Invasive Ductal Breast Cancer Patients Research Articles

Impact of gene polymorphism of TNF-α rs 1800629 and TNF-β rs 909253 on plasma levels of South Indian breast cancer patients.

Inflammation plays a lead role in the tumor microenvironment and promotes metastasis. Single-nucleotide polymorphism (SNP) in the tumor necrosis factor (TNF) gene locus may alter the expression of genes and proteins. The objective of the study is to find the distribution of genetic polymorphism in the sites of TNF-α -308G>A and TNF- β +252A>G in breast cancer and evaluate polymorphism effects on plasma levels. The study group consisted of 109 invasive ductal primary breast cancer patients and 75 age-matched healthy female controls. Plasma cytokine concentrations were measured by the MILLIPLEX® MAP Human Cytokine/Chemokine Panel magnetic bead kits. The genotyping procedure for SNP included allele-specific polymerase chain reaction for TNFα and restriction fragment length polymorphism for TNFβ. Odds ratio with 95% confidence interval showed that these polymorphisms were not a causative risk factor, and both polymorphisms were consistent with Hardy-Weinberg equilibrium. Plasma TNFα and TNFβ median concentrations were significantly higher in cases when compared to controls (P < 0.01). When plasma TNFα levels were grouped under polymorphic subtypes, patients with mutant TNF- α -308A allele showed significantly higher values (P < 0.001). In addition, plasma TNFα values were significantly elevated in mutant TNF-β +252G allele (P < 0.01). This study demonstrated that there is no significant association between SNPs and breast cancer susceptibility in South Indian population. However, plasma TNFα level is significantly elevated with mutant-recessive TNF-α -308 A and TNF-β +252 G alleles of patients.

MicroRNA-200, associated with metastatic breast cancer, promotes traits of mammary luminal progenitor cells.

MicroRNAs are critical regulators of gene networks in normal and abnormal biological processes. Focusing on invasive ductal breast cancer (IDC), we have found dysregulated expression in tumor samples of several microRNAs, including the miR-200 family, along progression from primary tumors to distant metastases, further reflected in higher blood levels of miR-200b and miR-7 in IDC patients with regional or distant metastases relative to patients with primary node-negative tumors. Forced expression of miR-200s in MCF10CA1h mammary cells induced an enhanced epithelial program, aldehyde dehydrogenase (ALDH) activity, mammosphere growth and ability to form branched tubuloalveolar structures while promoting orthotopic tumor growth and lung colonization in vivo. MiR-200s also induced the constitutive activation of the PI3K-Akt signaling through downregulation of PTEN, and the enhanced mammosphere growth and ALDH activity induced in MCF10CA1h cells by miR-200s required the activation of this signaling pathway. Interestingly, the morphology of tumors formed in vivo by cells expressing miR-200s was reminiscent of metaplastic breast cancer (MBC). Indeed, the epithelial components of MBC samples expressed significantly higher levels of miR-200s than their mesenchymal components and displayed a marker profile compatible with luminal progenitor cells. We propose that microRNAs of the miR-200 family promote traits of highly proliferative breast luminal progenitor cells, thereby exacerbating the growth and metastatic properties of transformed mammary epithelial cells.

T-cell immunoglobulin mucin-3 expression in invasive ductal breast carcinoma: Clinicopathological correlations and association with tumor infiltration by cytotoxic lymphocytes.

As a negative regulatory molecule, T-cell immunoglobulin and mucin domain-3 (Tim-3) is closely associated with tumor immunological tolerance. The aim of this study was to investigate Tim-3 expression in invasive ductal breast cancer (IDC), its effect on clinicopathological parameters and its association with cytotoxic lymphocyte infiltration. Tim-3 protein expression was measured in 150 paraffin-embedded IDC specimens and 100 paired normal breast tissue specimens by immunohistochemistry. It was demonstrated that the infiltration of the tumor by CD8+ T cells was significantly higher compared with that of normal tissue, and the Tim-3 expression on CD8+ T cells was higher in IDC tissue compared with that in normal tissue; the differences were statistically significant (both P-values=0.000). The median expression level of Tim-3 on tumor cells was significantly associated with clinicopathological parameters such as age, axillary lymph node metastasis and TNM stage (P=0.015, 0.001 and 0.027, respectively). The expression of Tim-3 on CD8+ T cells was correlated with lymph node metastasis, World Health Organization (WHO) grade and molecular classification (P=0.000, 0.004 and 0.000, respectively). Additionally, the number of tumor-infiltrating CD8+ T cells was associated with primary tumor size, lymph node metastasis, WHO grade, Ki-67 and molecular classification (P=0.017, 0.002, 0.007, 0.003 and 0.000, respectively). Thus, Tim-3 may promote the development and progression of breast cancer and affect the tumor microenvironment; thus, it may be used as an independent prognostic factor for IDC patients.

Predictive Value of 18F-FDG PET/CT for Axillary Lymph Node Metastasis in Invasive Ductal Breast Cancer.

This study assessed whether primary tumor maximum standardized uptake value (pSUVmax) measured by 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) could improve the prediction of axillary lymph node (ALN) metastasis in invasive ductal breast cancer (IDC). In this study, 128 IDC patients who underwent pretreatment 18F-FDG PET/CT and surgical resection of primary tumor with sentinel lymph node biopsy, ALN dissection, or both were analyzed. All the patients were classified as five molecular subtypes. The optimal cutoff values of pSUVmax for all the patients and each molecular subtype for the prediction of ALN metastasis were determined using receiver operating characteristic (ROC) analysis. Furthermore, the prognostic accuracy of ALN metastasis was assessed using c-statistics. The findings showed ALN metastasis in 52 patients (40.6%). The 18F-FDG PET/CT procedure had a sensitivity of 48.1% and a specificity of 94.7% for ALN metastasis. In the ROC analysis of pSUVmax for ALN metastasis, the optimal cutoff value was 3.9 for all the patients, 2.8 for the luminal A subtype, 3.3 for the luminal B (human epidermal growth factor receptor 2 [HER2]-negative) subtype, 5.3 for the luminal B (HER2-positive) subtype, 12.7 for the HER2-positive subtype, and 11.5 for the triple-negative subtype. A predictive ALN metastasis model using nodal 18F-FDG uptake finding gave a c-statistic of 0.714, and a model combination of nodal 18F-FDG uptake finding with pSUVmax of all the patients gave a c-statistic of 0.736 (P=0.3926). However, the combination of nodal the 18F-FDG uptake finding with the pSUVmax of each molecular subtype gave a c-statistic of 0.791 (P=0.0047). Combining the pSUVmax of each molecular subtype with the nodal 18F-FDG uptake finding can improve the prediction of ALN metastasis in IDC.

PET/MR in invasive ductal breast cancer: correlation between imaging markers and histological phenotype

Background:Differences in genetics and receptor expression (phenotypes) of invasive ductal breast cancer (IDC) impact on prognosis and treatment response. Immunohistochemistry (IHC), the most used technique for IDC phenotyping, has some limitations including its invasiveness. We explored the possibility of contrast-enhanced positron emission tomography magnetic resonance (CE-FDG PET/MR) to discriminate IDC phenotypes.Methods:21 IDC patients with IHC assessment of oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor-2 (HER2), and antigen Ki-67 (Ki67) underwent CE-FDG PET/MR. Magnetic resonance-perfusion biomarkers, apparent diffusion coefficient (ADC), and standard uptake value (SUV) were compared with IHC markers and phenotypes, using a Student’s t-test and one-way ANOVA.Results:ER/PR− tumours demonstrated higher Kepmean and SUVmax than ER or PR+ tumours. HER2− tumours displayed higher ADCmean, Kepmean, and SUVmax than HER2+tumours. Only ADCmean discriminated Ki67⩽14% tumours (lower ADCmean) from Ki67>14% tumours. PET/MR biomarkers correlated with IHC phenotype in 13 out of 21 patients (62%; P=0.001).Conclusions:Positron emission tomography magnetic resonance might non-invasively help discriminate IDC phenotypes, helping to optimise individual therapy options.

Value of volume-based metabolic parameters for predicting survival in breast cancer patients treated with neoadjuvant chemotherapy

We evaluated the role of metabolic parameters in the prediction of disease recurrence in operable invasive ductal breast cancer patients treated with neoadjuvant chemotherapy (NAC).We retrospectively evaluated 139 female patients (mean age, 46.5 years; range: 27–72 years) with invasive ductal breast cancer, treated with NAC followed by surgery. All patients underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography and magnetic resonance imaging at baseline and after completion of NAC before surgery. The prognostic significance of clinicopathological and imaging parameters for disease-free survival (DFS) was evaluated.Recurrence of cancer was detected in 31 of 139 patients (22.3%; follow-up period: 6–82 months). Baseline maximum standardized uptake value, metabolic tumor volume (MTV), and reduction rate (RR) of MTV after NAC were significant independent prognostic factors for DFS in a multivariate analysis (all P < 0.05). The survival functions differed significantly between low and high histological grades (P < 0.001). DFS of the patients with high baseline MTV (≥5.23 cm3) was significantly poorer than that of low MTV patients (P = 0.019). The survival function of the group with low RR of MTV after NAC (≤90.72%) was poorer than the higher RR of the MTV group (P = 0.008).Our findings suggest that breast cancer patients who have a high histological grade, large baseline MTV, or a small RR of MTV after NAC should receive great attention to check for possible recurrence.

Survival of breast cancer patients according to changes in expression of selected markers between primary tumor and lymph node metastases.

The differences between primary and metastatic tumor cells might be important for treatment selection and prognostication. Expression of ER, PR, HER2, CK5/6, EGFR, Ki-67, Ep-CAM, P-cadherin, CD24, CD44, ALDH was assessed immunohistochemically in primary tumor (T) and corresponding synchronous nodal metastases (LNM) in 156 invasive ductal breast cancer patients (T ≥1, N ≥1, M0). Independent negative prognostic factors for disease-free survival were pN3, ALDH immunopositivity in LNM, nonluminal A subtype in LNM, reduction of Ep-CAM expression in LNM, lack of changes or enhancement of CK5/6 and ALDH expression in LNM. Our results suggest that in some cases expression of markers in lymph node metastases might bring additional prognostic information to that obtained from primary tumor.

Relationship between erb-B2 mRNA Expression in Blood and Tissue of Invasive Ductal Carcinoma Breast Cancer Patients and Clinicopathological Characteristics of the Tumors.

Molecular detection methods such as RT-PCR for detecting breast cancer-associated gene expression in the peripheral blood have the potential to modify breast cancer (BC) staging and therapy. In this regard, we evaluated the potential of erb-B2 molecular marker in BC detection and analyzed the expression of erb-B2 mRNA in the peripheral blood and fresh tissue samples of 50 pretreated female BC patients and 50 healthy females by reverse transcription-PCR (RT-PCR) method. We also assessed the correlation of erb-B2 mRNA marker positivity in peripheral blood and tumor tissue samples with clinical and pathological factors in BC patients in order to evaluate its prognostic value. It was shown that there is a significant difference between healthy females and BC patients with expression of the erb-B2 molecular marker (p<0.01). A significant difference between the expression of erb-B2 in the peripheral blood and tissue samples of BC patients (p<0.01) and the frequency of circulating erb-B2 mRNA expression in peripheral blood and in tissue was detected by RT-PCR. No correlation was found between erb-B2 mRNA expression in blood or tumor tissue samples and lymph node, tumor grade, tumor stage, tumor size, patient's age, ki67, estrogen receptor (ER), progesterone receptor (PGR), P53, and HER-2 status. However, in a small subset of 31 BC patients we found that expression of erb-B2 in peripheral blood or in both peripheral blood and tumor tissue was directly correlated with lympho-vascular invasion and perineural invasion as poor prognostic features. The highest rates of erb-B2 expression in peripheral blood or tumor tissue were in the ER and PR negative and HER-2 positive group. This study suggests that the application of the RT-PCR and immunohistochemical methods for erb-B2 molecular marker detection would provide a higher detection rate, especially in early stage BC.

The organochlorine pesticides residues in the invasive ductal breast cancer patients.

Investigation of organochlorine pesticides residues (important environmental contamination causing malignant transformation) in breast cancer patients is valuable to understanding their roles in breast cancer. 75 invasive ductal carcinoma (IDC) patients were enrolled with control of 79 benign breast diseases patients and control of 80 healthy women. Morning fasting blood specimens and adipose tissue specimens beside the primary lesion were detected with gas chromatograph. In blood specimens, both levels of β-HCH and PCTA were higher in IDC than those in both controls (both p<0.05), and increasingly higher among the three IDC degrees. In adipose tissue specimens, all levels of β-HCH, PCTA and pp'-DDE were higher in IDC than those in control (all p<0.05) and increasingly higher among three IDC degrees. The levels of β-HCH, PCTA in both blood specimens and adipose tissue specimens were higher in estrogen receptor (ER) positive IDC than those in ER negative IDC (all p<0.05). The higher level of organochlorine pesticides residues in blood and adipose tissue specimens of IDC infers its association with IDC, but the details remains to reveal, and this study may helpful in this field.

Relation between Ki-67, ER, PR, Her2/neu, p21, EGFR, and TOP II-α expression in invasive ductal breast cancer patients and correlations with prognosis.

The aim of the present study was to investigate the expression of the transcription factor Ki-67, ER, PR, Her2/neu, p21, EGFR, and TOP II-α in the tumor tissue of patients with invasive ductal carcinoma(IDC); in addition, we examined correlations between these markers. Two hundred and sixteen IDC patients, who were not previously been treated with chemo- or radiotherapy, were included in the study. All tumors were grade I-III. Expression of molecular markers was determined by immunohistochemical analysis on paraffin-embedded tissue sections. Follow-up data were collected for 3 months to 10 years and analyzed for tumor recurrence, survival time, and prognostic risk factors. We determined Ki-67 expression correlates with the expression of ER, PR, HER-2, EGFR, and TOP-α, as well as lymph node involvement, high tumor grade, lymphovascular invasion, high tumor stage, and high TNM stage in IDC. Positive Ki-67 expression was a risk factor for rapid tumor recurrence and may help tumor progression, leading to poor prognosis in IDC. Ki-67 was directly correlated with EGFR, TOP II-α, lymph node involvement, high tumor grade, lymphovascular invasion, high tumor stage, and high TNM stage in the hormone receptor subtypes of breast cancer. In triple negative breast cancer, Ki-67 correlated with TOP II-α. Expression of Ki-67 correlated with that of ER, PR, HER-2, EGFR, TOP II-α, and p21. In addition, the biomarker Ki-67 has a role as a prognostic factor and indicates a poor prognosis in IDC.

Prospective trial of breast MRI versus 2D and 3D ultrasound for evaluation of response to neoadjuvant chemotherapy.

Preoperative imaging to assess response to neoadjuvant chemotherapy in breast cancer is routine but no single imaging modality is standard of practice. Our hypothesis is that ultrasound (US) is comparable to magnetic resonance imaging (MRI) in the prediction of residual disease. A single-institution, Institutional Review Board-approved prospective trial of primary invasive ductal breast cancer patients receiving neoadjuvant chemotherapy enrolled women from 2008 to 2012. Two-dimensional (2D) and three-dimensional (3D) US, as well as MRI images of pre- and post-neoadjuvant tumors were obtained. Skin involvement or inadequate images were excluded. Residual tumor on imaging was compared with surgical pathology. Differences of tumor volume on imaging and pathology were compared using the non-parametric Wilcoxon signed-rank test. US to MRI agreement was determined by the kappa coefficient. Tumor volumes in estrogen receptor (ER), progesterone receptor (PR), and Her2neu subgroups were compared using the Kruskal-Wallis test. ER/PR staining <5 % was considered negative; Her2neu status was determined by in situ hybridization. Forty-two patients were enrolled in the study; 39 had evaluable post-treatment data. Four patients were Her2neu positive, and 17 (46 %) patients had triple-negative tumors. Among 11 (28 %) patients with pathologic complete response (pCR), US correctly predicted pCR in six (54.5 %) patients compared with eight (72.7 %) patients when MRI was used. This is a substantial agreement between US and MRI in predicting pCR (kappa = 0.62). There was no difference between 2D and 3D US modalities. For the 39 patients, US and MRI had no significant difference in volume estimation of pathology, even stratified by receptor status. The estimation of residual breast tumor volume by US and MRI achieves similar results, including prediction of pCR.

Axillary Lymph Node-to-Primary Tumor Standard Uptake Value Ratio on Preoperative (18)F-FDG PET/CT: A Prognostic Factor for Invasive Ductal Breast Cancer.

PurposeThis study assessed the axillary lymph node (ALN)-to-primary tumor maximum standard uptake value (SUVmax) ratio (ALN/T SUV ratio) in invasive ductal breast cancer (IDC) on preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) to determine the effectiveness in predicting recurrence-free survival (RFS).MethodsOne hundred nineteen IDC patients (mean age, 50.5±10.5 years) with pathologically proven ALN involvement without distant metastasis and preoperative FDG PET/CT were enrolled in the study. SUVmax values of the ALN and primary tumor were obtained on FDG PET/CT, and ALN/T SUV ratio was calculated. Several factors were evaluated for their effectiveness in predicting RFS. These included several parameters on FDG PET/CT as well as several clinicopathological parameters: pathologic tumor/node stage; nuclear and histological grade; hormonal state; status with respect to human epidermal growth factor receptor 2, mindbomb E3 ubiquitin protein ligase 1 (MIB-1), and p53; primary tumor size; and ALN size.ResultsAmong 119 patients with breast cancer, 17 patients (14.3%) experienced relapse during follow-up (mean follow-up, 28.4 months). The ALN/T SUV ratio of the group with disease recurrence was higher than that of the group without recurrence (0.97±1.60 and 0.45±0.40, respectively, p=0.005). Univariate analysis showed that the primary tumor SUVmax, ALN SUVmax, ALN/T SUV ratio, ALN status, nuclear and histological grade, estrogen receptor (ER) status, and MIB-1 status were predictors for RFS. Among these variables, ALN/T SUV ratio with hazard ratio of 4.20 (95% confidence interval [CI], 1.74-10.13) and ER status with hazard ratio of 4.33 (95% CI, 1.06-17.71) were predictors for RFS according to multivariate analysis (p=0.002 and p=0.042, respectively).ConclusionOur study demonstrated that ALN/T SUV ratio together with ER status was an independent factor for predicting relapse in IDC with metastatic ALN. ALN/T SUV ratio on preoperative FDG PET/CT may be a useful marker for selecting IDC patients that need adjunct treatment to prevent recurrence.

Overexpression of MAGE-A9 predicts unfavorable outcome in breast cancer

Melanoma-associated antigens (MAGEs) are a group of well-characterized members of the cancer/testis antigen (CTA) family, which is one of the largest groups of human tumor-associated antigens. MAGE-A9 is a particular member in the context of the MAGE-A gene family and was defined as presenting prognostic relevance in certain type of human cancer. However, the expression of MAGE-A9 in invasive ductal breast cancer (IDC) and the relationship with the clinical attributes of IDC, especially prognostic characteristic, remain poorly understood. In this present study, one-step quantitative reverse transcription polymerase chain reaction (18 fresh-frozen IDC tissues and corresponding non-cancerous tissues) and immunohistochemistry by tissue microarrays (82 IDC tissue samples and 70 matched tumor-adjacent non-cancerous tissue samples) were performed to characterize expression of the MAGE-A9 gene in IDC. Kaplan–Meier survival and Cox regression analyses were performed to evaluate the prognosis of IDC. The results of qPCR and IHC analysis showed that the expression of MAGE-A9 in IDC was significantly higher than that in corresponding non-cancerous tissue. Moreover, the expression level of MAGE-A9 protein in IDC was significantly related to histological grade (p=0.011) and distant metastasis (p=0.019). Multivariate analysis with the Cox regression model showed that MAGE-A9 protein expression (p=0.009), histological grade (p=0.014), lymph node metastasis (p=0.012) and distant metastasis (p=0.011) were independent prognostic factors for overall survival of IDC patients. The data suggest that MAGE-A9 expression is correlated with malignant attributes of IDC and it may serve as a novel prognostic factor and an ideal candidate for targeted therapy in IDC treatment.

369P - Whole-Body Metabolic Tumor Volume on F-18 Fdg Pet/Ct As a Prognostic Factor in Breast Cancer Patients with Distant Metastasis

ABSTRACT Aim: This study was performed to evaluate the prognostic relevance of PET parameters measured by F-18 FDG PET/CT in invasive ductal breast cancer (IDC) patients with distant metastasis at initial diagnosis. Methods: Forty female IDC patients with distant metastasis at initial diagnosis that underwent pretreatment F-18 FDG PET/CT were enrolled. Clinicopathologic parameters [age, TNM stage, location of metastatic lesion, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor2 (HER2) status] and metabolic PET parameters [SUVmax of the primary tumor (pSUVmax), SUVmax of axillary lymph node (nSUVmax), SUVmax of whole malignant lesions (wSUVmax), whole-body metabolic tumor volume (WBMTV), and whole-body total lesion glycolysis (WBTLG)] were analyzed with respect to the prediction of overall survival (OS). Univariate and multivariate analyses were performed to assess the prognostic significances of parameters using Kaplan-Meier and Cox proportional hazards models. Results: Twenty of the 40 patients (50 %) died during follow-up (mean, 34.7 months; range, 0.8–71.4 months). Non-survivors had a significantly higher mean WBMTV than survivors (444.7 ± 695.0 cm3, vs. 88.0 ± 95.4 cm3, p = 0.0287). Receiver-operating-characteristic analysis showed that a WBMTV of 167.8 cm3 (sensitivity, 50.0 %; specificity, 90.0 %; area under the curve, 0.670) was an optimal cutoff for predicting OS. T stage, location of metastatic lesion, ER status, PR status, wSUVmax, WBMTV, and WBTLG were found to be prognostic factors of OS by univariate analysis, but age, N stage, pSUVmax, nSUVmax, and HER2 status were not. Multivariate analysis revealed only WBMTV independently predicted OS (HR, 4.70; 95 % CI, 1.33–16.56; p = 0.0165). Conclusions: WBMTV on pretreatment F-18 FDG PET/CT was found to be an independent prognostic factor of OS in invasive ductal breast cancer patients with distant metastasis at initial diagnosis. Disclosure: All authors have declared no conflicts of interest.

Survival Analysis Based on Clinicopathological Data from a Single Institution: Chemotherapy Intensity Would Be Enhanced in Patients with Positive Hormone Receptors and Positive HER2 in China Who Cannot Afford the Target Therapy

Background. Immunohistochemical markers were often used to classify breast cancer into subtypes. The aim of this study was to estimate death and tumor progression for patients with the major subtypes of breast cancer as classified using immunohistochemical assay and to investigate the patterns of benefit from the therapies over the past years. Methods. The study population included primary, operable 199 invasive ductal breast cancer patients, with the median age of 51.1 years old. All patients underwent local and/or systemic treatments. The clinicopathological characteristics and clinical outcomes were retrospectively reviewed. The expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki67 was analyzed by immunohistochemistry. All patients were classified into the following categories: luminal A, luminal B, HER2 overexpression, and triple-negative subtypes. Result. The median follow-up time was 33 months. Luminal A tumors had the lowest rate of tumor progression (0%, P = 0.006), while luminal B, HER2 over-expression, and triple-negative subtypes were associated with an increased risk of tumor progression (15.4, 19.2, 15.4%). Clinicopathological subtypes retained independent prognostic significance (P = 0.008). There were significant differences by Cox model analyzed in age, menopause, lymph node metastasis, and HER2 for the event of death and tumor progression (P < 0.05), and there were significant differences only in chemotherapy for the event, respectively (P < 0.05). Conclusion. Clinicopathological subtypes of breast cancer could robustly identify the risk of death and tumor progression and were significant in making therapeutic decision. HER2 was the important poor indicator. The chemotherapy intensity would be enhanced for patients with luminal B, especially for HER2 over-expression subgroup.

CD44/CD24 as potential prognostic markers in node-positive invasive ductal breast cancer patients treated with adjuvant chemotherapy

The hypothesis on cancer stem cells assumes the existence of small subpopulation of cells that possess the ability to undergo self-renewal and can give rise to the diversity of differentiated cells that form the tumour. It has been accepted that CD44(+)/CD24(-/low) phenotype is one of the features characterizing breast cancer stem cells. The aim of our study was to assess (1) prognostic significance of CD44/CD24 expression as well as (2) a relation between the above-mentioned phenotype and breast cancer subtypes [based on estrogen (ER), progesterone receptors, human epidermal growth factor receptor 2 and Ki67 status] and expression of selected markers such as fascin, laminin-5 gamma-2 chain, cytokeratin (CK) 5/6 and 8/18, epidermal growth factor receptor (EGFR), smooth muscle actin, P-cadherin and lymphocytic infiltration in invasive ductal breast cancer patients (T≥1, N≥1, M0), who underwent mastectomy followed by chemotherapy (with taxanes and/or anthracyclines) or/and hormonotherapy. We noted that most cancers with CD44-/CD24- and CD44-/CD24+ phenotype were ER positive. The majority of CD44-/CD24-, CD44-/CD24+ and CD44+/CD24- tumours were characterized by CK5/6 and EGFR negativity. In univariate analysis we demonstrated that patients with pN1/pN2 and with CD44+/CD24- carcinomas had significantly lower risk of progression or cancer-related death than those with pN3 or tumours characterised by other CD44/CD24 expression patterns. We also found 100% DFS in 12 patients with CD44+/CD24-/CK5/6+/ER- phenotype. Other analysed parameters were insignificant. We conclude that tumours with immunophenotypes: CD44+/CD24- and CD44+/CD24-/CK5/6+/ER- might be more sensitive for chemotherapy based on taxanes and/or anthracyclines.

HtrA3 is negatively correlated with lymph node metastasis in invasive ductal breast cancer

Breast cancer is the most common cancer in women worldwide. Studies have shown that the high temperature requirement factor A3 (HtrA3) is involved in important physiological processes including maintenance of mitochondrial homeostasis, cell death, and cell signaling. HtrA3 is reported to be downregulated in several cancers and has been correlated with advancing cancer stage. We performed a retrospective study using our breast cancer tissue bank to investigate whether the expression of HtrA3 correlated with lymphatic metastasis in breast cancer and whether the expression of HtrA3 was correlated with estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer. Breast cancer tissues from 156 invasive ductal breast cancer patients with or without lymphatic metastasis were collected and the levels of HtrA3 were measured by immunohistochemistry and western blotting. The expression of HtrA3 was lower in breast cancer. In particular, HtrA3 expression in breast cancer with lymphatic metastasis was lower than that in breast cancer without lymphatic metastasis. In breast cancers with no lymphatic metastasis, the expression of HtrA3 was lower in patients with ER- and PR-positive tumors, but when breast cancers with lymphatic metastasis were analyzed, there was no difference in HtrA3 expression between ER- and PR-positive or ER- and PR-negative tumors. These data suggest that the expression of HtrA3 was negatively correlated with lymphatic metastasis in breast cancer but not correlated with ER and PR positivity or negativity. A better understanding of the mechanism of HtrA3 may provide the basis for future development of a novel therapeutic target in breast cancer.

Factors affecting surgical margin positivity in invasive ductal breast cancer patients who underwent breast-conserving surgery after preoperative core biopsy diagnosis

PurposeThe aim of our study is to evaluate the factors affecting surgical margin positivity among patients with invasive ductal breast cancer who underwent breast-conserving surgery (BCS) after preoperative diagnostic core biopsy.MethodsTwo hundred sixteen patients with stage I, II invasive ductal breast carcinoma who had histological diagnosis with preoperative tru-cut biopsy and underwent BCS were included in the present study. Potential factors that affect the positive surgical margin were analyzed. In univariate analysis, the comparisons of the factors affecting the surgical margin positivity were made by chi-square test. Logistic regression test was used to detect the independent factors affecting the surgical margin positivity.ResultsPositive axillary lymph node (odds ratio [OR], 8.2; 95% confidence interval [CI], 3.01 to 22.12), lymphovascular invasion (LVI; OR, 3.9; 95% CI, 1.62 to 9.24), extensive intraductal component (EIC; OR, 6.1; 95% CI, 2.30 to 16.00), presence of spiculation (OR, 5.1; 95% CI, 2.00 to 13.10) or presence of microcalcification in the mammography (OR, 13.7; 95% CI, 4.04 to 46.71) have been found to be the independent and adverse factors affecting surgical margin positivity.ConclusionConsidering decision making for the extent of the excision and for achieving negative surgical margin before BCS, positive axillary lymph node, LVI, EIC, spiculation or microcalcification in mammography are related as predictor factors for positive surgical margin.

Relationships Between Immunophenotype, Ki-67 Index, Microvascular Density, Ep-CAM/P-cadherin, and MMP-2 Expression in Early-stage Invasive Ductal Breast Cancer

There is still a lack of complete consensus on immunohistochemical surrogate markers for luminal A (LA) and luminal B (LB), HER2, and basal-like subtypes of breast carcinomas and their correlation with cancer cell adhesion and invasion-promoting factors. Therefore, early-stage invasive ductal breast cancer patients (N=209) were recruited to the study and divided into 4 subtypes, on the basis of the expression of the estrogen/progesterone receptor and HER2 (LA: 74.4% of cases; LB: 7.8%; HER2: 5.6%; and triple-negative phenotype: 12.2%). Regardless of the above-mentioned classification, we divided all carcinomas into 2 groups: carcinomas expressing at least 1 basal marker [cytokeratine (CK)5/6, CK5, vimentin, epidermal growth factor receptor, or aberrant CK8/18 expression-membranous or in <10% of cells] versus carcinomas negative for basal markers. Then we studied the relationships between the above subtypes (2 classifications) and (i) the expression of adhesion molecules (Ep-CAM, P-cadherin), (ii) matrix metalloproteinases (MMP)-2, (iii) the proliferation index (MIB-1 LI), and (iv) the microvascular density. We confirmed that triple-negative phenotypes are characterized by basal marker expression, a high tumor grade, and high MIB-1 LI. In this subtype, we found MMP-2 expression in stromal leukocytes less frequently. Both LA carcinomas and carcinomas negative for basal markers were more often negative for epithelial cell adhesion molecule (Ep-CAM) and P-cadherin. Moreover, we noted a higher mean value of microvascular density in CK5/6 and Ep-CAM-immunopositive tumors, carcinomas with aberrant CK8/18 expression, and carcinomas with no or strong expression of MMP-2 in stromal fibroblast-like cells. These results might suggest that mechanisms of stroma remodeling and carcinogenesis (Ep-CAM is the suggested marker of breast progenitors) may differ between breast cancer subtypes.

Role of MRE11 in Cell Proliferation, Tumor Invasion, and DNA Repair in Breast Cancer

Previous studies have shown that altered forms of MRE11, a protein known to play a vital role in DNA double-strand break repair, DNA replication, and telomere maintenance are associated with cancer outcomes. We investigated the role of MRE11 in breast cancer in both clinical and in vitro settings. We examined MRE11 expression in tumor tissues from invasive ductal carcinoma breast cancer patients (n = 254) by immunohistochemistry, and associations with clinicopathological characteristics and overall survival were assessed using Cox proportional hazards regression models and Kaplan-Meier survival curves. Effect of MRE11 overexpression and knockdown on cell proliferation, invasion, and radioresistance was assessed in vitro using breast cancer cell lines (MCF-7 and MDA-MB-231). We also investigated the mechanisms involved. Effect of MRE11 overexpression on tumor growth was assessed in an orthotopic xenograft model (n = 8 mice per group). All statistical tests were two-sided. Of the 254 tissue samples, 69.3% and 30.7% showed high and low MRE11 expression, respectively. High MRE11 expression was statistically significantly associated with malignant cancer behavior compared with low MRE11 expression (eg, stages III and IV vs stage I, P = .004; poor overall survival, P = .005). MRE11 overexpression in breast cancer cell lines promoted cell proliferation through STAT3, cell cycle entry, invasion and migration, and radioresistance via enhanced DNA repair activity and also inhibited apoptosis; knockdown of MRE11 had the opposite effect. In xenograft tumor-bearing mice (n = 8 per group), increased tumor growth was observed in the MRE11-overexpressing group compared with the control group (tumor volume at week 8, control vs MRE11-overexpressing tumor originating from MCF-7 cells, mean = 280.4 mm(3), 95% confidence interval [CI] = 62.4 to 498.4 mm(3) vs mean = 631.0 mm(3), 95% CI = 296.9 to 965.0 mm(3), P = .043). High MRE11 expression was associated with a more malignant behavior in breast cancer. MRE11 may be a novel oncoprotein and may therefore serve as a new therapeutic intervention against breast cancer.