PI3K signaling was significantly higher in metastatic breast cancer of all subtypes in the four cohorts, and reproducibly in luminal A and luminal B. Both Rho GTPase and PI3K pathways promote primary tumor proliferation and survival111,112, but our results reveal that these pathways are further enriched in metastases and are thus ideal for therapeutic targeting together with S-drivers. Here, PIK3CA is linked to breast carcinoma.