CDK 4/6 Inhibitors in Breast Cancer: Current Controversies and Future Directions

Abstract

Purpose of Review: To describe the clinical role of CDK 4/6 inhibitors in hormone receptor-positive (HR+) metastatic breast cancer (HR+ MBC) as well as current controversies and evolving areas of research. Recent Findings: Palbociclib, ribociclib, and abemaciclib are each approved in combination with an aromatase inhibitor or fulvestrant for HR+ MBC. Abemaciclib is also approved as monotherapy for pre-treated patients. Key questions in the field include whether all patients with HR+ MBC should receive a CDK 4/6 inhibitor up front versus later line, impact on overall survival, role of continued CDK 4/6 blockade, mechanism of clinical resistance, and treatment sequencing. Summary: The development of CDK 4/6 inhibitors has changed the therapeutic management of HR+ MBC. Additional research is needed to determine optimal treatment sequencing, understand mechanisms governing resistance, and develop novel therapeutic strategies to circumvent or overcome clinical resistance and further improve the outcomes of patients with MBC.

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

“…[7][8][9][10][11] Although tremendous efforts have been made to nd new CDK4/6i, 12,13 the current array of inhibitors failed to discriminate between both homologues. 14,15 The majority of strategies to design CDK4/6i were focused on CDK4/6cyclin D dimer activities without considering CDK interacting protein/kinase inhibitory protein (CIP/KIP) family proteins. 16 Very recently, crystallographic studies demonstrated that p21 CIP and p27 KIP are assembly factors for active CDK4/6-cyclin D trimer complexes which are not sensitive to CDK4/6i.…”

The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer

“…The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have entered widespread use in both the first- and subsequent-line setting for patients with hormone-receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC). 1, 2 Their application has resulted in significant improvements in progression-free survival (PFS) and overall survival (OS) for treatment-naïve and previously treated patients in combination with anti-estrogens. 3–9 Abemaciclib has shown efficacy as a single agent in endocrine-refractory disease, and has been approved for use as monotherapy in pre-treated patients with HR+/HER2-MBC.…”

<p>Fulvestrant in Combination with CDK4/6 Inhibitors for HER2- Metastatic Breast Cancers: Current Perspectives</p>

“…The PALOMA-3 trial (fulvestrant with palbociclib/placebo) included women with HR+/HER2-MBC, ones who were pre-menopausal (goserelin was added for these women) or post-menopausal and who had relapsed or progressed during prior endocrine treatment (78% of the entire population). In this trial, there was no limit to previous endocrine therapies (2nd line or more) 25,26 and 34% of the patients had received prior chemotherapy for ABC. The addition of palbociclib resulted in an improvement in PFS from 4.6 months to 11.2 months (HR 0.50; p < 0.0001).…”