Whole genome sequencing of locally advanced and metastatic breast carcinoma unravels relevant molecular signatures and novel events.

Metastatic breast cancer remains the leading cause of cancer related mortality in women. While comprehensive genomic profiling of primary tumors has advanced, the whole genome landscape of metastatic disease remains incompletely characterized. We performed whole genome and transcriptome sequencing on 50 tumor samples from 37 patients with locally advanced or metastatic breast cancer. Based on immunohistochemistry, samples were classified as Luminal, triple-negative breast cancer (TNBC), or HER2-enriched. We assessed tumor mutational burden, homologous recombination deficiency, mutational signatures, structural variants, and therapeutic actionability. TNBC demonstrated highest median whole genome tumor mutational burden (5.8 mutations/Mb) compared to HER2-enriched (4.7) and Luminal (2.7) subtypes. Homologous recombination deficiency (confident or suspected) was detected in 27% of patients (10/37), enriched in TNBC (60%) versus Luminal tumors (17%). Notably, half of HRD cases were BRCA1/2 wild-type and harbored deleterious structural variants in other homologous recombination repair genes. Therapeutically actionable alterations were identified in 84% of patients, with FDA approved biomarkers in 30-46% across subtypes. We identified a novel ESR1::EP300 fusion with potential implications for endocrine resistance. Multi-region sequencing of two rapid autopsy cases revealed substantial spatial heterogeneity in mutational burden and structural variants, while core driver events remained conserved. Comprehensive whole-genome profiling of metastatic breast cancer reveals extensive genomic complexity, prevalent non-BRCA mechanisms of homologous recombination deficiency, and broad therapeutic actionability, supporting broader implementation of genome-wide sequencing approaches in advanced disease.