CD44 and neoplasm: If a major determinant of trastuzumab resistance in luminal and HER2e/cHER2+ tumors is the de novo occurrence of EMT phenomena, leading to the appearance of mesenchymal clones or cell clusters with a CD44+/CD24−/low/HER2-low phenotype, the selection pressure of trastuzumab treatment will similarly lead to the emergence of trastuzumab-refractory mesenchymal-CSCs, as well as a shift in the HER2 status of the tumor (Figure 3, BOX1).