Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer

TP53 has been implicated in regulation of the cell cycle, DNA repair, and a poptosis. We studied, in primary breast tumors through direct cDNA sequenci ng of exons 2-11, whether TP53 gene mutations can predict response in patie nts with advanced disease to either first-line tamoxifen therapy (202 patie nts, of whom 55% responded) or up-front (poly)chemotherapy (41 patients, of whom 46% responded). TP53 mutations were detected in 90 of 243 (37%) tumor s, and one-fourth of these mutations resulted in a premature termination of the protein. The mutations were observed in 32% (65 of 202) of the primary tumors of tamoxifen-treated patients and in 61% (25 of 41) of the primary tumors of the chemotherapy patients, TP53 mutation was significantly associ ated with a poor response to tamoxifen [31% versus 66%; odds ratio (OR), 0. 22; 95% confidence interval (CI), 0.12-0.42; P < 0.0001]. Patients with TP5 3 gene mutations in codons that directly contact DNA or with mutations in t he zinc-binding domain loop L3 showed the lowest response to tamoxifen (18% and 15% response rates, respectively). TP53 mutations were related, althou gh not significantly, to a poor response to up-front chemotherapy (36% vers us 63%; OR, 0.34; 95% CI, 0.09-1.24). In multivariate analysis for response including the classical parameters age and menopausal status, disease-free interval, dominant site of relapse, and levels of estrogen receptor and pr ogesterone receptor, TP53 mutation was a significant predictor of poor resp onse in the tamoxifen-treated group (OR, 0.29; 95% CI, 0.13-0.63; P = 0.001 4), TP53-mutated and estrogen receptor-negative (<10 fmol/mg protein) tumor s appeared to be the most resistant phenotype, Interestingly, the response of patients with TP53 mutations to chemotherapy after tamoxifen was not wor se than that of patients without these mutations (50% versus 42%; OR, 1.35, nonsignificant), The median progression-free survival after systemic treat ment was shorter for patients with a TP53 mutation than for patients with w ild-type TP53 (6.6 and 0.6 months less for tamoxifen and up-front chemother apy, respectively). In conclusion, TP53 gene mutation of the primary tumor is helpful in predicting the response of patients with metastatic breast di sease to tamoxifen therapy. The type of mutation and its biological functio n should be considered in the analyses of the predictive value of TP53.