GS03-09 Characterization and proposed therapeutic exploitation of fusion RNAs in metastatic breast cancers

Nolan Priedigkeit, MD, PhD 

Lay Summary 

Breast cancer is unique among cancers, in that there are many large structural changes in breast cancer DNA. Occasionally, these large genomic changes can result in two genes that are normally far apart in the genome to fuse together, producing a single mutant fusion gene. In this study, we set out to better characterize fusion genes—particularly in the metastatic setting—through analysis of a large cohort of sequencing data and implementing a rigorous “fusion-finding” method. We found the number of fusion genes differ between breast cancer subtypes; with basal/triple-negative breast cancers harboring the most. We identified rare fusion genes that may be druggable with existing drugs. Additionally, we discovered both known and novel Estrogen Receptor fusions. These Estrogen Receptor fusions were present in approximately 5% of treatment-resistant Estrogen Receptor positive tumors—and importantly lose the region targeted by existing endocrine therapies, making these common treatments ineffective. Lastly, we find that fusions can be present in many metastatic sites in an individual patient and are importantly absent in normal tissue, thereby presenting promising cancer-specific targets. In summary, we propose that fusion RNAs may represent an underrecognized driver of therapy-resistant disease and postulate fusion RNA sequences present a compelling therapeutic opportunity in metastatic breast cancer with recent advances in gene therapy.