PIK3CA and brain neoplasm: Loss of the PTEN tumor suppressor, which activates the PI3K-AKT pathway, was initially discovered as a highly recurrent event in primary brain tumors (GBMs).14 Interestingly, there is now growing data implicating activation of the PI3K-AKT pathway in brain metastases from melanoma and other tumor types.49 Multiple studies have identified increased activation of the PI3K-AKT pathway in MBMs, including in comparison to extracranial metastases from the same patients.16,50 It appears that this molecular phenotype could be caused by multiple mechanisms.