Although this finding may be biased by the small number of patients without PI3K activation in the present cohort, it appears to be in accordance with PI3K activation as a cause for trastuzumab resistance [48] and it also highlights the differences in disease biology in patients treated before the manifestation of metastases, as compared to those who present with metastatic disease at first diagnosis. The gene discussed is PIK3CA; the disease is metastatic neoplasm.