Gene expression profiles and the TP53 mutation status are powerful prognostic markers of breast cancer

Background

Gene expression profiling of breast carcinomas has increased our understanding of the heterogeneous biology of this disease, and promises to impact clinical care. The aim of this study was to evaluate the prognostic value of gene expression-based classification as well as established prognostic markers, including mutation status of the TP53 gene, in a group of breast cancer patients with long-term (>10 years) follow-up.

Methods

The clinical and histopathological parameters of 215 breast cancer patients were studied for their effects on clinical outcome using the Kaplan–Meier estimator, the log-rank test and univariate/multivariate Cox regression. The prognostic impact of mutations in the TP53 gene, identified using TTGE followed by sequencing, was also evaluated. Eighty of the samples were analyzed for gene expression using 42K spot cDNA microarrays.

Results

Both univariate and multivariate analysis showed that the TP53 mutation status was the strongest predictor of breast cancer survival for these 215 patients, superior to tumor size and nodal status. Hierarchical clustering of gene expression identified four groups of patients with statistically significant survival differences (P = 0.0008); 'luminal A' and 'normal-like' subgroups with good prognosis, a 'basal-like/ERBB2' group having a very poor outcome within the first 2 years, and a 'luminal non-A' group showing an even poorer prognosis at 10-year follow-up. The basal-like/ERBB2 subgroup had a significantly higher frequency of mutations in the TP53 gene than the other subgroups (P < 0.001). Adding the gene expression-based classification as a separate parameter in multivariate analysis showed that this classification was an even stronger predictor of outcome than any of the other markers, with TP53 mutations status being approximately equally significant.

Conclusion

Our results suggest that gene expression profiles provide additional prognostic information supplementing currently established clinical markers. The results also highlight the role of TP53 as a determinant of the expression profile and as an important prognostic marker of breast cancer.