PO-143 Recurrent transcriptional remodelling events represent clinically actionable targets in breast cancers brain metastasis

Abstract

Introduction Breast cancer brain metastases are defined by complex adaptation to both adjuvant treatment regimens and the brain microenvironment. Consequences of these alterations remain poorly understood, as does their potential for clinical targeting. We aimed to comprehensively elucidate the transcriptome evolution in breast to brain metastases and to define key regulators of metastatic spread, thus, aiding in the identification of novel therapeutic strategies. Material and methods 21 patient-matched primary breast tumours and their associated brain metastases from two academic institutions were RNA-sequenced. A comprehensive computational pipeline was used to investigate transcriptome evolution in breast to brain metastases. Gene expression changes were determined and prioritised based on clinical utility. To determine if these longitudinal alterations can be targeted in vitro, ex vivo and in vivo experiments were performed. Results and discussions Our studies revealed a comprehensive list of genes enriched in brain metastases compared to patientmatched primary breast tumours, including genes previously implicated in experimental models in the early events of vascular co-option, and those found to be essential for early survival and brain metastatic outgrowth. Our work also points to many novel candidate breast to brain metastasis genes. We observe that breast cancer-specific genes shift their expression profile upon brain metastasis, and demonstrate recurrent enrichment in druggable kinase-driven signalling (RET, ERBB2) and conclusive activation of the HER2 pathway in brain metastasis. In line with these observations, inhibition of aberrant RET and HER2 results in significant anti-tumour activity in breast cancer brain metastasis patient-derived xenograft models and patient resected brain metastasis cultured ex-vivo. We report on clinically and biologically relevant gene expression alterations occurring as breast cancer cells metastasize to the brain. Altogether, this study1 establishes recurrent, acquired vulnerabilities in brain metastasis that warrant immediate clinical investigation and2 suggests paired specimen expression profiling as a compelling and underutilised strategy to identify targetable dependencies in advanced cancers. Conclusion Our findings deliver compelling proof-of-principle for exploiting longitudinal transcriptional changes in advanced cancer, which is especially important given the field's current focus on DNA-level changes in tumour profiling.