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Predicting the evolution of metastatic disease in breast cancer: results from 50 years of autopsies

ABSTRACT: This is a genomic analysis of breast cancer metastasis using array based CGH and is part of a large study investigating the patterns and evolution of metastases from breast cancer using autopsy material accumulated over the last 50 years from a single institution. The samples used in the genomic profiling comprise the primary breast tumour and multiple matched metastases from each patient. The data demonstrate both the clonal nature of metastatic progression and the role of clonal evolution during progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46826 | GEO | 2013/11/11

SECONDARY ACCESSION(S): PRJNA202420

REPOSITORIES: GEO

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Project description:The goal of this dataset is to compare the gene expression patterns between primary and metastatic tumors Metastatic cancer patients typically have short survival times and their successful treatment represents one of most challenging aspects of patient care. This poor prognostic behavior is likely due to many factors, including increased clonal heterogeneity, multiple drug resistance mechanisms, and the role of the tumor microenvironment. The AURORA US Metastasis Project was established to collect and molecularly characterize specimens from 55 breast cancer (BC) patients representing 51 primary cancers and 102 metastases. The 153 unique tumors were assayed using RNAseq, tumor/germline DNA exomes and low pass whole genome sequencing, and global DNA methylation microarrays. We found intrinsic molecular subtype differences between primary tumors and their matched metastases to be rare in triple negative breast cancer (TNBC)/Basal-like subtype tumors. Conversely, tumor subtype changes were relatively frequent in estrogen receptor positive (ER+) cancers where ~30% of Luminal A cases switched to Luminal B or HER2-enriched (HER2E) subtype. Clonal evolution studies identified changes in expression subtype coincident with DNA clonality shifts, especially involving HER2 amplification and/or the HER2E expression subtype. Microenvironment differences varied according to tumor subtype where ER+/Luminal metastases had lower fibroblast and endothelial cell content, while TNBC/Basal-like metastases showed a dramatic decrease in adaptive immunity. In 17% of metastatic tumors, we identified DNA methylation and/or focal DNA deletions near HLA-A that were associated with its significantly reduced expression, and with lower immune cell infiltrates. We also identified low immune cell features in brain and liver metastases when compared to other metastatic sites, even within the same patient. These findings have direct implications for the treatment of metastatic breast cancer patients with immune- and HER2-targeting therapies and suggest potential novel therapeutic avenues for the improvement of outcomes for some MBC patients.

Dataset Information

Predicting the evolution of metastatic disease in breast cancer: results from 50 years of autopsies

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