The discovery of a natural transcriptional architecture of breast cancer in the form of the “intrinsic” subtypes had a tremendous impact on the prognostic stratification of ER-positive/HER2-negative disease, showing that an accurate distinction between a low-risk Luminal A and a high-risk Luminal B group of tumors is possible by means of measuring gene expression [5, 6]. This evidence concerns the gene ESR1 and breast cancer.