Activated Mammalian Target of Rapamycin Is an Adverse Prognostic Factor in Patients with Biliary Tract Adenocarcinoma

Purpose: The mammalian target of rapamycin (mTOR) is a protein kinase that plays a key role in cellular growth and homeostasis. Because its regulation is frequently altered in tumors, mTOR is currently under investigation as a potential target for anticancer therapy. The purpose of our study was to...

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Published in:Clinical cancer research 2007-08, Vol.13 (16), p.4795-4799
Main Authors: HERBERGER, Beata, PUHALLA, Harald, LEHNERT, Martina, WRBA, Fritz, NOVAK, Sabine, BRANDSTETTER, Anita, GRUENBERGER, Birgit, GRUENBERGER, Thomas, PIRKER, Robert, FILIPITS, Martin
Format: Article
Language:English
Subjects:
Adenocarcinoma - chemistry
Adenocarcinoma - mortality
Adenocarcinoma - therapy
Adult
Aged
Antineoplastic agents
biliary tract cancer
Biliary Tract Neoplasms - chemistry
Biliary Tract Neoplasms - mortality
Biliary Tract Neoplasms - therapy
Biological and medical sciences
Biomarkers
Female
Humans
Immunohistochemistry
Male
Medical sciences
Middle Aged
mTOR
Pharmacology. Drug treatments
Prognosis
Protein Kinases - analysis
Survival Rate
TOR Serine-Threonine Kinases
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Summary:Purpose: The mammalian target of rapamycin (mTOR) is a protein kinase that plays a key role in cellular growth and homeostasis. Because its regulation is frequently altered in tumors, mTOR is currently under investigation as a potential target for anticancer therapy. The purpose of our study was to determine the prognostic value of activated mTOR (p-mTOR) in patients with biliary tract adenocarcinoma (BTA), in order to strengthen the rationale for targeted therapy of BTA using mTOR inhibitors. Experimental Design: We determined expression of p-mTOR in paraffin-embedded surgical specimens of BTA by immunohistochemistry with a monoclonal antibody to phosphorylated mTOR. Overall survival was analyzed with a Cox model adjusted for clinical and pathologic factors. Results: Immunostaining for p-mTOR was positive in 56 of 88 (64%) tumors. Activated mTOR was not associated with any of the clinical or pathologic variables of the patients but predicted overall survival of the patients. Overall survival was significantly shorter in patients with p-mTOR–positive tumors as compared with patients with p-mTOR–negative tumors (hazard ratio for death 2.57; 95% confidence interval, 1.35-4.89; P = 0.004). Multivariate Cox proportional hazards regression analyses identified p-mTOR to be an independent prognostic factor for death (adjusted hazard ratio for death, 2.44; 95% confidence interval, 1.24-4.80; P = 0.01). Conclusions: Patients with BTA and p-mTOR–positive tumors have a significantly shorter overall survival than patients with p-mTOR–negative tumors and may benefit from targeted therapy with mTOR inhibitors in the future.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-07-0738