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

Abstract

Understanding the genomic landscape of breast cancer brain metastases (BCBMs) is key to elucidating their cause and developing novel treatments. In this study, comprehensive 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). Clinically-relevant genomic alterations were significantly enriched in BCBMs compared to local BCs and N-CNS metastases. Homologous recombination deficiency as measured by BRCA1/2alteration 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). Collectively, our data highlights that a high proportion of BCBMs are potentially amenable to treatment with targeted therapeutic agents including PARP inhibitors and ICIs.