Comparative analysis and clinical value of the expression of metalloproteases and their inhibitors by intratumour stromal mononuclear inflammatory cells and those at the invasive front of breast carcinomas.

AIMS: Matrix metalloproteases (MMPs) and their inhibitors (TIMPs) play an essential role in the degradation of stromal connective tissue and basement membrane components. The aim of this study was to determine whether the dynamic analysis of these components can help to predict tumour aggressiveness. METHODS AND RESULTS: An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs -1, -2, -7, -9, -11, -13 and -14 and TIMPs -1, -2 and -3. More than 5000 determinations on cancer specimens from 124 patients with invasive breast cancer were performed on the tumour centre core as well as on the invasive front. Immunostaining for MMPs/TIMPs on mononuclear inflammatory cells (MICs) was evaluated. To identify specific groups of tumours with distinct expression profiles, data obtained from both MICs populations were analysed by unsupervised hierarchical cluster analysis. When compared with MICs at the invasive front, intratumour MICs more frequently showed expression of MMP-7 and -1 and TIMP-3, but less frequently expression of MMP-9 and -11 and TIMP-2. CONCLUSIONS: Our data led us to consider the need of further studies in order to identify subsets of MICs and other protein elements of the microenvironment as attractive targets for new therapeutic strategies against cancer.

Relationship between morphological features and kinetic patterns of enhancement of the dynamic breast magnetic resonance imaging and clinico-pathological and biological factors in invasive breast cancer.

BACKGROUND: To investigate the relationship between the magnetic resonance imaging (MRI) features of breast cancer and its clinicopathological and biological factors. METHODS: Dynamic MRI parameters of 68 invasive breast carcinomas were investigated. We also analyzed microvessel density (MVD), estrogen and progesterone receptor status, and expression of p53, HER2, ki67, VEGFR-1 and 2. RESULTS: Homogeneous enhancement was significantly associated with smaller tumor size (T1: < 2 cm) (p = 0.015). Tumors with irregular or spiculated margins had a significantly higher MVD than tumors with smooth margins (p = 0.038). Tumors showing a maximum enhancement peak at two minutes, or longer, after injecting the contrast, had a significantly higher MVD count than those which reached this point sooner (p = 0.012). The percentage of tumors with vascular invasion or high mitotic index was significantly higher among those showing a low percentage (150%) of enhancement rate (p = 0.016 and p = 0.03, respectively). However, there was a significant and positive association between the mitotic index and the peak of maximum intensity (p = 0.036). Peritumor inflammation was significantly associated with washout curve type III (p = 0.042). CONCLUSIONS: Variations in the early phase of dynamic MRI seem to be associated with parameters indicatives of tumor aggressiveness in breast cancer.

Expression of metalloproteases and their inhibitors in primary tumors and in local recurrences after mastectomy for breast cancer.

AIMS: To investigate the expression of matrix metalloproteases (MMPs) and their inhibitors (TIMPs) in patients who develop local recurrence (LR) after mastectomy. METHODS: We analyzed the expressions of MMP-1, -2, -7, -9, -11, -13, -14, TIMP-1, -2, and -3, using immunohistochemical techniques, in primary tumors from patients without tumoral recurrence (n = 50), patients who developed distant metastasis (n = 50), and from patients who develop LRs (n = 25). LRs of the latter group were also analyzed for MMPs expression. All the patients underwent mastectomy. RESULTS: Score values for all MMPs and TIMPs were significantly higher in primary tumors of patients with distant metastasis. Primary tumors from patients with LR have lower expressions of MMPs and TIMPs compared with those from patients who developed distant metastasis, and with patients without recurrence for some MMPs. Remarkably, however, primary tumors from patients with LR showed significantly higher percentage of TIMP-1 and 2 expression in stromal cells compared to primary tumors from patients with distant metastasis or primary tumors from patients without tumoral progression. Furthermore, LRs had significantly higher MMP-9 expression than their corresponding primary tumors. CONCLUSIONS: Our data indicate differences in MMPs/TIMPs expression between primary tumors of patients with LRs and of those with distant metastasis, both after mastectomy for breast cancer.

Local recurrence after mastectomy for breast cancer: analysis of clinicopathological, biological and prognostic characteristics.

BACKGROUND: Despite the increasing use of breast-conserving therapy, modified radical mastectomy retains an important role in primary as well as in salvage treatment of breast cancer. Nevertheless, a significant number of patients will eventually develop a local recurrence (LR). AIMS: To identify the potential prognostic factors at the time of the first isolated LR, and to compare the expression of several parameters of the molecular biology of breast carcinomas by primary tumors and paired isolated LRs. METHODS: We analyzed the medical records from 1,087 women who underwent mastectomy for breast cancer, out of which 98 developed LRs as the first manifestation of tumor progression. We investigated the prognostic value of various classical prognostic factors, at the time of mastectomy as well as when the diagnosis of LR was made. In addition, by using tissue microarrays and immunohistochemical techniques, we analyzed the expression of estrogen (ER), progesterone (PR) and androgen receptors (AR), ki67, p53, c-erbB-2 and apolipoprotein D in primary tumors and paired isolated LRs from a subset of patients (n = 25). RESULTS: Patients who developed distant metastases as well as patients with local recurrent disease showed a significantly higher percentage of larger tumors, node-positive status and higher tumoral grade than patients without evidence of tumoral recurrence. Furthermore, patients with LR had a better outcome compared with those with distant metastases, although the former received less frequently adjuvant systemic therapy and/or radiotherapy. Tumor size, histological grade, ER and PR status, and a shorter disease-free interval (<12 months) were significantly associated with overall survival amongst mastectomized patients that developed isolated LR. There was a significant concordance between primary tumors and LRs regarding the expression of the following factors: ER, PR and p53. However, we were not able to demonstrate similar findings for AR, c-erbB-2 and ki67. In addition, ER, PR and p53 status in the LRs were significantly associated with a poorer overall survival. CONCLUSIONS: Based on classical clinicopathological factors as well as on some new biological parameters we have been able to identify subgroups of mastectomized patients with LR differing in their prognosis. Thus, at the present time it would be possible to select group of patients candidates for further and individualized therapeutic strategies.

Expression and clinical significance of pepsinogen C in epithelial ovarian carcinomas.

BACKGROUND: Pepsinogen C (pep C) is a gastric aspartic protease of which is associated with a favorable prognosis in breast cancer. Recently, it has been demonstrated in other tumors of extradigestive origin. STUDY DESIGN: We have analyzed pep C expression in 72 epithelial ovarian carcinomas by immunohistochemistry. RESULTS: Nineteen (26%) tumors stained positively for pep C. Overall this expression was not associated with the clinicopathologic characteristics or with outcome. However, in patients with serum levels of CA 125 less than 35 U/ml, pep C expression identified a group with a more favorable prognosis. CONCLUSION: Pepsinogen C is expressed in a quarter of ovarian carcinomas and might identify a subset of patients with different prognosis.