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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.05.028 on December 8, 2003

Annals of Surgical Oncology 11:45-51 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Human Telomerase Reverse Transcriptase (hTERT) and Ki-67 are Better Predictors of Survival than Established Clinical Indicators in Patients Undergoing Curative Hepatic Resection for Colorectal Metastases

David L. Smith, MD, Jean-Charles Soria, MD, PhD, Luc Morat, MS, Qinghua Yang, MD, Laure Sabatier, PhD, Diane D. Liu, MS, Rabih A. Nemr, Asif Rashid, MD, PhD and Jean-Nicolas Vauthey, MD

From the Departments of Surgical Oncology (DLS, RN, JNV), Biostatistics (DDL), and Pathology (QY,AR), The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA; the Division of Cancer Medicine, the Gustave Roussy Institute, Paris, France (JCS, LM); and Commissariat à l’Energie Atomique, Laboratoire de Radiobiologie et Oncologie, Fontenay aux Roses, France (JCS, LS).

Correspondence: Address correspondence and reprint requests to: Jean-Nicolas Vauthey, MD, Department of Surgical Oncology, Unit 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030–4009; Fax: 713-792-0722; E-mail: jvauthey{at}mdanderson.org; or Jean-Charles Soria, MD, PhD, Division of Cancer Medecine, Gustave Roussy Institute, 39 Rue Camille Desmoulins, 94805 Villejuif, France; Fax: 33-1-42-11-52-30; E-mail: soria{at}igr.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: We evaluated hTERT and Ki-67 expression in patients who underwent curative resection of hepatic colorectal metastases to determine if these markers of cell proliferation correlated better with survival than an established scoring system that is based on clinical predictors.

Methods: Patients operated on between 1993 and 1997 whose survival time was known were analyzed. For each patient, the clinical prognostic score was derived on the basis of primary node status, disease-free interval, number of hepatic tumors, largest tumor, and carcinoembryonic antigen level, and tumor specimens were analyzed for Ki-67 and hTERT with use of standard immunohistochemical techniques. The immunohistochemical analysis was blinded to all patient characteristics.

Results: The study included 66 patients. Twenty-six survived less than 2 years after surgery, 19 survived 2–5 years, and 21 survived more than 5 years. Ki-67 positivity and hTERT positivity (labeling indexes greater than or equal to 50%) were observed in 24 patients and 23 patients, respectively. The clinical score did not predict survival, although there was a weak trend toward a lower score in patients with better survival. Both Ki-67 (P = .04) and hTERT (P = .0001) correlated better with survival than did the clinical score.

Conclusions: In patients undergoing curative resection of hepatic colorectal metastases, hTERT and Ki-67 are better predictors of survival than is a score based on clinical features.

Key Words: Colorectal cancer • Hepatic metastases • Prognostic factors • Surgery • Survival


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatic metastasis is a common pattern of recurrence after resection of primary colorectal cancer. Although the majority of patients with hepatic colorectal metastases cannot be treated successfully with surgery, complete resection of hepatic metastases in patients without extrahepatic disease has resulted in 5-year survival rates of 30% to 40%.1,2 Several studies have evaluated prognostic factors for survival in these patients.3–5 In the largest study, Fong et al.5 evaluated clinical markers in 1001 patients and developed a clinical prognostic score that predicts the risk of recurrence after resection.

Other investigators have focused on the evaluation of various biologic markers in an effort to better predict the risk of recurrence and death after resection.6–11 Most of these efforts8–11 met with only limited success, but two large single-institution studies6,7 showed that proliferation markers such as Ki-67 and tritiated thymidine uptake independently correlate with survival after resection of hepatic colorectal metastases. Ki-67 is present in the nucleus only during cellular proliferation and is commonly used to measure proliferative activity. It has also been demonstrated to correlate with many other markers of cellular proliferation12 and therefore is an ideal marker with which to assess the relationship between cellular proliferation and outcome following potentially curative resection of hepatic colorectal metastases.

Multiple investigators have recently shown that telomerase activity may be useful in predicting the clinical and biologic behavior of different gastrointestinal cancers.13–15 Telomerase is a ribonucleoprotein responsible for the synthesis of guanine-rich repeat sequences (TTAGGG)n, known as telomeres, in human and other eukaryotic cells. In cancer cells, activated telomerase contributes to telomere stabilization and cellular immortality.16,17 Telomerase is expressed in the vast majority of human malignant cell lines and tumors but not in the corresponding benign tissues.16,17 Telomerase is composed of an RNA component (hTERC), a catalytic protein subunit (hTERT), and other telomerase-associated proteins whose functions remain to be established. Expression of hTERT is largely restricted to cells with telomerase activity.16,17 It has been shown that hTERT can be concentrated in the nucleolus and that functional assembly of telomerase takes place primarily in the nucleolus.18–20 Therefore, nucleolar hTERT expression is probably a good reflection of telomerase activity. This is of particular interest when no frozen tissue is available on which to directly evaluate telomerase activity in a patient. Telomerase activation has been correlated with tumor growth and venous invasion in sporadic colorectal cancer,13 but to date, its activity in hepatic colorectal cancer metastases has not been evaluated.

In this study, we evaluated hTERT and Ki-67 expression in patients who underwent potentially curative resection of hepatic colorectal metastases to determine if these markers correlated with survival better than the previously established Fong scoring system,5 which is based on clinical factors.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients who underwent potentially curative resection of hepatic colorectal metastases between 1993 and 1997 and whose length of survival after surgery was known were identified from our prospective hepatobiliary surgery database. Patients were divided into three groups on the basis of survival time: less than 2 years, 2 to 5 years, and more than 5 years. The patients’ records were reviewed, and a clinical prognostic score was derived for each patient according to the method of Fong et al.5 (Table 1). Resection specimens from the patients were analyzed for hTERT and Ki-67, as described in the following paragraphs.


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  		TABLE 1. Fong scoring system
 
Ki-67 Analysis
Immunohistochemical analysis of Ki-67 was performed with use of a monoclonal antibody (MIB1, DAKO, Carpinteria, CA). Five-micron sections of formalin-fixed, paraffin-embedded tissue were cut onto coated slides and baked in an oven overnight at 60°C. The sections were deparaffinized by routine techniques and incubated with primary antibody diluted 1:100 for 60 minutes. Labeling was detected with the DAKO Envision Plus detection kit, used according to the protocol suggested by the manufacturer. The sections were counterstained with hematoxylin. Sections from tonsils were used as positive and negative controls. Normal hepatocytes, stromal cells, or lymphocytes served as positive internal controls in every tissue section. The Ki-67 labeling index was defined as the number of neoplastic cells with nuclear labeling in five representative high-power fields of the tumor, divided by the total number of neoplastic cells in those fields, expressed as a percentage. At least 1000 neoplastic cells were examined in each case. All slides were scored concomitantly by two investigators (A. R. and Q. Y.). If 50% or more of the tumor cells were positive for Ki-67 at the nuclear level, the case was considered to be positive.

hTERT Analysis
For hTERT analysis, paraffin-embedded, 5-µm-thick tissue sections from all specimens were stained for hTERT with use of a primary mouse monoclonal antibody (NCL-hTERT; Novocastra, Newcastle, UK). Slides were deparaffinized through a series of xylene baths. The samples were rehydrated in graded alcohols. To retrieve the antigenicity, the tissue sections were treated at high temperature in 10 mM citrate buffer (pH, 6.0) for 60 minutes. The sections were then immersed in methanol containing 0.3% hydrogen peroxidase for 20 minutes to block the endogenous peroxidase activity and were incubated in 2.5% blocking serum to reduce nonspecific binding. Sections were incubated for 90 minutes at 37°C with primary anti-hTERT at a 1:50 dilution. The sections were processed with standard avidin-biotin immunohistochemistry according to the manufacturer’s recommendations (Vector Laboratories, Burlingame, CA). Diaminobenzidine was used as a chromogen, and commercial hematoxylin was used for counterstaining. The hTERT labeling index was defined as the number of neoplastic cells with nucleolar labeling in five representative high-power fields of the tumor, divided by the total number of neoplastic cells in those fields, expressed as a percentage. The cell line NCI-H460 (American Type Culture Collection, Manassas, VA) was used as an external positive control. At least 1000 neoplastic cells were examined in each case. All slides were scored concomitantly by two investigators (L. M. and J.-C. S.). If 50% or more of the tumor cells were positive for hTERT at the nucleolar level, the case was considered to be positive.

Statistical Analysis
The associations between Ki-67 and hTERT and survival were analyzed with two different statistical methods. The Cochran-Armitage trend test was used to analyze the association between the proportion of Ki-67-positive and hTERT-positive cases (i.e., proportion of cases with labeling index of at least 50%) and survival. The Kruskal-Wallis test was used to analyze the association between Ki-67 and hTERT labeling index and survival as a continuous variable. A P value < .05 was considered to be statistically significant. Immunohistochemical analysis was performed in a blinded manner with respect to the clinical information about the patients. The Spearman correlation test was used to measure the strength of association between the continuous variables hTERT and Ki-67.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 66 patients were identified who underwent potentially curative hepatic resection between 1993 and 1997 and whose survival time was known. The patients’ characteristics in relation to survival time are outlined in Table 2. The clinical score differed little by survival-based subgroup. In all three groups, the majority of patients had a score of 2 or less. Although there was a weak trend toward improved survival with decreasing score, this did not reach statistical significance (P = .4; Fig. 1).


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  		TABLE 2. Patient characteristics overall and by survival-based subgroupa
 


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  		FIG. 1. Mean clinical score versus survival.

 
Representative examples of Ki-67 and hTERT staining are presented in Fig. 2 A and B and Fig. 3 A and B, respectively. Three patients were not evaluable for Ki-67, and eight patients were not evaluable for hTERT. Ki-67 immunostaining was restricted to the cell nuclei. hTERT staining was located in the nucleolar structures, and in a few cases diffuse nucleoplasmic staining with nucleolar reinforcement was observed in a few cells, along with a dominant nucleolar pattern. Weak to very weak staining for hTERT was seen in tumor cells at the cytoplasmic level (Fig. 3B). However, since hTERT nucleolar staining is considered to be a specific pattern,19,20 only cells with nucleolar staining were taken into account in the calculation of the hTERT labeling index. hTERT nucleolar staining was restricted to the colon metastatic tumor cells, with no such staining observed in the adjacent liver tissue (Fig. 3A)



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  		FIG. 2. Immunohistochemical analysis of Ki-67, showing nuclear staining of the neoplastic cells of a tumor with a high proliferation index. Both low-magnification (A) and high-magnification (B) images are shown.

 


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  		FIG. 3. Immunohistochemical analysis of hTERT, showing nucleolar staining for hTERT. Both low-magnification (A) and high-magnification (B) images are shown.

 
The relationship between the proportion of Ki-67-positive cells and survival is shown in Fig. 4. Patients with a high labeling index tended to have shorter survival. The relationship between the proportion of hTERT-positive cells and survival is shown in Fig. 5. hTERT was a better predictor of survival (P = .0001) than was Ki-67 (P = .04). For hTERT, the difference in hTERT level between the survival-time groups was also significant (less than 2 years vs. 2–5 years, P = .01; 2–5 years vs. greater than 5 years, P = .04). On analysis of Ki-67 and hTERT labeling index as continuous variables, both Ki-67 (P = .02) and hTERT (P = .004) correlated with survival. The median labeling indices for Ki-67 and hTERT per survival group were as follows: less than 2 years, 51% and 63%; 2–5 years, 34% and 15%; and more than 5 years, 15% and 12%, respectively. In this analysis, too, hTERT was a better predictor of survival than Ki-67.



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  		FIG. 4. Ki-67 index versus survival.

 


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  		FIG. 5. hTERT index versus survival.

 
To determine whether a close association existed between Ki-67 and hTERT, a Spearman correlation test was performed. As shown in Fig. 6, a weak but statistically significant correlation (correlation coefficient = 0.35; P = .01) was found between hTERT index and Ki-67 score.



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  		FIG. 6. Correlation between hTERT labeling index and Ki-67 proliferative index for the study population.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we found that hTERT and, to a lesser extent, Ki-67 predicted survival after resection of hepatic colorectal metastases better than did a previously reported clinical score.

In our series, few patients, even in the group that survived for less than 2 years after resection, had a clinical score greater than 2, and only one patient had a carcinoembryonic antigen level greater than 200 ng/mL. Furthermore, the majority of patients in all groups had a score of 2 or less. Given this, the use of the clinical score to predict outcome or to guide management in our patient population appears limited. This provides a strong rationale to test biologic markers as potential predictors of survival.

Our finding that Ki-67 predicted survival confirms an association between proliferative activity and survival reported by Weber et al.,6 who found that Ki-67 was a more accurate predictor of survival than tumor growth pattern and tumor pseudocapsulation, and by Costa et al.,7 who found that cell proliferation as measured by tritiated thymidine uptake was a useful indicator of recurrence after surgery. Our results, however, suggest that hTERT may provide a better correlation with outcome than Ki-67.

In this study, heavy staining of hTERT in the nucleolus was a major prognostic factor for survival. The finding suggests that hTERT is a marker of a more aggressive behavior. Because the relationship between hTERT expression and cell proliferation remains controversial, we also compared hTERT status with the expression of Ki-67. As shown in Fig. 6, we found a weak association between hTERT expression and Ki-67 labeling index (r = .35). Furthermore, hTERT expression had a much stronger prognostic value than Ki-67 expression in the present series. Collectively, these observations suggest that high hTERT expression is not a mere consequence of cell proliferation but rather an indicator of a specific biologic behavior of colorectal metastasis. In contrast, Ki-67 reflects only the proliferative status of the cells; it does not represent per se a tumorigenic event. hTERT, a relevant marker of telomerase activity, is by itself the indicator of a major tumorigenic event.

In a seminal paper, Hahn et al.21 proved that disruption of the intracellular pathways regulated by large-T antigen, oncogenic ras, and telomerase suffices to create a human tumor cell. The presence of telomerase activity indicates that the cell has the ability to inactivate the telomeric "clock" that limits the proliferative capacity of normal somatic cells. The presence of hTERT, an indirect marker of immortality, gives the cell the proliferative capacity to accumulate the mutations necessary to become malignant and biologically aggressive.16 Furthermore, it has recently been shown that hTERT can maintain cell survival and proliferation independent of telomerase activity, by means of a clear prosurvival and antiapoptotic activity.22 Therefore, the overall value of hTERT as a predictor of survival is underlined by different molecular mechanisms: immortality and antiapoptotic activity. In that regard, it is interesting to highlight that in other solid tumors (such as primary lung tumors), hTERT also has prognostic value.23,24 A high percentage of cells expressing hTERT at the nucleolar level is an indicator of an aggressive tumor, not only immortalized but also resistant to apoptosis.

The current study may be criticized on the basis of the fact that survival subsets were retrospectively selected. The selection process of our database included the first consecutive patients who met the predetermined survival span. This selection process was specifically designed to avoid the difficulties associated with the analysis of large numbers of patients with negative markers.

Although this study confirms that proliferation activity correlates with survival, the much closer correlation between hTERT and survival confers to hTERT a more promising role than Ki-67 as a practical biologic marker of outcome. Larger studies, however, need to be performed to confirm hTERT as an independent predictor of outcome. Moreover, hTERT can reflect only part of the tumor biology. Therefore, the development of a panel of biomarkers may enable better prediction of the overall biologic behavior of hepatic colorectal metastases. Surrogate biomarkers of angiogenesis, tissue invasion, self-sufficiency in growth signals, and insensitivity to antigrowth signals need to be evaluated along with markers of limitless replicative potential, such as hTERT.25

In our study, we found that a high hTERT index was strongly correlated with a short survival following curative hepatic resection for colorectal metastases. These same patients with a high hTERT index, however, usually had a clinical score of 0 to 2, which on the basis of the clinical indicators would not normally lead to more aggressive therapy at the time of surgery, such as placement of a hepatic-artery infusion pump or additional chemotherapy postoperatively. In our series, all patients were treated prior to the routine use of preoperative chemotherapy for hepatic colorectal metastases, and only a small number who presented with synchronous metastatic (stage IV) disease received chemotherapy prior to planned staged resection. The use of chemotherapy either before or after hepatic resection was similarly distributed between the three groups, and therefore no conclusion can be drawn regarding the effect of chemotherapy on survival.

In conclusion, clinical indicators are insufficient to predict prognosis after resection of hepatic colorectal metastases. Nucleolar hTERT appears to correlate with a more aggressive tumor biology, and this information deserves to be taken into account in confirmatory series. In the future, a panel of biomarkers (including hTERT) may lead us to be more aggressive in the treatment of patients with a poor biologic profile.


   ACKNOWLEDGMENTS
 
The acknowledgments are available online in the full-text version at www.annalssurgicaloncology.org. They are not available in the PDF version.

This work was presented in abstract form at the 56th Annual Meeting of the Society of Surgical Oncology, Los Angeles, March 6–9, 2003. The work in the Laboratory of Radiobiology and Oncology was funded by Cec Susgeninradcar Figh-1999–00002.


   FOOTNOTES
 
In patients undergoing curative resection of hepatic colon cancer metastases, clinical parameters were unable to distinguish between long-term and short-term survivors. The molecular marker hTERT and, to a lesser degree, Ki-67 correlated better with survival.

Received for publication May 28, 2003. Accepted for publication October 7, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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