Comparisons of clinical characteristics, prognosis, epidemiological factors, and genetic susceptibility between HER2‐low and HER2‐zero breast cancer among Chinese females

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.