Elsevier

Human Pathology

Volume 36, Issue 4, April 2005, Pages 364-371
Human Pathology

Original contribution
Bax, a predictive marker for therapeutic response to preoperative chemoradiotherapy in patients with rectal carcinoma

https://doi.org/10.1016/j.humpath.2005.01.018Get rights and content

Summary

In an attempt to improve local control and survival in patients with advanced rectal carcinoma, neoadjuvant chemoradiation therapy (CRT) has been increasingly used in patient management. However, a significant proportion of patients shows poor response to adjuvant CRT. Thus, the ability to predict CRT responsiveness in patients with rectal cancer would benefit effective management. Several molecular markers related to regulation of cell cycle, apoptosis, or DNA repair have been proposed as candidate predictors of therapeutic response to CRT, but, to date, none has been definitively proven to be predictive of CRT response. To evaluate the use of various molecular markers as predictors of the response to CRT in rectal carcinoma, we investigated immunohistochemical expressions of p53, p21WAF1/CIP1, Bcl-2, Bax, Ki-67, Ku-70, and 2 new candidate markers (histone deacetylase 1 and metabotropic glutamate receptor 4) in pretreatment biopsy samples of 130 rectal carcinomas. We further compared the expressions of these molecular markers with the pathological responses of the tumors after therapy. We found that Bax expression, among the markers studied, was exclusively related to tumor regression. Its expression was significantly higher in the complete response group as compared with the partial response group (54% versus 29%, P = .017). This result confirms that apoptosis plays an important role in tumor response to CRT and provides evidence that Bax may serve as a predictable molecular marker for chemoradiosensitivity in rectal carcinoma.

Introduction

Preoperative chemoradiotherapy (CRT) followed by radical surgery is currently the preferred therapeutic modality for patients with locally advanced rectal carcinoma [1]. Preoperative CRT offers a number of benefits, such as (1) it can reduce tumor volume, (2) it can downstage the tumor, (3) it can change an unresectable tumor into a resectable tumor, (4) it can preserve the anal sphincter, (5) it can reduce local recurrence, and (6) it can improve patient survival [1], [2]. However, a significant proportion of patients shows poor responses to adjuvant CRT [2]. Thus, it is important to avoid application of an ineffective therapy by predicting therapeutic response.

Although the mechanisms responsible for the responses to CRT are not fully understood, the ability of CRT to eradicate tumor cells depends upon cell cycle arrest, apoptosis, and DNA repair. The ultimate target of radiation is DNA, and chemotherapeutic agents generally increase the effectiveness of radiotherapy by dysregulating the cell cycle [3], [4]. Thus, the p53 pathway has been regarded as a major key in the regulation of responses to CRT [3]. To date, p53 [5], [6], [7], [8], [9], [10]. and its downstream effectors, p21WAF1/CIP1 (a cell cycle regulator) [6], [8], [9], [10], Bcl-2 (an apoptosis inhibitor) [10], [11], and Bax (an apoptosis promoter) [8], [11] as well as Ki-67 or proliferating cell nuclear antigen (a proliferation marker) [8], [10], [12], thymidylate synthase (a rate-limiting enzyme in the DNA synthetic pathway) [7], [13], and Ku protein (a DNA repair enzyme) [14], have been correlated with therapeutic response to CRT. However, these results have been somewhat controversial, and no molecular maker has yet been definitively proven to be predictive of the response to CRT. Thus, we herein sought to evaluate the use of various molecular markers as predictors of response to preoperative CRT in patients with distal rectal cancer. We investigated immunohistochemical expressions of p53, p21 WAF1/CIP1, Bcl-2, BAX, Ki-67, Ku-70, and 2 new candidate markers, histone deacetylase 1 (HDAC1) [15] and metabotropic glutamate receptor 4 (mGluR4) [16], in pretreatment biopsy samples of rectal carcinoma and compared these expressions with the grades of tumor regression after therapy.

Our results indicated that of the studied markers, only expression of Bax was exclusively related to tumor regression. Thus, our data confirm that apoptosis plays an important role in tumor response to CRT.

Section snippets

Patients and samples

A total of 130 rectal adenocarcinoma tissues were obtained from patients with locally advanced distal rectal cancer (clinical and radiological T3 or T4 stage) before the initiation of therapy. Biopsies of the representative tumors were taken from the central area of each tumor and at least 5 pieces of carcinoma were obtained from the different foci of tumor at each biopsy; all patients received preoperative CRT consisting of 2 cycles of 5-fluorouracil (5-FU) (400 mg/m2 per day) or capecitabine

Pathological responses to CRT

Pathological evaluation of responses to preoperative CRT in resected rectums revealed that all cases showed irradiation effects with fibrosis and vascular changes. Twenty-eight (22%) of 130 patients showed pathological complete responses (regression grade 4) and 21 (16%) showed microscopic residual tumors (regression grade 3), whereas 50 (38%) and 31 (24%) of 130 patients showed moderate (regression grade 2) or minimal (regression grade 1) responses to preoperative CRT, respectively (Fig. 1).

Protein expression in pretreatment biopsy specimens

Discussion

To improve local control and survival in patients with advanced rectal carcinoma, neoadjuvant CRT has been increasingly used in patient management [1], [2]. However, previous studies showed poor CRT response rates; 17% to 41% of patients with rectal cancers were resistant or nonresponsive to CRT, although 5% to 30% showed complete pathological responses [2], [8], [14]. Consistent with the previous data, our results revealed that 24% of the patients who had undergone preoperative CRT showed

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    This work was supported by research grant from the National Cancer Center, Korea.

    1

    These authors contributed equally.

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