Abstract (136 words) 1 Whole genome sequencing (WGS) of prospectively collected tissue biopsies of 442 metastatic breast 2 cancer (mBC) patients reveals that, compared to primary BC, tumour mutational burden (TMB) 3 doubled, relative contributions of mutational signatures shifted, and mutation frequency of six known 4 driver genes increased in mBC. Significant associations with pre-treatment were observed as well. 5 The contribution of mutational signature 17 was significantly enriched in patients pre-treated with 5-6 FU, taxanes, platinum and/or eribulin, whereas the here identified de novo mutational signature I was 7 significantly associated with pre-treatment containing platinum-based chemotherapy. Clinically 8 relevant subgroups of tumours were identified exhibiting either homologous recombination deficiency 9 (13%), high TMB (11%) or specific alterations (24%) linked to sensitivity to FDA-approved drugs. This 10 study provides important novel insight into the biology of mBC and identifies clinically useful genomic 11 features for future improvement of patient management.