A Meta-analysisi Of The Efficacy And Safety Of PI3K/AKT/mTOR Inhibitors Combined Wiht Endocrine Therapy On Advanced Breast Cancer

Objective The activation of PI3 K / AKT / mTOR signaling pathway in breast cancer can lead to resistance to endocrine therapy.This study aimed to evaluate the efficacy and safety of the PI3 K / AKT / mTOR inhibitors combined with endocrine therapy for HR(+)/HER2(-)advanced breast cancer after failure of endocrine therapy.Methods We searched the electronic databases PubMed,Embase,Cochrane Library from inception to March 2020 for all relevant RCT.The bias risk assessment tool recommended by Cochrane collaborative network was used by two researchers for independent evaluation.And this meta-analysis was performed using Revmanv5.3.Results A total of 8 clinical trials were included in the final meta-analysis.The pooled results showed that the combination of endocrine therapy and PI3K/AKT/mTOR inhibitors improved ORR(RR=2.31,95%CI : 1.29-4.15,P=0.005),and decreased the risk of progression(HR=0.60,95%CI:0.49-0.73,P<0.00001).But the subgroup analysisshowed that this PFS benefit only occurred in the tumor tissue-PIK3 CA mutation subgroup(HR = 0.67,95% CI:0.57-0.79,P < 0.00001)and the plasma ctDNA-PIK3 CA mutation subgroup(HR = 0.52,95% CI:0.39-0.69,P < 0.00001),while it achieved no improvement in PFS in the tumor tissue-PIK3 CA mutation negative subgroup(HR = 0.81,95% CI:0.64-1.01,P = 0.07)and the plasma ctDNA-PIK3 CA mutation negative subgroup(HR = 0.89,95% CI: 0.63-1.27,P = 0.52).There was no significant difference in OS between combination group and monotherapy group(HR = 0.83,95% CI: 0.65-1.04,P = 0.11).In terms of adverse events,the combination therapy increased the incidence of grade 3/4 ALT ?(RR=11.02,95%CI:6.71-18.10,P<0.00001),AST?(RR=5.09,95%CI:3.40-7.64,P<0.00001),Hyperglycemia(RR=39.11,95%CI:17.03-89.83,P<0.00001),Stomatitis(RR=5.62,95%CI:2.33-13.60,P=0.0001)?Fatigue(RR=1.96,95%CI:1.25-3.09,P=0.004)? Rash(RR=21.55,95%CI:8.63-53.80,P<0.00001)? Diarrhea(RR=4.59,95%CI:2.61-8.08,P<0.00001).Conclusion PI3 K / Akt / mTOR inhibitors combined with endocrine therapy reduced the risk of disease progression in HR(+ / HER2(-)advanced breast cancer patients who has failed in endocrine therapy.However,the effect of prolonging the survival of patients has not yet been determined,and its relatively high incidence of serious side effects may affect its clinical application.Therefore,the strategy of PI3 K / Akt / mTOR inhibitor combined with endocrine therapy needs to be further explored,and the dominant population with significant efficacy and low toxicity should be found as far as possible.