O43: CLINICAL IMPACT OF GENE FUSIONS IN BREAST CANCER BRAIN METASTASES

Abstract

Introduction: The incidence of brain metastases is increasing despite longer survival rates for patients with advanced breast cancer. The identification of novel therapeutic targets for these patients is an urgent unmet clinical need. Sequencing of metastatic tumours have largely focused on mutations however gene fusions have an important, yet underappreciated role in tumorigenesis and disease progression. In this study, we investigate the role of gene fusions in brain metastatic disease and their impact on altered therapeutic responses. Method: RNA sequencing was performed on the largest reported cohort of patient matched primary and resected brain metastatic tumours (45 patients n=90 samples). Expressed gene fusions were detected computationally using STAR-Fusion and Arriba. Result: We identified differential gene fusion burden in brain metastatic tumours (medium of 58) vs. primary breast tumours (medium of 38) (p <0.05). Enrichment for fusions in pathways associated with tumour cell plasticity and proliferation with recurrent fusions in known cancer driver genes related to MAPK, HERsignaling identified. Of note, a fusion in CDK12 is of clinical importance. Increased genomic alterations and over expression of CDK12 is associated with brain metastases free survival in an independent cohort of primary breast tumourswith a recorded history of brain metastases. It has been proposed that inhibition of CDK12 may induce BRCAness in tumoursmaking them sensitive to PARP inhibition. Conclusion: These results highlight the significant role of gene fusions in breast cancer brain metastases.