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Intratumoral heterogeneity of breast cancer
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Poster Abstracts I / The Breast 32S1 (2017) S22–S77
Results: Altogether 47 cases (23.5%) achieved pathologic complete response (pCR). Among the single-nucleotide polymorphism loci of UGT2B7 gene, locus RS1826690, RS184623, RS338583 and RS7435335 showed statistically significant differences with pCR ( p < 0.05). Multivariate logistic analysis demonstrated that clinical stage, targeted therapy, molecular subtype, and the single-nucleotide polymorphisms of RS1826690 and RS7435335 were the independent predictors of pCR in all patients ( p < 0.05). The single-nucleotide polymorphism of RS1826690 was the only independent predictor of pCR for ER positive breast cancer. Conclusion: UGT2B7 gene polymorphism is associated with the epirubicin, docetaxel based chemotherapeutic effect, and may become a genetic predictor of the therapeutic effect of neoadjuvant chemotherapy in breast cancer. Genotype C in locus RS1826690 was associated with higher pCR rate in breast cancer patients. The genotype A in locus RS7435335 was associated with higher pCR rate only in ER positive breast cancer patients. Disclosure of Interest: No significant relationships. P056 Intratumoral heterogeneity of breast cancer S. Anistratov1 *, M. Mnikhovich2, A. Gallyamova2, V. Pechnikova2, K. Midiber2, V. Luchinin1, A. Shilov1. 1Laboratoires De Genie, Moscow, Russia, 2The Research Institute of Human Morphology, Russia In this study we observed intratumoral heterogeneity in breast cancer. The study included 160 patients with breast cancer of T14N0-2M0-1 stage at the age from 21 to 73 years; the prevalence of the disease was defined according to the TNM Classification of Malignant Tumours (1997). Morphological studies were conducted on surgical material. Immunohistochemical examination was carried out with the usage of the following panel of polyclonal antibodies: for estrogen receptors ER, progesterone PgR, Ki-67, Bcl-2, Her2, p63, smooth muscle actin (SMA), a general cytokeratin, cytokeratin 7, vimentin, Ecadherin (Dako, Lab Vision Flex). In all cases, histological form of breast cancer was presented by infiltrating ductal carcinoma. Demonstrated variable expression of Her2, receptors for estrogen and progesterone within the tumor. Invasive carcinoma of no special type(IC NST) makes up essential fraction of breast cancer (75% of all cases). Intratumoral morphological heterogeneity of IC NST is represented by the presence of five different types of infiltrative components or morphological structures including tubular, solid, trabecular, alveolar structures and discrete groups of tumor cells. All tumor cells have both necessary set of molecules for intercellular connections (cadherin-catenin-new complex and β1-integrins family) and integrin receptors that form contacts with the connective tissue matrix. The majority of tumor cells, which are connected to each other and have no connection with the stroma, defines the second subtype, which includes solid and alveolar structures. An exception is the outer layer of cells, which are in contact with the connective tissue. Most tumor cells of such structures express cadherin-catenin complex, but lose the integrin receptors, responsible for connection with the stroma. We discovered the connection between the morphological intratumoral heterogeneity and molecular subtypes. It turned out that three times-negative tumors are more frequently characterized by the presence of one (any) type of morphological structure, while in the luminal breast cancer, generally, there are tumors with five different types of structures. However, not in all patients basal-like breast tumors show significant intratumoral heterogeneity and triplenegative breast cancer is not always a clonally homogeneous tumor. Thus, the analysis of morphological and molecular heterogeneity of breast cancer is the basis for a better understanding of carcinogenesis and tumor progression mechanisms. Disclosure of Interest: No significant relationships.
P057 Structural and functional state of stroma and epithelium in ductal breast cancer M. Mnikhovich*, A. Gallyamova, V. Pechnikova, K. Midiber. The Research Institute of Human Morphology, Moscow, Russia Currently, scientists views are aimed at studying epithelial-stromal relationships, which play an important role in epithelial tumor progression in the direction of the undifferentiated, i.e. more malignant phenotype, where breast cancer (BC) is no exception. One of the reasons is severe desmoplastic reaction of the tumor stroma, which makes up to 70–80% of the tumor tissue and which is manifested in the hyperexpression of extracellular matrix proteins and proliferation of myofibroblasts. We performed an analysis of surgical specimens from 118 patients with ductal breast cancer between 2009 and 2015. The age of patients was ranged from 40 to 80 years old. The average age of patients −61 y/o. The material was studied with light and electron microscopy and with the usage of immunohistochemical methods. Immunohistochemical studies were performed using a following panel of polyclonal antibodies: p63, smooth muscle actin (SMA), total cytokeratin, cytokeratin 7, vimentin, E-cadherin (Dako, Lab Vision Flex). The classic version of ductal breast cancer in its histological structure is usually a heterogeneous tumor, which is represented by the areas of varied differentiation – from high to low, including anaplastic component. In the test series anaplastic component was present in 21.2% (25/118) of the cases. It has to be allocated even when it’s insignificant in the total amount of tumor mass, because tumors with anaplastic component have not only a difference in the histological structure, but also in their malignant potential, as well as in the expression of epithelial, mesenchymal and immunohistochemical myoepithelial markers. Histologically, desmoplasia of the stroma, which is typical of ductal breast cancer, is completely absent in anaplastic areas. Tumor cells, settling close to each other, create a semblance of stromal framework from themselves. Also, revealed cases of diffuse expression of vimentin, smooth muscle actin and p63 in anaplastic cells confirm that in the process of differentiation loss, tumor cells acquire myoepithelial and/or mesenchymal phenotype. This fact is associated with epithelial-mesenchymal transition in tumors, the main criteria of which is the loss of epithelial polarity, separation into individual cells and dispersion with the acquisition of cell motility. This results in the destruction of dense adhesion contacts (reduction and change in polarity of expression of E-cadherin) and the restructure of complexes, which provide the attachment of cells to the substrate. However, the partially preserved expression of cytokeratin and epithelial membrane antigen indicate preservation of cytokeratin receptors and possible reverse transformation under changes in microenvironments. Thus, the growing interest of researchers in the epithelial-stromal interactions in ductal breast cancer are due to its aggressive biological behavior, it’s resistance to chemotherapy and due to different survivability of patients depending on the differentiation of the tumor. Heterogeneity of ductal carcinoma is manifested by the anaplastic (sarcomatoid) component, where we can trace the ability of epithelial tumor cells to acquire a properties of mesenchymal cells, which do not require the stroma and have an aggressive malignant potential, affecting the survival of patients. Disclosure of Interest: No significant relationships.
Poster Abstracts I / The Breast 32S1 (2017) S22–S77
Results: Altogether 47 cases (23.5%) achieved pathologic complete response (pCR). Among the single-nucleotide polymorphism loci of UGT2B7 gene, locus RS1826690, RS184623, RS338583 and RS7435335 showed statistically significant differences with pCR ( p < 0.05). Multivariate logistic analysis demonstrated that clinical stage, targeted therapy, molecular subtype, and the single-nucleotide polymorphisms of RS1826690 and RS7435335 were the independent predictors of pCR in all patients ( p < 0.05). The single-nucleotide polymorphism of RS1826690 was the only independent predictor of pCR for ER positive breast cancer. Conclusion: UGT2B7 gene polymorphism is associated with the epirubicin, docetaxel based chemotherapeutic effect, and may become a genetic predictor of the therapeutic effect of neoadjuvant chemotherapy in breast cancer. Genotype C in locus RS1826690 was associated with higher pCR rate in breast cancer patients. The genotype A in locus RS7435335 was associated with higher pCR rate only in ER positive breast cancer patients. Disclosure of Interest: No significant relationships. P056 Intratumoral heterogeneity of breast cancer S. Anistratov1 *, M. Mnikhovich2, A. Gallyamova2, V. Pechnikova2, K. Midiber2, V. Luchinin1, A. Shilov1. 1Laboratoires De Genie, Moscow, Russia, 2The Research Institute of Human Morphology, Russia In this study we observed intratumoral heterogeneity in breast cancer. The study included 160 patients with breast cancer of T14N0-2M0-1 stage at the age from 21 to 73 years; the prevalence of the disease was defined according to the TNM Classification of Malignant Tumours (1997). Morphological studies were conducted on surgical material. Immunohistochemical examination was carried out with the usage of the following panel of polyclonal antibodies: for estrogen receptors ER, progesterone PgR, Ki-67, Bcl-2, Her2, p63, smooth muscle actin (SMA), a general cytokeratin, cytokeratin 7, vimentin, Ecadherin (Dako, Lab Vision Flex). In all cases, histological form of breast cancer was presented by infiltrating ductal carcinoma. Demonstrated variable expression of Her2, receptors for estrogen and progesterone within the tumor. Invasive carcinoma of no special type(IC NST) makes up essential fraction of breast cancer (75% of all cases). Intratumoral morphological heterogeneity of IC NST is represented by the presence of five different types of infiltrative components or morphological structures including tubular, solid, trabecular, alveolar structures and discrete groups of tumor cells. All tumor cells have both necessary set of molecules for intercellular connections (cadherin-catenin-new complex and β1-integrins family) and integrin receptors that form contacts with the connective tissue matrix. The majority of tumor cells, which are connected to each other and have no connection with the stroma, defines the second subtype, which includes solid and alveolar structures. An exception is the outer layer of cells, which are in contact with the connective tissue. Most tumor cells of such structures express cadherin-catenin complex, but lose the integrin receptors, responsible for connection with the stroma. We discovered the connection between the morphological intratumoral heterogeneity and molecular subtypes. It turned out that three times-negative tumors are more frequently characterized by the presence of one (any) type of morphological structure, while in the luminal breast cancer, generally, there are tumors with five different types of structures. However, not in all patients basal-like breast tumors show significant intratumoral heterogeneity and triplenegative breast cancer is not always a clonally homogeneous tumor. Thus, the analysis of morphological and molecular heterogeneity of breast cancer is the basis for a better understanding of carcinogenesis and tumor progression mechanisms. Disclosure of Interest: No significant relationships.
P057 Structural and functional state of stroma and epithelium in ductal breast cancer M. Mnikhovich*, A. Gallyamova, V. Pechnikova, K. Midiber. The Research Institute of Human Morphology, Moscow, Russia Currently, scientists views are aimed at studying epithelial-stromal relationships, which play an important role in epithelial tumor progression in the direction of the undifferentiated, i.e. more malignant phenotype, where breast cancer (BC) is no exception. One of the reasons is severe desmoplastic reaction of the tumor stroma, which makes up to 70–80% of the tumor tissue and which is manifested in the hyperexpression of extracellular matrix proteins and proliferation of myofibroblasts. We performed an analysis of surgical specimens from 118 patients with ductal breast cancer between 2009 and 2015. The age of patients was ranged from 40 to 80 years old. The average age of patients −61 y/o. The material was studied with light and electron microscopy and with the usage of immunohistochemical methods. Immunohistochemical studies were performed using a following panel of polyclonal antibodies: p63, smooth muscle actin (SMA), total cytokeratin, cytokeratin 7, vimentin, E-cadherin (Dako, Lab Vision Flex). The classic version of ductal breast cancer in its histological structure is usually a heterogeneous tumor, which is represented by the areas of varied differentiation – from high to low, including anaplastic component. In the test series anaplastic component was present in 21.2% (25/118) of the cases. It has to be allocated even when it’s insignificant in the total amount of tumor mass, because tumors with anaplastic component have not only a difference in the histological structure, but also in their malignant potential, as well as in the expression of epithelial, mesenchymal and immunohistochemical myoepithelial markers. Histologically, desmoplasia of the stroma, which is typical of ductal breast cancer, is completely absent in anaplastic areas. Tumor cells, settling close to each other, create a semblance of stromal framework from themselves. Also, revealed cases of diffuse expression of vimentin, smooth muscle actin and p63 in anaplastic cells confirm that in the process of differentiation loss, tumor cells acquire myoepithelial and/or mesenchymal phenotype. This fact is associated with epithelial-mesenchymal transition in tumors, the main criteria of which is the loss of epithelial polarity, separation into individual cells and dispersion with the acquisition of cell motility. This results in the destruction of dense adhesion contacts (reduction and change in polarity of expression of E-cadherin) and the restructure of complexes, which provide the attachment of cells to the substrate. However, the partially preserved expression of cytokeratin and epithelial membrane antigen indicate preservation of cytokeratin receptors and possible reverse transformation under changes in microenvironments. Thus, the growing interest of researchers in the epithelial-stromal interactions in ductal breast cancer are due to its aggressive biological behavior, it’s resistance to chemotherapy and due to different survivability of patients depending on the differentiation of the tumor. Heterogeneity of ductal carcinoma is manifested by the anaplastic (sarcomatoid) component, where we can trace the ability of epithelial tumor cells to acquire a properties of mesenchymal cells, which do not require the stroma and have an aggressive malignant potential, affecting the survival of patients. Disclosure of Interest: No significant relationships.