Nonclinical evidence demonstrating that estrogen receptor, cyclin-dependent kinases 4 and 6 (CDK4/6), and PI3K/AKT/mTOR (PAM) pathways cross-promote tumor proliferation in hormone receptor–positive (HR+)/HER2− breast cancer cell lines led to the development of CDK4/6 inhibitors and agents inhibiting single PAM pathway nodes to treat HR+/HER2− advanced breast cancer. Here, ESR1 is linked to breast carcinoma.