The present study indicates that the coexistence of HER2 over-expression and p53 protein accumulation has strong prognostic significance in invasive ductal carcinoma of the breast after a median follow-up period of 82 months.
HER2 encodes a 185-kDa transmembrane glycoprotein with intracellular tyrosine kinase activity that belongs to the epidermal growth factor receptor family [11
]. Although no ligand has been identified for HER2, several peptide growth factors bind to the other members of the family. Amplification or over-expression of HER2 is observed in 20–40% of human breast cancers. The prognostic significance of HER2 over-expression was first reported in 1987 [12
]. Subsequently, over 200 studies have been reported in which the role of amplification/over-expression of HER2 was investigated as a prognostic marker in breast cancer. Also, we previously reported that HER2 amplification was strongly associated with both disease free and overall survival in breast cancer [5
]. In the present study we extended our analysis of HER2 over-expression to more than 500 invasive ductal tumors, and showed that over-expression of HER2 was associated with poor prognosis.
Nearly one-third of breast cancers have mutations in the p53 gene, which are associated with high histological grade and clinical aggressiveness [3
]. Immunohistochemical assays generally detect nuclear accumulation of the protein, which is often related to conformational alterations and a prolonged half-life of the encoded protein [13
]. Accumulation of p53 protein was significantly associated with poor prognosis in our study and in other studies of patients with breast cancer [15
]. These studies suggest both a prognostic and a predictive role for p53 [1
Tumors with both HER2 over-expression and p53 protein accumulation were reported in several studies, and patients with such tumors were found to have poor prognosis [17
]; the findings reported here also indicate that both HER2 over-expression and p53 protein accumulation are associated with markedly poorer disease free and overall survival. On the other hand, some studies have shown a better prognosis in patients with breast cancers with HER2 overexpression and p53 protein accumulation [23
]. These differences may reflect the effect of various therapeutic regimens.
Most patients with early breast cancer receive adjuvant treatment, and the identification of predictive factors may help in selecting the optimal therapeutic strategy for individual patients. HER2 over-expression may be associated with reduced efficacy of adjuvant endocrine therapy with tamoxifen [24
]. The role of p53 mutations in the efficacy of endocrine therapy is still under evaluation. On the other hand, previous data suggested that HER2 positive tumors might be resistant to adjuvant treatment with CMF [27
]. There is evidence that women whose tumors over-express HER2 are likely to derive greater benefit from therapy with anthracycline-containing regimens than from alkylating agents [25
]. It was also reported that patients with both HER2 and p53 positive tumors had an improved 10-year survival when treated with a high dose FAC (fluorouracil, doxorubicin, cyclophosphamide) regimen [29
]. The patients included in the present study were treated with tamoxifen, fluorouracil, or a CMF regimen, and anthracycline based chemotherapy was not used. Further studies are needed to determine which endocrine or chemotherapeutic agents should be used in breast cancers with different expression profiles, especially in patients with poor prognosis.