P53 as a prognostic factor

Alteration of the p53 gene in breast cancer is associated with an unfavorable prognosis.76-79 Accumulation of nuclear p53, or expression of mutant p53, is associated with a number of histological, biological and clinical adverse prognostic factors including developing metastasis and reduced disease-free survival.80 Microarray approaches have identified a 32-gene expression signature which distinguishes mutant from wild-type p53 and outperforms sequence-based assessment of p53 in predicting prognosis,62 underlining that not all mutations are equal.81 p53 network changes may occur without mutation and the role of p53 in different therapeutic settings may vary. However, p53 overexpression may be a predictor of local recurrence in operable breast cancer.82

p53 aberrations vary between different his-tological types of breast cancers. They are more common in the invasive ductal carcinomas as opposed to lobular carcinomas, and less common in the well-differentiated types with more favorable prognosis.77 Recent microarray techniques have identified the basal pheno-type of breast cancer where p53 mutation features.80 There are exceptions: poorly differentiated medullary carcinomas displaying p53 gene mutations ironically have a more favorable prognosis.77 However, p53 abnormalities are generally associated with the higher grade cancers, aneuploid tumors and those with a high S-phase fraction (mitotic rate).72 Therefore, the histology of a specific breast tumor should be considered as an adjunct to p53 status when using p53 as a prognostic marker.

p53 expression is considered to be a marker of more aggressive cancer76,77 both for locally advanced and inflammatory cancers. There are reports of a higher tumor proliferation rate, early disease recurrence and early death in node-negative breast cancers,72 and correlation with tumor size, axillary nodal involvement and low hormone-receptor content for patients with breast cancer containing p53 mutation.77 p53 aberrations are associated with low levels of ER and PR, which are known to be markers of less aggressive tumors with better response rate to systemic hormonal therapies.45,72,77

The prognostic power of p53 may be best combined with other cellular and biological parameters. These include a p53-positive Bcl-2-negative phenotype independently associated with poor prognosis,83 c-erb-2 (HER2/ neu), Ki67 antigen, and tumor cell characteristics such as microvessel density and tumor cell proliferation rate.71 Concurrent p53 and c-erb-2 protein overexpression are associated with poor overall survival and metastasis-free interval74 in node-negative tumors, particularly those with missense mutations.84,85

With the appreciation of p53 as an independent biological marker for response to treatment and disease outcome, at least when p53 mutations have been detected,77 detecting p53 antibodies or p53 mutations in patient serum has been proposed as a diagnostic tool since such techniques may identify breast cancer patients.86

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