P53 PROTEIN ACCUMULATION PREDICTS POOR RESPONSE TO TAMOXIFEN THERAPY OF PATIENTS WITH RECURRENT BREAST-CANCER

Purpose: Mutations of the p53 gene are frequently observed in primary breast cancer and accumulation of p53 protein has been used as a surro gate marker of p53 inactivation. Previous studies have shown that p53 accumulation is related to poor prognosis in primary breast cancer. We studied whether p53 protein accumulation is a predictive factor for r esponse to tamoxifen treatment in patients with recurrent breast cance r. Patients and Methods: Levels of p53, estrogen receptor (ER), proges terone receptor (PgR), and urokinase-type plasminogen activator (uPA) were assayed in cytosolic extracts derived from primary tumors of 401 tamoxifen-naive patients who developed recurrent disease. All patients in the study received tamoxifen therapy upon relapse (median follow-u p, 69 months). Association of tested factors with response to tamoxife n treatment was studied by logistic regression analysis, and with surv ival after the start of treatment by Cox univariate and multivariate r egression analysis. Results: p53 levels (median, 0.23 ng/mg protein) w ere not related to ER or PgR levels, but positively correlated with uP A (P < .0001). In a test for trend, we observed an association of p53 protein levels with response to tamoxifen therapy When dichotomized (a t the median value), 42% in the p53-high versus 56% in the p53-low gro up showed a response. In multivariate analysis, including patient and tumor characteristics, p53 accumulation retained significance with the rate of response (odds ratio [OR], 0.48; 95% confidence interval [CI] , 0.31 to 0.74; p < .001). Also in multivariate analysis, reduced surv ival after the start of tamoxifen therapy was observed in the p53-high group (relative hazards rate [RHR], 1.56, 95% CI, 1.17 to 2.10; P = . 002). A statistically significant association between p53 levels and d ecreased tamoxifen response was seen only in the subset of patients wh ose tumors expressed low levels of ER or PgR (<75 fmol/mg protein). Co nclusion: Measurement of primary tumor p53 levels may be effective in predicting response to tamoxifen therapy in recurrent breast disease. However, more confirming studies on the association between p53 protei n accumulation and response to antiestrogen therapy are needed before tumor p53 levels can be used in routine clinical practice. (C) 1998 by American Society of Clinical Oncology.