Although the majority of clinical and molecular differences between HER2-low and HER2-zero breast cancer were no longer observed after correcting for HR status, some particular characteristics of HER2-low breast cancer compared to HER2-zero breast cancer still existed, including less ESR1 mutations and more de novo stage IV cancers, brain metastasis and initial lung metastasis in the HR+ subgroup. This evidence concerns the gene ESR1 and breast cancer.