CDK4/6 Inhibition in Breast Cancer

Cyclin-dependent kinase 4/6 (CDK4/6) is associated with cyclin D1 in the cell cycle pathway and helps regulate transcriptional processes. Phosphorylation of retinoblastoma (Rb), which also plays a role in cell cycle control, results in Rb inactivation, preventing it from checking cyclin D1 and CDK4/6, states Hope Rugo, MD. CDK inhibitors block the phosphorylation of Rb, allowing it to act as a tumor suppressor.

Palbociclib, a selective inhibitor of CDK4/6, is approved for the first-line treatment of estrogen receptor (ER)-positive and HER2-negative metastatic breast cancer. Additionally, the investigation CDK 4/6 inhibitor LEE011 has shown similar activity and toxicity to palbociclib. Both agents may cause neutropenia and are administered on a 3 weeks on, 1 week off schedule to allow bone marrow recovery.

Abemaciclib (LY2853219) is another developmental CDK4/6 inhibitor that can be administered continuously, since it causes less bone marrow suppression than LEE011 and palbociclib, notes Rugo. Adverse events with abemaciclib include diarrhea, which can be controlled with antidiarrheal medications. Importantly, abemaciclib appears to cross the blood-brain barrier and may have activity in brain metastases for patients with ER-positive breast cancer, says Rugo.

It is important to determine whether there is a survival advantage associated with the addition of CDK4/6 inhibitors to first-line endocrine therapy, says Ingrid A. Mayer, MD, MSCI. An individual with newly diagnosed metastatic disease who is treatment naïve may do well with endocrine therapy alone and may not require the addition of CDK4/6 inhibitor therapy to improve outcome or survival. The CDK inhibitors may play a role in circumventing resistance to endocrine therapies in patients who have disease recurrence, comments Mayer.