Fulvestrant Plus CDK4/6 Inhibitors Or PI3K/mTOR/AKT Inhibitors For HR+/HER2-advanced Breast Cancer That Failed In The First-line Endocrine Therapy:A Meta-analysis

Objective To systematically evaluate the efficacy and safety of fulvestrant plus CDK4/6 inhibitors or PI3K/mTOR/AKT inhibitors and fulvestrant monotherapy for HR+/HER2-advanced breast cancer patients who failed in the first-line endocrine therapy.Methods Pubmed,Embase and Cochrane library databases were electronically searched from establishment to March 2020.Inclusion criteria:(1)phase or phase ⅡⅢ randomized controlled trials;(2)HR+/HER2-advanced breast cancer patients who failed in the first-line endocrine therapy;(3)comparison of fulvestrant plus CDK4/6inhibitors or PI3K/AKT/mTOR inhibitors with fulvestrant monotherapy;(4)The dosage of fulvestrant is 500mg;(5)Although the treatment regimens were mixed with first-line and second-line endocrine therapies,the original data of second-line endocrine therapies could be extracted;(6)When two or more studies were reported by the same research center,higher quality literature or newly published research were selected.Exclusion criteria:(1)sample size is less than 100 cases;(2)reviews,case reports,theoretical essays;(3)the original data of any outcome indicators cannot be extracted from the research.The Cochrane risk of bias assessment tool was used to evaluate the quality of included literature.Stata 12.0 software was used for statistical analysis.Statistical heterogeneity among the studies was detected by Q test and I~2 statistic.Meanwhile,the funnel plot and Egger’s test were used to assess publication bias.Results A total of 9 randomized controlled trials involving 3880 patients were included in this study.Improvements of combination group were proven in terms of PFS(HR: 0.65,95%CI=0.58-0.73,P=0.000),OS(HR: 0.81,95%CI=0.73-0.90,P=0.000),ORR(RR: 1.80,95%CI=1.52-2.12,P=0.000)and CBR(RR:1.31,95%CI=1.15-1.50,P=0.000),the difference was statistically significant,indicating that fulvestrant plus CDK4/6 inhibitors or PI3K/mTOR/AKT inhibitors had better efficacy than fulvestrant monotherapy.The results of subgroup analysis showed that the efficacy of fulvestrant combined with CDK4/6 inhibitors was better than that of fulvestrant alone,PFS(HR:0.54,95%CI=0.47-0.61,P=0.000),OS(HR:0.77,95%CI=0.67-0.89,P=0.000),ORR(RR:2.26,95%CI=1.71-2.98,P=0.000),CBR(RR:1.45,95%CI=1.12-1.88,P=0.005);The efficacy of fulvestrant combined with PI3K/mTOR/AKT inhibitors was better than that of fulvestrant alone,PFS(HR: 0.73,95%CI=0.67-0.81,P=0.000),OS(HR:0.85,95%CI=0.74-0.98,P=0.03),ORR(RR:1.55,95%CI=1.26-1.90,P=0.000),CBR(RR:1.24,95%CI=1.08-1.43,P=0.003).In terms of safety,the addition of CDK4/6inhibitors significantly increased the incidence of blood system,including neutropenia(RR:59.33,95%CI=6.89-510.85,P=0.000),leukopenia(RR:48.83,95%CI=12.17-195.88,P=0.000),anemia(RR: 2.81,95%CI=1.44-5.47,P=0.002)CTCAE3/4,and fatigue(RR: 3.38,95%CI=1.19-9.62,P=0.022)incidence of CTCAE3/4.The addition of PI3K/mTOR/AKT inhibitors significantly improved the digestive system,including stomatitis(RR:7.08,95%c CI=2.92-17.16,P=0.000),diarrhea(RR:3.89,95%CI=2.13-7.10,P=0.000),elevated ALT(RR:14.90,95%CI=8.41-26.42,P=0.000),elevated AST(RR:5.78,95%CI=3.76-8.90,P=0.000)CTCAE3/4,and the incidence of rash(RR:21.19,95%CI=7.99-56.17,P=0.000),hyperglycemia(RR:26.23,95%CI=10.39-66.21,P=0.000)CTCAE3/4.Conclusion Fulvestrant combined with CDK4/6 inhibitors or PI3K/mTOR/AKT pathway inhibitors can prolong PFS,OS and improve ORR,CBR in patients with HR+/HER2-advanced breast cancer who failed in the first-line endocrine therapy.However,combination therapy increased the incidence of CTCAE3/4.