Prognostic impact of P53 status in Ewing sarcoma

BACKGROUND Disease stage at the time of diagnosis and response to therapy are the main prognostic factors for patients with Ewing sarcoma or peripheral neuroectodermal tumor (ES/PNET). The primary genetic alteration in ES/PNET, the fusion of the EWS gene with FLI1 or ERG, is diagnostically highly specific for these tumors, and molecular variation in the structure of the EWS‐FLI1 fusion gene also is of prognostic significance. In contrast, secondary genetic alterations, such as P53 alterations, are relatively uncommon in ES/PNET, and their prognostic impact has not been extensively studied. METHODS Prechemotherapy, paraffin embedded, nondecalcified, primary tumor material in a well‐characterized series of 55 patients with ES/PNET with defined EWS‐FLI1 fusion transcripts (32 patients with type 1 and 23 patients with other types) was studied retrospectively by immunohistochemical techniques for cell cycle regulators and proliferative markers, such as P53, P21WAF1, and Ki‐67, as well as by the terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling (TUNEL) technique for apoptosis. Nuclear P53 expression in > 20% of tumor cells was scored as aberrant overexpression. Histologic response to neoadjuvant chemotherapy was assessed. RESULTS Aberrant P53 expression (in > 20% of tumor cells) was present in 6 patients (11%) but showed no statistically significant correlation with disease stage, tumor size, proliferation rate (Ki‐67), apoptotic rate (TUNEL), or EWS‐FLI1 fusion type. By univariate analysis, the P53 > 20% group showed a significantly poorer overall survival among patients with localized disease (n = 43 patients) (P = 0.001) and in the entire study group (P = 0.01). In multivariate Cox analyses of overall survival, P53 > 20% was the strongest negative factor among prognostic factors available at the time of diagnosis (P = 0.001; relative risk [RR] = 9) and when chemotherapy response was included in the analysis (P53 > 20%: P = 0.01; RR = 10). CONCLUSIONS P53 alteration appears to define a small clinical subset of patients with ES/PNET with a markedly poor outcome. The current observations warrant a systematic prospective study with comprehensive P53 mutation analysis. [See related article on pages 793–9, this issue.] Cancer 2000;89:783–92. © 2000 American Cancer Society. A minority of patients with Ewing sarcoma show evidence of P53 mutation, and this is associated with a markedly poor clinical outcome. See also pages 793–9.