The observation that somatic alterations in receptor tyrosine kinase (RTK; e.g., HER, FGFR receptors), RAS [e.g., neurofibromatosis type 1 (NF1)] and PI3K/AKT/mTOR (e.g., AKT1) pathways occur at higher frequency in endocrine resistant/metastatic disease compared with primary disease highlight the importance of these growth processes in endocrine resistance [102]. This evidence concerns the gene AKT1 and metastatic neoplasm.