Approximately 50% of all [17–20], and around 60% of ER-positive/HER2-negative [1, 21] breast cancers are classified as histologic grade 2, which is a heterogenous group of tumors with variations in terms of aggressiveness and prognosis [22, 23], thus, associated with limited value to guide decisions on choice of therapy. This evidence concerns the gene ESR1 and breast cancer.