The genomic landscape of breast cancer brain metastases: a systematic review

Breast cancer brain metastases are an increasing clinical problem. Studies have shown that brain metastases from breast cancer have a distinct genomic landscape to that of the primary tumour, including the presence of mutations that are absent in the primary breast tumour. In this Review, we aim to review and evaluate genomic sequencing data for breast cancer brain metastases by searching PubMed, Embase, and Scopus for relevant articles published in English between database inception and May 30, 2020. Extracted information includes data for mutations, receptor status (eg, immunohistochemistry and Prediction Analysis of Microarray 50 [PAM50]), and copy number alterations from published manuscripts and supplementary materials. Of the 431 articles returned by the database search, 13 (3%) breast cancer brain metastases sequencing studies, comprising 164 patients with sequenced brain metastases, met all our inclusion criteria. We identified 268 mutated genes that were present in two or more breast cancer brain metastases samples. Of these 268 genes, 22 (8%) were mutated in five or more patients and pathway enrichment analysis showed their involvement in breast cancer-related signalling pathways, regulation of gene transcription, cell cycle, and DNA repair. Actionability analysis using the Drug Gene Interaction Database revealed that 15 (68%) of these 22 genes are actionable drug targets. In addition, immunohistochemistry and PAM50 data showed receptor discordancy between primary breast cancers and their paired brain metastases. This systematic review provides a detailed overview of the most commonly mutated genes identified in samples of breast cancer brain metastases and their clinical relevance. These data highlight the differences between primary breast cancers and brain metastases and the importance of acquiring and analysing brain metastasis samples for further study.