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Annals of Surgical Oncology 9:1017-1022 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

DNA-PKcs Expression in Esophageal Cancer as a Predictor for Chemoradiation Therapeutic Sensitivity

Tsuyoshi Noguchi, MD, Tomotaka Shibata, MD, Shoichi Fumoto, MD, Yuzo Uchida, MD, Wolfram Mueller, MD and Shinsuke Takeno, MD

From the Department of Oncological Science (Surgery II) (TN, TS, SF, YU, ST), Oita Medical University, Oita, Japan; and the Institute of Pathology (WM), Heinrich-Heine University, Düsseldorf, Germany.

Correspondence: Address correspondence and reprint requests to: Shinsuke Takeno, MD, Department of Oncological Science (Surgery II), Oita Medical University, Idaigaoka 1-1, Hasama-machi, 879-5593 Oita, Japan; Fax: 81-97-549-4449; E-mail: surg2{at}oita-med.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: It would be of considerable benefit to patients with esophageal cancer to be able to predict the effect of CRT before therapy, because critical side effects could be avoided and the therapeutic cost of CRT-resistant cases could be reduced. One of the biological parameters with the potential to indicate radioresponse is the DNA double-strand break repair enzyme DNA-PKcs. This study aims to clarify the correlation between DNA-PKcs expression and CRT effect.

Methods: Sixty-seven patients with progressive esophageal cancer treated with CRT were included in this study. The relationship between the expression of DNA-PKcs and the effect of CRT was examined by using immunohistochemistry. The relationships between DNA-PKcs expression, clinicopathologic parameters, and CRT effect were investigated statistically.

Results: A significant correlation was found between the expression of DNA-PKcs and the effect of CRT (P = .0149). The high—DNA-PKcs expression group showed greater therapeutic sensitivity than the low-expression group. Clinicopathologic factors had no relationship with DNA-PKcs expression or CRT effect.

Conclusions: This study suggests that high expression of DNA-PKcs correlates with CRT effect. DNA-PKcs expression could, therefore, be useful for predicting the effect of CRT. In addition, these results may make it possible to plan therapy taking patients’ quality of life into consideration.

Key Words: DNA-PKcs • Esophageal cancer • Chemoradiotherapy • Immunohistochemistry


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Esophageal cancer is a common malignant tumor with an unfavorable prognosis.1 Chemoradiotherapy (CRT) is a useful form of treatment for some progressive esophageal cancers, particularly cancers that are considered inoperable because of spread to adjacent organs; it helps to reduce tumor stage or improve quality of life (QOL), as well as prolong survival. However, many patients experience serious adverse effects, such as bone marrow suppression, gastrointestinal symptoms, and liver or renal dysfunction, after CRT. Furthermore, not all patients are sensitive to CRT, and the effect of CRT varies in each patient. This may be one of the reasons why CRT is not seen as contributing to prolonged survival.2–6 Therefore, to predict the sensitivity of CRT before its use would be beneficial to therapy because the critical adverse effects could be avoided and the therapeutic cost of CRT-resistant cases could be reduced. CRT may prolong the survival and improve the QOL of selected patients with esophageal cancer.

A number of molecular biological factors have been considered as possible predictors of CRT sensitivity. To date, the expression of some genes (jun, ras, raf-1, src, erbB, bcl-2, FGF, and HDGF) has been reported to correlate with the response to chemo- or radiotherapy.7–16 The tumor suppresser gene, p53, is also reported to play a role in CRT response.17–19 However, the precise role of p53 in CRT is undecided. In a previous publication,20 we demonstrated that heat shock protein 27, but not p53, expression correlated with CRT resistance. In addition, expression of the DNA double-strand break (DSB) repair gene, DNA-PKcs, was recently found.21 Correlation between DNA-PKcs, a member of a subgroup of the phosphatidyl inositol kinase superfamily,22 and irradiation response has also been reported.23 Therefore, DNA-PKcs expression may have the potential to indicate radioresponse. In this study, the correlation between DNA-PKcs expression and CRT response was analyzed with immunohistochemistry.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
Sixty-seven patients with esophageal carcinoma were included in this study (60 men and 7 women; mean age, 66.5 years). Sixty-four patients had squamous cell carcinoma, one had adenocarcinoma, and the rest had small-cell carcinoma. They were treated in our institute with CRT alone (34 patients) or CRT followed by surgery (33 patients). Tumor progression was evaluated with esophagography, computed tomography scan, and endoscopic examination before therapy. The effect of CRT was evaluated clinically but not histologically in the same manner 4 weeks after CRT because not all patients underwent surgery.

Chemoradiotherapy
CRT was performed as follows. One cycle consisted of a continuous intravenous drip of 5-fluorouracil (250 mg/day) and cis-platinum (10 mg/day) combined with radiation (2 Gy/day) for 5 days. For irradiation, conventional fractionation (2 Gy per fractionation per day) was used, with a margin of 2 to 3 cm from the tumor edge. Four cycles of this protocol were repeated in 4 weeks. The anticancer drugs were reduced in some older patients or in those with complications.

Immunohistochemical Staining
All biopsy specimens were fixed in 10% buffered formalin for 24 hours and embedded in paraffin. Sections (4 µm) were placed on silane-coated slides. After deparaffinization and rehydration, slides were put into 3% hydrogen peroxidase for 15 minutes. They were then autoclaved at 121°C in citrate buffer (10 mM; pH 6.0) for 10 minutes for antigen activation. After cooling at room temperature for 30 minutes, the specimens were incubated with normal rabbit serum for 15 minutes at room temperature. They were then incubated with an anti—DNA-PKcs monoclonal antibody (Neomarker, Fremont, CA) for 16 hours at 4°C. Immunohistochemical staining was performed with a standard avidin-biotin complex method with a streptavidin-biotin-peroxidase kit (Nichirei, Tokyo, Japan); 3,3'-diaminobenzidine was used as a chromogen. The counterstaining was performed with hematoxylin.

Two independent observers blinded to the clinicopathologic information performed scoring. Cancer cells reacting as positive for DNA-PKcs were counted in at least 500 cancer cells in a randomly selected field by each observer. The ratio of positive cells for DNA-PKcs was calculated, and the mean ratio of two observers was regarded as the positive ratio of the case. A high-expression case was defined as DNA-PKcs immunoreactivity in at least 30%, which was determined according to the mean ratio of 31% of the ratio in cancer cells.

Evaluation for Response
The response to CRT was defined as described below, according to the Guidelines for Clinical and Pathologic Studies on Carcinoma of the Esophagus, 9th ed.24 The evaluation for CRT response was determined by discussion in the conference of our institute. A complete response (CR) was defined as the disappearance of all measurable, assessable, and secondary lesions and no appearance of new lesions for at least 4 weeks. A partial response (PR) was defined as a decrease of >=50% in the size of two-dimensionally measurable lesions, a decrease of >=30% in the size of one-dimensionally measurable lesions, no progression of assessable lesions or secondary lesions due to tumor, and no appearance of new lesions. All these conditions had to last for at least 4 weeks. No change (NC) was defined as neither a 50% decrease in the size of two-dimensionally measurable lesions nor a 30% decrease in the size of one-dimensionally measurable lesions for 4 weeks. The rate of increase of any lesion was maintained within 25%. In addition, there could be no progression of secondary lesions due to tumor and no appearance of new lesions for at least 4 weeks. Progressive disease (PD) was defined as a >=25% increase in the size of measurable lesions or the progression of other lesions and the appearance of new lesions.

Statistical Analysis
The Mann-Whitney U-test was used to analyze the correlation between DNA-PKcs expression or clinicopathologic factors and the response to CRT. The correlation between DNA-PKcs expression and clinicopathologic factors was analyzed with the {chi}2 test or Fisher’s exact probability test. A level of P < .05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Immunostaining of DNA-PKcs
DNA-PKcs expression was detected in the nuclei of cancer cells (high-expression case, Fig. 1A; low-expression case, Fig. 1B). The DNA-PKcs expression level ranged from .2% to 80% (mean ratio, 31.0%). Specimens in which >=30% cancer cells stained positive were considered as high–DNA-PKcs expression cases. Of 67 cases, 36 were classified in the high-expression group, and 31 were included in the low-expression group.



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  		FIG. 1. DNA-PKcs was observed in the nuclei of cancer cells. (A) High-expression case; (B) low-expression case.

 
Correlation Between Expression of DNA-PKcs and Clinicopathologic Factors
DNA-PKcs immunostaining did not show significant correlation with either of the clinicopathologic factors (Table 1).


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  		TABLE 1. Imunohistochemical status of DNA-PKcs in esophageal cancer
 
Correlation Between CRT Effect and Clinicopathologic Factors
The response to CRT was defined as previously described.24 Of 67 patients, 6 were evaluated as CR, 47 were PR, 12 were NC, and 2 were PD. Patients were further divided into two groups. Fifty-three were included in the effective group (CR and PR), and the remaining 14 were included in the resistant group (NC and PD). The results indicate that there was no relationship between CRT effect and clinicopathologic factors (Table 2).


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  		TABLE 2. Correlation between chemoradiation effect and clinicopathologic parameters
 
Correlation Between Expression of DNA-PKcs and CRT Effect
A significant correlation was found between the expression of DNA-PKcs and the effect of CRT when patients were divided into the four groups CR, PR, NC, and PD (P = .035) (Table 3). Almost all cases included in the high-expression group tended to be classified as CR or PR. There were more low-expression cases in the NC and PD groups. In addition, the expression of DNA-PKcs correlated with CRT effect when the cases were divided into two (high or low) DNA-PKcs expression groups (P = .0149) (Table 3).


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  		TABLE 3. Correlation between DNA-PKcs expression and chemoradiation effect (divided into four groups)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Esophageal cancer is a form of cancer with an unfavorable outcome even when patients undergo multimodal therapy.1 However, radiotherapy plays an important role in the reduction of complaints or symptoms and in the improvement of QOL of patients with esophageal cancer.25–29 In contrast, radiotherapy may be accompanied by serious side effects, such as bone marrow suppression; furthermore, it is currently very difficult to predict the sensitivity of the therapy.

To date, several genes (p53, jun, ras, raf-1, src, erbB, bcl-2, FGF, HDGF, and DNA-PKcs) have been reported and discussed as possible biological markers indicating radiation sensitivity.7–19,30 Ionizing radiation causes single-strand breaks and DSBs in DNA and damages cells. In particular, DSBs play a critical role in cell death by ionizing radiation. Several proteins (Ku70, Ku80, Xrcc4, DNA ligase IV, Nbs1, and DNA-PKcs) have been reported as candidates in the DSB repair mechanism.31,32 DNA-PKcs is known to form heterodimers with Ku70 or Ku80.21,32,33 This heterodimer, DNA-PK, is also reported to be a candidate for playing a key role in the DSB repair mechanism, working upstream of p53, resulting in cell-cycle arrest or apoptosis.34–38

In this immunohistochemical study, a significant correlation was seen between DNA-PKcs expression and sensitivity to CRT, and patients in the DNA-PKcs high-expression group tended to respond to CRT. It has been suggested that cell-cycle arrest or apoptosis by DSB occurs through the p53 pathway in DNA-PKcs high-expression group. In a previous publication, we reported that heat shock protein 27, but not p53, immunohistochemical overexpression correlated with the response to CRT in esophageal cancer.20 In contrast to our previous results, another group reported that mutant p53, detected by polymerase chain reaction single-strand conformational polymorphism analysis, correlated with chemoradiosensitivity.39 However, taking the present results into consideration, the interaction between DNA-PKcs and the mutational status of p53 may play an important role through the CRT response pathway. No correlation between DNA-PKcs and radiosensitivity has been suggested in head-and-neck cancer.30 This discrepancy may result from a difference in experimental conditions, because our study was performed in vivo, in contrast to the previous study, which looked at cells in vitro.

In this study, the response to CRT was evaluated by esophagography, CT scan, and endoscopy but did not use the histopathology of viable cancer cells (sometimes this clinical examination does not indicate a reduction in cancer volume after CRT because of factors such as stenosis due to scarring). The authors consider that this type of evaluation is useful to patients, particularly when an improvement in QOL is indicated, because not all patients treated with CRT are suitable for surgery. Furthermore, even the previous report that suggested that CRT may not be sufficient to prolong survival confirmed the effectiveness of CRT on the improvement of QOL in patients with esophageal cancer.40 Therefore, the correlation indicated in this study between DNA-PKcs expression and sensitivity to CRT may prove beneficial to patients with esophageal cancer in predicting the improvement of QOL after CRT.

In conclusion, although predicting sensitivity to CRT in esophageal cancer seems difficult, the authors believe that the findings outlined in this article are of use and will be beneficial to clinicians as well as patients in avoiding adverse effects and reducing the therapeutic cost of resistant cases. The evaluation method described is relatively noninvasive and the immunostaining technique comparatively common, making such an evaluation feasible.


   Acknowledgments
 
The authors thank Naomi Kawano, Yoko Iwata, and Kaori Soe, Department of Surgery II, Oita Medical University, for technical assistance in immunohistochemical staining.


   Footnotes
 
TN and TS contributed equally to this work.

Esophageal cancer with high expression of DNA-PKcs exhibited good sensitivity to chemoradiotherapy. This finding may be of use to predict chemoradiation sensitivity in esophageal cancer before therapy.

Received for publication April 29, 2002. Accepted for publication August 12, 2002.


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 DISCUSSION
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