Abstract
BackgroundOne of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system that comprises of, among others, the urokinase Plasminogen Activator (uPA) and its main inhibitor, the Plasminogen Activator Inhibitor-1 (PAI-1). In this study, we investigated the prognostic value of uPA and PAI-1 at the mRNA level in lymph node- and hormone receptor-positive breast cancer.MethodsThe study included a retrospective series of 87 patients with hormone-receptor positive and axillary lymph node-positive breast cancer. All patients received radiotherapy, adjuvant anthracycline-based chemotherapy and five years of tamoxifen treatment. The median patient age was 54 and the median follow-up time was 79 months. Distant relapse occurred in 30 patients and 22 patients died from breast cancer during follow-up. We investigated the prognostic value of uPA and PAI-1 at the mRNA level as measured by real-time quantitative RT-PCR.ResultsuPA and PAI-1 gene expression was not found to be correlated with any of the established clinical and pathological factors. Metastasis-free Survival (MFS) and Breast Cancer specific Survival (BCS) were significantly shorter in patients expressing high levels of PAI-1 mRNA (p < 0.0001; p < 0.0001; respectively). In Cox multivariate analysis, the level of PAI-1 mRNA appeared to be the strongest prognostic factor for MFS (Hazard Ratio (HR) = 10.12; p = 0.0002) and for BCS (HR = 13.17; p = 0.0003). Furthermore, uPA gene expression was not significantly associated neither with MFS (p = 0.41) nor with BCS (p = 0.19). In a Cox-multivariate regression analysis, uPA expression did not demonstrate significant independent prognostic value.ConclusionThese findings indicate that high PAI-1 mRNA expression represents a strong and independent unfavorable prognostic factor for the development of metastases and for breast cancer specific survival in a population of hormone receptor- and lymph node-positive breast cancer patients.
Highlights
One of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system that comprises of, among others, the urokinase Plasminogen Activator and its main inhibitor, the Plasminogen Activator Inhibitor-1 (PAI-1)
In metastatic breast cancer, retrospective studies showed that elevated urokinase Plasminogen Activator (uPA) or PAI-1 present in the primary tumor are associated with a poor response to later palliative endocrine therapy [14] suggesting that high levels of uPA and/ or PAI-1 do reflect an aggressive phenotype that may be overcome by early systemic therapy in the adjuvant setting but not by palliative therapy at a later stage of the disease
It has recently been shown that PAI-1 mRNA expression increased with colorectal cancer and the oesophageal squamous carcinoma stage and was associated with poor prognosis suggesting that the gene expression of this marker may serve as a new prognostic factor in these two types of cancer [35,36]. These results demonstrate that a high PAI1 gene expression level represents a strong and independent unfavorable prognostic factor for the development of metastases and for overall survival in a population of lymph node- and receptor-positive breast cancer
Summary
One of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system that comprises of, among others, the urokinase Plasminogen Activator (uPA) and its main inhibitor, the Plasminogen Activator Inhibitor-1 (PAI-1). Several international research groups have demonstrated that the protein content of uPA and PAI-1 in the tumor correlates with disease aggressiveness and has a strong prognostic impact on disease-free survival and overall survival in patients with primary breast cancer [1,2,3,4,5,6]. In metastatic breast cancer, retrospective studies showed that elevated uPA or PAI-1 present in the primary tumor are associated with a poor response to later palliative endocrine therapy [14] suggesting that high levels of uPA and/ or PAI-1 do reflect an aggressive phenotype that may be overcome by early systemic therapy in the adjuvant setting but not by palliative therapy at a later stage of the disease
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