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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

Association of colXα1 expression with NAC response. a Box plot of the Col10A1 probeset on the Affymetrix HTA 2.0 microarray distinguishes good and poor responding ER+/HER2+ breast tumors. The one outlier on the array, has an intermediate colXα1 IHC score of 1. b Gene Set Enrichment Analysis reveals enrichment of the Gene Ontology (GO) category, collagens, in pCR resistant ER+/HER2+ breast tumors. Each black line represents one gene in the GO collagen gene set. c Heat map of mRNA expression changes for all measured collagens on the microarray. d qPCR of Col10A1 mRNA expression correlates with the microarray data
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Fig2: Association of colXα1 expression with NAC response. a Box plot of the Col10A1 probeset on the Affymetrix HTA 2.0 microarray distinguishes good and poor responding ER+/HER2+ breast tumors. The one outlier on the array, has an intermediate colXα1 IHC score of 1. b Gene Set Enrichment Analysis reveals enrichment of the Gene Ontology (GO) category, collagens, in pCR resistant ER+/HER2+ breast tumors. Each black line represents one gene in the GO collagen gene set. c Heat map of mRNA expression changes for all measured collagens on the microarray. d qPCR of Col10A1 mRNA expression correlates with the microarray data

Mentions: We aimed to identify a representative transcript of a pathway or group of transcripts that we could test by IHC in an extended cohort of tumors. The collagen Gene Ontology gene set is strongly biased towards poor responding tumors (NES = −1.9, FDR = 0.009) (Fig. 2) and three transcripts encoding collagens (Col10A1, Col14A1, and COL3A1) were among the most significant differentially expressed genes (see Additional file 4: Table S3).Fig. 2


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)

Association of colXα1 expression with NAC response. a Box plot of the Col10A1 probeset on the Affymetrix HTA 2.0 microarray distinguishes good and poor responding ER+/HER2+ breast tumors. The one outlier on the array, has an intermediate colXα1 IHC score of 1. b Gene Set Enrichment Analysis reveals enrichment of the Gene Ontology (GO) category, collagens, in pCR resistant ER+/HER2+ breast tumors. Each black line represents one gene in the GO collagen gene set. c Heat map of mRNA expression changes for all measured collagens on the microarray. d qPCR of Col10A1 mRNA expression correlates with the microarray data
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Association of colXα1 expression with NAC response. a Box plot of the Col10A1 probeset on the Affymetrix HTA 2.0 microarray distinguishes good and poor responding ER+/HER2+ breast tumors. The one outlier on the array, has an intermediate colXα1 IHC score of 1. b Gene Set Enrichment Analysis reveals enrichment of the Gene Ontology (GO) category, collagens, in pCR resistant ER+/HER2+ breast tumors. Each black line represents one gene in the GO collagen gene set. c Heat map of mRNA expression changes for all measured collagens on the microarray. d qPCR of Col10A1 mRNA expression correlates with the microarray data
Mentions: We aimed to identify a representative transcript of a pathway or group of transcripts that we could test by IHC in an extended cohort of tumors. The collagen Gene Ontology gene set is strongly biased towards poor responding tumors (NES = −1.9, FDR = 0.009) (Fig. 2) and three transcripts encoding collagens (Col10A1, Col14A1, and COL3A1) were among the most significant differentially expressed genes (see Additional file 4: Table S3).Fig. 2

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