Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR⁺/HER2^--) advanced breast cancer: a meta-analysis and systemic review of randomized clinical trials

Abstract

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, P<0.001), overall survival (pooled HR= 0.755, P<0.001), and tumor response rates (ORR, pooled OR= 1.478, P<0.001; CBR, pooled OR= 1.201, P<0.001) with manageable toxicities (pooled OR= 3.280, P<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, P<0.001) yet pronounced toxicities (pooled OR=2.154, P<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.

Keywords

endocrine-resistant / HR⁺/HER2⁻ advanced breast cancer / randomized clinical trials / meta-analysis / targeted therapy

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Conclusions

The addition of CDK 4/6 inhibitors to ET significantly improved clinical outcomes with manageable toxicities in HR⁺/HER2⁻ ABC. For other targeted therapies, predictive biomarkers need to be explored for the identification of responders. Future studies are warranted to optimize the dosing sequence of these available options.

Compliance with ethics guidelines

Wenjie Zhu and Binghe Xu declare no conflicts of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https ://doi.org/10.1007/s11684-020-0795-4 and is accessible for authorized users.

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