Absence of p53 Overexpression and Favorable Response to Cisplatin‐based Neoadjuvant Chemotherapy in Urothelial Carcinomas

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Abstract
It has been controversial whether cancer cells harboring loss or inactivation of the tumor suppressor p53 are resistant or sensitive to DNA‐damaging agents including cisplatin and doxorubicin. Overexpression of mdm2 oncoprotein, a negative regulator of p53, is assumed to be an alternative to p53 dysfunction. Archival urothelial carcinoma specimens obtained from 60 patients prior to cisplatin‐based chemotherapy were immunohistochemically studied for overexpression of p53 and mdm2. Thirty‐two patients (group I) were treated with chemotherapy in the neoadjuvant setting, while 28 patients (group II) underwent chemotherapy for distant metastases or inoperable locoregional tumors. In group I, the responsiveness was correlated with staining status of p53 (P=0.0225) and the combination of p53 and mdm2 (P=0.0497). Negative staining of p53 and negative for both p53 and mdm2 could have predicted favorable response to chemotherapy in 16 of 18 (88.9%) and in 12 of 13 (92.3%) tumors, respectively. On the other hand, p53‐positive and p53 and/or mdm2‐positive staining could have predicted poor response only in 7 of 14 (50.0%) and 8 of 19 (42.1%) tumors, respectively. Disease‐specific survival of the p53‐negative group was significantly superior to that of the p53‐positive group (P=0.0086). Difference in survival did not become more significant when overexpression of mdm2 was taken into consideration (P=0.0456). In contrast, in group II, there was no correlation of responsiveness to chemotherapy or survival with p53‐ or p53/mdm2‐staining status. The patients with urothelial carcinomas negative for overexpression of p53 will benefit from neoadjuvant chemotherapy. From clinical viewpoint, however, p53 status alone or the combination of p53 and mdm2 status is not enough to identify those patients who will not benefit from the treatment.