Dalpiciclib With Endocrine Therapy for Advanced Breast Cancer After CDK4/6 Inhibitor Failure (DAWNA-FES)

With the emergence of targeted therapies, the treatment landscape for patients with hormone receptor-positive (HR+) and HER2-negative (HER2-) metastatic breast cancer (MBC) is continuously evolving. The combination of cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) with endocrine therapy has become the standard treatment approach for first-line therapy or treatment after progression on endocrine therapy. Multiple large randomized studies have demonstrated that the combination of CDK4/6i and endocrine therapy significantly improves progression-free survival (PFS) in HR+/HER2- MBC patients. Updated analyses have also shown a significant improvement in overall survival (OS) with the combination of endocrine therapy and either Palbociclib or Ribociclib. Currently, regulatory agencies have approved four CDK4/6 inhibitors, namely Palbociclib, Abemaciclib, Ribociclib, and Dalpiciclib, for the treatment of HR+/HER2- breast cancer. All four CDK4/6 inhibitors are approved for use in combination with endocrine therapy for advanced HR+/HER2- breast cancer. Abemaciclib has also been approved for use as adjuvant therapy in early-stage breast cancer with HR+/HER2- subtype and high-risk recurrent factors, as well as for the treatment of advanced breast cancer. CDK4/6 inhibitors are currently the standard treatment for female breast cancer patients with HR+ tumors. However, there is no established standard treatment for patients who experience treatment failure with CDK4/6 inhibitors. Despite the extensive clinical experience with these drugs, our understanding of the long-term effects of CDK4/6 blockade in patients previously treated with CDK4/6 inhibitors is limited. The MAINTAIN study has shown clinical benefits by switching to Ribociclib and changing endocrine therapy after progression on CDK4/6 inhibitors. We hypothesize that combining Dalpiciclib with physician-selected endocrine therapy, following treatment failure with CDK4/6 inhibitors, would similarly lead to improved patient survival. 18F-fluorodeoxyglucose (FDG) PET imaging is widely utilized in the field of oncology to detect increased glucose metabolism activity. In the case of breast cancer, 18F-FDG PET/CT imaging is predominantly recommended for patients with unclear staging, advanced disease, or metastasis, when conventional imaging methods are inconclusive. On the other hand, 18F-fluoroestradiol (FES) is an endogenous estrogen analogue that specifically binds to estrogen receptors (ERs). Through PET imaging, FES enables dynamic, quantitative, and non-invasive assessment of ER expression levels and distribution within the patient's body. When combined with 18F-FDG PET or other imaging modalities, 18F-FES PET imaging can evaluate the heterogeneity of ER expression and has the potential to identify ER loss or dysfunction. It has been observed that 18F-FES PET exhibits good correlation with traditional immunohistochemistry for assessing ER expression. Moreover, published human studies have not reported any toxicity or adverse reactions associated with 18F-FES usage. In this study, 18F-FES PET/CT will be employed as a non-invasive alternative to biopsy techniques for evaluating the expression of ER in various systemic lesions of the patients.