Another possible mechanism of acquired resistance to trastuzumab is likely due to co-existing molecular alterations within the HER2 positive tumor clones, as clearly showed by Pietrantonio et al. [36]: mutations of EGFR/MET/KRAS/PIK3CA/PTEN or the amplifications of EGFR/MET/KRAS can co-occur in HER2 positive cells and could explain the lack of trastuzumab efficacy and/or the appearance of resistance. Here, PTEN is linked to neoplasm.