Journal of Clinical Oncology, Vol 16, 121-127, Copyright © 1998 by American Society of Clinical Oncology
p53 protein accumulation predicts poor response to tamoxifen therapy of patients with recurrent breast cancer
EM Berns, JG Klijn, WL van Putten, HH de Witte, MP Look, ME Meijer-van Gelder, K Willman, H Portengen, TJ Benraad and JA Foekens
Department of Medical Oncology, Rotterdam Cancer Institute, Daniel den Hoed Kliniek/University Hospital Rotterdam, The Netherlands. berns@bidh.azr.nl
PURPOSE: Mutations of the p53 gene are frequently observed in primary
breast cancer and accumulation of p53 protein has been used as a surrogate
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
response to tamoxifen treatment in patients with recurrent breast cancer.
PATIENTS AND METHODS: Levels of p53, estrogen receptor (ER), progesterone
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-up, 69 months).
Association of tested factors with response to tamoxifen treatment was
studied by logistic regression analysis, and with survival after the start
of treatment by Cox univariate and multivariate regression analysis.
RESULTS: p53 levels (median, 0.23 ng/mg protein) were not related to ER or
PgR levels, but positively correlated with uPA (P < .0001). In a test
for trend, we observed an association of p53 protein levels with response
to tamoxifen therapy. When dichotomized (at the median value), 42% in the
p53-high versus 56% in the p53-low group 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 survival 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 decreased tamoxifen response was seen only in the subset of
patients whose tumors expressed low levels of ER or PgR (<75 fmol/mg
protein). CONCLUSION: 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
protein accumulation and response to antiestrogen therapy are needed before
tumor p53 levels can be used in routine clinical practice.
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