HR+, HER2- Advanced Breast Cancer and CDK4/6 Inhibitors: Mode of Action, Clinical Activity, and Safety Profiles

Abstract

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapies have shown great promise in improving clinical outcomes for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer.

Objectives: 1. Discuss the mode of action of the three CDK4/6 inhibitors in late clinical development: palbociclib (PD-0332991; Pfizer), ribociclib (LEE011; Novartis), and abemaciclib (LY2835219; Lilly). 2. Describe the efficacy and safety data relating to their use in HR+, HER2- advanced breast cancer. 3. Discuss the key side effects associated with CDK4/6 inhibitors along with considerations for adverse event management and patient monitoring.

Method: Relevant information and data were assimilated from manuscripts, congress publications, and online sources.

Results: CDK4/6 inhibitors have demonstrated improved progression-free survival in combination with endocrine therapy compared with endocrine therapy alone. The side-effect profile of each agent is described, along with implications for patient monitoring, and considerations for patient care providers and pharmacists.

Conclusion: Addition of a CDK4/6 inhibitor to endocrine therapy increases efficacy and delays disease progression. Insight into the unique side-effect profiles of this class of agents and effective patient monitoring will facilitate the successful use of CDK4/6 inhibitor-based therapies in the clinic.

Keywords: Abemaciclib; CDK4/6 inhibitor; advanced breast cancer; hormone receptor-positive; palbociclib; ribociclib.

Fig. (1)

The cyclin D–CDK4/6–INK4–Rb pathway and cell cycle control. CDK, cyclin-dependent kinase; E2F, E2 transcription factor; ER, estrogen receptor; G, growth phase; INK4, inhibitor of CDK4; M, mitosis; P, phosphorylation; Rb, retinoblastoma; S, synthesis phase.

Fig. (2)

ER and cyclin D–CDK4/6–INK4–Rb pathway cross-talk. AKT, protein kinase B; CDK, cyclin-dependent kinase; CoA, 
co-activator; E2F, E2 transcription factor; ER, estrogen receptor; GATA3, GATA-binding protein 3; mTOR, mammalian target of rapamycin; 
P, phosphorylation; PI3K, phosphatidylinositol 3-kinase; pS167, phosphorylated serine-167; TFs, transcription factors; Rb, retinoblastoma; S6K, S6 kinase.