p53 protein accumulation predicts poor response to tamoxifen therapy of patients with recurrent breast cancer.
OBJECTIVE
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.


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).


CONCLUSIONS
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.
Berns
E M
EM
Department of Medical Oncology, Rotterdam Cancer Institute, Daniel den Hoed Kliniek/University Hospital Rotterdam, The Netherlands. berns@bidh.azr.nl
Klijn
J G
JG
van Putten
W L
WL
de Witte
H H
HH
Look
M P
MP
Meijer-van Gelder
M E
ME
Willman
K
K
Portengen
H
H
Benraad
T J
TJ
Foekens
J A
JA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D005260:Female; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000401:mortality; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012044:Regression Analysis; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen