p21 and p53 Immunostaining and survival following systemic chemotherapy for urothelial cancer

Abstract

Introduction: Induction of apoptosis and regulation of cell cycle checkpoints are important mechanisms of chemotherapy-induced cell death. The intact p53 tumor suppressor gene is required for efficient activation of apoptosis. The WAF1/p21 gene is transcriptionally activated by p53 and mediates p53-dependent G1 arrest following DNA damage. Therefore, p53 and p21 expression might be related to urothelial tumor response to cytotoxic therapy.

Methods: In a retrospective study, archival tumor specimens from 60 patients treated with cisplatinum-based systemic chemotherapy for locally advanced and/or metastatic urothelial cancer were immunohistochemically stained for p53 and p21. Response to chemotherapy and overall survival were correlated with the results of immunohistochemistry.

Results: Thirty-five tumors (58%) of the 60 specimens showed p53 accumulation, and 25 (42%) expressed detectable p21. No association between p53 accumulation and expression of p21 was observed. Correlation with complete and partial remissions following inductive chemotherapy (n = 39) demonstrated that patients with intact p53 responded significantly better (70 vs. 31%, p < 0.05). However, no difference in overall survival was observed with regard to p53 immunostaining (median 12 and 17 months for p53-positive and p53-negative tumors, respectively). The p21 expression was related neither to response nor to overall survival following inductive chemotherapy. In patients receiving adjuvant chemotherapy after cystectomy (n = 21), the outcome was correlated with the immunohistochemistry results. While the survival times for p53-negative patients (60 months) and p53-positive patients (23 months) did not translate into a significant difference, the median overall survival for patients with p21-positive or p21-negative tumors (60 vs. 21 months) was significantly different (p < 0.005).

Conclusions: The short survival of patients with metastatic bladder cancer may conceal putative differences between different prognostic groups in smaller trials. In contrast, p21 immunohistochemistry appears to be of prognostic value in patients receiving systemic adjuvant chemotherapy for locally advanced bladder cancer. The observations made in this retrospective study in a limited number of patients warrant further investigation on the correlation between G1/S checkpoint regulatory genes and adjuvant chemotherapy in larger prospective studies.