Abstract
BACKGROUND: Traditional human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) is recommended to be divided into HER2-low and HER2-zero subtypes due to different prognosis. However, few studies investigated their differences in clinical characteristics and prognosis among Chinese HER2-negative BC and their stratified differences by hormone receptor (HR), while fewer studies investigated their differences in epidemiological factors and genetic susceptibility. METHODS: A total of 11,911 HER2-negative BC were included to compare the clinical characteristics and prognosis between HER2-zero and HER2-low BC, and 4227 of the 11,911 HER2-negative BC were further compared to 5653 controls to investigate subtype-specific epidemiological factors and single nucleotide polymorphisms(SNPs). RESULTS: Overall, 64.2% of HER2-negative BC were HER2-low BC, and the stratified proportions of HER2-low BC were 61.9% and 75.2% for HR-positive and HR-negative BC, respectively. Compared to HER2-zero BC, HER2-low BC among HR-positive BC showed younger age at diagnosis, later stage, poorer differentiation, and higher Ki-67, while elder age at diagnosis and lower mortality were observed for HER2-low BC among HR-negative BC (all p values <0.05). Compared to healthy controls, both HER2-low and HER2-zero BC are associated with similar epidemiological factors and SNPs. However, stronger interaction between epidemiological factors and polygenic risk scores were observed for HER2-zero BC than HER2-low BC among either HR-positive [odds ratios: 10.71 (7.55-15.17) and 8.84 (6.19-12.62) for the highest risk group compared to the lowest risk group] or HR-negative BC [7.00 (3.14-15.63) and 5.70 (3.26-9.98)]. CONCLUSIONS: HER2-low BC should deserve more attention than HER2-zero BC, especially in HR-negative BC, due to larger proportion, less clinical heterogeneity, better prognosis, and less susceptibility to risk factors.