Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor receptor 2-negativ
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REVIEW
Overcoming resistance to endocrine therapy in hormone receptorpositive human epidermal growth factor receptor 2-negative (HR+/HER2–) advanced breast cancer: a meta-analysis and systemic review of randomized clinical trials Wenjie Zhu, Binghe Xu (
✉)
National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing 100021, China
© Higher Education Press 2020
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
Introduction As the most prevalent cancer and the leading cause of cancer death among women, breast cancer represents a large burden to global health. A total of 2 088 849 breast cancer cases were diagnosed in 2018 [1]. The hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+/HER2–) subtype, characterized by the expression of estrogen receptor (ER) and/or progesterone receptor (PR) without HER2 overexpression/amplification, accounts for approximately 70% of breast cancer patients [2]. Nearly 20% – 30% of patients with early stage disease become metastatic throughout the disease course [3].
Received September 25, 2019; accepted April 17, 2020 Correspondence: Binghe Xu, [email protected]
For decades, hormonally directed therapies, including blockade of estrogen signaling, have been the mainstay treatments for local, advanced, or metastatic HR+/HER2– breast cancer. However, some treatment-naïve patients display primary resistance to the treatment, and most of them eventu
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