Efficacies And Toxicities Associated With Poly ADP-Ribose Polymerase(PARP)Inhibitors In The Treatment Of Advanced Breast Cancer:A Meta-Analysis

Objective:The aim of this meta-analysis is to systematically evaluate the effectiveness and safety of poly ADP-ribose polymerase(PARP)inhibitors in the treatment of advanced or metastatic breast cancer and to explore possible drug administration strategies in order to provide reliable evidence-based evidence for the domestic clinical.Methods:The PubMed database,Web of Science,EMBASE,The Cochrane Library and Wan-fang database were searched for clinical trials of PARP inhibitors.The retrieval time limit is from the establishment of the database to January 2020.The references included in the study were also tracked to expand the scope of retrieval.Two researchers screened,extracted and evaluated the literature according to the inclusion criteria.The primary end points were progression free survival(PFS),overall survival(OS)and objective response rate(ORR),and the secondary end points were adverse events(AE),extract the relevant outcome index data and evaluate the literature quality according to the bias risk assessment tool provided by Cochrane system evaluator manual 5.1.0,use Rev man 5.3 software to analyze the data,summarize the risk ratio(HR)and 95%confidence interval(CI),and combine the effect quantity for meta analysis.Results:Six randomized controlled trials(RCTs)involving 1616 patients met our inclusion criteria.The results showed that compared with the traditional chemotherapy,the treatment strategy based on PARP inhibitor could significantly prolong the PFS(HR=0.67;95%CI:0.59-0.77;P<0.000001),OS(HR=0.80;95%Cl:0.70-0.92;P=0.002)and significantly increased the ORR of patients(RR=1.52;95%CI:1.10-2.11;P=0.01).In terms of safety,the incidence of all levels of adverse reactions was 98.8%in the experimental group,98.7%in the control group,and the RR was 1.01(95%CI:0.99-1.02;P=0.46;figure 6a).The difference was not statistically significant.In addition,the evaluation of the incidence of all adverse reactions above level 3 showed that 421(51.1%)of 824 patients in the experimental group had adverse events above level 3,and 329(61.2%)of 538 patients in the control group had adverse events(RR=0.99;95%CI:0.84-1.17;P=0.92;figure 6b).The difference was not statistically significant.In this study,subgroup analysis was conducted for each outcome variable,and the results were as follows:The results of subgroup analysis of PFS showed that PFS benefit was the most significant in patients with gBRCAm(HR=0.61;95%CI:0.49-0.75;P<0.00001).PARP inhibitor single drug treatment could better prolong the progression free survival time(HR=0.56;95%CI:0.45-0.69;P<0.00001).PFS benefit was also observed in the TNBC without BRCA status screening(HR=0.67;95%CI:0.58-0.78;P<0.00001).Compared with those who had previously used platinum chemotherapy,PFS benefits were only found in those who had not previously used platinum chemotherapy(HR=0.55;95%CI:0.44-0.69;P<0.00001).The results of subgroup analysis of OS showed that the use of PARP inhibitors not only prolonged the total survival of patients with gBRCAm(HR=0.81;95%CI:0.66-0.99;P=0.04),but also prolonged the total survival of TNBC in unfiltered BRCA(HR=0.79;95%CI:0.66-0.96;P=0.02).Compared with single drug PARP inhibitor treatment,OS prolongation was statistically significant only in PARP inhibitor combined with chemotherapy group(HR=0.78;95%CI:0.66-0.93;P=0.006);In the subgroup analysis of molecular subtypes,the benefit of OS only reached statistical significance in TNBC patients(HR=0.73;95%CI:0.61-0.8;P=0.0003).The results of subgroup analysis of orr showed that the trend of ORR statistical benefit was observed in the population with gBRCAm patients(RR=1.73;95%CI:1.01-2.98;P=0.05).Compared with PARP inhibitor combined chemotherapy,the improvement of ORR was statistically significant only in the single drug treatment group with PARP inhibitor(RR=2.21;95%CI:1.72-2.28;P<0.00001).The results of subgroup analysis of AE showed that PARP inhibitor could increase the risk of anemia,nausea and vomiting,but reduce the risk of neutropenia compared with traditional chemotherapy,while PARP inhibitor combined chemotherapy mainly increased the risk of headache and neutropenia above grade 3 compared with chemotherapy alone.Conclusion:The treatment strategy based on PARP inhibitors is safe and effective in advanced breast cancer.Compared with traditional chemotherapy,PARP inhibitor can prolong the progression free survival time and improve the objective remission rate of patients with advanced breast cancer,but the total survival time has not reached statistical significance.The combination of chemotherapy and chemotherapy can prolong the progression free survival time and total survival time of patients with advanced breast cancer,but the improvement of objective remission rate has not reached statistical significance.In terms of safety,single drug PARP inhibitor treatment reduced the risk of neutropenia,but increased the risk of anemia,nausea and vomiting above level 3.Combination with chemotherapy increased the risk of headache and neutropenia above grade 3.PARP inhibitor combined with chemotherapy is an active and effective treatment plan,which needs to strengthen the monitoring of adverse reactions during clinical use.