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

Abstract

BackgroundThe 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.MethodsWe 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.ResultsIncreased 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.ConclusionsIncreased 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2302-5) contains supplementary material, which is available to authorized users.

NRSN2 promotes breast cancer metastasis by activating PI3K/AKT/mTOR and NF‑κB signaling pathways

“…Tumor markers have been widely used for the diagnosis of early stage breast cancer in patients (19)(20)(21). The present study demonstrated that NRSN2 was significantly upregulated in breast cancer tissues compared with adjacent noncancerous tissues.…”

The role of collagen in cancer: from bench to bedside

“…Increased infiltration of macrophages and lymphocytes was also observed in subcutaneous adipose collagen in gastrointestinal cancer patients with cachexia [121]. However, increased stromal COL10A1 was accompanied by low numbers of total tumor-infiltrating lymphocytes in ER-positive/EGFR2-positive breast cancer [122]. The location and quantity of collagen with lymphocytes reinforce discrepant cancer progression via distinct signaling pathways.…”

Bioinformatics analysis of prognostic significance of COL10A1 in breast cancer

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