Molecular and Clinical Analyses of Gene Fusions Identify Therapeutic Targets in Paired Primary and Metastatic Breast Cancer from the AURORA Program (BIG 14-01)

Purpose: Gene fusions are molecular rearrangements with oncogenic potential. However, their role in disease progression and therapy resistance remains largely unexplored, particularly in breast cancer. Experimental Design: In this study, we utilized multiomics data from the AURORA program to characterize gene fusions in metastatic breast cancer. We analyzed RNA sequencing data from 325 primary tumors and 350 metastatic lesions across 476 patients to develop a high-confidence catalog of gene fusions. Results: In a subset of 398 matched samples from 199 patients, we observed a higher burden of gene fusions in metastatic tumors compared with their corresponding primary tumors. Metastaticspecific (acquired) gene fusions were characterized by few recurrent rearrangements and were generally absent in patients with de novo metastatic disease. We observed a colocalization of gene fusions with subtype-specific copy-number gains. Various scores indicative of genomic instability were found to be associated with the gene fusion burden. Fusions involving genes located within the same topologically associating domain (TAD) were common in HER2-positive tumors and frequently acquired in metastatic triplenegative breast cancer. The presence of gene fusions, particularly those that were acquired or involved in genes within the same TAD, was associated with poor prognosis in estrogen receptor– positive/HER2-negative tumors. Patients with acquired ESR1 fusions exhibited a more aggressive disease course, characterized by shorter treatment response and poorer clinical outcomes. Conclusions: The AURORA gene fusion catalog may serve as a valuable resource for identifying targetable genetic alterations, thereby supporting the development of more effective therapeutic strategies for breast cancer.