Comparative Analysis of BRCA1 and BRCA2 Mutation–Associated Breast Cancer in a Japanese Cohort

Inherited pathogenic alterations in BRCA1 and BRCA2 are established determinants of distinct breast cancer (BC) molecular subtypes. Nevertheless, real-world clinical evidence elucidating how these genomic disparities modulate tumor phenotype and therapeutic choices is scarce, particularly within Japanese cohorts. Given the recent regulatory expansion of PARP inhibitor indications in Japan, BRCA testing has been integrated more routinely into practice, amplifying the necessity for locally derived clinical data. To contrast the clinicopathological profiles, recurrence characteristics, and surgical decision-making between BRCA1-driven and BRCA2-driven BC among Japanese patients, prioritizing the analysis of estrogen receptor (ER)-positive disease. A retrospective cohort analysis was conducted at a single center. We performed a retrospective evaluation of 417 consecutive patients who underwent BRCA1/2 germline testing at one Japanese facility from April 2020 through November 2023. Deleterious variants were confirmed in 38 individuals (12 BRCA1, 26 BRCA2). Clinical and pathological parameters, patterns of relapse, and uptake of prophylactic surgical interventions were systematically compared across the two mutation carrier groups. Malignancies linked to BRCA1 were overwhelmingly triple-negative (75%) and typically detected while still localized (83.3% T1 classification). In contrast, BRCA2-driven tumors were predominantly ER-positive (69.2%) and more apt to present with extensive nodal involvement (⩾2 involved lymph nodes in 42.3%). Ki-67 proliferation indices proved higher among BRCA1 cancers, though this disparity was largely contingent on intrinsic subtype. Of particular note, ER-positive neoplasms harboring BRCA mutations showed a trend toward increased recurrence risk. Decisions regarding risk-reducing surgery also diverged by the specific gene mutated. This single-institution analysis delineates clinically salient distinctions between BRCA1- and BRCA2-associated BC in a Japanese population. BRCA2-linked tumors were predisposed to manifest with more adverse features, whereas BRCA1-associated cancers were more frequently captured at an incipient stage. These insights reinforce the utility of BRCA genotyping beyond PARP inhibitor qualification—extending its value to subtype-informed risk stratification and personalized prevention planning.