![]() ![]() To date, three CDK4/6-Is have been evaluated in clinical trials with published results: palbociclib (PD0332991 Ibrance, Pfizer, United States), ribociclib (LEE011 Kisquali, Novartis, Switzerland), and abemaciclib (LY2835219, Verzenio, Lilly, United States). Selective CDK 4/6 inhibitors (CDK4/6-Is) have been developed and tested in HR-positive BC patients, mainly in combination with endocrine therapy. ![]() 9 Given these data, pharmacological inhibition of CDK 4/6 represents an appealing and interesting therapeutic strategy to treat HR-positive BC. Furthermore, cyclin D1 and CDK 4 are able to guide cell proliferation also in an ER-independent manner. 6 On the other hand, cyclin E expression is reported as low in ER-positive BC 7 and RB mutations are rarely found, 8 reflecting the dependence of ER-positive BC cells on cyclin D1 to start G1-to-S phase transition. 4, 5 Cyclin D1 can also stimulate ER transcriptional activity in a CDK 4-independent manner. In addition, ER signaling pathway is able to activate CCND1 gene promoter. Cyclin D1 is highly expressed in estrogen receptor (ER)-positive BC, with or without concomitant amplification of the cyclin D1 gene (CCND1). Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) presents different degrees that makes itself susceptible for CDK4/6 inhibition. 3 Given that the CDK4/6-RB1 axis is critical to cell cycle progression, it is to be expected that several tumors disrupt these fine interactions to promote cancer growth. 2 The molecular mechanism underlying these functions includes the activation by D-type cyclin proteins leading to phosphorylation of retinoblastoma-associated protein and E2F protein-mediated transcription of cell cycle genes, such as cyclins A and E. 1 In this context, the action of cyclin-dependent kinases 4/6 (CDK4/6) is necessary for the transition from G1-to-S phase, being crucial for normal and cancer cell proliferation. ![]() The aim of this paper is to summarize the current evidences raised from preclinical and clinical studies on cyclin-dependent kinases 4/6 inhibitors in BC, focusing on differences in terms of pharmacological properties, toxicity profile, and patients’ quality of life.Ĭell cycle dysregulation promotes aberrant cell proliferation and is one of the widely recognized hallmark of cancer. Hence, pivotal trials provided comparable results among different cyclin-dependent kinases 4/6 inhibitors, there is an increasing interest in finding substantial differences in order to implement their use in clinical practice. Phase II–III clinical trials evaluating the addition of these agents to standard endocrine therapy reported consistent improvements in response rates and progression-free survival as well as manageable toxicity profiles and excellent impact on patients’ quality of life. The harnessing in clinical practice of cyclin-dependent kinases 4/6 inhibitors, namely palbociclib, ribociclib, and abemaciclib, has substantially changed the therapeutic approach for hormone receptor-positive metastatic breast cancer (BC). ![]()
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