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

Abstract

Data about the clinical impact of human epidermal growth factor receptor 2 (HER2)-low expression in <i>BRCA1/2</i>-mutated breast cancer (BC) are limited. This study aimed to clarify the clinical relevance of HER2-low in operable <i>BRCA1/2</i>-mutated BC. A total of 495 HER2-negative operable BC with germline <i>BRCA1/2</i> 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 <i>BRCA1/2</i>-mutated triple-negative BCs (TNBCs) was subjected to whole-exome sequencing. Among the 186 <i>BRCA1</i> 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 <i>BRCA1</i> subgroup; among 309 <i>BRCA2</i> 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 <i>BRCA2</i> subgroup. After a median follow-up of 10.9 years (range, 1.23-19.8 years), among <i>BRCA1</i>-mutated TNBC, HER2-low tumors were significantly associated with better recurrence-free survival (RFS; 10-year RFS: 90.3% <i>v</i> 75.1%; <i>P</i> = .015), distant recurrence-free survival (DRFS; 10-year DRFS: 92.4% <i>v</i> 76.5%; <i>P</i> = .010), and overall survival (OS; 10-year OS: 94.6% <i>v</i> 77.4%; <i>P</i> = .007) than HER2-zero tumors. However, the impact of HER2-low in survival was not observed either in <i>BRCA2</i>-mutated TNBC or in <i>BRCA1-</i> and <i>BRCA2</i>-mutated hormone receptor-positive/HER2-negative BC. Notably, <i>BRCA1-</i>mutated TNBC with HER2-low tumors showed higher homologous recombination deficiency scores than those with HER2-zero tumors. <i>BRCA1</i>-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.