Practical Treatment Strategies and Future Directions After Progression While Receiving CDK4/6 Inhibition and Endocrine Therapy in Advanced HR<sup>+</sup>/HER2<sup>-</sup> Breast Cancer.
CDK4/6 inhibitors in association with aromatase inhibitors have led to a paradigm shift in the management of metastatic positive hormone-receptors breast cancer.
In this review we provide an up to date overview of the development of anti-cancer agents, particularly the newly developed CDK4/6 inhibitors.<b>Material and methods:</b> A search of PubMed was conducted to identify preclinical data surrounding the development of endocrine therapy and CDK4/6 inhibitors in early and metastatic BC.
Consequently, combination treatment of CDK4/6 inhibitor palbociclib with the eukaryotic initiation factor (eIF) 4A inhibitor, CR-1-31-B, is synergistic in suppressing the growth of these cancer cells <i>in vitro</i> and <i>in vivo</i> Furthermore, ER<sup>+</sup> breast cancer and <i>KRAS</i>-mutant NSCLC cells that acquired resistance to palbociclib after chronic drug exposure are also highly sensitive to this combination treatment strategy.
Recently three different cyclin-dependent kinase 4 and 6 (CDK4/6) dual inhibitors were approved for the treatment of breast cancer (palbociclib, ribociclib, and abemaciclib), all of which offer comparable therapeutic benefits.
Our data suggest complementary roles of [<sup>18</sup>F]FLT and [<sup>18</sup>F]ISO-1 PET in evaluating tumor-proliferation after combined CDK4/6 inhibitor and endocrine therapy in breast cancer.
Relevance to Patient Care and Clinical Practice: Literature on the safety and efficacy of ribociclib as well as its place in therapy in comparison to other FDA-approved CDK4/6 inhibitors for breast cancer is discussed.
Relevance to Patient Care and Clinical Practice: This review considers the use of the 3 commercially available CDK 4/6 inhibitors for treatment of hormone receptor-positive breast cancer, including data on each of the 3 agents in newly advanced and treatment refractory disease.
Three Cyclin Dependent Kinase 4/6 (CDK) inhibitors have been approved by the United Stated Food and Drug Administration for front line treatment of advanced hormone receptor positive breast cancer based on improvements in progression free survival against endocrine monotherapy.
As the new standard-of-care in some countries, there is the clinical emergence of patients with breast cancer that is both CDK4/6 inhibitor and endocrine therapy resistant.
Here, we investigated the potential mechanism of resistance by establishing a CDK4/6 inhibitor palbociclib-resistant breast cancer cell line (MCF-7pR).
Although the mechanisms by which the CDK4/6 complex is involved in the control of cell growth in triple negative breast cancer (TNBC) are still unclear, some TNBCs might be sensitive to CDK4/6 inhibitors.<b>Areas covered</b>: The authors provide an overview of the treatments that target cell cycle machinery in breast cancer and provide their perspectives for the future.<b>Expert opinion</b>: CDK 4/6 inhibitors are active drugs in HR+ MBC, but some unresolved issues remain.
We showed that a CDK4/6 inhibitor palbociclib and activin-SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal-type breast cancer cell line T47D.
Lasting effects of CDK4/6 inhibition after drug withdrawal on differentiation and the immune response could impact the approach to treatment of early-stage ER(-) breast cancer.
Therefore, the purpose of our study was to overview the clinical trials about the beneficial effects of Palbociclib, Ribociclib and Abemaciclib in breast cancer with their tolerable adverse effects, and discuss their resistant mechanisms thus looking for useful biomarkers to predict the efficiency of the CDK4/6 inhibitors.