Robust Automated Tumour Segmentation on Histological and Immunohistochemical Tissue Images

Tissue microarray (TMA) is a high throughput analysis tool to identify new diagnostic and prognostic markers in human cancers. However, standard automated method in tumour detection on both routine histochemical and immunohistochemistry (IHC) images is under developed. This paper presents a robust automated tumour cell segmentation model which can be applied to both routine histochemical tissue slides and IHC slides and deal with finer pixel-based segmentation in comparison with blob or area based segmentation by existing approaches. The presented technique greatly improves the process of TMA construction and plays an important role in automated IHC quantification in biomarker analysis where excluding stroma areas is critical. With the finest pixel-based evaluation (instead of area-based or object-based), the experimental results show that the proposed method is able to achieve 80% accuracy and 78% accuracy in two different types of pathological virtual slides, i.e., routine histochemical H&E and IHC images, respectively. The presented technique greatly reduces labor-intensive workloads for pathologists and highly speeds up the process of TMA construction and provides a possibility for fully automated IHC quantification

MiR-34b is associated with clinical outcome in triple-negative breast cancer patients

<p>Abstract</p> <p>Background</p> <p>Breast cancer is the most common malignancy with the highest incidence rates among women worldwide. Triple-negative breast cancer (TNBC) represents the major phenotype of basal-like molecular subtype of breast cancer, characterized by higher incidence in young women and a very poor prognosis. MicroRNAs (miRNAs) are small non-coding RNAs playing significant role in the pathogenesis of many cancers including breast cancer. Therefore, miRNAs are also potential prognostic and/or predictive biomarkers in triple-negative breast cancer patients.</p> <p>Methods</p> <p>Thirty-nine TNBC patients with available formalin-fixed paraffin-embedded (FFPE) tissues were enrolled in the study. MiR-34a, miR-34b, and miR-34c were analyzed using qRT-PCR and correlated to clinico-pathological features of TNBC patients.</p> <p>Results</p> <p>Expression levels of miR-34b significantly correlate with disease free survival (DFS) (<it>p </it>= 0.0020, log-rank test) and overall survival (OS) (<it>p </it>= 0.0008, log-rank test) of TNBC patients. No other significant associations between miR-34a, miR-34b, and miR-34c with available clinical pathological data were observed.</p> <p>Conclusions</p> <p>MiR-34b expression negatively correlates with disease free survival and overall survival in TNBC patients. Thus, miR-34b may present a new promising prognostic biomarker in TNBC patients, but independent validations are necessary.</p

Failure patterns and survival outcomes in triple negative breast cancer (TNBC): a 15 year comparison of 448 non-Hispanic black and white women

Purpose: Triple negative breast cancer (TNBC) is a distinct subtype of breast cancer with unique pathologic, molecular and clinical behavior. It occurs more frequently in young blacks and has been reported to have a shorter disease-free interval. We undertook this study to analyze the demographic characteristics, failure patterns, and survival outcomes in this disease. Methods: A total of 448 non-Hispanic black and white women were identified over a 15 year period from 1996 to 2011. Demographic and clinical information including age, race, menopausal status, stage, tumor characteristics, and treatments were collected. Fisher’s exact test and multivariable Cox regression were used to compare failure patterns and survival outcomes between races. Results: 49 % (n = 223) were black. 59 % patients were between 41 and 60 years, with 18 % ≤40 years. 57 % were premenopausal and 89 % had grade 3 tumors. Stage II (47 %) was most frequent stage at diagnosis followed by stage III (28 %). 32 % had lymphovascular invasion. Adjusting for age, stage, and grade, there was no difference in survival outcomes (OS, DFS, LFFS, and DFFS) between the two races. 62 (14 %) patients failed locally either in ipsilateral breast or chest wall, and 19 (4 %) failed in the regional lymphatics. Lung (18 %) was the most frequent distant failure site with <12 % each failing in brain, liver and bones. Conclusion: Failure patterns and survival outcomes did not differ by race in this large collection of TNBC cases. Lung was the predominate site of distant failure followed by brain, bone, and liver. Few patients failed in the regional lymphatics

The Relevance of Breast Cancer Subtypes in the Outcome of Neoadjuvant Chemotherapy

BACKGROUND: Breast cancer is increasingly considered a heterogeneous disease. The aim of this study was to assess the differences between histological and receptor-based subtypes in breast-conserving surgery and pathological complete response (pCR) after neoadjuvant chemotherapy. METHOD: A consecutive series of 254 patients with operable breast cancer treated with neoadjuvant chemotherapy was analyzed. Tumors were classified according to their receptor status in estrogen receptor (ER)-positive tumors (HER2-negative), triple-negative tumors, and HER2-positive tumors. The type of surgery feasible prior to neoadjuvant chemotherapy was compared with the actual surgery performed. RESULTS: The overall increase in breast-conserving surgery was 37% (73 of 198). In patients with ductal and lobular carcinomas this increase was 41% (63 of 152, 95% confidence interval [95% CI] 0.34-0.49) and 20% (7 of 35, 95% CI 0.10-0.36), respectively (P = 0.02). Half of the patients with lobular carcinoma had to undergo a secondary mastectomy because of incomplete resection margins. In ER-positive, triple-negative and HER2-positive tumors, the increase in breast-conserving surgery was 39% (42 of 109, 95% CI 0.30-0.48), 24% (11 of 45, 95% CI 0.14-0.38), and 45% (20 of 44, 95% CI 0.32-0.60) (P = 0.11). The pCR rate in ductal and lobular carcinomas was 12% (23 of 195) and 2% (1 of 42), respectively (P = 0.09). In ER-positive, triple-negative and HER2-positive tumors the pCR rates were 2% (3 of 138), 28% (16 of 57), and 18% (10 of 56), respectively. Multivariate analysis showed that the receptor-based subtype was the only significant predictor of pCR (P = 0.004). CONCLUSION: In lobular tumors the benefit with regard to breast-conserving surgery of neoadjuvant chemotherapy is questionable. Although in ER-positive tumors the pCR rate is low, the increase in breast-conserving surgery was remarkable in ductal ER-positive tumor

Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours

The expression of additional genes, other than oestrogen receptor (ER), may be important to the hormone-responsive phenotype of breast cancer. Microarray analyses have revealed that forkhead box A1 (FOXA1) and GATA binding protein 3 (GATA-3) are expressed in close association with ERalpha, both encoding for transcription factors with a potential involvement in the ERalpha-mediated action in breast cancer. The purpose of this study was to explore if the expression of FOXA1 and GATA-3 may provide an opportunity to stratify subsets of patients that could have better outcome, among the ERalpha-negative/poor prognosis breast cancer group.The present study was supported by a research grant (SFRH/BD/15316/ 2005 to AA) financed by the Portuguese Science and Technology Foundation (FCT). The authors thank Prof. Raquel Seruca ( coordinator from the Cancer Genetics group at IPATIMUP) for scientific assistance, Dr Jose Luis Costa (postdoctorate at IPATIMUP) for critically reading the manuscript before submission, and Dr Nuno Marcos ( PhD student at IPATIMUP) for artwork assistance

ARRDC3 suppresses breast cancer progression by negatively regulating integrin β4

Large-scale genetic analyses of human tumor samples have been used to identify novel oncogenes, tumor suppressors and prognostic factors, but the functions and molecular interactions of many individual genes have not been determined. In this study we examined the cellular effects and molecular mechanism of the arrestin family member, ARRDC3, a gene preferentially lost in a subset of breast cancers. Oncomine data revealed that the expression of ARRDC3 decreases with tumor grade, metastases and recurrences. ARRDC3 overexpression represses cancer cell proliferation, migration, invasion, growth in soft agar and in vivo tumorigenicity, whereas downregulation of ARRCD3 has the opposite effects. Mechanistic studies showed that ARRDC3 functions in a novel regulatory pathway that controls the cell surface adhesion molecule, β-4 integrin (ITGβ4), a protein associated with aggressive tumor behavior. Our data indicates ARRDC3 directly binds to a phosphorylated form of ITGβ4 leading to its internalization, ubiquitination and ultimate degradation. The results identify the ARRCD3-ITGβ4 pathway as a new therapeutic target in breast cancer and show the importance of connecting genetic arrays with mechanistic studies in the search for new treatments

The Met oncogene and basal-like breast cancer: another culprit to watch out for?

Recent findings suggest the involvement of the MET oncogene, encoding the tyrosine kinase receptor for hepatocyte growth factor, in the onset and progression of basal-like breast carcinoma. The expression profiles of basal-like tumors - but not those of other breast cancer subtypes - are enriched for gene sets that are coordinately over-represented in transcriptional signatures regulated by Met. Consistently, tissue microarray analyses have revealed that Met immunoreactivity is much higher in basal-like cases of human breast cancer than in other tumor types. Finally, mouse models expressing mutationally activated forms of Met develop a high incidence of mammary tumors, some of which exhibit basal characteristics. The present review summarizes current knowledge on the role and activity of Met in basal-like breast cancer, with a special emphasis on the correlation between this tumor subtype and the cellular hierarchy of the normal mammary gland