Genomics of Breast Cancer Brain Metastases: A Meta-Analysis and Therapeutic Implications

SIMPLE SUMMARY: Breast cancer brain metastases are a challenging daily practice, and the biological link between gene mutations and metastatic spread to the brain remains to be determined. We performed a meta-analysis on genomic data obtained from primary tumors, extracerebral metastases and brain metastases, to identify gene alterations associated with brain metastatic processes. Fifty-seven publications were selected for this meta-analysis, including 37,218 patients in all, 11,906 primary tumor samples, 5541 extracerebral metastasis samples, and 1485 brain metastasis samples. Using a threshold of 1% for mutation prevalence in the primary tumor, we identified 53 genes, among which 21 were associated with significant differences in prevalence between subgroups (primary tumor, extracerebral metastases, and brain metastases). In particular, we identified six genes with a higher mutation prevalence in brain metastases than in extracerebral metastases: ESR1, ERBB2, EGFR, PTEN, BRCA2 and NOTCH1. These mutated genes could be responsible for the crossing of the blood–brain barrier by cancer cells, and thus have considerable potential therapeutic implications, underlining the added value of obtaining biopsies from brain metastases to develop personalized treatments. ABSTRACT: Breast cancer brain metastases are a challenging daily practice, and the biological link between gene mutations and metastatic spread to the brain remains to be determined. Here, we performed a meta-analysis on genomic data obtained from primary tumors, extracerebral metastases and brain metastases, to identify gene alterations associated with metastatic processes in the brain. Articles with relevant findings were selected using Medline via PubMed, from January 1999 up to February 2022. A critical review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement (PRISMA). Fifty-seven publications were selected for this meta-analysis, including 37,218 patients in all, 11,906 primary tumor samples, 5541 extracerebral metastasis samples, and 1485 brain metastasis samples. We report the overall and sub-group prevalence of gene mutations, including comparisons between primary tumors, extracerebral metastases and brain metastases. In particular, we identified six genes with a higher mutation prevalence in brain metastases than in extracerebral metastases, with a potential role in metastatic processes in the brain: ESR1, ERBB2, EGFR, PTEN, BRCA2 and NOTCH1. We discuss here the therapeutic implications. Our results underline the added value of obtaining biopsies from brain metastases to fully explore their biology, in order to develop personalized treatments.