Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival.

INTRODUCTION: Cytokeratin (CK) 14, one of several markers expressed in normal myoepithelial/basal cells, is also expressed in a proportion of breast carcinomas. Previous studies have suggested that expression of such 'basal' markers predicts different biological behaviour, with more frequent lung and brain metastases and poorer prognosis than other carcinomas. METHODS: We performed CK14 immunohistochemistry on 443 grade III invasive ductal carcinomas with extended clinical follow-up (mean 116 months), and we correlated CK14 immunopositivity (basal-like phenotype) with clinicopathological criteria. RESULTS: Eighty-eight of 443 (20%) tumours showed CK14 expression. CK14-positive tumours were more likely to be oestrogen receptor-negative (p < 0.0001) and axillary node-negative (p = 0.001) than were CK14-negative cases. CK14-positive cases developed less bone and liver metastases (hazard ratio [HR] 0.49, p = 0.01, and HR 0.53, p = 0.035, respectively) but more frequent brain metastases (HR 1.92, p = 0.051). In patients without metastatic disease, disease-free survival in CK14-positive cases was significantly better than in CK14-negative cases (HR 0.65, p = 0.005). In patients with metastatic disease, however, CK14 positivity was associated with a poorer prognosis (HR 1.84, p = 0.001). The overall survival in CK14-positive and -negative patients was similar at 5 years (60% and 59%, respectively), but the long-term survival was better in CK14-positive patients (HR 0.69, p = 0.02). CONCLUSION: These results demonstrate that basal-like tumours differ in their biological behaviour from other tumours, with a distinct pattern of metastatic spread. Compared to other grade III tumours, basal-like tumours appear to have a relatively good long-term survival but survival after metastases is poor.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

A Case Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic and Tractable Biomarkers in Male Breast Cancer

Purpose: Breast cancer (BC) affects both genders, but is understudied in men. Although still rare, male BC is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar. Experimental design: A transcriptomic investigation of male and female BC was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n=477, training; n=220, validation set) and quantified in pre- and post-treatment samples from a male BC patient receiving Everolimus and PI3K/mTOR inhibitor. Results: Gender-specific gene expression patterns were identified. eIF transcripts were up-regulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (Log rank; p=0.013; HR=1.77, 1.12-2.8 and p=0.035; HR=1.68, 1.03-2.74, respectively), or when co-expressed (p=0.01; HR=2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis (eIF4E p=0.016; HR 2.38 (1.18-4.8), eIF5 p=0.022; HR 2.55 (1.14-5.7); co-expression p=0.001; HR=7.04 (2.22-22.26)). Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/Everolimus, with extended survival. Conclusions: Translational initiation pathway inhibition could be of clinical utility in male BC patients overexpressing eIF4E and eIF5. With mTOR inhibitors which target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required

The effect of the stromal component of breast tumours on prediction of clinical outcome using gene expression microarray analysis

INTRODUCTION: The aim of this study was to examine the effect of the cellular composition of biopsies on the error rates of multigene predictors of response of breast tumours to neoadjuvant adriamycin and cyclophosphamide (AC) chemotherapy. MATERIALS AND METHODS: Core biopsies were taken from primary breast tumours of 43 patients prior to AC, and subsequent clinical response was recorded. Post-chemotherapy (day 21) samples were available for 16 of these samples. Frozen sections of each core were used to estimate the proportion of invasive cancer and other tissue components at three levels. Transcriptional profiling was performed using a cDNA array containing 4,600 elements. RESULTS: Twenty-three (53%) patients demonstrated a 'good' and 20 (47%) a 'poor' clinical response. The percentage invasive tumour in core biopsies collected from these patients varied markedly. Despite this, agglomerative clustering of sample expression profiles showed that almost all biopsies from the same tumour aggregated as nearest neighbours. SAM (significance analysis of microarrays) regression analysis identified 144 genes which distinguished high- and low-percentage invasive tumour biopsies at a false discovery rate of not more than 5%. The misclassification error of prediction of clinical response using microarray data from pre-treatment biopsies (on leave-one-out cross-validation) was 28%. When prediction was performed on subsets of samples which were more homogeneous in their proportions of malignant and stromal cells, the misclassification error was considerably lower (8%–13%, p < 0.05 on permutation). CONCLUSION: The non-tumour content of breast cancer samples has a significant effect on gene expression profiles. Consideration of this factor improves accuracy of response prediction by expression array profiling. Future gene expression array prediction studies should be planned taking this into account

Pathologic quiz case: A 93-year-old woman with an enlarged and tender left breast

[Excerpt] A 93-year-old woman presented with a gradual onset of an enlarging, tender, and erythematous left breast. She had no other relevant history. Clinical examination suggested an inflammatory carcinoma, along with an area of diffuse thickening in the upper outer quadrant. She underwent mammography, the results of which were unremarkable, followed by a core biopsy of the thickened area. Following this, she underwent a left mastectomy with axillary dissection. Macroscopically, the specimencomprised a disk of fibrofatty breast tissue, 150 3 80 3 50 mm, covered by a nipple-bearing ellipse of skin measuring 130 3 80 mm. On sectioning, the entire breast was diffusely pale and firm, with a more distinct irregular, firm area that measured 30 3 20 3 50 mm in the upper outer quadrant, close to the deep margin. [...]info:eu-repo/semantics/publishedVersio

Pathologic quiz case: a 62-year-old woman with a 4.5-cm nodule in the rigth breast

World Pathology Foundations - Gordon Signy Foreign Fellowship.Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BD/5386/2001

p63-driven nuclear accumulation of beta-catenin is not a frequent event in human neoplasms

DeltaN-p63 isoforms may act as oncogenes owing to their ability to bind to p53-reporter genes without inciting their transcription, thus blocking the p53-driven cell cycle arrest and apoptosis. A novel mechanism linking p63 and Wnt pathways has recently been proposed. Briefly, in vitro studies using squamous cell carcinoma cell lines have suggested that DeltaN-p63 may block the phosphorylation of beta-catenin, leading to its nuclear accumulation and triggering beta-catenin-responsive transcription of genes related to proliferation and oncogenic biological behavior. To test this new mechanism, the coexpression of DeltaN-p63 and beta-catenin was evaluated in a large cohort of human neoplasms