The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic and macrophage infiltration, microvessel density and survival in patients with primary operable breast cancer

The significance of the inter-relationship between tumour and host local/systemic inflammatory responses in primary operable invasive breast cancer is limited. The inter-relationship between the systemic inflammatory response (pre-operative white cell count, C-reactive protein and albumin concentrations), standard clinicopathological factors, tumour T-lymphocytic (CD4+ and CD8+) and macrophage (CD68+) infiltration, proliferative (Ki-67) index and microvessel density (CD34+) was examined using immunohistochemistry and slide-counting techniques, and their prognostic values were examined in 168 patients with potentially curative resection of early-stage invasive breast cancer. Increased tumour grade and proliferative activity were associated with greater tumour T-lymphocyte (P<0.05) and macrophage (P<0.05) infiltration and microvessel density (P<0.01). The median follow-up of survivors was 72 months. During this period, 31 patients died; 18 died of their cancer. On univariate analysis, increased lymph-node involvement (P<0.01), negative hormonal receptor (P<0.10), lower albumin concentrations (P<0.01), increased tumour proliferation (P<0.05), increased tumour microvessel density (P<0.05), the extent of locoregional control (P<0.0001) and limited systemic treatment (Pless than or equal to0.01) were associated with cancer-specific survival. On multivariate analysis of these significant covariates, albumin (HR 4.77, 95% CI 1.35–16.85, P=0.015), locoregional treatment (HR 3.64, 95% CI 1.04–12.72, P=0.043) and systemic treatment (HR 2.29, 95% CI 1.23–4.27, P=0.009) were significant independent predictors of cancer-specific survival. Among tumour-based inflammatory factors, only tumour microvessel density (P<0.05) was independently associated with poorer cancer-specific survival. The host inflammatory responses are closely associated with poor tumour differentiation, proliferation and malignant disease progression in breast cancer

Estrogenic microenvironment generated by organochlorine residues in adipose mammary tissue modulates biomarker expression in ERα-positive breast carcinomas

INTRODUCTION: Breast cancer is the most frequent malignant disease in women. Exposure to estrogens throughout a woman's life is a risk factor for the development of breast cancer. Organochlorine compounds (OCCs), such as pesticides and polychlorinated biphenyls, are persistent lipophilic chemicals identified as endocrine disruptors, mainly with estrogenic effects. To test the hypothesis that the amount and quality of organochlorine residues in adipose tissue adjacent to breast carcinoma affect the biological behavior of the tumor, we studied biomarker expression in breast carcinoma and the OCC body burden in patients from an urban area adjacent to Paraná fluvial system, Argentina. METHODS: The studied patients were 55 women who had undergone excision biopsies of a breast lesion diagnosed as invasive breast carcinoma. Analysis of OCC residues in breast adipose tissue was conducted by electron-capture gas–liquid chromatography. Estrogen receptor alpha (ERα), progesterone receptor (PR) and proliferative activity (Ki-67) levels were measured in paraffin-embedded biopsies of breast tumors by immunohistochemistry. RESULTS: All patients had high levels of organochlorine pesticides in their breast adipose tissue. The most frequently detected compounds were p,p'-dichlorodiphenyldichloroethylene, hexachlorobenzene and β-hexachlorocyclohexane. When the whole sample was analyzed, no correlation between ERα or PR expression and OCC levels were found. In the subgroup of ERα-positive breast carcinoma patients, however, there was a positive correlation between PR expression (an estrogen-induced protein) in the neoplastic cells and OCC levels in adipose tissue surrounding the tumor. More significantly, all the ERα-positive breast carcinomas from postmenopausal women exhibited high proliferation when organochlorine levels in the surrounding adipose tissue reached levels higher than 2600 ppb. No associations were found between the organochlorine body burden and any other marker of tumor aggressiveness, such as node involvement or tumor size. CONCLUSION: The present results support the hypothesis that organochlorine residues in adipose tissue adjacent to breast carcinoma generate an estrogenic microenvironment that may influence the biological behavior of the tumor through ERα activation and ERα-dependent proliferation. These findings may have therapeutic implications, since interference between organochlorine compounds and hormonal therapy could be expected to occur

Potential prognostic value of heat-shock protein 90 in the presence of phosphatidylinositol-3-kinase overexpression or loss of PTEN, in invasive breast cancers

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract Introduction Evaluating the expression of signaling molecule proteins from the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3-kinase (PI3K) pathway in invasive breast cancers may identify prognostic marker(s) associated with early relapse. Methods Immunohistochemical analyses of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), PI3K-p110α, phospho-AKT, phospho-p70S6 kinase, phospho-S6 ribosomal protein, phospho-RAF, phospho-p44/42 MAPK, and heat-shock protein 90 (HSP90) were performed on tumor samples from 212 patients with invasive breast cancer. Statistically significant relations between protein expression, clinicopathologic factors, and relapse-free survival (RFS) were analyzed. Results Expression of HSP90 was associated with 5-year RFS, as well as T stage, N stage, histologic grade, estrogen receptor (ER) expression, human epidermal growth factor receptor 2 (HER2) expression, and the Ki-67 proliferation index. On multivariate analysis, coexpression of HSP90 and PI3K-p110α or expression of HSP90 along with PTEN loss demonstrated significantly worse RFS. In subgroup analyses, both exhibited strong prognostic significance in HER2-positive cases, but not in HER2-negative cases. Conclusions The coexpression of HSP90 with PI3K-p110α or expression of HSP90 along with PTEN loss has a potential as a molecular prognostic marker to predict early relapse in patients with invasive breast cancers

Factors that predict early treatment failure for patients with locally advanced (T4) breast cancer

Locally advanced breast cancer (LABC) is associated with dire prognosis despite progress in multimodal treatments. We evaluated several clinical and pathological features of patients with either noninflammatory (NIBC, cT4a-c) or inflammatory (IBC, cT4d) breast cancer to identify subset groups of patients with high risk of early treatment failure. Clinical and pathological features of 248 patients with LABC, who were treated with multimodality treatments including neoadjuvant chemotherapy followed by radical surgery and radiotherapy were reassessed. Tumour samples obtained at surgery were evaluated using standard immunohistochemical methods. Overall, 141 patients (57%) presented with NIBC (cT4a-c, N0-2, M0) and 107 patients (43%) with IBC (cT4d, N0-2, M0). Median follow-up time was 27.5 months (range: 1.6–87.8). No significant difference in terms of recurrence-free survival (RFS) (P=0.72), disease-free survival (DFS) (P=0.98) and overall survival (OS) (P=0.35) was observed between NIBC and IBC. At the multivariate analysis, patients with ER- and PgR-negative diseases had a significantly worse RFS than patients with ER- and/or PgR-positive diseases (hazard ratio: 2.47, 95% CI: 1.33–4.59 for overall). The worst RFS was observed for the subgroup of patients with endocrine nonresponsive and HER2-negative breast cancer (2-year RFS: 57% in NIBC and 57% in IBC) A high Ki-67 labelling index (>20% of the invasive tumour cells) and the presence of peritumoral vascular invasion (PVI) significantly correlated with poorer RFS in overall (HR 2.69, 95% CI: 1.61–4.50 for Ki-67>20% and HR 2.27, 95% CI: 1.42–3.62 for PVI). Patients with endocrine nonresponsive LABC had the most dire treatment outcome. High degree of Ki-67 staining and presence of PVI were also indicators of higher risk of early relapse. These factors should be considered in therapeutic algorithms for LABC

Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12 155 patients

The Ki-67 antigen is used to evaluate the proliferative activity of breast cancer (BC); however, Ki-67's role as a prognostic marker in BC is still undefined. In order to better define the prognostic value of Ki-67/MIB-1, we performed a meta-analysis of studies that evaluated the impact of Ki-67/MIB-1 on disease-free survival (DFS) and/or on overall survival (OS) in early BC. Sixty-eight studies were identified and 46 studies including 12 155 patients were evaluable for our meta-analysis; 38 studies were evaluable for the aggregation of results for DFS, and 35 studies for OS. Patients were considered to present positive tumours for the expression of Ki-67/MIB-1 according to the cut-off points defined by the authors. Ki-67/MIB-1 positivity is associated with higher probability of relapse in all patients (HR=1.93 (95% confidence interval (CI): 1.74–2.14); P<0.001), in node-negative patients (HR=2.31 (95% CI: 1.83–2.92); P<0.001) and in node-positive patients (HR=1.59 (95% CI: 1.35–1.87); P<0.001). Furthermore, Ki-67/MIB-1 positivity is associated with worse survival in all patients (HR=1.95 (95% CI: 1.70–2.24; P<0.001)), node-negative patients (HR=2.54 (95% CI: 1.65–3.91); P<0.001) and node-positive patients (HR=2.33 (95% CI: 1.83–2.95); P<0.001). Our meta-analysis suggests that Ki-67/MIB-1 positivity confers a higher risk of relapse and a worse survival in patients with early BC

Impact of intratumoural heterogeneity on the assessment of Ki67 expression in breast cancer

In breast cancer (BC), the prognostic value of Ki67 expression is well-documented. Intratumoural heterogeneity (ITH) of Ki67 expression is amongst the several technical issues behind the lag of its inclusion into BC prognostic work-up. The immunohistochemical (IHC) expression of anti-Ki67 antibody (MIB1 clone) was assessed in four full-face (FF) sections from different primary tumour blocks and their matched axillary nodal (LN) metastases in a series of 55 BC. Assessment was made using the highest expression hot spots (HS), lowest expression (LS), and overall/average expression scores (AS) in each section. Heterogeneity score (Hes), co-efficient of variation, and correlation co-efficient were used to assess the levels of Ki67 ITH. Ki67 HS, LS, and AS scores were highly variable within the same section and between different sections of the primary tumour, with maximal variation observed in the LS (P\0.001). The least variability between the different slides was observed with HS scoring. Although the associations between Ki67 and clinicopathological and molecular variables were similar when using HS or AS, the best correlation between AS and HS was observed in tumours with high Ki67 expression only. Ki67 expression in LN deposits was less heterogeneous than in the primary tumours and was perfectly correlated with the HS Ki67 expression in the primary tumour sections (r = 0.98, P\0.001). In conclusion, assessment of Ki67 expression using HS scoring method on a full-face BC tissue section can represent the primary tumour growth fraction that is likely to metastasise. The association between Ki67 expression pattern in the LN metastasis and the HS in the primary tumour may reflect the temporal heterogeneity through clonal expansion

Perineural invasion: An independent risk factor for cervical cancer prognosis and a possible pathway for a future targeted treatment?

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