Introduction

Breast cancer (BC) is the most common malignancy among women worldwide, and defects in homologous recombination repair (HRR) represent one of the most clinically actionable genomic vulnerabilities. Germline pathogenic variants in BRCA1 and BRCA2 are well-established drivers of homologous recombination deficiency (HRD) and confer marked sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors through synthetic lethality.Pivotal clinical trials, including OlympiAD and EMBRACA, demonstrated significant clinical benefit of PARP inhibition in germline BRCA-mutant BCs, establishing BRCA status as a central biomarker in precision oncology.

Beyond PARP inhibitors, accumulating evidence suggests that BRCA gene alterations may influence response to other systemic therapies. Several studies suggest that patients with germline BRCA mutations may derive less benefit from endocrine therapy plus cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors than noncarriers. In addition, BRCA deficiency has been associated with altered tumor immune microenvironments and increased genomic instability, which may influence sensitivity to immune checkpoint blockade. These findings suggest that BRCA alterations may influence therapeutic response beyond PARP inhibition, serving as broader determinants of treatment sensitivity and resistance.

Somatic BRCA alterations are increasingly identified through comprehensive genomic profiling of tumors in routine clinical practice. While germline BRCA pathogenic variants reflect inherited susceptibility and early HRD, somatic BRCA alterations arise within an established tumor genome during tumor evolution and may be heterogeneous or subclonal events. These differences suggest that the clinical significance of BRCA alterations may depend on their origin (germline versus somatic) and allelic status, which is often not captured by tumor-only sequencing. Notably, the TBCRC048 trial demonstrated PARP inhibitor activity in BCs with somatic BRCA mutations, and ongoing phase II trials continue to evaluate a molecularly defined subgroup. Nevertheless, clinical trials evaluating BRCA-directed therapies have largely focused on germline carriers, and systematic comparisons between germline and somatic BRCA alterations within the same clinical framework are lacking.

Addressing this question has been challenging because paired germline and somatic BRCA data linked to longitudinal outcomes are limited. Consequently, it remains unclear whether somatic BRCA alterations confer the same HRD seen in germline carriers or reflect distinct tumor evolutionary processes with different therapeutic implications. To address this unmet need, we leveraged a large national real-world genomic database integrating germline testing, comprehensive tumor genomic profiling, clinical subtype annotation, and treatment history. By jointly evaluating germline and somatic BRCA status, we classified BCs into four genomic-context categories and examined their mutational landscapes, HRD-related genomic features, specimen origin, and treatment outcomes across major systemic therapies. Through this approach, we sought to determine whether the significance of BRCA alterations differs according to germline and somatic status, while recognizing that allelic context may also contribute.