Concomitant endocrine positive status (ER+ and ER−ve HER2-amplified tumor), intrinsic subtypes, ERBB2 mRNA levels, BRCA1/BRCA2 mutations, ERBB2 mutation/amplification, PIK3CA mutation, and immune microenvironments, such as TILs, PD-L1, and FcyR alleles, all contribute to the heterogeneity of HER2-amplified breast cancers [73,74]. This evidence concerns the gene ESR1 and breast cancer.