Resumen
Cyclin-dependent kinase inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)), targeting aberrant cell-cycle activity have been evaluated extensively in clinical trials. Significant delays in progression free survival and overall survival are now documented with each agent in estrogen receptor positive and human epidermal growth factor receptor two negative advanced breast cancer including luminal B breast cancer. Therapy resistance, driven by chromosomal instability, results in genomic rearrangements, activation of cell-cycle components (cyclin E/cdk2 in Rb- tumors, cyclin D1 in growth factor activated pathways), and the immune response. Molecular analysis of therapy resistant tumors may provide the rational basis for new therapies (brivanib, CYC065, WEE1 kinase and other inhibitors). Luminal B breast cancer is enriched for cyclin D1 overexpression and the chromosomal instability gene signature. The molecular mechanisms governing chromosomal instability in luminal B breast cancer remain poorly understood. Co-targeting of chromosomal instability may potentially reduce the prevalent escape mechanisms that reduce the effectiveness of cyclin-dependent kinase inhibitors.