This strategy is necessary, because, as discussed above, HER2-positive breast cancers are heterogeneous and the distribution of intrinsic subtypes within HER2-positive tumors greatly differs according to ER status: approximately 75% of HER2+/ER- tumors and 30% of HER2+/ER+ pertains to the HER2-enriched subtype, whereas about 70% of HER2+/ER+ tumors are luminal A/B. This evidence concerns the gene ESR1 and breast cancer.