Perturbations of the p53 pathway are associated with more aggressive and therapeutically refractory tumors. However, molecular assessment of p53 status, by using sequence analysis and immunohistochemistry, are incomplete assessors of p53 functional effects. We posited that the transcriptional fingerprint is a more definitive downstream indicator of p53 function. Herein, we analyzed transcript profiles of 251 p53-sequenced primary breast tumors and identified a clinically embedded 32-gene expression signature that distinguishes p53-mutant and wild-type tumors of different histologies and outperforms sequence-based assessments of p53 in predicting prognosis and therapeutic response. Moreover, the p53 signature identified a subset of aggressive tumors absent of sequence mutations in p53 yet exhibiting expression characteristics consistent with p53 deficiency because of attenuated p53 transcript levels. Our results show the primary importance of p53 functional status in predicting clinical breast cancer behavior.

Introduction Adjuvant breast cancer therapy significantly improves survival, but overtreatment and undertreatment are major problems. Breast cancer expression profiling has so far mainly been used to identify women with a poor prognosis as candidates for adjuvant therapy but without demonstrated value for therapy prediction.

To investigate the clinical value of somatic TP53 mutations in breast cancer, we assembled clinical and molecular data on 1,794 women with primary breast cancer with long-term follow-up and whose tumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing. TP53 mutations were more frequent in tumors of ductal and medullar types, aggressive phenotype (high grade, large size, node positive cases, and low hormone receptor content) and in women <60 years old. TP53 mutations within exons 5 to 8 conferred an elevated risk of breast cancer^specific death of 2.27 (relative risk >10 years; P < 0.0001) compared with patients with no such mutation. The prognostic value of TP53 mutation was independent of tumor size, node status, and hormone receptor content, confirming and reconciling previous findings in smaller series. Moreover, an interaction between TP53 mutation and progesterone receptor (PR) status was revealed, TP53 mutation combined with the absence of progesterone receptor being associated with the worst prognosis. Whereas previous studies have emphasized the fact that missense mutations in the DNA-binding motifs have a worse prognosis than missense mutations outside these motifs, we show that non^missense mutations have prognostic value similar to missense mutations in DNA-binding motifs. Nonetheless, specific missense mutants (codon 179 and R248W) seem to be associated with an even worse prognosis. These results, obtained on the largest series analyzed thus far, show that TP53 mutations identified by gene sequencing have an independent prognostic value in breast cancer and could have potential uses in clinical practice.The tumor suppressor gene TP53 plays a key role in many cellular pathways controlling cell proliferation, cell survival, and genomic integrity. It acts as a proliferation brake when cells experience stress conditions, such as DNA-damage, hypoxia, or oncogene activation. Disrupting TP53 function promotes checkpoint defects, genomic instability, and inappropriate survival, leading to the uncontrolled proliferation of damaged cells. The proliferative advantage given by its inactivation, and the fact that it is ubiquitously expressed, explains why it is frequently found to be mutated in almost every type of cancer (1). It has been shown in various experimental in vitro systems, as well as in mouse models, that cell cycle arrest or apoptosis induced by radiotherapy and various chemotherapeutic drugs depends on an intact TP53 pathway (2, 3). These results have raised the hypothesis that TP53 could be a key player in defining tumor sensitivity to a broad range of anticancer treatments in patients with cancer. Moreover, the presence of a TP53 mutation could be one of the underlying causes of drug resistance, the major cause of treatment failure and cancer death.Several studies have investigated the predictive value of TP53 mutation status for tumor response to treatment and patient outcome in various cancers. Different clinical and methodologic