The Role of Cyclin-Dependent Kinases (CDK) 4/6 in the Ovarian Tissue and the Possible Effects of Their Exogenous Inhibition

SIMPLE SUMMARY: CDK4/6 inhibitors combined with endocrine therapy are currently the standard of care for the treatment of patients with hormone-receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2-negative (HER2−) advanced breast cancer and those with high-risk early disease. Oncofertility counseling is a crucial component of the care of young women with newly diagnosed cancer. While the gonadotoxicity of chemotherapy is well established, little is known about the impact of newer targeted agents on ovarian function and fertility. This review aims to clarify the role of the CDK4/6 complex in ovarian tissue by summarizing the preclinical and clinical data available on this topic in order to provide some preliminary guidance on how to counsel women receiving CDK4/6 inhibitors on their potential gonadotoxicity. Dedicated research efforts are needed to improve our understanding of this important issue and perform better oncofertility counseling for young women candidates selected to receive endocrine therapy with a CDK4/6 inhibitor. ABSTRACT: The combination of cyclin-dependent kinase (CDK) 4/6 inhibitors with endocrine therapy is the standard treatment for patients with HR+/HER2− advanced breast cancer. Recently, this combination has also entered the early setting as an adjuvant treatment in patients with HR+/HER2− disease at a high risk of disease recurrence following (neo)adjuvant chemotherapy. Despite their current use in clinical practice, limited data on the potential gonadotoxicity of CDK4/6 inhibitors are available. Hence, fully informed treatment decision making by premenopausal patients concerned about the potential development of premature ovarian insufficiency and infertility with the proposed therapy remains difficult. The cell cycle progression of granulosa and cumulus cells is a critical process for ovarian function, especially for ensuring proper follicular growth and acquiring competence. Due to the pharmacological properties of CDK4/6 inhibitors, there could be a potentially negative impact on ovarian function and fertility in women of reproductive age. This review aims to summarize the role of the cyclin D-CDK4 and CDK6 complexes in the ovary and the potential impact of CDK4/6 inhibition on its physiological processes.