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Clinical Cancer Research 13, 4795, August 15, 2007. doi: 10.1158/1078-0432.CCR-07-0738
© 2007 American Association for Cancer Research
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Imaging, Diagnosis, Prognosis

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

Beata Herberger1, Harald Puhalla2, Martina Lehnert1, Fritz Wrba3, Sabine Novak1, Anita Brandstetter1, Birgit Gruenberger1, Thomas Gruenberger2, Robert Pirker1 and Martin Filipits1

Authors' Affiliations: Departments of 1 Medicine I, 2 Surgery, and 3 Clinical Pathology, Medical University of Vienna, Vienna, Austria

Requests for reprints: Martin Filipits, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria. Phone: 43-14277-65237; Fax: 43-14277-65196; E-mail: martin.filipits{at}meduniwien.ac.at.


   Abstract
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 Abstract
Patients and Methods
 Results
 Discussion
 References
 
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.

Adenocarcinoma of the biliary tract (BTA) is a rare disease and the prognosis of patients with this disease is poor. Despite improvements in diagnosis and surgery, overall survival even of patients who underwent complete resection of their carcinomas is short (1). Due to the lack of characteristic early symptoms, a definitive diagnosis is often established only at an advanced stage in the majority of the patients (1). Knowledge of molecular biomarkers associated with the prognosis of BTAs may help to devise new treatment strategies to improve clinical outcome.

A potential candidate biomarker is the mammalian target of rapamycin (mTOR), a Ser/Thr protein kinase which plays a key role in cellular growth and homeostasis (2, 3). Its regulation is frequently altered in various tumors. mTOR is activated by phosphorylation through Akt via the phosphatidylinositol 3-kinase/AKT signaling pathway at Ser2448 and by autophosphorylation at Ser2481 (4, 5). An important function of mTOR is the regulation of protein translation. It activates the eukaryotic translation initiation factor 4E (elF4E), which has been implicated in tumor development, and the p70 ribosomal S6 kinase. mTOR also participates in the inactivation of the eIF4E inhibitor, 4E-BP1. These events result in the translation of specific mRNA subpopulations. Because of its key function in cellular growth, mTOR is currently under investigation as a potential target for anticancer therapy (6).

The purpose of the present study was to determine the prognostic value of activated mTOR (p-mTOR) in patients with BTA, in order to strengthen the rationale for targeted therapy of BTA using mTOR inhibitors.


   Patients and Methods
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 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Patients. One hundred and one consecutive patients with BTA who underwent complete (R0) resection at the Department of Surgery, Medical University of Vienna, between 1993 and 2006 were identified from a database. Informed consent was obtained according to institutional guidelines. The study population consisted of patients with hilar, distal and intrahepatic cholangiocarcinoma, and gallbladder carcinoma. Clinical data of the patients were obtained from the database and supplemented with review of the medical record.

Thirty-eight patients (43%) were treated with chemotherapy (7–9). Thirteen patients received gemcitabine monotherapy and 15 patients were treated with gemcitabine-based combination chemotherapy. Capecitabine monotherapy was given in two patients and two patients received capecitabine-based combination chemotherapy. Five patients were treated with 5-fluorouracil–based chemotherapy and one patient received chemotherapy consisting of cyclophosphamide, doxorubicin, and vincristine. Three patients had been included in previous studies evaluating the clinical role of p27Kip1 expression and p53 gene mutations (10, 11).

Specimen collection. For the current research project, the participating pathologist from our institution was asked to provide a representative formalin-fixed, paraffin-embedded tumor block from each patient. All tumor specimens were obtained at the time of surgery before adjuvant therapy. Paraffin blocks were stored at room temperature and were identified only by an identification number. An H&E-stained section of each tumor block was prepared and used for pathologic confirmation of the presence of BTA. Additional 4-µm sections were obtained for the immunohistochemical analysis.

Immunostaining for p-mTOR. Immunohistochemistry was done and evaluated in a single lab at the Department of Medicine I, Medical University of Vienna by means of a standard protocol.

Briefly, tissue sections were deparaffinized and rehydrated. To reduce nonspecific background staining due to endogenous peroxidase, slides were incubated in 0.3% H2O2 for 10 min. For epitope retrieval, specimens were heated for 10 min in 10 mmol/L of citrate buffer (pH 6.0) in a pressure cooker. After incubation with Ultra V Block (UltraVision LP detection system, Lab Vision Corporation) for 7 min at room temperature to block background staining, the tissues were incubated overnight at 4°C with a rabbit monoclonal antibody specific for p-mTOR (Phospho-mTOR, Ser2448, 49F9; dilution 1:100; Cell Signaling Technology). This antibody detects mTOR only when phosphorylated at Ser2448. Antibody binding was detected by means of the UltraVision LP detection system according to the manufacturer's recommendations (Lab Vision Corporation). Color development was done with 3-3'-diaminobenzidine and counterstained with hematoxylin. Sections of gallbladder cancer specimens known to express p-mTOR served as external positive controls and expression of p-mTOR in normal bile ducts was used as internal positive controls.

Expression of p-mTOR was examined by an investigator who was blinded to clinical data of the patients. At least 100 tumor cells per case were evaluated. Immunostaining was classified based on staining intensity and percentage of p-mTOR–positive tumor cells. Staining intensity was determined as 0 (absent), 1 (weak), and 2 (strong). For comparison with clinical variables and survival, expression levels of the biomarkers were semiquantified using an immunohistochemistry score (range, 0-200) calculated by multiplying staining intensity with the percentage of positive tumor cells. Patients with an immunohistochemistry score of ≤20 were considered as p-mTOR–negative and those with a score of >20 as p-mTOR–positive.

Statistical analyses. The primary end point of our study was overall survival. Disease-free survival was analyzed as a secondary end point. The 5-year overall survival rate of all 88 patients was 35%. We assumed a 5-year overall survival rate of 20% for p-mTOR–positive patients and 50% for p-mTOR–negative patients. The estimated power for 88 patients was 85% for detecting a 30% absolute survival difference at 5 years with a two-sided type I error of 5% (assuming that marker-positive and marker-negative patients were equally distributed). The sample size calculation was based on recently published results in breast cancer and cervical cancer (12, 13).

To identify any selection bias, the baseline characteristics of patients with or without tumor blocks were compared using {chi}2 tests and the overall rates of survival were compared with the use of a Cox model. Baseline data according to p-mTOR status were compared in univariate analyses with the use of {chi}2 tests. Survival time was defined as the period between the time of surgery and death (overall survival) or the period between the time of surgery and relapse or tumor-related death (disease-free survival). Survival rates were estimated by means of the Kaplan-Meier method. Differences between survival curves were analyzed by means of a log-rank test. The independent prognostic value p-mTOR was studied with the use of a Cox model, which was adjusted for age (<65 or ≥65 years), gender, anatomic location (hilar cholangiocarcinoma, distal cholangiocarcinoma, intrahepatic cholangiocarcinoma, or gallbladder carcinoma), tumor stage (T1, T2, T3, or T4), lymph node status (negative or positive), tumor grade (G1, G2, or G3), and chemotherapy (yes or no). All reported P values are two-sided. All analyses were done with the use of SPSS software, version 12.0 (SPSS).


   Results
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 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Tumor blocks were available from 94 of the 101 patients with BTA. Among these 94 blocks, six contained no tumor material and were excluded from our study. The remaining 88 blocks were of sufficient amount and quality for sectioning. Expression of p-mTOR was evaluated in these 88 specimens and all further statistical analyses were done on this patient population. The 88 patients, and the remaining 13 who were excluded from the study, had similar baseline characteristics and overall rates of survival.

We assessed p-mTOR expression using standard immunohistochemistry. Immunostaining of p-mTOR was cytoplasmatic and partly membranous. Strong p-mTOR immunoreactivity was observed in normal bile duct epithelia (Fig. 1 ). Staining intensity was absent in three specimens, weak in three tumor samples (two tumors with 10% p-mTOR–positive cells, one tumor with 70% p-mTOR–positive cells), and strong in 82 samples. Immunostaining ranged from 0% to 80% of the tumor cells. The median value of p-mTOR expression of the series was 30%. Figure 1 shows representative examples of p-mTOR immunostaining. Comparisons of p-mTOR expression with clinical variables including survival of the patients were done with p-mTOR expression as a continuous variable (immunohistochemistry score) and as a dichotomized variable classified as positive (immunohistochemistry score of >20) or negative (immunohistochemistry score of ≤20). Of the 88 tumors, 56 (64%) were p-mTOR–positive. Table 1 compares the characteristics of the patients according to p-mTOR expression in a univariate analysis. We observed no significant association between p-mTOR expression status and clinical and pathologic variables (Table 1).


Figure 1
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  		Fig. 1. Examples of p-mTOR immunostaining. Strong p-mTOR immunostaining of normal bile ducts (A-B), p-mTOR–negative BTAs (C-D), and p-mTOR–positive BTAs (E-F). Bar, 100 µm.

 

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  		Table 1. Characteristics of the patients with BTA according to p-mTOR status

 
At a median follow-up of 5 years, 54 of 88 (61%) patients had died. More deaths occurred in patients with p-mTOR–positive tumors than in patients with p-mTOR–negative tumors (42 versus 12; P = 0.001). In univariate survival analyses, only age [hazard ratio (HR) for death, 1.75; 95% confidence interval (CI), 1.02-2.99; P = 0.04] and p-mTOR (HR for death, 2.57; 95% CI, 1.35 to 4.89; P = 0.004) were significantly associated with overall survival (Table 2 ). The median overall survival of all 88 patients was 2.8 years (95% CI, 1.6-4 years). Patients with p-mTOR–positive tumors had a significantly shorter overall survival than those with p-mTOR–negative tumors (Table 2; Fig. 2A ). The median overall survival was 2 years for patients with p-mTOR–positive tumors, whereas it was 5.5 years for patients with p-mTOR–negative tumors (P = 0.004; Fig. 2A). There was a statistically significant difference in overall survival between patients with 10% positive tumor cells and those with 20% positive tumor cells (HR for death, 4.02; 95% CI, 1.40-11.51; P = 0.01) but no difference was observed between patients with 50% to 60% positive tumor cells and those with 70% to 80% positive tumor cells (HR for death, 0.92; 95% CI, 0.41-2.07; P = 0.84). Disease-free survival was also shorter in patients with p-mTOR–positive tumors than in patients with p-mTOR–negative tumors (HR for recurrence or death, 1.93; 95% CI, 1.10-3.39; P = 0.02; Fig. 2B). Comparable results were obtained when p-mTOR expression was analyzed as a continuous variable (HR for death, 1.01; 95% CI, 1.00-1.02; P = 0.05, and HR for recurrence or death, 1.01; 95% CI, 1.00-1.02; P = 0.03, respectively).


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  		Table 2. Univariate survival analyses

 

Figure 2
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  		Fig. 2. Kaplan-Meier estimates of the probability of survival. Overall survival (A) and disease-free survival (B) of all 88 patients according to p-mTOR status. The adjusted HR for death in patients with p-mTOR–negative tumors as compared with patients with p-mTOR–positive tumors was 2.44 (95% CI, 1.24-4.80; P = 0.01). The adjusted HR for recurrence or death was 1.94 (95% CI, 1.05-3.58; P = 0.04).

 
The independent effect of p-mTOR expression on overall survival and disease-free survival was assessed by Cox proportional hazards regression models adjusted for age, gender, anatomic location, tumor stage, lymph node status, tumor grade, and chemotherapy (Table 3 ). In these analyses, p-mTOR expression was significantly associated with overall survival (adjusted HR for death, 2.44; 95% CI, 1.24-4.80; P = 0.01) and disease-free survival (adjusted HR for recurrence or death, 1.94; 95% CI, 1.05-3.58; P = 0.04; Table 3). Thus, p-mTOR is an independent prognostic factor in patients with BTA.


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  		Table 3. Multivariate survival analysis

 

   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
In our study, we showed that p-mTOR status is an independent prognostic factor in patients with BTA. Overall survival was significantly shorter in patients with p-mTOR–positive tumors than in patients with p-mTOR–negative tumors. Our finding is consistent with previous reports which showed a prognostic value of p-mTOR in breast cancer and cervical cancer (12, 13). In breast cancer, 70% of the samples were p-mTOR–positive and patients with p-mTOR–positive tumors had a significantly shorter disease-free survival (P = 0.01). In cervical cancer, p-mTOR was detected in 52% of the patients and correlated significantly with both response to neoadjuvant cisplatin-based chemotherapy (P = 0.01) and shorter overall survival (P = 0.02). p-mTOR expression retained its significance as an independent poor prognostic marker in multivariate analyses (P = 0.02).

The phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway is frequently altered in human cancers and represents an attractive target for anticancer therapy. mTOR is inhibited by rapamycin, an immunosuppressive agent that arrests cells in the G1 phase of the cell cycle and induces apoptosis. Rapamycin (sirolimus) or its analogues CCI-779 (temsirolimus), RAD-001 (everolimus), and AP23573 are specific small molecule inhibitors of mTOR. They inhibit proliferation and induce apoptosis in cell lines derived from several human cancers including small cell lung cancer, prostate cancer, breast cancer, glioblastoma, osteosarcoma, pancreatic carcinoma, and renal cell carcinoma (14). Rapamycin initially binds to the intracellular receptor FKBP-12 (FK 506-binding protein; ref. 15). The rapamycin/FKBP-12 complex then binds with high affinity to mTOR, leading to dephosphorylation of both p70 ribosomal S6 kinase and 4E-BP1. This in turn leads to inhibition of mTOR signaling, translation initiation, and cell growth. In addition to the inhibition of p70 ribosomal S6 kinase and 4E-BP1, rapamycin also targets several components involved in cell cycle progression (16). These data provide additional rationale to target the phosphatidylinositol 3-kinase/AKT/mTOR pathway for cancer therapy.

The clinical relevance of mTOR inhibitors is currently under investigation in clinical trials. Several phase II studies evaluating the effects of temsirolimus in patients with renal cell carcinoma, mantle cell lymphoma, breast cancer, and glioblastoma have been completed (17–20).

A randomized phase II study in patients with advanced renal cell carcinoma showed that treatment with temsirolimus produced an objective response rate of 7% and minor responses in 26% of the patients (17). In patients with recurrent glioblastoma, radiographic improvement was observed in 36% of the patients who were treated with temsirolimus. This improvement was associated with a significantly longer time to progression in patients who responded to temsirolimus treatment. Furthermore, a significant correlation was observed between radiographic improvement and high levels of phosphorylated p70 ribosomal S6 kinase in tumor samples (P = 0.04; ref. 18). Heavily pretreated patients with locally advanced or metastatic breast cancer were randomly assigned to receive either 75 or 250 mg of temsirolimus given i.v. weekly. The overall partial response rate of 9.2% was similar for both dosages but the toxicity was decreased in patients who received the 75 mg dosage (19). Patients with relapsed or refractory mantle cell lymphoma received 250 mg of temsirolimus i.v. every week as a single agent. The overall response rate was 38% (13 of 34 patients) with one complete response (3%) and 12 partial responses (35%). The median time to progression was 6.9 months in responders compared with 6.5 months in all patients (20). Because of the favorable results in the phase II trials, phase III trials are in progress to evaluate the efficacy of temsirolimus for the treatment of renal cell carcinoma and locally advanced or metastatic breast cancer.

In conclusion, patients with p-mTOR–negative BTA have a significantly longer overall survival compared with patients with p-mTOR–positive BTA. Our finding suggests that patients with BTA may benefit from targeted therapy with mTOR inhibitors. If the clinical relevance of mTOR inhibitors in cancer patients is confirmed in future clinical trials and/or even the predictive value of the p-mTOR status can be shown, inhibition of mTOR may be evaluated as therapeutics in patients with BTA.


   Footnotes
 
Grant support: Institute of Cancer Research grant (M. Filipits).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/30/07; revised 5/15/07; accepted 6/ 1/07.


   References
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 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

  1. de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med 1999;341:1368–78.[Free Full Text]
  2. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994;78:35–43.[CrossRef][Medline]
  3. Brown EJ, Albers MW, Shin TB, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994;369:756–8.[CrossRef][Medline]
  4. Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 1999;344 Pt 2:427–31.[CrossRef][Medline]
  5. Peterson RT, Beal PA, Comb MJ, Schreiber SL. FKBP12-rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. J Biol Chem 2000;275:7416–23.[Abstract/Free Full Text]
  6. Huang S, Houghton PJ. Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol 2003;3:371–7.[CrossRef][Medline]
  7. Raderer M, Hejna MH, Valencak JB, et al. Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer. Oncology 1999;56:177–80.[CrossRef][Medline]
  8. Scheithauer W. Review of gemcitabine in biliary tract carcinoma. Semin Oncol 2002;29:40–5.[Medline]
  9. Kornek GV, Schuell B, Laengle F, et al. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol 2004;15:478–83.[Abstract/Free Full Text]
  10. Filipits M, Puhalla H, Wrba F. Low p27Kip1 expression is an independent prognostic factor in gallbladder carcinoma. Anticancer Res 2003;23:675–9.[Medline]
  11. Puhalla H, Kandioler D, Ludwig C, et al. p53 analysis in gallbladder cancer: comparison of gene analysis versus immunohistochemistry. Anticancer Res 2004;24:1201–6.[Abstract/Free Full Text]
  12. Zhou X, Tan M, Stone Hawthorne V, et al. Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res 2004;10:6779–88.[Abstract/Free Full Text]
  13. Faried LS, Faried A, Kanuma T, et al. Predictive and prognostic role of activated mammalian target of rapamycin in cervical cancer treated with cisplatin-based neoadjuvant chemotherapy. Oncol Rep 2006;16:57–63.[Medline]
  14. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004;4:335–48.[CrossRef][Medline]
  15. Choi J, Chen J, Schreiber SL, Clardy J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 1996;273:239–42.[Abstract]
  16. Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 2000;19:6680–6.[CrossRef][Medline]
  17. Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004;22:909–18.[Abstract/Free Full Text]
  18. Galanis E, Buckner JC, Maurer MJ, et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2005;23:5294–304.[Abstract/Free Full Text]
  19. Chan S, Scheulen ME, Johnston S, et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 2005;23:5314–22.[Abstract/Free Full Text]
  20. Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005;23:5347–56.[Abstract/Free Full Text]



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