Clinical Impact and Genomic Features of Human Epidermal Growth Factor Receptor 2–Low Tumors in BRCA1/2 -Mutated Triple-Negative Breast Cancer

PURPOSE Data about the clinical impact of human epidermal growth factor receptor 2 (HER2)–low expression in BRCA1/2 -mutated breast cancer (BC) are limited. This study aimed to clarify the clinical relevance of HER2-low in operable BRCA1/2 -mutated BC. MATERIALS AND METHODS A total of 495 HER2-negative operable BC with germline BRCA1/2 pathogenic variants treated at our institute between October 2003 and September 2020 were included. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+/fluorescence in situ hybridization–negative, while HER2-zero as IHC 0. Tumor DNA from 25 BRCA1/2 -mutated triple-negative BCs (TNBCs) was subjected to whole-exome sequencing. RESULTS Among the 186 BRCA1 carriers, 38.8% of TNBC (n = 121) and 52.3% of hormone receptor–positive/HER2-negative BC (n = 65) exhibited HER2-low tumors in the BRCA1 subgroup; among 309 BRCA2 carriers, 44.9% of TNBC (n = 49) and 68.1% of hormone receptor–positive/HER2-negative BC (n = 260) exhibited HER2-low tumors in the BRCA2 subgroup. After a median follow-up of 10.9 years (range, 1.23-19.8 years), among BRCA1 -mutated TNBC, HER2-low tumors were significantly associated with better recurrence-free survival (RFS; 10-year RFS: 90.3% v 75.1%; P = .015), distant recurrence-free survival (DRFS; 10-year DRFS: 92.4% v 76.5%; P = .010), and overall survival (OS; 10-year OS: 94.6% v 77.4%; P = .007) than HER2-zero tumors. However, the impact of HER2-low in survival was not observed either in BRCA2 -mutated TNBC or in BRCA1- and BRCA2 -mutated hormone receptor–positive/HER2-negative BC. Notably, BRCA1- mutated TNBC with HER2-low tumors showed higher homologous recombination deficiency scores than those with HER2-zero tumors. CONCLUSION BRCA1 -mutated TNBC patients with HER2-low tumors have a significantly favorable survival, highlighting the possibility of stratifying these patients into two subgroups on the basis of HER2-low status.