TP53Mutation is an Independent Prognostic Marker for Poor Outcome in Both Node-negative and Node-positive Breast Cancer

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Abstract
TP53 gene-mutation and protein expression of p53 are described as being of prognostic importance for the outcome of breast cancer. The present study was therefore carried out to evaluate whether TP53 mutation would be a feasible prognostic marker in the routine diagnostic evaluation of breast cancer, and, in particular, to analyse the relationship between TP53 mutation and nodal status. Tumour material was obtained from women with sporadic early breast cancer. Gene mutations in exon 2-11 were identified using denaturing gradient gel electrophoresis (DGGE) as the initial scanning procedure and characterized by sequencing. All patients were treated according to the guidelines of the Danish Breast Cancer Cooperative Group for the DBCG 89 protocols. The results were correlated with clinico-pathological parameters and the prognosis evaluated by uni- and multivariate analysis using local control, freedom from distant metastasis, disease-free survival, and overall survival as endpoints. The study included 294 patients. TP53 mutations were found in 23% of cases. Mutations were significantly more frequent in tumours from patients who were node-positive and with tumours characterized as being ductal, large of size, with a high degree of anaplasia, and oestrogen receptor negative. Using univariate analysis, it was found that distant metastasis, disease-free, and overall survival were correlated to tumour size, nodal status, degree of anaplasia, oestrogen receptor status, and TP53 mutation. In addition, overall survival was also correlated to age and menopausal status. When analysed according to nodal status, TP53 mutation was found to have a significantly poor survival probability in each of the subgroups. A Cox proportional hazard analysis, including all 294 patients, demonstrated that positive nodal status and TP53 mutation were the only parameters that had an independent poor influence on the risk of developing distant metastasis and reduced recurrence-free survival. The same factors together with postmenopausal status were found to be significantly associated with increased risk of death. TP53 mutation is a strong marker for the prediction of overall and disease-free survival in breast cancer, irrespective of nodal status. A better understanding of the role of the p53 pathway, including analysis of different types of TP53 mutations, is required in order further to investigate the prognostic potential of this marker.