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Annals of Surgical Oncology 8:418-424 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

p53, BCL-2, and Ki-67 Expression According to Tumor Response After Concurrent Chemoradiotherapy for Advanced Rectal Cancer

Nam Kyu Kim, MD, Jae Kun Park, MD, Kang Yong Lee, MD, Woo IK Yang, MD, Seong Hyeon Yun, MD, JinSil Sung, MD and Jin Sik Min, MD

From the Departments of Surgery (NKK, JKP, KYL, SHY, JSM), Pathology (WIY), and Radiation Oncology (JS), Yonsei University College of Medicine, Seoul, Korea.

Correspondence: Address correspondence and reprint requests to: Nam Kyu Kim, MD, Department of Surgery, Yonsei University College of Medicine, Seodamun-Gu, Shinchon-dong 134, CPO 8044, Seoul, Korea; Fax: 822-313-8289; E-mail: namkyuk{at}yumc.yonsei.ac.kr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Concurrent chemoradiotherapy (CCRT) for locally advanced rectal cancer is an important modality for curative resection, but tumors show wide spectrum response. The purpose of this study was to investigate any correlation among related genetic mutations, proliferative index, and tumor response after CCRT.

Methods: This study included 23 patients with rectal cancer, who were preoperatively staged as at least T3 N1 or T4 (determined by transrectal ultrasonography and MRI). Enrolled patients were given 5-FU 450 mg/m2/day and leucovorin 20 mg/m2/day intravenously for 5 days during weeks 1 and 5 of radiotherapy (45–54 Gy). Surgical resection was performed 4 weeks after completion of the scheduled treatment. Tumor response was classified as CR (complete response), PR (partial response: 50% diminution of tumor volume and downstaging), and NR (no response). Paraffin-embedded tissue obtained before chemoradiotherapy was studied by immunohistochemical staining for p53, BCL-2, and Ki-67. The extent of tumor response was correlated with proliferative activity and was measured by immunostaining Ki-67 proliferative antigen and the expression of p53 and BCL-2 oncoproteins.

Results: All patients were resectable. CR was obtained in 4 patients, PR in 10 patients, and NR in 9 patients. The p53 mutation was noted in 16 patients: NR in 5 patients, PR in 9 patients, and CR in 2 patients (P = .638). BCL-2 expression was noted in 11 patients: NR in 4 patients, PR in 3 patients, and CR in 4 patients (P = .799). The Ki-67 labeling index was NR: 615.4 ± 47.2; PR: 663.2 ± 20.4; and CR: 765.5 ± 58.3 (CR + PR vs. NR, P = .029).

Conclusions: Immunohistochemical expression of p53 and BCL-2 does not correlate with tumor response after CCRT, but Ki-67 labeling may be a useful parameter for radiosensitive tumors selected for CCRT.

Key Words: Rectal cancer • Preoperative chemoradiotherapy • Tumor response • p53 • BCL-2 • Ki-67


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The main purpose of preoperative chemoradiotherapy for locally advanced rectal cancer is to reduce the volume of and downstage the tumor, and, ultimately, to increase resectability and reduce the local recurrence rate postoperatively. Reported results have shown that resectability is achieved in over 80%, and complete tumor response in 10% to 20%, of cases after preoperative concurrent chemoradiotherapy (CCRT).1,2,3 Interestingly, tumor response after CCRT shows a wide spectrum of response, ranging from none to complete. Many clinicopathologic factors seem to be related to tumor response, such as tumor size, shape, cellular differentiation, and tumor mobility. Recently, molecular genetic studies have been used to identify some of the genetic factors related to the wide spectrum of tumor radioresponsiveness. Willet et al.4 observed that tumor components with a low proliferative index do not respond well and that highly proliferative tumors generally show good response. Recently, the tumor suppressor genes, p53 and p21, which regulate the cell cycle and apoptosis, have been proposed to play major roles in tumor response to radiotherapy and chemotherapy. The purpose of this study was to determine the relation between the expression of p53, BCL-2, and Ki-67 and tumor response after CCRT in rectal cancer.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
This study included 23 patients with adenocarcinoma of the rectum who had undergone preoperative CCRT and surgical resection between March 1997 and March 1999 at the Department of Surgery in Severance Hospital, Yonsei University. The enrolled patients were staged as at least T3 N1 or T4 by transrectal ultrasonography and magnetic resonance imaging. These cases showed fixation to the rectal wall, invasion to the surrounding pelvic organs, and metastasis to the perirectal tissue. Chemotherapy was administered intravenously with 5-FU 450 mg/m2/day and leucovorin 20 mg/m2/day during weeks 1 and 5 of radiotherapy (4500–5400 cGy). Tissue was sampled from patients before CCRT by sigmoidoscopic biopsy forceps.

Surgical resection was usually performed 4 weeks after the completion of CCRT. Tumor response was classified as CR (complete response: no residual tumor); PR (partial response: tumor volume diminished over 50% and/or downstaging); and NR (no response) after postoperative pathological analysis of tumor specimens.

Immunohistochemical Staining
Paraffin-embedded tissue was prepared and sectioned; 5 µm sections were then pretreated with fresh xylene for 10 minutes and rehydrated using graded alcohol. Oncoprotein p53 and BCL-2 were immunostained with antimouse monoclonal antibody p53 (Dako, Carpinteria, CA) and BCL-2 (Dako). Sections were microwaved at high power for 25 minutes in citrate buffer, pH 6.0, allowed to cool, and then washed in PBS (Phosphate Buffer Saline). Endogenous peroxidase activity was blocked by incubating in 0.3% hydrogen peroxide for 15 minutes followed by a PBS wash. Before the addition of antibody, all samples were routinely blocked for 30 minutes in 1:10 normal horse serum diluted in PBS. Both antibodies were diluted 1:100 and then incubated with the sections overnight at 4°C. After a PBS wash, the preparations were incubated with biotinylated horse antimouse antibody (Dako) and diluted 1:200 in PBS for 60 minutes; Ki-67 proliferative antigen was immunostained with monoclonal antibody MIB1 (Immunotech, France). Slides were then preincubated for 15 minutes, with 10% normal goat serum at room temperature at a dilution of 1:200 in PBS, and then overnight at 4°C. Subsequently, slides were incubated for 30 minutes with biotinylated goat antimouse antibody at a dilution of 1:200. Final staining was achieved using the avidin-biotin-peroxidase method. Diaminobenzidine tetrahydrochloride was used as the chromogen; hematoxylin was used for counterstaining.

Methods of Analysis
A semiquantitative grading system was used. Negative indicated no immunoreaction or <10% of the tumor cells stained; (+): 10% to 25% staining; (++): 25% to 50% staining; and (+++): over 50% staining (Figs. 1 and 2).



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  		FIG. 1. The p53 oncoprotein in a well-differentiated adenocarcinoma. Cell nuclei show intense p53 immunoreactivity (right), x100.

 


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  		FIG. 2. Upper left: BCL-2 immunoreactivity of a lymphocyte (indicated by arrow). Lower right: strong expression of BCL-2 oncoprotein in a well-differentiated adenocarcinoma, x100.

 
Ki-67 reactivity was evaluated by counting the number of positive and negative epithelial cell nuclei in several randomly selected fields in each section, using a 10x10 mm eyepiece grid. Tumor reactivity was expressed as the Ki-67 index (i.e., the number of stained tumor cells per 1000 cells in each section) (Fig. 3).



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  		FIG. 3. Lower numbers of Ki-67 positive cells (left) and a high percentage of Ki-67 stained cells. Note the prominent nucleolar positivity in tumor cells (right), x100.

 
Statistical analysis was performed using the {chi}2 test and the Mann-Whitney test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Therapeutic Responsiveness After CCRT
A complete pathologic response (no residual tumor in the surgical specimen) was achieved in 4 of 23 patients (17%). Partial response (PR) was obtained in 10 of 23 patients (43.4%) and NR (no response) was found in 9 of 23 patients (39.3%). (Table 1).


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  		TABLE 1. Tumor response after preoperative chemoradiation
 
p53 Expression of the Tumor Before CCRT and Tumor Response
The p53 expression of the tumor before CCRT included 16 of 23 cases (70%). Of these 16 cases, complete response was obtained in 2 (12.5%), partial response in 9 (56.2%), and no response in 5 (31.3%) (Table 2). There was no correlation between p53 status and tumor response (P = .638).


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  		TABLE 2. p53 and BCL-2 status of rectal cancer before concurrent chemoradiation treatment
 
BCL-2 Expression of the Tumor Before CCRT and Tumor Response
Eleven of 23 patients (48%) showed tumor response. Complete response was obtained in four (36.3%) of these cases, partial response in three (28.4%), and no response in four (36.3%). All four cases that showed strong positive (+++) expression also showed complete response (Table 2). No correlation was found between BCL-2 expression and tumor response (P = .799).

Correlation Between Intensity of p53 and BCL-2 Expression and Tumor Response
Among nine cases showing no response, there were five cases of p53-expressing tumors showing strong positive (+++). Of 10 cases showing partial response, 9 cases showed strong positive (+++) p53 expression. The four cases (of the nine cases showing no tumor response) showed: strong expression (+++) in two cases, ++ in one case, and + in one case. All four cases of complete response showed strong (+++) BCL-2 expression.

Correlation Between Ki-67 Labeling Index (Mean ± SD) and Tumor Response
The Ki-labeling index was 615.4 ± 47.2 in no response, 663.2 ± 20.4 in partial response, and 765.5 ± 58.3 in complete response. Tumor response (CR + PR) compared with no response (NR) was 692.4 ± 38.9 and 615.4 ± 47.2, respectively (P = .029) (Fig. 4).



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  		FIG. 4. Correlation between Ki-67 labeling index and tumor response after CCRT in rectal cancer. CR+PR, complete response + partial response. NR, no response.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Preoperative concurrent chemoradiotherapy has been a mainstay of treatment for locally advanced rectal cancer because chemoradiotherapy can decrease the tumor’s bulk and alter its form, from fixed and unresectable to mobile and resectable. The ultimate purpose of chemoradiotherapy is to increase the rate of curative resection and to decrease the rate of local recurrence after operation. Tumor response has been reported to vary between 60% and 80%. Among those tumors showing response, complete pathologic response occurs in 12% to 20% of patients after conventional CCRT.1–3 As with this study, 61% of the tumors responded significantly to preoperative CCRT. Among them, complete pathologic response was achieved in 17%.

A wide spectrum of tumor responses occur and are known to be related to various factors, such as tumor size, total radiation dose, cellular differentiation, and tumor mobility. Detection of tumor radiosensitivity and selection of more radiosensitive tumors have interested oncologic surgeons. Recently, molecular genetic factors that affect tumor response have been studied; results indicated that p53 and p21 mutations and a high proliferative index may be involved.4–6 Experimental studies revealed that p53 status is deeply related to radioresponsiveness.9–11 The p53-dependent induction of apoptosis by r-irradiation is of particular interest because of observations that p53 mutations increase resistance to ionizing radiation.9,10 Radiation-induced apoptosis is abrogated in cells lacking wild-type p53 protein. It has also been shown that thymocytes from p53-deficient mice are completely resistant to the induction of apoptosis after r-radiation.9–12

Recently, Fu et al.5 reported that, in rectal cancer, immunohistochemical results of no expression of p53 and positive expression of p21 showed more radiosensitivity than rectal cancer showing expression of p53 oncoprotein. Thus, p53 and p21, through their cell cycle and apoptosis-regulating roles, may also play a part in tumor response to cytotoxic agents, such as radiation and chemotherapy. Damaged DNA activates p21 (cyclin-dependent kinase inhibitors) via the p53 gene, which results in G1 phase cell-cycle arrest or apoptosis.7,8 Loss of p53 function results in a deficiency of p53-mediated G1 arrest, which is known to be the main cause of radioresistance.10–12 However, sensitization of tumor cells to r-radiation and/or anticancer agents cannot be predicted solely on the basis of p53 status. Some authors have reported that the p53 gene is not related to radioresponsiveness; the independence of radiosensitivity from the p53 function has also been reported in colon adenocarcinoma RKO cells and head and neck cancer cell lines.13–15 In a study of combined treatment with radiation, hyperthermia, and 5-fluorouracil suppositories for advanced rectal cancer, Sakakura et al.6 reported that there is no relationship between therapeutic efficacy and p53 status. The basis of these results indicated that other factors may exist for determining tumor radioresponsiveness in rectal cancer. Therefore, p53 status alone cannot reflect whether or not a tumor will respond to radiation and chemotherapy. In our series, the p53 protein expression, detected in rectal cancer tissue by the immunohistochemical method, is presumed to be a mutated p53 gene status (p53 positive patients). Seventy percent of advanced rectal cancer patients showed p53 oncoprotein accumulation, 11 patients (68.7%) showed tumor response, and 5 patients (31.1%) show no response. Among seven p53-negative patients, four patients (60%) showed no tumor response. We could not find any correlation between p53 status and tumor responsiveness for preoperative CCRT. In the present study, p53 status in advanced rectal cancer seems to serve no major role in determining tumor response after CCRT. A p53-independent apoptotic mechanism may be particularly important for the deletion of cells with damaged DNA in tissues, such as the colon in which p53-dependent apoptosis may be inefficient.9

Ki-67 proliferative activity is probably associated with the downstaging of highly proliferative tumors and the greater populations of quiescent cells in tumors resistant to downstaging. Willet et al.4 reported that tumor downstaging is influenced by growth fractions, such as PCNA (proliferative cell nuclear antigen) or Ki-67 staining. Moreover, rectal cancer with evidence of high growth fraction was found to be more likely to be downstaged. A population of quiescent cells may be responsible for resistance to downstaging. Using the Ki-67 labeling index, Lanza et al.16 assessed growth fraction in colorectal carcinoma, which proved to be high in mucinous adenocarcinomas and in the tumors of patients younger than 45 years. Du et al.17 reported that a high rate of apoptosis correlates with Ki-67 proliferative index in the gastrointestinal lymphoma of mucosa-associated lymphoid tissue (MALT). In our series of advanced rectal cancer, the assessment of proliferative activity (Ki-67 index) by immunohistochemical assay showed a wide range in the percentage of Ki-67 reacting cells. In our study, we have observed a significant positive correlation between cellular proliferative index and tumor response in rectal cancer after CCRT, even though small numbers of patients were enrolled.

The BCL-2 gene was discovered because of its involvement in the t chromosomal translocations commonly found in B cell lymphoma. BCL-2 expression has been reported in a wide variety of human cancers, including a high percentage of prostate, colon, and lung cancers, as well as many other types of solid tumor.18,19 BCL-2 protein can block the induction of apoptosis by anticancer drugs. It is also expressed at the base of colonic crypts at presumed stem cell locations, whereas its expression is much reduced in small intestinal crypts. Some controversy remains about BCL-2 expression because overexpression of BCL-2 may cause resistance to apoptosis-inducing chemotherapeutic drugs, and, on the other hand, may also enhance apoptotic activity. This proto-oncogene suppresses the apoptosis induced by a variety of stimuli, including radiation and chemotherapeutic agents. Therefore, tumors with high levels of BCL-2 expression, especially in lymphoma, leukemia, and prostate cancer, are associated with poor responses to chemotherapy and shorter disease-free and overall survival.20 In contrast, though high levels of BCL-2 expression are correlated with poor clinical outcome, they have been associated paradoxically with a favorable response in lung, thyroid, and breast cancer.21–23 Oefner et al.21 studied the correlation among BCL-2 expression, stage, and survival rate in the colorectal cancer, and showed that a BCL-2-expressing tumor was less aggressive and was associated with good prognosis. Krajewska et al.24 observed that BCL-2 expression was low in colon cancer and particularly low in undifferentiated cancer, but that Bcl-x expression was high.

Recent studies of other members of the BCL-2 protein family, particularly Bax, have suggested a potential explanation for these observations. Tumor cells are also rendered resistant to chemotherapeutic drugs and radiation by reduced Bax expression as opposed to increased BCL-2 levels. The BCL-2/Bax ratio was found to be more important in predicting tumor response.25,26 Despite the high levels of BCL-2 protein found in >85% of follicular B cell lymphomas, most patients with this disease respond well to therapy. Recently, it has also been shown that genotoxic stress markedly stimulates Bax protein production, which results in increased Bax protein levels and may overcome the effect of high levels of BCL-2. Therefore, the amount of expression of the Bax gene in a tumor may be important for predicting tumor response to radiation or anticancer treatment. Overexpression of Bax can negate the barrier effect of BCL-2 and allow the apoptotic signals generated by currently available anticancer agents. Charalambous et al.27 reported that a high expression of Bax protein and a negative BCL-2 expression show good prognosis in gastric lymphoma. In our series, 11 patients (48%) showed expression of BCL-2 oncoprotein, and no correlation was found between tumor response and BCL-2 expression. Fu et al.5 also observed that there was no correlation between BCL-2 expression and radiosensitivity in rectal cancer. But, interestingly, in our series, all four tumors with complete pathologic response showed strong expression (+++) of BCL-2 oncoprotein. Tumors with no BCL-2 expression showed no complete pathologic response. Possibly related factors were high Bax protein production or some other unknown factors. Therefore, Bax protein and BCL-2 expression should be determined concurrently, to facilitate a prediction of tumor response to radiation or chemotherapy with any precision.

Based upon our results, immunohistochemical detection of p53 and BCL-2 expression in rectal cancer did not show any correlation with tumor response after preoperative concurrent chemoradiotherapy. But, high Ki-67 index tumors might be more radiosensitive than low index tumors after preoperative chemoradiotherapy, even though these results were not entirely reliable because of the small number of patients enrolled in the study.

The overexpression of BCL-2 in a tumor showing complete tumor response was exhibited. This is an observation that warrants further study.

Received for publication August 21, 2000. Accepted for publication January 3, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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