Efficacy And Safety Of Fulvestrant Monotherapy/Combination Treatment For Advanced Breast Cancer:A Meta-analysis

Background and objective:Treatment of patients with advanced breast cancer is to relieve symptom,improve quality of life and prolong the survival time.Endocrine therapy including selective estrogen receptormodulator(tamoxifen),the third-generation aromatase inhibitors(letrozole,anastrozole and exemestane)and selective estrogen receptor downregulators(fulvestrant)is effective and safe.Andit is believed that TAM and AIs are the standard treatment of patients with HR-positive advanced breast cancer,but side effects and endocrine resistance of TAM/AIs prompt research on new alternative.NCCN recommend that fulvestrant might be used as first-line medicine which is also an effective choice to endocrine-resistant patients.In this study,a meta-annalysis regarding efficacy and safety of fulvestrant monththerapy/combined with other endocrine therapies or targeted therapies are conducetd to explore the reasonable clinical strategies of women with HR-positive advanced breast cancer.Methods:Electronic databases including PubMed,Embase,Web of Science,Cochrane,CNKI,Wanfang,Chongqing VIP,Chinese Biological Medical Literature were searched.Search terms included selective estrogen receptor downregulator OR fulvestrant OR faslodex,breast neoplasm OR breast cancer,and randomized controlled trials concerning fulvestrant monththerapy/combination therapy were screened and selected.EngaugeDigitizer4.1,RevMan5.3 and Stata11.0 were used for meta-analysis.Results:(1)Three RCTs related to five included studies compared fulvestrant as the intervention against TAM/AIs,meta-analysis obversed that pooled HR of TTP,TTF and OS were0.85(95%CI:0.63-1.14),0.92(95%CI:0.58-1.46)and 0.78(95%CI:0.62-0.99),respectively.And we found siginifant difference in PFS with fulvestrant compared to anastrozole(HR=0.75,95%CI:0.63-0.90).Moreover,pooled OR of ORR,CBR,SAE and discontinue were 1.08(95%CI:0.77-1.50),1.02(95%CI:0.79-1.32),1.05(95%CI:0.69-1.59)and1.41(95%CI:0.69-2.86),respectively.Different does of fulvestrant might be an influenced factor of heterogeneity.(2)Three clinical researchs compared fulvestrant plus anastrozole as the intervention against the monththerapy(fulvestrant or anastrozole),the pooled HR of TTP and OS were 0.92(95%CI:0.79-1.06)and 0.86(95%CI:0.72-1.04),respectively.Moreover,pooled OR of ORR,ORR of patients with measurable disease,CTCAE>3 and discontinue were 0.97(95%CI:0.64-1.49),1.22(95%CI:0.82-1.83),1.08(95%CI:0.78-1.48)and 2.27(95%CI:1.14-4.54),respectively.(3)Six included studies compared fulvestrant combined with targeted therapies as the intervention against the monththerapy,meta-analysis observed that pooled HR of TTP and OS were 0.80(95%CI:0.59-1.10)andl.04(95%CI:0.80-1.35),respectively.Andpooled HR of PFS in patients with PIK3CA mutation was 0.65(95%CI:0.48-0.90).Furthermore,pooled OR of ORR,CBR,CTCAE>3,SAE and discontinue were 1.07(95%CI:0.35-3.26),1.26(95%CI:0.52-3.02),3.36(95%CI:1.66-6.81),1.24(95%CI:0.91-1.70)and 4.68(95%CI:2.51-8.75),respectively.Moreover,pooled OR of ORR and CBR in patients with measurable disease were 2.66(95%CI:1.64-4.30)and 2.60(95%CI:1.78-3.81).Sensitivity analysis observed PALOMA-3and sample size<100 were important factors of heterogeneity.Conclusion:(1)To endocrine threapy-navie postmenopausal women with HR-positive advanced breast cancer,the efficacy and safety of fulvestrant is not significantly superior than tamoxifen/anastrozole,but TTP and OS of women receiving fulvestrant at a high does are longer than anastrozole.(2)To postmenopausal women with HR-positive advanced breast cancer,the efficacy of combination therapy(fulvestrant plus anastrozole)is not significantly superior than monththerapy,and toxicity of combination therapy are more severe.(3)To postmenopausal women with HR-positive advanced breast cancer,the additionof targeted tharepy to fulvestrant has not show improving efficacy and was poorly tolerated.But to patients with PIK3CA mutation,PFS of patients receiving combination treatment is longer,besides,ORR and CBR in patients with measurable disease receiving combination treatment is higher than monththerapy.(4)Included studies concerning fulvestrant monththerapy/combined threaphy are infrequent,and evaluation of publicationbias,subgroup analysis and sensitivity analysis are partial,therefore,the reliability of results and the source of heterogeneity need to be explored further.