Journal name: OncoTargets and Therapy Article Designation: Original Research Year: 2018 Volume: 11 OncoTargets and Therapy Dovepress Running head verso: Zhang et al Running head recto: Effect of first-line endocrine therapy in advanced breast cancer open access to scientific and medical research DOI: 165681 Open Access Full Text Article ORIGINAL RESEARCH Effect of first-line endocrine therapy in patients with hormone-sensitive advanced breast cancer: a network meta-analysis Tingting Zhang1 Background: Endocrine therapy is the cornerstone treatment for patients with hormone Fubin Feng2 receptor-positive advanced breast cancer. We aimed to assess the effectiveness of various Wenge Zhao3 first-line endocrine monotherapies or combinations to determine the optimal sequence in a Jinhui Tian4 network meta-analysis. Yan Yao3 Materials and methods: We searched PubMed, EMBASE, and the Cochrane Library for Chao Zhou2 randomized controlled trials (RCTs) from inception up to November 21, 2017. We included only RCTs that assessed the effectiveness of the following treatments as a monotherapy or in Shengjie Dong5 combination as the first-line treatment: tamoxifen, anastrozole, letrozole, exemestane, fulves- Congcong Wang6 trant, palbociclib, and ribociclib. The results were presented with pooled odds ratio or hazard Chuanxin Zang1 For personal use only. ratio (HR), and 95% credible interval (CrI). The primary outcomes were objective response 7 Qingliang Lv rate (ORR) and progression-free survival/time to progression. 2,8 Changgang Sun Results: A total of 16 eligible articles (14 RCTs) involving 6,602 patients treated with 10 dif- 1College of Traditional Chinese ferent first-line endocrine therapies were assessed in our network meta-analysis. Palbociclib plus Medicine, Shandong University letrozole was superior to anastrozole, letrozole, exemestane, fulvestrant 500 mg, and anastrozole of Traditional Chinese Medicine, WeiFang, China; 2Department of plus fulvestrant (loading dose) (HR=0.44, 95% CrI: 0.33–0.58; HR=0.56, 95% CrI: 0.45–0.68; Oncology, Weifang Traditional Chinese HR=0.45, 95% CrI: 0.32–0.61; HR=0.58, 95% CrI: 0.42–0.81; HR=0.50, 95% CrI: 0.37–0.68; 3 Hospital, WeiFang, China; Department respectively). However, there is no significant advantage compared with ribociclib plus letrozole of Oncology, Clinical Medical Colleges, Weifang Medical University, (HR=1.00, 95% CrI: 0.72–1.39). In terms of ORR, ribociclib plus letrozole is more effective WeiFang, China; 4Evidence-Based than palbociclib plus letrozole (odds ratio=1.30, 95% CrI: 0.83–2.02). Medicine Center, School of Basic Palbociclib plus letrozole and ribociclib plus letrozole might be the optimal first- Medical Sciences, Lanzhou University, Conclusion: OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 08-Dec-2018 Lanzhou, China; 5Department of the line endocrine therapeutic choices for hormone receptor-positive/human epidermal growth factor Joint and Bone Surgery, Yantaishan receptor 2-negative advanced breast cancer due to a longer progression-free survival/time to Hospital, Yantai, China; 6Department of Oncology, Zibo Maternal and progression and a more efficacious ORR. Child Health Hospital, Zibo, China; Keywords: first-line endocrine therapy, progression-free survival, objective response rate, 7 Department of Radiology, Weifang advanced breast cancer, network meta-analysis, randomized controlled trial people’s Hospital, WeiFang, China; 8Department of Oncology, Affiliated Hospital of Weifang Medical University, WeiFang, China Introduction Worldwide, breast cancer is by far the highest incidence of cancer in women and the leading cause of cancer deaths, accounting for 25% of all cancer cases (1.68 million) and 15% of cancer deaths (520,000).1,2 Approximately 30%–40% of patients diag- Correspondence: Changgang Sun nosed at early stages could develop advanced breast cancer (ABC), with ~20% 5-year Department of Oncology, Affilited survival time.3 Although ABC is not curable,4 patients can be treated with systemic Hospital of Weifang Medical University, No. 2428, Yuhe Road, Kuiwen District, therapy to control the symptoms of the disease, possibly prolonging survival time and WeiFang, ShanDong Province, China maintaining a better quality of life. Endocrine therapy, representing the standard of Tel +86 135 8369 0699 Email [email protected] care for first-line treatment,5 plays a crucial role in ABC in postmenopausal women submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 2647–2656 2647 Dovepress © 2018 Zhang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/OTT.S165681 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Zhang et al Dovepress with hormone receptor-positive (HR+) disease.6 The first- Materials and methods line endocrine therapy consists of tamoxifen, fulvestrant, Literature and search strategy and third-generation aromatase inhibitors (AIs), such as We performed this NMA based on the Preferred Reporting anastrozole, letrozole, and exemestane.7,8 Items for Systematic Reviews and Meta-Analysis extension Third-generation AIs, with improved time to progression to NMA.21 (TTP) and better tolerability compared with tamoxifen, are We searched PubMed, EMBASE, and the Cochrane considered the standard of care for first-line treatment.9–13 Library for RCTs from inception up to November 21, Fulvestrant is a selective estrogen receptor (ER) downregu- 2017. The search for titles/abstracts was restricted to lator, which binds, blocks, and increases the degradation of English language articles. We used the Medical Subject ER proteins, inhibiting estrogen signaling.14 The 500 mg Headings/Emtree combined with free text words of breast dose of fulvestrant was approved based on data from an cancer, advanced or metastatic, randomized controlled international, randomized, double-blind, Phase III trial by the trial, and all known spellings of tamoxifen, anastrozole, name of Fulvestrant and Anastrozole Compared in Hormonal letrozole, exemestane, fulvestrant, palbociclib, and riboci- Therapy Naive Advanced Breast Cancer (FALCON). The clib. (Detailed information of search strategies in different trial compared fulvestrant 500 mg with anastrozole 1 mg databases is shown in Figures S1, S2 and S3). Addition- in patients with HR+ locally advanced or metastatic breast ally, reference lists of eligible published clinical trials cancer who had not received previous endocrine therapy.15 and meta-analyses were also tracked manually to identify In FALCON, progression-free survival (PFS) was signifi- other relevant studies. cantly longer in the fulvestrant group than in the anastrozole group (HR=0.797, 95% CI: 0.637–0.999, P=0.0486). Selection criteria Additionally, cyclin-dependent kinase (CDK)4 and CDK6 Inclusion criteria were drawn based on the framework of inhibitors have shown activity in ER-positive (ER+) breast population, intervention, comparison, outcome and study cancer in either preclinical or clinical trials.16 Palbociclib is design.22 The type of participants was HR (ER and/or For personal use only. + + the first CDK4/6 approved by the Food and Drug Admin- progesterone receptor-positive) postmenopausal women in istration (FDA) for advanced or metastatic breast cancer.17 ABC (inoperable locally ABC and metastatic breast cancer),7 Clinical data favoring palbociclib plus letrozole rather than who had not received previous treatment for the advanced letrozole alone was suggested in PALOMA-2, a double-blind disease or had not received endocrine therapy as an adjuvant Phase III study in the initial treatment of postmenopausal treatment within 12 months before study entry. The type of women with ER+, human epidermal growth factor receptor intervention was assessing the effectiveness of one of the 2-negative (HER2−) ABC.18 In terms of median PFS, the pal- following treatments as a monotherapy or in combination bociclib plus letrozole group presented a longer median PFS as the first-line treatment: tamoxifen, anastrozole, letrozole, than letrozole alone (24.8 months vs 14.5 months, HR=0.58; exemestane, fulvestrant, palbociclib, and ribociclib. The type 95% CI: 0.46–0.72; P,0.000001). Beyond that, ribociclib, OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 08-Dec-2018 of primary outcome was the ORR and PFS/TTP. The type as a small-molecule inhibitor of CDK4/6, combined with of study was RCTs that evaluated different endocrine thera- letrozole, could also extend the median PFS versus letrozole pies as the first-line therapy for treating ABC. We excluded alone (HR=0.56; 95% CI: 0.43–0.72).19 studies where endocrine therapy was used as a neoadjuvant There are many first-line endocrine therapy regimens treatment for advanced disease. Two authors (Tingting Zhang at present; however, the optimal sequence for HR+ ABC and Wenge Zhao) independently assessed the titles/abstracts is still not established. In a previous network