Evidence for a dose-response effect between p53 (but not p21(WAF1/Cip1)) protein concentrations, survival, and responsiveness in patients with epithelial ovarian cancer treated with platinum-based chemotherapy

The prognostic values of p53 and of its downstream mediator p21(WAF1/Cip1) in patients receiving adjuvant chemotherapy for epithelial ovarian cancer h ave not been dearly established. Tumor extracts from a series of 120 patien ts treated postsurgically with cisplatin or carboplatin alone or together w ith other chemotherapeutics for primary ovarian carcinoma were assayed both for p53 protein by an immunofluorometric assay developed by us and for p21 protein by a commercially available immunoassay, Relative risks (RRs) for cancer relapse and death after 24 months of follow-up were determined by mu ltivariate Cox regression analysis, Disease-free (DFS) and overall survival (OS) probabilities were also examined by the Kaplan-Meier method and log-r ank tests, All other procedures were similarly nonparametric and based on t wo-sided tests of significance. Concentrations of p53 were elevated in pati ents with advanced stage disease (P = 0.02) or poorly differentiated (P = 0 .03), suboptimally debulked tumors (P = 0.02), as well as in patients who f ailed to respond to chemotherapy (P = 0.03), as assessed by computed tomogr aphy scanning, serum CA125 determination, and second-look laparotomy, Stati stically significant associations between concentrations of p53 and p21 wer e not found, nor were relationships demonstrated between concentrations of p21 and other clinicopathological variables or treatment response, Univaria te analysis showed that p53 concentrations above the median indicated signi ficantly higher risks for relapse (P = 0.04) and death (P < 0.01) and showe d trends for increasing risks for relapse (P = 0.01) and death (P < 0.01) w hen p53 was considered as a four-level categorical variable, Multivariate a nalyses adjusted for age, stage, grade, and residual tumor size confirmed t hese observations (RR = 1.50; P = 0.05 for DFS and RR = 1.92; P = 0.03 for OS) for median-dichotomized p53, but the trends were of borderline signific ance (P = 0.09 for DFS and P = 0.07 for OS), In contrast, p21 positivity wa s not a significant predictor of favorable outcome in univariate survival a nalysis, and use of a three-level variable combining positivity or negativi ty status for both p53 and p21 did not yield greater separation of patients into risk groups (P = 0.07 for DFS and P = 0.06 for OS) than the use of p5 3 alone, Assessment of p53 expression may be an independent indicator of po or prognosis in ovarian cancer patients treated with adjuvant chemotherapy. The prognostic value of p21 expression, however, could not be demonstrated in our series of ovarian cancer patients.