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Frontiers of Medicine >> 2021, Volume 15, Issue 2 doi: 10.1007/s11684-020-0795-4

Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing 100021, China

Received: 2020-10-16 Accepted: 2020-11-12 Available online: 2020-11-12

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New targeted therapies have been developed to overcome resistance to endocrine therapy (ET) and improve the outcome of HR /HER2 advanced breast cancer (ABC). We conducted a meta-analysis and systemic review on randomized controlled trials evaluating various targeted therapies in combination with ET in HR /HER2 ABC. PUBMED and EMBASE databases were searched for eligible trials. Hazard ratios (HRs) for progression-free survival (PFS), odds ratios (ORs) for objective response rate (ORR), clinical benefit rate (CBR), and toxicity were meta-analyzed. Twenty-six studies with data on 10 347 patients were included and pooled. The addition of cyclin-dependent kinase 4/6 inhibitors to ET significantly improved median PFS (pooled HR= 0.547, <0.001), overall survival (pooled HR= 0.755, <0.001), and tumor response rates (ORR, pooled OR= 1.478, <0.001; CBR, pooled OR= 1.201, <0.001) with manageable toxicities (pooled OR= 3.280, <0.001). The mammalian targets of rapamycin inhibitors and exemestane were not clinically beneficial for this pooled population including ET-naïve and ET-resistant patients. Moderate improvement in PFS (pooled HR= 0.686, <0.001) yet pronounced toxicities (pooled OR= 2.154, <0.001) were noted in the combination of phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors with fulvestrant. Future studies are warranted to optimize the population and the dosing sequence of these available options.

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