Targeting CDK 4/6 in ER+ Breast cancer

Abstract

Significant improvements in outcomes have been achieved in hormone receptor positive (HR+) breast cancer with the use of anti‐hormonal agents including tamoxifen, aromatase inhibitors (AIs), and fulvestrant. Still, patients with will have either de novo or develop acquired resistance to these approaches. Several alternative signalling pathways have been pursued clinically to overcome resistance including receptor tyrosine kinase signalling, angiogenesis, and intracelullar targets. Except for the mTOR inhibitor everolimus, none of these approaches have improved outcomes. There has been an effort to target the cellular machinery that controls progression through the cell cycle to control cancer growth. These strategies have been hindered by non‐selective compounds and the lack of a targeted population for trial selection. Cyclin‐dependent kinases (CDKs) are a large family of serine‐threonine kinases that play a pivotal role in cell cycle control. Pre‐lcinical work identified a role for the first‐in‐class CDK 4/6 inhibitor palbociclib in HR+ breast cancer and demonstrated its ability to work synergistically with anti‐estrogens and reverse endocrine resistance. This lead to the randomized Phase 2 PALOMA1 study that demonstrated a 10 mos improvement in PFS with palbociclib and letrozole vs letrozole alone. These data supported the accelerated approval of this combination in advanced ER+breast cancer by the US FDA in 2015. Since this time, these findings have been validated in several phase 3 studies with not only palbociclib, but now with other CDK 4/6 inhibitors including ribociclib and abemaciclib. In addiition, these findings are consistent with combinations with other AIs and fulvestrant. CDK 4/6 inhibitors have changed the landscape of ER+ breast cancer and ongoing studies will define their role in early breast cancer. In the lecture we will discuss there development, clinical efficacy and side effects, and future opportunities.