p53 protein accumulation predicts resistance to endocrine therapy and decreased post-relapse survival in metastatic breast cancer

Endocrine therapy has become the most important treatment option for women with estrogen receptor (ER)-positive breast cancer. Nevertheless, many breast cancer patients with tumours expressing high levels of ER are unresponsive to endocrine therapy, and all patients with advanced disease eventually develop resistance to the therapy. The potential mechanisms behind either intrinsic or acquired endocrine resistance involve ER-coregulatory proteins and cross-talk between the ER pathway and other growth factor-signaling networks [1, 2]. An understanding of the molecular mechanisms that modulate the activity of the estrogen-signaling network has enabled new ways of overcoming endocrine resistance to be developed.

Several specific proteins have been suggested to contribute to endocrine therapy resistance. HER2 overexpression might be associated with reduced efficacy of adjuvant endocrine therapy with tamoxifen [3‐5]. De Laurentiis and colleagues recently conducted a meta-analysis and found that HER2-positive metastatic breast cancer was less responsive to any type of endocrine therapy [6].

Nearly one third of breast tumours have mutations in the p53 gene, which are associated with high histological grade and rapid progression [7]. 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 [8, 9]. Mutation of the p53 gene or overexpression of its protein product has been identified in 14% to 52% of primary breast tumour specimens, and these alterations were found to be associated with poor prognosis in an analysis of more than 3,000 patients with primary breast cancer [10]. We recently analysed the expression of HER2, p53, and Ki67 in 506 invasive ductal carcinoma tissues and showed that the coexistence of HER2 overexpression and p53 protein accumulation was a strong prognostic molecular marker in breast cancer [11].

Apoptosis may represent a common mechanism whereby a variety of antitumour treatments results in cell death. Cells with loss of p53 gene function may be unable to undergo apoptosis and thus be resistant to these forms of therapy [12]. Because mutated protein might accumulate in cells, immunohistochemical staining has been a popular surrogate marker for p53 mutational status. Studies have been published that examined the predictive value of p53 alterations at the gene level, or p53 expression status by immunohistochemistry (IHC), for response to chemotherapy. Many of these studies reported that p53 alterations predict resistance to anthracyclins [13‐19]; cyclophosphamide, methotrexate, and fluorouracil (CMF); or other agents [20‐22]. However, of the few studies that have examined the association between p53 status and response to endocrine therapy [23‐27], one study [27] reported a value for p53 in predicting endocrine resistance.

We previously described that expression of ER-α and progesterone receptor (PR) by IHC in primary breast tumours is predictive of response to endocrine therapy in patients with metastatic breast cancer who received endocrine therapy on relapse [28]. In this study, we examined the expression of HER2, p53, and Ki67 by IHC in primary breast tumour specimens from 73 patients with metastatic breast cancer who received first-line treatment with endocrine therapy on relapse, and analysed whether expression of these molecular markers affected the response to endocrine therapy.

The present study indicates that p53 protein accumulation predicts resistance to endocrine therapy and decreased post-relapse survival in patients with metastatic breast cancer who received first-line treatment with endocrine therapy on relapse.

Experimental data suggest a complex cross-talk between HER2 and ER, and it has been hypothesised that HER2-positive tumours may be less responsive to certain endocrine treatments. However, it has yet to be established whether HER2 overexpression is predictive of resistance to endocrine therapy, whether used as an adjuvant therapy after excision of localised breast cancer or as treatment for metastatic disease. In the metastatic setting, several groups have identified a correlation between HER2 overexpression and a lower response rate to endocrine therapy, whereas others have not. De Laurentiis and colleagues recently conducted a meta-analysis of the published studies to obtain an overall pooled estimate of the association between HER2 overexpression and treatment failure rate [6]. They found that HER2-positive metastatic breast cancer was less responsive to any type of endocrine therapy. Our data failed to show an association between HER2 overexpression and resistance to endocrine therapy, possibly due to the small number of patients in our study. Nevertheless, HER2 overexpression significantly reduced post-relapse survival.

It has been reported from three groups of clinical trials that p53 status by IHC does not predict response to tamoxifen [23‐25]. Elledge et al. found that p53 expression as measured by IHC was not associated with response to tamoxifen in 205 patients with metastatic breast cancer, although patients with higher p53 had a worse survival [25]. It has also been reported not to predict tamoxifen resistance in ER-positive, node-positive breast cancer [24] or in high-risk postmenopausal breast cancer [23] in adjuvant studies. In contrast, Berns et al. found that in 401 patients with metastatic breast cancer, p53 expression as measured by enzyme immunoassay of cytoplasmic extracts from primary tumours was a predictor of tamoxifen resistance [27]. Our results indicate that p53 protein accumulation by IHC was predictive of endocrine therapy resistance and decreased post-relapse survival in metastatic breast cancer. The antibody for p53 that Elledge et al. [25] used was also used in our study. Their results may have differed from ours because not only tamoxifen, but also aromatase inhibitors and/or LHRH (luteinising hormone-releasing hormone) agonists, were used as endocrine therapy in our study. Further studies to analyse the correlation between response to each endocrine therapy agent and p53 status are necessary to understand the role of p53 in endocrine therapy resistance. Moreover, the conflicting results may be caused by the different evaluation methods of p53 status. Geisler et al. demonstrated that nearly 30% of all mutations in primary breast cancer, in particular those of the nonsense type, are not detected by IHC and that most studies evaluating p53 status by IHC have failed to show a predictive value of p53 for chemotherapy, whereas studies evaluating p53 status by DNA sequencing have reported mutations that predict resistance to chemotherapy [15]. Therefore, mutational analysis of p53 might be helpful in evaluating the association between p53 status and endocrine therapy resistance.

The present study indicates that p53 protein accumulation predicts resistance to endocrine therapy and decreased post-relapse survival in patients with metastatic breast cancer who received first-line treatment with endocrine therapy on relapse. Our data suggest that p53 protein accumulation is helpful in selecting patients who may benefit from endocrine therapy and is a prognostic marker in metastatic breast cancer.