Multi-institutional evaluation of the prognostic significance of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper-tract urothelial carcinoma (UTUC).

Media type: E-Article

Title: Multi-institutional evaluation of the prognostic significance of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper-tract urothelial carcinoma (UTUC)

Contributor: Bagrodia, Aditya; Krabbe, Laura-Maria; Gayed, Bishoy A.; Kapur, Payal; Darwish, Oussama M.; Bernstein, Ira; Xie, Xian-Jin; Wood, Christopher G.; Zigeuner, Richard; Weizer, Alon Z.; Raman, Jay D.; Remzi, Mesut; Langner, Cord; Roscigno, Marco; Bolenz, Christian; Bensalah, Karim; Sagalowsky, Arthur I.; Shariat, Shahrokh F.; Lotan, Yair; Margulis, Vitaly

imprint: American Society of Clinical Oncology (ASCO), 2014

Language: English

DOI: 10.1200/jco.2014.32.4_suppl.323

ISSN: 0732-183X; 1527-7755

Keywords: Cancer Research ; Oncology

Origination:

Footnote:

Description: 323 Background: Alterations in the MTOR and HIF pathways may have prognostic significance in bladder carcinoma. We evaluated the predictive value of altered MTOR-pathway biomarkers in upper tract urothelial carcinoma (UTUC). Methods: Multi-institutional review of clinicopathological data on patients receiving extirpative surgery for UTUC from 1990-2008. Immunohistochemistry for phosphorylated-S6, mTOR, phosphorylated-mTOR, PI3K, p4E-BP, phosphorylated-AKT, PTEN, HIF-1a, Raptor and Cyclin D was performed on tissue microarrays from radical nephroureterectomy specimens. Predictive markers were identified by regression analyses. Significance of altered markers was assessed with Kaplan-Meier and Cox regression analysis. Results: 620 patients with a mean age of 69 years were included. 37% of patients had non-organ confined (T3/T4 and/or N+) disease. 74% of patients had high-grade disease and 22% had LVI on final pathology. Over a median follow-up of 27.3 months, 24.6% of patients recurred and 21.8% died of UTUC. On multivariable analysis, PI3K (OR 1.28, p=0.001) and Cyclin D (OR 3.45, p=0.05) were significant predictors of clinical outcomes. Cumulative marker-score was defined as low-risk (zero/one 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<0.001), non-organ confined disease (61% vs. 33%, p<0.001), LVI (35% vs. 20%, p=0.001), and lymph node metastases (22% vs. 6%, p<0.001). Kaplan-Meier analysis demonstrated a significant difference in CSM based on risk groups. On multivariable analysis for CSM incorporating non-organ confined disease, grade, LVI, tumor architecture, and marker-score, high-risk biomarker-score was an independent predictor of CSM (HR 1.5, 95%CI 1.04-2.3, p=0.03). Conclusions: 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.

Access State: Open Access

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