Group Of Breast Carcinomas Research Articles

Prognostic value of androgen receptor expression and molecular alterations in metastatic triple-negative or low hormone receptor breast carcinomas

Metastatic breast carcinomas (BCs) with phenotype of triple-negative (TNBC) or low hormonal receptor levels [estrogen receptor (ER)/progesterone receptor (PR)<10% and HER2-] are mainly treated with cytotoxic chemotherapy. Targeting androgen receptor (AR) pathway may represent a potential new therapeutic strategy in such group of BCs. We evaluated AR expression by immunohistochemistry and genetic alterations by next-generation sequencing. Among 114 metastatic BCs, 37 (32.5%) cases showed AR expression and 77 (67.5%) lacked AR expression. Statistical analysis revealed that AR expression is associated with older age, lobular carcinoma, positive ER and positive PR in primary tumors, and lymph node metastasis. Patients with AR-positive tumors had significantly longer metastatic intervals and overall survivals. In addition, AR-positive tumors had significantly higher rate of PI3CA mutation. Our results demonstrated that AR expression has prognostic value in this subgroup of metastatic BCs and tumors with AR expression had different molecular alterations compared with those without AR expression.

Expression of epidermal growth factor receptor (EGFR) in blood and tumor in patients with breast carcinoma: Prognostic analysis.

e15013 Background: EGFR acts on tumor progression and can be quantified in the blood (bEGFR) and in the tumor (tEGFR). This study analyzed the impact of these biomarkers on overall survival (OS) in different subtypes of breast carcinoma (BC). Methods: Prospective study with 214 patients with BC and 89 women with normal mammography and without a history of cancer (control), matched by age. All signed the free and informed consent form. Blood collection for bEGFR analysis, detected by the ELISA method using the R&amp;D Systems DY231 kit, was performed before surgery (stages I and II; 80 patients), before neoadjuvant chemotherapy (CHT) (stages II and III; 103 patients) or before palliative CHT (stage IV; 31 patients). The material for analysis of tEGFR was from tumor biopsy, before any treatment, by immunohistochemistry using Dako clone 31G7. Continuous Kaplan-Meier analysis and Cox regression were used for statistical tests. Statistical significance was established at p &lt; 0.05. Results: At an average follow-up of 35.40 months (±15.65 months), 50 deaths occurred in an average time of 20.92 months (±11.80 months). The control group showed significantly higher bEGFR (p &lt; 0.0005) [40.45 ng/ml (18.10 – 117.15 ng/ml)] than the BC group [29.90 ng/ml (4.78 – 100.85 ng/ml)]. There was no correlation between tEGFR and bEGFR (Spearman's rho of -0.022). There was no impact on OS (p = 0.518) according to the negativity (0%) or positivity (≥1%) of tEGFR. Tumors with negative estrogen receptor (ER), compared to positive ER, showed higher expression of tEGFR (p &lt; 0.0001). No significant differences were found between high and low expression of bEGFR in patients Luminal A (n = 45; p = 0.588), Luminal B (n = 79; p = 0.742) or in positive HER2 (n = 38; p = 0.7520). Patients with Triple Negative BC (TN) (n = 46) and bEGFR ≤47.8 ng/ml had a higher OS [29.1 months (6.63 – 62.4)] than patients with bEGFR &gt; 47.7 ng/ml [13.36 months (3.66 – 60.43), (p = 0.020)]. In multivariate analysis on TN tumors, covariated with the stage, an increased risk of death was demonstrated by about 330% [HR = 4.301 (1.476 – 12.538), p = 0.008] for patients with bEGFR &gt; 47.8 ng/ml. In initial patients (I + II), covariate with the molecular subtype, an increased risk of death was demonstrated by about 420% [HR = 5,210 (1,237 – 21,948), p = 0.024] for bEGFR &gt; 45.9 ng/ml. There was no significant correlation of bEGFR according to the histological grade of the tumor (G1, G2 or G3), the Ki67 (&lt; or ≥14%) or body mass index. Conclusions: There was no correlation between bEGFR and tEGFR. Increased expression of bEGFR in patients with TN tumors is a significant predictor of lower SG. bEGFR was able to define patients with high and low risk of death in both initial and advanced TN tumors. The methodology for quantifying bEGFR expression is simple and inexpensive. In view of these findings, future studies should evaluate different therapeutic options according of the expression of this biomarker.

A Comparison of the Circulating Endocan Levels between the Inflammatory and Malignant Diseases of the Same Organ: The Breast

Purpose Idiopathic granulomatous mastitis (IGM) is a benign inflammatory breast disease that can clinically mimic breast carcinoma (BC). The aim of this study was to compare the endocan levels between inflammatory and neoplastic diseases of the breast, and to determine whether endocan is a convenient diagnostic biomarker for early stage BC and for the differentiation from IGM. Material and methods A total of 65 patients, consisting of 35 newly diagnosed with BC and 30 with IGM proven by core biopsies, and 20 healthy volunteer women with similar demographic characteristics were enrolled in the study. Endocan was assayed by a commercially available enzyme-linked immunosorbent assay kit. Results The endocan level was found to be significantly higher in the BC group than in the control group (p = 0.003). Although the endocan level was higher in the IGM group compared to the control group, there was no statistically significant difference (p = 0.057). No significant distinctive difference was observed between the BC and IGM groups in terms of the endocan level (p = 0.373). The serum endocan level was found to be positively correlated with BMI and vitamin D levels in the BC group (p = 0.043 and p = 0.023, respectively). Conclusions We demonstrated that the serum endocan level was increased in patients with BC compared to healthy subjects, whereas in our enrolled study patient population, endocan was not a statistically valid biomarker for the differential diagnosis between BC and IGM. These findings indicate the potential role of endocan in the pathogenesis of BC.

Abstract P4-12-11: Up-regulation of SPARC is associated with breast tumor progression and epithelial SPARC expression is correlated with poor survival and MMP-2 expression in patients with breast carcinoma

Abstract Background: Secreted protein acidic and rich in cysteine (SPARC) plays a crucial role in the process of tumor invasion and metastasis in many cancers. Matrix metalloproteinases (MMPs) degrade the extracellular matrix and participate in several key processes of invasion and metastasis. The aims of this study were to evaluate the potential involvement of SPARC in the progression of breast tumor and to determine its association with outcome variables and MMPs expression in patients with breast carcinoma (BC). Materials and Methods: SPARC expression was examined in 8 pairs of BC tissues and surrounding normal tissues at mRNA and protein levels by quantitative real-time PCR (qRT-PCR), RNAscope in situ hybridization (ISH), Western blotting, and immunohistochemistry techniques. Immunohistochemical staining of SPARC on tissue microarray was done in 26 normal breasts, 76 ductal carcinoma in situ (DCIS), and 198 BC samples. In addition, we performed immunohistochemical staining for MMP-2 and MMP-9 in BC. Results: SPARC expression at mRNA and protein levels by qRT-PCR and Western blotting was significantly increased in BC tissues compared to the surrounding normal tissues (p &amp;lt; 0.05 and p &amp;lt; 0.01, respectively). RNAscope ISH and immunohistochemistry of SPARC confirmed that SPARC expression was increased in BC tissues compared with their normal tissues and its expression was more pronounced in the stromal compartment than in epithelial compartment. SPARC expression was different among the normal, DCIS and BC groups and epithelial SPARC expression increased progressively from normal breast through DCIS to BC (p &amp;lt; 0.001). In patients with BC, high epithelial SPARC expression was associated with worse disease-free and overall survival (p = 0.002 and p = 0.048, respectively) and independently predicted worse disease-free survival (p = 0.002). Epithelial SPARC expression was significantly correlated with MMP-2 expression (p &amp;lt; 0.05). Conclusion: Our results suggest that up-regulation of SPARC contributes to breast tumor progression. SPARC expression may be a useful biomarker for the prognostic prediction in patients with BC. SPARC can control extracellular matrix degradation through up-regulation of MMP-2. Citation Format: Lee JS, Kim G-E, Park MH, Yoon JH. Up-regulation of SPARC is associated with breast tumor progression and epithelial SPARC expression is correlated with poor survival and MMP-2 expression in patients with breast carcinoma [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-11.

Altered PPP2R2A and Cyclin D1 expression defines a subgroup of aggressive luminal-like breast cancer.

BackgroundPPP2R2A deletions were recently linked to a subgroup of luminal breast carcinoma (BC) that exhibits poor survival. This subgroup also exhibited amplification of a chromosome region containing the Cyclin D1 coding gene, CCND1. Therefore, we aimed to investigate whether a combination of PPP2R2A (B55α) and Cyclin D1 expression statuses evaluated by immunohistochemistry (IHC) could define a subgroup of luminal BC that exhibits poor survival.MethodsFirst we conducted a retrospective cohort study using sequencing data from The Cancer Genome Atlas initiative to correlate PPP2R2A copy number alteration (CNA) status with its expression level and the corresponding overall survival (OS). Next, also using a retrospective cohort study design, we evaluated the PPP2R2A (B55α) expression levels by IHC in a total of 807 BC patients from two independent cohorts (discovery cohort n = 349 and validation cohort n = 458). Cyclin D1 expression was also evaluated, and the PPP2R2A (B55α)-/low/Cyclin D1high phenotype was evaluated as a predictor of disease-free survival (DFS) and OS in luminal-like BC patients.ResultsDeletions in the PPP2R2A gene strongly correlate with lower mRNA expression and poorer OS. PPP2R2A (B55α)-/low carcinomas have significantly shorter DFS and OS. Furthermore, in univariate analysis, the PPP2R2A (B55α)-/low/Cyclin D1high phenotype is significantly associated with poorer DFS and OS. In a multivariate analysis, the PPP2R2A (B55α)-/low/Cyclin D1high phenotype is significantly associated with poor DFS, thus defining a group of luminal-like BC with higher risk of relapse.ConclusionWe demonstrate that BCs harboring PPP2R2A deletions are associated with worse OS. Moreover, this is the first study to demonstrate that the combination of altered PPP2R2A (B55α) and high Cyclin D1 expression by IHC defines a subgroup of luminal-like BC patients with a high risk of relapse and death.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1266-1) contains supplementary material, which is available to authorized users.

Abstract 5127: Incidence of molecular variants with and without Her-2-Neu expression and amplification in brain metastases of breast carcinoma and its prognostic significance.

Abstract Background: Her-2-neu is one of the major genes and proteins, whose amplification and expression is widely used in modern medical practice in patients with breast carcinoma (BC). . This is a marker of poor prognosis and the "target" for Herceptin. The role of this marker in brain metastases is not very well investigated as it is in a primary tumor. Aim: To investigate the incidence of molecular variants of breast carcinoma in brain metastases (BM), to analyze Her-2-neu presence in them and evaluate its prognostic significance in patients with BMBC. Patients and methods: 90 FFPE tumor tissues and clinical data from consented patients with BMBC treated with surgery at the NN Burdenko Neurosurgery Institute (median age 52, age range 29-73 years) and 71 FFPE tumor tissues and clinical data from consented patients with primary BC without BM treated with surgery in AI Burnacyan Institute (median age 58, age range 28-80 years) have been obtained and evaluated. IHC staining of all 161 cases was performed with monoclonal antibodies to ER, PR, Ki-67and Her-2-neu (DAKO); Fluorescence in situ hybridization Her-2-neu LSI and CEP17 was also performed . Her-2 neu expression and amplification were estimated according to the standard ASCO recommendations. A special questionnaire was completed in order to obtain information about outcome of the patients. Statistical analysis was performed using the STATISTICA 8.0 software. Results: There were 5 molecular variants in BC and BMBC groups according to the ER, PR, Ki-67 and Her-2-Neu IHC expression and Her-2-Neu amplification. Their incidence among two groups were: luminal A - 42% vs. 9%, luminal B -10% vs. 3%, luminal Her-2-Neu positive - 14% vs. 27%, classical her-2-Neu positive -21% vs. 22%, and triple negative -13% vs. 27%, correspondingly. Patients in the BM group were in average 6 years younger than patients in ‘pure’ BC group. In BMBC group median time of BM's development among Her-2-Neu (amplified Her-2-neu gene) patients was significantly shorter than that among Her-2-neu -negative (without amplification) patients: 40 months (range 8-288) versus 84 months (range 24-131 (p&amp;lt;0,05). The general survival time from first signs of BM was 8 months (ranges 0-89) in Her-2-neu- positive patients versus 13 months (ranges 0-72) in Her-2-neu -negative patients. Conclusions: Despite the fact that luminal A variant of BC is the most common one among primary tumors, in patients with BMBC triple negative and luminal Her-2-neu variants occurred more frequently. As age analysis showed, patients from BMBC group were younger than patients without BM. Therefore we believe that ‘brain metastatic’ carcinomas occur in a much younger population. Patients with BMBC Her-2-neu amplification have more aggressive development of disease and shorter survival time, than without Her-2-neu amplification. Citation Format: Daniil Rotin, Oxana Paklina, NV Lobanova, GL Kobyakov, Olga Potapova. Incidence of molecular variants with and without Her-2-Neu expression and amplification in brain metastases of breast carcinoma and its prognostic significance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5127. doi:10.1158/1538-7445.AM2013-5127