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Simple Summary  Advanced stage breast cancer is incurable, and a leading cause of cancer-related death in women. Recently, novel treatment options have improved clinical outcomes of breast cancer patients. Combined CDK4/6 inhibitor and endocrine therapy have been shown to be highly effective, improving both progression-free and overall survival, but resistance inevitably develops and disease progression occurs. Identification of clinically useful biomarkers predicting therapeutic response/failure and resistance mechanisms are essential for optimal patient stratification and the development of novel therapeutic strategies for patients who have progressed on combined CDK4/6 inhibitor and endocrine therapy. However, finding a universal single predictive biomarker is unlikely mainly due to the heterogenicity of the cancers and the associated resistance mechanisms. Here, we review the current state of knowledge on resistance mechanisms to combined CDK4/6 inhibitor and endocrine therapy and associated predictive molecular biomarkers, including the use of liquid biopsy.    Abstract  The introduction of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has revolutionized the treatment landscape for patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) and has become the new standard treatment. However, resistance to this combined therapy inevitably develops and represents a major clinical challenge in the management of ER+ ABC. Currently, elucidation of the resistance mechanisms, identification of predictive biomarkers, and development of novel effective combined targeted treatments to overcome the resistance are active areas of research. Given the heterogeneity of the resistance mechanisms towards combined CDK4/6i and ET, identification of a single universal predictive biomarker of resistance is unlikely. Novel approaches are being explored, including examination of multiple genetic alterations in circulating cell-free tumor DNA in liquid biopsies from ABC patients with disease progression on combined CDK4/6i and ET treatment. Here, we review the molecular basis of the main known resistance mechanisms towards combined CDK4/6i and ET and associated potential biomarkers. As inhibiting key molecules in the pathways driving resistance may play an important role in the selection of therapeutic strategies for patients who experience disease progression on combined CDK4/6i and ET, we also review preclinical and early phase clinical data on novel combination therapies for these patients.

cancers

Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies