Targetable genomic profiling of breast cancer brain metastases identifies alterations and genomic signatures relevant to immune-checkpoint and PARP inhibitors

Abstract Introduction: Understanding the genomic landscape of breast cancer brain metastases (BCBMs) is key to developing targeted treatments. Materials and Methods In this study, targetable genomic profiling was performed on 822 BCBMs, 11,988 local breast cancer (BC) biopsies and 15,516 non-central nervous system (N-CNS) metastases (all unpaired samples) collected during the course of routine clinical care by Foundation Medicine Inc (Cambridge, MA). Results Clinically relevant genomic alterations were significantly enriched in BCBMs compared to local BCs and N-CNS metastases. Homologous recombination deficiency as measured by BRCA1/2 alteration prevalence and loss-of-heterozygosity and immune checkpoint inhibitor (ICI) biomarkers Tumour mutation burden (TMB)-High, Microsatellite instability (MSI)-High, PD-L1/L2) were significantly more prevalent in BCBM than local BC and N-CNS. High PD-L1 protein expression was observed in ER-negative/HER2-negative BCBMs (48.3% vs 50.0% in local BCs, 21.4% in N-CNS). Conclusion Collectively, our data highlights that a high proportion of BCBMs are potentially amenable to treatment with targeted therapeutic agents including PARP inhibitors and ICIs.