p53 Protein overexpression is associated with increased cell proliferation in patients with locally recurrent prostate carcinoma after radiation therapy

BACKGROUND The biologic changes in recurrent prostate carcinoma following radiation therapy are not fully understood. The authors sought to determine the level of p53 protein overexpression and its association with cellular proliferation (Ki-67 labeling index), glutathione S-transferase-π (GST-π) expression, and other clinical pathologic findings in patients with locally persistent prostate carcinoma after radiation therapy. METHODS The authors investigated p53 nuclear accumulation, cellular proliferation activity (Ki-67 labeling index by digital image analysis), and GST-π expression in 55 patients with persistent or recurrent prostate carcinoma after radiation therapy. All patients underwent salvage radical prostatectomy and bilateral pelvic lymphadenectomy following irradiation failure. The interval from radiation therapy to cancer recurrence ranged from 6 months to 17 years (mean, 3.8 years). Age at surgery ranged from 51 to 78 years (mean, 65 years). Mean follow-up after surgery was 5.7 years (range, 1–13 years). RESULTS p53 protein overexpression was associated with increased cell proliferation (Spearman rank correlation coefficient = 0.29, P = 0.03). A substantial proportion (62%) of recurrent cancer also showed GST-π immunoreactivity. No apparent correlation was observed between p53 protein overexpression, cellular proliferation (Ki-67 labeling index), or GST-π expression and Gleason score, pathologic stage, DNA ploidy, or patient outcome. There was an inverse correlation between GST-π expression and Gleason score (P = 0.06). The majority of prostate carcinomas (95%) were proliferative (mean Ki-67 labeling index, 7.0; range, 0–20), whereas concurrent prostatic intraepithelial neoplasia (PIN) had a lower Ki-67 labeling index (mean, 3.1; range, 0–11.5). Nineteen of 28 (68%) concurrent PIN demonstrated p53 immunoreactivity. A trend toward adverse clinical outcome was observed in patients with a higher Ki-67 labeling index in recurrent cancer. CONCLUSIONS In this study cohort selected for salvage prostatectomy, recurrent cancers were biologically aggressive following radiation therapy. Whether this represents selective persistence and regrowth of prognostically unfavorable tumor clonogens or stepwise clonogenic progression is uncertain. Further investigation is needed to elucidate the correlation between p53 overexpression and the presence of other biologic changes after radiation therapy. Cancer 1999;85:1293–9. © 1999 American Cancer Society.