Germline BRCA1/2 Mutation Prevalence in Unselected ER-Low/HER2-Negative Breast Cancer

Estrogen receptor (ER)-low breast cancers, defined as tumors with 1-10% ER expression, exhibit clinicopathologic and molecular features, as well as chemotherapy responses, resembling triple-negative breast cancer (TNBC), leading to updated guidelines. However, current BRCA1/2 testing guidelines classify ER-low tumors alongside ER-strong-positive cancers, potentially overlooking mutation carriers. Thus, the purpose of this study was to determine whether BRCA1/2 genetic testing in patients with ER-low/HER2-negative breast cancer should be the same as those with TNBC.

This multicenter retrospective study included 271 unselected patients with ER-low/HER2-negative invasive breast cancer from four Korean institutions (2014-2022). BRCA1/2 genetic testing was performed via Sanger sequencing or next-generation sequencing. A previously published unselected TNBC cohort (n = 920) served as a comparator. Clinical and pathological characteristics and BRCA1/2 mutation prevalence were compared between groups.

Among 271 ER-low/HER2-negative patients, 41 (15.1%) carried pathogenic BRCA1/2 mutations (BRCA1: 11.8%, BRCA2: 3.3%), comparable to the TNBC cohort (13.2%; p = 0.404). BRCA1 predominance was observed, with the highest prevalence in patients ≤ 40 years (25.4% versus 20.0% in TNBC). Mutation carriers were younger (≤40 years: 41.5% versus 21.7%; p = 0.006), more often premenopausal (85.4% versus 50.0%; p < 0.001), and more frequently had a family history of breast/ovarian cancer (48.8% versus 16.1%; p < 0.001).

ER-low/HER2-negative breast cancers demonstrate BRCA1/2 mutation prevalence and features comparable to TNBC. Applying testing criteria based solely on ER expression may underdiagnose mutation carriers. These findings support expanding BRCA1/2 testing eligibility to include ER-low/HER2-negative tumors to ensure timely identification and access to targeted therapies.