Analysis of Breast Cancer Brain Metastases Reveals an Enrichment of Cyclin-Dependent Kinase 12 Structural Rearrangements in Human Epidermal Growth Factor Receptor 2–Positive Disease

PURPOSE Genomic alterations have been identified in patients with breast cancer brain metastases (BCBMs), but large structural rearrangements have not been extensively studied. MATERIALS AND METHODS We analyzed the genomic profiles of 822 BCBMs and compared them with 11,988 local, breast-biopsied breast cancers (BCs) and 15,516 non-CNS metastases (Non-CNS M) derived from formalin-fixed paraffin-embedded material using targeted capture sequencing. RESULTS Nine genes with structural rearrangements were more prevalent within BCBMs as compared with local BCs and Non-CNS M (adjusted- P < .05) and displayed a prevalence of >0.5%. The most common rearrangements within BCBMs involves cyclin-dependent kinase 12 ( CDK12; 3.53%) as compared with the local BC (0.86%; adjusted- P = 7.1 × 10 –8 ) and Non-CNS M specimens (0.68%; adjusted- P = 3.7 × 10 –10 ). CDK12 rearrangements had a significantly higher frequency within human epidermal growth factor receptor 2 (HER2)–positive BCBMs (14.59%) compared with HER2-positive BCs (7.80%; P = 4.6 × 10 –3 ) and HER2-positive Non-CNS M (7.87%; P = 4.8 × 10 –3 ). CONCLUSION The most common structural rearrangements involve CDK12 with the higher prevalence in HER2-positive BCBMs. These data support more detailed investigation of the role and importance of CDK12 rearrangements in BCBMs.