Correlation of breast cancer risk factors with HER-2/neu protein overexpression according to menopausal and estrogen receptor status

BACKGROUND: Several researchers have claimed that classification of tumours on the basis of HER-2/neu overexpression or amplification may define a subset of breast cancer in which the net effect of a risk factor could be rather more obvious and its impact on breast cancer development more clear. We decided to investigate, in a group of patients from a geographical area with a low incidence of breast cancer, whether HER-2/neu positive tumours are correlated with established or suspected risk factors for breast cancer and thus to identify distinct subgroups of high risk women. METHODS: This study analysed data from patients who attended the Breast Unit at the University Hospital of Heraklion, Crete, Greece between 1996 and 2002. 384 women with primary invasive breast cancer were compared with 566 screened women who were referred to the Unit and had not developed breast neoplasm by the time the data were analysed. Risk factor data were obtained from each subject by personal interviews using a structured questionnaire. The detection and scoring of the HER-2/neu protein, estrogen and progesterone receptor expression were performed using immunochemistry. Odds ratios and 95% confidence intervals were determined by chi-square test and logistic regression analysis. Case-case odds ratios were calculated in order to measure the risk heterogeneity between HER-2/neu+ and HER-2/neu-tumours. Separate analyses were performed for premenopausal and postmenopausal women and according to estrogen receptor status. RESULTS: In multivariate analysis without HER-2/neu stratification, an increased breast cancer risk was associated with only four of the factors examined: use of oral contraceptives (OR = 4.40, 95%C.I: 1.46–13.28), use of HRT (OR = 7.34, 95%C.I: 2.03–26.53), an age at first full pregnancy more than 23 years (OR = 1.91, 95%C.I: 1.29–2.83) and body mass index more than 29 kg/m(2 )(OR = 3.13, 95%C.I: 2.02–4.84). Additionally, a history of abortion or miscarriage (OR = 0.56, 95%C.I: 0.38–0.82) was correlated with a decreased risk of breast cancer. In the case to case comparison only BMI >29 kg/m(2 )revealed a relative connection that was stronger with positive than with negative HER-2/neu tumours (ratio of OR's = 2.23, 95%C.I: 1.20–4.15, p = 0.011). This may indicate evidence of heterogeneity of a rather significant degree for this factor. In the ER negative group an age at first full pregnancy >23 years and a BMI >29 kg/m(2 )were associated with an increased risk in both HER-2/neu groups, but the association was significantly stronger for the latter factor in the positive HER-2/neu tumours (ratio of OR's = 2.46, 95%CI: 0.97–6.21). CONCLUSIONS: Our study did not confirm that the established or putative hormonal breast cancer risk factors differ regarding their relations with HER-2/neu+ versus HER-2/neu-breast tumours, with the exception of increased BMI. Further innovative studies with larger sample sizes are needed to examine how the status of these potentially modifiable breast cancer risk factors interacts with biological markers such as HER-2/neu oncoprotein

Expression of TNF-superfamily members BAFF and APRIL in breast cancer: Immunohistochemical study in 52 invasive ductal breast carcinomas

<p>Abstract</p> <p>Background</p> <p>Recent studies suggest an association between chronic inflammation, modulating the tissue microenvironment, and tumor biology. Tumor environment consists of tumor, stromal and endothelial cells and infiltrating macrophages, T lymphocytes, and dendritic cells, producing an array of cytokines, chemokines and growth factors, accounting for a complex cell interaction and regulation of differentiation, activation, function and survival of tumor and surrounding cells, responsible for tumor progression and spreading or induction of antitumor immune responses and rejection. Tumor Necrosis Factor (TNF) family members (19 ligands and 29 receptors) represent a pleiotropic family of agents, related to a plethora of cellular events from proliferation and differentiation to apoptosis and tumor reduction. Among these members, BAFF and APRIL (CD257 and CD256 respectively) gained an increased interest, in view of their role in cell protection, differentiation and growth, in a number of lymphocyte, epithelial and mesenchymal structures.</p> <p>Methods</p> <p>We have assayed by immunohistochemistry 52 human breast cancer biopsies for the expression of BAFF and APRIL and correlated our findings with clinicopathological data and the evolution of the disease.</p> <p>Results</p> <p>BAFF was ubiquitely expressed in breast carcinoma cells, DCIS, normal-appearing glands and ducts and peritumoral adipocytes. In contrast, APRIL immunoreactive expression was higher in non-malignant as compared to malignant breast structures. APRIL but not BAFF immunoreactivity was higher in N+ tumors, and was inversely related with the grade of the tumors. Neither parameter was related to DFS or the OS of patients.</p> <p>Conclusion</p> <p>Our data show, for the first time, an autocrine secretion of BAFF and APRIL from breast cancer cells, offering new perspectives for their role in neoplastic and normal breast cell biology and offering new perspectives for possible selective intervention in breast cancer.</p

Serum interleukin-17 and its relationship to angiogenic factors in multiple myeloma

Background: Interleukin-17 (IL-17) is a CD4 T-cell-derived mediator of angiogenesis that stimulates vascular endothelial cell migration and regulates the production of a variety of proangiogenic factors, such as tumor necrosis factor-α (TNF-α) and vascular endothelial cell growth factor (VEGF). Angiogenesis is implicated in the progression of multiple myeloma (MM). Methods: We measured serum levels of IL-17, TNF-α, and VEGF, as well as microvessel density (MVD) in 40 untreated MM patients. Results: Levels of IL-17 in the sera of patients with MM were higher than those in matched controls; however, the difference did not reach statistical significance. Serum levels of both TNF-α and VEGF in MM patients were significantly higher than those in controls (

Serum levels of Interleukin-15 and Interleukin-10 and their correlation with proliferating cell nuclear antigen in multiple myeloma

In order to determine prognostic factors characterizing multiple myeloma (MM) cell kinetics, bone marrow proliferative activity and serum Interleukin-10 (IL-10), and Interleukin-15 (IL-15) levels were measured in 40 newly diagnosed MM patients, compared with 10- age and sex-matched-healthy controls. Cell proliferation was evaluated by employing a monoclonal antibody directed against the proliferating cell nuclear antigen (PCNA), whereas IL-10 and IL-15 were measured with quantitative sandwich enzyme immunoassay methods. IL-15, IL-10 and PCNA were higher in the patient group than in controls (P \u3c 0.001). IL-10 levels, and PCNA increased significantly with increasing Durie-Salmon disease stage (I-III, P \u3c 0.002, and P = 0.001, respectively). Serum IL-15 levels in MM stage III patients were elevated in comparison with stages I and II, the difference however, did not reach statistical significance. There was a significant positive correlation between serum IL-15 and IL-10 levels (r: 0.372, P \u3c 0.01), and between serum IL-10 and PCNA (r: 0.608, P \u3c 0.0001), as well as a positive correlation of serum IL-15 with PCNA, which marginally failed to reach statistical significance. Serum IL-15 levels are elevated in MM patients, increase with advancing stage, and correlate with Il-10 and PCNA. These proliferative factors may be useful in assessing disease progression in MM

Her-2 protein expression, cellular localization, and gene amplification in colorectal carcinoma

This study was sought to evaluate the relationship between Her-2 protein expression, cellular localization, gene amplification, and other clinicopathologic parameters in colorectal carcinomas. Her-2 protein expression and gene amplification were assessed in paraffin sections from 106 primary colorectal adenocarcinoma cases using immunohistochemistry and fluorescence in situ hybridization. Both membranous and cytoplasmic immunostaining was evaluated. The results were correlated with each other and with tumor grade, stage, and overall survival. Membranous and cytoplasmic protein expression was identified in 6 (5.6%) and 13 (12.26%) cases, respectively. Gene amplification was detected in 4 (3.7%) cases. There was a high concordance between membranous protein expression and gene amplification (kappa = 0.791). No apparent association with any of the clinicopathologic parameters was identified. Membranous Her-2 protein expression and gene amplification are encountered in a small subset of colorectal carcinomas and are highly concordant events. Cytoplasmic protein expression might be either artifactual or it might represent a cross-reacting protein or a precursor form of the mature protein

Serum interleukin-17 and its relationship to angiogenic factors in multiple myeloma

Background: Interleukin-17 (IL-17) is a CD4 T-cell-derived mediator of angiogenesis that stimulates vascular endothelial cell migration and regulates the production of a variety of proangiogenic factors, such as tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial cell growth factor (VEGF). Angiogenesis is implicated in the progression of multiple myeloma (MM). Methods: We measured serum levels of IL-17, TNF-alpha, and VEGF, as well as microvessel density (MVD) in 40 untreated MM patients. Results: Levels of IL-17 in the sera of patients with MM were higher than those in matched controls; however, the difference did not reach statistical significance. Serum levels of both TNF-alpha and VEGF in MM patients were significantly higher than those in controls (P&lt;0.001 in both instances). Levels of IL-17 in MM patients, both stage 11 and stage 111, were significantly higher than those of stage I patients (p=0.001 and p&lt;0.001, respectively). Similarly, higher values of VEGF (p&lt;0.001), TNF-a (p&lt;0.001), and MVD (p&lt;0.035) were associated with advanced disease stage. Serum values of IL-17 in MM patients correlated positively not only with VEGF (Spearman’s rho=0.606) and TNF-alpha (r=0.552; p&lt;0.001 in both instances), but also with MVD (r=0.385, p=0.014). In addition, a positive correlation was found between serum values of VEGF and TNF-alpha (r=0.657, p&lt;0.001), MVD and VEGF (r=0.353, p=0.026), and between MVD and TNF-alpha (r=0.506,p=0.001) in MM patients. Conclusion: These results suggest that IL-17 plays a role in the promotion of angiogenesis and associated disease progression in MM. (C) 2006 European Federation of Internal Medicine. Published by Elsevier B.V All rights reserved

Molecular detection and prognostic value of circulating cytokeratin-19 messenger RNA-positive and HER2 messenger RNA-positive cells in the peripheral blood of women with early-stage breast cancer.

PURPOSE: The aim of this study was to evaluate the clinical relevance of the simultaneous detection of cytokeratin (CK)-19 messenger RNA (mRNA)- and HER2 mRNA-positive cells in peripheral blood of women with early-stage breast cancer. PATIENTS AND METHODS: CK-19 mRNA- and HER2 mRNA-positive cells were detected using a real-time and a nested reverse-transcriptase polymerase chain reaction assay, respectively, in a cohort of 185 women with early-stage breast cancer before the initiation of any adjuvant systemic treatment. Detection of CK-19 mRNA- and HER2 mRNA-positive cells in the peripheral blood was correlated with clinical outcome. RESULTS: Overall, 63 of the 185 patients (34%) had detectable CK-19 mRNA-positive cells, and 33 (52.3%) also had detectable HER2 mRNA-positive cells. Patients with CK-19/HER2 mRNA-negative cells showed a trend toward longer disease-free survival (DFS) compared with patients with CK-19 mRNA-positive/HER2 mRNA-negative cells (P = .054) and had longer DFS than patients with CK-19/HER2 mRNA-positive cells (P < .001). Similarly, overall survival (OS) was higher in patients with CK-19/HER2 mRNA-negative cells compared with patients with CK-19 mRNA-positive/HER2 mRNA-negative cells (P = .039) or CK-19/HER2 mRNA-positive cells (P < .001). Patients with CK-19/HER2 mRNA-positive cells had shorter DFS but not OS compared with patients with CK-19 mRNA-positive/HER2 mRNA-negative cells. In multivariate analysis, the simultaneous detection of CK-19 mRNA- and HER2 mRNA-positive cells was independently associated with early relapse. CONCLUSION: The simultaneous detection of CK-19 mRNA- and HER2 mRNA-positive cells in peripheral blood predicts poor clinical outcome for women with early-stage breast cancer.Journal Articleinfo:eu-repo/semantics/publishe

Different prognostic value of cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer.

PURPOSE: To examine the prognostic value of cytokeratin-19 (CK-19) mRNA-positive circulating tumor cells (CTCs) in early-stage breast cancer patients focusing on clinically relevant subgroups based on estrogen receptor (ER) and HER2 expression. PATIENTS AND METHODS: CK-19 mRNA-positive CTCs were detected by real-time reverse transcriptase polymerase chain reaction in the blood of 444 consecutive, stage I-III, breast cancer patients before initiation of adjuvant chemotherapy. The association between detection of CK-19 mRNA-positive CTCs and clinical outcome was analyzed for patients with ER-positive, ER-negative, triple-negative, HER2-positive, and ER-positive/HER2-negative tumors. RESULTS: CK-19 mRNA-positive CTCs were detected in 181 (40.8%) of 444 patients; 109 (41.9%) of 260 patients with ER-positive tumors; 71 (40.6%) of 175 patients with ER-negative tumors; 27 (35%) of 77 patients with triple-negative tumors; 35 (39.8%) of 88 patients with HER2-positive tumors; and 82 (44.1%) of 186 patients with ER-positive/HER2-negative tumors. After a median follow-up of 53.5 months, patients with CK-19 mRNA-positive CTCs experienced reduced disease-free survival (DFS; P < .001) and overall survival (OS; P < .001); this was mainly observed in patients with ER-negative (P < .001 and P < .001, respectively) but not ER-positive tumors (P = .172 and P = .425, respectively) and in patients with triple-negative (P = .008 and P = .001, respectively) and HER2-positive (P = .023 and P = .040, respectively) but not ER-positive/HER2-negative tumors (P = .210 and P = .578, respectively). In multivariate analysis, the interaction between CK-19 mRNA-positive CTCs and ER status was the strongest independent prognostic factor for reduced DFS (hazard ratio [HR], 3.808; 95% CI, 2.415 to 6.003; P < .001) and OS (HR, 4.172; 95% CI, 2.477 to 9.161; P < .001). CONCLUSION: Detection of CK-19 mRNA-positive CTCs before adjuvant chemotherapy predicts poor clinical outcome mainly in patients with ER-negative, triple-negative, and HER2-positive early-stage breast cancer.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Histological expression of angiogenic factors: VEGF, PDGFR alpha, and HIF-1 alpha in Hodgkin lymphoma

Angiogenesis is a prerequisite for solid tumor growth, but there is relatively limited data regarding Hodgkin lymphoma. The purpose of this study was to examine the immunohistochemical expression of angiogenic and proliferation markers in Hodgkin biopsies in relation to clinical parameters. Immunostaining was performed on 65 Hodgkin biopsies with vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 alpha (HIF-1 alpha), platelet-derived growth factor receptor alpha (PDGFR alpha), Ki-67, and p53. Microvessel density (MVD) was determined by CD31 staining. In all cases, neoplastic cells and reactive background cells were evaluated. The neoplastic population expressed VEGF in 48% of the cases, HIF-1 alpha in 54% of the cases, and PDGFR alpha in 95% of the cases. Both Ki-67 and p53 were positive in neoplastic cells in over 60% of the cases. The MVD had a median of 2.6/0.0625 mm(2) which was not different from normal lymph nodes. VEGF in the non-neoplastic compartment showed increased staining in Ann Arbor stage I-II versus III-IV. In conclusion, VEGF, HIF-1 alpha, and predominantly PDGFRa are expressed in neoplastic cells in the majority of Hodgkin lymphomas. As microvessel formation is not increased in Hodgkin, additional functions of these angiogenic molecules should be investigated. (C) 2008 Elsevier GmbH. All rights reserved