Therapy for Hormone Receptor-Positive, Human Epidermal Growth Receptor 2-Negative Metastatic Breast Cancer Following Treatment Progression via CDK4/6 Inhibitors: A Literature Review

Abstract

Endocrine therapy (ET) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the first-line standard treatment for most patients with hormone receptor-positive (HR+) and human epidermal growth receptor 2-negative (HER2-) metastatic or advanced breast cancer. However, the majority of tumors response to and eventually develop resistance to CDK4/6is. The mechanisms of resistance are poorly understood, and the optimal postprogression treatment regimens and their sequences continue to evolve in the rapidly changing treatment landscape. In this review, we generally summarize the mechanisms of resistance to CDK4/6is and ET, and describe the findings from clinical trials using small molecule inhibitors, antibody-drug conjugates and immunotherapy, providing insights into how these novel strategies may reverse treatment resistance, and discussing how some have not translated into clinical benefit. Finally, we provide rational treatment strategies based on the current emerging evidence.

Keywords:

• breast cancer
• human epidermal growth receptor 2
• hormone receptor
• cyclin- dependent kinases 4 and 6 inhibitor
• endocrine resistance
• molecular mechanism

Acknowledgments

I would like to thank Dr Yi Dai and Dr Yuxingzi Chen who have contributed substantially to the completion of this study, and they made a significant contribution to the work reported.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was funded by Medical Science and Technology Project of Zhejiang Province (2022KY1078 and 2023KY1030).