Editorial to “Palbociclib and letrozole in advanced breast cancer”
Palbociclib is a first-in-class inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) that inhibits cell proliferation and DNA synthesis by preventing cell-cycle progression from G1 to S phase (1). In cell line models of ER-positive breast cancer, estrogen activates CDK4/6 via cyclin D1, resulting in hyperphosphorylation of retinoblastoma (Rb) gene product, which leads to entry of the cell cycle (2). Endocrine resistance has been shown to be depends on cyclin D1 and CDK4/6 in vitro. Based on the impressive progression-free survival (PFS) found in the phase 2 study PALOMA-1 (3), palbociclib was granted accelerated approval in 2015 by the Food and Drug Administration (FDA) for treatment of estrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC).