Originally published as JCO Early Release 10.1200/JCO.2003.07.077 on July 28 2003

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Dynamic Expression Profile of p21^WAF1/CIP1 and Ki-67 Predicts Survival in Rectal Carcinoma Treated With Preoperative Radiochemotherapy

Beate Rau, Isrid Sturm, Hermann Lage, Stefan Berger, Ulrike Schneider, Steffen Hauptmann, Peter Wust, Hanno Riess, Peter M. Schlag, Bernd Dörken, Peter T. Daniel

From the Charité Medical School, Humboldt University of Berlin; Campus Berlin-Buch, Robert-Rössle Klinik, Department of Surgery and Surgical Oncology; Campus Berlin-Buch, Robert-Rössle Klinik, Department of Hematology, Oncology and Tumor Immunology; Campus Mitte, Institute for Pathology; Campus Virchow-Klinikum, Department of Radiation Oncology; Campus Virchow-Klinikum, Department of Hematology and Oncology; and Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Address reprint requests to Beate Rau, MD, Charité Medical School, Campus Berlin-Buch, Humboldt University, Department of Surgery and Surgical Oncology, Robert-Roessle Klinik, Lindenberger Weg 80, 13125 Berlin, Germany; e-mail: rau{at}rrk-berlin.de.

Purpose: We investigated p53 and its downstream effectors p21^WAF1/CIP1, BAX, and hMSH2 as well as the proliferation marker Ki-67 (mki-67/MIB-1) in patients undergoing preoperative radiochemotherapy for rectal carcinoma to identify prognostic and predictive factors. The focus of this study was on the dynamics of these genetic markers in a longitudinal study—that is, before and after radiochemotherapy.

Patients and Methods: Expression of p53, BAX, p21^WAF1/CIP1, Ki-67, and hMSH2 was investigated by immunohistochemistry in pre- and posttherapeutic tumor samples in 66 patients. Tumor DNA was screened for p53 mutations by single-strand conformation polymorphism–polymerase chain reaction (SSCP-PCR). Paired tumor samples (pretherapy and posttherapy) were collected prospectively.

Results: Patients with a decrease in p21 expression following radiochemotherapy had better disease-free survival (P = .03). Similarly, patients with an increase in proliferative activity as measured by increased Ki-67 expression posttherapy had better disease-free survival (P < .005). In addition, we observed a significantly better prognosis for patients with high hMSH2 expression. In contrast, pretherapeutic levels of p53, BAX, or p21 expression and p53 mutation had no prognostic value, indicating that the combination of radiotherapy and chemotherapy might override defects in these genes.

Conclusion: These findings are novel and support the clinical relevance of p21 in the suppression of both proliferation and apoptosis. Thus, the dynamic induction of p21^WAF1/CIP1 was associated with a lower proliferative activity but an ultimately worse treatment outcome following neoadjuvant radiochemotherapy and tumor resection. Induction of p21, therefore, represents a novel resistance mechanism in rectal cancer undergoing preoperative radiochemotherapy.

Supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 273 and 506, and grant No. Da238/4.

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