ESR1 and breast cancer: With our present understanding of the biological importance of pS294 formation under exclusive mechanistic control by CDK2, innovative breast cancer clinical opportunities become apparent given the therapeutic development of increasingly more specific CDK inhibitors [19–22] and the important recent findings of LBD hotspot mutations in ESR1 arising during breast cancer metastatic progression and driving clinical resistance to both aromatase inhibitors and antiestrogens like tamoxifen [14–18].