Elsevier

The Lancet

Volume 395, Issue 10226, 7–13 March 2020, Pages 817-827
The Lancet

Therapeutics
Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future

https://doi.org/10.1016/S0140-6736(20)30165-3Get rights and content

Summary

The development and approval of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer represents a major milestone in cancer therapeutics. Three different oral CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have significantly improved progression-free survival by a number of months when combined with endocrine therapy. More recently, improvement in overall survival has been reported with ribociclib and abemaciclib. The toxicity profile of all three drugs is well described and generally easily manageable with dose reductions when indicated. More myelotoxicity is observed with palbociclib and ribociclib, but more gastrointestinal toxicity is observed with abemaciclib. Emerging data is shedding light on the resistance mechanisms associated with CDK4/6 inhibitors, including cell cycle alterations and activation of upstream tyrosine kinase receptors. A number of clinical trials are exploring several important questions regarding treatment sequencing, combinatorial strategies, and the use of CDK4/6 inhibitors in the adjuvant and neoadjuvant settings, thereby further expanding and refining the clinical application of CDK4/6 inhibitors for patients with breast cancer.

Introduction

The approval of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer has transformed the treatments landscape of breast oncology, arguably representing one of the most important new treatment in breast oncology over the past two decades. Pivotal studies1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 of the three approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, established the combinatorial strategy of endocrine therapy plus targeted therapy as the preferred upfront treatment approach for most patients with hormone receptor-positive and HER2-negative metastatic breast cancer. Given the success of CDK4/6 inhibitors for hormone receptor-positive, HER2-negative metastatic breast cancer, these drugs are being explored in other settings, including for early stage hormone receptor-positive and HER2-negative breast cancer, and for other clinical breast cancer subtypes. Substantial progress is also being made in understanding which patients derive the most benefit, and the mechanisms of resistance to therapy. In this review we detail the clinical development of CDK4/6 inhibitors for breast cancer, summarise the key developments, and discuss future directions.

Section snippets

CDK4/6–retinoblastoma protein axis and the cell cycle

Transition through the G1 phase of the cell cycle, and the commitment to enter the S phase and divide, is modulated by a complex network of regulatory proteins including the tumour suppressor retinoblastoma protein (RB1).12 RB1 is a crucial negative regulator of the cell cycle acting through the assembly of multiprotein complexes that prevent premature cell division by binding the E2F transcription factors to inhibit G1 transition.12 RB1 is regulated by phosphorylation: the protein is fully

Approved CDK4/6 inhibitors for breast cancer

There are currently three approved, orally bioavailable, highly selective, small molecule inhibitors of CDK4/6, palbociclib, abemaciclib and ribociclib, for the treatment of advanced hormone receptor-positive and HER2-negative metastatic breast cancer.32, 33, 34, 35, 36 The selectivity of all three compounds is theorised to reflect structural preference for the specialised ATP-binding pocket of CDK4/6 because of specific interactions with residues in the ATP-binding cleft.37 The specificity of

Safety and tolerability

In general, the CDK4/6 inhibitors are well tolerated and adverse events are typically easily managed with dose modification and supportive care measures. Haematological toxicities, primarily neutropenia (although febrile neutropenia is rare), are commonly seen with all three inhibitors, but they are more frequent with palbociclib and ribociclib than abemaciclib. The cytopenias seen with CDK4/6 inhibitors are considered an on-target effect because CDK6 plays a key role in the proliferation of

When should CDK4/6 inhibitors be used (first line or later)?

A number of important questions exist surrounding CDK4/6 inhibitors (appendix p 1). For patients who relapse early during or shortly after completion of the adjuvant endocrine therapy, the general consensus is that CDK4/6 inhibitors should be used as the first-line regimen because progression-free survival to endocrine monotherapy might only range from 4 to 6 months. However, considerable debate exists over whether all patients should receive a CDK4/6 inhibitor in the first-line setting when

Future directions

Given the success of CDK4/6 inhibitors for hormone receptor-positive and HER2-negative metastatic breast cancer, there is great interest in exploring these drugs in other settings—selected ongoing and completed trials are summarised in the appendix (p 2). The most important set of trials are those assessing whether CDK4/6 inhibitors can improve survival in women treated for primary breast cancer, and CDK4/6 inhibitors have been, and continue to be, explored in the neoadjuvant and adjuvant

Conclusions

The integration of CDK4/6 inhibitors in the treatment of hormone receptor-positive and HER2-negative metastatic breast cancer represents a major advancement in breast cancer therapy. The addition of CDK4/6 inhibitors to endocrine therapy appears to benefit all clinicopathological subgroups with hormone receptor-positive and HER2-negative metastatic breast cancer, as suggested by a large pooled analysis by the FDA.81 Not surprisingly, these drugs have entered widespread clinical practice and

Search strategy and selection criteria

We searched PubMed from inception until Dec 31, 2019, for articles using the search terms “breast cancer”, “cyclin-dependent kinases 4 and 6”, “CDK 4/6”, and “palbociclib; ribociclib; abemaciclib”. 490 results were found, the abstracts of which were reviewed to identify pivotal clinical and preclinical studies based on author consensus. The reference lists of relevant articles were also searched for additional articles and abstracts of interest. Abstracts of selected major oncology annual

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