Whole genome sequencing of locally advanced and metastatic breast carcinoma unravels relevant molecular signatures and novel events.
Summary
This study performed whole genome and transcriptome sequencing on 50 tumor samples from 37 patients with locally advanced or metastatic breast cancer. It uncovered extensive genomic complexity, with triple-negative breast cancer (TNBC) showing the highest tumor mutational burden. Homologous recombination deficiency (HRD) was found in 27% of patients, frequently in BRCA1/2 wild-type cases due to deleterious structural variants in other repair genes. Therapeutically actionable alterations were identified in 84% of patients, including a novel ESR1::EP300 fusion potentially linked to endocrine resistance. These findings underscore the utility of whole-genome sequencing for characterizing metastatic disease and guiding therapies.
Analysis
This study is of paramount importance for the management of metastatic breast cancer, as it demonstrates the value of whole-genome sequencing in identifying complex molecular signatures and genomic alterations not always detected by more limited approaches. The discovery of non-BRCA1/2 homologous recombination deficiency (HRD) mechanisms and a novel ESR1::EP300 fusion opens avenues for new therapeutic targets and personalized treatment strategies, particularly for overcoming endocrine resistance. The identification of actionable alterations in a large proportion of patients justifies the broader implementation of whole-genome sequencing in clinical practice for advanced cancers.