p53 and p27 as predictors of clinical outcome for rectal-cancer patients receiving neoadjuvant therapy

doi:10.1016/j.suronc.2007.01.001

Surgical Oncology

Volume 15, Issue 4, December 2006, Pages 211-216

https://doi.org/10.1016/j.suronc.2007.01.001 Get rights and content

Summary

Our aim was to examine whether certain molecular markers, specifically p53, p21, p27, and Bcl-2, could be used to predict the tumor response of rectal cancer to neoadjuvant therapy and determine the overall and disease-free survival rates of patients following neoadjuvant therapy.

Seventy-seven patients with rectal cancers were used in this study. All of them received neoadjuvant therapy and 53 of them were given radical surgery. Immunohistochemical tests were performed for the four markers mentioned above using biopsy specimens obtained from 70 of the patients prior to radiation. The identical tests were performed for the same markers using excised specimens from the patients after radical surgery.

For the pre-radiation specimens, the positive rate for having p27 and Bcl-2 markers was 32.7% and 16.6%, respectively. This rate increased to 73.5% and 41.6% (p=0.001 and 0.012, respectively) in the specimens obtained after the surgery. With respect to “fair response (FR)” of patients, the pre-radiation biopsy specimens showed significant difference for the p53 (−) and p27 (+) markers (p=0.006). Patients with a 3-year overall survival rate were found to have, from their surgical specimens, 92% of the p27 (+) and 75% of p27 (−) markers (p=0.0058).

Our study showed: first, the rate of positive identification of molecular markers, p27 and Bcl-2, increased following neoadjuvant therapy. Second, either the p53 (−) or p27 (+) status was a good predictor for FR in the pre-radiation biopsy specimens. Third, patients with p27 (+) markers in the surgical specimens lived longer at 3 years.

Introduction

Neoadjuvant radiation, administered alone or in combination with chemotherapy, has been used to shrink the tumor [1] and achieve complete resectability of the rectal cancer with a sphincter-saving procedure. Other advantages of neoadjuvant radiotherapy include lower total dose of radiation and easier displacement of small bowel from the radiation field. However, the response to radiation varies among individual patients. It is thus imperative to determine the different clinico-pathological factors which may be used to predict the radiosensitivity of each patient that will enable us to understand their clinical outcome.

p53, p21, p27, and Bcl-2 are four important proteins involved in the control of the cell cycle [2], [3], [4], [5], [6], [7]. Their status in the cell cycle has been widely investigated for a variety of cancers including those in the rectum. At this time, there are questions as to whether these markers can be the useful indicators to predict patient responses to neoadjuvant radiotherapy or chemoradiotherapy for rectal cancer. This study examines whether these molecular markers could be used to predict tumor response and also evaluate the relationship between them and overall survival rate, including disease-free survival rate.

Section snippets

Patients and methods

This is a retrospective study composed of 77 patients treated between January 1998 and June 2002 (Table 1). All patients in the study were: (A) histologically confirmed with diagnosis of adenocarcinoma of the rectum, (B) the inferior margin of the tumor being no farther than 15 cm from the anal verge, (C) without distant metastases, (D) previously not having radiotherapy in pelvic region, and (E) treated with pre-operative radiotherapy with or without simultaneous chemotherapy. The protocol used

Results

The percentage of patients showing DS and FR was, respectively, 50% and 17.7%. For the pre-radiation biopsy specimens, the positive rates for the presence of p53, p21, p27, and Bcl-2 were 63.3%, 16.3%, 32.7%, and 16.6%. On the other hand, for the post-operative specimens, the positive rates increased to 69.4%, 20.4%, 73.5%, and 41.6% (Table 2). With respect to the pre-radiation biopsy specimens for DS patients, no significant difference was observed in positive rate for molecular markers (Table

Discussion

Adjuvant radiotherapy or chemoradiotherapy, administered either prior or subsequent to surgery, prevents tumor regrowth and improves survival rate for selected patients suffering from rectal cancer [10], [11], [12], [13], [14], [15], [16], [17]. Tumor response to radiation therapy is typically quite variable, with complete regression occurring from 4% to 30% of patients and significantly down staging for 30–61% of patients [18], [19], [20]. The response would also appear to vary significantly

Acknowledgments

The authors would like to acknowledge Joeming W. Dung, MD, for his assistance in proofreading and editing the paper with respect to the English language.

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REVIEWp53 and p27 as predictors of clinical outcome for rectal-cancer patients receiving neoadjuvant therapy

Summary

Introduction

Section snippets

Patients and methods

Results

Discussion

Acknowledgments

Biochemical and Biophysical Research Communications

Gastroenterology

Journal of the American College of Surgeons

Preoperative radiotherapy for resectable rectal cancer: a meta-analysis

Journal of the American Medical Association

A p53 and apoptotic independent role for p21waf1 in tumour response to radiation therapy

Oncogene

Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs

Oncogene

Disruption of p53 in human cancer cells alters the responses to therapeutic agents

Journal of Clinical Investigation

Protein expression of p53, p21 (WAF1/CIP1), bcl-2, Bax, cyclin D1 and pRb in human colon carcinomas

Virchows Archiv

p21WAF1/CIP1 antisense therapy radiosensitizes human colon cancer by converting growth arrest to apoptosis

Cancer Research

Prognostic significance and correlation with survival of bcl-2 and TGF-beta RII in colon cancer

Digestive Diseases and Sciences

Pre-operative irradiation in operable cancer of the rectum: report of Toronto trial

Canadian Journal of Surgery

Preoperative irradiation for rectal cancer: improved local control and long-term survival

Annals of Surgery

Preoperative radiotherapy as adjuvant treatment in rectal cancer: final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC)

Annals of Surgery

Preoperative radiotherapy for locally advanced rectal carcinoma: results of a prospective randomized trial

Diseases of the Colon and Rectum

REVIEW
p53 and p27 as predictors of clinical outcome for rectal-cancer patients receiving neoadjuvant therapy