Breast Neoplasms: Vyberg M

Yaziji H, Taylor CR, Goldstein NS, Dabbs DJ, Hammond EH, Hewlett B, Floyd AD, Barry TS, Martin AW, Badve S, Baehner F, Cartun RW, Eisen RN, Swanson PE, Hewitt SM, Vyberg M, Hicks DG, Anonymous00020. · Vitro Molecular Laboratories, Miami, FL daggerKeck School of Medicine, University of Southern California, Los Angeles, USA. · Appl Immunohistochem Mol Morphol. · Pubmed #18931614 No free full text.

Abstract: Estrogen receptor (ER) status in breast cancer is currently the most important predictive biomarker that determines breast cancer prognosis after treatment with endocrine therapy. Although immunohistochemistry has been widely viewed as the gold standard methodology for ER testing in breast cancer, lack of standardized procedures, and lack of regulatory adherence to testing guidelines has resulted in high rates of "false-negative" results worldwide. Standardized testing is only possible after all aspects of ER testing--preanalytical, analytical, and postanalytical, have been closely controlled. A meeting of the "ad-hoc committee" of expert pathologists, technologists, and scientists, representing academic centers, reference laboratories, and various agencies, issued standardization testing recommendations, aimed at optimization of clinical ER testing environment, as a step toward improved standardized testing.

Worrillow LJ, Smith AG, Scott K, Andersson M, Ashcroft AJ, Dores GM, Glimelius B, Holowaty E, Jackson GH, Jones GL, Lynch CF, Morgan G, Pukkala E, Scott D, Storm HH, Taylor PR, Vyberg M, Willett E, Travis LB, Allan JM. · Department of Biology, University of York, Heslington, York, UK. · J Med Genet. · Pubmed #17959715 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy. METHODS: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. RESULTS: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent. CONCLUSIONS: These data support the hypothesis that the common polymorphism at position -93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.

Konstantinovsky S, Nielsen S, Vyberg M, Kvalheim G, Nesland JM, Reich R, Davidson B. · Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. · Breast Cancer Res Treat. · Pubmed #16142438 No free full text.

Abstract: The objective of this study was to analyze site-related expression of angiogenic molecules in breast carcinoma, with the aim of characterizing phenotypic alterations along the clinical progression from primary tumor to pleural effusion. A total of 49 malignant pleural effusions and 68 corresponding solid tumors were studied for protein and mRNA expression of vascular endothelial growth factor (VEGF) and its receptor KDR, interleukin-8 (IL-8), basic fibroblast growth factor (bFGF) and the alphaV integrin subunit using immunohistochemistry, mRNA in situ hybridization (ISH) and reverse transcription polymerase chain reaction (RT-PCR). Expression was analyzed for possible association with mRNA expression of the Ets-1 and PEA3 transcription factors. The predictive value of angiogenic molecules, PEA3 and Ets-1, and clinical parameters was analyzed for 18 patients. ISH showed the presence of VEGF, IL-8 and bFGF mRNA in the majority of specimens, irrespective of anatomic site (p > 0.05). However, protein expression of IL-8 and bFGF was lower in effusions compared to primary tumors (p = 0.001 for IL-8, p < 0.001 for bFGF). Expression of alphaV integrin showed an opposite change, with higher level in effusions compared to primary tumors (p = 0.03). bFGF and alphaV integrin expression in effusions was also altered compared to lymph node metastases (p = 0.041 and p = 0.016, respectively). IL-8 and Ets-1 (p = 0.035) and VEGF and PEA3 (p = 0.026) mRNA was co-expressed in effusions. In univariate survival analysis, bFGF protein expression in effusions (p = 0.015), PEA3 mRNA expression in primary tumors (p = 0.02) and previous radiation therapy (p = 0.034) predicted shorter disease-free survival. PEA mRNA expression in primary tumors (p = 0.002) and previous chemotherapy (p = 0.048) predicted poor overall survival, with a similar trend for advanced disease stage at diagnosis (p = 0.05). Our data provide evidence regarding molecular changes that occur along the progression of breast carcinoma from primary tumor to effusion, and suggest altered requirement of angiogenic factors in body cavities. The poor disease-free survival for patients with bFGF-positive effusions suggests a role for this growth factor in mediating tumor survival rather than angiogenesis at this site.

Lynge E, Afonso N, Kaerlev L, Olsen J, Sabroe S, Ahrens W, Eriksson M, Guénel P, Merletti F, Stengrevics A, Suarez-Varela M, Costa-Pererra A, Vyberg M. · Institute of Public Health, University of Copenhagen, Blegdamsvej 3, DK 2200 København N, Denmark. · Eur J Cancer. · Pubmed #15737566 No free full text.

Abstract: To search for occupational risk factors, we conducted a case-control study in nine European countries of cancers of the small intestine, male gall bladder, thymus, bone, male breast, melanoma of the eye, and mycosis fungoides. Recruitment was population based in Denmark, Latvia, France, Germany, Italy, and Sweden, from hospital areas in Spain and Portugal, and from one United Kingdom (UK) hospital. We recruited 1457 cases (84% interviewed). Numbers identified corresponded to those in the EUROCIM database for Denmark, but were below those observed for France, Italy and Sweden in the database. We recruited 3374 population (61% interviewed) and 1284 colon cancer controls (86% interviewed). It was possible to undertake this complicated study across Europe, but we encountered three main problems. It was difficult to ensure complete case ascertainment, for population controls, we found a clear divide in the response rate from 75% in the South to only 55% in the North, and a somewhat selective recruitment was noted for the colon cancer controls. The study showed there is a clear dose-response relationship between alcohol intake and the risk of male breast cancer, and an excess risk of mycosis fungoides among glass formers, pottery and ceramic workers. Further data are expected.

Davidson B, Konstantinovsky S, Nielsen S, Dong HP, Berner A, Vyberg M, Reich R. · Department of Pathology, The Norwegian Radium Hospital, Montebello, University of Oslo, Oslo, Norway. · Clin Cancer Res. · Pubmed #15534110 links to  free full text

Abstract: PURPOSE: The aim of this study was to characterize phenotypic alterations along the progression of breast carcinoma from primary tumor to pleural effusion through analysis of the expression of proteases, laminin receptors (LRs), and transcription factors involved in invasion and metastasis. EXPERIMENTAL DESIGN: The material studied consisted of 60 malignant pleural effusions from breast cancer patients and 68 corresponding solid tumors (37 primary and 31 metastatic tumors). Expression of matrix metalloproteinases [MMPs (MMP-1, MMP-2, MMP-9, and MMP-14)], the MMP inhibitor tissue inhibitor of metalloproteinase-2, the MMP inducer EMMPRIN, the 67-kDa LR, the alpha6 integrin subunit, and the transcription factors AP-2, Ets-1, and PEA3 was studied using immunohistochemistry, mRNA in situ hybridization, reverse transcription-polymerase chain reaction, zymography, and flow cytometry. Hormone receptor (estrogen receptor and progesterone receptor) status and c-erbB-2 status were also studied. RESULTS: Significantly reduced estrogen receptor (P < 0.001) and progesterone receptor (P = 0.001) expression was seen in effusions compared with primary tumors, with opposite findings for c-erbB-2 (P = 0.003). Tumor cell MMP-2 protein expression in effusions was higher than that in primary tumors (P < 0.001) and lymph node metastases (P = 0.01). In situ hybridization demonstrated higher MMP-2 (P = 0.007), PEA3 (P = 0.038), and EMMPRIN (P = 0.026) mRNA expression in effusions. The time to progression from primary tumor to effusion was significantly shorter for patients whose primary tumors expressed MMP-1 (P = 0.016) and who expressed the 67-kDa LR protein in primary tumor (P = 0.007) and effusion (P = 0.015). CONCLUSIONS: Our data provide documented evidence of molecular events that occur during the progression of breast carcinoma from primary tumor to effusion. The coordinated up-regulation of MMP-2 and Ets transcription factors in carcinoma cells in effusions is in full agreement with our previous reports linking these factors to poor prognosis in ovarian cancer. The rapid progression to effusion in cases showing MMP-1 and 67-kDa LR expression in primary tumor cells links aggressive clinical behavior with expression of metastasis-associated molecules in this setting.

Cox G, Vyberg M, Melgaard B, Askaa J, Oster A, O'Byrne KJ. · Department of Medical Oncology, Leicester Royal Infirmary, Leicester, United Kingdom. · Int J Cancer. · Pubmed #11304680 No free full text.

Abstract: HER2 is an erbB/HER type 1 tyrosine kinase receptor that is frequently over-expressed in malignant epithelial tumours. Herceptin, a humanised mouse monoclonal antibody to HER2, is proven therapeutically in the management of metastatic breast cancer, significantly prolonging survival when combined with cytotoxic chemotherapeutic agents. Immunohistochemical studies suggest that non-small-cell lung cancer (NSCLC) tumours may over-express HER2. Our aim was to evaluate HER2 gene amplification and semi-quantitative immuno-expression in NSCLC. A total of 344 NSCLC cases were immunostained for HER2 expression in 2 centres using the HercepTest. Fluorescence in situ hybridisation (FISH) analysis for HER2 gene amplification was performed on most positive cases and a subset of negative cases. Fifteen cases (4.3%) demonstrated 2+ or 3+ membranous HER2 immuno-expression. There was no correlation between immuno-expression and tumour histology or grade. Tumours from higher-stage disease were more often HercepTest-positive (p < 0.001). All 4 HercepTest 3+ cases demonstrated gene amplification. One of the 5 2+ cases tested for gene amplification showed areas of borderline amplification and areas of polyploidy. None of the 19 HercepTest-negative cases demonstrated gene amplification or polyploidy (p < 0.001). Gene amplification was demonstrated in all HercepTest 3+ scoring NSCLC cases. Unlike breast cancer, gene amplification and HER2 protein over-expression assessed by the HercepTest appeared to be uncommon in NSCLC. Herceptin may therefore target only a small proportion of NSCLC tumours and be of limited clinical value in this disease, particularly in the adjuvant setting.