CDK4/6 blockade in breast cancer: current experience and future perspectives

ABSTRACT

Introduction: Dysregulated cellular proliferation, one of the hallmarks of cancer, is mediated by aberrant activation of the cell cycle machinery through the biological effects of cyclin-dependent kinases (CDKs). The clinical development of non-selective CDK inhibitors failed due to combined lack of efficacy and excessive toxicity reported by clinical trials across different cancer types. The clinical development of second generation, CDK4/6-selective inhibitors, namely palbociclib, abemaciclib and ribociclib, led to practice-changing results in the setting of breast cancer.

Areas covered: This review illustrates how CDK4/6-selective inhibitors got approval for the treatment of patients with either newly diagnosed or pretreated advanced hormone receptor positive, HER2-negative breast cancer. Furthermore, data about potential predictive biomarkers, as well as preclinical and preliminary clinical evidence for potential antitumor activity of CDK4/6 inhibition in other breast cancer subtypes is provided.

Expert opinion: Future clinical development of CDK4/6 inhibitors in breast cancer will focus on the following aspects: i) optimization of treatment sequencing for patients with advanced disease, ii) early-stage disease, iii) other subtypes of breast cancer in rationally chosen therapeutic combinations and iv) the identification of predictive biomarkers.

KEYWORDS:

• Breast cancer
• CDK4/6 inhibitors
• cell-cycle regulation
• palbociclib
• abemaciclib
• ribociclib

Article highlights

• “-The cyclin-CDK-retinoblastoma pathway is an important regulator of the cell cycle, frequently deregulated in human breast cancer.

• -The first-generation CDK inhibitors were nonselective, pan-CDK blocking agents that exhibited limited antitumor activity, coupled with excessive toxicity.

• -To the present day, three selective CDK4/6 inhibitors have been successfully developed in the setting of metastatic luminal breast cancer, i.e. palbociclib, ribociclib and abemaciclib.

• -No robust predictive biomarkers have been identified, despite rich correlative studies that have been performed.

• -Preclinical evidence supports the assessment of CDK4/6 inhibition in other breast cancer subtypes within the context of rationally chosen treatment combinations.”

Declaration of interest

D. Zardavas has received research funding from Roche, Genentech, Pfizer, Novartis, TESARO and Puma Biotechnology (all to institution). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.