One of the first evidences of PI3K and ER signaling crosstalk came from the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) phase III clinical trial which demonstrated improvement in progression-free survival (PFS) in endocrine resistant ER+ breast cancer patients treated with the mTOR inhibitor everolimus and exemestane (24). The gene discussed is ESR1; the disease is breast carcinoma.