PMID- 25443916 OWN - NLM STAT- MEDLINE DCOM- 20150212 LR - 20211203 IS - 1527-9995 (Electronic) IS - 0090-4295 (Linking) VI - 84 IP - 5 DP - 2014 Nov TI - Evaluation of the prognostic significance of altered mammalian target of rapamycin pathway biomarkers in upper tract urothelial carcinoma. PG - 1134-40 LID - S0090-4295(14)00831-0 [pii] LID - 10.1016/j.urology.2014.07.050 [doi] 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. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Bagrodia, Aditya AU - Bagrodia A AD - Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. FAU - Krabbe, Laura-Maria AU - Krabbe LM AD - Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Urology, University of Muenster Medical Center, Muenster, Germany. FAU - Gayed, Bishoy A AU - Gayed BA AD - Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. FAU - Kapur, Payal AU - Kapur P AD - Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX. FAU - Bernstein, Ira AU - Bernstein I AD - Division of Biostatistics, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX. FAU - Xie, Xian-Jin AU - Xie XJ AD - Division of Biostatistics, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX. FAU - Wood, Christopher G AU - Wood CG AD - Department of Urology, MD Anderson Cancer Center, Houston, TX. FAU - Karam, Jose A AU - Karam JA AD - Department of Urology, MD Anderson Cancer Center, Houston, TX. FAU - Weizer, Alon Z AU - Weizer AZ AD - Department of Urology, University of Michigan Cancer Center, Ann Arbor, MI. FAU - Raman, Jay D AU - Raman JD AD - Department of Urology, Penn State Hershey Medical Center, Hershey, PA. FAU - Remzi, Mesut AU - Remzi M AD - Department of Urology, Medical University of Vienna, Vienna, Austria. FAU - Rioux-Leclerq, Nathalie AU - Rioux-Leclerq N AD - Department of Pathology, Centre Hospitalier Universitaire de Rennes, Rennes, France. FAU - Haitel, Andrea AU - Haitel A AD - Department of Pathology, Medical University Vienna, Vienna, Austria. FAU - Roscigno, Marco AU - Roscigno M AD - Department of Urology, Ospedali Riuniti of Bergamo, Bergamo, Italy. FAU - Bolenz, Christian AU - Bolenz C AD - Department of Urology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany. FAU - Bensalah, Karim AU - Bensalah K AD - Department of Urology, Centre Hospitalier Universitaire de Rennes, Rennes, France. FAU - Sagalowsky, Arthur I AU - Sagalowsky AI AD - Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. FAU - Shariat, Shahrokh F AU - Shariat SF AD - Department of Urology, Medical University of Vienna, Vienna, Austria. FAU - Lotan, Yair AU - Lotan Y AD - Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. FAU - Margulis, Vitaly AU - Margulis V AD - Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address: Vitaly.margulis@utsouthwestern.edu. LA - eng PT - Journal Article DEP - 20141024 PL - United States TA - Urology JT - Urology JID - 0366151 RN - 0 (Biomarkers, Tumor) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Biomarkers, Tumor/metabolism MH - Carcinoma/*metabolism/mortality MH - Disease-Free Survival MH - Female MH - Humans MH - Immunohistochemistry MH - Kaplan-Meier Estimate MH - Male MH - Middle Aged MH - Multivariate Analysis MH - Phosphatidylinositol 3-Kinases/metabolism MH - Prognosis MH - Proportional Hazards Models MH - Recurrence MH - Retrospective Studies MH - TOR Serine-Threonine Kinases/*metabolism MH - Treatment Outcome MH - Urologic Neoplasms/*metabolism/mortality/pathology MH - Urothelium/*pathology EDAT- 2014/12/03 06:00 MHDA- 2015/02/13 06:00 CRDT- 2014/12/03 06:00 PHST- 2014/03/09 00:00 [received] PHST- 2014/07/09 00:00 [revised] PHST- 2014/07/29 00:00 [accepted] PHST- 2014/12/03 06:00 [entrez] PHST- 2014/12/03 06:00 [pubmed] PHST- 2015/02/13 06:00 [medline] AID - S0090-4295(14)00831-0 [pii] AID - 10.1016/j.urology.2014.07.050 [doi] PST - ppublish SO - Urology. 2014 Nov;84(5):1134-40. doi: 10.1016/j.urology.2014.07.050. Epub 2014 Oct 24.