Sporadic invasive breast carcinomas with medullary features display a basal-like phenotype - An immunohistochemical and gene amplification study
ABSTRACT It is not clear whether invasive breast carcinomas with medullary features (IBCMFs, atypical medullary carcinomas) constitute a specific phenotype of breast cancer that is of biologic significance. Because medullary features are common in BRCA1-associated carcinomas and these tumors frequently show a basal-like phenotype, we examined whether IBCMFs expressed basal/myoepithelial markers and had a basal-like phenotype. We studied the immunohistochemical expression of 15 markers in tissue microarrays containing samples from 35 IBCMFs and 39 grade 3 invasive ductal carcinomas (IDCG3s) of no special type. In addition, we analyzed EGFR, C-MYC, and CCNE gene amplification by fluorescence in situ hybridization, because the expression of these genes is known to be associated with the basal-like phenotype. We defined the basal-like phenotype according to the criteria of Nielsen et al as being those tumors that were ER/HER2-negative and cytokeratin (CK) 5/6- and/or epidermal growth factor receptor-positive. IBCMFs were more frequently hormone receptor- and HER2-negative, but had greater expression of proliferation markers and p53. In addition, IBCMFs more frequently expressed basal/myoepithelial markers, such as CK5/6 and P-cadherin. A basal-like phenotype was found in 62.9% of IBCMFs but in only 18.9% of IDCG3s. No differences in gene amplification were found between IBCMFs and IDCG3s, although C-MYC amplification was more common in tumors without a basal-like phenotype. The identification of IBCMF as an independent group of tumors could be of clinical significance, given the high incidence of cases with a basal-like phenotype, which is a group of tumors with different prognosis and chemotherapy response from those of IDCG3s of no special type.
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ABSTRACT: Recent publications of breast cancer classification based on gene expression profile analyses indicate that medullary breast carcinomas (MBC) may be considered part of the basal-like carcinoma spectrum made up of ER-negative, PR-negative and HER-2-negative cells ("triple-negative phenotype"). On the other hand, there are also data showing that a proportion of MBC and atypical MBC (AMBC) is ER, PR and/or HER-2 positive. Therefore, we have decided to immunohistochemically analyze ER, PR, HER-2 and basal/myoepithelial markers CK 5/6, p63 and EGFR expression in our archival paraffin-embedded MBC and AMBC samples from 48 patients. Immunohistochemical evaluation of samples which were derived from patients operated on at our two hospitals between 1999 and 2005. Typical MBC was found in 39 patients and AMBC in 9 patients. The patients ranged in age from 32 to 84 years (median 55). Modified radical mastectomy with axillary dissection was performed in 30/48 patients (63%) while breast segmentectomy with axillary dissection was performed in 18/48 patients (37%). Metastases in axillary lymph nodes were observed in 15/48 patients (31%). ER positivity was present in 3/48 patients (6%), PR positivity in 8/48 (17%), and a positive HER-2 reaction was present in 14/48 patients (29%). CK 5/6 was positive in 20/48, p63 in 24/48 and EGFR in 8/48 patients. Adjuvant therapy was applied in all but 2 patients. Alive were 45/48 (94%) of patients. With the exception of PR expression, 39 patients with typical MBC and 9 patients with AMBC were comparable in the analyzed parameters. Positive HER-2 antigen expression in the analyzed sample was not found to be associated to a statistically significant degree with the MBC or AMBC histological tumor type, tumor size, axillary lymph node metastases, ER and PR status nor with patient survival. The data from our study seem to be generally comparable with the relatively scarce published data on clinicopathological parameters of MBC and AMBC.Tumori 94(6):838-44. · 1.09 Impact Factor
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ABSTRACT: Advances in the analysis of expression profiles, using genomic techniques, have revealed the high heterogeneity present in breast cancers. These approaches have served to identify different breast cancer subgroups with specific molecular characteristics that could sub-classify these tumours as carcinomas expressing hormone receptors, denominated Luminal subtype, and tumours with negative expression of hormone receptors, the Basal and HER2+ phenotypes. Therefore, during recent years, identification of markers characteristic of each subtype has been the focus of many research groups. All of these breast tumour subtypes probably have specific clinical and morphological features; however, this hypothesis needs to be confirmed by analysing more homogenous series. Although this “new” classification has limitations, it could be useful in the clinical practice, allowing not only a more accurate prognosis in breast cancer patients but also a selective treatment for each predefined subtype.Clinical and Translational Oncology 12/2008; 10(12):777-785. DOI:10.1007/s12094-008-0290-x · 1.60 Impact Factor
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ABSTRACT: Breast cancers arising in carriers of germline BRCA1 mutations frequently have a basal-like phenotype. Basal-like cancers are characterized by high histological grade, central necrotic areas, foci with metaplastic differentiation, lack of hormone receptor and HER2 (ErbB2) expression, and consistent positivity for basal markers, including CK5/6, CK14, and EGFR. We have used germline manipulation to generate a conditional mouse model of Brca1 deficiency. Transgenic expression of Cre recombinase in the mammary gland of these mice results in deletion of exons encoding the C-terminus of Brca1 and leads to tumour formation when combined with heterozygosity for a p53 mutation. Histologically, these mammary gland tumours were characterized by high histological grade, central necrotic areas, and presence of homologous metaplastic elements. These metaplastic elements consisted of neoplastic spindle cells or squamous cell differentiation in the form of keratin pearls or individual cell keratinization. Immunohistochemical analysis revealed expression of basal-like markers in all cases. The tumour phenotype generated in our mouse model was compared with published data on human basal-like breast carcinomas and also with metaplastic breast cancers with a basal-like phenotype; the comparison showed that we have generated a mouse model of basal-like breast cancer, which should prove useful in testing new and targeted treatments for this type of breast cancer.The Journal of Pathology 03/2007; 211(4):389-98. DOI:10.1002/path.2124 · 7.33 Impact Factor