The PI3K/AKT/mTOR intracellular signal pathway regulating the cell growth and proliferation is frequently dysregulated in breast cancer and mediates primary or secondary resistance to anti-HER2 agents.163,164 In preclinical models, everolimus, as an mTOR inhibitor, has demonstrated efficacy in trastuzumab-resistant breast cancer.165. This evidence concerns the gene PIK3CA and breast carcinoma.