Molecular intrinsic subtypes, genomic, and immune landscapes of BRCA-proficient but HRD-high ER-positive/HER2-negative early breast cancers

Purpose: The vast majority of research studies that have described the links between DNA damage repair or homologous recombination deficiency (HRD) score, and tumor biology, have concerned either triple negative breast cancers or cancers with mutation of BRCA 1/2. We hypothesized that ER + /HER2- early breast tumors without BRCA 1/2 mutation could have high HRD score and aimed to describe their genomic, transcriptomic, and immune landscapes.

Patients and methods: In this study, we reported BRCA 1/2 mutational status, HRD score, and mutational signature 3 (S3) expression, in all early breast cancer (eBC) subtypes from the TCGA database, with a particular focus in ER + /HER2-. In this subtype, bioinformatics analyses of tumor transcriptomic, immune profile, and mutational landscape were performed, according to HRD status. Overall survival (OS), progression free-interval (PFI), and variables associated with outcome were also evaluated.

Results: Among the 928 tumor samples analyzed, 46 harbored BRCA 1/2 mutations, and 606 were ER + /HER2- (of which 24 were BRCA 1/2 mutated). We found a subset of BRCA-proficient ER + /HER2- eBC, with high HRD score. These tumors displayed significantly different immune, mutational, and tumor molecular signatures landscapes, compared to BRCA-mutated and BRCA-proficient HRD-low tumors. Outcome did not significantly differ between these 3 groups, but biological factors associated with survival are not the same across the 3 entities.

Conclusion: This study highlights possible novel biological differences among ER + /HER2- breast cancer related to HRD status. Our results could have important implications for translational research and/or the design of future clinical trials, but require prospective clinical evaluation.