We hypothesized that in patients with metastatic LBC that becomes resistant to endocrine therapy, the hyperactivation of PI3K/AKT signaling may promote an intrinsic resistance to CDK4/6i through the activation of cyclin E/CDK2—amplification of cyclin E is the only factor that showed a correlation with resistance to a CDK 4/6i (palbociclib) in trials [22,23]. The gene discussed is CCNE1; the disease is CDH1-related diffuse gastric and lobular breast cancer syndrome.