Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis–Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer

Abstract

in collaboration with the TEX study group Abstract Purpose: The complete molecular basis of the organ-specificity of metastasis is elusive. This study aimed to provide an independent characterization of the transcriptional landscape of breast cancer metastases with the specific objective to identify liver metastasis-selective genes of prognostic importance following primary tumor diagnosis.Experimental Design: A cohort of 304 women with advanced breast cancer was studied. Associations between the site of recurrence and clinicopathologic features were investigated. Fine-needle aspirates of metastases (n ¼ 91) were subjected to whole-genome transcriptional profiling. Liver metastasis-selective genes were identified by significance analysis of microarray (SAM) analyses and independently validated in external datasets. Finally, the prognostic relevance of the liver metastasis-selective genes in primary breast cancer was tested.Results: Liver relapse was associated with estrogen receptor (ER) expression (P ¼ 0.002), luminal B subtype (P ¼ 0.01), and was prognostic for an inferior postrelapse survival (P ¼ 0.01). The major variation in the transcriptional landscape of metastases was also associated with ER expression and molecular subtype. However, liver metastases displayed unique transcriptional fingerprints, characterized by downregulation of extracellular matrix (i.e., stromal) genes. Importantly, we identified a 17-gene liver metastasis-selective signature, which was significantly and independently prognostic for shorter relapse-free (P < 0.001) and overall (P ¼ 0.001) survival in ER-positive tumors. Remarkably, this signature remained independently prognostic for shorter relapse-free survival (P ¼ 0.001) among luminal A tumors.Conclusions: Extracellular matrix (stromal) genes can be used to partition breast cancer by site of relapse and may be used to further refine prognostication in ER positive primary breast cancer.

A Population-Based Study on Liver Metastases in Women with Newly Diagnosed Breast Cancer

“…Remarkably, a higher incidence of liver metastases was found in patients with breast cancer with HER2-positive status. This is consistent with previous studies that showed organ specificity associated with specific gene (14,25,30,31). An early study suggested that decreased or abnormal expression of a number of cell adhesion/junctional proteins, including claudin 4, 7, ZO-1, and g-catenin, correlated with breast cancer liver metastases (30).…”

“…As a result, the changes caused by distant relapse and treatment exposure could be potential confounding factors in the prognostic assessment (12). In addition, the prognosis of patients with liver metastases from breast cancer is usually extremely poor, with 5-year survival rates of only 3.8% to 12% (6,(13)(14)(15). Because liver metastases have a significant influence on the morbidity and prognosis of patients with breast cancer, the early detection of liver metastases is of utmost importance.…”

Microenvironment‐induced TIMP2 loss by cancer‐secreted exosomal miR‐4443 promotes liver metastasis of breast cancer

“…In addition, it is well‐known that liver is the third most common site for the metastasis of BCa, resulting in the poorer prognosis than local/regional, bone, and lung metastases (Kimbung et al, 2016; Ma et al, 2015; C. Zhang et al, 2018). The standard of care for patients with BCa liver metastasis is palliative therapy, including the sequential application of hormonal agents and/or cytotoxic chemotherapy agents (Gradishar et al, 2014).…”

“…In addition, it is well-known that liver is the third most common site for the metastasis of BCa, resulting in the poorer prognosis than local/ regional, bone, and lung metastases (Kimbung et al, 2016;Ma et al, 2015;C. Zhang et al, 2018).…”

Increased risk of brain metastases in women with breast cancer and p16 expression in metastatic lymph-nodes

“…However, very few genomic studies have been performed on metastatic samples of breast cancer; they have usually been smaller in size and performed on tumor samples that were not laser-microdissected [25–28]. In a larger series of 80 patients [29], the samples were fine-needle aspirates and the histological sub-type was unknown, more than 60% matched-primary tumors being estrogen-receptor positive. In our study, only triple negative and HER2-overexpressing breast cancers were considered.…”