The purpose of this work was to determine whether there are differences in PIK3CA mutation status and PTEN protein expression between primary and matched metastatic breast tumors as this could influence patient management. Fifty-micron paraffin sections were used for DNA extraction and 3-micron slides for immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH). ER, PR and HER2 IHC were repeated in a central laboratory for both primary and metastasis. PTEN levels were assessed by IHC and PI3K pathway mutations detected by a mass spectroscopy-based approach. Median age was 48 years (range, 30 to 83 years). Tumor subtype included 72% hormone receptor-positive/HER2-negative, 20% HER2-positive, and less than 7.8% triple receptor negative. Tissues were available for PTEN IHC in 46 primary tumors and 52 metastases. PTEN was lost in 14 (30%) primary tumors and 13 (25%) metastases. There were 5 cases of PTEN loss and eight cases of PTEN gain from primary to metastasis (26% discordance). Adequate DNA was obtained on 46 primary tumors and on 50 metastases for PIK3CA analysis. PIK3CA mutations were detected in 19 (40%) of primary tumors and 21 (42%) of metastases. There were five cases of PIK3CA mutation loss, and four cases of mutation gain (18% discordance). There was an increase of the level of PIK3CA mutations in four cases, and decrease in one from primary to metastasis. There is a high level of discordance in PTEN level, PIK3CA mutations, and receptor status between primary and metastatic disease that may influence patient selection and response to PI3K-targeted therapies.