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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

Flow diagram of the approach to identify and test Col10A1 in ER+/HER2+ breast tumors. From 538 patients, 74 ER+/HER2+ breast tumors were selected for analysis. 11 ER+/HER2+ tumors were selected for expression profiling using Affymetrix HTA 2.0 microarrays. After qPCR verification, we evaluated the level of colXα1 protein in primary tumors before NAC using immunohistochemistry to test the expression of colXα1 protein levels in 50 ER+/HER2+ breast tumors with available tissue
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Fig1: Flow diagram of the approach to identify and test Col10A1 in ER+/HER2+ breast tumors. From 538 patients, 74 ER+/HER2+ breast tumors were selected for analysis. 11 ER+/HER2+ tumors were selected for expression profiling using Affymetrix HTA 2.0 microarrays. After qPCR verification, we evaluated the level of colXα1 protein in primary tumors before NAC using immunohistochemistry to test the expression of colXα1 protein levels in 50 ER+/HER2+ breast tumors with available tissue

Mentions: Among 538 patients who received NAC at the participating hospital, we identified 74 ER+/HER2+ patients for whom we had pathologic response data and sufficient pretreatment tissue for analysis (Fig. 1). Their clinical and pathologic data are summarized in Table 1; 92 % (68 of 74) were clinical stage ≥ IIB. Most received either doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab (n = 33) or docetaxel, carboplatin and trastuzumab (n = 35). The addition of pertuzumab to the neoadjuvant regimen for HER2+ cancer had not yet been routinely adopted. 19 % (14 of 74) of patients achieved a complete pCR (RCB class 0), and 40.54 % (30 of 74) had a good pathologic response (RCB class 0 or I). There were no significant statistical differences in the post-treatment response between patients who received TCH vs. AC-TH treatment options.Fig. 1


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)

Flow diagram of the approach to identify and test Col10A1 in ER+/HER2+ breast tumors. From 538 patients, 74 ER+/HER2+ breast tumors were selected for analysis. 11 ER+/HER2+ tumors were selected for expression profiling using Affymetrix HTA 2.0 microarrays. After qPCR verification, we evaluated the level of colXα1 protein in primary tumors before NAC using immunohistochemistry to test the expression of colXα1 protein levels in 50 ER+/HER2+ breast tumors with available tissue
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Flow diagram of the approach to identify and test Col10A1 in ER+/HER2+ breast tumors. From 538 patients, 74 ER+/HER2+ breast tumors were selected for analysis. 11 ER+/HER2+ tumors were selected for expression profiling using Affymetrix HTA 2.0 microarrays. After qPCR verification, we evaluated the level of colXα1 protein in primary tumors before NAC using immunohistochemistry to test the expression of colXα1 protein levels in 50 ER+/HER2+ breast tumors with available tissue
Mentions: Among 538 patients who received NAC at the participating hospital, we identified 74 ER+/HER2+ patients for whom we had pathologic response data and sufficient pretreatment tissue for analysis (Fig. 1). Their clinical and pathologic data are summarized in Table 1; 92 % (68 of 74) were clinical stage ≥ IIB. Most received either doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab (n = 33) or docetaxel, carboplatin and trastuzumab (n = 35). The addition of pertuzumab to the neoadjuvant regimen for HER2+ cancer had not yet been routinely adopted. 19 % (14 of 74) of patients achieved a complete pCR (RCB class 0), and 40.54 % (30 of 74) had a good pathologic response (RCB class 0 or I). There were no significant statistical differences in the post-treatment response between patients who received TCH vs. AC-TH treatment options.Fig. 1

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