, K, Sagalowsky, AI, Shariat, SF, Lotan, Y & Margulis, V 2014, 'Evaluation of the prognostic significance of altered mammalian target of rapamycin pathway biomarkers in upper tract urothelial carcinoma', Urology, vol. 84, no. 5, pp. 1134-1140. https://doi.org/10.1016/j.urology.2014.07.050

Evaluation of the prognostic significance of altered mammalian target of rapamycin pathway biomarkers in upper tract urothelial carcinoma. / Bagrodia, Aditya; Krabbe, Laura Maria; Gayed, Bishoy A.; Kapur, Payal; Bernstein, Ira; Xie, Xian Jin; Wood, Christopher G.; Karam, Jose A.; Weizer, Alon Z.; Raman, Jay; Remzi, Mesut; Rioux-Leclerq, Nathalie; Haitel, Andrea; Roscigno, Marco; Bolenz, Christian; Bensalah, Karim; Sagalowsky, Arthur I.; Shariat, Shahrokh F.; Lotan, Yair; Margulis, Vitaly.

In: Urology, Vol. 84, No. 5, 01.01.2014, p. 1134-1140.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Evaluation of the prognostic significance of altered mammalian target of rapamycin pathway biomarkers in upper tract urothelial carcinoma

AU - Bagrodia, Aditya

AU - Krabbe, Laura Maria

AU - Gayed, Bishoy A.

AU - Kapur, Payal

AU - Bernstein, Ira

AU - Xie, Xian Jin

AU - Wood, Christopher G.

AU - Karam, Jose A.

AU - Weizer, Alon Z.

AU - Raman, Jay

AU - Remzi, Mesut

AU - Rioux-Leclerq, Nathalie

AU - Haitel, Andrea

AU - Roscigno, Marco

AU - Bolenz, Christian

AU - Bensalah, Karim

AU - Sagalowsky, Arthur I.

AU - Shariat, Shahrokh F.

AU - Lotan, Yair

AU - Margulis, Vitaly

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Objective To evaluate the prognostic value of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper tract urothelial carcinoma (UTUC).Materials and 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).Conclusion 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.

AB - Objective To evaluate the prognostic value of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper tract urothelial carcinoma (UTUC).Materials and 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).Conclusion 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.

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