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Identification of stromal ColXα1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer.

Brodsky AS, Xiong J, Yang D, Schorl C, Fenton MA, Graves TA, Sikov WM, Resnick MB, Wang Y - BMC Cancer (2016)

Bottom Line: We performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients.Increased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response.ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, USA. alex_brodsky@brown.edu.

ABSTRACT

Background: The influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and immunohistochemistry with pathologic response.

Methods: We performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients. Gene set enrichment analysis identified potentially relevant pathways, and immunohistochemical staining of pre-treatment biopsies was used to measure protein levels of those pathways, which were correlated with pathologic response in both univariate and multivariate analysis.

Results: Increased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response. Lower TILs in tumor biopsies correlated with reduced likelihood of achieving an optimal pathologic response, but increased expression of the Col10A1 gene product, colXα1, had greater predictive value than stromal abundance for poor response (OR = 18.9, p = 0.003), and the combination of increased colXα1 expression and low TILs was significantly associated with poor response in multivariate analysis. ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.

Conclusions: Increased expression of stromal colXα1 and low TILs correlate with poor pathologic response in ER+/HER2+ breast tumors. Further studies are needed to confirm their predictive value and impact on long-term outcomes, and to determine whether this collagen exerts a protective effect on the cancer cells or simply reflects other factors within the tumor microenvironment.

No MeSH data available.


Related in: MedlinePlus

Col10A1 expression is correlated with epithelial-mesenchymal transition gene sets. GSEA reveals the Epithelial-Mesenchymal Transition Hallmark gene set is strongly enriched in Col10A1 positively correlated genes in both the RIH dataset and in 123 TCGA ER+/HER2+ breast tumors
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Fig5: Col10A1 expression is correlated with epithelial-mesenchymal transition gene sets. GSEA reveals the Epithelial-Mesenchymal Transition Hallmark gene set is strongly enriched in Col10A1 positively correlated genes in both the RIH dataset and in 123 TCGA ER+/HER2+ breast tumors

Mentions: To assess how colXα1 may be inducing chemoresistance, we evaluated the genes correlated with ColXA1 mRNA expression. Pathways associated with increased metabolism, chemoresistance and oncogenicity are strongly correlated with ColXA1 expression (see Additional file 5: Table S4). GSEA analysis of the ranked list of ColXA1 correlated genes revealed that the Epithelial-Mesenchymal Transition (EMT) hallmark gene set was strongly enriched (Fig. 5). Collagens are reported to help drive the mesenchymal state in tumors [21]. To further test the potential connection between ColXA1 and EMT we evaluated the co-expression in 123 TCGA invasive ER+/HER2+ breast tumors with RNA-seq expression data. Collagen positively correlated transcripts include EMT enrichment including the EMT transcription factor, SNAI2, GPX8, thought to help protect cells from oxidative damage, other collagens (Col12A1 and Col11A1) and collagen binding proteins including fibronectin, suggesting a broad network of a ColXA1 based network (see Additional file 5: Table S4). Collagens are known to increase matrix stiffness, which can induce EMT [22]. Other pathways enriched in highly correlated Col10A1 genes include TGFB signaling (TGFB3 and MAPK3). These findings support a connection between the expression of colXa1, EMT, the expression of putative resistance mechanisms, and response in the neoadjuvant setting.Fig. 5


Identification of stromal ColXα1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer.

Brodsky AS, Xiong J, Yang D, Schorl C, Fenton MA, Graves TA, Sikov WM, Resnick MB, Wang Y - BMC Cancer (2016)

Col10A1 expression is correlated with epithelial-mesenchymal transition gene sets. GSEA reveals the Epithelial-Mesenchymal Transition Hallmark gene set is strongly enriched in Col10A1 positively correlated genes in both the RIH dataset and in 123 TCGA ER+/HER2+ breast tumors
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835834&req=5

Fig5: Col10A1 expression is correlated with epithelial-mesenchymal transition gene sets. GSEA reveals the Epithelial-Mesenchymal Transition Hallmark gene set is strongly enriched in Col10A1 positively correlated genes in both the RIH dataset and in 123 TCGA ER+/HER2+ breast tumors
Mentions: To assess how colXα1 may be inducing chemoresistance, we evaluated the genes correlated with ColXA1 mRNA expression. Pathways associated with increased metabolism, chemoresistance and oncogenicity are strongly correlated with ColXA1 expression (see Additional file 5: Table S4). GSEA analysis of the ranked list of ColXA1 correlated genes revealed that the Epithelial-Mesenchymal Transition (EMT) hallmark gene set was strongly enriched (Fig. 5). Collagens are reported to help drive the mesenchymal state in tumors [21]. To further test the potential connection between ColXA1 and EMT we evaluated the co-expression in 123 TCGA invasive ER+/HER2+ breast tumors with RNA-seq expression data. Collagen positively correlated transcripts include EMT enrichment including the EMT transcription factor, SNAI2, GPX8, thought to help protect cells from oxidative damage, other collagens (Col12A1 and Col11A1) and collagen binding proteins including fibronectin, suggesting a broad network of a ColXA1 based network (see Additional file 5: Table S4). Collagens are known to increase matrix stiffness, which can induce EMT [22]. Other pathways enriched in highly correlated Col10A1 genes include TGFB signaling (TGFB3 and MAPK3). These findings support a connection between the expression of colXa1, EMT, the expression of putative resistance mechanisms, and response in the neoadjuvant setting.Fig. 5

Bottom Line: We performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients.Increased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response.ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, USA. alex_brodsky@brown.edu.

ABSTRACT

Background: The influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and immunohistochemistry with pathologic response.

Methods: We performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients. Gene set enrichment analysis identified potentially relevant pathways, and immunohistochemical staining of pre-treatment biopsies was used to measure protein levels of those pathways, which were correlated with pathologic response in both univariate and multivariate analysis.

Results: Increased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response. Lower TILs in tumor biopsies correlated with reduced likelihood of achieving an optimal pathologic response, but increased expression of the Col10A1 gene product, colXα1, had greater predictive value than stromal abundance for poor response (OR = 18.9, p = 0.003), and the combination of increased colXα1 expression and low TILs was significantly associated with poor response in multivariate analysis. ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.

Conclusions: Increased expression of stromal colXα1 and low TILs correlate with poor pathologic response in ER+/HER2+ breast tumors. Further studies are needed to confirm their predictive value and impact on long-term outcomes, and to determine whether this collagen exerts a protective effect on the cancer cells or simply reflects other factors within the tumor microenvironment.

No MeSH data available.


Related in: MedlinePlus