Molecular Subtypes Of Breast Carcinoma Research Articles

Abstract 3743: Magnetic resonance imaging shrinkage patterns after neoadjuvant chemotherapy for breast carcinomas: Correlation with molecular subtypes

Abstract Background: Neoadjuvant chemotherapy (NAC) is widely performed for patients with locally advanced breast carcinomas. It is important to obtain precise information using imaging modalities about the distribution of residual carcinomas after NAC to predict the success of breast conserving surgery. However, the relationship between magnetic resonance imaging (MRI) shrinkage patterns and molecular subtypes of breast carcinomas has not yet been investigated. Methods: We analyzed the MRI shrinkage and pathological patterns of residual carcinomas after NAC in 54 consecutive breast carcinomas. The shrinkage patterns were classified into five categories: Type I and II (concentric shrinkage with or without any surrounding lesion), type III (shrinkage with residual multinodular lesions), type IV (diffuse contrast enhancement in the entire quadrant), and non-visualization. Results: The most common MRI shrinkage pattern was type I (39%) followed by non-visualization (26%). The most common pathological shrinkage pattern was type III (33%), followed by type II (28%) and non-visualization (22%). The concordance rates of the MRI patterns of non-visualization and type I were significantly lower than those of the MRI patterns of type II, III, and IV (p = 0.018). Moreover, in the luminal subtypes, the concordance rates of the MRI patterns of non-visualization and type I were significantly lower than those of the MRI patterns of type II, III, and IV (p = 0.026); however, in the non-luminal subtypes, this correlation was not significant. Conclusions: The results of the present study suggest that the cases with MRI shrinkage patterns of non-visualization and type I require caution regarding the surgical margins compared with the other types, especially the luminal subtypes. Citation Format: Tsuyoshi Mori, Kaori Tomida, Mina Kitamura, Sachiko Sakai, Yuki Kawai, Tomoharu Shimizu, Tomoko Umeda, Tomoyuki Ueki, Sachiko Kaida, Toru Miyake, Hiroya Iida, Hiroya Akabori, Naomi Kitamura, Tsuyoshi Yamaguchi, Hiromichi Sonoda, Shigeyuki Naka, Masaji Tani. Magnetic resonance imaging shrinkage patterns after neoadjuvant chemotherapy for breast carcinomas: Correlation with molecular subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3743. doi:10.1158/1538-7445.AM2017-3743

Expressions of HIF-1α and CA9 in breast carcinoma and their relationships with basal-like subtype

Objective To study the expressions of hypoxia inducible factor-1α (HIF-1α) and carbo-nic anhydrase 9 (CA9) in different molecular subtypes of breast carcinoma and their relationships with basal-like subtype. Methods The expressions of HIF-1α and CA9 were detected by immunohistochemistry in five subtypes of breast carcinoma (n=803). The relationships of the expressions of HIF-1α and CA9 with the clinicopathologic parameters of basal-like subtype and with the prognosis of patients were analyzed. Results The positive expression rates of HIF-1α and CA9 protein in breast carcinoma were much higher than those in para-tumor breast tissues (43.96% vs. 3.86%, χ2=354.858, P<0.001; 19.80% vs. 4.61%, χ2=86.495, P<0.001). The positive expression rates of HIF-1α in Luminal A, Luminal B, epidermal growth factor receptor-2 (HER-2) over-expression, basal-like and normal breast-like subtypes were 31.97%, 25.00%, 56.06%, 77.89% and 55.76% respectively, and the positive expression rates of CA9 were 7.48%, 5.56%, 60.61%, 40.00% and 27.88% respectively, with significant differences (χ2=88.628, P<0.001; χ2=147.128, P<0.001). The positive expression rates of HIF-1α and CA9 in estrogen receptor (ER)-negative breast carcinomas (HER-2 over-expression, basal-like and normal breast-like) were significantly higher than those in ER-positive subtypes (Luminal A and Luminal B, all P<0.005). There was a significant positive correlation between HIF-1α and CA9 (C=0.315, P=0.001), and both were correlated with the lymph node metastasis (χ2=4.542, P=0.033; χ2=7.025, P=0.008), pTNM stage (χ2=5.390, P=0.020; χ2=10.179, P=0.001) and poor prognosis (χ2=4.353, P=0.037; χ2=6.056, P=0.014) of basal-like subtype. Conclusion Over-expressions of HIF-1α and CA9 may be related to the ER-negative breast cancer more closely, and both may play important roles in the occurrence and development of basal-like subtype. Over-expressions of HIF-1α and CA9 may suggest the poorer prognosis of patients with basal-like breast carcinoma. Key words: Breast neoplasms; Hypoxia-inducible factor 1, alpha subunit; Carbonic anhydrases; Basal-like subtype

Breast cancer biomarkers at Niger delta university hospital: Comparisons with national and international trends and clinical significance

Breast cancer biology is heterogeneous and patients with the same diagnostic profile have markedly different clinical outcomes. Gene expression profiling and its surrogate IHC markers classified breast cancer into four molecular subtypes with different prognosis, targeted therapies, and/or clinical outcomes. The present study was conducted to investigate breast cancer subtypes among women in NDUTH Bayelsa state and compared them with similar studies in other populations of international and national origin. Archived formalin fixed paraffin embedded tissue blocks were retrieved from January 2010-December 2014 provided 20 cases of microscopically confirmed invasive ductal breast carcinoma that were evaluable for histology and IHC (ER, PR, HER2, and Cytokeratin 5/6) immunostain. All the patients were females and most of them were under 50 years at presentation. The molecular subtypes were luminal A (54.1%), luminal B (25.0%), HER2 (12.5%), basal-like (4.2%), and unclassified (4.2%). Triple negative carcinoma (basal-like and unclassified combined) was 4.2%, ER+ (65%) and (PR+70%).Breast carcinoma in Bayelsa state women presents at a younger age. We note that the prevalence of the molecular subtypes of breast carcinoma appears to have variation in geographical distribution. The reasons for these differences could be technical, quality of fixation and processing, varying staining techniques, and different criteria in scoring and reporting. This study indicates that the majority of breast cancer in NDUTH lies at the two ends of the molecular spectrum, that is, luminal A (54.1%), sensitive to hormonal therapy and with a good prognosis, and “triple negative” (4.2%) not hormonally sensitive and with a poor prognosis.

P248 - Cancer stem cell marker, CD44 expression in Indian breast carcinoma patients and its association with the molecular subtypes of breast carcinoma

P248 - Cancer stem cell marker, CD44 expression in Indian breast carcinoma patients and its association with the molecular subtypes of breast carcinoma

Expression of chemokine CXCL12 and its receptor (CXCR4 and CXCR7) in different molecular subtypes of human breast carcinoma and the clinical significance

To study the expressions and the clinical significance of chemokine CXCL12 and its receptor CXCR4, CXCR7 in the human breast carcinoma (BC) with different molecular subtypes. Methods: The mRNA expressions of CXCL12, CXCR4 and CXCR7 in tissues from 80 patients with different molecular subtype of BC were measured by qRT-PCR. The protein expressions of CXCL12, CXCR4 and CXCR7 in paraffin-embedded samples from 160 patients with different molecular subtypes were detected by immunohistochemical staining. Results: The mRNA expression levels of CXCL12, CXCR4 and CXCR7 in HER-2 positive BC and TNBC tissues were significantly higher than those in luminal A and luminal B subtype BC tissues (all P<0.05), but their expressions were not different between luminal A and luminal B subtype BC tissues or between HER-2 positive BC and TNBC tissues. The positive expression rates of CXCL12 protein in HER-2 positive BC and TNBC tissues were significantly higher than those in luminal A and luminal B subtype BC tissues (all P<0.05), while their expressions were not different between luminal A and luminal B subtype BC tissues or between HER-2 positive BC and TNBC tissues. High expressions of the gene CXCL12 and its receptor CXCR4 and CXCR7 in HER-2 positive BC and TNBC may be closely associated with their poor prognosis. Inhibition of their expressions in HER-2 positive BC and TNBC may provide a strategy for treating BC in clinic.

Metastatic breast carcinoma in pleural fluid: Correlation of receptor and HER2 status with the primary carcinoma-a pilot study.

Documenting the four molecular subtypes of breast carcinoma is significant as they determine response to therapy, disease free interval and survival. Our aim was to document the subtypes defined by immunohistochemistry (IHC) expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2): namely ER + PR+ HER2+; ER + PR + HER2-; ER-PR-HER2+; and ER-PR-HER2- in metastatic breast carcinoma in pleural fluid and compare them with their expression in the primary breast tumor. Over a period of 18 months, 13 cases of invasive breast carcinoma with metastases to the pleural cavity were studied for subtypes. ER, PR, and HER2 were determined by IHC in the primary breast tumor and the cell blocks of the pleural fluid with metastatic carcinoma. Age ranged from 33 to 75 years. The primary tumor was ER + PR + HER2+; ER + PR + HER2-; ER-PR-HER2+ and ER-PR-HER2- in 2,9,0 and two cases, respectively while the metastatic tumor in pleural fluid was ER + PR + HER2+; ER + PR + HER2-; ER-PR- HER2+ and ER-PR-HER2- in 6, 3, 3, and 1, respectively. In five cases there was complete correlation between the primary and metastatic tumor. In 7 cases with HER2- primary tumor the metastases was HER2+. One from ER + PR+ HER2- primary tumor showed triple negative expression in the metastasis. Determining the molecular subtype in metastatic breast carcinoma is of importance as it affects the management. In our series 63% of metastatic tumors to the pleural fluid became HER2 positive and would thus require appropriate therapy. Diagn. Cytopathol. 2016;44:980-986. © 2016 Wiley Periodicals, Inc.

The Impact of Gene Expression Patterns in Breast Cancer.

Featured Article: Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001;98:10869–74.2 In our 2001 article highlighted here, my colleagues and I demonstrated for the first time the clinical impact of the main 5 “intrinsic” molecular subtypes of breast carcinomas. Shortly before, we had published the identification of unique “molecular portraits” of human breast tumors based solely on variation in gene expression patterns (1). The pervasive order and interpretation of these patterns indicated that the tumors could be classified into distinct biological groups based on overall molecular commonalities. The basal-like, ERBB2 (erb-b2 receptor tyrosine kinase 2)-positive,3 and normal-like subtypes all showed low or no expression of the estrogen receptor (ER) and other genes characteristic of luminal epithelial cells and had additional features specific for each of the 3 subtypes. For example, basal-like tumors showed high expression of the basal cytokeratins 5 and 17 and epidermal growth factor receptor and represented the predominant breast cancer subtype among BRCA1 (breast cancer 1) carriers (2). Luminal …

Molecular subtypes of breast carcinoma in Saudi Arabia. A retrospective study.

Objectives:To determine the distribution of various molecular subtypes of breast cancer in Saudi Arabia and to assess the association between these subtypes and age at diagnosis, tumor size, histopathological type, grade, presence of carcinoma in-situ, and lymph node status.Methods:This observational retrospective study, between January 2010 and December 2014, was conducted at King Khalid University Hospital, Riyadh, Saudi Arabia. We classified 359 breast cancers into 4 molecular subtypes, using immunohistochemistry: luminal A (estrogen receptor [ER], or progesterone receptor [PR] positive and human epidermal growth factor receptor 2 [HER2] negative), luminal B (ER and/or PR positive and HER2 positive), HER2-positive (ER and PR negative and HER2 positive), and triple negative (ER, PR, and HER2 negative). We evaluated the relationship between these subtypes and clinicopathological features using Chi square test.Results:The most prevalent subtype was luminal A (58.5%), followed in descending order of frequency by triple negative (14.8%), luminal B (14.5%), and HER2-positive (12.3%). The average age at diagnosis was 49.8 years, and average tumor size at diagnosis was 3.19 cm.Conclusion:Luminal A tumor was the most common molecular subtype and HER2-positive was the least common. Most lobular carcinomas were luminal A tumors. Human epidermal growth factor receptor 2-positive and triple negative tumors had a higher histologic grade and a larger tumor size at diagnosis, and they were more common in women under 50 years. Carcinoma-in-situ was least common in triple negative tumors. We found no association between lymph node status and molecular subtypes.

Androgen Receptor Expression in Breast Carcinoma of Egyptian Patients.

Breast carcinoma (BC) is a heterogeneous disease, with distinctive molecular sub-types, influencing BC patients prognosis and therapeutic options. Androgen Receptor (AR) is a steroid nuclear receptor involved in complex signaling pathways, that are thought to play a role in cell proliferation. AR expression in relation to different molecular sub-types of BC is not clearly understood. The aim of this study was to evaluate the expression of AR in BC from Egyptian patients and correlate it with the standard clinico-pathologic variables, molecular sub-type of BC and the Overall Survival (OS). This retrospective study was conducted on 81 cases of BC from egyptian patients, stained immunohistochemically with AR. Chi-Square and Kaplan-Meier tests were applied to study the correlation between AR expression and clinicopathologic variables and the OS of BC patients respectively. Among studied BC cases, 37.04% were immunoreactive to AR. AR immunoreactivity was significantly corrrelated with older age (p=0.03), post-menopausal status (p=0.001), lower grade (p=0.003), the presence of in-situ component (p= 0.014), early stage of presentation (p=0.03) and good-moderate NPI (0.009). It was also correlated with Positive ER, negative HER-2/neu, low Ki-67 proliferation index and luminal A subtype. AR expression didn't correlate with the OS in the studied cases. AR was found to be related to favourable prognostic factors in BC but not to OS. It was particularly expressed in luminal A group and in significant proportion in Triple Negative Breast Carcinoma (TNBC), providing an opportunity for AR targeted therapy.

Expression of PTEN, p53 and EGFR in the molecular subtypes of breast carcinoma and the correlation among them

To study the expression of PTEN, p53 and epidermal growth factor receptor (EGFR) in the molecular subtypes of breast carcinoma and to evaluate the correlations with triple-negative breast cancer. Immunohistochemical MaxVision(TM) method was used to detect the expression of PTEN, p53, EGFR, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in 291 cases of infiltrating ductal carcinoma of breast. The positive expression of PTEN, p53 and EGFR protein in breast carcinoma was 57.0%, 57.0% and 38.5%, respectively, which were significantly different from those in benign breast diseases (P<0.05). The expression of PTEN or EGFR in breast cancer was correlated with tumor size, histological grade, lymph node metastasis, TNM stage, ER and HER2 status (P<0.05); the expression of p53 was correlated with tumor size, histological grade and ER status (P<0.05). The difference of positive expression rates of PTEN, p53 and EGFR protein among different subtypes including luminal A, luminal B (HER2-), luminal B (HER2+), HER2 over-expression and triple-negative was statistically significant (P<0.05). There were close correlations among PTEN, p53 and EGFR in the triple-negative subtype (P<0.05). Low expression of PTEN and high expression of EGFR and p53 are observed in triple-negative breast cancer, which may synergistically contribute to the pathogenesis of triple-negative breast cancer.

Molecular Classification of Breast Carcinoma: From Traditional, Old-Fashioned Way to A New Age, and A New Way.

Breast carcinoma comprises a group of diseases with specific clinical, histopathologic and molecular properties. Traditional classification use morphology to divide tumors into separate categories with differing behavior and prognosis. However, there are limitations of traditional classification systems, and new molecular methods are expected to improve classification systems. Molecular subtypes of breast carcinomas have been characterized in the last 11 years, and have been studied extensively. Much of the information accumulated in recent years, and molecular taxonomy seems to be still developing and undergoing change. The main question is whether new molecular techniques such as gene expression profiling will be accepted as gold standard in determining breast cancer subtypes, and whether molecular classification is useful in specific subtypes of breast cancer as it is in ductal carcinoma (nonspecific type). In addition, critical review of the literature reveals major problems such as poor definition, lack of reproducibility and lack of quality control in current molecular techniques and classifications. Therefore, current molecular approaches are not yet used in routine clinical practice and treatment guidance since they are immature and can even lead to incorrect assessment.

Targeted pathways in breast cancer: molecular and protein markers guiding therapeutic decisions.

Breast carcinoma is currently considered as a group of diseases, differing not only in histopathologic phenotype, as indicated by histologic type and grade, but also in their protein, genetic and epigenetic molecular profile. The standard of care indicates that the core information for patient management includes data on Estrogen Receptor (ER), Progesterone Receptor (PgR) and Human Epidermal Growth Factor Receptor 2 (HER2), while there is an emerging role for the proliferation marker Ki67. These indices can be provided even in low resource settings and are indispensable for prognostication and therapeutic patient management. With the progress in molecular and translational research, there is a growing body of information on the molecular subtypes of breast carcinoma and their significance, and multigene signature assays are used to dictate prognosis and guide therapeutics in high resource settings. In addition, several cellular pathways involved in tumor growth and spread are dissected and targeted in clinical trials. Among these are the p53, RB, PI3K/Akt/mTOR and Ras/MAPK pathways, alterations associated with genetic instability and epigenetic alterations including histone methylation and acetylation, DNA methylation and microRNAs expression. The tumor immune microenvironment, including the tumor infiltrating lymphocytes (TILs) is attracting significant research interest. This review summarizes the mechanisms of function of the above factors in breast tumorigenesis with emphasis on their prognostic and predictive value and their use as therapeutic targets.

CD99 correlates with low cyclin D1, high topoisomerase 2 status and triple negative molecular phenotype but is prognostically irrelevant in breast carcinoma.

CD99 is a protein initially described in the Ewing sarcoma family of tumors, but growing evidence has shown its expression in other tumors of mesenchymal, hematopoietic and even epithelial origin. Some articles report CD99 in metaplastic carcinoma of the breast, a subtype of breast carcinoma (BC) with pronounced epithelial to mesenchymal (EMT) phenotype. Our aim was to analyse the potential relationship between CD99 and selected EMT (vimentin, E-cadherin, Twist) and proliferation markers (Ki-67, c-myc, cyclin D1, topoisomerase 2), molecular subtypes of BC, as well as overall survival (OS) and progression-free survival (PFS). In a group of 122 cases CD99 membrane expression was seen in 14 (11.5%) cases: strong in 11 (9%) and moderate in 3 (2.5%). Expression of CD99 correlated with low cyclin D1 index, high level of topoisomerase 2 expression and lack of progesterone receptor (PR) but not with EMT characteristics. Additionally, strong expression of CD99 correlated with triple negative molecular BC phenotype. CD99 was prognostically irrelevant for OS and PFS. CD99 correlates with selected proliferative markers and low ER/PR receptor status but not with patients' outcome in BC. Further studies are required to explain precisely its role in molecular pathogenesis of BC.

Overexpression of C35 in breast carcinomas is associated with tumor progression and lymphnode metastasis.

To investigate C35 protein expression in breast carcinoma and to investigate its clinicopathological significance, a total of 68 cases of breast carcinoma and 20 cases of normal breast tissue samples were obtained from the clinic. Protein expression of C35, ER, PR and HER-2 were determined using immunohistochemistry. The correlations between C35 expression and clinicopathological parameters were analyzed on the basis of individual clinicopathologic records. Overexpression of C35 was detected in 56 of 68 (82.35%) breast carcinoma samples and only 3 of 20 (15%) normal breast tissue samples, and frequency of C35 expression was significantly associated with clinical Tumor Node Metastasis staging and Scarff-Bloom-Richardson grade (p < 0.05), but was not related to patients age, menstrual status and tumor diameter. C35 expression was positively related with the expression of HER-2 (r = 0.207), whereas negatively related with the expression of ER and PR. Further, C35 was prevalent in all four molecular subtypes of breast carcinoma with no significant difference of expression frequency. However, they have significant differences in lymphatic metastasis cases compared to the non-metastasis cases (p < 0.05). Since C35 protein was extensively expressed in all stages of breast carcinoma, and was closely associated with tumor progression and lymph node metastasis, it might be used as a reliable biomarker or therapeutic target for diagnosis and treatment.

Expression of matrix metalloproteinases and their inhibitors in different immunohistochemical-based molecular subtypes of breast cancer.

BackgroundMetalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key pathways of tumor growth, invasion and metastasis, but little is known about their expression according to different molecular subtypes of breast cancer. The aims of this study were to assess the prevalence and clinical significance of MMP and TIMP expression in invasive breast cancer and to determine its association with immunohistochemical-based molecular classification.MethodsTissue microarray sections were immunostained for estrogen receptor-α (ER-α), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and with specific antibodies against MMP-1, 2, 7, 9, 11, 13, and 14 and TIMP-1, 2, and 3. Based on the immunostaining data from five of the markers used (ER-α, PR, HER2, EGFR and CK5/6), three major subtypes (123 luminal A, 31 basal-like, and 17 HER2-overexpressing) were selected.ResultsStatistically significant differences in the expression of MMPs and TIMPs among the three subtypes were found in tumoral MMP7 (P = 0.005), tumoral MMP-9 (P = 0.000), tumoral MMP-13 (P = 0.016) and stromal MMP-13 (P = 0.016). The incidence of tumoral MMP-9 expression in the HER2-overexpressing subtype was significantly higher than in the luminal A subtype (P = 0.021). Tumoral MMP-9 and stromal MMP-13 expression were significantly higher in the HER2-overexpressing subtype than in the basal-like subtype (P = 0.000 and P = 0.016, respectively). Tumoral MMP-7 expression was significantly higher in the basal-like subtype compared to luminal A (P = 0.007) and HER2-overexpressing subtype (P = 0.004). Tumoral MMP-13 showed a higher expression in the basal-like subtype than in the HER2-overexpressing subtype (P = 0.010). In multivariate analysis, stage and stromal MMP-1 expression were significantly related to overall survival. Stage was of independent prognostic significance for disease-free survival.ConclusionWe found some variations in MMP and TIMP expression among the immunohistochemical-based molecular subtypes of breast carcinomas, suggesting differences in their tumor pathophysiology. Additional studies are needed to determine the mechanisms underlying the differences of MMP and TIMP expression in the molecular subtypes for the development of specific therapeutic targets for breast cancer subtypes.

Expression of DNA methylation marker of paired-like homeodomain transcription factor 2 and growth receptors in invasive ductal carcinoma of the breast.

Paired-like homeodomain transcription factor 2 (PITX2) is another new marker in breast carcinoma since hypermethylation at P2 promoter of this gene was noted to be associated with poor prognosis. We investigated the expression of PITX2 protein using immunohistochemistry in invasive ductal carcinoma and its association with the established growth receptors such as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth receptor 2 (HER2). We conducted a cross sectional study using 100 samples of archived formalin-fixed paraffin embedded tissue blocks of invasive ductal carcinoma and stained them with immunohistochemistry for PITX2, ER, PR and HER2. All HER2 with scoring of 2+ were confirmed with chromogenic in-situ hybridization (CISH). PITX2 protein was expressed in 53% of invasive ductal carcinoma and lack of PITX2 expression in 47%. Univariate analysis revealed a significant association between PITX2 expression with PR (p=0.001), ER (p=0.006), gland formation (p=0.044) and marginal association with molecular subtypes of breast carcinoma (p=0.051). Combined ER and PR expression with PITX2 was also significantly associated (p=0.003) especially in double positive cases. Multivariate analysis showed the most significant association between PITX2 and PR (RR 4.105, 95% CI 1.765-9.547, p=0.001). PITX2 is another potential prognostic marker in breast carcinoma adding significant information to established prognostic factors of ER and PR. The expression of PITX2 together with PR may carry a very good prognosis.

Long-term use of metformin and the molecular subtype in invasive breast carcinoma patients - a retrospective study of clinical and tumor characteristics.

BackgroundMetformin may exhibit inhibitory effects on cancer cells by inhibiting mTOR signaling pathway. The aim of our retrospective study was to examine if patients with breast carcinoma (BC) and diabetes mellitus (DM) receiving metformin have a lower stage of carcinoma in comparison to patients not receiving metformin, and if the use of metformin correlates with the molecular subtype of BC.MethodsA chart review of 253 patients with invasive BC and DM (128 on metformin and 125 not on metformin) was performed. Control group consisted of 320 consecutive patients with invasive BC without DM. BC subtypes were classified by immunohistochemical surrogates as luminal A (estrogen receptor [ER] + and/or progesterone receptor [PR]+, HER-2-), luminal B (ER + and/or PR+, HER-2+), HER-2 (ER-, PR-, HER-2+), triple-negative/basal (ER-, PR-, HER-2-).ResultsPatients on metformin had a lower proportion of T3 or T4 tumors than patients who were not receiving metformin (16% vs. 26%; p = 0.035). No statistical difference was found between the two study groups in N stage. Patients with DM on metformin, with DM not on metformin and the control group had different molecular subtypes of BC (p = 0.01): the luminal A subtype was found in 78%, 83% and 71%, the luminal B in 12.6%, 9% and 11%, HER-2 in 0.8%, 1.6% and 8%, and the triple-negative/basal-like subtype in 8.6%, 6.4% and 10%, respectively.ConclusionOur data indicate that long-term use of metformin use correlates with molecular subtype of BC in diabetics on metformin in comparison to diabetics not on metformin and patients without DM. However, most likely, different distribution of the molecular subtypes of BC in these three groups of patients was caused by other risk factors for breast carcinoma, such as age of patients or obesity.

Expression of Neuroendocrine Markers in Different Molecular Subtypes of Breast Carcinoma

Background. Carcinomas of the breast with neuroendocrine features are incorporated in the World Health Organization classification since 2003 and include well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas/small cell carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. Neuroendocrine differentiation is known to be more common in certain low-grade histologic special types and has been shown to mainly cluster to the molecular (intrinsic) luminal A subtype. Methods. We analyzed the frequency of neuroendocrine differentiation in different molecular subtypes of breast carcinomas of no histologic special type using immunohistochemical stains with specific neuroendocrine markers (chromogranin A and synaptophysin). Results. We found neuroendocrine differentiation in 20% of luminal B-like carcinomas using current WHO criteria (at least 50% of tumor cells positive for synaptophysin or chromogranin A). In contrast, no neuroendocrine differentiation was seen in luminal A-like, HER2 amplified and triple-negative carcinomas. Breast carcinomas with neuroendocrine differentiation presented with advanced stage disease and showed aggressive behavior. Conclusions. We conclude that neuroendocrine differentiation is more common than assumed in poorly differentiated luminal B-like carcinomas. Use of specific neuroendocrine markers is thus encouraged in this subtype to enhance detection of neuroendocrine differentiation and hence characterize the biological and therapeutic relevance of this finding in future studies.

Basal-Like Breast Cancer: Update on Clinicopathologic, Immunohistochemical, and Molecular Features

Basal-like breast carcinoma (BLBC) is a distinct molecular subtype of breast carcinoma identified through gene expression profiling studies. To provide the clinical background, the histologic profile, and the immunohistochemical profile of these tumors and discuss the current knowledge of their molecular signature and their implications on targeted molecular therapy. Data were obtained from review of the pertinent peer-reviewed literature. Basal-like breast carcinomas are aggressive tumors with poor prognosis. Lack of targeted therapy makes their treatment a challenging task. Traditional chemotherapy is still associated with a high risk of relapse and death in a high percentage of patients. Platinum-based chemotherapy has been considered as a candidate for the treatment of BLBCs owing to their BRCA1 phenotype. Approximately 22% of patients treated with single-agent cisplatin show pathologic complete response, which is a comparable rate to that seen with nonplatinum agents. Antiangiogenic agents have been promising, but their currently demonstrated limited response is considered disappointing. Additionally, epidermal growth factor receptor was not shown to be a helpful target for BLBC. A recent study has shown that BLBC appears to be especially sensitive to MEK inhibitors, making it a promising therapeutic possibility. The list of new targets is still evolving and the "magic" therapeutic target is yet to be discovered.

Tumor Secretion of CCL22 Activates Intratumoral Treg Infiltration and Is Independent Prognostic Predictor of Breast Cancer

It has been reported that dense intratumoral infiltration of Foxp3 +Tregs (Tregs) was an independent factor for poor prognosis of breast cancer (BC) patients. However, the cytokines activating the Treg infiltration are not known. This study was undertaken to evaluate the role of CCL22 and TGF-β1 in this cascade and their prognostic significance for BC patients. 417 cases of invasive breast cancer were selected from the prior study cohort and the expressions of CCL22 and TGF-β1 were assessed by immunohistochemistry. It was identified that tumor secretion of CCL22 was positively correlated with the intratumoral Treg infiltration (P<0.0001), but its association with lymphoid aggregates surrounding the tumor was not proven to be significant (P=0.056). Moreover, CCL22 expression was found to be associated with the tumor histological features known to be related with unfavorable prognosis of patients, including high histological grade (P<0.0001), negative ER (P<0.0001), negative PR (P=0.001), and HER2 amplification (P=0.028). Similar to intratumoral Treg infiltrates, CCL22 tumor secretion correlated with the prognosis of the molecular subtypes of breast carcinoma (P<0.0001). Univariate analysis revealed CCL22 to be an independent prognostic factor for overall survival (OS, P<0.0001) and progression-free survival (PFS, P<0.0001) of BC patients that were confirmed by multivariate analysis (P=0.011 and P=0.010 respectively). In contrast, although TGF-β1 expression was positively correlated with both Tregs infiltrates into the tumor bed and lymphoid aggregates surrounding the tumor (P=0.023; P=0.046, respectively), its expression was not significantly associated with the molecular subtypes of breast carcinoma and the prognosis of the patients. Our study indicates that both CCL22 and TGF-β1 are candidate chemoattractants for intratumoral Foxp3 +Tregs infiltration; however, unlike the later, CCL22 is an independent prognostic predictor of BC patients, and it therefore may have the potential to serve as a target for immunotherapeutic strategy of BC.