High-grade Invasive Breast Carcinomas Research Articles

Histologic subtyping affecting outcome of triple negative breast cancer: a large Sardinian population-based analysis

BackgroundTriple Negative breast cancer (TNBC) includes a heterogeneous group of tumors with different clinico-pathological features, molecular alterations and treatment responsivity. Our aim was to evaluate the clinico-pathological heterogeneity and prognostic significance of TNBC histologic variants, comparing “special types” to high-grade invasive breast carcinomas of no special type (IBC-NST).MethodsThis study was performed on data obtained from TNBC Database, including pathological features and clinical records of 1009 TNBCs patients diagnosed between 1994 and 2015 in the four most important Oncology Units located in different hospitals in Sardinia, Italy. Kaplan-Meier analysis, log-rank test and multivariate Cox proportional-hazards regression were applied for overall survival (OS) and disease free survival (DFS) according to TNBC histologic types.ResultsTNBC “special types” showed significant differences for several clinico-pathological features when compared to IBC-NST. We observed that in apocrine carcinomas as tumor size increased, the number of metastatic lymph nodes manifestly increased. Adenoid cystic carcinoma showed the smallest tumor size relative to IBC-NST. At five-year follow-up, OS was 92.1, 100.0, and 94.5% for patients with apocrine, adenoid cystic and medullary carcinoma, respectively; patients with lobular and metaplastic carcinoma showed the worst OS, with 79.7 and 84.3%, respectively. At ten-years, patients with adenoid cystic (100.0%) and medullary (94.5%) carcinoma showed a favourable prognosis, whereas patients with lobular carcinoma showed the worst prognosis (73.8%). TNBC medullary type was an independent prognostic factor for DFS compared to IBC-NST.ConclusionsOur study confirms that an accurate and reliable histopathologic definition of TNBC subtypes has a significant clinical utility and is effective in the therapeutic decision-making process, with the aim to develop innovative and personalized treatments.

Expression of calretinin in high-grade hormone receptor-negative invasive breast carcinomas: correlation with histological and molecular subtypes.

Calretinin expression has been reported in neoplasms arising in various organs, including the breast. We investigated the relationship of calretinin expression with different histological and molecular subtypes of invasive breast carcinomas (IBCs) and its prognostic significance in high-grade female hormone receptor-negative IBCs. A total of 196 cases of IBCs of different histological subtypes were analyzed for immunohistochemical expression of calretinin, human epidermal growth factor receptor 2 (HER2), basal-like (BL), apocrine, and proliferative markers and grouped in different molecular subtypes. We found significant morphological differences in the group of formally classified invasive ductal carcinoma of no special type (IDC-NST), which we further subdivided into two types (type I IDC-NST and type II IDC-NST) according to their morphology. Calretinin expression was found in 55.1% of the IBCs and was strongly associated with carcinoma with medullary features (P=0.014) and type II IDC-NST (P<0.001), while type I IDC-NST correlated (P<0.001) with a lack of calretinin expression. Among the molecular subtypes of IBC, calretinin expression was identified in a significant portion of BL breast cancers (BLBCs), while expression was poor in HER2-overexpressing and molecular-apocrine (MA) HER2-negative subtypes and even less in MA/HER2+ ones. Calretinin expression was significantly associated with high (≥50) Ki-67 (P=0.02), but not with parameters like age, tumor size, lymph node status, overall survival (OS), and disease-free survival. Calretinin expression is most common in high-grade IBCs with histological medullary features, type II IDC-NST and BL phenotype, and is associated with high neoplastic proliferative index.

Correlation between 3 T apparent diffusion coefficient values and grading of invasive breast carcinoma

PurposeThe aim of this study was to evaluate whether the apparent diffusion coefficient (ADC) provided by 3.0T (3T) magnetic resonance diffusion-weighted imaging (DWI) varied according to the grading of invasive breast carcinoma. Materials and methodsA total of 92 patients with 96 invasive breast cancer lesions were enrolled; all had undergone 3T magnetic resonance imaging (MRI) for local staging. All lesions were confirmed by histological analysis, and tumor grade was established according to the Nottingham Grading System (NGS). MRI included both dynamic contrast-enhanced and DWI sequences, and ADC value was calculated for each lesion. ADC values were compared with NGS classification using the Mann–Whitney U and the Kruskal–Wallis H tests. Grading was considered as a comprehensive prognostic factor, and Rho Spearman test was performed to determine correlation between grading and tumor size, hormonal receptor status, HER2 expression and Ki67 index. Pearson's Chi square test was carried out to compare grading with the other prognostic factors. ResultsADC values were significantly higher in G1 than in G3 tumors. No significant difference was observed when G1 and G3 were compared with G2. Tumor size, hormonal receptor status, HER2 expression and Ki67 index correlated significantly with grading but there was a significant difference only between G1 and G3 related to the ER and PR status, HER2 expression and Ki67 index. There was no statistically significant difference in lesion size between the two groups. ConclusionADC values obtained on 3T DWI correlated with low-grade (G1) and high-grade (G3) invasive breast carcinoma. 3T ADC may be a helpful tool for identifying high-grade invasive breast carcinoma.

Dual-Color Fluorescence In Situ Hybridization Reveals an Association of Chromosome 8q22 but Not 8p21 Imbalance with High Grade Invasive Breast Carcinoma

We previously reported molecular karyotype analysis of invasive breast tumour core needle biopsies by comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) (Walker et al, Genes Chromosomes Cancer, 2008 May;47(5):405-17). That study identified frequently recurring gains and losses involving chromosome bands 8q22 and 8p21, respectively. Moreover, these data highlighted an association between 8q22 gain and typically aggressive grade 3 tumors. Here we validate and extend our previous investigations through FISH analysis of tumor touch imprints prepared from excised breast tumor specimens. Compared to post-surgical tumor excisions, core needle biopsies are known to be histologically less precise when predicting tumor grade. Therefore investigating these chromosomal aberrations in tumor samples that offer more reliable pathological assessment is likely to give a better overall indication of association. A series of 60 breast tumors were screened for genomic copy number changes at 8q22 and 8p21 by dual-color FISH. Results confirm previous findings that 8p loss (39%) and 8q gain (74%) occur frequently in invasive breast cancer. Both absolute quantification of 8q22 gain across the sample cohort, and a separate relative assessment by 8q22:8p21 copy number ratio, showed that the incidence of 8q22 gain significantly increased with grade (p = 0.004, absolute and p = 0.02, relative). In contrast, no association was found between 8p21 loss and tumor grade. These findings support the notion that 8q22 is a region of interest for invasive breast cancer pathogenesis, potentially harboring one or more genes that, when amplified, precipitate the molecular events that define high tumor grade.

Increased shedding of soluble fragments of P‐cadherin in nipple aspirate fluids from women with breast cancer

Breast cancer, a worldwide disease with increasing incidence, develops from ductal/lobular epithelium. Nipple aspirate fluid (NAF), secreted from the breast ducts and lobules, can be analyzed to assess breast metabolic activity. P-cadherin is frequently over-expressed in high-grade invasive breast carcinomas and has been reported to be an enhancer of migration and invasion of breast cancer cells, being correlated with tumor aggressiveness. The present study analyzed the soluble fragment of P-cadherin in milk, NAF and matched plasma samples of healthy subjects and in women with precancer conditions and breast cancer. Soluble P-cadherin was detected in all plasma and milk samples, and in about 31.3% of NAF samples. The lowest levels of soluble P-cadherin were found in plasma, with no significant difference among NoCancer, PreCancer and Cancer patients. The highest concentration of soluble P-cadherin was detected in milk collected during the first trimester of lactation, significantly with respect to all NAF samples. There were significantly higher levels of soluble P-cadherin in NAF from Cancer patients than those in women with NoCancer and PreCancer (P < 0.0001). Although no significant difference was found between in situ and invasive breast cancer, soluble P-cadherin levels were found at high concentrations in c-erbB-2-positive tumors, showing a positive correlation with disease stage grouping and tumor grade, and an inverse relationship with estrogen/progesterone receptor status. High levels of the soluble fragment of P-cadherin in Cancer NAF suggest its possible release via proteolytic processing, favoring cancer cell detachment from breast duct, and suggesting that measuring soluble P-cadherin in NAF may improve the identification of women with increased breast cancer risk.

Association of chromosome band 8q22 copy number gain with high grade invasive breast carcinomas by assessment of core needle biopsies

Genetic analysis of breast tumor core needle biopsies may provide early diagnostic information that is useful to direct subsequent clinical management. We report metaphase comparative genomic hybridization (CGH) analysis of 42 core needle biopsies prospectively sampled from invasive ductal breast carcinomas of 41 patients, and show that recurrent chromosomal copy number changes are associated with histologically defined tumor features. As far as is known, this is the first time CGH profiles from diagnostic breast tumor core needle biopsies have been reported in association with pathological data in such detail. A comparison of Grade 1 (n = 7), Grade 2 (n = 16), and Grade 3 tumors (n = 19) revealed a chromosomal copy number gain involving 8q22 that was associated with higher grade (1/7 vs. 16/19, respectively) and therefore altered cell differentiation status. CGH results were validated using tumor touch imprints prepared from a subgroup from the same sample set (n = 18) by fluorescence in situ hybridization (FISH) and two probes selected from regions of interest within 8p21 and 8q22. Overall concordance between CGH and FISH for 8p21 and 8q22 imbalances was 9/18 (50%) and 12/18 (67%), respectively. When FISH and CGH data were combined, and tumors classified according to better defined resected tumor histology available for 34cases, 19/19 Grade 3 tumors showed 8q22 gain compared with 0/6 Grade 1 tumors and 4/9 Grade 2 tumors. Further comprehensive studies are required to verify the biological significance of this association and its potential to facilitate early clinicopathological assessment of breast cancer. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

Measurement of pharmacokinetic parameters in histologically graded invasive breast tumours using dynamic contrast-enhanced MRI

Dynamic contrast-enhanced MRI (DCE-MRI) has demonstrated high sensitivity for detection of breast cancer. Analysis of correlation between quantitative DCE-MRI findings and prognostic factors (such as histological tumour grade) is important for defining the role of this technique in the diagnosis of breast cancer as well as the monitoring of neoadjuvant therapies. This paper presents a practical clinical application of a quantitative pharmacokinetic model to study histologically confirmed and graded invasive human breast tumours. The hypothesis is that, given a documented difference in capillary permeability between benign and malignant breast tumours, a relationship between permeability-related DCE-MRI parameters and tumour aggressiveness persists within invasive breast carcinomas. In addition, it was hypothesized that pharmacokinetic parameters may demonstrate stronger correlation with prognostic factors than the more conventional black-box techniques, so a comparison was undertaken. Significant correlations were found between pharmacokinetic and black-box parameters in 59 invasive breast carcinomas. However, statistically significant variation with tumour grade was demonstrated in only two permeability-related pharmacokinetic parameters: k(ep) (p<0.05) and K(trans) (p<0.05), using one-way analysis of variance. Parameters k(ep) and K(trans) were significantly higher in Grade 3 tumours than in low-grade tumours. None of the measured DCE-MRI parameters varied significantly between Grade 1 and Grade 2 tumours. Measurement of k(ep) and K(trans) might therefore be used to monitor the effectiveness of neoadjuvant treatment of high-grade invasive breast carcinomas, but is unlikely to demonstrate remission in low-grade tumours.

P-cadherin expression in breast cancer: a review

P-cadherin is frequently over-expressed in high-grade invasive breast carcinomas and has been reported to be an enhancer of migration and invasion of breast cancer cells, being correlated with tumour aggressiveness. In addition, expression of P-cadherin is well established as an indicator of poor prognosis in human breast cancer, which has stimulated our interest in studying its role in this setting. This review describes the most important findings on P-cadherin expression and function in normal mammary tissue and breast cancer cells, emphasizing that further research is required to elucidate the role played by this protein in human mammary tumours.